[Federal Register Volume 69, Number 226 (Wednesday, November 24, 2004)]
[Rules and Regulations]
[Pages 68612-68688]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-25798]
[[Page 68611]]
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Part IV
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 16, 1270, and 1271
Current Good Tissue Practice for Human Cell, Tissue, and Cellular and
Tissue-Based Product Establishments; Inspection and Enforcement; Final
Rule
Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 /
Rules and Regulations
[[Page 68612]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 16, 1270, and 1271
[Docket No. 1997N-484P]
Current Good Tissue Practice for Human Cell, Tissue, and Cellular
and Tissue-Based Product Establishments; Inspection and Enforcement
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is requiring human
cell, tissue, and cellular and tissue-based product (HCT/P)
establishments to follow current good tissue practice (CGTP), which
governs the methods used in, and the facilities and controls used for,
the manufacture of HCT/Ps; recordkeeping; and the establishment of a
quality program. The agency is also issuing new regulations pertaining
to labeling, reporting, inspections, and enforcement that will apply to
manufacturers of those HCT/Ps regulated solely under the authority of
the Public Health Service Act (PHS Act), and not as drugs, devices,
and/or biological products. The agency's actions are intended to
improve protection of the public health while keeping regulatory burden
to a minimum, which in turn would encourage significant innovation.
DATES: This rule is effective May 25, 2005.
FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Introduction
A. Background
B. Legal Authority
II. Revisions to the Proposed Rule
A. Plain Language
B. HCT/P Definition
C. Function and Integrity
D. Core CGTP Requirements
E. Other Revisions
III. Comments on the Proposed Rule and FDA's Responses
A. General
B. Definitions (Sec. 1271.3)
C. Part 1271, Subpart D--Current Good Tissue Practice
D. Part 1271, Subpart E--Additional Requirements for Establishments
Described in Sec. 1271.10
E. Part 1271, Subpart F--Inspection and Enforcement of
Establishments Described in Sec. 1271.10
F. Economic Impacts
IV. Effective Date of 21 CFR Part 1271 and Applicability of 21 CFR Part
1270
A. Effective Date for Part 1271
B. Applicability of Part 1270
V. Analysis of Economic Impacts
A. Risks Associated with HCT/Ps
B. Estimated Cost Impact
VI. Environmental Impact
VII. Federalism Assessment
VIII. The Paperwork Reduction Act of 1995
IX. References
I. Introduction
This rule represents the culmination of FDA's efforts to establish
a comprehensive new system for regulating HCT/Ps. The regulations now
being issued require certain HCT/Ps to be manufactured in compliance
with CGTP. The rule also contains provisions relating to establishment
inspection and enforcement, as well as certain labeling and reporting
requirements, which are applicable to those HCT/Ps regulated solely
under the authority of section 361 of the PHS Act (42 U.S.C. 264) and
the regulations in part 1271 (21 CFR part 1271), and not as drugs,
devices, and/or biological products under the Federal Food, Drug, and
Cosmetic Act (the act).
At this time we (FDA) are not responding to comments submitted on
subparts D and E of the proposed rule relating to reproductive HCT/Ps.
With two minor exceptions, the regulations in subparts D and E are not
being finalized with respect to reproductive HCT/Ps described in Sec.
1271.10 and regulated solely under section 361 of the PHS Act and the
regulations in part 1271. The docket will remain open, and we ask that
interested parties submit comments on communicable disease risks
associated with reproductive HCT/Ps and appropriate regulation to
minimize those risks (other than that stipulated in part 1271 subparts
A, B, C, and F, and Sec. Sec. 1271.150(c) and 1271.155 in subpart D).
A. Background
In February 1997, FDA proposed a new, comprehensive approach to the
regulation of human cellular and tissue-based products (now called
human cells, tissues, and cellular and tissue-based products or HCT/
Ps). The agency announced its plans in two documents entitled
``Reinventing the Regulation of Human Tissue'' and ``A Proposed
Approach to the Regulation of Cellular and Tissue-based Products''
(hereinafter ``proposed approach document''). FDA requested written
comments on its proposed approach and, on March 17, 1997, held a public
meeting to solicit information and views from the interested public (62
FR 9721, March 4, 1997).
Since that time, the agency has published two final rules and one
interim final rule to implement aspects of the proposed approach. On
January 19, 2001, we issued regulations to create a new, unified system
for registering HCT/P establishments and for listing their HCT/Ps
(registration final rule, 66 FR 5447). Part of the definition of
``human cells, tissues, or cellular or tissue-based products'' became
effective on January 21, 2004. On January 27, 2004 (69 FR 3823), we
issued an interim final rule to except human dura mater and human heart
valve allografts from the scope of that definition until all of the
tissue rules became final. On May 25, 2004, we issued regulations
requiring most cell and tissue donors to be tested and screened for
relevant communicable diseases (donor-eligibility final rule, 69 FR
29786).
This rulemaking was initiated with a proposed rule on January 8,
2001 (Current Good Tissue Practice for Manufacturers of Human Cellular
and Tissue-Based Products; Inspection and Enforcement (66 FR 1508)
(hereinafter ``proposed rule'')). In the proposed approach document,
the agency stated that it would require that cells and tissues be
handled according to procedures designed to prevent contamination and
to preserve tissue function and integrity. The proposed rule would
require establishments that manufacture HCT/Ps to comply with CGTP,
which would include, among other things, proper handling, processing,
labeling, and recordkeeping procedures. In addition, the proposed
regulations would require each establishment to maintain a ``quality
program'' to ensure compliance with CGTP.
The proposed CGTP and other regulations would be contained in part
1271, along with provisions relating to establishment registration and
donor eligibility that have previously been issued. We are now making
those proposed regulations final for HCT/Ps collected on or after the
effective date of this rule. We are also amending part 1270 (21 CFR
part 1270), which now applies to certain HCT/Ps collected before the
effective date of this rule, by modifying the definition of human
tissue intended for transplantation (21 CFR 1270.3(j)) to limit its
applicability to tissue collected before the effective date. We are not
revoking part 1270 as previously proposed (66 FR 1508 at
[[Page 68613]]
1509). See section IV.B. of this document for further discussion.
Part 1271 contains six subparts. Subpart A of part 1271 sets forth
scope and purpose as well as definitions. Subpart B of part 1271
contains registration procedures. Subpart C of part 1271 sets forth
provisions for the screening and testing of donors to determine their
eligibility. This rule puts in place three additional subparts. Subpart
D of part 1271 contains the provisions on CGTP. Subpart E of part 1271
contains certain labeling and reporting requirements, and subpart F of
part 1271 contains the inspection and enforcement provisions. The
subparts apply as follows:
Subparts A through D apply to all HCT/Ps, i.e., to those
HCT/Ps described in Sec. 1271.10 and regulated solely under section
361 of the PHS Act, and to those regulated as drugs, devices, and/or
biological products; and
Subparts E and F, which pertain to labeling, reporting,
inspection, and enforcement, apply only to those HCT/Ps described in
Sec. 1271.10 and regulated solely under section 361 of the PHS Act.
However, as previously noted in section I of this document, with the
exception of two provisions (Sec. Sec. 1271.150(c) and 1271.155)
subparts D and E are not being implemented for reproductive HCT/Ps
described in Sec. 1271.10 and regulated solely under section 361 of
the PHS Act.
The publication of this final rule completes the set of regulations
that implements FDA's proposed approach to regulating HCT/Ps. We
recognize that over the course of this rulemaking, inadvertent errors
or inconsistencies may have been introduced into the regulations.
Accordingly, we anticipate that we may need to issue technical
corrections in the future.
B. Legal Authority
FDA is issuing these new regulations under the authority of section
361 of the PHS Act. Under that section, by delegation from the Surgeon
General and the Secretary of Health and Human Services, FDA may make
and enforce regulations necessary to prevent the introduction,
transmission, or spread of communicable diseases between the States or
from foreign countries into the States. It is important to recognize
that HCT/P manufacturing inevitably has interstate effects. HCT/Ps
recovered in one State may be sent to another for processing, then
shipped for use throughout the United States, or beyond. FDA has been
involved in many recalls where HCT/Ps processed in a single
establishment have been distributed in many States. In any event,
intrastate transactions affecting interstate communicable disease
transmission may also be regulated under section 361 of the PHS Act.
(See Louisiana v. Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977).)
Section 361 of the PHS Act authorizes FDA to issue regulations
necessary to prevent the introduction, transmission, or spread of
communicable diseases. Certain diseases, such as those caused by the
human immunodeficiency virus (HIV) and the hepatitis B and C viruses
(HBV and HCV respectively), may be transmitted through the
implantation, transplantation, infusion, or transfer of HCT/Ps derived
from infected donors. The agency required, in another rule, that most
cell and tissue donors be screened and tested for these and other
relevant communicable diseases (donor-eligibility final rule, 69 FR
29786 at 29830). However, donor screening and testing, although
crucial, are not sufficient to prevent the transmission of disease by
HCT/Ps. Rather, each step in the manufacturing process needs to be
appropriately controlled. Errors in labeling, mixups of testing
records, failure to adequately clean work areas, and faulty packaging
are examples of improper practices that could produce a product capable
of transmitting disease to its recipient. Similarly, as noted in the
proposed approach document, improper handling of an HCT/P can lead to
bacterial or other pathogenic contamination of the HCT/P, or to cross-
contamination between HCT/Ps, which in turn can endanger recipients.
The agency has determined that the procedural provisions of this rule
are necessary to ensure that the important protections created by these
regulations are actually effected and are not simply empty promises.
Only manufacturing conducted in accordance with established procedures
can assure that HCT/Ps meet the standards in these rules. When
processes are made up as the manufacturer goes along, mistakes
inevitably are made. Moreover, review of procedures can be critical to
determining the cause of a disease transmission. Without that analysis,
it would be impossible to prevent a future occurrence, with possibly
fatal consequences.
The record requirements of this rule are similarly necessary. A
single donor may be the source of a large number of HCT/Ps. It may be
discovered, long after the donation and transplantations have been
completed, that, due to an error in processing, the donor tissue was
infected and capable of spreading communicable disease. Although it
might be too late to prevent infections in the recipients, it would not
be too late for the recipient to obtain treatment and take steps to
avoid infecting others, such as close family members. Unless adequate
records were maintained, and maintained for the period of time
throughout which infections may be identified, it would be impossible
to identify the recipients potentially infected by the donor's HCT/Ps.
This would be a critical breakdown in the prevention of disease
transmission.
Moreover, a single processing error, such as an improper practice
that permitted bacterial contamination of all tissue processed at a
location during a limited period of time, may also have wide ranging
effects. Without reporting and study of adverse events involving the
transmission of communicable disease, or involving the release of HCT/
Ps presenting an increased risk of such transmission, common causes of
seemingly isolated incidents would never come to light. Affected HCT/Ps
would continue to place patients at risk of communicable disease.
Accordingly, FDA has also determined that HCT/P tracking, maintenance
and retention of records, and reporting of adverse reactions and HCT/P
deviations are necessary to prevent the transmission of communicable
disease through HCT/Ps.
The CGTP regulations govern the methods used in, and the facilities
and controls used for, the manufacture of HCT/Ps. CGTP requirements are
a fundamental component of FDA's risk-based approach to regulating HCT/
Ps. HCT/Ps regulated solely under section 361 of the PHS Act and the
regulations in part 1271 are not regulated under the act or section 351
of the PHS Act (42 U.S.C. 262). By requiring that HCT/Ps meeting the
criteria listed in Sec. 1271.10 (361 HCT/Ps) be manufactured in
compliance with CGTP, in combination with the other requirements in
part 1271, the agency can ensure that 361 HCT/Ps are subject to
sufficient regulatory controls to protect the public health.
HCT/Ps regulated as drugs, devices, and/or biological products, and
not as 361 HCT/Ps, must be manufactured in accordance with CGTP, in
addition to existing requirements. The CGTP regulations supplement the
current good manufacturing practice (CGMP) and quality system (QS)
regulations applicable to drugs, devices, and biological products in
parts 210, 211, and 820 (21 CFR parts 210, 211, and 820). Thus, in
keeping with the plan outlined in the proposed approach document, those
HCT/Ps regulated as drugs, devices, and/or biological products are
subject to CGMP regulations as well as to CGTP regulations. In the
donor-eligibility final
[[Page 68614]]
rule, the agency amended the existing CGMP regulations for drugs and
the QS requirements for devices to reference the testing and screening
provisions of part 1271, subpart C, as well as the CGTP procedures of
part 1271, subpart D.
FDA is also relying on its authority under section 361 of the PHS
Act for several reporting, labeling, inspection, and enforcement
provisions. Because products regulated as drugs, devices, or biological
products are already subject to similar requirements, these provisions
in subparts E and F would apply only to 361 HCT/Ps. Subpart E of part
1271 contains regulations on reporting and labeling pertaining to 361
HCT/Ps and is discussed in section III.D. of this document. Subpart F
of part 1271 contains inspection and enforcement provisions also
applicable only to 361 HCT/Ps; the relevant discussion appears in
section III.E of this document.
In addition, under section 368(a) of the PHS Act (42 U.S.C. 271),
any person who violates a regulation prescribed under section 361 of
the PHS Act may be punished by imprisonment for up to 1 year.
Individuals may also be punished for violating such a regulation by a
fine of up to $100,000 if death has not resulted from the violation or
up to $250,000 if death has resulted. For organizational defendants,
fines range up to $200,000 and $500,000. Individuals and organizations
also face possible alternative fines based on the amount of gain or
loss. (18 U.S.C. 3559 and 3571(b) to (d)). Federal District Courts also
have jurisdiction to enjoin individuals and organizations from
violating regulations implementing section 361 of the PHS Act. (See
Califano v. Yamasaki, 442 U.S. 682, 704-05 (1979); United States v.
Beatrice Foods Co., 493 U.S. 961 (1975).)
II. Revisions to the Proposed Rule
A. Plain Language
On June 1, 1998, the Presidential Memorandum on Plain Language in
Government Writing was issued in the Federal Register (63 FR 31885).
The purpose of the plain language initiative is to create government
documents that are easier to understand.
In response to this initiative, we have written the CGTP
regulations in plain language. We have:
Reorganized some regulatory sections for greater clarity,
and
Followed other plain-language conventions, such as using
``must'' instead of ``shall.''
The resulting codified language is easier to read and understand
than the proposed regulation. These editorial changes are for clarity
only and do not change the substance of the requirements.
B. HCT/P Definition
In the registration final rule, we discussed our decision to
replace the term ``human cellular and tissue-based products'' with
``human cells, tissues, and cellular and tissue-based products''
(abbreviated ``HCT/Ps'') (66 FR 5447 at 5455). For consistency, we have
made the same change in this final rule.
Also in the registration final rule, we put into place a two-part
definition of HCT/P to stagger the effective dates of the registration
and listing regulations for different types of HCT/Ps. We stated in the
registration final rule that, when all the regulations that make up
part 1271 are issued, we would revoke Sec. 1271.3(d)(1) and renumber
paragraph (d)(2) as a conforming amendment. At that time the new
regulatory framework contained in part 1271 would be instituted as a
whole (66 FR 5447 at 5450). We recognized that unanticipated delays in
completing the rulemaking for the remainder of part 1271 could occur,
and we noted that, should the rulemaking proceedings be delayed past
the anticipated 2-year timeframe, we would consider whether to maintain
the 2-year effective date for the HCT/Ps described in Sec.
1271.3(d)(2) or whether to extend that date (66 FR 5447 at 5449). Since
the rulemaking proceedings were delayed past the original 2-year
effective date of January 21, 2003, we delayed the effective date of
Sec. 1271.3(d)(2) until January 21, 2004(68 FR 2690, January 21,
2003), on which date Sec. 1271.3(d)(2) became effective.
On January 27, 2004, we issued an interim final rule excepting
human dura mater and human heart valve allografts from the definition
of HCT/P in Sec. 1271.3(d) (69 FR 3823). We stated that, when the
comprehensive framework is in place, FDA intends that human dura mater
and human heart valves will be subject to it, and that FDA intends to
revoke the interim rule at that time (69 FR 3823 and 3824). With the
effective date of this final rule, we are revoking the interim rule and
revising the language in Sec. 1271.3(d).
C. Function and Integrity
The proposed rule contained provisions addressing our concerns
about the spread of communicable disease through the use of products
whose function or integrity have been impaired (66 FR 1508 at 1510). As
discussed in Comment 9, we have removed from the regulations all
references to function or integrity.
D. Core CGTP Requirements
In drafting this rule, we have re-evaluated each requirement of the
proposed rule to ensure that it either directly prevents the
introduction, transmission, or spread of communicable diseases (e.g.,
the requirement to store HCT/Ps at an appropriate temperature), or that
it supports such a requirement (e.g., the requirement to periodically
review recorded temperatures to ensure that the temperatures have been
within acceptable limits). We have removed requirements where the
connection to the prevention of the introduction, transmission, or
spread of communicable diseases may be more attenuated.
As a result of this analysis, these final regulations are organized
differently from the proposed regulations and contain fewer
requirements. ``Core CGTP requirements'' are listed in Sec.
1271.150(b); these requirements are directly related to preventing the
introduction, transmission, or spread of communicable diseases. Certain
requirements in subparts D and E are now limited in their applicability
to these core CGTP requirements (e.g., the required records management
system in Sec. 1271.270(b) relates solely to core CGTP requirements).
We have also reorganized sections within these subparts so that the
core CGTP requirements appear first within a section, with supporting
requirements following (e.g., Sec. 1271.190 on facilities has been
reorganized so that requirements for procedures and records, which are
not core requirements, occur in paragraph (d)).
Due to the more limited nature of these final regulations, we have
removed certain proposed requirements, despite their potential
importance to an establishment's operations. We stress that their
absence from these final regulations should not be seen as a
determination that they are without value. Rather, at this time, we are
issuing a more limited set of requirements than proposed. These
requirements represent minimum expectations, but an establishment may
decide to do more than this minimum.
E. Other Revisions
We are amending, rather than revoking, the regulations in part
1270. See section IV of this document for further discussion.
We have made changes from the proposal throughout the regulations
to be more clear; to link the regulations more closely to preventing
the transmission of communicable diseases,
[[Page 68615]]
as discussed in section II.D of this document; and in response to
comments discussed in section III of this document. These revisions
include:
Adding Sec. 1271.145, which requires establishments to
manufacture HCT/Ps in a way that prevents the introduction,
transmission, or spread of communicable diseases;
Revising the definitions for ``adverse reaction,''
``available for distribution,'' ``complaint,'' ``distribution,''
``product deviation,'' ``processing,'' ``quality audit,'' and ``quality
program'';
Adding Sec. 1271.215, which requires establishments to
recover HCT/Ps in a way that does not cause contamination or cross-
contamination during recovery, or otherwise increase the risk of the
introduction, transmission, or spread of communicable disease through
the use of the HCT/P;
Deleting proposed Sec. 1271.220(b) Processing material
and the definition of that term in proposed Sec. 1271.3(hh);
Adding paragraph (b) to Sec. 1271.265;
Adding language in Sec. 1271.420 to facilitate rapid
admissibility decisions for imported HCT/Ps that meet requirements, and
to except cells and tissues from a sexually intimate partner, and
peripheral blood stem/progenitor cells from the requirement for an
admissibility decision; and
Adding pertinent references to ``preventing the
introduction, transmission, or spread of communicable diseases,'' where
it is useful to explain the purposes or scope of a requirement.
We have also made technical amendments to Sec. Sec. 1271.10(a)(3)
and 1271.22(b) and (c). Section 1271.10(a)(3) is revised by adding
``water'' and ``crystalloids'' to the exceptions because, as with
sterilizing, preserving and storage agents, these substances generally
do not raise safety concerns. Water or crystalloids (e.g., saline
solution, Ringer's lactate solution, or 5% dextrose in water) are
typically added to lyophilized HCT/Ps by the user to reconstitute the
HCT/P. We have also revised Sec. 1271.10(a)(3) by replacing ``the
combination of the cell or tissue component with a drug or device''
with ``the combination of cells or tissues with an article.'' We found
that establishments were confused by the reference to drugs and devices
in this context, and did not understand how to evaluate the drug or
device function of the additive in the context of the product. By
substituting the term ``article,'' we eliminate this ambiguity, we
focus more directly on the risks presented by such additives, and we
therefore make this provision more consistent with the risk-based
approach supporting the balance of the rule.
Section 1271.22 is revised by updating the mailcodes in paragraphs
(b)(i) and (c)(i), by removing paragraph (b)(iv) since the Fax
Information System is no longer in service, and by providing
information for the electronic submission of Form FDA 3356.
Section 1271.45(a) is amended by adding that other CGTP
requirements are set out in subpart D of part 1271. This statement
clarifies that subparts C and D together constitute CGTP requirements.
III. Comments on the Proposed Rule and FDA's Responses
We received 47 comments on the proposed rule. Several comments
raised issues that were addressed in the registration final rule (e.g.,
determining the regulatory categorization of HCT/Ps). Responses to
these comments may be found in the registration final rule at Comment 7
(66 FR 5447 at 5451), Comment 8 (66 FR 5447 at 5452), and Comment 30
(66 FR 5447 at 5459). Other comments on this rule raised issues
relating to the donor-eligibility rule; we addressed these comments in
the donor-eligibility final rule at Comment 25 (69 FR 29786 at 29796),
Comment 32 (69 FR 29786 at 29799), Comment 48 (69 FR 29786 at 29806),
Comment 59 (69 FR 29786 at 29809), and in section III.D.3 (69 FR 29786
at 29797).
A. General
1. General Comments
(Comment 1) Numerous comments supported the proposed rule. These
comments called the rule well written and organized, easy to
understand, comprehensive, and reasonable. One comment appreciated the
philosophy we adopted in defining objectives rather than specific
methodologies. Another comment stated that the formulation of the
proposed rule and the development of the entire regulatory framework
were an enormous undertaking of great importance and timeliness.
(Response) We appreciate these supportive comments. We agree with
those comments recognizing both the importance of this rule and the
fact that it represents the culmination of our efforts to develop a
comprehensive new system of regulation for HCT/Ps.
We also note that most of the comments we received on this rule
were helpful and well organized. For example, many comments were
arranged by section number of the proposed regulation and contained
specific suggestions on how to revise each section, often including new
language. We appreciate the care with which these comments were
prepared.
(Comment 2) Some comments stated general opposition to the proposed
rule. One comment stated that tissue banks are self-regulating and that
the rules are unnecessary. This comment further asserted that smaller
tissue banks have not been informed and have been ignored, while we
worked only with large organizations.
(Response) We recognize that some comments oppose the proposed rule
as a general matter and do not consider the new regulations necessary
or beneficial. We disagree with those comments. We also disagree with
the statement that, in developing these rules, we have consulted only
large professional organizations and have ignored the concerns of small
banks or failed to inform them of our rulemaking. Even before this
rulemaking began, we took pains to make our intentions clear to all
interested parties by issuing notices and rulemakings in the Federal
Register, which is accessible to both large and small organizations. We
have held several public meetings on issues affecting the rulemaking
that were open to all interested parties. We also prepared an analysis
of the impact of the rulemaking on small entities in the proposed rule
(66 FR 1508 at 1545). Moreover, this final rule incorporates many
changes made in response to comments from a range of interested
parties, including many small entities. We also will be issuing a small
entity compliance guide, which will assist small entities in complying
with part 1271.
(Comment 3) Several comments compared the proposed rule to industry
standards. Three comments complimented us for the proposed rule's
consistency with current good industry practice. In contrast, one
comment argued that the proposed rule offered little additional benefit
over industry standards currently in place. One comment asserted that
the rule is reasonable to the extent it mirrors good manufacturing
practice (GMP)/QS regulations for in vitro diagnostics and current
bloodborne pathogen guidelines, but that many provisions are
duplicative of the regulations and guidelines in place and create
another layer of unnecessary recordkeeping. This comment stated that
the rule goes beyond its original intent and places an undue regulatory
burden, which would bring a halt to innovative activities.
(Response) The proposed requirements were based on current good
industry practice and were intended to address what we consider to
[[Page 68616]]
be important minimum criteria for the manufacture of HCT/Ps in a manner
that effectively reduces the risk of communicable disease transmission.
In developing the proposed CGTP regulations, we reviewed several sets
of industry standards (66 FR 1508 at 1511). These comments indicate
that we were successful in reflecting current good practices. We note
that, to the extent that industry standards are consistent with and at
least as stringent as CGTP requirements and are appropriate for the
operations conducted, an establishment may adopt industry's standard
procedures as a way of complying with these regulations (Sec.
1271.180(d)). However, we decline to mandate compliance with the
standards of a particular professional organization. Industry
associations are welcome to submit their standards to the agency for
potential adoption as guidance subject to public comment. (See 21 CFR
10.115.)
We disagree that these regulations require unnecessary
recordkeeping or create an undue regulatory burden. In this final rule,
we have made numerous changes to the regulatory provisions in response
to comments; many of these changes will have the effect of reducing the
regulatory burden from that originally proposed while still addressing
communicable disease risks.
With respect to the comment on duplicative requirements applicable
to HCT/Ps regulated as devices, drugs, and/or biological products, we
note that Sec. 1271.150(d) states that CGTP and CGMP regulations in
parts 210 and 211 and the QS regulations in part 820 supplement each
other unless the regulations explicitly provide otherwise. In the event
of a conflict between applicable requirements, the regulations more
specifically applicable to the product will supersede the more general
requirements. FDA believes that, in the event of such a conflict, the
more specifically applicable regulation would be found in part 1271. It
is unnecessary to maintain two sets of records to indicate compliance
with both CGTP and CGMP or QS requirements; a single set of records is
adequate.
(Comment 4) Several comments requested that these regulations be
phased in over time. Two comments requested a grace period of 1 to 2
years; one comment requested a 2-year implementation period; and
another comment requested an extension of the compliance deadline to 1
year after publication.
(Response) We understand the request for a long implementation
period. However, recent reports of bacterial infections in patients who
received HCT/Ps support the implementation of the CGTP requirements as
soon as possible. (Ref. 1) The effective date of the CGTP final rule
will coincide with the effective date of the previously issued donor
eligibility requirements. We believe that this will provide an adequate
amount of time to comply with the requirements in part 1271.
(Comment 5) Two comments opposed the retrospective application of
any regulation or guidance to tissue recovered before its issuance,
because tissue may have a shelf life of up to 5 years. The comments
suggested that the final rule should apply to HCT/Ps recovered after
the effective date, and that for tissues recovered before the effective
date of the final rule, the regulations in part 1270 would continue to
apply.
(Response) We agree that the final rule will apply to HCT/Ps
recovered on or after the rule's effective date. Cells and tissue
recovered before that date are subject to the regulations in effect at
the time of recovery. The regulations in part 1270 are being amended in
this rulemaking so that those regulations will continue to apply only
to human tissue for transplantation recovered before the effective date
of this rule. See section IV.B of this document for further discussion.
(Comment 6) One comment asserted that the regulations should cover
the procurement and storage of human organs for transplant,
reproductive cells (sperm and ova), and the storage of human milk.
(Response) Part 1271 does not apply to human organs or to human
milk. Subparts D and E are not being implemented with respect to
reproductive HCT/Ps, except for Sec. Sec. 1271.150(c) and 1271.155.
(Comment 7) Several comments objected to the terms ``manufacture''
and ``product'' as inappropriate for use with respect to donated human
tissue. One comment asserted that corneas are recovered and evaluated,
not manufactured. Some comments suggested substitute terminology: e.g.,
``donor program'' or ``tissue service organization'' instead of
``manufacturer''; ``handle'' instead of ``manufacture''; and ``human
cellular and tissue-based material'' instead of ``product.'' One
comment asserted that, because the terminology used in the rule does
not correlate with eye bank practices, it was difficult to determine
which sections apply to eye banking; this comment cited the additional
terms ``process,'' ``processing,'' ``processing material,''
``validation,'' and ``verification.''
(Response) In the registration final rule, we changed the term
``human cellular or tissue-based product'' to ``human cells, tissues,
and cellular and tissue-based products,'' or ``HCT/Ps.'' We made this
change in response to comments that opposed calling donated tissue a
``product.'' In that final rule, we noted that we needed a term broad
enough to cover both cells and tissues, and one that would include
within its scope such diverse articles as unprocessed tissue, highly
processed cells, and tissues that are combined with certain drugs or
devices (66 FR 5447 at 5455). We believe the term ``HCT/P'' addresses
the concerns expressed in the comments, and we will use that term in
these regulations.
In the registration final rule, we also considered substituting a
different term for ``manufacture,'' in response to similar comments,
but were unable to find a satisfactory replacement. Among other terms,
we considered ``handling,'' but rejected it as too limited in scope.
Thus, we have continued to use the word ``manufacture'' as an umbrella
term to capture the many different actions that HCT/P establishments
might take in preparing HCT/Ps for use (66 FR 5447 at 5455).
Many different types of establishments are involved in the
recovery, screening, testing, processing, storage, labeling, packaging,
and distribution related to HCT/Ps. Some of these may accurately be
called tissue service organizations, donor programs, or tissue
procurement organizations, and may certainly continue to call
themselves by these names. However, these terms are too limited to
cover those establishments that perform other manufacturing functions,
and for that reason we decline to adopt any of these suggested terms in
this regulation. We note that, although these rules at times refer to
``manufacturers,'' the more frequently used term is ``establishment.''
With respect to the comment on the applicability of these
regulations to eye banks, we discuss the applicability of specific
sections throughout this final rule. We note that each establishment is
required to comply only with those requirements that apply to the
activities in which it engages. We are working, with input from
industry and others, to develop guidances specific to different types
of HCT/Ps; this effort is intended to help establishments comply with
these CGTP requirements to control the risk of communicable disease
transmission.
(Comment 8) Comments from eye banking organizations stated that eye
and cornea banking differ from other tissue banking.
[[Page 68617]]
(Response) We acknowledge that, in some ways, eye banking differs
from other tissue banking. However, since 1993, ocular tissue has been
regulated under the regulatory model for all human tissues for
transplantation. Eye banks are similar to tissue banks in that they
recover, process (although minimally), store, label, package, or
distribute human tissue, screen and test the tissue donor, report
adverse reactions, and track tissue. We have intentionally crafted
broad CGTP regulations for flexibility with the expectation that each
bank will specify its own operating procedures. In addition, we have
stated that an establishment need only comply with those requirements
that are applicable to the operations in which it engages.
2. Function and Integrity
The proposed CGTP requirements were intended, in part, to prevent
the introduction, transmission, or spread of communicable disease by
helping to ensure that the function and integrity of HCT/Ps are not
impaired through improper manufacturing (proposed Sec. 1271.150(a);
see 66 FR 1508 at 1510). Many of the provisions of the proposed rule
contained requirements intended to help ensure HCT/P function and
integrity. For example, proposed Sec. 1271.260 would require an
establishment to control its storage areas to prevent conditions that
may adversely affect function or integrity.
(Comment 9) Approximately nine comments objected to the proposed
rule's provisions on function and integrity. Some of these comments
criticized our justification for these provisions as weak or
theoretical; these comments questioned whether the impairment of an
HCT/P's function and integrity actually increases the risk of disease
transmission. Other comments argued that section 361 of the PHS Act
cannot be interpreted to cover an HCT/P's function and integrity.
Several comments requested that the phrase be defined or deleted.
Several comments expressed concern that the provisions on function
and integrity could be interpreted to mean that an establishment assess
each HCT/P's function and integrity. These comments agreed generally
with the concept of ensuring function and integrity, which they
described as ensuring that an HCT/P is ``fit for use,'' but asked the
agency to clarify the relationship between the concept and a risk-based
system.
Most comments on the general issue of function and integrity also
objected to specific sections of the proposed rule where that term
appears. These comments requested the deletion of, or a substitution
for, the phrase ``function and integrity,'' as well as related terms.
(Response) To increase clarity, and because of the confusion
expressed by comments about the term ``function and integrity,'' we
have removed from the regulations all references to function or
integrity. For the same reason, we have also removed references to the
related terms, ``deterioration'' and ``adverse effect.''
To avoid repetition throughout this document, comment summaries do
not contain references to function and integrity (or related terms),
where we received comments on that issue. Moreover, references to
function and integrity, deterioration, and adverse effect, have been
removed from summaries of the provisions proposed in the proposed rule.
References to function and integrity have been removed from discussions
of the following proposed provisions: Sec. Sec. 1271.3(bb) and (kk),
1271.160, 1271.200, 1271.210, 1271.220, 1271.260, 1271.265, 1271.350,
and 1271.420.
B. Definitions (Sec. 1271.3)
We have grouped all definitions pertinent to part 1271 in a single
definitions section (Sec. 1271.3), among the general provisions of
subpart A. The proposed rule contained proposed definitions from Sec.
1271.3(ff) through (tt); these have been renumbered from Sec.
1271.3(y) through (ll). We have also reordered the definitions to
maintain some alphabetical order, and they are discussed according to
their new order.
We have revised Sec. 1271.3(d) by deleting paragraph (d)(1), as it
is no longer applicable with the effective date of this rulemaking. We
have added the terms ``repair'' and ``reconstruction'' to the
definition of ``homologous use'' at Sec. 1271.3(c) (the registration
final rule, 66 FR 5447 at 5467), to provide a more complete and
accurate description of the definition.
1. Adverse Reaction (Sec. 1271.3(y))
The proposed rule would define ``adverse reaction'' as a noxious
and unintended response to any HCT/P for which there is a reasonable
possibility that the response may have been caused by the product
(i.e., the relationship cannot be ruled out) (66 FR 1508 at 1520).
Adverse reaction reporting requirements are set out in proposed Sec.
1271.350(a).
(Comment 10) Several comments argued that the proposed definition
of ``adverse reaction'' is too broad. One comment asserted that a
transplant recipient could experience a reaction to a substance in a
tissue even though the manufacturer followed CGTP requirements. One
comment suggested changing ``reasonable possibility'' to ``reasonable
probability.''
(Response) The definition of ``adverse reaction'' is intended to
capture those situations that may indicate a problem with an HCT/P and
that a manufacturer should therefore investigate. A noxious and
unintended response to a substance in an HCT/P would meet the
definition of ``adverse reaction,'' and an establishment should
evaluate the situation.
The receipt of adverse reaction reports enables us to evaluate
potential relationships between reports. For example, if several
separate establishments reported that a recipient of tissue that the
establishments made available for distribution developed a wound
infection with Clostridium sp., FDA might determine that a single
establishment recovered or processed all of those tissues. An FDA
investigation would be initiated.
It is important to note that not all adverse reactions are required
to be investigated and reported. Section 1271.350(a) sets out those
situations in which an establishment must make an adverse reaction
report to us. An investigation is required when an adverse reaction
involves a communicable disease. A report is required when such an
adverse reaction is fatal or life-threatening; results in permanent
impairment or damage; or necessitates medical or surgical intervention.
The criteria set out in Sec. 1271.350(a) limit the scope of the
adverse reaction reporting requirement. As discussed in the preamble to
the proposed rule (66 FR 1508 at 1520), this approach, and the
definition of adverse reaction, are consistent with other rules we are
developing and with international standards (See, e.g., ``International
Conference on Harmonisation; Guideline on Clinical Safety Data
Management: Definitions and Standards for Expedited Reporting;
Availability'' (ICH guideline), 60 FR 11284, March 1, 1995).
We decline to replace the word ``possibility'' with the suggested
term, ``probability.'' We interpret ``reasonable possibility'' to mean
that there is a possible causal relationship between an adverse
experience and an HCT/P; ``there are facts (evidence) or arguments to
suggest a causal relationship.'' (ICH guidance, 60 FR 11284 at 11286).
(Comment 11) One comment questioned the phrase ``the relationship
cannot be ruled out.'' This comment noted that there may be multiple
possible causes of a patient's problems,
[[Page 68618]]
and that in some instances it may be unlikely that the HCT/P is
responsible.
(Response) We have removed the phrase ``the relationship cannot be
ruled out'' from the definition of ``adverse reaction.'' On further
examination, we believe it is not helpful in explaining what is meant
by ``reasonable possibility.'' We recognize that there may be
situations in which there are multiple possible causes of a patient's
problem. Nevertheless, if one of the reasonable possibilities is that
the HCT/P caused the problem, then this would meet the definition of
``adverse reaction.'' This would include situations in which the
relationship between the response and the HCT/P is ``unlikely'' but
nevertheless possible.
2. Available for Distribution (Sec. 1271.3(z))
The proposed regulations in Sec. 1271.3(ff) would define
``available for distribution'' to mean that an HCT/P has been
determined to meet all release specifications and to be suitable for
distribution.
(Comment 12) One comment suggested this definition should be
harmonized with the final rule on biologic product deviations (65 FR
66621 at 66634, November 7, 2000; 21 CFR 600.14) to clarify that
reporting product deviations is only necessary after an HCT/P has left
control of the establishment (i.e., has been distributed).
(Response) We agree that, under Sec. 1271.350(b), you are required
to report an HCT/P deviation only when the HCT/P has been distributed.
However, we disagree that there is any need to modify the definition of
``available for distribution'' as requested by the comment. The phrase
``available for distribution'' does not appear in Sec. 1271.350(b). We
have, however, removed the words ``and to be suitable for
distribution'' from the definition of ``available for distribution.''
As defined in the final rule, an HCT/P is ``available for
distribution'' if it has been determined to meet all release criteria.
We discuss the definition of ``distribution'' in Comment 16.
3. Complaint (Sec. 1271.3(aa))
Proposed Sec. 1271.3(ii) would define ``complaint'' as any
written, oral, or electronic communication that alleges that an HCT/P
has transmitted or may have transmitted a communicable disease; or any
other problem with an HCT/P that could result from the failure to
comply with CGTP (66 FR 1508 at 1520).
(Comment 13) One comment stated that the definition is vague and
would leave eye banks open to baseless accusations by recipients,
family members, or physicians for graft failure that may have been due
to other causes. According to this comment, eye banks should be given
an opportunity to filter out unfounded complaints.
(Response) We have revised the definition to specify that
information must relate to the potential for transmission of
communicable disease, such as the failure to comply with current good
tissue practice (which would include the donor eligibility
regulations). However, we note that a complaint may come from any
source and may be a written, oral, or electronic communication. Section
1271.320 requires each establishment to have procedures in place to
evaluate complaints that relate to core CGTP requirements and to
determine whether investigation is necessary.
(Comment 14) Several comments noted their belief that the proposed
requirements on complaints would apply only to HCT/Ps that have been
released to distribution.
(Response) We agree with these comments and revised the definition
to apply to distributed HCT/Ps only.
(Comment 15) Two comments requested the deletion of proposed Sec.
1271.3(ii)(3), which covered any other problem with an HCT/P that could
result from the failure to comply with CGTP. Two other comments
suggested that we revise proposed Sec. 1271.3(ii)(3) to refer to
deficiencies related to the identity, quality, durability, reliability,
safety, or performance of a product after it is released for
distribution. A third comment recommended that paragraph (ii)(3) be
deleted or clarified to indicate its application to tissues released to
distribution.
(Response) We decline to delete proposed Sec. 1271.3(ii)(3), which
has been renumbered as Sec. 1271.3(aa)(2). As previously noted, we
intend the requirements with respect to complaints to apply to HCT/Ps
that have been distributed. It is necessary for all establishments to
have in place a system to handle communications about problems with its
distributed HCT/Ps. Some problems may be traced to a failure to comply
with CGTP, which could lead to additional problems that increase the
risk of communicable disease transmission if not corrected. Deleting
proposed Sec. 1271.3(ii)(3) would unduly narrow the scope of the
definition, allowing establishments to ignore important communications
about their products. (However, we note that, as discussed in Comment
13, we have specified that information under this paragraph must relate
to the potential for transmission of communicable disease.)
4. Distribution (Sec. 1271.3(bb))
We proposed to define ``distribution'' in Sec. 1271.3(jj) as any
conveyance or shipment of HCT/Ps (including importation and
exportation), whether or not such conveyance or shipment is entirely
intrastate and whether or not possession of the product is taken. We
originally described our intended definition of ``distribution'' in the
preamble to the registration proposed rule (63 FR 26744 at 26750), and
we responded to several comments on ``distribution'' in the
registration final rule (66 FR 5447 at 5456).
(Comment 16) One comment asserted that the definition of
distribution in the proposed rule is inconsistent with the definition
in the registration final rule. The comment pointed out that, in the
preamble to the registration final rule, we agreed that an entity that
does not take possession of HCT/Ps is not distributing them for the
purposes of this rule.
(Response) The proposed rule, which contained the proposed codified
definition of ``distribution,'' preceded the registration final rule,
in which we indicated we would make changes to the proposed definition.
We are now making the change to the definition that we discussed in the
registration final rule; i.e., we have removed the phrase ``whether or
not possession is taken'' from the definition and replaced it with ``If
an entity does not take physical possession of an HCT/P that entity is
not considered a distributor.''
(Comment 17) One comment requested that we clarify that
intracompany transfers of HCT/Ps are not included within the definition
of ``distribution,'' consistent with FDA's policy with respect to other
medical products.
(Response) In response to this comment, we have modified the
definition of ``distribution'' to mean any conveyance or shipment of an
HCT/P ``that has been determined to meet all release criteria.'' This
change is intended to make clear that the shipment of an HCT/P before
it is ready for release would not be considered distribution (e.g., the
movement of an HCT/P from a recovering establishment to a processing
establishment). This sort of predistribution shipment might also take
place between establishments that are part of the same company. On the
other hand, not all intracompany shipments are appropriately excepted
from the definition of ``distribution.'' For example, releasing an HCT/
P from a collection/processing facility to an
[[Page 68619]]
operating room in the same facility would be considered distribution.
5. Establish and Maintain (Sec. 1271.3(cc))
Proposed Sec. 1271.3(ll) would define ``establish and maintain''
as define, document (in writing or electronically), and implement, then
follow, review, and, as needed, revise on an ongoing basis.
We received no comments on the proposed definition of ``establish
and maintain.''
6. HCT/P Deviation (Sec. 1271.3(dd))
Proposed Sec. 1271.3(kk) would define ``product deviation'' as an
event that represents a deviation from CGTP, applicable standards, or
established specifications; or an unexpected or unforeseeable event
that may relate to the transmission or potential transmission of a
communicable disease agent or disease from an HCT/P to a recipient, or
may lead to product contamination.
In response to comments on the term ``product,'' we have changed
the defined term from ``product deviation'' to ``HCT/P deviation'' (see
66 FR 5447 at 5455). We have also narrowed the definition of HCT/P
deviation by revising the phrase ``a deviation from current good tissue
practice, applicable standards, or established specifications'' to read
``a deviation from applicable regulations in this part or from
applicable standards or established specifications that may relate to
the prevention of communicable disease transmission or to the
prevention of HCT/P contamination.''
Proposed Sec. 1271.350(b) would require you to report those HCT/P
deviations that could reasonably be expected to lead to a reportable
adverse reaction.
(Comment 18) One comment suggested that we use the term ``process
deviation'' instead of ``product deviation,'' because the definition
refers to an event rather than to a deviation in the HCT/P.
(Response) We decline to make the suggested change because to do so
could exclude problems that occur in areas of manufacture other than
``processing,'' such as recovery and storage, and would therefore be
narrower than ``HCT/P deviation.'' Moreover, the term ``process
deviation'' might introduce inconsistency with our reporting
requirements in Sec. 600.14 (21 CFR 600.14) for biological products
other than blood and blood components. Establishments that manufacture
HCT/Ps regulated under section 351 of the PHS Act will report under
Sec. 600.14. Establishments that manufacture HCT/Ps regulated as drugs
or devices under the act will make any reports under drug and device
reporting provisions.
(Comment 19) One comment noted that there are no established
specifications for corneas, although there are proxy indicators (e.g.,
cell counts and cell morphology) that can be taken into account when
evaluating tissue, and that outcomes may be dependent upon factors
beyond an eye bank's control.
(Response) We understand that an eye bank might not set
specifications for corneas. However, we expect that an establishment
will generally set out acceptable criteria for its HCT/Ps in its
standard operating procedures. These criteria may relate to such
factors as storage temperature, and although not considered
specifications by the establishment, they serve much the same role.
Since storage temperature may relate to the prevention of communicable
disease transmission or HCT/P contamination, a deviation from these
criteria would be considered an HCT/P deviation You must review the
deviation to determine if it must be reported under Sec. 1271.350(b).
7. Importer of Record (Sec. 1271.3(ee))
Proposed Sec. 1271.3(tt) would define ``importer of record'' as
``the person, establishment, or its representative responsible for
making entry of imported goods in accordance with all laws affecting
such importation.'' (66 FR 1508 at 1552).
We received no comments on the proposed definition of ``importer of
record.''
8. Processing (Sec. 1271.3(ff))
Processing is one of the activities listed in the definition of
``manufacture'' in Sec. 1271.3(e). The proposed rule would define
``processing'' in Sec. 1271.3(mm) as any activity performed on an HCT/
P other than recovery, donor screening, donor testing, storage,
labeling, packaging, or distribution. Processing would include, but not
be limited to, preparation, sterilization, steps to inactivate and
remove adventitious agents, preservation for storage, and removal from
storage. We have added to the definition ``testing for microorganisms''
because this activity may occur at this stage of manufacturing.
(Comment 20) One comment requested clarification of the terms
``process'' and ``processing'' as those terms are used in proposed
Sec. Sec. 1271.220 (process controls) and 1271.225 (process changes).
(Response) We believe that ``process'' is a generally understood
term; one accepted definition of ``process'' is a ``set of interrelated
or interacting activities which transfers inputs into outputs''
(International Standards Organization (ISO) 9000:2000, 3.4.1). In the
context of this final rule, the set of processing activities that an
establishment performs on an HCT/P would be considered a ``process.''
We consider the proposed definition of ``processing'' to be
sufficiently clear and have made no substantive changes to it.
(Comment 21) One comment from an eye bank requested clarification
of ``preparation,'' ``preservation for storage,'' and ``removal from
storage.'' The comment noted that corneas are stored in media to
maintain viability but are not preserved for long-term storage.
(Response) We believe that these terms are generally understood;
however, not all of them may be applicable to eye banks. We agree that
corneas are usually not preserved for long-term storage, but
nevertheless, they are preserved in a corneal storage media, even for
short-term storage.
Examples of corneal processing may include gross and microscopic
examination of the cornea, microbiological culture of the rim,
preservation in a corneal storage media, and placement into and removal
from the refrigerator.
9. Processing Material
The proposed rule would define ``processing material'' in Sec.
1271.3(hh) as any material or substance that is used in, or to
facilitate, processing, but which is not intended by the manufacturer
to be included in the HCT/P when it is made available for distribution.
We have deleted the relevant provision on processing material, in
proposed Sec. 1271.220(b), and as a result are also deleting this
definition.
10. Quality Audit (Sec. 1271.3(gg))
We proposed to define ``quality audit'' in Sec. 1271.3(nn) as a
documented, independent inspection and review of an establishment's
activities, including manufacturing and tracking, performed according
to procedures, to verify, by examination and evaluation of objective
evidence, the degree of compliance with those aspects of the quality
program under review.
We have revised the definition of quality audit to mean a
documented, independent inspection and review of an establishment's
activities related to core CGTP requirements. The definition further
states that the purpose of a quality audit is to verify, by examination
and evaluation of objective evidence, the degree of compliance with
those aspects of the quality program under review.
[[Page 68620]]
(Comment 22) One comment recommended that we define ``independent''
or insert a reference to proposed Sec. 1271.160(d)(2), which would
require that a quality audit be performed by an individual who does not
have direct responsibility for the processes being audited. Another
comment asked us to clarify ``independent inspection'' and asked
whether an employee could perform the independent inspection. A third
comment asked whether an outside accreditation process could constitute
an independent review.
(Response) We do not believe it is necessary to define
``independent.'' We consider an inspection and review by an individual
who does not have direct responsibility for the processes being audited
to be ``independent.'' This individual could be someone outside the
firm, or could be an individual within the firm who does not have
direct responsibility for the matters being audited. If an
accreditation process is equivalent to an internal quality audit, it
would be acceptable. We decline to add a reference to the quality audit
provision of Sec. 1271.160, which has been revised.
11. Quality Program (Sec. 1271.3(hh))
We proposed to define ``quality program'' in Sec. 1271.3(oo) as an
organization's comprehensive system for manufacturing and tracking HCT/
Ps. As defined, the program would include preventing, detecting, and
correcting deficiencies that may lead to circumstances that increase
the risk of introduction, transmission, or spread of communicable
diseases.
We have revised the definition of ``quality program'' for clarity.
The definition now states, in part, that a quality program is designed
to prevent, detect, and correct deficiencies that may lead to
circumstances that increase the risk of introduction, transmission, or
spread of communicable diseases.
(Comment 23) One comment endorsed the concept of a quality program
but noted that the preamble referred to an organization's ``method,''
while the proposed definition used the term ``system for
manufacturing.'' The comment suggested that we change the codified
definition to reflect the preamble.
(Response) We decline to make the suggested change; rather, we note
that it would have been clearer if we had referred in the preamble to a
``system'' rather than to a ``method.'' As stated in the preamble to
the proposed rule (66 FR 1508 at 1513), we use the term ``quality
program'' to refer to the set of activities, including management
review, training, audits, and corrective and preventive actions, that
represent a commitment on the part of an establishment's management to
the quality of its products. Whether this set of activities is regarded
as a part of manufacture or as a separate system for overseeing
manufacture, as preferred by the comment, is not material.
12. Recovery (Sec. 1271.3(ii))
Proposed Sec. 1271.3(pp) would define ``recovery'' as the
``process of obtaining from a donor cells or tissues that are intended
for use in human implantation, transplantation, infusion, or
transfer.'' (66 FR 1508 at 1551 and 1552).
(Comment 24) One comment suggested rewording the definition of
``recovery'' to avoid referring to recovery as a process.
(Response) We agree with this comment. The word ``process'' in the
definition of ``recovery'' could be confused with the definition of
``processing'' in proposed Sec. 1271.3(mm), which does not include
recovery. The definition now reads: Recovery means obtaining from a
donor cells or tissues that are intended for use in human implantation,
transplantation, infusion, or transfer.
13. Storage (Sec. 1271.3(jj))
Storage is one of the activities listed in the definition of
manufacture in Sec. 1271.3(e). We proposed to define ``storage'' in
Sec. 1271.3(qq) as holding HCT/Ps for future processing and/or
distribution.
(Comment 25) One comment recommended that we clarify that the
definition does not refer only to finished HCT/Ps ready for shipment
and suggested that the definition refer also to ``materials.''
(Response) Although we agree that the term ``storage'' does not
apply only to finished HCT/Ps, but to HCT/Ps at any stage of
processing, we do not consider a revision of the definition to be
necessary. The term HCT/P encompasses HCT/Ps at any stage of
manufacture, from recovery to distribution (66 FR 5447 at 5448).
Moreover, the definition of ``storage'' refers to ``future
processing,'' which indicates that the definition applies not only to
finished products but also to cells or tissues that may be subject to
future processing.
14. Validation (Sec. 1271.3(kk))
Proposed Sec. 1271.3(rr) would define ``validation'' as
confirmation by examination and provision of objective evidence that
particular requirements can consistently be fulfilled. The definition
went on to define validation of a process, or ``process validation,''
as establishing by objective evidence that a process consistently
produces a result or product meeting its predetermined specifications.
(Comment 26) One comment requested that we harmonize the proposed
definition with that of the International Conference on Harmonisation
(ICH). The comment suggested that the new definition read:
A documented program that provides a high degree of assurance
that a specific process, method, or system will consistently produce
a result meeting predetermined acceptance criteria.
(Response) We decline to make this change. Harmonization of the two
definitions is unnecessary, because the proposed definition is
consistent with the language suggested by the comment. The proposed
definition is preferable, however, because it explains in more specific
terms what is expected (e.g., ``confirmation by examination'';
``provision of objective evidence''). In addition, the proposed
definition is consistent with the ISO 9000:2000 definition of
validation (Quality management system--Fundamentals and vocabulary).
(Comment 27) Two comments questioned the use of the term
``validation'' throughout the proposed rule. These comments cited
industry standards that require a level of review tailored to the type
of processing used for a particular tissue (e.g., validation of certain
shipping containers versus verification of other aspects of
processing). The comments requested clarification that compliance with
these standards would be deemed compliance with the rule's validation
requirements.
(Response) Where the appropriate action depends on the type of
tissue or processing, the rule provides establishments with the
flexibility to determine whether verification or validation is
appropriate (e.g., Sec. Sec. 1271.210(c) and 1271.225). Verification
activities may be sufficient for certain processes if the results can
be adequately determined through inspection and testing methods. When
full and complete verification cannot be achieved, the process must be
validated. The manufacturer should have the requisite knowledge of the
processes and operations conducted at its facility to determine which
actions are needed.
FDA cannot make a determination that compliance with professional
standards ensures compliance with the validation requirements of this
rule. Each establishment will need to assess its operations to make
sure the applicable requirements of the CGTP regulation are met. We
encourage
[[Page 68621]]
professional organizations and others to submit drafts of proposed
guidance in this area for FDA to consider for possible adoption.
15. Verification (Sec. 1271.3(nn))
Proposed Sec. 1271.3(ss) would define ``verification'' as
``confirmation by examination and provision of objective evidence that
specified requirements have been fulfilled.'' (66 FR 1508 at 1552).
We received no comments on the proposed definition of
``verification, `` and it is unchanged.
C. Part 1271, Subpart D--Current Good Tissue Practice
Part 1271, subpart D, sets forth CGTP requirements. We have added,
in Sec. 1271.145, an explicit statement of the basic requirement that
underpins all of the provisions of this subpart. Section 1271.145
states that you must recover, process, store, label, package, and
distribute HCT/Ps, and screen and test cell and tissue donors, in a way
that prevents the introduction, transmission, or spread of communicable
diseases.
1. Current Good Tissue Practice Requirements (Sec. 1271.150)
General (Sec. 1271.150(a))
Proposed Sec. 1271.150(a) states in part that the CGTP
requirements are intended to prevent the introduction, transmission, or
spread of communicable disease through the use of HCT/Ps by helping to
ensure that they do not contain communicable disease agents and that
they do not become contaminated during manufacturing. We have revised
this sentence for clarity, have added the phrase ``that they are not
contaminated,'' and have included the statement that ``you must follow
CGTP requirements.''
We have also added to Sec. 1271.150(a) the statement that
communicable diseases include, but are not limited to, those
transmitted by viruses, bacteria, fungi, parasites, and transmissible
spongiform encephalopathy (TSE) agents. Although the proposed CGTP
requirements were intended to prevent contamination of HCT/Ps with
these agents (e.g., see 66 FR 1508 at 1509, 1510, 1514, and 1515), we
believe that these examples of communicable disease make this provision
more clear.
A 2002 Morbidity and Mortality Weekly Report (MMWR) discusses 26
cases of bacterial infection associated with musculoskeletal allografts
and reinforces the importance of following CGTP to prevent the
contamination of HCT/Ps with such communicable disease agents. In the
MMWR, the Centers for Disease Control and Prevention (CDC) make several
significant recommendations on preventing bacterial contamination.
Among other things, the CDC states that ``[s]terilization of tissue
that does not adversely affect the functioning of tissue when
transplanted into patients is the best way to reduce the risk for
allograft-associated infections.'' Throughout this final rule, we
discuss the CDC's recommendations and note the applicability of
specific provisions of the final rule to the prevention of bacterial
contamination (Ref. 1).
Core CGTP Requirements (Sec. 1271.150(b))
Paragraph (b) lists the core CGTP requirements, discussed in
section II.D of this document. We have identified the following as core
CGTP requirements: Sec. 1271.190(a) and (b) (relating to facilities);
Sec. 1271.195(a) (environmental controls); Sec. 1271.200(a)
(equipment); Sec. 1271.210(a) and (b) (supplies and reagents); Sec.
1271.215 (recovery); Sec. 1271.220 (processing and process controls);
Sec. 1271.250(a) and (b) (labeling controls); Sec. 1271.260(a)
through (d) (storage); Sec. 1271.265(a) through (d) (receipt,
predistribution shipment, and distribution); and Sec. Sec. 1271.50,
1271.75, 1271.80, and 1271.85 (donor eligibility determinations, donor
screening, and donor testing).
Compliance With Applicable Requirements (Sec. 1271.150(c)(1))
Proposed Sec. 1271.150(b)(1) states that an establishment that
engages in only some operations subject to the regulations in this
subpart and subpart C of this part need only comply with those
requirements applicable to the operations in which it engages. It
further states that when an establishment engages a second
establishment to perform any step in manufacturing, the second
establishment would be required to comply with the requirements
applicable to that manufacturing step. In addition, the first
establishment would be responsible for ensuring that the work at the
other establishment is performed in compliance with subparts C and D.
Proposed paragraph (b) of Sec. 1271.150 has been redesignated as
paragraph (c).
The following table summarizes the responsibilities that are
assigned in the final rule to each manufacturer when multiple
establishments are involved in manufacturing an HCT/P:
Table 1a
----------------------------------------------------------------------------------------------------------------
If you: You must:
----------------------------------------------------------------------------------------------------------------
Perform any step in the manufacture of Follow CGTP (subparts C and D) (Sec. 1271.150(a)) as it relates to
an HCT/P that step.
----------------------------------------------------------------------------------------------------------------
Perform only some and not all 1. Follow only those requirements applicable to the operations you
operations of manufacturing, and do perform (Sec. 1271.150(c)(1).
not make the HCT/P available for 2. When you receive the HCT/P, determine whether the HCT/P meets all
distribution pre-established criteria, designed to prevent communicable disease
transmission, for acceptance or rejection, and place the HCT/P in
quarantine as appropriate (Sec. 1271.265(a)).
3. When you prepare to ship an HCT/P, ship the HCT/P only in quarantine
and after determining criteria designed to prevent communicable
disease are met (Sec. 1271.265(b)).
4. Investigate all HCT/P deviations related to a distributed HCT/P for
which you performed a manufacturing step and report any deviation
related to core CGTP requirements that occurred in your facility or in
a facility that performs a manufacturing step for you under contract,
agreement, or other arrangement (Sec. 1271.350(b)(1) and (b)(2)).
----------------------------------------------------------------------------------------------------------------
Engage another establishment to perform 1. Enter into and maintain such an arrangement only with a reliable
any step in manufacturing for you establishment that complies with applicable CGTP requirements. (Sec.
under contract, agreement, or other 1271.150(c)(1)).
arrangement 2. Investigate all HCT/P deviations related to a distributed HCT/P for
which you performed a manufacturing step and report any deviation
related to core CGTP requirements that occurred in your facility or in
a facility that performs a manufacturing step for you under contract,
agreement, or other arrangement (Sec. 1271.350(b)(1) and (b)(2)).
----------------------------------------------------------------------------------------------------------------
[[Page 68622]]
Make the HCT/P available for 1. Review manufacturing and tracking records to determine that the HCT/
distribution P meets all the release criteria (Sec. Sec. 1271.150(c)(2) and
1271.265(c)) and maintain records relevant to the release
determination (Sec. 1271.270(a)).
2. Ensure that manufacturing and tracking records demonstrate that the
HCT/P has been manufactured and tracked from recovery to the consignee
following CGTP (Sec. Sec. 1271.150(c)(2) and 1271.290).
3. Investigate and report any adverse reaction involving a communicable
disease (Sec. 1271.350(a)).
4. Investigate all HCT/P deviations related to any step in the
manufacture of a distributed HCT/P that you performed, and report any
HCT/P deviation relating to core CGTP requirements if the deviation
occurred in your facility or in a facility that performed a
manufacturing step for you under contract, agreement, or other
arrangement (Sec. 1271.350(b)(1) and (b)(2)).
----------------------------------------------------------------------------------------------------------------
(Comment 28) Several comments objected to the statement in proposed
Sec. 1271.150(b)(1) that an establishment that engages another
establishment under a contract, agreement, or other arrangement, to
perform any step in the manufacturing process, is responsible for
ensuring that the work is performed in compliance with the CGTP and
donor-eligibility requirements. One comment asserted that the language
is too broad and open to interpretation, and could make eye banks
responsible for ensuring that entities such as couriers, medical
examiner's offices, and laboratories meet regulatory requirements
applicable to the subcontracted function. Another comment asked whether
an establishment must inspect Federal Express, UPS, or the Postal
Service to ensure that they comply with the regulations when shipping
corneas.
(Response) We have revised the language of the proposed rule. Under
Sec. 1271.150(c)(1), if an establishment (e.g., an eye bank) engages
another establishment to perform a manufacturing step, under a
contract, agreement, or other arrangement, it must enter into and
maintain such an arrangement only with a reliable establishment that
complies with applicable CGTP requirements. Under this provision, an
establishment should choose its partners with care. This requirement
extends to relationships with establishments such as medical examiner
offices and laboratories, but it does not apply with respect to
carriers, such as Federal Express, UPS, or the Postal Service, who are
exempt from the regulations in this part as noted in Sec. 1271.15(c).
(Comment 29) One comment stated that it is unrealistic to require
validation of a subcontractor's work on each tissue, and that it is
expensive and nearly impossible to find staff with specific expertise
to review each type of subcontractor. Another comment stated that eye
banks are not qualified to be responsible for ensuring compliance by
subcontractors and recommended that compliance by subcontractors be
deemed met by a letter of intent from the subcontractor. This comment
also asserted that eye banks do not have the expertise to inspect or
validate a blood testing laboratory or Bausch & Lomb.
One comment suggested that an initial audit of the contractor
should be sufficient. Another comment suggested that each establishment
have a system in place designed to ensure that the contractor's work is
performed in compliance with the regulatory requirements.
(Response) Section 1271.150(c)(1) is intended to clarify the
relationship between you and another establishment that performs one or
more steps in manufacture for you (e.g., a procurer engages an outside
testing laboratory to perform communicable disease tests for it; a
processor engages an outside firm to perform terminal sterilization,
such as irradiation, on the final HCT/P). (We have added these examples
to the regulation.) You do not have to validate the processes of these
outside firms (who are themselves subject to the regulations in part
1271), and we appreciate the fact that you may lack the expertise to do
so. However, you are required to enter into and maintain such
arrangements only with establishments that comply with applicable CGTP
requirements.
We note that there are many ways of performing the due diligence
necessary when entering into a manufacturing arrangement with another
establishment. The example of an initial audit provided by the comment
is one method. Other ways of learning about another establishment
before you enter into an arrangement with it might include reviewing
test kit package inserts and a testing laboratory's standard operating
procedures (SOPs); and reviewing an establishment's compliance history.
If you intend to enter into an arrangement with an establishment that
does not have a compliance history, review of that establishment's SOPs
might assist in ascertaining that entity's compliance status.
Although we recognize the usefulness of an initial audit before
entering into an arrangement with another establishment, we note that
an initial audit would not satisfy this requirement throughout the term
of a continuing relationship. Under Sec. 1271.150(c)(1), you may not
ignore information that indicates that a company that performs work for
you is not in compliance with applicable CGTP requirements. For
example, if you have reason to suspect that an establishment performing
work for you is not in compliance with those requirements, you would
need to take appropriate action and determine whether the establishment
is still in compliance with CGTP. Other regulations in part 1271 may
also apply with regard to products manufactured, in part, by an
establishment that does not comply with applicable requirements. For
example, Sec. 1271.145 provides, ``You must * * * store * * * and
distribute HCT/Ps * * * in a way that prevents the introduction,
transmission, or spread of communicable diseases.'' You may also have
obligations under Sec. Sec. 1271.160, 1271.265, 1271.320, and
1271.350. If you determine that the establishment is not in compliance
with applicable CGTP requirements, you must terminate your contract,
agreement, or other arrangement with that establishment. If you
determine that an exemption or alternative from this requirement would
be consistent with the goals of protecting the public health and/or
preventing the introduction, transmission, or spread of communicable
diseases, and you either have information that would justify an
exemption, or have a proposed alternative that would satisfy the
[[Page 68623]]
purpose of this requirement, you may seek an exemption or alternative
under Sec. 1271.155.
We intend to issue guidance, which will further elaborate on your
responsibilities for ensuring that another establishment that performs
one or more steps in manufacture for you is in compliance with part
1271. Our economic impact analysis also indicates that the methods
described in this response are not overly costly or burdensome.
(Comment 30) One comment suggested limiting an establishment's
responsibility toward contractors to ensuring that the contractor is a
registered tissue bank establishment.
(Response) We agree that establishments under contract must
register with FDA. However, we note that some individuals who recover
cells or tissue under contract, agreement, or other arrangement are
excepted from registration under Sec. 1271.15(f); this is one reason
that it would not be sufficient to limit an establishment's
responsibility to ensuring that a contractor is registered. Moreover,
although registration is an important component of the regulation of
HCT/P establishments, such a requirement would not go far enough toward
safeguarding the public against the communicable disease risks
associated with HCT/Ps. Therefore, if you engage another establishment
under a contract, agreement, or other arrangement to perform any step
in manufacture for you, you must first determine that the establishment
complies with applicable CGTP requirements, and you must investigate
further if you receive information suggesting that the establishment
may no longer be in compliance with those requirements.
Compliance With Applicable Requirements (Sec. 1271.150(c)(2))
Proposed Sec. 1271.150(b)(2) explained how we would assign
ultimate responsibility for an HCT/P. That paragraph states that the
establishment that determines that an HCT/P meets release criteria and
makes it available for distribution, whether or not it is the actual
distributor, is responsible for ensuring that the HCT/P has been
manufactured in compliance with the requirement of subparts C and D and
any other applicable requirements. In Sec. 1271.150(c)(2), we have
added the responsibility for tracking (consistent with Sec. 1271.290).
(Comment 31) Under proposed Sec. 1271.150(b)(2), the establishment
that determines that an HCT/P meets release criteria and makes it
available for distribution would be responsible for ensuring that the
HCT/P has been manufactured in compliance with the requirements in
subparts C and D and any other applicable requirements. Several
comments agreed with this allocation of responsibility or with the
``cascading'' set of responsibilities discussed in the preamble to the
proposed rule, under which
* * * an establishment would be responsible for ensuring that
its own operations comply with applicable requirements, and also
would bear the burden of proof that operations performed by other
establishments prior to its receipt of the cells or tissue were
performed in compliance with applicable requirements (66 FR 1508 at
1512).
One comment asserted that, although the proposed allocation of
responsibility was the most reasonable of those considered, it was
unclear what sort of documentation would be sufficient to ensure that
establishments that handled the HCT/P before receipt were in compliance
(in particular, international donor centers), and another comment
asserted that proposed Sec. 1271.150(b) would require every company to
collect and store documents for all other companies participating in
the manufacturing process.
One comment stated that the more prudent approach would be to hold
each establishment specifically responsible for the activities that
went before. Another proposed that, since more than one establishment
may actually make an HCT/P available for distribution, the last
establishment that releases the product should be responsible. Another
comment recommended that overall responsibility for compliance be
assigned only to establishments within the United States.
(Response) We have revised proposed Sec. 1271.150(b)(2) (and
renumbered it Sec. 1271.150(c)(2)) to state that if you are the
establishment that determines that an HCT/P meets all release criteria
and makes the HCT/P available for distribution, whether or not you are
the actual distributor, you are responsible for reviewing manufacturing
and tracking records to determine that the HCT/P has been manufactured
and tracked in compliance with the requirements of this subpart and
subpart C of this part and any other applicable requirements. This
record review would include, for example, reviewing documentation of
donor test results for relevant communicable disease agents to
determine that results are negative or nonreactive and that appropriate
testing was performed (Sec. Sec. 1271.80 and 1271.85); matching the
distinct identification code on the HCT/P container with the code in
the summary of records (Sec. 1271.290)c); reviewing records pertaining
to donor screening for risk factors for and clinical evidence of
relevant communicable disease agents (Sec. 1271.75); reviewing records
pertaining to storage temperature (Sec. 1271.260), processing (Sec.
1271.220), and other manufacturing steps. The requirement applies to
any establishment that makes an HCT/P available for distribution,
whether it is foreign or domestic, and whether or not another
establishment may later make it again available for distribution. An
establishment that makes the HCT/P available for distribution must
maintain the records in question.
Section 1271.150(c)(2) ties in closely with Sec. 1271.265, which
covers receipt, predistribution shipment, and distribution of an HCT/P.
Section 1271.265(c) sets out requirements for making an HCT/P available
for distribution, including reviewing records pertaining to the HCT/P,
and, on the basis of that record review, verifying and documenting that
the release criteria have been met.
(Comment 32) One comment discussed the following scenario. If the
first establishment releases the HCT/P to a consignee under its own
label, releases it to another distributor, or releases it back to the
contracting firm (which may in turn serve as a distributor), then the
first establishment is responsible for ensuring that the HCT/P has been
manufactured in compliance with CGTP. This comment stated that, if its
interpretation of the proposal was correct, then it endorsed the
proposal.
(Response) The examples provided by the comment illustrate three
different ways in which an establishment might make an HCT/P available
for distribution. Under Sec. 1271.150(c)(2), the establishment has the
same responsibility in each case: To review manufacturing and tracking
records to determine that the HCT/P has been manufactured and tracked
in compliance with regulatory requirements.
(Comment 33) One comment asked for further clarification, stating
that it is not clear whether the responsibility pertains to the
manufacturing facility or just the distributor. If the distributor were
an institutional laboratory that receives an HCT/P that was processed
at a commercial laboratory, then the requirement would be unduly
burdensome, according to the comment.
(Response) In the situation described, the institutional laboratory
is not the establishment that makes the HCT/P available for
distribution, and would not be ultimately responsible. In fact, an
institutional laboratory (e.g., hospital bone bank) that does no
further manufacturing of the HCT/P, but only
[[Page 68624]]
receives the finished HCT/P from a commercial tissue processor, and
``distributes'' the HCT/P in the same facility, is excepted from these
regulations (Sec. 1271.15(d)). However, if the institutional
laboratory performs additional manufacturing steps on the HCT/P, this
laboratory is then considered a ``processor'' and is subject to the
CGTP requirements.
(Comment 34) One comment asserted that responsibility should be
apportioned appropriately among the entities involved. This comment
recommended avoiding a situation where screening by various entities
would lead to numerous re-contacts of donor families.
(Response) It is not our intention to have various establishments
re-contact the donor's family to reconfirm the medical history, for
example. The initial establishment that performed the donor medical
history interview would document the findings. The establishment that
made the HCT/P available for distribution would review the records of
the findings to make sure that all release criteria (including donor
eligibility) were met, and would retain the documented findings.
(Comment 35) When there are multiple establishments involved in the
manufacture of an HCT/P, one comment suggested that we limit the
penalties only to the noncompliant establishment.
(Response) Generally, we will not take enforcement action against
all parties involved in the manufacturing of HCT/Ps. We will evaluate
all available information related to the violative activities and the
circumstances concerning the event. If circumstances indicate that
multiple parties have not complied with the applicable regulations, we
may take enforcement action as appropriate.
Compliance With Applicable Requirements (Sec. 1271.150(c)(3))
Paragraph (c)(3) of Sec. 1271.150 states that with the exception
of Sec. Sec. 1271.150(c) and 1271.155 of this subpart, the regulations
in this subpart are not being implemented for reproductive HCT/Ps
described in Sec. 1271.10 and regulated solely under section 361 of
the PHS Act and the regulations in this part, or for the establishments
that manufacture them.
Compliance With Parts 210, 211, and 820 of this Chapter (Sec.
1271.150(d))
Proposed 1271.150(c) explains, in part, that for HCT/Ps regulated
as biological drugs or devices, the procedures contained in this
subpart and in subpart C, and the procedures contained in parts 210,
211, and 820, supplement rather than supersede each other.
(Comment 36) We received one comment on proposed Sec. 1271.150(c).
This comment asserted that the last sentence in that paragraph provides
no useful guidance and should be deleted. The last sentence in proposed
Sec. 1271.150(c) stated
In the event that it is impossible to comply with all applicable
regulations in these parts, the regulations specifically applicable
to the biological drug or device in question shall supersede any
other requirements. (66 FR 1508 at 1552.)
(Response) In the preamble of the proposed rule, we explained why
an HCT/P regulated as a biological drug or device must comply with part
1271 (CGTP) as well as parts 210 and 211 (CGMP) or 820 (QS). CGMP and
QS do not contain requirements written explicitly to prevent the spread
of communicable disease. CGTP is focused on preventing circumstances
that increase the risk of the introduction, transmission, or spread of
communicable disease, which makes CGTP regulations less extensive than
CGMP and QS regulations. Therefore, CGTP and CGMP or QS are intended to
supplement each other. In the event that a regulation in part 1271 is
in conflict with a requirement in parts 210, 211, or 820 of this
chapter, the regulations more specifically applicable to the product in
question will supersede the more general. FDA believes that, in the
event of such a conflict, the more specifically applicable regulation
would be found in part 1271.
Where Appropriate (Sec. 1271.150(e))
``Where appropriate'' in proposed Sec. 1271.150(d) would mean that
a practice is required unless the establishment can document
justification otherwise. A requirement would be considered
``appropriate'' if nonimplementation could reasonably be expected to
result in the product's not meeting its specified requirements related
to prevention of introduction, transmission, or spread of communicable
disease agents and diseases, or in the establishment's inability to
carry out any necessary corrective action.
We received no comments on this section.
2. Exemptions and Alternatives(Sec. 1271.155)
Proposed Sec. 1271.155 sets out the procedures that an
establishment must follow to request an exemption from, or an
alternative to, a CGTP requirement, as well as the criteria that the
Center Director will follow in considering such a request. In the final
rule, we have modified Sec. 1271.155(b) to allow requests for
exemptions or alternatives to be submitted to the appropriate Center
Director (e.g., the Center for Biologics Evaluation and Research (CBER)
or the Center for Devices and Radiological Health), rather than only
the CBER Director. We have revised Sec. 1271.155(d) for clarity;
instead of referring to ``limited circumstances,'' the final regulation
states that, if circumstances make it difficult (e.g., there is
inadequate time) to submit your request in writing, you may make the
request orally.
We have also added Sec. 1271.155(g), which in a public health
emergency permits the Director to issue an exemption or alternative to
any requirement in part 1271 of title 21 of the Code of Federal
Regulations. An exemption or alternative under this section may be
necessary to help ensure that certain HCT/Ps will be available in a
specified location to respond to an unanticipated immediate need for
such HCT/Ps.
(Comment 37) One comment recommended that Sec. 1271.155 should be
implemented first, and that the remaining provisions of the rule should
be implemented 2 years later.
(Response) We do not agree with this comment. It is not clear why
implementation of the exemption provisions should precede
implementation of the rest of the final rule. If the requirements are
not in effect, then an exemption request is not necessary.
(Comment 38) One comment noted that international establishments
that produce peripheral blood stem cells and umbilical cord blood units
are subject to their own national and regional regulatory requirements.
The comment stated its assumption that these establishments would
submit their foreign government's regulations to FDA under Sec.
1271.155.
(Response) The comment's assumption is incorrect. A foreign
establishment that distributes HCT/Ps in this country must comply with
FDA regulations. It is a foreign establishment's responsibility to
determine whether complying with the foreign government's requirements
would also satisfy FDA requirements. If a foreign establishment
identifies a discrepancy (e.g., an area where FDA regulations are more
stringent or in conflict), the establishment may request an exemption
or alternative under Sec. 1271.155, and FDA will consider whether the
request is justified by the evidence submitted.
(Comment 39) One comment recommended that the rule establish a
maximum time period of 30 working
[[Page 68625]]
days for an agency decision on a request for an exemption or
alternative.
(Response) Although we agree that timely decisions are important,
we disagree that this regulation should contain a specific timeframe.
Depending on the nature of the request, more or less time may be needed
to give the request adequate consideration. We note that other FDA
regulations dealing with exemptions do not specify a deadline for a
reply (see, e.g., Sec. 640.120 (21 CFR 640.120) and 21 CFR 803.19).
The time for our review of requests under Sec. 640.120 for variances
related to the blood regulations has varied from two weeks to four
months, depending on the complexity and urgency of the request. We
intend to respond to variance requests under Sec. 1271.155 within
similar timeframes, with our time to respond tied to the complexity and
urgency of the request.
(Comment 40) One comment asserted that the criteria in proposed
Sec. 1271.155(c) for granting an exemption or alternative are too
narrow, in that they do not afford an establishment an exemption or
alternative to a particular requirement not relevant to the tissue in
question. The comment suggested adding the phrase: ``and that such
goals are not impaired by an exemption or alternative.''
(Response) We disagree with this comment. The suggested language is
unnecessary and would narrow the criteria for granting an exemption or
alternative. We note that if a requirement is not relevant to a
particular establishment's operations, it is not necessary to request
an exemption (Sec. 1271.150(c)(1)).
We have, however, modified the criteria for granting an exemption
or alternative in Sec. 1271.155(c) to permit the Center Director
greater flexibility in responding to critical medical needs. That
paragraph now reads, in part
The Director may grant an exemption or alternative if he or she
finds that such action is consistent with the goals of protecting
the public health and/or preventing the introduction, transmission,
or spread of communicable disease.
(Comment 41) One comment noted that proposed Sec. 1271.155(d) and
(e) are internally inconsistent, because paragraph (d) would allow for
an oral request and reply, but paragraph (e) states that an
establishment must not begin operating under the terms of a requested
exemption or alternative until it had been granted in writing. The
comment asked us to clarify that orally granted exemptions and
alternatives would have immediate effect, and that an establishment
would not be required to wait for a written statement from the agency.
(Response) We agree with this comment and have deleted the words
``in writing'' from Sec. 1271.155(e).
(Comment 42) Another comment stated that FDA should evaluate how a
small entity may qualify for reasonable exemptions and alternatives.
(Response) We have written Sec. 1271.155(b) to apply to both large
and small entities. Supporting documentation that either justifies a
requested exemption, or describes a proposed alternative, must
accompany a request. To assist all establishments, large and small, in
pursuing appropriate exemptions and alternatives, we intend to make
available to the public on the CBER Web site information concerning
exemptions and alternatives that have been granted, while following
statutory requirements prohibiting public disclosure of confidential
information.
3. Quality Program (Sec. 1271.160)
Proposed Sec. 1271.160 would require an establishment that
performs any step in the manufacture of an HCT/P to establish and
maintain a quality program that is appropriate for the specific HCT/Ps
manufactured and the manufacturing steps performed, and that meets the
requirements of subpart D of part 1271.
Section 1271.160 of this final regulation requires instead that the
quality program address all core CGTP requirements. We have also
removed two items from the list in Sec. 1271.160(b) of a quality
program's functions: Proposed paragraph (b)(5) (on monitoring systems)
and proposed paragraph (b)(6) (on record maintenance systems).
(Comment 43) One comment strongly supported the requirement for a
quality program. Another comment appreciated the differentiation
between the quality program and the quality system requirement for
devices and blood products. This comment stated that giving tissue
banks flexibility in how defined functions are accomplished, and not
requiring the employment of staff free of other responsibilities,
recognizes the undue burden that it would create. In contrast, two
other comments asserted that eye banks would have to hire separate
quality control employees, which would be time consuming and expensive.
(Response) We appreciate the comments supporting the requirement.
We note that the regulation does not require an establishment to hire a
separate quality control employee; moreover, we have removed the
requirement for the designation of an individual with authority over
the program (proposed Sec. 1271.160(c)).
(Comment 44) Two comments supported the idea that a quality program
should be commensurate with the manufacturing steps performed and the
types of tissues involved. These comments requested that FDA
distinguish between ``quality programs'' and other quality
requirements, to ensure that establishments are not held to unsuitable
quality requirements.
(Response) The quality program required under Sec. 1271.160 is a
system that each establishment sets up to ensure its compliance with
core CGTP requirements. These regulations do not contain generalized
quality requirements.
(Comment 45) We received three comments on proposed Sec.
1271.160(b)(2), which would require procedures for sharing with other
establishments that are known to have recovered cells or tissue from
the same donor any information pertaining to the possible contamination
of the HCT/P or the potential transmission of communicable disease by
the HCT/P. One comment asserted that it would not be appropriate to
share information about an autologous donor's baseline viral status
with another establishment. This comment also expressed concern that
the required procedure would be inconsistent with the requirement in
proposed Sec. 1271.270 pertaining to donor confidentiality. The other
two comments suggested narrowing the provision so that establishments
would not be required to disclose proprietary information to
competitors.
(Response) We decline to modify the requirement as requested. The
purpose of this requirement is to ensure that, if an establishment
learns that a donor is ineligible or that an HCT/P is contaminated, the
establishment has a procedure in place for informing consignees and
other establishments that are known to have recovered cells or tissues
from the same donor. Recognizing that other establishments may have
received HCT/Ps from the same donor, even if they did not recover them,
we have added to this list, ``other establishments that are known to
have performed manufacturing steps with respect to the same HCT/P.''
There is no requirement that an establishment disclose customer
lists, manufacturing processes, or other proprietary information to
competitors. Moreover, these procedures can be designed so that patient
confidentiality is not compromised.
With respect to the comment on sharing information about an
autologous donor, we are unable to envision a
[[Page 68626]]
situation where this requirement would necessitate such a disclosure.
Since HCT/Ps for other recipients would not be recovered from the
autologous donor, there would be no need to share information regarding
the donor's baseline viral status.
(Comment 46) Proposed Sec. 1271.160(b)(7) would require
establishments to investigate and document all product deviations in
manufacturing. (These are now referred to as ``HCT/P deviations.'') One
comment asserted that product deviation review and analyses should be
treated in the same manner as internal audits (i.e., not available for
review on inspection). Two comments asserted that the periodic audit of
product deviations and collation of complaint files are tools of
quality management and that FDA should guarantee the confidentiality of
these quality management activities.
(Response) We have renumbered proposed paragraph (b)(7) as (b)(6)
and removed the requirement for a periodic review and analysis of HCT/P
deviations. Under the final regulation, you are required to investigate
and document HCT/P deviations and trends of HCT/P deviations relating
to core CGTP requirements and to make reports if required to do so
under Sec. 1271.350(b) or other applicable regulations.
(Comment 47) One comment requested that we limit the requirement
for reporting product deviations to those identified post-release.
(Response) The reporting requirement in Sec. 1271.350(b)(1)
applies only to distributed HCT/Ps, regardless of the time at which the
deviation is identified.
(Comment 48) Two comments asked us to clarify that Sec.
1271.160(b)(7) includes only product deviations in manufacturing that
would increase the risk of disease transmission.
(Response) The term ``HCT/P deviation'' is defined in Sec.
1271.3(dd) of this final rule to include events that may increase the
risk of communicable disease transmission, because they: (1) Represent
a deviation from applicable regulations in this part or from applicable
standards or established specifications relating to the prevention of
communicable disease transmission or HCT/P contamination, or (2)
constitute an unexpected or unforeseeable event that may relate to the
transmission or potential transmission of a communicable disease or may
lead to HCT/P contamination.
(Comment 49) Under proposed Sec. 1271.160(c), one or more
designated persons would have authority over the quality program, and
these persons would report to management at least once a year on the
performance of the quality program, unless more frequent reports are
necessary. If these persons also perform other tasks in the
establishment, they must not have final oversight over their own work.
Two comments on this provision asserted that the requirement for
independent oversight is too stringent. One comment stated that, in
small laboratories with only a single technician, it may not be
possible for an independent person to have oversight. The other comment
recommended that the oversight requirement be dropped as costly and
impracticable.
(Response) We have removed this requirement from the final rule.
Audits
(Comment 50) One comment requested more flexible language to
replace the requirement for a comprehensive quality audit no less than
once in 12 months. Another comment asserted that the requirement for an
annual comprehensive audit is more stringent than the requirements
applicable to blood component processing.
(Response) In response to these comments, we have revised proposed
Sec. 1271.160(d). Section 1271.160(c) now requires only that a quality
audit of core CGTP activities be performed periodically for management
review. The new language provides establishments with a greater degree
of flexibility in determining how and when to audit their quality
programs. We also may issue future guidance making recommendations on
what we would consider to be a periodic audit.
(Comment 51) Two comments asserted that internal audit findings
should not be available to FDA representatives.
(Response) With respect to quality audits, while some firms choose
to provide quality audits to FDA, FDA's current practice is generally
not to review or copy the actual quality audit reports during routine
inspections and investigations except in certain limited circumstances
(FDA Compliance Policy Guide 130.300). However, the firm should have a
mechanism to demonstrate to the FDA representative that quality audits
are being performed and that corrective actions are being implemented
when problems are identified.
Computers
Proposed Sec. 1271.160(e) would require establishments to validate
computer software used as part of manufacturing or tracking or for
maintaining data relating to those activities.
(Comment 52) One comment asserted that it is reasonable to require
that computer systems used in manufacturing and data maintenance be
tested to confirm that they perform as intended, and that the testing
and results be documented. This comment asked us to confirm that we are
distinguishing between this limited requirement and the term
``validation'' as it has been applied to computer systems identified as
medical devices.
(Response) We agree with this comment. Therefore, we revised the
requirement in Sec. 1271.160(d) to permit verification or validation
of the computer software for its intended use.
(Comment 53) Several comments opposed the proposed requirement on
computer software validation. One comment asserted that software
validation can be a financial burden and stated that the requirement
should be implemented to the extent validation will minimize the risk
of disease transmission during the manufacturing process. The comment
further noted that there was no exemption in this provision for
general-purpose software (e.g., spreadsheet, database, and word
processing software) intended for broad general use, which are
currently exempt from most of the general controls under the act. Two
comments suggested limiting the scope of the requirement to the most
necessary areas, to encourage the use of software programs in lieu of
manual recordkeeping. Another comment asked that we amend the provision
to reflect that software must be validated only if it is relied upon as
the sole data source for the decisionmaking processes of the quality
system.
(Response) We do not intend that the requirements for computer
validation be unduly burdensome. As a result of these comments, we are
modifying the requirements in Sec. 1271.160(d). This section now
applies only to software that you rely upon to comply with core CGTP
requirements. You must validate the performance of software for its
intended use only if the software is custom software or commercially
available software that has been customized or programmed (including
software programmed to perform a user-defined calculation or table) to
perform a function related to core CGTP requirements. If you rely on
commercially distributed, noncustom, software to perform a function
related to core CGTP requirements, then you are only required to verify
the performance of that software for its intended use. With these
changes, we have limited the scope of this provision so that it applies
to computer software that directly
[[Page 68627]]
affects communicable disease transmission risks. If such software is
inappropriately designed, implemented, or used, the software may
increase the risk of communicable disease transmission, perhaps by
authorizing the release of HCT/Ps from an infectious donor, or by
recording screening test results inaccurately. However, we recognize
that commercially distributed general use software has undergone more
rigorous testing before it is distributed. When such general use
software is used without modification to comply with core GTP
requirements, it is adequate for the establishment only to verify the
performance of the software for its intended use, rather than
undertaking more onerous validation.
For example, an eye bank that uses commercially distributed
software (e.g., spreadsheet, database, word processing) to comply with
a core CGTP requirement such as control of storage areas (Sec.
1271.260(a)), but not for making decisions or determinations, must
verify that this general purpose software can be used reliably in such
a way, but would not have to validate the software. Verification in a
situation such as this is not intended to be onerous. However, if the
eye bank decided to modify and use commercially available computer
software for determining donor eligibility, the modifications would
increase the risk of problems and the eye bank would then be required
to validate the software for this intended use.
(Comment 54) One comment noted that eye banks do not use computers
as decisionmaking instruments, but only for information storage and
retrieval, word processing, and form printing. This comment asserted
that appropriate validation in this instance should entail: (1) Routine
backup of computer system, (2) physical check of computer printout
against paper chart, and (3) signoff by final supervisor before tissue
release.
(Response) The examples provided are not core CGTP requirements and
so the requirements of Sec. 1271.160(d) would not apply.
4. Organization and Personnel (Sec. 1271.170)
Proposed Sec. 1271.170 would require establishments to maintain an
adequate organizational structure and sufficient personnel with the
necessary education, experience, training and retraining to ensure
competent performance of their assigned functions. Personnel records
documenting these requirements would be required.
(Comment 55) Two comments supported Sec. 1271.170 as proposed. One
comment agreed that tissue bank personnel should be educated concerning
the possible consequences of improperly performing their duties, and
noted that unacceptable tissue practices could have monumental
implications in disease transmission. This comment further asserted
that recordkeeping on personnel training is appropriate.
(Response) We appreciate the supportive comments. However, we have
removed both of these proposed requirements from Sec. 1271.170.
Section 1271.170 also does not require an establishment to maintain an
adequate organization structure.
(Comment 56) One comment asserted that FDA should set guidelines
for the credentials of tissue bank directors.
(Response) We have not included in the regulations requirements for
specific credentials. Instead, we require that personnel have the
necessary education, experience, and training to ensure competent
performance of their assigned functions. Professional organizations,
accrediting bodies, and States may decide to develop guidelines for
certain personnel credentials.
(Comment 57) One comment from a professional organization suggested
replacing the phrase ``education and experience'' in proposed Sec.
1271.170(b) with ``training and documentation of competency.''
(Response) We agree with the comment that ``training'' should be
added to the requirements in Sec. 1271.170(b), and we have made this
change; however, we disagree with the proposal to remove ``education
and experience.'' As revised, Sec. 1271.170(b) requires you to have
personnel with the necessary education, experience, and training to
ensure competent performance of their assigned functions.
(Comment 58) One comment on proposed Sec. 1271.170(c) asserted
that it is unclear what criteria a company should use to determine the
qualifications of laboratory personnel.
(Response) There are a variety of ways to comply with the
requirement in Sec. 1271.170(c) that an establishment train all
personnel to perform their assigned responsibilities adequately. Each
establishment should establish its own criteria. Some examples of
criteria an establishment might use to determine the qualifications of
laboratory personnel include: Achievement of a minimum score on a
written test, direct observation and evaluation by a supervisor,
successful completion of continuing education courses (e.g., passing an
examination), accreditation or proficiency testing by an outside
organization.
5. Procedures (Sec. 1271.180)
Proposed Sec. 1271.180 would require establishments to establish
and maintain procedures for all significant steps that it performs in
the manufacture of HCT/Ps.
We have reorganized Sec. 1271.180 by dividing it into paragraphs
for greater clarity and ease of reading. In addition, Sec. 1271.180
now requires you to establish and maintain procedures appropriate to
meet core CGTP requirements for all steps that you perform in the
manufacture of HCT/Ps and further requires that these procedures be
designed to prevent circumstances that increase the risk of the
introduction, transmission, or spread of communicable diseases through
the use of HCT/Ps.
We note that, depending on the activities that you perform, your
procedures may need to cover such issues as the length of time a
cadaver may be stored, or the conditions of storage (e.g.,
temperature). Moreover, to prevent the recovery of contaminated cells
or tissues, you need to establish and maintain procedures to prevent
the recovery of cells or tissue from a septic donor or from an area of
the body where there is a localized infection. The MMWR report cited in
section III.C.1 of this document (Ref. 1) discussed a case in which
tissue probably became hematogenously seeded by bowel flora before
harvesting. The report noted that factors that may contribute to such
contamination include the time interval between death and tissue
retrieval, delays in refrigeration, and mode of death (e.g., trauma).
The procedures of an establishment that recovers cells and tissue
should appropriately address these possible causes of HCT/P
contamination to comply with Sec. 1271.180(a).
(Comment 59) One comment supported the section as proposed. Another
comment asked for examples of what does or does not constitute a
``significant step'' and asked how it differs from ``any step'' in the
quality program requirements.
(Response) A ``significant step'' is a step in manufacturing listed
in the definition of ``manufacture'' in current Sec. 1271.3(e), i.e.,
all steps in the recovery, processing, storage, labeling, packaging, or
distribution, and the screening and testing of the donor, and is not
considered different from ``any step in the manufacture of human
cellular and tissue-based products.'' Therefore, we have removed the
term ``significant'' from Sec. 1271.180(a).
(Comment 60) Proposed Sec. 1271.180 would require establishments
to review
[[Page 68628]]
and, if necessary, revise all procedures at least once in a 12-month
period. One comment objected to the specificity of this requirement,
citing the more flexible requirements in the CGMP and QS regulations.
(Response) We agree with this comment and note that the comparable
requirements in the CGMP and QS regulations (Sec. Sec. 211.100 and
820.40) do not require an annual review of procedures. For this reason,
we are deleting the proposed requirement in Sec. 1271.180 that all
procedures be reviewed on an annual basis. However, we note that the
periodic quality audit required under Sec. 1271.160(c) should include
a review of an establishment's SOPs.
(Comment 61) Several comments objected to the proposed requirement
that deviations from procedures be authorized in advance, because
deviations are not foreseeable and cannot be authorized before they
occur. One comment suggested requiring a justification for the
deviation to be recorded at the time of the occurrence, and requiring
approval of the deviation by a responsible person before release of the
tissue.
(Response) We agree with these comments and have modified the
requirement in accordance with the suggestion; the requirement, which
is now located in Sec. 1271.265, requires an establishment to record
and justify any departure from a procedure at the time of its
occurrence, rather than before. (We replaced the word ``deviation''
with the word ``departure'' to avoid confusion with the defined term
``HCT/P deviation.) The provision further states that you must not make
available for distribution any HCT/P manufactured under a departure
from a procedure designed to protect against risks of communicable
disease transmission, unless a responsible person has determined that
the departure does not increase the risk of communicable disease
transmission through the use of the HCT/P. For example, if the
technician at the recovery site uses a different brand of sterile gauze
because the brand stated in the standard operating procedures is not
available, the establishment may make the HCT/P available for
distribution provided that the departure was recorded and justified at
the time, and the responsible person determines that the substitution
did not increase the risks of communicable disease transmission.
(Comment 62) Proposed Sec. 1271.180 would require obsolete
procedures to be archived for at least 10 years. One comment suggested
that a longer retention period of 10 years after transplantation would
be more appropriate and consistent with record retention requirements
in Sec. 1271.270.
(Response) We have removed this requirement from the final
regulation. However, although we do not require you to retain obsolete
procedures, under Sec. 1271.270(d) you are required to retain records
for 10 years unless otherwise stated.
6. Facilities (Sec. 1271.190)
Proposed Sec. 1271.190 would require that any facility used in the
manufacture of products be of suitable size, construction, and location
to facilitate cleaning, relevant maintenance, and proper operations; be
maintained in a good state of repair; and have adequate lighting,
ventilation, plumbing, drainage, and washing and toilet facilities.
Proposed Sec. 1271.190 also contained requirements relating to the
division of a facility into operational areas, and relating to facility
cleaning and sanitation.
Section 1271.190 has been reorganized.
(Comment 63) Three comments objected that proposed Sec. 1271.190
is too broad and asserted that it should be limited to requirements for
preventing the transmission of disease. Two comments suggested new
language.
(Response) In response to these comments, we have revised the
language of Sec. 1271.190, reflecting the suggested language. The
first sentence of Sec. 1271.190(a) now states that any facility used
in the manufacture of HCT/Ps ``must be of suitable size, construction,
and location to prevent contamination of HCT/Ps with communicable
disease agents and to ensure orderly handling of HCT/Ps without
mixups.''
(Comment 64) One comment on proposed Sec. 1271.190(a) questioned
the interpretation of ``suitable size, construction, and location.''
Another comment asked us to clarify the meaning of ``location.''
(Response) As discussed in the previous comment, we have changed
the wording of Sec. 1271.190(a) to make it clear that the suitability
of a facility's size, construction, and location relates to preventing
the contamination of HCT/Ps with communicable disease agents and
ensuring orderly handling of HCT/Ps. We do not believe any other change
is necessary. We decline to dictate specific requirements for an HCT/P
establishment's size, construction, and location; it is more
appropriate for establishments to make these determinations for
themselves, based on the objectives set out in this regulation.
By location, the regulation refers to the facility's site. Some
examples of unsuitable locations for an HCT/P establishment, because of
the risk of transmission of communicable disease, might include a site
on a loading dock or in the same building as a slaughterhouse.
(Comment 65) One comment asserted that, if an establishment is a
tenant in a building, then bringing a problem to the attention of the
building management, with the understanding that a response would occur
in a reasonable time period, should be an acceptable way of complying
with this section.
(Response) An establishment that is a tenant should ensure that,
under its rental agreement, the landlord will undertake the activities
required in this section on a routine basis and within a reasonable
amount of time. In this situation, a responsible establishment would
communicate regularly with the landlord to bring problems to the
landlord's attention in a timely manner. However, if a facility's
conditions are such that the establishment is unable to manufacture
HCT/Ps in an acceptable manner, then manufacturing activities should
stop immediately; in this situation, where immediate repairs are
required, simply notifying the landlord is not sufficient.
(Comment 66) One comment requested a modification to proposed Sec.
1271.190(a) to delete the requirement for toilet facilities.
(Response) We decline to delete the requirement for toilet
facilities. However, we have modified the requirement so that it now
refers to ``access to sinks and toilets.'' As modified, the regulation
requires toilets to be accessible, but not necessarily within the
establishment. We have further revised the last sentence of paragraph
(a) to state that you must provide lighting, ventilation, plumbing,
drainage, and access to sinks and toilets to prevent the introduction,
transmission, or spread of communicable disease.
(Comment 67) One comment on proposed Sec. 1271.190(c) asserted
that developing and maintaining procedures for routine cleaning and
maintenance, such as trash removal, cleaning toilets, and sweeping
floors, would be a waste of time and resources.
(Response) We disagree. Maintaining a clean facility is fundamental
to an establishment's ability to prevent the contamination of HCT/Ps.
Without procedures in place, this important responsibility may be left
to chance. An establishment's procedures might state, for example, how
often a particular floor
[[Page 68629]]
is to be mopped and which disinfectant must be used. Such procedures
are basic elements of communicable disease prevention and are not
trivial matters.
We recognize, however, that not all cleaning and sanitation that
you may perform will relate to these requirements (e.g., vacuuming the
lobby); thus, we have modified paragraph (d)(1) to limit its scope to
procedures for facility cleaning and sanitation for the purpose of
preventing transmission of communicable disease. We have made a similar
change to paragraph (b)(1), which now requires you to maintain
facilities in a clean, sanitary, and orderly manner, to prevent the
transmission of communicable disease.
The requirements for facility cleaning in proposed paragraphs
(c)(1) and (c)(2) are now in paragraph (b); the requirement for
procedures in proposed Sec. 1271.190(c)(3) is contained in Sec.
1271.190(d)(1); and the requirement for record retention in proposed
Sec. 1271.190(c)(4) is contained in Sec. 1271.190(d)(2).
(Comment 68) Another comment asked for clarification of the phrase
``significant cleaning and sanitation activities'' in proposed Sec.
1271.190(c)(4). This comment opposed a requirement to keep mopping
records for 10 years, but supported keeping records of changing the air
handling filters.
(Response) For clarity, we have removed the word ``significant''
from Sec. 1271.190(c)(4), now renumbered as paragraph (d)(2). This
paragraph now requires you to document and maintain records of ``all
cleaning and sanitation activities performed to prevent contamination
of HCT/Ps.'' Generally, cleaning and sanitation activities performed in
the manufacturing area would be performed to prevent contamination of
HCT/Ps, while these activities performed elsewhere in the establishment
(e.g., business offices, lobby) would not be performed for that
purpose. Thus, all sanitation activities in certain areas would need to
be documented. Although it is not necessary to maintain actual mopping
records, you do need to document that cleaning in accordance with
procedures took place (e.g., by having the person performing this task
initial a log).
We also agree with the comment regarding record retention and we
have revised the requirement for retaining records of facility cleaning
and sanitation activities from 10 years to 3 years, which allows the
records to be available for an inspection cycle.
7. Environmental Control and Monitoring (Sec. 1271.195)
Proposed Sec. 1271.195 would require establishments to establish
and maintain procedures to adequately control and monitor environmental
conditions and to provide proper conditions for operations. It would
also require inspections and recordkeeping.
We have reorganized Sec. 1271.195. The requirement for
environmental monitoring in proposed paragraph (a) is now contained in
paragraph (c). Moreover, paragraph (a) no longer requires the
establishment and maintenance of procedures for the control and
monitoring of environmental conditions. That paragraph now states, in
part, that ``you must adequately control environmental conditions.''
(Comment 69) Three comments discussed the applicability of this
section to eye banking. One comment asserted that because corneas
remain in closed, sealed vials once final placement in media occurs,
the requirement for control and monitoring of ventilation and air
filtration systems would not apply. Two other comments cited the use of
laminar flow hoods in work on eye tissue and argued that the
installation of a major environmental control system would be cost
prohibitive and unnecessary.
(Response) Rather than require environmental control and monitoring
by all establishments in all situations, we have adopted a flexible
approach that allows each establishment to assess its particular needs.
Thus, Sec. 1271.195(a) requires environmental control and monitoring
``where environmental conditions could reasonably be expected to cause
contamination or cross-contamination of HCT/Ps or equipment, or
accidental exposure of HCT/Ps to communicable disease agents.'' In
those situations, you must adequately control environmental conditions
and provide proper conditions for operations. The regulation lists
control activities or systems that must be employed, where appropriate.
(``Where appropriate'' is explained in Sec. 1271.150(e).) It may not
be necessary to institute a facility-wide control system in situations
where work on HCT/Ps is performed in a controlled environment (e.g.,
use of a laminar hood that is subject to control).
(Comment 70) Proposed Sec. 1271.195(a)(3) would require cleaning
and disinfecting of rooms and equipment to ensure aseptic processing
operations, where appropriate. Two comments asserted that, where other
control systems to prevent contamination are in place, cleaning and
disinfection of rooms and equipment are not necessary.
(Response) The regulation allows establishments to develop
environmental control systems that are appropriate to their activities.
If control systems are in place to prevent contamination, then an
establishment should institute measures to ensure that these controls
are performing as intended. It appears unlikely, however, that cleaning
and disinfection would not be a necessary component of controls.
(Comment 71) Proposed Sec. 1271.195(a)(5) would require
environmental monitoring for organisms, where appropriate. One comment
asserted that there is no expert consensus on which organisms to
monitor and that the regulation should be more specific.
(Response) We agree that there is no expert consensus on a single
list of organisms for which all facilities should monitor; however, we
disagree that it is necessary for us to provide a list in this
regulation. Conditions may differ from facility to facility (and even
from room to room within a facility), with common microorganisms found
in one area but not another. Each establishment should determine the
microorganisms that may exist in its facilities and design its
monitoring program accordingly.
FDA has issued a draft guidance document entitled ``Guidance for
Industry: Sterile Drug Products Produced by Aseptic Processing, Current
Good Manufacturing Practice,'' dated August 2003, (http://www.fda.gov/cber/gdlns/steraseptic.htm) that may provide useful information to an
HCT/P establishment that is developing procedures on environmental
control and monitoring. Information on environmental monitoring may
also be found in the U.S. Pharmacopoeia.
The requirement for monitoring for microorganisms in proposed Sec.
1271.195(a)(5) has been moved to Sec. 1271.195(c).
8. Equipment (Sec. 1271.200)
Proposed Sec. 1271.200 would require that equipment used in the
manufacture of HCT/Ps be appropriately designed for its use, and be
suitably located and installed to facilitate operations, including
cleaning and maintenance. It also contained requirements for procedures
and schedules, calibration of equipment, inspections, and records.
(Comment 72) One comment asserted that the proposed requirement is
overly broad and that the regulation should allow establishments to
write and
[[Page 68630]]
maintain procedures for use of equipment, cleaning, and calibration
that prevent circumstances that increase the risk of introduction,
transmission, or spread of communicable disease. Another comment asked
whether the requirements in Sec. 1271.200 should be limited to
concerns of communicable disease transmission.
(Response) We agree with the comments that Sec. 1271.200 should be
limited to concerns of communicable disease transmission. Therefore,
the first sentence of Sec. 1271.200(a) now reads
To prevent the introduction, transmission, or spread of
communicable diseases, equipment used in the manufacture of HCT/Ps
must be of appropriate design for its use and must be suitably
located and installed to facilitate operations, including cleaning
and maintenance.
Under Sec. 1271.200(b), an establishment must establish and
maintain procedures for cleaning, sanitizing, and maintaining equipment
to prevent malfunctions, contamination or cross-contamination,
accidental exposure of HCT/Ps to communicable disease agents, and other
events that could reasonably be expected to result in the introduction,
transmission, or spread of communicable diseases.
(Comment 73) Several comments asked that vendor validation and
maintenance records be acceptable for compliance with Sec. 1271.200.
(Response) You may use vendor validation and maintenance records to
demonstrate compliance with Sec. 1271.200; however, you are still
responsible for having a system in place designed to ensure that the
services provided by the contractor are adequate and in compliance with
applicable requirements. Section 1271.150 addresses the question of
work performed by other establishments or contractors.
(Comment 74) Proposed Sec. 1271.200(a) would require, in part,
that any automated, mechanical, electronic, computer, or other
equipment used for inspection, measuring, and testing be capable of
producing valid results. One comment asked us to clarify the meaning of
``valid results'' in proposed Sec. 1271.200(a). The comment stated
that valid results may be obtained through appropriate validation and/
or calibration of equipment.
(Response) We agree that ``capable of producing valid results''
does not mean validation of equipment. The requirement is for the
equipment to work properly, thereby providing ``valid results.'' This
may be accomplished by calibrating, inspecting, and maintaining
equipment. (See e.g., ``Medical Devices; Current Good Manufacturing
Practice (CGMP) Final Rule; Quality System Regulation,'' 61 FR 52602,
October 7, 1996.)
(Comment 75) Proposed Sec. 1271.200(c) would require calibration
of all automated, mechanical, electronic, computer, or other equipment
used for inspection, measuring, and testing. One comment objected to
the requirement for calibration of computers because computers do not
make measurements, and asserted that validation should be sufficient.
Another comment stated that the calibration of slit lamps is not
practical.
(Response) We have revised paragraph (c) in response to these
comments. First, we have removed computers from the listed types of
equipment in this paragraph and in paragraph (a). Second, we have added
``where appropriate'' to the first sentence of the paragraph. We have
made these changes because we recognize that there are certain pieces
of equipment that cannot be calibrated (e.g., computers, slit lamps).
We have also removed the second and third sentences of proposed
paragraph (c), which related to direction for calibration; accuracy and
precision limits; and corrective actions.
(Comment 76) Approximately eight comments objected to the
requirement in proposed Sec. 1271.200(e) that records of recent
maintenance, cleaning, sanitizing, calibration, and other activities be
kept ``at each piece of equipment.'' One comment recommended that
facilities be allowed the flexibility to maintain the records in a
location that is easily accessible to the equipment but not directly at
the equipment site. Another comment agreed that these records must be
maintained but noted that it is important to keep the amount of paper
to a minimum in a clean room environment and suggested that the
documents need only be readily retrievable. One comment noted that
records cannot physically be kept on small instruments such as pipettes
and suggested the use of a central repository.
(Response) We agree with these comments and have revised the
regulation. Section 1271.200(e) now states, in part, that you must
display records of recent maintenance, cleaning, sanitizing,
calibration, and other activities on or near each piece of equipment,
or make the records readily available to the individuals responsible
for performing these activities and to the personnel using the
equipment. This new language, which is based on Sec. 820.72, provides
establishments with more flexibility than the proposed provision would
have given.
(Comment 77) One comment asserted that the records requirement in
proposed Sec. 1271.200(e) should be limited to major equipment and
should not include simple instruments that are regularly washed and
disinfected or disposable equipment that has a validated procedure for
cleaning and disinfecting.
(Response) We disagree with the suggestion to exempt simple
instruments from the requirements of this rule. Records for cleaning
and maintenance of instruments, tools, and other equipment used or
reused in the manufacturing of HCT/Ps must be kept to document that the
items were adequately cleaned and maintained to prevent their
contamination or cross-contamination by communicable disease agents.
Single-use instruments, tools, or other equipment would not be subject
to the requirement if they are used only one time and are disposed of
after use.
9. Supplies and Reagents (Sec. 1271.210)
Proposed Sec. 1271.210 would require the establishment to
establish and maintain procedures for receiving supplies and reagents
used in the manufacture of HCT/Ps. These items would be verified to
meet specifications designed to prevent circumstances that increase the
risk of introduction, transmission, or spread of communicable disease
through HCT/P contamination. Supplies and reagents are materials that
might be used during manufacture, but do not include any material that
might become a component of an HCT/P (66 FR 1508 at 1515).
We have reorganized Sec. 1271.210. The requirement for validation
or verification of the production of in-house reagents is now in
paragraph (c) and refers to processes instead of procedures; records
requirements are now in paragraph (d).
(Comment 78) One comment supported the regulation as proposed,
noting however that compliance would be costly.
(Response) We address concerns about compliance costs separately,
in section V of this document.
(Comment 79) One comment on proposed Sec. 1271.210(a) questioned
whether the receipt requirements pertained to supplies used solely in
the recovery of human tissues.
(Response) Section 1271.210 applies to all steps in the manufacture
of HCT/Ps, including recovery. Use of a contaminated or otherwise
defective supply or reagent in the manufacture of an HCT/P could lead
to such problems as the introduction of a disease agent or
[[Page 68631]]
the failure to properly preserve the HCT/P. It is important for
establishments to establish and maintain procedures for receiving
supplies and reagents, including verification, at each step of
manufacture, beginning with recovery. We note that Sec. 1271.210(a) no
longer contains a requirement for procedures. However, Sec.
1271.210(a) and (b) are core CGTP requirements listed in Sec.
1271.150(b); therefore, the requirement for establishing procedures
under Sec. 1271.180 applies to these two paragraphs.
(Comment 80) One comment asked whether vendor verification is
required for all supplies or only for those that come in contact with
the donor or the recovered tissue.
(Response) Verification by you or the supply vendor is required for
all supplies and reagents that may be used in the course of
manufacture, not simply those that may come in contact with a donor or
an HCT/P. For example, a reagent used in donor testing must be
verified, even if it does not come into contact with the donor or the
donated tissue.
(Comment 81) One comment asserted that the requirement is overly
broad and requested that we allow establishments to write and maintain
procedures for use of supplies and reagents that prevent circumstances
that increase the risk of introduction, transmission, or spread of
communicable disease.
(Response) We have narrowed Sec. 1271.210 to apply more
specifically to preventing the introduction, transmission, or spread of
communicable diseases.
(Comment 82) Proposed Sec. 1271.210(c) contains records
requirements, and paragraph (c)(3) would require records of the use of
each supply or reagent, including the identification of each HCT/P
manufactured with the supply or reagent. One comment noted that, for
many HCT/Ps, lots are small, and a requirement for separate records
would present an enormous burden. Another comment questioned the
utility of listing each product processed by each pipette or bottle of
medium. A third comment asserted that, although the processing records
for each hematopoietic stem/progenitor cell preparation should identify
supplies and reagents used for processing, it would be prohibitively
time-consuming to maintain separate records of each transplant prepared
with each reagent.
(Response) You should establish a system under which particular
lots of supplies and reagents can be linked to individual HCT/Ps. This
does not require an individual record for each HCT/P prepared with each
reagent, as the comment suggested. Therefore, we have added ``lot'' to
renumbered paragraph (d)(3) to make clear the lesser burden. We have
also added ``quantity'' so that the establishment may find all supplies
and reagents received in the event of a recall by the manufacturer.
Maintaining the records required in paragraph (d)(3) will enable you to
do a cross-check to determine which lots of supplies and reagents were
used at a particular time and which HCT/Ps were processed during that
same time period (e.g., if there is a recall of a particular lot of
reagent or supplies).
10. Recovery (Sec. 1271.215)
This final rule includes a new section specific to the recovery of
cells and tissues, Sec. 1271.215. This section states that, if you are
an establishment that recovers HCT/Ps, you must recover each HCT/P in a
way that does not cause contamination or cross-contamination during
recovery, or otherwise increase the risk of the introduction,
transmission, or spread of communicable disease through the use of the
HCT/P. This requirement was implicit in the proposed rule (e.g., Sec.
1271.180); however, in reorganizing the rule we have determined that it
is necessary to make this requirement explicit. Section 1271.215 is
listed as a core CGTP requirement in Sec. 1271.150(b). As discussed in
section III.C.5 of this document, you must establish and maintain
procedures for cell and tissue recovery.
11. Processing and Process Controls (Sec. 1271.220)
Proposed Sec. 1271.220 would require an establishment engaged in
processing to develop, conduct, control, and monitor its manufacturing
processes to ensure that each HCT/P conforms to specifications, is not
contaminated, and is manufactured so as to prevent transmission of
communicable disease by the HCT/P. Proposed Sec. 1271.220 also
contains requirements with respect to processing materials, pooling,
and in-process monitoring.
We have moved the provision on dura mater from proposed Sec.
1271.230(c) to Sec. 1271.220(d); we address comments on the proposed
provision with other comments on proposed Sec. 1271.230.
(Comment 83) One comment requested an exemption for eye banks from
this section, because corneas are not processed in accordance with
FDA's definition. Another comment asserted that the section is
inapplicable to eye banks.
(Response) We disagree. Eye banks that perform even minimal
processing must control their processes. At Comment 21, we explain the
applicability of the term ``processing'' to eye banking.
(Comment 84) Proposed Sec. 1271.220(a) would require, in part,
that each establishment develop, conduct, control, and monitor its
manufacturing processes to ensure that each HCT/P conforms to
specifications. One comment required that we define ``specifications.''
Another comment noted that there are no specifications set for corneas,
but that criteria are determined by local medical directors in
conjunction with professional standards.
(Response) Requirements with respect to in-process control and
testing are now contained in Sec. 1271.220(c). We have also removed
references to specifications from Sec. 1271.220(a). That paragraph now
requires that, if you are an establishment that processes HCT/Ps, you
must process each HCT/P in a way that does not cause contamination or
cross-contamination during processing, and that prevents the
introduction, transmission, or spread of communicable disease through
the use of the HCT/P.
We recognize, however, that the term ``specifications'' appears
elsewhere in this regulation (e.g., Sec. 1271.3(dd), definition of
``HCT/P deviation''). We noted in the preamble to the proposed rule
that, by ``specifications,'' we meant those criteria established by a
manufacturer for an HCT/P that must be met at defined stages in the
manufacturing process and before the product is made available for
distribution (66 FR 1508 at 1516). Ordinarily, an establishment will
set specifications for various operations within its facility, not just
processing. Because we believe the term is generally well understood,
we do not consider it necessary to define the term in this rule.
As noted in our response to Comment 19, we understand that an eye
bank might not set specifications for corneas. However, we expect that
an establishment will generally set out acceptability criteria for its
HCT/Ps in its standard operating procedures.
(Comment 85) One comment requested clarification of the requirement
for monitoring and control of validated processes. This comment asked
if the quality review is sufficient to ensure that specific processes
continue to be met.
(Response) We have removed from Sec. 1271.220(a) the specific
requirement for monitoring and control of processes. However, we
believe that, to ensure that you are processing HCT/Ps in a way that
does not cause contamination or cross-
[[Page 68632]]
contamination during processing, and that prevents the introduction,
transmission, or spread of communicable disease through the use of the
HCT/P, a firm should establish appropriate, objective mechanisms to
control and monitor each validated process. This may include a variety
of activities, e.g., statistical process-control methods, review of
product acceptance criteria and results, as well as a meaningful
quality audit.
(Comment 86) One comment asserted that we seem to be requiring that
tissue be sterile and that decontamination processes be validated to
produce tissue that is not contaminated or is sterile. The comment
asserted that viable tissue cannot be made sterile and that reducing
bioburden is not the same as eradicating contamination.
(Response) FDA is not requiring at this time that tissue be
sterile, but we do expect aseptic techniques to be used during
manufacturing to prevent contamination and cross-contamination. Indeed,
it is the current industry practice to use aseptic techniques during
recovery and processing. Whenever an activity is used in the processing
of HCT/Ps, that activity must be controlled to limit the introduction
of disease agents. When technology progresses to the extent that viral
clearance or sterilization is feasible, FDA may revise these CGTPs to
require that HCT/Ps be sterile. FDA welcomes submissions as to when
technology will have progressed to this point.
(Comment 87) One comment on proposed Sec. 1271.220(a) requested
clarification of the term ``manufacturing process.''
(Response) We have re-examined our use of the phrase
``manufacturing process'' in Sec. 1271.220(a) and have concluded that
it is confusing. Processing is one of the steps in manufacture, as
defined in Sec. 1271.3(e). Because Sec. Sec. 1271.220, 1271.225, and
1271.230 pertain only to processing, rather than to the other steps in
manufacture, we have replaced ``manufacturing process'' with
``process.''
(Comment 88) We received five comments on proposed Sec.
1271.220(b), which addressed processing materials. Two comments noted
that it is not always possible to document that a processing material
has been removed from an HCT/P, and that validated procedures should be
sufficient. One comment proposed the use of published data and industry
practice to determine whether a processing material or its residues may
elicit an adverse reaction. This comment also recognized that product
labeling may be used to warn potential users with respect to the
possible presence of residues.
(Response) We have removed proposed paragraph (b) in its entirety
from Sec. 1271.220 and renumbered the paragraphs accordingly.
Pooling.
Proposed Sec. 1271.220(c) states that human cells or tissues from
two or more donors shall not be pooled (placed in physical contact or
mixed in a single receptacle) during manufacturing. We noted that
commingling of cells or tissues from a single infected donor with cells
or tissues from other donors could contaminate the entire pooled
quantity, greatly increasing the risk of exposure to infectious agents
to recipients of the pooled materials (66 FR 1508 at 1516). Proposed
paragraph (c) has been renumbered as (b).
(Comment 89) Approximately six comments agreed with the proposed
prohibition on pooling. Several comments pointed to an increased risk
of infectious disease transmission associated with pooling, and
asserted that pooling could increase the threat of previously unknown
transmissible diseases. One comment asserted that there is a
particularly high risk for Rh-negative women of childbearing age who
receive tissue from Rh-positive donors. Two comments argued that
pooling would impair the effectiveness of tissue recalls, because
tracing to the source of a problem would be impossible. Comments also
questioned the efficacy of processes used to manufacture pooled HCT/Ps
and noted that no process entirely eliminates the risk of infectious
disease transmission. Two comments asserted that pooling would be
distasteful to donors and their families.
(Response) These comments raise valid concerns. We agree in
particular with the concerns expressed about the increased risk of
communicable disease transmission and the difficulty of tracking pooled
HCT/Ps.
(Comment 90) Approximately 10 comments opposed our proposal to
prohibit the pooling of cells or tissues. Several comments argued that
the proposed regulation is too restrictive and could stifle new
technologies.
(Response) Although we are aware of promising new technologies that
involve the pooling of cells from two or more donors, we remain
concerned about the infectious disease risks inherent in pooling. On
June 26, 2002, FDA consulted the Transmissible Spongiform
Encephalopathies Advisory Committee (TSEAC) about the validation of
procedures to prevent contamination and cross-contamination of HCT/Ps
by TSE agents. At this meeting, speakers presented information on the
three approaches that could be taken to reduce the risk of TSE
transmission:
Careful screening of the donor for TSE and risk factors
for TSE;
Control of the recovery and processing of cells and
tissues to prevent contamination and cross-contamination; and
Use of steps during processing to remove or inactivate any
TSE agents that may be present.
One of the processing controls discussed was the use of single
donor aseptic recovery and processing, rather than a process that would
involve pooling of cells or tissues from two or more donors. When asked
about specific measures and controls appropriate to prevent TSE agent
transmission (e.g., single donor aseptic processing), the committee
voted unanimously that single donor processing should be considered the
gold standard, but that a pooled process may be appropriate under
certain circumstances with adequate controls. The committee members did
not discuss which circumstances and what controls would be adequate.
Under Sec. 1271.155, an establishment may submit a request for an
alternative or exemption from the prohibition from pooling provided
that it has data showing that the processing method adequately
addresses the risks associated with pooling.
(Comment 91) Two comments opposed our assertion that commingling
cells or tissues from different donors, who have been screened and
tested, would increase the risk to recipients of exposure to infectious
agents.
(Response) We disagree with these comments. Screening and testing
of donors, although crucial, does not completely eliminate infectious
disease risk, for several reasons. The donor may be in the ``window
period'' during which he or she may be infectious (i.e., have viral
marker levels that are below detection by current tests). Chronic
carriers of a disease may be immuno-silent; i.e., they do not mount an
antibody response. In addition, laboratory errors may be made, or an
HCT/P may be released improperly. Moreover, current tests may not
detect all genetic variants of a particular virus, or a donor may be
infected with an ``emerging infectious disease,'' for which screening
measures or tests have not been developed. Finally, there may be
questions about the accuracy of current tests that are not approved by
FDA for use with cadaveric specimens and about the reliability of donor
histories obtained from another person
[[Page 68633]]
(not the donor). Each of these risks is small, and presents a small
chance of leading to communicable disease transmission to a single HCT/
P recipient. However, the risk is magnified when HCT/Ps from different
donors are pooled during manufacture. Information provided at the TSEAC
meeting described previously showed that the risk of exposing a
recipient to an infectious disease agent contained in a pool, where one
or more units in the pool were recovered from an infected donor, is
directly proportional to the prevalence of the agent in the donor
population and the size of the pool.
(Comment 92) Several comments pointed out benefits of pooling. Two
comments pointed to the need for pooling to obtain a sufficient dose of
an HCT/P, especially in adults (e.g., from cord blood). One comment
stated that pooling contributes to product consistency and uniformity.
(Response) We are retaining the prohibition on pooling during
manufacturing in Sec. 1271.220(b). We continue to believe that, in
general, the risks of pooling HCT/Ps (increased risk of communicable
disease transmission) outweigh the benefits of pooling. For some
biological products, e.g., plasma derivatives, the benefits of pooling
outweigh the risks. In the case of plasma derivatives, pooling
contributes to product consistency. In fact, 21 CFR 640.102(d) requires
that material from not less than 1,000 donors be pooled to make immune
globulin. For plasma derivatives, it is necessary to pool plasma from
many donors to obtain an adequate amount of product to treat one
recipient (i.e., a sufficient dose). In addition, pooling plasma may
dilute the viral burden or provide neutralizing antibodies that may
inactivate any virus present in the pool. However, these benefits of
pooling do not apply, in general, to the pooling of HCT/Ps from many
donors. For instance, tendons from different donors would not need to
be pooled to provide consistency or to obtain a sufficient dose.
Neither would bones pooled from different donors provide neutralizing
antibodies to inactivate any virus present in the pool, since
neutralizing antibodies are present in plasma. In the case of cord
blood, most of the plasma is removed during processing, so that pooling
of cord blood from different donors would not provide sufficient
neutralizing antibodies to neutralize any virus present in the pool.
Furthermore, when cord blood units from more than one donor are
administered to an adult recipient to obtain a sufficient dose, the
units are generally given sequentially and are not pooled.
In order for us to determine whether any benefits to pooling HCT/Ps
from different donors outweigh the risks in a particular case, we would
need additional data. Such data may be submitted and evaluated under a
request for an alternative or exemption in Sec. 1271.155.
(Comment 93) Several comments asserted that the risks of pooling
could be mitigated through validated procedures for clearing pathogens
or sterilizing the pooled HCT/Ps. One of these comments suggested
additional regulatory language that would permit pooling where it is
necessary and does not create an unreasonable risk of communicable
disease transmission. Another comment proposed that the final rule
should allow the pooling of stem cell products from two or more donors,
as long as the resulting pooled product is transplanted into only one
recipient.
(Response) We agree that, in some instances, it may be appropriate
to assess the risks and benefits of pooling. Such assessment could be
submitted under Sec. 1271.155 in a request for an exemption or
alternative to the prohibition on pooling in Sec. 1271.220(b).
However, we decline to modify the proposed regulation as suggested and,
for the reasons explained in Comments 89 through 92, we have retained
the general prohibition on pooling.
(Comment 94) One comment that supported proposed Sec. 1271.220(c)
asserted that no waivers or exceptions should be allowed that would
permit pooling.
(Response) We disagree with this comment. Although we remain very
concerned about the communicable disease risks associated with pooling,
we do not rule out the possibility that pooling may be appropriate in
some specific situations. We will consider requests for exemptions from
or alternatives to Sec. 1271.220(b) under the provisions of Sec.
1271.155. At the June 2002 TSEAC meeting described previously, the
committee members supported the possibility that exemptions from the
proposed pooling prohibition might be appropriate, but did not discuss
criteria upon which to grant such an exemption.
In-process control and testing.
Proposed Sec. 1271.220(d) would require procedures to ensure that
specified requirements for in-process HCT/Ps are met. These procedures
must ensure that an in-process HCT/P is controlled until the required
inspection and tests or other verification activities have been
completed or necessary approvals are received and documented. In
addition, sampling of in-process HCT/Ps must be representative of the
material to be evaluated.
There were no comments on this provision, which has been renumbered
paragraph (c). We have revised this paragraph to cover in-process
control and testing. Paragraph (c) requires you to ensure that
specified requirements, consistent with paragraph (a) of this section,
for in-process controls are met, and that each in-process HCT/P is
controlled until the required inspection and tests or other
verification activities have been completed, or necessary approvals are
received and documented. Sampling of in-process HCT/Ps must be
representative of the material to be evaluated.
We note that paragraph (c) includes the prevention of bacterial and
other contamination. Compliance with this paragraph requires checking
the results of testing at various steps in processing (for example, by
sampling in-process HCT/Ps). The sample selected for testing (e.g.,
culture) must be representative of the entire HCT/P. This may not be
the case if a small snip of the HCT/P or companion tissue (i.e., tissue
adjacent to the HCT/P that is processed along with the HCT/P) is
cultured. The MMWR cited in section III.C.1 of this document
recommended that performing both destructive (i.e., performed on tissue
that had been ground up) and swab cultures (of the tissue surface)
should be considered (Ref. 1).
Dura mater.
Proposed Sec. 1271.230(c) would require dura mater to be processed
using a validated procedure that reduces TSE while preserving the
clinical utility of the product. We have moved proposed Sec.
1271.230(c) to Sec. 1271.220(d) because it relates more closely to
processing and process controls than to process validation.
(Comment 95) Three comments objected to proposed Sec. 1271.230(c).
One comment urged us to eliminate the provision, because FDA should not
endorse the concept of an acceptable level of TSE risk, and another
comment asserted that there is no acceptable level of TSE
contamination. Another comment opined that the proposed rule is
arbitrary because FDA has not validated methods for decontaminating
tissue contaminated with prions.
(Response) We disagree that FDA is endorsing the concept of an
acceptable level of TSE risk. The donor-eligibility rule requires
screening of all HCT/P donors for TSE risk factors and testing of dura
mater donors (see Sec. Sec. 1271.75(a) and 1271.85(e)). In this rule,
we are requiring additional processing safeguards to reduce the level
of the TSE agent that may be present in dura mater,
[[Page 68634]]
even after a donor has been determined to be eligible based on
screening and testing. Taken together, these requirements are intended
to help prevent the transmission of TSE by dura mater and should by no
means be considered to endorse an acceptable level of risk. Eliminating
proposed Sec. 1271.230(c) would decrease the safeguards in place and
elevate the risk; we decline to take this step.
We disagree that the requirement to use a validated procedure is
arbitrary or that it is necessary for FDA to validate procedures for
the removal of the TSE agent in human tissue. TSEAC has recommended
treating human dura mater with sodium hydroxide (June 26, 2002), and in
the preamble to the proposed rule we cited a sodium hydroxide (NaOH)
protocol as an example of a validated procedure (66 FR 1508 at 1517).
The TSEAC recommendation was based on a study in an animal model, in
which 1.0N NaOH treatment reduced Creutzfeld Jakob Disease (CJD)
infectivity (Refs. 2, 3, and 4). However, we realize that this method
is not being used for reducing TSE infectivity in human dura mater
distributed at this time, and that there are no other validated methods
currently available. Although 1.0N NaOH treatment reduces infectivity,
this process can also decrease the clinical utility of the dura mater.
Therefore, Sec. 1271.220(d) requires use of a published validated
process when one becomes available.
As new validated processes become available, they will be published
in the literature. You do not have to validate the published procedure;
rather you must verify that the previously validated process has been
fully and properly implemented in your establishment. We recognize that
processing methods may be developed that reduce the risk of TSE but
that render the HCT/P no longer useful for its purpose. Accordingly,
you are not required to implement a process if it adversely affects the
clinical utility of the dura mater. Alternatively, you may validate an
equivalent procedure for use in your establishment that is at least as
effective as the published procedure, without adversely affecting the
clinical utility of the dura mater.
We recognize that, due to a variety of circumstances, you may not
be aware when there is a published, validated process that reduces the
risk of TSE. We intend to follow the good guidance practices set out in
21 CFR 10.115 to advise you when we have identified the existence of a
published, validated process that reduces the risk of TSE, and we would
ordinarily solicit public comment before issuing a final guidance.
12. Process Changes (Sec. 1271.225)
Proposed Sec. 1271.225 would require the establishment to
establish and maintain procedures for making changes to a process. Such
changes would be verified or validated, and approved by a responsible
person before implementation. We have removed from Sec. 1271.225 the
requirement that establishments have procedures for making process
changes.
(Comment 96) One comment asserted that this section does not apply
to eye banks and that they should not be required to comply. Another
comment from an eye bank stated that the section is too broad and
should be narrowed.
(Response) Section 1271.225 applies to establishments engaged in
the processing of HCT/Ps, including eye banks that perform processing
activities. For example, a switch from one brand of storage solution to
another would be a process change. In this situation, the eye bank must
verify that the new process performs as intended in a manner that does
not introduce, transmit, or spread communicable disease agents.
Under Sec. 1271.150(b), an establishment need only comply with
those requirements applicable to the operations in which it engages
(Sec. 1271.150(b)). Thus, if you are an establishment that does not
engage in the processing of HCT/Ps, you do not need to comply with
Sec. 1271.225. We have discussed the meaning of ``processing'' at
Comment 20. We disagree that it is necessary to narrow the provision,
which is intended to apply to the full range of HCT/P establishments
engaged in processing.
(Comment 97) One comment on proposed Sec. 1271.225(a) asserted
that most, but not all, changes will need to be verified or validated.
As examples of simple changes that should not require verification or
validation, the comment cited requirements for additional training or
changes in location or storage of records. The comment suggested that
we add the phrase ``if appropriate as determined by a risk
assessment.''
(Response) Under Sec. 1271.225, if you are an establishment
engaged in the processing of HCT/Ps, you are required to verify or
validate any change to a process, to ensure that the change does not
create an adverse impact elsewhere in the operation. The examples cited
by the comment are not examples of process changes.
(Comment 98) Proposed Sec. 1271.225(b) contained requirements for
maintaining change records. One comment agreed that records of the
rationale for each change should be maintained, calling this
requirement a real time saver. Another comment asserted that Sec.
1271.225(b) is more stringent than the comparable requirement for
blood.
(Response) We have removed the requirement for documenting all
changes to an established process and the rationale for such a change.
We have maintained the proposed requirement for communicating approved
changes to appropriate personnel in a timely manner; however, it no
longer appears in paragraph (b), which has been deleted.
13. Process Validation (Sec. 1271.230)
Where the results of a process cannot be fully verified by
subsequent inspection and tests, proposed Sec. 1271.230 would require
the process to be validated and approved according to established
procedures. The validation activities, results, and the date and
signature of the individual approving the validation would be
documented. Re-validation would be required where appropriate in the
case of changes to a validated procedure.
We have revised Sec. 1271.230. Paragraph (a) now refers to
processing described in Sec. 1271.220. Paragraph (b) now refers to
written representations, rather than claims, and is more limited than
proposed. Paragraph (c) on dura mater is now Sec. 1271.220(d).
Paragraph (d) requiring procedures for the monitoring and control of
validated processes has been deleted. For clarity, we have deleted the
word ``deviations'' from proposed Sec. 1271.230(e), now Sec.
1271.230(c); that paragraph now refers only to changes to a validated
process.
(Comment 99) Several comments asserted that the requirement for
process validation in proposed Sec. 1271.230 does not apply to eye
banking. One comment cited the use of annually validated mechanical
devices used in processing eye tissue and the evaluation of tissue by
trained personnel.
Another comment asserted that the rule is vague as to which
processes a company should validate and approve and how the validation
and approval should be conducted. This comment further asserted that
the rule fails to take into account the unique biological
characteristics of the various human cell and tissue types (e.g.,
musculoskeletal tissue).
(Response) We have carefully worded Sec. 1271.230 to take into
account the uniqueness of various HCT/Ps. Thus, Sec. 1271.230(a)
requires validation of a process where the results of processing
described in Sec. 1271.220 cannot be fully
[[Page 68635]]
verified by subsequent inspection and tests. Rather than being vague,
this language recognizes that an establishment has specific knowledge
of the HCT/Ps it manufactures, including when verification activities
will suffice and when process validation is required because results
cannot be fully verified. We agree that the control and results of the
processes performed at eye banks may be able to be achieved through
verification activities; in this case, validation would not be
required.
(Comment 100) One comment asserted that the documentation of eye
and tissue banking successes in medical literature should constitute
sufficient objective evidence for procedures that have been in use for
years and that documentation of meeting predetermined specifications
should only be required for new procedures that are not consistent with
pre-existing standards and practices.
(Response) We disagree. Medical literature alone is insufficient to
verify or validate the processes performed at a specific establishment.
Each establishment that performs steps in the processing of HCT/Ps must
demonstrate that it has validated or verified a given process at that
particular establishment and that it is capable of controlling that
process. These steps must be taken for all processes conducted by an
establishment, regardless of when the process was initiated or how long
the process has been in place.
(Comment 101) Proposed Sec. 1271.230(a) states, in part, that
where the results of a process cannot be fully verified by subsequent
inspection and tests, the process shall be validated and approved
according to established procedures. Two comments recommended deleting
the word ``fully'' from this provision, arguing that it is too broad
and could be subject to inconsistent application. These comments
asserted that, once a process has been validated, if changes are
required that do not increase the risk of communicable disease
transmission to the recipient, a written justification for not
revalidating should be sufficient.
(Response) We disagree with the comments' suggestion to delete
``fully.'' The term ``fully verified'' has been used with respect to
process validation in ISO standards for years. Moreover, the term is
used in the QS regulation on process validation applicable to medical
devices (Sec. 820.75(a)).
The MMWR discussed at III.C.1 of this document cited CDC concerns
with bacteriostasis (i.e., the arrestment or inhibition of bacterial
growth and reproduction) (Ref. 1). The report surmised that because
tissues later implicated in patient deaths were cultured only after
suspension in an antibiotic/antifungal solution, residual antibiotics
on the tissues might have caused a false-negative culture result
because of bacteriostasis. Undetected organisms in stasis can later
multiply (e.g., once an HCT/P has been transplanted into a patient and
the residual antibiotic is metabolized so that it no longer inhibits
growth of the bacteria). Therefore, we recommend that a validated
microbiological culturing process include bacteriostatic and
fungistatic testing.
In accordance with Sec. 1271.150(e) (``where appropriate''), we
agree that an assessment with written justification for not
revalidating a change to a validated process would be sufficient under
Sec. 1271.230(c) if the establishment can show that the change does
not increase the risk of communicable disease transmission to the
recipient.
(Comment 102) Proposed Sec. 1271.230(b) states, in part, that any
process-related claim in labeling or promotional materials, e.g., a
claim for sterility or viral inactivation, must be based on a validated
process. One comment asked why, if verification is performed on each
and every finished product, this could not be claimed in labeling.
Three comments asked us to allow sterility claims based on verification
rather than validation when technology limitations exist and when
established manufacturing approaches have not led to clinical problems.
(Response) We agree with these comments and have modified Sec.
1271.230(b) to include verification as well as validation. That
paragraph now requires that any written representation that your
processing methods reduce the risk of transmission of communicable
disease by an HCT/P, including but not limited to a representation of
sterility or pathogen inactivation of an HCT/P, be based ``on a fully
verified or validated process.''
(Comment 103) One comment suggested deleting claims for sterility
or viral inactivation from proposed Sec. 1271.230(b) and creating a
new paragraph that specifically addresses the validation of processes
intended to achieve sterility or viral clearance.
(Response) We decline to make this change. Providing specific
methods for validation or verification of processes is not within the
scope of this rulemaking. However, we have narrowed paragraph (b) so
that it no longer covers ``any process-related claim,'' but now is
limited to any written representation that your processing methods
reduce the risk of transmission of communicable disease by an HCT/P,
including but not limited to, a representation of sterility or pathogen
inactivation of an HCT/P.
14. Labeling Controls (Sec. 1271.250)
Proposed Sec. 1271.250 would require procedures to control the
labeling of HCT/Ps, designed to ensure proper product identification
and prevent mixups. These procedures would include verification of
label accuracy, legibility, and integrity; they would further ensure
that each HCT/P be labeled in accordance with all applicable
requirements.
We have reorganized this section into three paragraphs for clarity
and have corrected the cross-references to labeling requirements in
part 1271.
Two comments supported this section as consistent with industry
standards applicable to eye banking.
(Comment 104) One comment criticized as burdensome the proposed
requirement for procedures to ensure that each product made available
for distribution is accompanied by documentation of the donor
eligibility determination as required under Sec. 1271.55. This comment
asserted that, if the product is going from the laboratory to the
clinical unit of the same program, detailed documentation of donor
testing does not need to accompany the HCT/P, as it can be found in the
laboratory. According to the comment, such documentation of testing
only makes sense if distribution means distribution outside of the
institution.
(Response) We disagree with this comment. As discussed at Comment
17, distribution includes the intracompany shipment of a finished HCT/
P; e.g., the release of an HCT/P from a collection/processing facility
to an operating room in the same facility. Similarly, the release of an
HCT/P from a laboratory to the clinical unit of the same program is
distribution, and the HCT/P must be accompanied by the documentation
required by Sec. 1271.55. We have modified Sec. 1271.55 in the donor-
eligibility final rule (69 FR 29786 at 29831) to remove the requirement
that an HCT/P be accompanied either by the relevant medical records or
a summary of those records; that section now requires HCT/Ps to be
accompanied by a distinct identification code, a statement of whether
or not the donor has been determined eligible, and a summary of the
records used to determine donor eligibility. This requirement is not
burdensome. Moreover, it is very important that the administering
physician have in hand specific and accurate information about the HCT/
P; availability of the
[[Page 68636]]
documentation in another part of a facility is insufficient.
(Comment 105) One comment asserted that the type of information
called for is exorbitant for the identification of individual
transplant products. This comment requested that the rules be
streamlined along the lines of industry standards that provide for
coded identification of donor, identification of intended recipient,
and critical information regarding donor eligibility and type of
processing used.
(Response) We disagree that the labeling information required by
these rules is excessive. A review of the industry standards cited by
the comment indicates that they specify the same information as
required by these regulations, as well as additional information not
required under these regulations; e.g., the identification of intended
recipient, the type of processing used (Foundation for the
Accreditation of Cellular Therapy (FACT) 2002; American Association of
Blood Banks (AABB) 2002).
15. Storage (Sec. 1271.260)
Proposed Sec. 1271.260 would require each establishment to control
its storage areas and stock rooms to prevent mixups, commingling,
deterioration, contamination, and cross-contamination of HCT/Ps and
supplies, and to prevent improper release for distribution. The
establishment would also be required to store the HCT/Ps at an
appropriate temperature, assign an expiration date for the HCT/P where
appropriate, and take and document corrective action when indicated.
One comment supported this section as proposed.
(Comment 106) We received several comments on the storage
temperature and period requirements in proposed Sec. 1271.260(b). Some
comments asked whether establishments must validate storage
temperatures and periods, and noted that many of these have been
established by the tissue industry based on experience. Another comment
cited specific industry standards for eye banks. One comment asserted
that the proposed parameters for setting storage temperature may not be
optimal at the same temperature.
(Response) Voluntary standards issued by professional organizations
exist for many aspects of these regulations, and we agree that
establishments may follow these established industry standards where
the standards meet the requirements set forth in this section. However,
these standards may only apply to specific HCT/P types (e.g., corneas)
and, moreover, are not always sufficiently comprehensive to include all
of the requirements in this rule. Alternatively, establishments may
establish and validate their own criteria for storage temperature and
storage period, as determined for specific HCT/Ps stored in their
facilities.
The regulation (Sec. 1271.260(b)) now requires storage at an
appropriate temperature. Section 1271.260(e)) requires you to establish
acceptable temperature limits to inhibit the growth of infectious
agents.
(Comment 107) Proposed Sec. 1271.260(c) would require
establishments to assign expiration dates to their HCT/Ps, where
appropriate. Two comments stated that the safe duration of
cryopreservation for hematopoietic stem/progenitor cells is unknown and
will take years to validate.
(Response) The requirement for establishing an expiration date is
qualified by the term, ``where appropriate.'' Section 1271.150(e)
explains that a requirement is ``appropriate'' unless an establishment
can justify otherwise, and maintains documentation of that
justification. We consider it appropriate to assign expiration dates
for ``fresh'' (i.e., noncryopreserved) HCT/Ps, and for those HCT/Ps
that are thawed after cryopreservation and storage. If such applicable
expiration dates have been established by industry or medical practice
and meet the requirements of this section, you may use those dates for
your HCT/Ps, whether ``fresh'' or cryopreserved. If scientific data do
not exist for establishing expiration dates, then no expiration date is
required at this time. We encourage the industry to perform studies to
establish expiration dates for those HCT/Ps that currently do not have
expiration dates.
We have modified Sec. 1271.260(c)(2) to refer to ``processing,''
rather than ``processing procedures,'' to avoid redundancy.
16. Receipt, Predistribution Shipment, and Distribution of an HCT/P
(Sec. 1271.265)
Proposed Sec. 1271.265 would require establishments to establish
and maintain procedures for receipt, acceptance or rejection,
distribution, and destruction or other disposition of HCT/Ps; and
document these activities.
Several comments supported proposed Sec. 1271.265. One comment
indicated that the provisions are worthwhile, and another comment
supported documenting the identity of the consignee.
We have reorganized Sec. 1271.265. Paragraphs (a) through (d) now
contain substantive requirements with respect to receipt,
predistribution shipment, distribution, packaging and shipping. Each of
these is a core CGTP requirement. Paragraph (e) requires you to
establish and maintain procedures for activities under paragraphs (a)
through (d) and to document these activities. (This documentation must
include, for example, the identification of the HCT/P; in this rule we
have specified that you must also document the establishment that
supplied the HCT/P (e.g., by maintaining receipt records).) Paragraph
(f) relates to returns to inventory, as proposed.
(Comment 108) One comment asked for clarification to ensure that
all donated materials are subject to Sec. 1271.265, regardless of
their processing status.
(Response) We agree that all donated materials are subject to this
section. The definition of HCT/P covers cells and tissues at all stages
of manufacture, from recovery through distribution (66 FR 5447 at
5448).
Although we do not believe it is necessary to modify Sec. 1271.265
as suggested by the comment, we have made a related change, by adding a
new provision on ``pre-distribution shipment'' (Sec. 1271.265(b)).
This change is necessitated by our revision of the definition of
``distribution,'' discussed at Comment 17, to refer to the conveyance
or shipment of an HCT/P that has been determined to meet all release
criteria. Predistribution shipment includes, for example, shipment of
an HCT/P within your establishment or to another establishment, or
shipment from an establishment that recovers cells or tissue to an
establishment that packages them.
Section 1271.265(b) states that if you ship an HCT/P within your
establishment or between establishments (e.g., procurer to processor)
and the HCT/P is not available for distribution as described in
paragraph (c) of this section, you must ship the HCT/P in quarantine.
(Comment 109) Proposed Sec. 1271.265(b) would require each
incoming HCT/P to be inspected according to established procedures. Two
comments on proposed Sec. 1271.265(b) asked if it is sufficient to
inspect a shipping container for physical damage, or if the containers
must be opened.
(Response) You should tailor your acceptance procedures to the
specific HCT/P and circumstances. As the comments point out, in some
instances opening a sealed shipping container could potentially damage
an HCT/P. In
[[Page 68637]]
designing your acceptance procedures, you should take into account this
possibility, as well as alternate ways of inspecting the HCT/P (e.g.,
inspection of container, ensuring proper temperature has been
maintained during transit). If, after receiving the HCT/P, you hold it
in storage, your storage conditions must comply with Sec. 1271.260.
The MMWR cited at section III.C.1 of this document recommended
that, to minimize the potential of bacterial contamination, tissue
should be cultured before suspension in antimicrobial solutions, and if
bacteria are isolated, all tissue from the same donor should be
discarded if it cannot be sterilized (Ref.1). Where appropriate, your
acceptance procedures should include tests and should spell out
criteria for rejecting incoming HCT/Ps. Preprocessing cultures may be
appropriate in some situations.
(Comment 110) One comment on proposed Sec. 1271.265(c)
(availability for distribution) asserted that ``deterioration'' is
vague and open to interpretation.
(Response) By ``deterioration,'' we mean decay or decomposition.
However, in response to Comment 9 we have removed references to
``deterioration'' from the CGTPs, including Sec. 1271.265.
(Comment 111) One comment on proposed Sec. 1271.265(c) asserted
that the requirements for making an HCT/P available for distribution
should not apply to distributors themselves.
(Response) The requirements in Sec. 1271.265(c) are intended to
apply to the establishment that first makes an HCT/P available for
distribution (defined in Sec. 1271.3(z)). This establishment, which
may or may not be the actual distributor, needs to have procedures in
place under Sec. 1271.265(e) for determining that an HCT/P may be made
available for distribution, including release criteria designed to
prevent communicable disease transmission. The regulation specifies
that you must not make available for distribution any HCT/P that is in
quarantine, is contaminated, is recovered from a donor who has been
determined to be ineligible or for whom a donor-eligibility
determination has not been completed (except as provided under
Sec. Sec. 1271.60, 1271.65, and 1271.90), or that otherwise does not
meet release criteria designed to prevent communicable disease
transmission. Release criteria include criteria for releasing a product
under Sec. 1271.60, Sec. 1271.65, or Sec. 1271.90 that ensure, among
other things, that the conditions for such release are met and that the
HCT/P is labeled with the warnings required by the regulations.
(Comment 112) Proposed Sec. 1271.265(d) would require packaging
and shipping containers to be designed, validated, and constructed to
protect the HCT/P from contamination during customary conditions of
processing, storage, handling, and distribution. The final rule
requires that packaging and shipping containers protect HCT/Ps from
contamination.
Three comments on proposed Sec. 1271.265(d) suggested that
verification of packaging containers is more appropriate than
validation.
(Response) We agree that either validation or verification may be
appropriate ways of ensuring the adequacy of packaging and shipping
containers. Please note, however, that the final rule has been revised
so that it does not require either verification or validation of
packaging and shipping containers.
(Comment 113) Proposed Sec. 1271.265(e) would require that
appropriate shipping conditions be defined for each type of product to
be maintained during transit. One comment questioned whether shipping
conditions must be defined for each type of graft (e.g., femur ring,
bone powder) or for each type of tissue (freeze-dried bone).
(Response) The final rule renumbers this provision as Sec.
1271.265(d), combines it with the provision on packaging, and provides
each establishment with the flexibility to determine whether to
establish shipping conditions for each type of graft or for each type
of tissue. Either approach may be appropriate.
(Comment 114) One comment on proposed Sec. 1271.265(f) stated that
the requirement to establish procedures for returning HCT/Ps to
inventory is not applicable to all HCT/Ps.
(Response) We agree that some establishments may not engage in all
activities covered by the CGTPs. Under Sec. 1271.150(c),
establishments need only comply with the requirements that are
applicable to the operations in which they engage. Thus, an
establishment that does not return HCT/Ps to inventory is not required
to establish procedures for that activity.
17. Records (Sec. 1271.270)
Proposed Sec. 1271.270 would require establishments to maintain
records concurrently with the performance of each significant step
required in subparts C and D. A records management system would be
established and maintained. Records would be maintained:
Electronically, as original paper records, or as true copies; 10 years
after their creation; and for contracts, agreements, and other
arrangements with another establishment to perform a step in
manufacturing. One comment from a professional organization supported
the goal of this provision, which it identified as chain of custody.
(Comment 115) One comment on Sec. 1271.270(b) asserted that
maintaining records organized by product type is not practical and that
it is more useful to organize records by donor. Another comment
asserted that detailing how to organize records is an unnecessary
intrusion and that the example given was unduly complicated.
(Response) In response to the first comment, we have deleted the
words ``of each type'' from the third sentence of Sec. 1271.270(b), so
that it now reads: ``Records pertinent to the manufacture of HCT/Ps * *
* must also be maintained and organized under the records management
system.'' In response to the second comment, we note that, although
paragraph (b) requires you to establish and maintain a records
management system, it does not specify the details of such a system. It
is the responsibility of the establishment to organize its records in a
useful manner. The example given in the preamble to the proposed rule
was intended simply to explain, to those unfamiliar with the term, what
is meant by a ``records management system'' (66 FR 1508 at 1518). We
have revised paragraph (b) so that the requirement for a records
management system applies only to core CGTP requirements.
(Comment 116) We received two comments on the requirement in
proposed Sec. 1271.270(c) that information on the identity and
relevant medical records of a donor must be in English or, if in
another language, must be translated to English and accompanied by a
statement of authenticity by the translator that specifically
identifies the translated document.
(Response) Proposed paragraph (c) of Sec. 1271.270 would relate to
the donor-eligibility requirements in subpart C of part 1271. In the
donor-eligibility final rule (69 FR 29786 at 29831), we incorporated
the contents of proposed Sec. 1271.270(c) into the records
requirements in Sec. 1271.55 and responded to these comments. We are
now removing proposed paragraph (c) from Sec. 1271.270.
(Comment 117) Proposed Sec. 1271.270(e) would require records to
be kept for 10 years. We specifically requested comments on whether
there are specific types of record for which retention period shorter
than 10 years
[[Page 68638]]
would be appropriate (66 FR 1508 at 1518).
Two comments responded that a 10-year record retention is
appropriate, and one of these comments cited an industry standard
requiring records to be maintained 10 years.
(Response) We have maintained the 10-year record retention
requirement for all records. Proposed Sec. 1271.270(e) has been
renumbered Sec. 1271.270(d).
(Comment 118) Three comments pointed out that the record retention
requirement in proposed Sec. 1271.270(e) is confusing, and each of
these comments suggested new language. One suggestion would require
that the establishment retain records for 10 years after
transplantation, or after expiration if transplant date is unknown. Two
comments suggested that we require the retention of records for a
minimum of 10 years after creation, 10 years after the expiration of a
HCT/P, or 10 years after the appropriate disposition of dura mater.
(Response) We have revised proposed paragraph (e) by replacing the
words ``implantation, transplantation, infusion, or transfer'' with
``administration.'' The second sentence of Sec. 1271.270(d) now reads
However, you must retain the records pertaining to a particular
HCT/P at least 10 years after the date of its administration, or if
the date of administration is not known, then at least 10 years
after the date of the HCT/P's distribution, disposition, or
expiration, whichever is latest.
(Comment 119) Proposed paragraph (e) would require an establishment
to make provisions for all records to be maintained for the required
period in the event that the establishment ceases operation. One
comment asserted that it is not practical for an establishment to
retain records if it has gone out of business.
(Response) We encourage you to make provisions for keeping records
in the event that your establishment goes out of business, because some
communicable disease have very long incubation periods before symptoms
appear (e.g., CJD). However, because of difficulties in enforcing the
proposed requirement, we have removed it from the final regulation.
18. Tracking (Sec. 1271.290)
Proposed Sec. 1271.290 would require each establishment that
performs any step in manufacturing to set up a system for tracking each
HCT/P so that the HCT/P may be tracked from donor to recipient and
recipient to donor.
We have clarified that tracking requirements apply to those
facilities that handle the HCT/P. If you do not handle the HCT/P (e.g.,
you are the testing laboratory that receives a blood specimen, but you
do not actually handle the HCT/P), you do not have to participate in
the tracking requirements.
We have also added language to clarify that the purpose of a
tracking system is to facilitate the investigation of actual or
suspected transmission of communicable disease and any appropriate and
timely corrective action.
Finally, we have revised the tracking provisions to require a
system that enables tracking to and from the consignee, rather than to
and from the recipient, and have added that labeling includes
information designed to facilitate effective tracking, using the
distinct identification code, from the donor to the recipient and from
the recipient to the donor.
(Comment 120) We received several comments in support of the
proposed requirements. One comment responded to our request for
comments from establishments that have already developed and
implemented tracking systems about the success or failure of those
systems (66 FR 1508 at 1519). This comment described its successful
tracking system and noted that tracking fulfills its ongoing
responsibility to the patients who have received its tissues. The
establishment provides hospitals with peeloff labels that identify each
unique product and the bank that provided it, and also with tracking
logs for the hospitals to use to control inventory. Information on the
use of the HCT/P is returned to the tissue bank by the hospital in a
self-addressed envelope and then entered into the establishment's
database. The establishment sends regular reminders to hospitals
notifying them of tissue for which it has not received transplant
records. The comment noted that hospitals willingly participate, and it
cited a high (85 to 100 percent) return of transplant records.
(Response) We appreciate this detailed information and believe it
demonstrates both the feasibility and the importance of developing a
functioning tracking system.
(Comment 121) Two comments argued that the proposed requirements
could not be justified based on risk and were inconsistent with
industry standards. The comments also asserted that the proposed
tracking requirement would require collection of confidential patient
information in conflict with privacy regulations issued under the
Health Insurance Portability and Accountability Act (45 CFR parts 160
and 164). Those regulations were finalized on December 28, 2000 (65 FR
82462), and amended on August 14, 2002 (67 FR 53182).
(Response) We disagree. Not only are these requirements justified
by the communicable disease risks posed by HCT/Ps, but they are
consistent with industry standards. AATB standards require traceability
and dispensing records by the tissue dispensing service (medical,
dental, hospital facility, physician's office) (See the American
Association of Tissue Banks (AATB) Standards 2002, L4.000). The Eye
Bank Association of America (EBAA) medical standards require that
recipient identification readily traceable to each unique graft number
be retained in the eye banks' records (See EBAA Medical Standards 2002,
M1.400).
The proposed tracking requirements are not inconsistent with the
HIPAA privacy regulation, which sets up protections for individually
identifiable health information. The privacy rule applies only to
``covered entities'': e.g., health plans, health care clearinghouses,
and health care providers conducting certain transactions in electronic
form (45 CFR 164.104). HCT/P establishments subject to the tracking
requirements are unlikely to meet the definition of a covered entity.
Thus, the privacy regulation would not apply to their activities, and
the use in product tracking of a distinct identification code by an
entity that is not covered by that rule would not be subject to the
privacy rule.
In the unusual event that an establishment met the definition of
covered entity, the establishment's disclosure of individually
identifiable health information would be subject to the privacy rule.
However, the privacy rule allows covered entities to share de-
identified health information for any purpose and includes requirements
for determining whether information is de-identified. (45 CFR
164.502(d), 164.514(a)-(c)). Further, a covered entity may assign a
code to otherwise de-identified data, if the code is not derived from
or related to information about the individual and is not otherwise
capable of being translated so as to identify the individual, and if
the covered entity does not use or disclose the code or other means of
record identification for any other purpose, and does not disclose the
mechanism for reidentification (45 CFR 164.514(c). Thus, an
establishment that is a covered entity is not in violation of the
privacy rule if it discloses information de-identified in accordance
with 45 CFR 164.514(a)-(c), including a distinct identification code
that meets the requirements of 45 CFR 164.514(c).
[[Page 68639]]
Consignees are likely to meet the definition of a covered entity,
and would therefore be covered by the privacy rule. However, the
tracking provision does not require consignees to provide individually
identifiable health information; it requires only that establishments
be able to track HCT/Ps to consignees.
We note that a consignee may on occasion wish to disclose protected
health information to an establishment. For example, a consignee may
wish to report to the establishment that a recipient of an HCT/P
developed an infection at the site of the transplant. Under the public
health activities provisions of the privacy rule, the rule permits, but
does not require, entities that meet the definition of a covered entity
to disclose protected health information to persons subject to the
jurisdiction of FDA with respect to an FDA-regulated product or
activity for which that person has responsibility, for the purpose of
activities related to the quality, safety or effectiveness of such FDA-
regulated product or activity (45 CFR 164.512(b)(1)(iii)). The rule
specifically identifies tracking FDA-regulated products as a purpose
permitting such disclosures, along with collecting and reporting
adverse events and enabling product recalls, repairs, replacement, or
lookback (45 CFR 164.512(b)(1)(iii)(A), (b)(1)(iii)(B), and
(b)(1)(iii)(C)). Finally, in the event that one of the previously
mentioned provisions is not applicable, covered entities may disclose
protected health information pursuant to an authorization from the
individual or the individual's personal representative (45 CFR
164.502(g)(1) and 164.508). We further discuss the applicability of the
privacy rules in the context of donor eligibility in Comment 4 to the
donor eligibility rule (69 FR 29786 at 29790).
(Comment 122) One comment suggested that the regulations should
refer to ``tracing'' instead of ``tracking,'' to avoid confusion with
device tracking.
(Response) We disagree. The term ``tracking'' adequately defines
the operations being performed with respect to the HCT/P and is a term
that is recognizable by industry.
(Comment 123) Several comments from eye banks asked for an
exception for corneas that are distributed internationally, noting the
difficulty of obtaining information on recipients. One of these
comments asked that the consignee's signature and intended disposition
be acceptable.
(Response) We decline to grant an exception for corneas that are
distributed internationally. However, we note that the tracking
requirements in Sec. 1271.290 do not require tracking to the recipient
level, but rather to the consignee. In the case of international
distribution, obtaining the consignee's signature and intended
disposition is acceptable.
(Comment 124) Two comments asserted that it would be impossible to
comply with proposed Sec. 1271.290 unless all establishments adopt a
uniform tracking method, and further opined that many vendors may elect
not to participate in tracking due to the potential disclosure of
proprietary information.
(Response) We disagree with these comments. We prefer to provide
establishments with flexibility in complying with Sec. 1271.290, and
for that reason we decline to mandate a uniform tracking method. It is
unclear why it would be impossible to comply with the requirement in
the absence of uniformity. It is also unclear what proprietary
information would be disclosed via a tracking system. However, we note
that each establishment has the choice of maintaining its own tracking
method or participating in the system developed by another
establishment; a vendor who shares the concerns expressed by these
comments may choose not to participate in another establishment's
tracking system. We have revised Sec. 1271.290 to clarify that a
``system'' involves the tracking of an HCT/P from the donor to the
consignee or from the consignee to the donor; and that a ``method'' is
an action that enables tracking.
(Comment 125) One comment on proposed Sec. 1271.290(b) asserted
that a single designated establishment should collect tracking
information and maintain the entire history of collection, processing,
and release. Another comment argued that tracking responsibilities
should be placed on the entity that makes the product available for
distribution, and that subsequent entities (i.e., distributors) should
be allowed to follow that entity's existing tracking procedures.
(Response) Section 1271.290(b) provides establishments with the
flexibility to participate in the tracking system set up by another
establishment, provided that the system complies with all requirements
in this section. However, the responsibility lies with each
establishment involved in the manufacture of an HCT/P. For example, if
only the establishment that made the HCT/P available for distribution
were responsible for tracking, establishments ``upstream'' would not
necessarily participate. This would not enable tracking from donor to
consignee because the distributor would not have the information for
linking the consignee to the donor, since the establishment performing
recovery would be the only entity that would know the identity of the
donor.
(Comment 126) Proposed Sec. 1271.290(c) would require
establishments to ensure that each HCT/P that it manufactures is
assigned and labeled with a distinct identification code that relates
the HCT/P to the donor and to all records pertaining to the HCT/P. One
comment on this provision asked us to clarify that a single
identification code may be used for an entire lot of morselized
structural tissue of the same type from the same donor, even if the lot
is distributed in more than one immediate container.
(Response) We agree with this comment's interpretation of the
regulation.
We have added to paragraph (c) the requirement that labeling
include information designed to facilitate effective tracking, using
the distinct identification code, from the donor to the recipient and
from the recipient to the donor. Although Sec. 1271.290 does not
require establishments to establish a tracking system from the
recipient to the donor and from the donor to the recipient, this
labeling requirement will enable such tracking to be performed. An
example of a labeling statement that would comply with this requirement
is: ``IMPORTANT NOTICE TO END-USER: Please record this distinct
identification code in your records and in the patient's file.''
(Comment 127) One comment asked us to permit tracking from
production lot rather than from donor. This method would apply to lot-
processed or batch-processed products manufactured using a validated
sterilization method.
(Response) We decline to modify the regulation to make the
requested change. However, we would consider a request for an
alternative submitted under Sec. 1271.155. The requestor should show
that the proposed alternative tracking method satisfies the purposes of
the requirement in Sec. 1271.290(e).
(Comment 128) Proposed Sec. 1271.290(d) would require an
establishment to ensure that the identifier and type of HCT/P that is
implanted into a recipient be recorded in the recipient's medical
records, or in other pertinent records, to enable tracking from the
recipient to the donor.
One comment asserted that the manufacturer has no authority over
the content of the medical record and suggested that the manufacturer
provide paper documentation appropriate for the medical record and
notice of the Federal regulations requiring that the
[[Page 68640]]
information be placed in the medical record. Another comment asserted
that, because of tissue establishment's inability to mandate hospital
compliance, FDA should revise proposed Sec. 1271.290(d) to allow
tracking to the production lot, or eliminate the provision altogether.
(Response) We have revised paragraph (d) to remove the requirement
for ensuring that information on an HCT/P is recorded in a recipient's
medical records or other pertinent records. That paragraph now requires
an establishment to establish and maintain a method for recording the
distinct identification code and type of each HCT/P distributed to a
consignee to enable tracking from the consignee to the donor.
In response to Comment 126, we discuss the new requirement in
paragraph (c) for label information designed to facilitate tracking
between recipient and donor.
(Comment 129) Proposed Sec. 1271.290(e) would require
establishments to document, and maintain records of, the disposition of
each HCT/P, to enable tracking from the donor to the recipient or final
disposition. This information must permit the prompt identification of
the recipient of the HCT/P, if any.
One comment asked us to specify an acceptable timeframe for the
identification of the recipient. Another comment asked whether, with
regard to ``prompt'' identification, the name and hospital or social
security number are sufficient information to allow identification. A
third comment suggested requiring tracking, not to the recipient, but
to the distributor, transplant facility, or transplanting surgeon, as
appropriate. This comment asserted that neither tissue banks nor the
agency has the authority to mandate hospital or physician compliance
with the tissue banks request for recipient information.
(Response) FDA agrees that it cannot mandate hospital or physician
compliance, and we have revised paragraph (e) to require tracking to
the consignee, rather than to the recipient. However, as described in
Comment 119, we note that successful tracking systems have been
implemented, in which hospitals readily participate. In addition,
hospitals accredited by the Joint Commission on Accreditation of
Healthcare Organizations (JCAHO) are required to keep records that
permit tracking of any tissue from the donor or source facility to all
recipients or other final disposition. (Joint Committee, 2000-2001,
``Comprehensive Accreditation Manual for Pathology and Clinical
Laboratory Services,'' pp. QC 36-37.)
We decline to specify a timeframe for the identification of the
consignee, because the timeframe may vary with the circumstances.
(Comment 130) One comment asked for a clarification of the term
``consignee.'' This comment asked whether a hospital that receives an
HCT/P is considered the consignee, or if the surgeon who uses the HCT/P
is the consignee.
(Response) Either or both parties may be the consignee, depending
on the particular situation. Generally, the person and/or entity to
which an HCT/P is distributed would be considered the consignee.
(Comment 131) Proposed Sec. 1271.290(f) would require
establishments, at or before the time of distribution of an HCT/P, to
inform the consignee in writing of the regulatory requirements and of
the tracking method that the establishment has put into place. The
establishment would also be required to document that the consignee
agreed to participate in its tracking method and to take all necessary
steps to ensure compliance with the requirements of Sec. 1271.290.
Several comments questioned how proposed Sec. 1271.290(f) would
work. One comment asked whether a signed agreement would have to be
obtained before sending the tissue, and noted that this would be
difficult. This comment also asked who should be authorized to sign the
agreement. Another comment noted that it sends a ``tissue usage form''
with its tissues, but that many facilities do not return the form; this
comment further noted that a contract does not always exist between a
tissue bank and the end user. Several comments asserted that tissue
banks lack the authority or means to ensure compliance with the
regulation and should not be held responsible for gathering tracking
information, and one comment asked how far an eye bank must go to
demonstrate that it has attempted to obtain an agreement from the
consignee. One comment stated that a tissue facility cannot and should
not withhold tissue for a prior failure of a facility to provide
required documentation, and that if it did so, another source of
tissues would be sought.
One comment expressed concern that: (1) Establishments may develop
agreements that are least burdensome rather than most effective; (2) an
establishment would not be able to provide an HCT/P to a consignee in
an emergency until the consignee developed a tracking system; (3) the
tracking requirements conflict with the new privacy rules, because a
tissue establishment must review recipient records to ascertain whether
a consignee maintained an adequate system; (4) patients change
practitioners or localities without providing their new addresses; and
(5) it would be unwieldy and unrealistic for an establishment with
thousands of consignees to take all necessary steps to ensure their
compliance.
(Response) We have removed the requirement in proposed paragraph
(f) to obtain agreement from a consignee to participate in an
establishment's tracking system.
19. Complaint Files (Sec. 1271.320)
Proposed Sec. 1271.320 would require each establishment to
establish and maintain procedures for the prompt review, evaluation,
and documentation of all complaints, and the investigation of
complaints as appropriate. We defined ``complaint'' in proposed Sec.
1271.3(ii) and have made several changes to that definition, now
renumbered Sec. 1271.3(aa), which are discussed at Comment 13.
We have revised Sec. 1271.320 so that its requirements relate to
the core CGTP requirements.
(Comment 132) One comment asked us to clarify the meaning of
``promptly.''
(Response) We expect complaints to be investigated quickly enough
to meet the reporting requirements, in case the complaint necessitates
reporting. However, because the interpretation of the term ``promptly''
is somewhat vague, we have replaced ``promptly'' in paragraph (c) with
``as soon as practical.''
(Comment 133) Two comments raised concerns about the requirement in
proposed Sec. 1271.320(b) that confidential complaint files be made
available for review and copying upon request from an authorized FDA
employee.
(Response) We recognize the comments' concerns about maintaining
donor and patient confidentiality. When copying complaint files, the
agency will take steps to protect the identity of the donor or patient
in conformance with 21 CFR parts 20 and 21.
D. Part 1271, Subpart E--Additional Requirements for Establishments
Described in Sec. 1271.10
1. Applicability (Sec. 1271.330)
Proposed Sec. 1271.330 explained that the regulations in subpart E
would be applicable only to HCT/Ps described in Sec. 1271.10, i.e.,
regulated solely under section 361 of the PHS Act and the regulations
in part 1271.
We received no comments on this section. We have, however, modified
[[Page 68641]]
Sec. 1271.330 to state that the provisions in subpart E (on reporting
and labeling) are currently being implemented only for nonreproductive
HCT/Ps described in Sec. 1271.10 and regulated solely under 361 of the
PHS Act and the regulations in this part, and the establishments that
manufacture them.
2. Reporting Requirements (Sec. 1271.350)
Proposed Sec. 1271.350(a) sets out requirements for reporting
adverse reactions, and Sec. 1271.350(b) deals with reports of product
deviations (now called ``HCT/P deviations'').
(Comment 134) One comment on proposed Sec. 1271.350 stated that
the section is unnecessarily burdensome because a professional
organization already requires reporting, and requested ``deemed
status'' for that organization.
(Response) We disagree that these reporting requirements are
duplicative. Reporting to professional organizations is not required
under these regulations. More importantly, we do not receive reports of
adverse reactions and HCT/P deviations from professional organizations.
Adverse Reaction Reporting (Sec. 1271.350(a))
(Comment 135) Several comments asserted that our authority to
require adverse reaction reports is limited to those that involve the
transmission of communicable disease or product contamination. Three
comments requested that reportable adverse reactions be defined, for
corneas, as any communicable or other disease transmitted by and
attributable to transplantation of donor eye tissue, including
infection and biologic dysfunction, and any systemic infectious disease
that develops in a recipient. One comment requested that the rule be
revised to take into account that transplants can be rejected or cause
reactions such as graft-versus-host disease.
(Response) You are now required to investigate any adverse reaction
involving a communicable disease. You must make a report if the adverse
reaction meets one of the criteria set out in Sec. 1271.350(a)(1). We
decline to set out specific requirements for corneas but note that the
situations described in the comments would meet the requirements in
Sec. 1271.350(a) for reporting adverse reactions. Problems not
connected with communicable disease transmission are not required to be
reported e.g., primary graft failure.
(Comment 136) One comment suggested limiting reporting requirements
to adverse reactions ``directly related to the product'' to reflect
that an HCT/P establishment is not responsible for reporting
communicable disease transmission from other sources (e.g., blood
products administered during surgery).
(Response) We decline to make the suggested change. It may take
longer than 15 days for an establishment to determine whether or not an
adverse reaction is directly related to an HCT/P. For the protection of
the public health, it is more important for information about the
transmission of a communicable disease or HCT/P contamination to be
reported to us within 15 days, even if further followup indicates that
communicable disease transmission came from a source other than the
HCT/P.
However, we note that in cases where there is no reasonable
possibility of a relationship between an unintended and noxious
response and the HCT/P, then the event would not be considered an
adverse reaction under Sec. 1271.3(y), and reporting would not be
required under Sec. 1271.350(a).
(Comment 137) One comment asked whether, if the investigation of a
complaint points to a cause other than a failure of an eye bank's good
tissue practice, the eye bank is required to report these results.
(Response) If immediate investigation indicates that there is not a
reasonable possibility of a relationship between an unintended and
noxious response and the HCT/P, then the event is not considered an
adverse reaction and you are not required to report it. If, however,
there exists a reasonable possibility that the HCT/P caused the event,
then the event is an adverse reaction and it may be reportable under
Sec. 1271.350(a). If, after you have made a required report, you
discover additional information, you must report this information to
the agency under Sec. 1271.350(a)(3) within 15 calendar days of
receipt of the new information. If your investigation determines that
the HCT/P did not cause the unintended and noxious response, then you
must submit this information to FDA.
(Comment 138) Proposed Sec. 1271.350(a) would require you to make
reports of adverse reactions to us within 15 calendar days of the
initial receipt of the information. Several comments suggested
extending this timeframe to 30 days to allow for more thorough follow-
up; one comment suggested 30 to 60 days; and another comment suggested
30 days, in the absence of death or disease transmission.
(Response) We disagree with these comments. The timeframe set out
in Sec. CFR 1271.350(a) is consistent with adverse reaction reporting
requirements for other regulated products (see 21 CFR 314.80 and
600.80; Medical Device Reporting is required within 10 days (21 CFR
803.10)). The adverse reactions that must be reported to the agency
under Sec. 1271.350(a) warrant action in less than 1 or 2 months. It
is reasonable for us to require reporting without delay of an adverse
reaction that is fatal or life-threatening, results in permanent
impairment of a body function or permanent damage to body structure, or
necessitates medical or surgical intervention, including
hospitalization. We recognize that followup may be appropriate, and
Sec. 1271.350(a)(3) sets out procedures for submitting new information
to the agency or responding to an agency request for additional
information.
(Comment 139) Several comments objected to the breadth of the
proposed requirement for reporting cases where medical or surgical
intervention is required. Two comments suggested adding the phrase ``to
preclude permanent impairment of a body function or permanent damage to
a body structure'' for consistency with medical device reporting
regulations (see Sec. 803.3(bb)).
(Response) We decline to make the suggested change because the
communicable disease risks with HCT/Ps are different from the types of
risks associated with most medical devices. It is important for FDA to
know of infections that may have been caused by HCT/Ps even if
permanent impairment of a body function or permanent damage to a body
structure is not likely, because such infections may alert us to
broader issues (e.g., a positive donor who was the source of additional
HCT/Ps; CGTP failures in the establishment). For this reason, we would
generally consider that an infection at the site of a transplant would
be reportable under Sec. 1271.350(a).
(Comment 140) One comment stated that it is unclear which
establishment must report adverse reactions to FDA.
(Response) Any establishment that receives information (e.g.,
through a complaint) about an adverse reaction related to an HCT/P that
it made available for distribution must comply with Sec. 1271.350(a).
We have inserted this language into Sec. 1271.350(a) for clarity.
(Comment 141) One comment noted that it may be important to specify
the need to facilitate, encourage, and even solicit adverse reaction
information by establishments themselves. The comment further noted
that the probability of receiving this information may be determined in
part by the
[[Page 68642]]
presence or absence of a well-defined active followup program
implemented by the establishment.
(Response) We agree with this comment and encourage establishments
to develop programs to help them comply with the reporting requirements
in Sec. 1271.350.
HCT/P Deviation Reporting (Sec. 1271.350(b))
(Comment 142) One comment on proposed Sec. 1271.350(b) asserted
that the regulation should not require reporting of minor or
unimportant deviations. Two comments criticized the proposed reporting
requirement as burdensome and questioned the agency's capacity to
review submitted reports. These comments suggested limiting reports to
instances involving issues of disease transmission.
(Response) We have modified the proposed definition of HCT/P
deviation. An HCT/P deviation as defined in Sec. 1271.3(dd) is limited
to an event that represents a deviation from applicable regulations or
established specifications that may relate to the prevention of
communicable disease transmission or HCT/P contamination; or that is an
unexpected or unforeseeable event that may relate to the transmission
or potential transmission of a communicable disease or may lead to HCT/
P contamination.
(Comment 143) Two comments asked for clarification of whether
deviations must be reported if the HCT/P is not distributed.
(Response) As in the proposed rule, reporting of HCT/P deviations
is required only when the involved HCT/P has been distributed.
We have also clarified that the establishment must investigate all
HCT/P deviations related to a distributed HCT/P for which the
establishment performed a manufacturing step.
(Comment 144) One comment suggested changing the requirement to
report ``as soon as possible'' to a maximum reporting period of 45
days.
(Response) We agree with this comment and have made the suggested
change. In this regard, we wish to emphasize that HCT/P establishments
should not wait to report deviations until after completing their
corrective actions. Rather, HCT/P establishments should submit
deviation reports as soon as possible but no later than 45 days after
the date that the establishment first discovers information reasonably
suggesting a reportable event has occurred. The reports should include
information on the intended followup to be taken if followup is not
completed prior to submission of the report.
(Comment 145) One comment pointed out discrepancies between
proposed Sec. 1271.350(b) and the biologic product deviations final
rule, and suggested that reporting requirements be harmonized.
(Response) We have largely harmonized Sec. 1271.350(b) with Sec.
600.14(b), as suggested by the comment. In addition, we have clarified
in Sec. 1271.350(b)(2) your obligation to report an HCT/P deviation
relating to the core CGTP requirements, if the HCT/P deviation occurs
in your facility or in a facility that performs a manufacturing step
for you under contract, agreement, or other arrangement. The
establishment responsible for reporting HCT/P deviations relating to
the core CGTP requirements would receive the necessary information from
a contract establishment in accordance with Sec. 1271.160(b)(2).
3. Labeling (Sec. 1271.370)
Proposed Sec. 1271.370 would have required clear and accurate
labels for each HCT/P.
Proposed Sec. 1271.370 would apply only to 361 HCT/Ps; HCT/Ps
regulated as drugs, devices, and/or biological products are subject to
labeling requirements currently in place. The regulations under 21 CFR
parts 201 and 610 will apply to HCT/Ps regulated as drugs and/or
biological products, as will relevant statutory provisions and any
conditions of product licensure or approval. HCT/Ps regulated as
devices are subject to the labeling requirements in 21 CFR part 801, in
addition to the provisions of the act and any applicable conditions of
approval or clearance. In the proposed rule, we proposed to interpret
several current regulations as encompassing the information set out in
proposed Sec. 1271.370(a), and stated that we would expect the
information listed in that section to appear on the label or package
insert of those products regulated as biological drugs or devices (66
FR 1508 at 1522). We received no comments on this proposal.
To coordinate with the requirement in Sec. 1271.290(c) that you
label each HCT/P with a distinct identification code, we have added to
Sec. 1271.370 the requirement that this code be affixed to the HCT/P
container.
(Comment 146) One comment stated that the required label
information would not fit on vials and requested that this information
be permitted on labeling. Another comment asserted that putting the
name and address of the establishment that determined donor eligibility
on the label would breach donor/recipient confidentiality and suggested
that this information appear instead in the package insert.
(Response) The establishment name and address information is
important to enable traceability if needed. However, we recognize the
difficulty in fitting this information on the HCT/P label, and we have
changed the regulation in Sec. 1271.370(c) to require that this
information must either appear on the HCT/P label or accompany the HCT/
P. We also note that when we use the term ``label'' in this subpart, we
mean either: (1) Affix to the HCT/P container, or (2) attach a tie-tag
with the appropriate information to the container.
(Comment 147) Proposed Sec. 1271.370(a)(3)(ii) would require
warnings on the label or package insert, where appropriate. One comment
stated that guidance is needed on ``warnings.''
(Response) In Sec. Sec. 1271.60, 1271.65, and 1271.90 of the
donor-eligibility final rule, we now require warning statements related
to informing the recipient about certain unusual circumstances, e.g.,
``WARNING: Advise patient of communicable disease risk'' when an HCT/P
is distributed before completion of the donor eligibility
determination. These warning statements must appear on the HCT/P label.
In addition, the establishment should determine what other information
the user needs to know before using an HCT/P; this information would be
considered ``other warnings'' (we have revised Sec. 1271.370(c)(3)).
Other warnings would include information about risks resulting from
procedures to reduce communicable disease risks during the manufacture
of an HCT/P. An example would be a warning that the product was
processed aseptically and is not sterile (e.g., may harbor
microorganisms).
Because certain warnings are required to appear on the label
itself, we have added Sec. 1271.370(b)(4), which lists, as information
that must appear on the label, warnings required under Sec. 1271.60,
Sec. 1271,65, or Sec. 1271.90, if applicable.
(Comment 148) One comment stated that some of the labeling
provisions exceed the statutory authority because the relationship to
communicable disease transmission is too attenuated.
(Response) We have revised Sec. 1271.370 to strengthen the
connection between the labeling requirements and the prevention of
communicable disease. For example, Sec. 1271.370(c)(4) now requires
instructions for use when related to the prevention of the
introduction, transmission, or spread of communicable diseases. Other
information we have required to be included in the labeling is intended
to facilitate proper use and tracking of the HCT/P; both are essential
to prevent the
[[Page 68643]]
spread of communicable disease. We have removed proposed paragraph (b);
Sec. 1271.370 no longer covers claims.
(Comment 149) One comment on proposed Sec. 1271.370(b) asserted
that HCT/Ps with claims for reconstruction or repair should be
regulated under section 351 of the PHS Act because it cannot be
assumed, in the absence of substantial clinical evidence, that these
products perform as intended. The comment provided as an example
autologous expanded cartilage.
(Response) As previously noted, we have removed the proposed
provision on claims from Sec. 1271.370. However, the comment's scope
extends beyond the proposed language, and for that reason we note our
disagreement. HCT/Ps with claims for ``reconstruction or repair'' can
be appropriately regulated solely under section 361 of the PHS Act if
such HCT/Ps meet all of the criteria in Sec. 1271.10, including
minimal manipulation and homologous use. To further clarify this point,
we have added the terms ``repair'' and ``reconstruction'' to the
definition of ``homologous use'' under Sec. 1271.3(c).
The example provided by the comment is not appropriate. Autologous
expanded cartilage cells are not regulated solely under section 361
because they are more than minimally manipulated when they are cultured
and, thus, do not meet the criteria in Sec. 1271.10.
(Comment 150) Two comments asserted that proposed Sec.
1271.370(b)(2) is unnecessary and could create confusion regarding the
definition of homologous use. These comments suggested removing the
paragraph in question and allowing the existing definition of
``homologous use'' to stand as the sole definition.
(Response) We agree with this comment and have removed the proposed
paragraph on claims from Sec. 1271.370. ``Homologous use'' is defined
in Sec. 1271.3(c)(the registration final rule) as ``the replacement or
supplementation of a recipient's cells or tissues with an HCT/P that
performs the same basic function or functions in the recipient as in
the donor.'' As previously noted, we have added reconstruction and
repair to the definition of ``homologous use'' under Sec. 1271.3(c).
(Comment 151) One comment asserted that we should clarify this rule
to identify examples of homologous use claims.
(Response) This rule no longer contains language relating to
homologous use claims. However, we take this opportunity to note that
the examples of homologous and nonhomologous claims given in the
registration final rule are still valid, with one exception (see 66 FR
5447 at 5458). After reviewing additional data from one manufacturer,
we now consider the use of that manufacturer's minimally manipulated
amniotic membrane alone for ocular repair as homologous. However, when
amniotic membrane is combined with limbal stem cells, such an HCT/P is
regulated under section 351 of the PHS Act.
E. Part 1271, Subpart F--Inspection and Enforcement of Establishments
Described in Sec. 1271.10
1. Applicability (Sec. 1271.390)
Proposed subpart F of part 1271 contains provisions on inspections;
HCT/Ps offered for import; and orders of retention, recall,
destruction, and cessation of manufacturing. Subpart F would apply only
to those establishments described in Sec. 1271.10 (i.e., those
establishments that manufacture HCT/Ps regulated solely under the
authority of section 361 of the PHS Act and the regulations in part
1271, and not as drugs, devices, and/or biological products). We
received no comments on this section.
2. Inspections (Sec. 1271.400)
Proposed Sec. 1271.400 would require an establishment to permit an
authorized representative of FDA at any reasonable time and in a
reasonable manner to inspect the establishment.
(Comment 152) In the proposed rule, we invited comments on possible
alternative inspection and enforcement provisions that would leverage
our resources, be cost-effective, and achieve the public health goals
of the proposed rule (66 FR 1508 at 1523). We received four comments in
response to this request. These comments suggested third-party
inspections, training of FDA representatives by professional
organizations, and special recognition for accreditation.
(Response) We appreciate these helpful comments. Instituting a
third-party inspectional process would require additional resources
(for startup) and would also require that establishments have an
inspectional history. Because many HCT/P establishments do not have an
inspectional history, and because of resource limitations, we decline
to adopt this approach at present. However, we intend to reconsider the
idea in the future.
The suggestion that the agency and industry organizations partner
to train FDA representatives is also a good idea, and would represent
the continuation of existing FDA practice. To date, both EBAA and AATB
have participated in regional training courses for FDA representatives,
and we hope to continue this useful practice.
The suggestion that special recognition be given to establishments
that are accredited by a professional association has already been
implemented, in that we give establishments that are not accredited a
higher priority for inspection.
(Comment 153) One comment suggested amending Sec. 1271.400 to
require that FDA representatives be appropriately trained to examine
establishments that manufacture HCT/Ps according to the type of tissue
manufactured by the facility.
(Response) We decline to modify Sec. 1271.400 as suggested. FDA
representatives receive significant training on an ongoing basis, and
they will continue to do so.
(Comment 154) One comment expressed concern that inspections would
disrupt the practice of reproductive medicine.
(Response) FDA inspections involve document review; interviewing
employees; and physical inspection of equipment, products, labeling,
facilities, and operations. We conduct these activities in a manner
that is as unobtrusive as possible, and our expectation is that an
establishment will be able to conduct business as usual during the
course of an inspection. FDA has extensive experience conducting
inspections in a variety of clinical settings (e.g., hospital
bloodbanks performing time-critical activities and confidential donor
screening).
We recognize and understand that responsible personnel at times may
be involved in procedures that make them temporarily unavailable to the
FDA representative. In this situation, the FDA representative will
perform some other aspect of the inspection that does not require the
responsible person's presence until that person is again available to
be interviewed.
Inspections will focus on assessing compliance with applicable
requirements; to make this clear, we have added the word ``applicable''
to the first sentence of Sec. 1271.400(a). For example, the inspection
of an establishment that engages solely in processing would address
processing-related requirements, rather than donor testing and
screening. With respect to establishments that manufacture reproductive
HCT/Ps regulated solely under section 361 of the PHS Act and these
regulations, an inspection would be limited to issues of compliance
with the donor-eligibility requirements
[[Page 68644]]
contained in subpart C of this part, but would not consider compliance
with the requirements in subparts D and E.
(Comment 155) One comment stated that it is not appropriate for the
interpretation of SOPs and the validation of tissue banks to be subject
to the individual regulatory representative's judgment and that a more
standard approach is needed.
(Response) We agree with the concerns expressed by this comment,
and note that for several years FDA has used a standard approach for
tissue establishment inspections. Compliance Program 7341.002
(Inspection of Tissue Establishments) provides standard inspectional,
regulatory, and administrative guidance to all FDA representatives
involved in conducting inspections of human tissue establishments and
to management personnel who evaluate the results of those inspections.
FDA representatives evaluate the adequacy of a firm's SOPs and process
validation or verification on site. All observations they may record on
a Form FDA-483 are subject to further review by FDA management, to
ensure consistency with FDA regulations, before any regulatory action
is taken. The firm can respond to items recorded on the Form FDA-483
during the discussion with the FDA representative at the conclusion of
the inspection or subsequently in writing, if the firm wishes to do so.
(Comment 156) Two comments on proposed Sec. 1271.400(a) requested
that we provide from 1 to 5 days notice before an inspection.
(Response) FDA has tried a variety of announced and unannounced
inspection procedures in the past. Our current practice is generally
not to preannounce inspections because such a commitment affects the
overall productivity of field staff. An establishment must be in
compliance at all times, which should make it unnecessary to
preannounce an inspection for the establishment to ``prepare'' for an
inspection. For clarity, we have modified the language of the final
regulation to state that an inspection may be made with or without
``prior notification.''
(Comment 157) Proposed Sec. 1271.400(c) states that FDA's
representative will call upon the most responsible person available at
the time of an inspection. Three comments requested that this
representative be the executive director or a person functioning in
that position at the time of the inspection. One comment pointed out
that eye banks are usually small and that key staff may be out of the
bank performing other duties.
(Response) We decline to modify the regulation as requested. Firms
should have a plan in place to instruct their staff exactly who would
accompany an FDA representative in the absence of the most responsible
person. The FDA representative will determine whether or not a
meaningful inspection can be conducted, given the available personnel.
(Comment 158) Proposed Sec. 1271.400(c) also states that the FDA
representative conducting an inspection may question the personnel of
the establishment, as the representative deems necessary. One comment
objected to the exercise of our discretion, if unfettered, to question
any employee and stated that, historically, FDA has allowed companies
to designate spokespeople. Another comment asserted that FDA should
question a senior official who is well acquainted with the SOPs of the
facility (not just the most responsible person available).
(Response) It is agency practice for the FDA representative
conducting an inspection to observe and interview employees to
determine if they are performing their various functions in accordance
with the firm's current SOPs, to determine if activities are being
documented concurrently with the performance of each significant step,
and to evaluate if employees are properly trained and supervised. We
agree that it is a good idea to make a spokesperson available to
accompany the FDA representative and provide historical, statistical,
and administrative information about the company. All employees at an
establishment should be well acquainted with the SOPs related to their
work in that establishment.
(Comment 159) Under proposed Sec. 1271.400(d), FDA's
representative may review and copy any records required to be kept
under part 1271 and may take photographs or make videotapes. One
comment questioned FDA's intentions with respect to records of quality
assurance activities. Another comment asked that this section be
revised to exempt from FDA review records of management review, quality
audits, supplier evaluations, and other types of information (e.g.,
financial). One comment suggested new language limiting reproduction to
data that would relate to possible communicable disease transmission
and/or biologic dysfunction of tissue.
(Response) The FDA representative may review and copy any records
required to be kept under part 1271. Financial records and personnel
records are not required records under part 1271. Given the scope of
the requirements in part 1271 and their focus on preventing the
introduction, transmission, or spread of communicable disease, it is
unnecessary to limit Sec. 1271.400 as suggested. With respect to
quality audits, while some firms choose to provide quality audits to
FDA, FDA's current practice is generally not to request or copy the
actual quality audit reports except in certain limited circumstances
(FDA Compliance Policy Guide 130.300). However, the firm should have a
mechanism to demonstrate to the FDA representative that quality audits
are being performed and that corrective actions are being implemented
when problems have been identified.
(Comment 160) Several comments questioned the provisions of
proposed Sec. 1271.400(d) on photography and videos. Two comments
questioned the agency's authority to do so.
(Response) FDA's practice is to record images (e.g., by way of
photographs or videotapes) to accurately record the conditions in an
establishment. These tools may be employed as long as the inspection is
lawful. See United States v. Gel Spice Co., 601 F. Supp. 1214, 1220
(E.D.N.Y. 1985); United States v. Acri Wholesale Grocery Co., 409 F.
Supp. 529, 532-533 (S.D. Iowa 1976). Inspections conducted under
regulations issued under section 361 of the PHS Act are lawful.
However, we have modified the wording of Sec. 1271.400(d) to delete
the specific references to photographs and videotapes, and to state
instead that FDA's representatives may use other appropriate means to
record evidence of observations during inspections conducted under this
subpart.
FDA also has the authority to take samples to support observational
findings. To clarify this previously implied capability, we have added
to Sec. 1271.400(d) that FDA also may take samples.
4. Imports (Sec. 1271.420)
When an HCT/P is offered for entry, proposed Sec. 1271.420 would
require the importer of record to notify the director of the district
of the FDA having jurisdiction over the port of entry. The HCT/P would
be held intact until it is released by FDA.
We have made several revisions to Sec. 1271.420(a) and (b) for
clarity and for consistency with agency import policy. We have replaced
the phrase ``offered for entry'' with the more accurate phrase,
``imported or offered for import.'' Consistent with other agency
regulations, HCT/Ps ``imported or offered for import'' include, not
only
[[Page 68645]]
those HCT/Ps imported or offered for import into the United States for
use, storage, or distribution in the United States, but also those
imported or offered for import for transshipment through the United
States to another country, for future export, or for use in a United
States Foreign Trade Zone. (See, e.g., ``Prior Notice of Imported Food
Under the Public Health Security and Bioterrorism Preparedness and
Response Act of 2002,'' interim final rule, 68 FR 58974 at 58990 and
58991, October 10, 2003.)
We have specified in paragraph (a) that notification of the
director of the FDA district having jurisdiction over the port of entry
may occur either before or at the time of importation. The term ``port
of entry'' is defined in 19 CFR 101.1 as any place designated by
Executive order of the President, by order of the Secretary of the
Treasury, or by act of Congress, at which a Customs officer is
authorized to accept entries of merchandise, to collect duties, and to
enforce the various provisions of the Customs and navigation laws. To
make certain that importers understand our expectations (e.g.,
accompanying records required under Sec. 1271.55, and entry
information required by United States Bureau of Customs and Border
Protection), we have added the requirement that the importer of record
must provide sufficient information for FDA to make an admissibility
decision.
Finally, we have replaced the phrase in proposed paragraph (b),
``until it is released by FDA,'' with ``until an admissibility decision
is made,'' which more accurately reflects FDA's actions.
(Comment 161) One comment suggested the addition of language to
clarify that the regulation only applies to HCT/Ps ``intended for
clinical use.''
(Response) We agree that Sec. 1271.420 applies only to HCT/Ps
intended for clinical use, but we do not consider it necessary to
modify the regulation as suggested. The regulations in part 1271 do not
apply to establishments that use HCT/Ps solely for nonclinical
scientific or educational purposes (Sec. 1271.15(a)); moreover, Sec.
1271.3(d) defines an HCT/P as intended for implantation,
transplantation, infusion, or transfer into another human (i.e.,
clinical use).
(Comment 162) One comment requested an exemption for reproductive
HCT/Ps imported under the authority of the owner of the reproductive
materials.
(Response) We have modified Sec. 1271.420 to except from its
provisions reproductive HCT/Ps regulated solely under section 361 of
the PHS Act and the regulations in this part, and donated by a sexually
intimate partner of the recipient for reproductive use. (See Sec.
1271.420(c).)
(Comment 163) One comment asked about the relationship between the
proposed FDA inspection and inspections of hematopoietic stem/
progenitor cells currently performed by other agencies, such as the
Department of Transportation (DOT).
(Response) The inspection that FDA will conduct with respect to
imported HCT/Ps is distinct from inspections conducted by other
agencies. For example, DOT inspects for compliance with its labeling
and packaging regulations, whereas FDA inspects for compliance with the
regulations that require accompanying documentation and labeling
information about donor screening and testing.
(Comment 164) Proposed Sec. 1271.420(b) would require that an HCT/
P offered for import must be held intact until it is released by FDA.
Four comments on this provision raised strong objections to this
provision because of its potential adverse effect on imported
hematopoietic stem/progenitor cells. These comments asserted that any
delay is life-threatening and that these HCT/Ps should be immediately
cleared through customs.
(Response) Prior to infusion, recipients of peripheral blood stem/
progenitor cells undergo a myeloablative treatment regimen (i.e., high
dose chemotherapy and total body irradiation), which may have begun
before importation takes place. We agree with the comments' concerns
about the risk of delay in this situation and have accordingly revised
Sec. 1271.420. Section 1271.420(d) states that this section does not
apply to peripheral blood stem/progenitor cells regulated solely under
section 361 of the PHS Act and the regulations in this part, except
that paragraphs (a) and (b) apply when circumstances occur under which
such imported peripheral blood stem/progenitor cells may present an
unreasonable risk of communicable disease transmission, which indicates
the need to review the information referenced in paragraph (a). We
believe this provision affords access to peripheral blood stem/
progenitor cells and appropriate public health protection. We also
believe that situations in which information would be needed for review
under paragraph (a) will be rare or unlikely to occur. Because the
regulations in subpart F apply only to those HCT/Ps regulated solely
under section 361 of the PHS Act and the regulations in part 1271, the
exception in paragraph (d) affects only the subset of peripheral blood
stem/progenitor cells that are regulated in this way (e.g., those for
autologous use, or allogeneic use in a first-degree or second-degree
blood relative). In the event that issues arise with respect to imports
of peripheral blood stem/progenitor cells that are regulated as
biological drugs, and so are subject to the import provisions in
section 801 of the act (21 U.S.C 381), we would consider those issues
and take appropriate actions.
Consideration of these comments has led us to make a clarification
to Sec. 1271.420(b) that will apply to HCT/Ps that are not excepted
from these import provisions. Paragraph (b) states that an HCT/P
offered for import must be held intact by the importer or the
consignee, under conditions necessary to prevent transmission of
communicable disease, until an admissibility decision is made by FDA.
Under paragraph (b), the HCT/P may be transported under quarantine to
the consignee, while FDA reviews the documentation accompanying the
HCT/P. While the HCT/P is being held intact pending an admissibility
determination, under conditions that prevent the transmission of
communicable disease, the HCT/P cannot be manipulated in any way or
administered. If the FDA district office determines that the entry is
in compliance with the appropriate FDA regulations, the district office
will notify the importer of record. Under paragraph (a), the importer
can facilitate the entry process by notifying the FDA district office
before the actual import occurs.
3. Orders of Retention, Recall, Destruction, and Cessation of
Manufacturing (Sec. 1271.440)
Proposed Sec. 1271.440 describes the procedures FDA would use to
issue orders for the retention, recall, and destruction of HCT/Ps and
for the cessation of manufacturing operations. Under the proposed rule,
we would issue such orders upon an agency finding that an HCT/P or
establishment is in violation of the regulations in subparts C and D.
(Comment 165) Several comments asserted that these enforcement
actions are too dramatic and far-reaching. One comment argued that the
standard for taking these actions should be higher than mere CGTP
deficiencies and should involve imminent danger to public health. One
comment asserted that the regulation should define procedures to be
followed to protect the rights of the manufacturer to due process.
(Response) We disagree with the view that the proposed enforcement
procedures for noncompliance with CGTP regulations are too dramatic and
[[Page 68646]]
far-reaching. However, to address the concerns raised in these
comments, FDA has revised the proposed procedures for serving upon an
establishment an order to cease manufacturing. We have clarified that
an order to cease manufacturing will be effective immediately only when
the agency finds that there are reasonable grounds to believe that
there is a danger to health. In other circumstances, the order will be
effective after one of the following events, whichever is later:
Passage of 5 working days from the establishment's receipt
of the order; or
If the establishment requests a hearing in accordance with
paragraph (e) and part 16 (21 CFR part 16), a decision in, and in
accordance with, those proceedings.
FDA reiterates that, as stated in Sec. 1271.440(e), part 16
provides an opportunity to request a hearing concerning any matter
related to orders of retention, recall, destruction, and cessation of
manufacturing of HCT/Ps (Sec. 16.1(b)(2)). Part 16 permits FDA to
* * * take such action pending a hearing * * * as the
Commissioner concludes is necessary to protect the public health,
except where expressly prohibited by statute or regulation. A
hearing to consider action already taken, and not stayed by the
Commissioner, will be conducted on an expedited basis. (Emphasis
added). (Sec. 16.24(d))
If FDA issues an order to cease one or more steps in the
manufacture of an HCT/P, or issues an immediately effective order to
retain, recall, and/or destroy the HCT/P, and the Commissioner of Food
and Drugs (the Commissioner) does not stay the order upon receiving a
hearing request, FDA will provide an opportunity for an expedited
hearing. (See Sec. 1271.440(e).) As a technical amendment, we are
revising Sec. 16.1(b)(2) by adding Sec. 1271.440(e).
(Comment 166) One comment stated that these enforcement actions
should relate to a violation that may result in communicable disease
transmission.
(Response) We agree. This final rule, issued under the authority of
section 361 of the PHS Act, is intended to help prevent the
introduction, transmission, or spread of communicable disease. In
response to this comment, we have revised paragraph (a) to state that a
violative HCT/P includes an HCT/P that is infected or contaminated so
as to be a source of dangerous infection to humans. We have also
revised that paragraph in two other ways. Rather than simply referring
to an HCT/P or an establishment ``in violation of the regulations of
this part,'' the regulation now refers to
* * * reasonable grounds to believe that an HCT/P is a violative
HCT/P because it was manufactured in violation of the regulations in
this part and, therefore, the conditions of manufacture of the HCT/P
do not provide adequate protections against risks of communicable
disease transmission * * * or an establishment is in violation of
the regulations in this part and, therefore, does not provide
adequate protections against the risks of communicable disease
transmission.
(Comment 167) One comment asked for clarification of the term
``recall'' and suggested that ``notification'' might be a more
appropriate term in cases where the tissue has already been
transplanted.
(Response) Recall is an effective method of removing or correcting
consumer products that are in violation of laws administered by FDA
(Sec. 7.40(a)) (21 CFR 7.40(a)). Public notification is an important
part of a recall strategy (see 21 CFR 7.50), especially where physical
recall may be impossible or impractical. Guidelines on voluntary
recalls, including public notification, are set out in Sec. Sec. 7.40
through 7.59 (21 CFR 7.40 through 7.59). To the extent applicable, FDA
follows the same policy regarding notifications for mandatory recalls.
The term ``recall'' encompasses all elements of a recall strategy,
including notification, and no change to the rule is necessary.
(Comment 168) One comment noted that issuance of a recall or
destruction order creates a potential for raising public alarm, and
suggested the addition of a new paragraph requiring FDA to conduct a
followup investigation to determine the reasonableness and necessity of
its initial findings.
(Response) Concerns about raising public alarm upon issuance of an
order of recall or destruction are no greater than those associated
with ordered recalls of other regulated products. FDA does not intend
to pursue minor violations of part 1271, but would take regulatory
action in urgent situations to protect public health.
(Comment 169) One comment requested that FDA acknowledge the
limitations on corrective actions arising from the ownership status of
reproductive HCT/Ps.
(Response) We acknowledge the difficulty of the issues raised by
the comment, and we note that the provisions of Sec. 1271.440 provide
the agency with a range of enforcement options. For example, in some
instances a firm working with FDA could develop a recall strategy that
involved notification of affected parties. We have added paragraph (f)
to Sec. 1271.440, which states that FDA will neither issue an order
for the destruction of reproductive tissue, nor will it carry out such
destruction itself.
(Comment 170) One comment asserted that the order to cease
manufacturing under proposed Sec. 1271.440 violates the Due Process
Clause of the Fifth Amendment of the United States Constitution. Citing
Bell v. Burson, 402 U.S. 535, 542 (1971), the comment stated that,
under the Due Process Clause, before a State seeks to terminate an
entitlement (e.g., pursuit of a profession), it must provide notice and
opportunity for hearing appropriate to the nature of the case before
the termination becomes effective, ``except in emergency situations.''
The comment noted that although proposed Sec. 1271.440 permits a
facility to request a hearing, it does not provide a date on which a
hearing must be held or that a hearing must be held at all. This
provision also does not specify when a decision regarding the validity
of the order is to be made. The comment also observed that an order
under proposed Sec. 1271.440 could be of potentially infinite
duration, lasting as long as the agency believes that regulatory
compliance has not been achieved. Another comment also asserted that,
under American Bus Ass'n v. Slater, 231 F.3d 1 (D.C. Cir. 2000), this
provision exceeds FDA's statutory authority under section 361 of the
PHS Act and is invalid.
(Response) We disagree that Sec. 1271.440 is either
unconstitutional or outside the agency's statutory authority. Under
section 361 of the PHS Act, FDA is expressly authorized to enforce the
regulations it issues to prevent the introduction, transmission, or
spread of communicable disease through such means as inspection,
disinfection, sanitation, destruction, and ``other measures as in
[FDA's] judgment may be necessary.'' Orders to retain, recall, destroy,
or cease manufacturing are such other measures that we have concluded
are necessary to prevent communicable disease transmission. An order to
cease manufacturing does not terminate any interest or right related to
the pursuit of a profession. Such an order is intended for use in
situations when needed to prevent the spread of communicable disease
and is lawful so long as we provide an opportunity for a hearing ``at a
meaningful time and in a meaningful manner''; the hearing does not need
to be provided before the order issues. Armstrong v. Manzo, 380 U.S.
545, 552 (1965). To clarify this intent we have added language to Sec.
1271.440(a)(3) stating that an order to cease manufacturing until
compliance with the regulations in part 1271 has been achieved will
have immediate effect
[[Page 68647]]
only when FDA determines that there are reasonable grounds to believe
that there is a danger to health if the establishment continues to
manufacture (see Comment 165 of this document).
Under Sec. 1271.440 of this final rule, any person who receives an
order to cease manufacture will have the opportunity to request an
expedited hearing in accordance with part 16. We have also included a
statement in Sec. 1271.440(e) that FDA will provide an opportunity for
an expedited hearing on an order of cessation that is not stayed by the
Commissioner, when a request for a hearing is made in accordance with
part 16. We decline to provide a specific timeframe within which a
hearing must be held or within which a final decision must be rendered.
Each request for a hearing should be reviewed within the timeframe
appropriate for its specific circumstances. Some cases may need
resolution within a few days, while other, more complicated cases may
need more time to prepare for a hearing or to resolve the issues.
The comment's reliance on American Bus Ass'n v. Slater is
misplaced. In American Bus, the United States Court of Appeals for the
District of Columbia invalidated a Federal regulation that imposed
money penalties (a fine), which was not expressly authorized under the
Americans with Disabilities Act (ADA). The ADA explicitly provided for
injunctive or similar preventive relief and permitted civil proceedings
for money damages, but was silent about the imposition of money
penalties. The Court held that ``Congress unambiguously intended to
preclude [the Department of Transportation] from authorizing money
damages.'' (231 F.3d at 4.) By contrast, section 361 of the PHS Act
expressly authorizes FDA to enforce regulations using such means as
* * * inspection, fumigation, disinfection, sanitation, pest
extermination, destruction of animals or articles found to be so
infected or contaminated as to be sources of dangerous infection to
human beings, and other measures, as in [FDA's] judgment may be
necessary.
Like an order of fumigation, disinfection, and sanitation, an order
to cease manufacturing is a remedial action taken to put important
protections in place to prevent communicable disease transmission.
Unlike the fine in American Bus, it is not a punitive action.
As explained in the proposed rule and earlier in this response, it
is FDA's judgment that an order to cease manufacture of an HCT/P may be
necessary to prevent the introduction, transmission, or spread of
communicable diseases. Such an order would be issued where violations
created an urgent situation involving a communicable disease, because
an establishment is in violation of the regulations in this part and,
therefore, does not provide adequate protections against the risks of
communicable disease transmission (e.g., an establishment fails to test
donors in compliance with subpart C of part 1271). By contrast, we
would not issue an order to cease manufacture to punish an
establishment for past violations or violations that do not result in
an urgent situation.
(Comment 171) One comment asserted that the 5-day timeframe for
recall or destruction in proposed Sec. 1271.440(c) is inadequate.
(Response) FDA disagrees that 5 days is an insufficient timeframe.
However, we recognize that circumstances may exist or occur that would
require a time period other than the prescribed 5 working days for the
implementation of corrective action or recall and/or destruction of
HCT/Ps. Accordingly, we note that Sec. 1271.440(c)(1), which states
that ``[a] written order issued under paragraph (a)(1) of this section
will ordinarily provide that the HCT/P be recalled and/or destroyed
within 5 working days from the date of receipt of the order'' (emphasis
added), provides for circumstances where we determine that an alternate
timeframe is appropriate. The response to comment 167 describes the
recall guidelines. In the event that FDA issues an order of destruction
for HCT/Ps, such destruction would occur in accordance with applicable
local, State, and Federal laws (i.e., Environmental Protection Agency)
and under FDA supervision.
F. Economic Impacts
(Comment 172) Three comments suggested that the CGTP rule would
impose significant cost burdens on affected entities and that FDA has
significantly underestimated the compliance costs.
(Response) We disagree. Our analysis of economic impacts suggests
that the cost burden of the CGTP final rule will not be significant.
Further, these comments did not provide any data that refute FDA's cost
estimates or suggest alternative estimates of compliance costs.
(Comment 173) Three comments provided alternative estimates of the
financial impact/compliance costs of the CGTP rule for eye banks
ranging from $41,533 to $180,000 per year. One of these comments
suggested that the financial impact of the CGTP rule could force many
eye banks out of business.
(Response) FDA is unable to assess these comments as no information
or data were provided to support the estimates of financial impact/
compliance costs. The agency does not anticipate a significant economic
impact on the eye bank industry because nearly all eye banks are
believed to be following the current EBAA standards, which meet or
exceed most requirements of the CGTP rule. We therefore disagree that
the impact of the rule could force many eye banks out of business.
(Comment 174) One comment stated that most of the requirements of
the CGTP rule are not difficult to meet but will require additional
steps and documentation. The comment also suggested that all eye banks
will have to increase quality control efforts and hire a separate
quality control employee to track each provision of the program which
will be time consuming and expensive.
(Response) FDA realizes that the CGTP rule will impose some
additional financial burden on affected entities. However, eye bank
personnel who oversee the quality assurance program currently required
under EBAA standards perform duties similar to those required under the
CGTP final rule. Therefore, the agency does not believe that a separate
quality control employee will be required. Further, FDA's analysis of
economic impacts suggests that these requirements will not be overly
time consuming or expensive.
(Comment 175) One comment indicated that all eye banks would have
to add or revise a procedure to handle complaints and that FDA's
estimate of two complaints per year is too low, especially for large
volume eye banks.
(Response) The agency recognizes that some eye banks may experience
a greater number of complaints. However, this estimate is designed to
be representative of the number of complaints handled annually by a
typical entity. The comment did not provide an alternative estimate of
the number of complaints reported annually.
(Comment 176) One comment suggested that FDA (implicitly) assumed
that all primary graft failures will be prevented under the rule, and
provided no evidence to support any reduction in re-transplants
required. Two comments suggested that FDA misinterpreted the results of
a study of eye banks by Wilhelmus, et al. (1995), and failed to
acknowledge the author's conclusion that no clearly defined factor
accounted for most cases of primary graft failure. Two comments
suggested that FDA has
[[Page 68648]]
overstated both the risk of primary corneal graft failure and the
benefits of the rule, and that it is unlikely that CGTPs will have a
significant impact.
(Response) The analysis of economic impacts has been revised to
eliminate the implicit assumption that all cases of primary corneal
graft failure will be prevented by the CGTP rule. The evidence on the
risk, incidence and causes of primary graft failure is limited, and
mostly mixed and inconclusive. While no clearly defined factor accounts
for most cases of primary corneal graft failure, storage conditions
(i.e. preservation media and duration) are identified in a number of
studies as a possible explanatory factor, and are regulated under the
CGTP final rule. The possibility that implementation of CGTPs may
reduce the risk of primary corneal graft failure and generate public
health benefits cannot be ruled out.
(Comment 177) One comment noted that a study reported in the
journal Cornea (1994), found that eye bank-related factors were not
important in explaining primary corneal graft failure despite the
author's initial suspicions and hypothesis. Thus, FDA's cost savings
estimate is greatly exaggerated.
(Response) FDA has revised its estimate of the benefits of
implementing the CGTP final rule for eye banks in response to comments
received, and based on additional and more recent information. However,
the study cited in the comment also reports, ``interpretation of the
results of this study is limited by the small sample size, which may
preclude the detection of some associations,'' and, ``(m)issing data
for relevant variables, most notably eye bank factors, make
interpretation of related results difficult.'' (emphasis added). The
comment does not provide any alternative estimates of benefits.
(Comment 178) One comment indicated that, in 1999, primary corneal
graft failure occurred in only 42 cases and intraocular infection in
only 14 cases out of approximately 40,000 transplants. Another comment
noted that the 1994 Agency for Health Care Policy Research data
referenced by FDA suggests 7,443 corneal transplants were performed
that year, while the actual number reported to EBAA was 35,022.
(Response) FDA has revised the analysis of impacts of the CGTP
final rule to address these comments and to incorporate the most
current information available.
(Comment 179) One comment objected to the use of 1996 labor
statistics to derive tissue bank employee wages.
(Response) The agency has updated the wage estimates used in the
analysis of impacts of the CGTP final rule to reflect current labor
costs.
(Comment 180) One comment objected to FDA's identification of the
laboratory director and medical director as the same individual.
(Response) According to industry consultants, the medical director
often serves as the laboratory director, particularly in small tissue
facilities. Since all 134 eye banks, and a majority of facilities in
the other HCT/P industry sectors, are believed to meet the criteria
characterizing small entities in the relevant industry sector, FDA
viewed this as an appropriate simplifying assumption.
(Comment 181) One comment noted that FDA did not add clerical
expense for the revision of minor policies and procedures.
(Response) We agree that clerical expense may be incurred in the
revision or preparation of a minor procedure. Therefore, FDA has added
clerical expense for both the revision and preparation of a minor
procedure to the cost impact estimates for the CGTP final rule.
(Comment 182) One comment objected to FDA's bundling of the cost of
preparing or revising procedures with training costs.
(Response) As procedural changes generally necessitate the training
or retraining of employees, the agency views such bundling as both
logical and reasonable.
(Comment 183) One comment suggested that several sections of the
rule lack cost estimates because no basis for predicting such costs
exists.
(Response) Some requirements reviewed in the analysis of economic
impacts show no costs because they are expected to impose no new
financial burden on affected entities, not because there is no basis
for predicting these costs. More specifically, no cost estimate is
provided for a section or provision of the CGTP rule if analysis showed
the requirement: (1) Does not apply, (2) has no new cost impact, or (3)
is met by another subsection of the rule.
(Comment 184) One comment argued that FDA has underestimated the
compliance costs for stem cell facilities, and presents alternative
compliance cost figures based on FDA's analysis of economic impacts.
(Response) The compliance cost figures provided in the comment are
not comparable to FDA's cost estimates for a number of reasons. First,
the cost estimates provided in the comment fail to recognize and
reflect an important difference between one-time costs and annual or
recurring costs. Second, FDA's cost estimates are weighted based on the
proportion of entities in each sector of the HCT/P industry estimated
to be noncompliant with individual provisions of the CGTP rule. These
noncompliance rates (weights) are based on information obtained from
industry professional associations and communication with industry
consultants. The cost estimates in the comment are not adjusted to
reflect the estimated rates of industry noncompliance.
(Comment 185) One comment noted that the Foundation for the
Accreditation of Cellular Therapy (FACT) is already inspecting to
standards that are very close to the proposed regulations.
(Response) FDA does not dispute this, but following the FACT
standards is voluntary, and evidence does not show that 100 percent of
entities in the stem cell sector are currently following these
standards. FDA believes that mandatory requirements are necessary to
adequately protect public health and safety.
(Comment 186) One comment suggested that the requirement for
oversight and audits would impose costs that might significantly reduce
the number of participants in the National Marrow Donor Program.
(Response) We disagree. With respect to provisions governing
oversight and audits, the agency notes the following. Section
1271.160(c) is expected to impose no new financial burden on affected
entities. Section 1271.160(d) is expected to impose an additional
burden of $228 on entities currently following FACT standards, and
$1,140 in additional costs on firms not following these standards.
Thus, the maximum burden on any one firm of these provisions is $1,140
per year. The agency does not view this as a significant cost burden,
nor do we believe that these provisions will significantly reduce the
number of donor centers participating in the National Marrow Donor
Program.
(Comment 187) One comment expressed serious concerns and
reservations regarding the accuracy of FDA's estimates of the risks
associated with hematopoietic stem/progenitor cell transplants, and the
costs and benefits of the proposed rule. Two comments argued that the
costs for a bone marrow transplant are much different in 2001 than they
were in 1994, and that much of the cost is for supportive care and not
due to contamination of the graft. Therefore, the benefits of the rule
are overstated.
(Response) FDA has revised the analysis of impacts for stem cell
facilities to reflect the most recent
[[Page 68649]]
available risk and cost information. The agency points out that the
cost for a bone marrow transplant was presented in the analysis of
impacts of the proposed rule for illustrative purposes only, and was
not used directly in generating an estimate of the benefits of the CGTP
rule for stem cell facilities.
(Comment 188) One comment suggested that the impact of the software
validation requirements on small tissue facilities would be beyond the
means of many and could force them out of business. The comment
suggested that Sec. 1271.160(e) be amended to require software
validation only if it is relied upon as the sole source of data for
quality-related decisionmaking.
(Response) With respect to computer software validation FDA
assumed: (1) None of the affected entities currently validate custom
software, (2) 10 percent of all facilities in each sector have
developed custom software requiring validation, and (3) validation of
custom software will require 60 hours of laboratory supervisor time
($36 per hour, total cost = $2,160 per affected entity). We have
modified Sec. 1271.160(e) to indicate that either validation or
verification can be performed, whichever is appropriate. Verification
is less burdensome.
(Comment 189) One comment suggested that annual human heart valve
allograft distribution is likely ten-fold lower (5,000-6,000) than the
61,000 annually referenced in the preamble and, further, that fewer
than 10 infections per year are caused by contaminated valves since
direct reports by implanting surgeons suggests less than 1 per year.
(Response) FDA has revised the analysis of impacts of the CGTP
final rule to reflect both information provided in the comment and
information on the risks associated with human heart valve allograft
reported in the clinical literature.
(Comment 190) One comment expressed concern that the CGTP rule will
be particularly onerous on small business, and would like FDA to ensure
that they are not creating artificial market barriers by implementing
the rule.
(Response) Nearly all facilities in the HCT/P industry are
recognized as small entities and most would be similarly affected by
the rule. Further, the requirements of the CGTP final rule are largely
met, and in some cases exceeded, by the voluntary standards firms are
required to meet to gain accreditation by professional associations in
their respective HCT/P industry sectors. Finally, the agency's analysis
suggests that the cost burden of the CGTP rule will not be significant
(expressed as a percentage of average annual firm revenues) and,
therefore, should not constitute a market barrier to small business.
(Comment 191) One comment noted that FDA chose not to certify that
the rule would not have a significant economic impact on a substantial
number of small entities. The comment suggested that FDA should
increase its outreach to small entities in an effort to obtain the
information necessary to fully assess the rule's impacts before
finalization.
(Response) FDA's analysis of economic impacts is based on:
Information obtained under the registration final rule; administrative
data on the number of facilities within each industry sector; and the
number of entities accredited by various industry associations. FDA
also obtained information from individual experts identified through
contact with the various industry professional associations. We
explicitly recognized the uncertainty of our estimates with respect to
the number of facilities in each sector, degree of compliance with
current industry standards and impact of the rule on affected entities.
In the proposed rule, FDA requested detailed industry comment regarding
our analysis of impacts, and data sources and underlying assumptions.
Finally, the agency made presentations at the annual conferences of
several industry professional associations, and held individual
meetings with many of these groups at their request. We believe this
represents a significant level of outreach and information gathering
effort.
(Comment 192) One comment suggested that, upon publication of the
final rule, FDA should address all comments received regarding small
business impacts and provide an assessment of small business revenues
that are likely to be affected.
(Response) FDA has provided responses to all comments received in
the preamble to the final rule. A comprehensive assessment of the
rule's effects on small business entities is provided in the analysis
of economic impacts as required under the Regulatory Flexibility Act.
(Comment 193) One comment noted that if FDA significantly
underestimated firm revenues, the rule's resultant costs to firms could
be far greater than those estimated.
(Response) FDA believes that if average firm revenues were
significantly underestimated, then the rule's resultant costs would
appear greater (as a percentage of revenues) than they really are,
thereby overstating the impact of the rule. We believe the comment
intended to address the effect of FDA having overestimated firm
revenues. In this case, compliance costs (expressed as a percentage of
revenues) would appear smaller than they really are, thereby
understating the impact of the rule.
Nevertheless, FDA's estimates of average annual revenues were
obtained from a variety of sources including a published study of the
tissue banking industry, information obtained from industry consultants
and other published data sources. In the CGTP proposed rule, FDA
requested detailed industry comment on the distribution of firm
revenues in the HCT/P industry, and also on our estimates of average
revenue per firm. We received no detailed information in response to
our request, and no comments provided alternative estimates of annual
firm revenues.
(Comment 194) One comment suggested that Sec. 1271.155 of the rule
seems to allow all businesses affected by the regulation to seek an
exemption or alternative from the requirements of the rule.
(Response) While an exemption from or an alternative to a
particular provision of the rule may be requested by any business, the
granting of such a request is by no means assured. The entity
requesting an exemption or alternative must demonstrate that the
exemption is justified based on scientific data and other evidence, and
that the alternative satisfies the purpose of the requirement. Section
1271.155 does not provide a mechanism by which all businesses may
become generally exempt from compliance with the CGTP rule.
(Comment 195) One comment assumes that Sec. 1271.155 is FDA's
attempt to comply with section 603(c) of the Regulatory Flexibility
Act, which requires agencies to identify any significant alternatives
available to small entities in their initial regulatory flexibility
analysis.
(Response) This assumption is incorrect. The agency has written the
CGTP rule broadly so as to allow comprehensive regulatory oversight of
the diverse HCT/P industry. Section 1271.155 is designed to provide
some flexibility, recognizing that an exemption from, or alternative
to, a specific provision may be appropriate given the unique properties
of a particular HCT/P.
(Comment 196) One comment noted that the FDA estimates between 75
percent and 100 percent of affected entities are already compliant with
the provisions of the CGTP rule, and
[[Page 68650]]
questions whether the rule will create another layer of unnecessary
recordkeeping and training requirements for the affected firms.
(Response) Because compliance with current voluntary industry
standards is less that 100%, FDA believes the CGTP rule is the best way
to establish a consistent standard of safety for marginal firms not
currently following voluntary industry standards and guidelines, and to
protect public health and safety. We believe that the recordkeeping and
training requirements are necessary to achieve the desired public
health and safety goals.
(Comment 197) One comment expressed concern that the ultimate
responsibility is placed in the hands of the firm distributing the HCT/
P, while other firms will also be involved in manufacturing. Noting
that the distributor is responsible for maintaining documentation from
all other companies involved in manufacturing the HCT/P, the comment
expressed concern that this will place an unacceptable burden on small
entities, and suggests that, to minimize this burden, FDA should adopt
an alternative approach, discussed in the proposed rule, using a
cascading set of responsibilities.
(Response) Before Comment 28, we set out a table to assist
establishments in understanding their responsibilities when multiple
establishment are involved in manufacturing an HCT/P. At Comments 28
through 35 we discuss the allocation of responsibilities in Sec.
1271.150(c) and 1271.265. FDA believes that this approach is largely
consistent with the cascading set of responsibilities described in the
comment and discussed at Comment 31. Both approaches place
responsibility on each establishment that performs manufacturing
functions, with the establishment that makes the product available for
distribution ultimately responsible for ensuring that the manufacturing
and tracking records for an HCT/P demonstrate that it has been
manufactured and tracked in compliance with the requirements of this
subpart and subpart D.
IV. Effective Date of 21 CFR Part 1271 and Applicability of 21 CFR Part
1270
A. Effective Date for Part 1271
This final rule is effective May 25, 2005. All HCT/Ps recovered on
or after the effective date must be in compliance with applicable
requirements in part 1271.
As of the effective date, establishments that manufacture HCT/Ps
defined in Sec. 1271.3(d) that are regulated solely under the
authority of section 361 of the PHS Act (as described in Sec. 1271.10)
must comply with all applicable requirements in part 1271, whether or
not the HCT/P enters into interstate commerce.
The regulations under 21 CFR 207.20(f) and 807.20(d) require
establishments that manufacture HCT/Ps that are regulated as drugs,
devices, and/or biological products under section 351 of the PHS Act
and/or the act to register and list their HCT/Ps following the
procedures in subpart B of part 1271. Section 1271.21 requires HCT/P
establishments to register and list every HCT/P that the establishment
manufactures within 5 days after beginning operations, or within 30
days of the effective date of the registration regulation, whichever is
later. HCT/P establishments that manufacture HCT/Ps subject to
investigational new drug (IND) or investigational device exemption
(IDE) provisions are not required to register and list their HCT/Ps
until the investigational HCT/P is approved through a Biologics License
Application (BLA), a New Drug Application (NDA), or a Premarket
Approval Application (PMA); or cleared through a Premarket Notification
Submission (510(k)).
As required by Sec. Sec. 210.1(c), 211.1(b), and 820.1(a),
establishments that manufacture HCT/Ps that are regulated as drugs,
devices, and/or biological products under section 351 of the PHS Act
also must comply with the requirements in subparts C and D of part 1271
in addition to all other applicable regulations.
B. Applicability of Part 1270
The retrospective application of part 1271 to human tissue, defined
in Sec. 1270.3(j), recovered before the effective date of the final
rule would be overly burdensome and impractical. Therefore, we are not
concurrently revoking part 1270 with the effective date of part 1271 as
stated in the proposed rule (66 FR 1508 at 1524). However, we intend to
revoke part 1270 in the future when we are confident that there is no
human tissue regulated under 1270 available for use.
Part 1270 applies now only to human tissue defined in Sec.
1270.3(j) and recovered before May 25, 2005. We have amended Sec.
1270.3(j) to implement this provision. Products that meet the
definition of HCT/P in Sec. 1271.3(d) that are recovered before May
25, 2005, and that have been regulated as drugs, devices, and/or
biological products under section 351 of the PHS Act and/or the act
will continue to be subject to the applicable requirements for drugs,
devices, and/or biological products.
V. Analysis of Economic Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is consistent with the principles identified in
Executive Order 12866. The Office of Management and Budget (OMB) has
determined that this final rule is a significant regulatory action as
defined by the Executive order and so is subject to review.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The majority of establishments within the HCT/P
industry that will be affected by this final rule can be classified as
small business entities, and a number of these establishments will
incur new costs. Because of the limited information with which to
characterize the current good tissue practice at many of these
establishments, and thus the increased effort required to meet the
standards of the final rule, the cost impact on small business entities
is uncertain. Therefore, the following analysis, along with other
relevant sections of this preamble, represents FDA's final regulatory
flexibility analysis.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing
* * any rule that includes any Federal mandate that may result
in the expenditure by State, local and tribal governments, in the
aggregate, or by the private sector, of $100,000,000 or more
(adjusted annually for inflation) in any one year.
The current threshold after adjustment for inflation is $ 110
million. FDA does not expect this final rule to result in any 1-year
expenditure that would meet or exceed this amount.
Based on the following economic analysis, FDA estimates that the
total one-time costs to comply with this final rule will be
approximately $6.91
[[Page 68651]]
million, and that the total annual or recurring costs will be about
$7.13 million. These figures imply a total annualized cost estimate for
the CGTP final rule of approximately $7.94 million to $8.11 million.
The average annualized cost of CGTPs per affected small entity,
expressed as a percentage of average annual revenue, ranges from 0.6
percent to 3 percent. This range of small entity impacts reflects
uncertainty with respect to the current practices of affected entities
and differences in the impact of the CGTP final rule across the various
sectors of the HCT/P industry.
A. Risks Associated with HCT/Ps
FDA has conducted an extensive search for information with which to
quantitatively assess and characterize the risks associated with HCT/
Ps, but has found very little information available. The primary reason
for this lack of information is the absence of mandatory reporting
requirements for adverse events, including the incidence of
communicable disease transmission and graft failure, associated with
HCT/Ps. The CGTP final rule will help to improve upon this situation by
requiring entities that make HCT/Ps available for distribution to
report to the agency any adverse reaction that meets the requirements
of Sec. 1271.350(a), as well as reports of HCT/P deviations required
in Sec. 1271.350(b). This information will be highly valuable to the
agency in identifying and addressing areas of existing and emerging
public health and safety risks associated with HCT/Ps. The available
information regarding the risks associated with HCT/Ps known to the
agency is summarized in the discussion that follows. Specific examples
of risks associated with individual HCT/Ps are discussed in detail in
section C of this analysis of economic impacts.
The HCT/P industry is currently growing and evolving rapidly. Since
the CGTP proposed rule was published in January 2001, there have been
significant increases in both the number of tissue donors and
manufacturing establishments, as well as the number of HCT/Ps
processed, distributed, and transplanted. Estimates of the current
number of establishments in each sector of the HCT/P industry are
presented in table 1b, along with recent information reflecting the
approximate numbers of tissue donors and tissue products produced
annually.
Table 1b.--Numbers of HCT/P Establishments, Tissue Donors and Products Produced By Major Industry Sector
----------------------------------------------------------------------------------------------------------------
Number of Products
Type of HCT/P Number of Establishments\1\ Number of Donors Produced Annually
----------------------------------------------------------------------------------------------------------------
Eye Tissue\2\ 134 47,796 94,186
----------------------------------------------------------------------------------------------------------------
Conventional Tissue\3\ 166 20,000 750,000
----------------------------------------------------------------------------------------------------------------
Hematopoietic Stem/Progenitor 425 5,700 6,031
Cells\4\
----------------------------------------------------------------------------------------------------------------
Reproductive Tissue\5\ 510 4,640 122,200
----------------------------------------------------------------------------------------------------------------
\1\ Information obtained under the registration and listing final rule or provided by HCT/P industry
professional associations. See section B.1 and table 3 of this analysis of economic impacts for additional
details.
\2\ EBAA, 1999.
\3\ AATB, 1999.
\4\ AABB/FACT, 1999.
\5\ The American Society of Reproductive Medicine (ASRM), 1999.
One source of potential communicable disease transmission risk
associated with HCT/Ps is a lack of standard quality assurance
procedures and recordkeeping requirements intended to ensure compliance
with such procedures. Currently, in every major sector of the HCT/P
industry, professional organizations have in place standards specifying
appropriate operating procedures that establishments should follow to
ensure that the products produced are safe for use and of high quality.
Individual establishments in the various sectors of the HCT/P industry
may also apply for accreditation through these professional
organizations, which periodically inspect member establishments to
ensure that they are following the appropriate standards. However, as
discussed in detail in V.B and C of this economic analysis, following
industry standards and seeking accreditation through the professional
organizations is voluntary, and the rates of compliance and
accreditation within the various sectors of the HCT/P industry vary
significantly. Furthermore, there are currently no comprehensive
monitoring or enforcement mechanisms governing establishments that
choose not to follow voluntary industry standards or seek
accreditation, and that may produce and distribute for use HCT/Ps that
may present a serious threat to public health and safety.
The agency is aware of numerous reports of adverse health events
and several patient deaths that have been linked to HCT/Ps.
Transplantation of tissue has resulted in transmission of viral,
bacterial, fungal, and other diseases, although such instances are
rare. Some of these adverse events have been associated with HCT/Ps
produced by large entities that do not follow voluntary industry
standards and are not accredited by their respective professional
associations. In March of 2002, the CDC published the results of their
investigation of 26 reported cases of tissue allograft-associated
infection, one of which resulted in the death of the patient (Ref.1).
The CDC concluded that of the 26 reported cases, ``14 (were) associated
with a single tissue processor,'' and further suggested that their
* * * findings * * * have important implications for patient
safety and indicate that current federal regulations and industry
standards on processing and quality control methods need to be
enhanced and implemented to prevent * * * allograft-associated
infections.
Problems due to inadequate product processing and quality controls,
contributing to post-operative infection and/or graft failure, are one
category of the many potential causes of the reported adverse health
events associated with HCT/Ps. Implementation of the CGTP final rule,
by establishing an enforceable set of product quality assurance
procedures and standards, is expected to reduce the risk of
communicable disease transmission as well as the incidence of other
types of adverse health events associated with HCT/Ps.
[[Page 68652]]
Recent information on the number of infections following surgery,
incidence of communicable disease transmission, graft failures, and
additional surgeries required as a result for various types of HCT/Ps
is summarized in table 2 of this document. Although these numbers
suggest that the risks associated with the various types of HCT/Ps are
relatively low, it is important to consider the limitations of these
data.
It is highly unlikely that the available data provide an accurate
accounting of the true risks associated with HCT/Ps because there is
currently no mandatory reporting requirement for adverse health events,
including communicable disease transmission and graft failure,
associated with tissues. Thus, the case reports that are known to the
agency are almost certainly not representative of the risks associated
with HCT/Ps, because a significant number of these events may go
unreported. In the eye banking industry, the EBAA requests that adverse
event information be voluntarily reported, but acknowledges that not
all members provide this information. The AATB does not request
information on the number of adverse events reported to accredited
conventional tissue banks. Further, the New York Department of Health
indicated that they know of no entity that collects information on
graft failures or repeat surgeries due to complications associated with
musculoskeletal tissues. Thus, despite a significant effort on the part
of the agency, very little information with which to identify and
quantify the risks associated with various types of HCT/Ps was found.
In summary, the limited information presented in this analysis of
impacts is not likely representative of the true risks associated with
HCT/Ps, because no mandatory adverse event reporting requirements
exist, the information that is available is reported voluntarily and,
in some sectors of the tissue industry, the necessary information is
not available because it is not collected by any source.
Table 2.--Summary of Available HCT/P Risk Information\1\
----------------------------------------------------------------------------------------------------------------
Number of Number of Graft Additional
Type of HCT/P Number of Transplants Infections Failures Surgeries Required
----------------------------------------------------------------------------------------------------------------
Ocular (Eye)\2\ 33,035 9 37 37
----------------------------------------------------------------------------------------------------------------
Musculoskeletal\4\ NDF\3\ 52 NDF 4
----------------------------------------------------------------------------------------------------------------
Heart Valve Allografts\5\ 4,000 26 41 41
----------------------------------------------------------------------------------------------------------------
Hematopoeitic Stem/ 18,123 (in 1997) NDF NDF NDF
Progenitor Cells;
Peripheral Blood\6\
----------------------------------------------------------------------------------------------------------------
Hematopoeitic Stem/ 2000 (from 1988 to NDF NDF NDF
Progenitor Cells; Cord 2002, inclusive)
Blood\7\
----------------------------------------------------------------------------------------------------------------
\1\ Annual data except as noted otherwise.
\2\ EBAA, 2001 Statistical Report.
\3\ NDF: Denotes No Data Found or Available.
\4\ AATB, 2001.
\5\ FDA, CDRH, Office of Surveillance and Biometrics, 2001.
\6\ Transfusion, vol. 42, 2002.
\7\ Current Opinion in Oncology, vol. 14, No. 2, March 2002.
The agency obtained additional information on the risks associated
with HCT/Ps by reviewing establishment inspection reports (EIRs) filed
by agency inspectors. The following information summarizes some of the
inspector's observations made in the course of their inspections of
establishments processing human tissues. This information was obtained
from a manual search of approximately 150 EIR reports filed in 2000 and
2001, and reflects observations from 15 of the 150 EIRs that were not
citable under 21 CFR part 1271, but would be citable under 21 CFR part
1271. As such, this discussion is not a comprehensive assessment of the
results of FDA inspections of HCT/P processing establishments. Instead,
it is intended to provide an illustration of the type of processing and
quality assurance problems that currently exist in the tissue industry,
and that would be addressed through implementation of the CGTP final
rule.
Failure to validate procedures for various stages of HCT/P
processing was identified in 8 of the 15 reports. More specifically,
observations included failure to validate procedures for the prevention
of infectious disease contamination and cross-contamination during
processing, and failure to prepare written procedures for designating
and identifying quarantined tissue. Failure to document the destruction
or disposition of human tissue, failure to designate and identify the
person responsible for making the determination that an HCT/P was
suitable for transplantation, and/or failure to accompany quarantined
tissue with records indicating the tissue was not determined to be
suitable for transplantation were identified in 5 of the 15 reports.
Failure to maintain adequate records of each significant step in the
processing of human tissues and/or performance of infectious disease
screening, as well as failure to maintain accurate records thereof,
were cited in 6 of the 15 inspection reports. Finally, failure to
prepare and follow written procedures for all significant steps for
obtaining, reviewing, and assessing the relevant medical records of
tissue donors, or failure to provide along with dispensed tissue a
summary of the records of the donor eligibility determination, were
cited in 7 of the 15 inspection reports. Although this summary of
examples of FDA inspector's observations related to provisions under
part 1270 is not comprehensive, it does indicate the type of procedures
and quality control problems observed in HCT/P processing
establishments in 2000 and 2001. Each example could have an adverse
impact on the HCT/P, and all are further addressed by various
provisions of the CGTP final rule.
To gain additional insights into the risks associated with HCT/Ps,
FDA also reviewed reports of adverse events associated with human
tissue products submitted through the MedWatch
[[Page 68653]]
system. Between 2000 and 2001, FDA received 21 voluntary MedWatch
reports of problems associated with HCT/Ps. Because there is no
mandatory requirement for reporting adverse reactions involving tissue
products, the extent to which these reported events are representative
of the risks associated with HCT/Ps during this period is unclear. It
is likely, however, that a significant number of adverse events
associated with HCT/Ps are unreported under the current voluntary
MedWatch system. The 21 reported adverse events included: 4 patient
deaths (3 of which were probably due to underlying disease and not
directly attributable to HCT/Ps); 5 life-threatening situations; 5
surgical or other medical interventions; 2 cases of permanent
disability; 9 additional hospitalizations; and 7 cases of mold
contamination of HCT/P packaging material. Many of the potential
underlying causes of these voluntarily reported adverse events are
addressed by various provisions of the CGTP final rule, implementation
of which is expected to reduce communicable disease transmission risks
and the number of adverse events associated with the various types of
HCT/Ps.
B. Estimated Cost Impact
With the CGTP final rule, FDA is furthering completion of the set
of proposals that represent a comprehensive new system for regulating
the rapidly evolving HCT/P industry. Manufacturers of HCT/Ps may need
to make certain changes to their operations to comply with this rule,
such as creating new procedures revising existing procedures, and
providing additional documentation. This final rule, in its entirety,
affects several types of entities involved in the manufacture of HCT/Ps
including eye banks, conventional tissue banks and establishments
processing hematopoietic stem/progenitor cells. As explained elsewhere
in this preamble, Assisted Reproductive Technology (ART) establishments
and semen banks are subject only to the inspection and enforcement
provisions of the CGTP final rule as they apply to donor eligibility
requirements under subpart C. As such, reproductive tissue
establishments will be only minimally affected by this final rule.
Information obtained under the registration final rule forms the
basis for FDA's estimates of the number of affected eye banks and
conventional tissue banks. The agency's estimates of the number of
affected eye banks, hematopoietic stem/progenitor cell establishments,
ART establishments, and semen banks rely heavily on information
obtained from various professional organizations associated with the
HCT/P industry. Where good statistical data are not available, FDA's
cost impact estimates have incorporated the quantitative judgments of
individual experts identified through contacts with HCT/P industry
professional associations. Because of the lack of comprehensive data
with which to characterize patterns of current practice within each
affected industry sector, and the importance of this data for
development of an accurate assessment of cost impact, FDA requested
detailed industry comment on the number of establishments involved in
the manufacture of HCT/Ps, and the net change in quality assurance
efforts needed for those establishments to comply with the CGTP
proposed rule. To the extent possible, this information has been
incorporated into FDA's analysis of the economic impact of this final
rule.
1. The Number and Type of Entities Affected
The analysis of the economic impact of this final rule is organized
around four major subgroups: Eye banks, conventional tissue banks,
hematopoietic stem/progenitor cell establishments, and reproductive
tissue establishments. The number of establishments and the percentage
of establishments that follow current industry standards are summarized
in table 3 of this document. In estimating net new costs for eye banks,
conventional tissue banks and hematopoietic stem/progenitor cell
establishments, it is critical to account for establishment compliance
with existing industry standards. In a number of these HCT/P sectors,
current industry standards for many manufacturing operations meet or
exceed the specifications in this final rule. Establishments following
those standards will experience very little impact in complying with
the new FDA standards.
As presented in table 3 of this document, FDA has a record of 134
registered establishments listing eye tissue including 96 eye banks,
approximately 93 of which are currently accredited by the EBAA.
According to industry experts, virtually all operating eye banks
currently comply with EBAA medical and procedural standards for quality
control. For affected eye banks, the incremental costs associated with
this final rule result from additional quality assurance steps and
process documentation as specified under the CGTP final rule.
FDA has a record of 166 registered tissue banks involved in the
manufacture of other conventional HCT/Ps, e.g., skin allografts, bone
allografts, fascia, tendons and ligaments (hereafter referred to as
``conventional tissue banks''). The AATB lists approximately 75
accredited tissue banks and projects another 40 to 60 members
unaccredited. Industry sources report that approximately 75 to 80
percent of these establishments currently follow the voluntary
standards established by the AATB. For these establishments, there will
be some additional cost associated with review of this final rule and
with alignment of their current SOPs with FDA's new requirements. There
may also be some additional recurring cost, where documentation and
quality control required under the CGTP final rule extend beyond
current practice. For the remaining 20 to 25 percent of establishments
not following the AATB standards, the cost of compliance will be
somewhat higher. These establishments may need to establish more formal
procedures and quality control measures, and may need to devote
additional staff hours to performing these procedures and processing
controls.
Establishments that produce hematopoietic stem/progenitor cells
from peripheral blood or from umbilical cord blood will also be
affected by this final rule. FDA finds that available data with which
to estimate the number of peripheral blood stem/progenitor cell (PBSC)
establishments and evaluate current practices are quite limited, and
the actual number of PBSC establishments may range from 200 to 400. As
of April 2002, CBER has a record of 178 voluntarily registered
establishments listing ``stem cell'' as a type of product or
establishment. The National Marrow Donor Program (NMDP), which includes
establishments that recover PBSCs, lists approximately 92 donor centers
and 113 collection centers. Approximately 150 establishments involved
with PBSCs are currently accredited by the AABB and an estimated 107
are accredited by the Foundation for the Accreditation of Cellular
Therapy (FACT). Industry sources estimate that 80 of these
establishments are seeking dual AABB/FACT accreditation, suggesting an
unduplicated count of approximately 200 PBSC establishments assumed to
be accredited by AABB and/or FACT. However, the number and
manufacturing practices of nonaccredited establishments are unknown.
The International Bone Marrow Transplant Registry/Autologous
[[Page 68654]]
Blood and Marrow Transplant Registry (IBMTR/ABMTR) estimates that the
total number of peripheral blood or bone marrow establishments may be
as high as 400 (e.g., 200 more than the number estimated to be
accredited by AABB and/or FACT), but the number of IBMTR/ABMTR-
estimated establishments that actually process peripheral blood (as
opposed to bone marrow) is uncertain. For the purposes of this
analysis, FDA has assumed that 400 PBSC establishments will be affected
by this final rule.
Although there is no single national organization that keeps track
of the number of establishments for umbilical cord blood banking, FDA
estimates that there are approximately 25 cord blood banks currently
operating in the United States. These establishments would also seek
accreditation through FACT or AABB. Based on this information, the
agency estimates that a total of 425 establishments involved in
manufacturing hematopoietic stem/progenitor cells would be affected by
this final rule.
In addition, 67 establishments produce licensed biological products
or approved medical devices that are currently regulated under the act
and/or section 351 of the PHS Act, but would be subject to the
provisions of this final rule. The impact of CGTPs on these firms is
expected to be minimal because they are already subject to existing
CGMP regulations for drugs or QS regulations for medical devices. Those
requirements are largely consistent with the requirements of this final
rule.
Finally, the inspection and enforcement provisions of this final
rule, as they apply to donor eligibility requirements under subpart C,
will affect establishments involved with reproductive tissue, primarily
ART establishments and semen banks. For purposes of this discussion,
references to ART establishments include infertility clinics, as well
as andrology and embryology laboratories. The ASRM has a membership of
approximately 400 fertility centers, 370 of which have provided reports
for the 1999 Society for Assisted Reproductive Technology registry
(Ref. 29). The ASRM also has a 1996 list of approximately 110 semen
banks operating in the United States. Based on conversations with
consultants, most ART and commercial semen banking establishments
currently adhere to industry standards similar to those in the CGTP
final rule. There are currently 11 semen banks accredited by the AATB
and, according to industry consultants, the remaining commercial semen
banks are licensed by State health agencies, including the California
Department of Health and the New York Department of Health.
Semen banks and andrology laboratories at ART establishments are
also regulated under the Clinical Laboratory Improvement Amendment
(CLIA) of 1988.
The Committee on Laboratory Accreditation and JCAHO also inspect
embryo laboratories for accreditation. The requirements for
accreditation by the College of American Pathologists (CAP), which
accredits ART establishments, closely resemble those in the CGTP final
rule, with a few exceptions. Consultants estimate that as many as 80
percent of ART establishments may currently comply with the CAP
requirements.
Table 3.--Estimated Percentage of Establishments That Follow Voluntary
Industry Standards
------------------------------------------------------------------------
Percentage of
Relevant Firms Following
Affected Industry Voluntary Voluntary
Industry Industry
Standards Standards
------------------------------------------------------------------------
Eye Tissue: 134 FDA Registered EBAA 100 %
Establishments
------------------------------------------------------------------------
Conventional Tissue: (e.g., AATB 75 to 80%
pericardium, dura mater, heart
valves, skin allograft, bone
allograft, fascia, tendons,
ligaments, other viable)
166 FDA Registered Establishments
------------------------------------------------------------------------
Stem/Progenitor Cells: AABB or FACT 85 % of
Peripheral Blood (PB): 400 AABB or FACT accredited PB
establishments establishments
Cord Blood (CB): 25 establishments 100 % of all CB
establishments
------------------------------------------------------------------------
Reproductive Tissue: AATB; CAP 20 largest
Semen Banks: 110 establishments accreditation;St establishments
ate Licensed (accounting for
(e.g., NY, CA); 95% of total
and/or CLIA- production)
certified
------------------------------------------------------------------------
Reproductive Tissue: CAP 80 %
ART Establishments: 400 accreditation;
establishments State Licensed
(e.g., NY, CA);
ASRM guidelines
------------------------------------------------------------------------
2. Estimated Impact on Eye Banks, Conventional Tissue Banks and
Hematopoietic Stem/Progenitor Cell Establishments
In the sections that follow, the agency considers each of the
provisions of this final rule and estimates the impact on
establishments in those sectors of the HCT/P industry subject to CGTPs
in their entirety. The impact analysis distinguishes expected cost
impacts based on both facility size and estimated rates of current
adherence to voluntary industry standards. Based on size standards
established by the U.S. Small Business Administration (SBA), a small
establishment in this industry sector (the North American Industry
Classification Scheme (NAICS) code 621991, Blood and Organ Banks) has
annual receipts of less than $8.5 million (Refs. 21 and 22).
[[Page 68655]]
Table 4.--Estimated Cost Per Establishment and Estimated Percentage of Establishments Affected By the CGTP Final
Rule\1\
----------------------------------------------------------------------------------------------------------------
Stem/Progenitor
21 CFR Section Title Eye Tissue Conventional Tissue Cell
Establishments Sm./Lrg. Establishments
----------------------------------------------------------------------------------------------------------------
1271.150 Current Good Tissue Practice -- -- --
Requirements.
----------------------------------------------------------------------------------------------------------------
1271.155 Exemptions and Alternatives... -- -- --
----------------------------------------------------------------------------------------------------------------
1271.160 Establishment and Maintenance ............... ....................... .................
of a Quality Program: General.
-Establishment with Minor $511 (95%) $511/$1,278 (23%) $511 (80%)
Deficiencies.
-Establishment with Major $2,498 (5%) $2,498/$4,832 (5%) $2,498 (5%)
Deficiencies.
-Cost for Additional Quality $1,344 (95%) $1,344 (23%) $1,344 (80%)
Control Work.
(b)(2) Procedures for Sharing $380 (95%) $760/$2,172 (23%) $760 (80%)
Information.
(b)(3) Corrective Actions.......... $456 (95%) $912 (23%) $912 (80%)
(b)(6) Investigations.............. $2,214 (95%) $2,214 (23%) $2,214 (80%)
(c) Audits...................... $456 (95%) $912/$1,824 (23%) $912 (80%)
(d) Validate Custom Computer $2,160 (10%) $2,160 (10%) $2,160 (10%)
Software.
----------------------------------------------------------------------------------------------------------------
1271.170 Organization and Personnel:... ............... ....................... .................
(b) Competent Personnel......... -- $15,560 (23%) $15,560 (95%)
(c) Training.................... -- $2,476/$3,104 (23%) $2,476 (95%)
----------------------------------------------------------------------------------------------------------------
1271.180 Procedures--General $9,120 (5%) $9,120 (23%) $9,120 (95%)
Requirements.
----------------------------------------------------------------------------------------------------------------
1271.190 Establishments:............... ............... ....................... .................
(d)(1) Cleaning and Sanitation $348 (5%) $348/$532 (23%) $348 (95%)
Procedures.
(d)(2) Cleaning and Sanitation -- -- --
Records.
----------------------------------------------------------------------------------------------------------------
1271.195 Environmental Control and ............... ....................... .................
Monitoring:.
(a) Environmental Control....... -- $348/$532 (23%) $348 (95%)
(b)(c) Inspections and Monitoring.. $1,000 (5%) -- $1,000 (95%)
(d) Records..................... $174 (95%) $174/$348 (23%) $174 (95%)
----------------------------------------------------------------------------------------------------------------
1271.200 Equipment:.................... ............... ....................... .................
(b) Procedures/Schedules-- -- $1,460/$2,979 (23%) $1,460 (95%)
Cleaning, Sanitizing and
Maintenance.
(c) Calibration................. -- $1,460/$2,979 (23%) $1,460 (95%)
(d) Inspections................. $216 (95%) $432/$684 (23%) $216 (95%)
(e) Records..................... ............... ....................... .................
-of Cleaning, Sanitizing $174 (95%) $348/$696 (23%) $174 (95%)
and Calibration Activities.
-of the Use of Each Piece $696 (95%) $1,392/$2,784 (23%) $1,392 (95%)
of Equipment.
----------------------------------------------------------------------------------------------------------------
1271.210 Supplies and Reagents:........ ............... ....................... .................
(a) Verification................ $131 (95%) $348/$532 (23%) $348 (95%)
(c) In-house Reagents........... -- $348/$532 (23%) $348 (95%)
(d)(1) Records of Receipt, $174 (95%) $174/$348 (23%) $174 (95%)
Verification, and Lot.
----------------------------------------------------------------------------------------------------------------
1271.220 Process Controls:............. ............... ....................... .................
In-Process Monitoring $380 (95%) $380/$1,086 (23%) $760 (95%)
Procedures.
----------------------------------------------------------------------------------------------------------------
1271.225 Process Changes:.............. ............... ....................... .................
Validation of Process $760 (95%) $760/$2,172 (23%) $760 (95%)
Changes.
Records/Documentation....... $456 (95%) $456/$912 (95%) $456 (95%)
----------------------------------------------------------------------------------------------------------------
1271.230 Process Validation:........... ............... ....................... .................
(a) General..................... $1,700 (95%) $1,700 (95%) $1,700 (95%)
Procedures.................. $1,520 (95%) $760/$2,172 (95%) $1,520 (95%)
(c) Validation/Revalidation of $850 (95%) $1,700 (95%) $1,140 (95%)
Process Changes.
----------------------------------------------------------------------------------------------------------------
1271.250 Labeling Controls:............ ............... ....................... .................
(a)(b) Procedures.................. $380 (5%) $380/$1,086 (5%) $380 (95%)
----------------------------------------------------------------------------------------------------------------
1271.260 Storage....................... -- -- --
----------------------------------------------------------------------------------------------------------------
1271.265 Receipt, Pre-Distribution ............... ....................... .................
Shipment and Distribution:.
Recordkeeping and $864 (5%) $1,728/$3,456 (5%) $3,456 (5%)
Documentation.
(a) Procedures--Receiving -- $380/$1,086 (23%) $760 (95%)
Activities.
(c) Procedures--Availability for -- $380/$1,086 (23%) $760 (95%)
Distribution.
(d) Packaging and Shipping...... $1,392 (95%) $1,392 (95%) $576 (95%)
(f) Procedures--Return to -- $348/$532 (23%) $348 (95%)
Inventory.
----------------------------------------------------------------------------------------------------------------
1271.270 Records:...................... ............... ....................... .................
(a) General..................... $728 (95%) $728/$1,618 (95%) $728 (95%)
(b) Records Management System... $3,040 (95%) $3,040/$6,080 (23%) $3,040 (95%)
[[Page 68656]]
(d) Length of Retention......... $18 (5%) $18 (23%) $18 (95%)
----------------------------------------------------------------------------------------------------------------
1271.290 Tracking:..................... ............... ....................... .................
(b)(c) System of Product Tracking: $760 (5%) $380/$1,086 (23%) $380 (95%)
General Requirements.
(d)(e) System of Product Tracking: $1,728 (5%) $3,456/$6,912 (23%) $3,456 (95%)
Specific Requirements.
(f) Consignees.................. $1,520 (5%) $1,520 (23%) $1,520 (95%)
----------------------------------------------------------------------------------------------------------------
1271.320 Complaint File:............... ............... ....................... .................
(a) Procedures.................. $131 (95%) $348/$532 (23%) $348 (95%)
(b) Complaint File.............. -- -- --
(c) Review and Evaluation of $608 (95%) $608/$1,216 (23%) $608 (95%)
Complaints.
----------------------------------------------------------------------------------------------------------------
1271.350 Reporting..................... $592 (100%) $592 (100%) $592 (100%)
----------------------------------------------------------------------------------------------------------------
1271.370 Labeling...................... -- -- --
----------------------------------------------------------------------------------------------------------------
1271.400 Inspections................... ............... ....................... .................
(a) General..................... $768 (100%) $768 (100%) $768 (100%)
----------------------------------------------------------------------------------------------------------------
1271.420 HCT/Ps Offered for Import..... -- -- --
----------------------------------------------------------------------------------------------------------------
1271.440 Orders of Retention, Recall, -- -- --
Destruction and Cessation of
Manufacturing.
----------------------------------------------------------------------------------------------------------------
\1\ Only subsections expected to impose new compliance costs for a particular industry sector are shown. No cost
is estimated for a subsection if analysis revealed that the requirements: (1) do not apply, (2) have no new
cost impact, or (3) are met by another subsection of the CGTP final rule. Estimated noncompliance rates are in
parentheses.
As indicated by the information in table 4 of this document, the
impact of the CGTP final rule varies significantly, depending upon the
sector of the HCT/P industry, size of the affected entity and the
particular provision. For many of the CGTP provisions, the
establishment level impact will entail development of new procedures,
or revision of existing procedures. The scope and degree of complexity
of these changes will vary. FDA expects that the staff typically
involved in the development, revision, and finalization of
establishment procedures will include technicians, clerical staff, lab
supervisors, and the lab director. Although FDA did not specify
personnel requirements for individual provisions of the CGTP final
rule, for purposes of industry-wide estimation, the agency's cost
analysis relies on standardized estimates of the type of personnel,
level of effort, and hourly labor cost for revising or establishing
each type of procedure. Table 5 of this document summarizes the
agency's assumptions, which are based on published wage and benefits
data and input from HCT/P industry consultants.\1\
---------------------------------------------------------------------------
\1\ A detailed presentation of level of effort and cost
assumptions for nonreproductive tissue establishments is provided in
FDA's Cost Impacts of the Proposed Current Good Tissue Practice Rule
on Eye Banks, Conventional Tissue Banks, and Stem Cell Facilities:
Background Paper, April 1999, and for reproductive tissue facilities
in Cost Impacts of the Proposed Current Good Tissue Practice Rule on
Semen Banks and ART Facilities, February 1999, prepared by Eastern
Research Group (ERG), Inc. These documents are available in docket
97N-484P.
Table 5.--Estimated Level of Effort and Cost Per Procedure Revised or Prepared to Comply With the CGTP Final
Rule
----------------------------------------------------------------------------------------------------------------
Minor Procedures Major Procedures
---------------------------------------------------------------
Category: Revise Revise
Existing Prepare New Existing Prepare New
----------------------------------------------------------------------------------------------------------------
Small Establishment
----------------------------------------------------------------------------------------------------------------
Total level of staff effort 3 hrs. 7 hrs. 8 hrs. 16 hrs.
----------------------------------------------------------------------------------------------------------------
Cost (rounded) $131 $348 $380 $760
----------------------------------------------------------------------------------------------------------------
Large Establishment
----------------------------------------------------------------------------------------------------------------
Total level of staff effort 5 hrs. 13 hrs. 27 hrs. 54 hrs.
----------------------------------------------------------------------------------------------------------------
Cost (rounded) $192 $532 $1,086 $2,172
----------------------------------------------------------------------------------------------------------------
[[Page 68657]]
The analysis of cost impacts for HCT/P industry sectors subject to
CGTPs in their entirety is summarized in the following discussion of
the rule's individual provisions, and the expected type and extent of
industry impact. The pertinent section of the final rule is noted to
facilitate reference to the related cost estimates presented in table 4
of this document.
a. Section 1271.150--current good tissue practice: general. The
final rule requires manufacturers of HCT/Ps to follow CGTPs. Section
1271.150(a) provides an overview of CGTPs but does not present specific
compliance requirements. The specific requirements are addressed in
subsequent sections. Section 1271.150(b) lists the core CGTP
requirements, and Sec. 1271.150(c) addresses compliance with
applicable requirements for those entities subject to CGTPs. Section
1271.150(d) explains the relationship between the CGTP rule and
regulations specifically applicable to biological drugs or devices, and
paragraph (e) defines the term ``where appropriate'' in relation to the
rule. Section 1271.150(b) through (e) will not generate any compliance
costs for the HCT/P industry because no specific requirements are
specified.
b. Section 1271.155--exemptions and alternatives. The CGTP final
rule allows establishments to request an exemption or alternative from
FDA for certain provisions of the rule. There is currently no basis for
predicting the number of industry requests for exemptions or
alternatives, or for predicting the effect of these actions on
compliance costs. Because of a high degree of similarity between CGTPs
and current voluntary industry standards, FDA anticipates that very few
establishments will consider it appropriate to be exempted from the
provisions of this final rule.
c. Section 1271.160--establishment and maintenance of a quality
program. The final rule requires that establishments establish and
maintain a quality program. The quality program must include:
Procedures relating to core CGTP requirements, procedures for
exchanging information with other establishments known to have
recovered cells or tissue from the same donor, appropriate corrective
actions related to core CGTP requirements, proper training and
education of personnel involved in activities related to core CGTP
requirements, appropriate monitoring systems, investigation and
documentation of HCT/P deviations related to core CGTP requirements,
audits, computer software validation or verification, and other
procedures specific to the quality program. Several of these functions
are further specified in subsequent provisions of the rule, and the
impact is estimated in the context of those provisions.
In general, FDA anticipates that almost all of the establishments
in the affected industry sectors have the appropriate facilities,
equipment, and systems to support a quality program, but only those
already following industry standards are expected to have comprehensive
quality programs in place. Some establishments may need to upgrade
their quality program for several of the CGTP requirements. These
include procedures for sharing information, corrective actions, and
investigations. Further, some establishments may need to take
additional steps to administer corrective actions and conduct
investigations if they currently do so only when major deficiencies
arise.
Although the sharing of information is an industry-wide practice,
some small establishments, particularly those not following current
industry standards, may not have written procedures and forms for this
task. FDA estimates that 95 percent of eye banks, 23 percent of
conventional tissue banks not following the current AATB standards, and
80 percent of the hematopoietic stem/progenitor cell establishments not
following the FACT or AABB standards, will need to prepare a major
procedure to address this requirement.
Although FDA anticipates that most industry establishments take
steps to administer corrective actions and conduct investigations, some
may currently do so only when major deficiencies arise.
FDA estimates that 95 percent of eye banks, 23 percent of
conventional tissue banks, and 80 percent of hematopoietic stem/
progenitor cell establishments not following industry standards will
need to invest additional time to meet these new requirements. The
incremental time burden to administer corrective actions and document
these activities is estimated to be an additional 1/2-hour per month of
laboratory director time at establishments that already perform this
activity to a lesser extent, and an additional hour per month at all
other establishments that will be newly affected by this provision. As
discussed in the background papers prepared by FDA and Eastern Research
Group (ERG), and shown in table 4 of this document, for newly required
investigations in tissue establishments, FDA estimates an additional
cost per year of $2,214 for an additional 2 hours per month for the
laboratory director to investigate and document deficiencies, and an
additional 1/2 hour each for the laboratory supervisor and lab
technician to participate in the investigations.
A number of establishments will also need to institute other
requirements of the quality program, including periodic audits,
computer software validation or verification, and procedures specific
to the quality program. Audits are part of the industry standards
published by the AATB, EBAA, FACT, and AABB. However, some
establishments following these standards may need to do some additional
recordkeeping, and establishments not following standards will need to
begin to conduct audits. Referring to table 4 of this document, FDA
assumes that up to 95 percent of eye banks will increase their audit
efforts, including additional lab director time to prepare for and
perform the periodic audit. An estimated 23 percent of conventional
tissue banks will allocate additional resources for audits, with a
higher allocation of hours at larger establishments, to prepare for,
and to conduct, the audit. For hemapoietic stem/progenitor cell
establishments, FDA estimates that there will be no additional auditing
required at establishments following FACT or AABB standards, but an
estimated 80 percent of establishments not following industry standards
will need to spend additional time to prepare for and to conduct
periodic audits.
Section 1271.160 of the CGTP final rule further stipulates that
establishments must validate or verify, as appropriate, the computer
software used in their operations when it is used in the performance of
core (good tissue practice (GTP) functions. Validation would be
required for custom software used in core GTP functions. However, for
off the shelf commercial software packages (e.g., for data storage and
retrieval, recordkeeping, etc.) used as intended by the software
manufacturer, it would be adequate for the establishment, when using
such products in the performance of core GTP functions, to verify the
product's performance. Such products are already validated or verified
by the software vendor.
FDA assumes that none of the affected establishments currently
validate or verify their custom software and that approximately 10
percent of eye banks, conventional tissue banks and hematopoietic stem/
progenitor cell establishments have developed custom software that will
require full validation or verification under this final rule. Because
we received no specific comments regarding these assumptions in
response to the proposed rule, we have retained them here. Although the
[[Page 68658]]
scope of such work can vary, FDA estimates that the custom software in
use has a limited scope of application, and that an average of 60 hours
of work by the laboratory supervisor will be required to validate or
verify custom computer software at an establishment. Detailed
presentations of these assumptions are provided in section 2.4.3 of the
background papers (see footnote 1 of this document) by FDA and ERG.
The last requirement for the quality control program is for
procedures that stipulate how the quality program should be operated.
Industry consultants indicated that establishments have quality systems
in place, but that most establishments are not aware of some minor
elements of CGTPs that should be included in their procedures.
Consequently, inspectors for accreditation groups often find a few
deficiencies during initial visits. FDA estimates that about 95 percent
of eye banks, 23 percent of conventional tissue banks, and up to 80
percent of hematopoietic stem/progenitor cell establishments will have
minor deficiencies that will require them to revise one minor and one
major procedure. In addition, FDA estimates that 5 percent of all eye
banks, and conventional tissue banks and hematopoietic stem/progenitor
cell establishments not following voluntary industry standards may
identify major deficiencies, and will need to prepare five minor
procedures and one major procedure to address those problems.
The agency further assumes that establishments may generally need
to perform some additional quality control work to comply with the
quality program requirements in the CGTP final rule. Although some
tasks will not require any additional time to perform, FDA estimates
that approximately 1 hour per month each for the laboratory director
and supervisor may be needed. The agency estimates that 95 percent of
all eye banks, 23 percent of conventional tissue banks, and
approximately 80 percent of hematopoietic stem/progenitor cell
establishments will need to allocate additional staff time for this
purpose.
d. Section 1271.170--personnel. This final rule requires
establishments to employ sufficient personnel with the necessary
education, experience, and training to ensure competent performance of
their assigned functions. The EBAA, AATB, FACT, and AABB standards for
quality assurance all include provisions for appropriate personnel
qualifications and training, and recordkeeping related to this
requirement. It is expected that most eye banks, conventional tissue
banks and hematopoietic stem/progenitor cell establishments will
already be compliant with these provisions of the CGTP rule. Those
establishments in the conventional tissue and hematopoietic stem/
progenitor cell manufacturing sectors that do not follow industry
standards will incur new costs. The cost of this staffing effort is
estimated to be approximately $15,560 per affected establishment.
FDA anticipates that the 23 percent of conventional tissue banks
and 95 percent of hematopoietic stem/progenitor cell establishments not
following industry standards will incur new training costs to comply
with the personnel provisions of the CGTP final rule. For a small
tissue establishment, these costs are estimated to average $2,476. The
CGTP final rule also requires that records of personnel qualifications
and training be maintained, but because existing industry standards
address personnel recordkeeping, FDA assumes that the cost to comply
with this requirement will be negligible. Details of these assumptions
are provided in section 2.4.4 of the background papers (see footnote 1
of this document) by FDA and ERG.
e. Section 1271.180--procedures: general requirements. The CGTP
final rule requires establishments to establish and maintain written
procedures appropriate to meet core CGTP requirements for all steps
performed in the manufacture of HCT/Ps. FDA anticipates a negligible
incremental cost for most establishments following industry standards,
and an additional 120 hours of laboratory director time for
establishments not following the current industry standards. FDA
estimates that 5 percent of eye banks will need to expand their current
efforts, and that 23 percent of conventional tissue banks and 95
percent of hematopoietic stem/progenitor cell establishments will incur
new costs.
f. Section 1271.190--facilities. This final rule stipulates a
number of requirements regarding facilities covering operations, size,
construction, location, lighting, ventilation, plumbing, drainage and
access to sinks and toilets. A facility used in the manufacture of HCT/
Ps must be of suitable size, construction, and location to prevent
contamination of HCT/Ps with communicable disease agents and to ensure
orderly handling of HCT/Ps without mix-ups. Cleaning and sanitation
requirements are also outlined, including requirements for written
procedures, schedules, and documentation of these activities.
Based on discussions with industry experts, FDA estimates that
nearly all establishments that follow industry standards will not incur
any new costs under these provisions of the CGTP final rule. However,
some establishments that generally adhere to cleaning standards do not
have written procedures. Thus, FDA estimates that 5 percent of all eye
banks, in addition to 23 percent of the conventional tissue banks and
95 percent of all hematopoietic stem/progenitor cell establishments,
will incur the cost of writing a minor procedure for cleaning. The
facilities provision of the CGTP final rule also requires that records
of cleaning be maintained. This requirement is met by establishments
following industry standards, and is expected to have a negligible
impact on establishments not following the current voluntary standards.
g. Section 1271.195--environmental control and monitoring. Where
environmental conditions could reasonably be expected to cause
contamination or cross-contamination, or accidental exposure of HCT/Ps
to communicable disease agents, environmental conditions must be
adequately controlled. The final rule also requires that environmental
control systems be monitored and periodically inspected, and that
environmental control and monitoring activities be documented. The
impact of this provision of the CGTP rule varies by industry sector.
For affected eye banks, the EBAA standards already contain similar
provisions, however, some additional costs may be incurred for periodic
inspection of environmental control systems and for keeping records of
environmental control and monitoring activities. It is estimated that 5
percent of eye banks may incur new costs for inspection of equipment.
FDA anticipates that conventional tissue banks following AATB standards
will experience no new costs, but that the remaining 23 percent of
establishments will need to prepare a minor procedure for control and
monitoring of ventilation and air filtration.
The current FACT and AABB standards do not require written
procedures for environmental control and monitoring. FDA therefore
estimates that 95 percent of all hematopoietic stem/progenitor cell
establishments will need to develop a minor procedure for control and
monitoring of ventilation and air filtration systems to comply with the
CGTP rule. However, because the industry standards do provide for
appropriate environmental controls, FDA assumes that some
establishments
[[Page 68659]]
are performing the necessary control and monitoring activities. The
agency estimates that as many as half of the establishments currently
following industry standards may already be conducting routine
inspections of their environmental control equipment. It is assumed
that the remaining 50 percent of those establishments, and 95 percent
of hematopoietic stem/progenitor cell establishments assumed not to be
following industry standards, will incur additional costs to
periodically inspect equipment and perform recordkeeping related to
environmental control. Table 4 of this document provides estimates of
cost per establishment associated with these efforts.
h. Section 1271.200--equipment. This final rule requires that
appropriate equipment be used in processing HCT/Ps to prevent the
introduction, transmission, or spread of communicable disease.
Cleaning, sanitizing, maintenance, and calibration of equipment must be
performed according to established schedules and procedures; equipment
must be regularly inspected for adherence to applicable procedures and
schedules; and all such activities must be documented. In addition,
establishments must keep records of each use of each piece of
equipment, including the identification of each HCT/P manufactured with
that piece of equipment.
The standards related to equipment, as specified by AATB, EBAA,
FACT, and AABB, generally address maintenance procedures, and
recordkeeping related to maintenance. However, this final rule extends
beyond industry standards of EBAA, FACT, and AABB in the areas of
equipment inspection and recordkeeping. Based on information provided
by industry sources, FDA believes that some of the larger HCT/P
establishments may already be performing the required equipment
inspection and recordkeeping.
FDA therefore estimates that 95 percent of all eye banks will
allocate an additional 1/2-hour per month for the laboratory supervisor
to inspect equipment, an additional 1/2-hour per month of technician
time to document equipment cleaning and calibration, and 2 additional
hours per month for a technician to record each use of the equipment.
The estimated 23 percent of conventional tissue banks that
currently do not follow AATB standards will also incur new costs
related to the equipment provisions. FDA estimates that small
establishments will prepare one minor procedure for calibration, and
for cleaning and other maintenance for each of six pieces of equipment.
In addition, small establishments will allocate an additional hour per
month of lab supervisor time for routine inspection of equipment, an
additional hour per month of technician time for documentation of
cleaning and calibration, and 4 hours per month of technician time to
record each use of the equipment. FDA estimates that large
establishments will need to write minor procedures for each of eight
pieces of equipment, will allocate an additional 2 hours per month of
lab supervisor time for routine inspection of equipment, an additional
2 hours per month of technician time to record cleaning and calibration
activities, and an additional 8 hours of technician time per month to
record each use of each piece of equipment. It is anticipated that
establishments simultaneously preparing multiple procedures related to
equipment will realize some economies of scale because of similarities
across procedures. This is expected to result in a savings of 30
percent in the total amount of staff time required to prepare six to
eight minor equipment maintenance procedures.
It is expected that hematopoietic stem/progenitor cell
establishments will also be required to perform additional work to
align current practice with the CGTP requirements. Current FACT
procedures provide for routine maintenance and calibration of
equipment. In addition, the AABB standards recommend that SOPs be
established for proper equipment maintenance and monitoring. To further
develop procedures to address routine maintenance and recordkeeping
under the CGTP rule, FDA estimates that 95 percent of all hematopoietic
stem/progenitor cell establishments will prepare a minor procedure for
calibration of each of six pieces of equipment. In addition to the
preparation of procedures, lab personnel will be involved in carrying
out the necessary maintenance work, estimated to require an additional
1/2 hour of lab supervisor time per month for routine inspection of
equipment, an additional 1/2 hour per month for lab technicians to
document cleaning and calibration work, and an additional 4 hours per
month of lab technician time to record each use of equipment. In
addition, most cell establishments that do not currently follow FACT or
AABB standards will incur the cost of preparing a minor procedure for
cleaning and sanitizing, and for routine maintenance of each of six
pieces of equipment. Section 2.4.8 of the FDA and ERG background papers
(see footnote 1 of this document) provide detailed presentations of
these assumptions.
i. Section 1271.210--supplies and reagents. The CGTP rule requires
manufacturers to verify that supplies and reagents used in the
manufacture of HCT/Ps meet specifications designed to prevent
circumstances that increase the risk of introduction, transmission, or
spread of communicable disease. Verification of quality may be
accomplished by the establishment that uses the supply or reagent, or
the vendor of the supply or reagent. This final rule also requires
documentation of the receipt and verification of supplies or reagents
used in HCT/P processing, and of the lot of supply or reagent used in
the manufacture of each HCT/P.
The existing industry standards address some or all of these
activities, and the estimated impact per establishment varies
accordingly. EBAA standards specify that sterilized supplies and
reagents must contain sterilization dates and method, or appropriate
expiration dates. However, the agency estimates that up to 95 percent
of eye banks will need to devote additional resources to receipt and
verification activities, and will devote additional staff time to
recording the receipt of supplies and reagents. Similarly, FACT and
AABB standards contain provisions for quality control in the storage,
handling and use of supplies and reagents, including maintenance of
records. However, FDA expects that approximately 95 percent of
hematopoietic stem/progenitor cell establishments will expand on their
current supply and reagent related recordkeeping to comply with these
CGTP provisions.
The current AATB standards address most of the requirements for
supplies and reagents included in the final rule. FDA assumes that the
estimated 23 percent of conventional tissue establishments that do not
follow these standards will require additional resources for in-house
reagent receipt and verification, and will devote additional staff time
to keeping records of the receipt and verification of supplies and
reagents. The estimated costs per establishment for these provisions
are presented in table 4 of this document.
j. Section 1271.215--recovery. The CGTP final rule requires that
each HCT/P be recovered in a way that does not cause contamination or
cross contamination during recovery, or otherwise increase the risk of
the introduction, transmission, or spread of
[[Page 68660]]
communicable disease through the use of the HCT/P. Because this section
does not impose any specific requirements it is not expected to impose
any identifiable compliance costs.
k. Section 1271.220--processing and process controls. The CGTP
final rule requires establishments to process HCT/Ps in a way that does
not cause contamination or cross-contamination during processing, and
that prevents the introduction, transmission, or spread of communicable
disease. An establishment processing HCT/Ps is responsible for ensuring
that each in-process HCT/P is controlled until the results of any
required inspections, testing, verification activities or approvals are
received and documented. The standards for tissue banking specified by
the AATB include activities to address these process controls, but the
EBAA, FACT, and AABB standards do not include specific requirements for
in-process monitoring. FDA estimates that 95 percent of eye banks, 23
percent of conventional tissue banks, and 95 percent of hematopoietic
stem/progenitor cell establishments will need to prepare a minor
procedure related to process monitoring.
l. Section 1271.225--process changes. This final rule requires
establishments to verify or validate any changes to established
procedures to ensure that the change does not create an adverse impact
elsewhere in the operation. Process changes must be approved before
implementation by a responsible person and approved changes must be
communicated to appropriate personnel in a timely manner. The current
standards for AATB, FACT, and the AABB provide for SOPs for process
changes, although recordkeeping procedures are not specified. Current
EBAA standards do not provide for SOPs for process changes. FDA
therefore estimates that nearly all eye banks will need to prepare a
major procedure for process changes, and will allocate an additional 1/
2 hour of lab director time to document process changes.
FDA anticipates that the 23 percent of conventional tissue banks
not following the AATB standards will need to prepare a major procedure
related to process changes, and that nearly all tissue banks will
increase related recordkeeping. The agency estimates that small
conventional tissue banks will spend an additional 1/2 hour per month
of lab director time to document process changes, and that large
establishments would allocate an additional hour of lab director time
per month for this activity. FDA anticipates that almost all
hematopoietic stem/progenitor cell establishments that do not follow
FACT or AABB standards will need to prepare a major procedure to
address process changes. In addition, FDA estimates that 95 percent of
all hematopoietic stem/progenitor cell establishments will also
allocate an additional half hour of lab director time per month to
document process changes. The associated costs per establishment are
presented in table 4 of this document.
m. Section 1271.230--process validation. This final rule requires
establishments to validate processes that cannot be verified through
subsequent inspection and testing, and that the validation activities
and results be documented. Current EBAA standards do not require
process validation. Based on information provided by industry sources,
FDA believes that some of the larger eye banks may already be
performing the required process validation. Although current AATB,
FACT, and AABB standards include provisions for process validation and
related recordkeeping, industry experts indicate that additional
validation work will be required at nearly all establishments under the
CGTP final rule. FDA therefore estimates that 95 percent of all eye
banks, conventional tissue banks, and all hematopoietic stem/progenitor
cell establishments not following AABB or FACT voluntary standards,
will prepare two major procedures related to process validation, and 95
percent of conventional tissue banks and hematopoietic stem/progenitor
cell establishments will revise two major procedures. Further, FDA
estimates that 95 percent of all establishments in each sector of the
HCT/P industry will devote additional staff time to perform process
validation. Details of these assumptions are provided in section 2.4.12
of the background papers (see footnote 1 of this document) by ERG and
FDA.
In addition to the initial validation work, the CGTP final rule
requires revalidation when changes to a validated process occur. The
agency estimates that approximately 95 percent of eye banks,
conventional tissue banks, and hematopoietic stem/progenitor cell
establishments will need to allocate an additional 20 to 40 hours of
laboratory staff time annually for procedure revalidation. Costs for
these provisions of the CGTP rule are presented in table 4.
n. Section 1271.250--labeling controls. The CGTP rule requires
establishments to establish and maintain written procedures for
controlling the labeling of products. These procedures must ensure
proper identification of products and include various checks and
verifications. Each product must also be accompanied by a summary of
donor eligibility information, if applicable.
According to consultants and industry contacts, labeling controls
are usual and customary practice in all sectors of the HCT/P industry.
FDA anticipates that only about 5 percent of eye banks, conventional
tissue banks and hematopoietic stem/progenitor cell processing
establishments will need to perform additional work to comply with the
CGTP labeling controls. FDA estimates that such establishments will
need to revise a major procedure for proper identification of products.
o. Section 1271.260--storage. The CGTP final rule requires that
storage areas be controlled to prevent mixups, contamination, cross-
contamination, and to prevent an HCT/P from being improperly made
available for distribution. Temperature must be monitored and limits
established, including expiration dating where appropriate. Each of the
relevant HCT/P industry standards contains provisions regarding storage
practices. Based on agency review of current industry standards, and
conversations with experts about current practices at HCT/P
establishments, FDA anticipates that virtually all establishments
already comply with these provisions of the CGTP rule. These provisions
are therefore expected to produce no new cost impact for eye banks,
conventional tissue banks and hematopoietic stem/progenitor cell
processing establishments.
p. Section 1271.265--receipt, predistribution shipment, and
distribution. The CGTP final rule requires that procedures be
established and maintained for receipt (e.g., determination of whether
to accept, reject, or place the HCT/P in quarantine), predistribution
shipment, and distribution of HCT/Ps. Documentation of each of the
aforementioned activities, when performed, is also required. Packaging
and shipping containers must be designed and constructed to protect the
HCT/P from contamination, and appropriate shipping conditions must be
established and maintained during transit. Procedures must also be
established to determine whether products returned to an establishment
are suitable to be returned to inventory. Agency review of current
industry standards indicates that most provisions related to this area
of quality control are included in each of the relevant industry
standards.
[[Page 68661]]
The primary impact of the CGTP provisions for product receipt,
predistribution shipment, and distribution, thus, involves procedures
development for establishments that do not currently follow industry
standards. FDA estimates that 5 percent of eye banks, conventional
tissue banks, and hematopoietic stem/progenitor cell establishments
will increase lab supervisor time to document the receipt of products.
The agency estimates that conventional tissue banks not following
AATB standards will need to revise one major procedure for receiving
products, revise one major procedure related to distribution of
products, and prepare a minor procedure for return of products to
inventory. FDA estimates that 95 percent of hematopoietic stem/
progenitor cell establishments will write one major procedure
addressing receiving activities. Establishments following FACT or AABB
standards will also need to revise a major procedure for product
distribution, while all other establishments will need to prepare a new
major procedure for product distribution, as well as a minor procedure
for the handling of products returned to inventory. Details of these
assumptions are presented in section 2.4.15 of the background papers
(see footnote 1 of this document) by ERG and FDA and the estimated
costs per establishment for these activities are presented in table 4
of this document.
q. Section 1271.270--records. The CGTP rule requires that records
be maintained for all steps required in this subpart and subpart C of
this part. A records management system relating only to core CGTP
requirements must be established and maintained. Records pertaining to
a particular HCT/P must be maintained for at least 10 years after the
date of administration, if known, or at least 10 years after the date
of the HCT/P's distribution, disposition or expiration, whichever is
latest. This final rule also requires that records be kept of any
contracts or agreements. Although many components of the required
recordkeeping system are addressed under individual provisions of the
CGTP rule, there may be a few minor gaps in the records system of an
establishment that would be addressed under this general provision. The
agency therefore estimates that approximately 95 percent of all eye
banks, conventional tissue banks, and hematopoietic stem/progenitor
cell establishments that do not follow FACT or AABB standards, will
write at least one minor procedure, and revise one major procedure
related to recordkeeping.
The agency also estimates that additional lab director time will be
allocated (an estimated 40 hours at small establishments and 80 hours
at large establishments) to set up enhanced recordkeeping where a
system is already in place. System enhancement will be performed at an
estimated 95 percent of eye banks, 23 percent of conventional tissue
banks and 95 percent of hematopoietic stem/progenitor cell
establishments.
Various industry standards specify record retention, although the
time periods vary somewhat. Of those establishments following industry
standards, approximately 95 percent of eye banks and 75 percent to 80
percent of conventional tissue banks retain records for at least 10
years, and the remainder retain records for a minimum of 5 years. For
these establishments, and the hematopoietic stem/progenitor cell
establishments that do not currently follow industry standards, FDA
estimates increased record retention costs based on the cost of storing
an additional five boxes (2.4 cubic feet each) of records per year for
5 years. The estimated record retention costs should be viewed as
maximum potential burdens since affected entities have the option to
retain the required records in more cost-effective (e.g., electronic)
formats and because some establishments already retain records for 10
years.
The retention standards of FACT and AABB for records related to
products are different from those concerned with facility and equipment
maintenance, and personnel education and training. All records related
to hematopoietic stem/progenitor cell products must be retained
indefinitely whereas records related to facility and equipment
maintenance and personnel training must be retained for only 5 years.
FDA estimates that half of the records at hematopoietic stem/
progenitor cell establishments following industry standards will need
to be retained for an additional 5 years, and that the annual cost will
be comparable to that of other small eye banks and conventional tissue
banks. The agency also estimates that nearly all hematopoietic stem/
progenitor cell establishments that are not following industry
standards will need to increase record retention efforts. Almost all
hematopoietic stem/progenitor cell establishments that do not follow
industry standards are also expected to prepare at least one minor
procedure and to revise a major procedure related to recordkeeping. The
laboratory director at these establishments is expected to allocate 40
hours of additional time to improving the establishment's current
recordkeeping system.
r. Section 1271.290--tracking. This final rule stipulates the steps
needed to properly track a product from donor to consignee or final
disposition and vice versa. The CGTP rule requires that establishments
maintain a method for product tracking and that each product is
assigned and labeled with a distinct identification code (identifier).
If a new identifier is assigned during the manufacturing process,
procedures must be in place for relating the new identifier to the old
identifier. The establishment that manufactured the product must also
keep track of the disposition of each product, so that the consignee
can be easily identified. Establishments must also inform consignees in
writing of the requirements of this section and of the established
tracking method. In addition, labeling must include information
designed to facilitate effective tracking from the donor to the
recipient and from the recipient to the donor.
Product ``traceability'' is a familiar concept and common practice
in the eye banking, conventional tissue and hematopoietic stem/
progenitor cell processing industries. Eye banks following EBAA
standards maintain records with information that permits tracing of
product from the donor source to the patient recipient, working through
the surgeon who performed the procedure. FDA anticipates that only 5
percent of eye banks will need to enhance current tracking systems,
prepare one major procedure related to product tracking, spend
additional staff time each month to identify and document consignee
information, and allocate additional laboratory director time to inform
the consignees who receive products and ensure the tracking
requirements are met.
Conventional tissue banks following AATB standards are able to
trace all products from donation source to product recipient.
Conventional tissue establishments not following AATB requirements will
need to revise a major procedure to address product tracking, and to
allocate additional staff time each month to obtain and record
information about product consignees. The FACT and AABB standards for
product tracking in hematopoietic stem/progenitor cell establishments
recommend that the establishment be able to trace products to final
distribution or disposition, but do not specify that formal agreements
be established with consignees to assure timely tracking of products.
FDA therefore estimates that 95 percent of
[[Page 68662]]
hematopoietic stem/progenitor cell establishments will, on a one-time
basis, allocate an additional 20 hours of laboratory supervisor time to
inform consignees who will receive products of tracking systems and
requirements. In addition, FDA estimates that 95 percent of
hematopoietic stem/progenitor cell establishments that are not
following FACT or AABB standards will need to revise a major procedure
related to product tracking, and will need to allocate additional staff
hours each month for consignee documentation. The estimated costs per
establishment to perform these activities are presented in table 4 of
this document.
s. Section 1271.320--complaint file. The CGTP final rule requires
establishments to maintain procedures for the review, evaluation, and
documentation of complaints relating to core CGTP requirements, and the
investigation of complaints as appropriate. Establishments are required
to review and evaluate complaints as soon as practical and to determine
whether each complaint represents an event that must be reported to
FDA. Documentation of the review and evaluation is required, even if no
reporting is made. FDA finds that the AATB, FACT, and AABB standards
explicitly address procedures for, or recordkeeping related to,
complaints. Based on discussions with industry experts, the agency
anticipates that nearly all establishments currently track, albeit
informally, the complaints received from consignees and recipients.
Establishments that must prepare new written procedures for review and
handling of complaints would incur additional costs under these CGTP
provisions. The agency estimates that the additional costs for
establishments to maintain a complaint file would be negligible.
To fully comply with these provisions of the CGTP rule, FDA
estimates that 95 percent of all eye banks will revise a minor
procedure to include the required handling of complaints, and allocate
some additional staff time each year to review complaints. FDA assumes
that conventional tissue banks following AATB standards will already be
performing the necessary activities, but the estimated 23 percent of
establishments not following AATB standards will need to prepare a
minor procedure for complaint handling, and allocate additional
laboratory director time each year to review any complaints received.
Although the industry standards for hematopoietic stem/progenitor
cell processing require that records be maintained of both donor and
recipient complaints, the CGTP rule requires that establishments also
have written procedures for complaint review. FDA therefore estimates
that 95 percent of hematopoietic stem/progenitor cell establishments
will write a minor procedure to handle complaints, and that 95 percent
of all establishments that do not follow industry standards will also
allocate additional time for yearly review and handling of complaints.
Details of these assumptions are presented in section 2.4.18 of the
background papers (see footnote 1 of this document) by FDA and ERG.
t. Section 1271.350--reporting. This final rule requires
establishments to investigate adverse reaction reports and report to
FDA any adverse reactions, involving a communicable disease, that are
fatal, life-threatening, result in permanent impairment of the body, or
necessitate medical or surgical intervention, including
hospitalization. In addition, the final rule requires establishments to
investigate all HCT/P deviations and report to FDA any deviation
related to core CGTP requirements if the deviation occurs in the
establishment's facility or in a facility that performs a manufacturing
step under contract, agreement, or other arrangement with the
establishment. In our economic analysis of the proposed CGTP rule, we
assumed that these provisions would result in negligible new costs for
affected entities. However, because these are new FDA reporting
requirements, the agency believes that additional costs will be
incurred by all eye banks, conventional tissue banks, and hematopoietic
stem/progenitor cell establishments. The agency further estimates that
a typical affected establishment will submit an average of six Form FDA
3500A (adverse reaction) reports and two Form FDA 3486 (HCT/P
deviation) reports per year, requiring an additional 8 hours of
laboratory director time. The associated costs are presented in table 4
of this document.
u. Section 1271.370--labeling. The CGTP rule requires that products
be labeled clearly and accurately, with information including a
description of the HCT/P along with its distinct identification code,
the name and address of the manufacturer, a description of the product
and the product expiration date. The storage temperature, appropriate
warnings, and adequate instructions for use when related to the
prevention of the introduction, transmission, or spread of communicable
disease must also be provided on the label or on a package insert.
Industry consultants inform FDA that the required elements are
typically present on the labels of products manufactured by eye banks,
conventional tissue banks, and hematopoietic stem/progenitor cell
establishments. Proper labeling is considered very important to these
industries, to prevent the misuse of their products. FDA assumes,
therefore, that establishments in the various sectors of the HCT/P
industry are already compliant with these provisions of the CGTP final
rule, and that the cost impact will be negligible.
v. Section 1271.400--inspections. FDA could conduct inspections of
any facility subject to the CGTP final rule. FDA will typically
interact primarily with one responsible person for each establishment,
but other personnel may also be involved in the inspection. FDA could
inspect facilities, equipment, processes, products, procedures,
labeling, and records, and could review and copy any records required
to be kept under this final rule. The agency estimates that all
industry establishments, both domestic and foreign, will be subject to
this provision of the CGTP final rule, and inspections will occur
periodically. FDA estimates that up to 16 hours of laboratory
technician time will be necessary, to accompany the FDA inspector
through the facility and to support the inspector's information needs,
and that up to 4 hours of laboratory director time will be needed for
activities related to the inspection. This is expected to impose a cost
of approximately $768 per establishment per inspection.
w. Section 1271.420--HCT/Ps offered for import. The CGTP final rule
requires importers of HCT/Ps to notify the FDA district director having
jurisdiction over the port of entry through which the HCT/P is imported
or offered for import. The HCT/P must be held intact or transported
under quarantine until it is inspected and released by FDA. There is
currently very limited use of imported HCT/Ps that would trigger
activities for compliance with this provision of the CGTP final rule.
FDA therefore estimates the current cost for industry compliance with
this requirement to be negligible.
x. Section 1271.440--orders of retention, recall, and cessation of
manufacturing. Firms in the HCT/P industry may incur costs to comply
with orders issued under this provision. There is little available data
on which to base estimates of the future frequency and scope of HCT/P
industry conditions and practices that would necessitate such actions
on the part of FDA. The agency anticipates that orders issued under
this provision of the CGTP final rule will be rare. FDA estimates that
the
[[Page 68663]]
yearly costs to the HCT/P industry resulting from such orders will
therefore be negligible.
3. Estimated Impact on Reproductive Tissue Establishments
As explained elsewhere in this preamble, establishments involved
with reproductive tissue (e.g., ART establishments and semen banks) are
subject only to the CGTP inspection and enforcement provisions of Sec.
1271.400 as they apply to donor eligibility requirements under subpart
C. The impact of these provisions is described in the following section
and the estimated cost impact is presented in table 6 of this document.
Table 6.--Estimated Cost Per Establishment and Estimated Percentage of Reproductive Tissue Establishments
Affected By the CGTP Final Rule
----------------------------------------------------------------------------------------------------------------
21 CFR Section Title ART Establishments Semen Banks
----------------------------------------------------------------------------------------------------------------
1271.400 Inspections $768 (100%) $768 (100%)
----------------------------------------------------------------------------------------------------------------
a. Section 1271.400--inspections. FDA could conduct inspections of
any facility subject to subpart F. This provision affects reproductive
tissue establishments only insofar as it applies to the donor
eligibility requirements under subpart C, and not to CGTPs generally.
FDA will typically interact primarily with one responsible person for
each establishment, but other personnel may also be involved in the
inspection. FDA could inspect the donor eligibility related procedures
and records of reproductive tissue establishments, and could review and
copy any records required to be kept under this final rule.
The agency estimates that all ART and semen bank establishments,
whether domestic or foreign, will be subject to this provision of the
CGTP final rule, and inspections will occur periodically. FDA estimates
that up to 16 hours of laboratory technician time will be necessary, to
accompany the FDA inspector through the establishment and to support
the inspector's information needs, and that up to 4 hours of laboratory
director time will be needed for activities related to the inspection.
This is expected to impose a cost of approximately $768 per
establishment per inspection. This is the only provision of the CGTP
final rule that applies to establishments involved with reproductive
tissues.
4. Summary of Estimated One-Time, Annual, and Annualized Cost Impacts
The costs for each section of the CGTP final rule are computed as
the product of the estimated number of affected establishments (table 3
of this document), the estimated compliance cost per establishment, and
the estimated percentage of establishments not currently following
CGTPs (table 4 of this document), and are presented by HCT/P industry
sector in tables 7 through 11 of this document. The total one-time and
annual compliance costs, summed over all provisions of the CGTP rule,
are also presented by HCT/P industry sector in these tables. The
aggregate one-time and annual compliance costs for all sectors of the
HCT/P industry are summarized in table 12 of this document. The total
annualized cost estimates presented in tables 7 through 12 of this
document include both the estimated annual and one-time costs, such as
are incurred to prepare new procedures, and are annualized over 10
years using both 7 percent and 3 percent discount rates.
Table 7.--Aggregate Compliance Costs for Eye Banks
----------------------------------------------------------------------------------------------------------------
Total Total
21 CFR Section Title One-Time Costs Annual Costs Annualized Annualized
Costs\1\ Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.150 CGTP Requirements $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.155 Exemptions & Alternatives $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.160 Quality Program $159,038 $569,031 $591,674 $587,675
----------------------------------------------------------------------------------------------------------------
1271.170 Personnel $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.180 Procedures $0 $61,104 $61,104 $61,104
----------------------------------------------------------------------------------------------------------------
1271.190 Facilities 2,328 $0 $331 $273
----------------------------------------------------------------------------------------------------------------
1271.195 Environmental Control & $0 $28,550 $28,850 $28,850
Monitoring
----------------------------------------------------------------------------------------------------------------
1271.200 Equipment $0 $138,248 $138,248 $138,248
----------------------------------------------------------------------------------------------------------------
1271.210 Supplies & Reagents $16,613 $22,150 $24,515 $24,098
----------------------------------------------------------------------------------------------------------------
1271.215 Recovery $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.220 Processing and Process $48,374 $0 $6,887 $5,671
Controls
----------------------------------------------------------------------------------------------------------------
1271.225 Process Changes $96,748 $58,049 $71,824 $69,391
----------------------------------------------------------------------------------------------------------------
1271.230 Process Validation $409,906 $108,205 $166,566 $156,258
----------------------------------------------------------------------------------------------------------------
1271.250 Labeling Controls $2,456 $0 $362 $298
----------------------------------------------------------------------------------------------------------------
[[Page 68664]]
1271.260 Storage $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.265 Receipt, Predistribution $0 $182,990 $182,990 $182,990
Shipment & Distribution
----------------------------------------------------------------------------------------------------------------
1271.270 Records $479,603 $121 $68,405 $56,345
----------------------------------------------------------------------------------------------------------------
1271.290 Tracking $15,276 $11,578 $13,753 $13,368
----------------------------------------------------------------------------------------------------------------
1271.320 Complaint File $16,613 $77,398 $79,764 $79,364
----------------------------------------------------------------------------------------------------------------
1271.350 Reporting $0 $81,472 $81,472 $81,472
----------------------------------------------------------------------------------------------------------------
1271.370 Labeling $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.400 Inspections $0 $102,912 $102,912 $102,912
----------------------------------------------------------------------------------------------------------------
1271.420 HCT/Ps Offered for Import $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.440 Orders of Retention, Recall, $0 $0 $0 $0
Destruction and Cessation of
Manufacturing
----------------------------------------------------------------------------------------------------------------
Total All Sections $1,247,044 $1,442,108 $1,619,659 $1,588,300
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.
Table 8.--Aggregate Compliance Costs for Conventional Tissue Establishments
----------------------------------------------------------------------------------------------------------------
Total Total
21 CFR Section Title One-Time Costs Annual Costs Annualized Annualized
Costs\1\ Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.150 CGTP Requirements $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.155 Exemptions & Alternatives $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.160 Quality Program $127,960 $213,246 $231,464 $228,247
----------------------------------------------------------------------------------------------------------------
1271.170 Personnel $594,081 $101,444 $186,028 $171,088
----------------------------------------------------------------------------------------------------------------
1271.180 Procedures $0 $348,202 $348,202 $348,202
----------------------------------------------------------------------------------------------------------------
1271.190 Facilities $14,838 $0 $2,113 $1,739
----------------------------------------------------------------------------------------------------------------
1271.195 Environmental Control & $14,838 $8,124 $10,237 $9,863
Monitoring
----------------------------------------------------------------------------------------------------------------
1271.200 Equipment $137,313 $101,411 $120,961 $117,508
----------------------------------------------------------------------------------------------------------------
1271.210 Supplies & Reagents $29,676 $8,124 $12,349 $11,603
----------------------------------------------------------------------------------------------------------------
1271.215 Recovery $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.220 Processing and Process $20,516 $0 $2,921 $2,405
Controls
----------------------------------------------------------------------------------------------------------------
1271.225 Process Changes $41,033 $87,940 $93,782 $92,750
----------------------------------------------------------------------------------------------------------------
1271.230 Process Validation $437,574 $268,090 $330,391 $319,387
----------------------------------------------------------------------------------------------------------------
1271.250 Labeling Controls $4,460 $0 $635 $523
----------------------------------------------------------------------------------------------------------------
1271.260 Storage $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.265 Receipt, Predistribution $55,871 $237,058 $245,012 $243,607
Shipment & Distribution
----------------------------------------------------------------------------------------------------------------
1271.270 Records $287,965 $687 $41,687 $34,446
----------------------------------------------------------------------------------------------------------------
1271.290 Tracking $78,550 $161,361 $172,544 $170,569
----------------------------------------------------------------------------------------------------------------
1271.320 Complaint File $14,837 $28,388 $30,500 $30,127
----------------------------------------------------------------------------------------------------------------
1271.350 Reporting $0 $100,928 $100,928 $100,928
----------------------------------------------------------------------------------------------------------------
[[Page 68665]]
1271.370 Labeling $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.400 Inspections $0 $127,488 $127,488 $127,488
----------------------------------------------------------------------------------------------------------------
1271.420 HCT/Ps Offered for Import $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.440 Orders of Retention, Recall, $0 $0 $0 $0
Destruction and Cessation of
Manufacturing
----------------------------------------------------------------------------------------------------------------
Total All Sections $1,859,510 $1,792,489 $2,057,241 $2,010,480
----------------------------------------------------------------------------------------------------------------
\a.\ Over 10 years at 7 percent interest
\b.\ Over 10 years at 3 percent interest
Table 9.--Aggregate Compliance Costs for Hematopoietic Stem/Progenitor Cell Establishments
----------------------------------------------------------------------------------------------------------------
Total Total
Section Title One-Time Costs Annual Costs Annualized Annualized
Costs\a\ Costs\b\
----------------------------------------------------------------------------------------------------------------
1271.150 CGTP Requirements $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.155 Exemptions & Alternatives $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.160 Quality Program $208,354 $457,200 $486,865 $481,625
----------------------------------------------------------------------------------------------------------------
1271.170 Personnel $739,100 $117,610 $222,841 $204,255
----------------------------------------------------------------------------------------------------------------
1271.180 Procedures $0 $433,200 $433,200 $433,200
----------------------------------------------------------------------------------------------------------------
1271.190 Facilities $90,784 $665,000 $677,926 $675,643
----------------------------------------------------------------------------------------------------------------
1271.195 Environmental Control & $90,784 $205,458 $218,383 $216,100
Monitoring
----------------------------------------------------------------------------------------------------------------
1271.200 Equipment $450,621 $465,548 $529,706 $518,374
----------------------------------------------------------------------------------------------------------------
1271.210 Supplies & Reagents $135,185 $8,265 $27,512 $24,113
----------------------------------------------------------------------------------------------------------------
1271.215 Recovery $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.220 Processing and Process $198,550 $0 $28,269 $23,276
Controls
----------------------------------------------------------------------------------------------------------------
1271.225 Process Changes $36,100 $119,130 $124,270 $123,362
----------------------------------------------------------------------------------------------------------------
1271.230 Process Validation $678,775 $297,825 $394,467 $372,398
----------------------------------------------------------------------------------------------------------------
1271.250 Labeling Controls $5,225 $0 $744 $613
----------------------------------------------------------------------------------------------------------------
1271.260 Storage $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.265 Receipt, Predistribution $482,861 $28,080 $96,829 $84,686
Shipment & Distribution
----------------------------------------------------------------------------------------------------------------
1271.270 Records $178,956 $2,880 $28,359 $23,859
----------------------------------------------------------------------------------------------------------------
1271.290 Tracking $415,150 $164,160 $223,268 $212,828
----------------------------------------------------------------------------------------------------------------
1271.320 Complaint File $90,784 $158,840 $171,766 $169,483
----------------------------------------------------------------------------------------------------------------
1271.350 Reporting $0 $167,200 $167,200 $167,200
----------------------------------------------------------------------------------------------------------------
1271.370 Labeling $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.400 Inspections $0 $211,200 $211,200 $211,200
----------------------------------------------------------------------------------------------------------------
1271.420 HCT/Ps Offered for Import $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.440 Orders of Retention, Recall, $0 $0 $0 $0
Destruction and Cessation of
Manufacturing
----------------------------------------------------------------------------------------------------------------
Total All Sections $3,801,230 $3,501,595 $4,042,805 $3,947,215
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.
[[Page 68666]]
Table 10.--Aggregate Compliance Costs for ART Establishments
----------------------------------------------------------------------------------------------------------------
Total Total
21 CFR Section Title One-Time Costs Annual Costs Annualized Annualized
Costs\1\ Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.400 Inspections $0 $307,200 $307,200 $307,200
----------------------------------------------------------------------------------------------------------------
Total All Sections $0 $307,200 $307,200 $307,200
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.
Table 11.--Aggregate Compliance Costs for Semen Banks
----------------------------------------------------------------------------------------------------------------
Total Total
21 CFR Section Title One-Time Costs Annual Costs Annualized Annualized
Costs\1\ Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.400 Inspections $0 $84,480 $84,480 $84,480
----------------------------------------------------------------------------------------------------------------
Total All Sections $0 $84,480 $84,480 $84,480
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.
Table 12.--Aggregate Compliance Costs for All HCT/P Industry Sectors
----------------------------------------------------------------------------------------------------------------
Total Total
21 CFR Section Title One-Time Costs Annual Costs Annualized Annualized
Costs\1\ Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.150 CGTP Requirements $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.155 Exemptions & Alternatives $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.160 Quality Program $495,351 $1,239,477 $1,310,003 $1,297,547
----------------------------------------------------------------------------------------------------------------
1271.170 Personnel $1,333,181 $219,054 $408,869 $375,343
----------------------------------------------------------------------------------------------------------------
1271.180 Procedures $0 $842,506 $842,506 $842,506
----------------------------------------------------------------------------------------------------------------
1271.190 Facilities $107,950 $665,000 $680,370 $677,655
----------------------------------------------------------------------------------------------------------------
1271.195 Environmental Control & $105,622 $242,432 $257,470 $254,814
Monitoring
----------------------------------------------------------------------------------------------------------------
1271.200 Equipment $587,933 $705,206 $788,914 $774,130
----------------------------------------------------------------------------------------------------------------
1271.210 Supplies & Reagents $181,473 $38,539 $64,377 $59,813
----------------------------------------------------------------------------------------------------------------
1271.215 Recovery $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.220 Processing and Process $267,440 $0 $38,077 $31,352
Controls
----------------------------------------------------------------------------------------------------------------
1271.225 Process Changes $173,881 $265,118 $289,875 $285,503
----------------------------------------------------------------------------------------------------------------
1271.230 Process Validation $1,526,255 $674,120 $891,424 $853,044
----------------------------------------------------------------------------------------------------------------
1271.250 Labeling Controls $12,231 $0 $1,741 $1,434
----------------------------------------------------------------------------------------------------------------
1271.260 Storage $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.265 Receipt, Predistribution $538,732 $448,128 $524,831 $511,284
Shipment & Distribution
----------------------------------------------------------------------------------------------------------------
1271.270 Records $946,524 $3,688 $138,452 $114,649
----------------------------------------------------------------------------------------------------------------
1271.290 Tracking $508,976 $337,098 $409,565 $396,766
----------------------------------------------------------------------------------------------------------------
1271.320 Complaint File $122,235 $264,626 $282,029 $278,956
----------------------------------------------------------------------------------------------------------------
1271.350 Reporting $0 $349,600 $349,600 $349,600
----------------------------------------------------------------------------------------------------------------
1271.370 Labeling $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
1271.400 Inspections $0 $833,280 $833,280 $833,280
----------------------------------------------------------------------------------------------------------------
1271.420 HCT/Ps Offered for Import $0 $0 $0 $0
----------------------------------------------------------------------------------------------------------------
[[Page 68667]]
1271.440 Orders of Retention, Recall, $0 $0 $0 $0
Destruction and Cessation of
Manufacturing
----------------------------------------------------------------------------------------------------------------
Total All Sections $6,907,784 $7,127,872 $8,111,384 $7,937,674
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.
As shown in table 7 of this document, the total one-time costs for
the eye banking industry are estimated to be $1.25 million, and annual
costs are estimated at $1.44 million. These figures generate a total
annualized cost estimate of $1.59 million to $1.62 million. For the
conventional tissue industry (table 8 of this document), aggregate one-
time costs and annual costs are estimated at $1.86 million and $1.79
million, respectively. These figures correspond to an estimated
annualized cost of $2.01 million to $2.06 million. The hematopoietic
stem/progenitor cell industry (table 9 of this document) is estimated
to incur a one-time cost of $3.8 million and annual costs of $3.5
million, yielding an annualized cost estimate of $3.95 million to $4.04
million. ART establishments and semen banks are expected to incur no
one-time costs under the CGTP final rule because they are subject only
to the inspection and enforcement provisions as they relate to donor
eligibility requirements under subpart C. The total annual and
annualized costs for ART establishments and semen banks are estimated
to be $0.31 million and $0.08 million, respectively. These cost
estimates are presented in tables 10 and 11 of this document.
Table 12 of this document summarizes the total estimated cost
impacts for all HCT/P industry sectors. FDA estimates the aggregate
one-time compliance costs of the CGTP final rule to be $6.9 million.
Annual costs, aggregated across all sectors of the HCT/P industry, are
estimated to be $7.13 million. These estimates correspond to a total
annualized cost estimate of $7.94 million to $8.1 million for the CGTP
final rule applied to all major sectors of the HCT/P industry.
C. Estimated Benefits of the CGTP Final Rule
The purpose of the CGTP final rule is to prevent the introduction,
transmission, or spread of communicable disease through the use of HCT/
Ps. Although voluntary industry standards exist for most of the
affected products, FDA finds that public safety cannot be assured or
effectively protected through reliance on these informal mechanisms.
The existing industry standards also vary to some extent in their
comprehensiveness, and there are variations in the extent to which
firms in the affected industry sectors follow these voluntary
standards.
For example, most industry consultants providing input for this
analysis agreed that quality standards, such as those in the CGTP final
rule, and similar standards recommended by industry, could
substantially reduce the risk of HCT/P product contamination by
communicable disease agents. However, most of these experts also agreed
that, because additional costs are associated with maintaining higher
quality standards, and because there is no explicit patient demand for
higher quality standards to prevent contamination risks, some
establishments are not currently following adequate quality control
procedures. A regulatory requirement for quality systems and
recordkeeping would provide the incentives needed to bring marginal
establishments to a more uniform and appropriately high standard of
quality in HCT/P processing.
The primary beneficiaries of the CGTP final rule are the patients
who receive HCT/Ps. Benefits to patients result from improved outcomes
due to reduced risks of communicable disease transmission. Society as a
whole will benefit from implementation of CGTPs due to improved safety
of the supply of HCT/Ps, and reductions in health care and other costs
associated with treating the complications arising from the use of
contaminated tissue products. The discussion that follows considers
some of the potential benefits of CGTPs based on a survey of the
clinical literature.
Recent clinical literature indicates that each type of HCT/P
affected by the CGTP final rule has documented communicable disease
transmission risk that may be the result of contamination or other
problems resulting from processing, or other steps in manufacturing.
Although the limited number of adverse events reported in the clinical
literature suggests a relatively low risk of communicable disease
transmission associated with HCT/Ps, it is important to note that this
evidence is generally based on analysis of a limited number of
voluntarily reported incidents. The reported HCT/P problems provide a
basis for assessing the magnitude of the potential benefit from further
reducing the incidence of events that contribute to or increase the
risk of communicable disease transmission. In some cases involving eye
tissue, conventional tissue, or hematopoietic stem/progenitor cell
products, HCT/P problems have required medical intervention to treat
infection, or to replace an implanted HCT/P. In some clinical
applications, HCT/P related problems have increased the risk of patient
morbidity or mortality. In general, FDA anticipates that the risk of
communicable disease transmission will decline, and patient outcomes
will improve, as a result of industry compliance with the provisions of
the CGTP final rule.
The sections that follow describe specific product-related problems
associated with communicable disease transmission that are at least
partly attributable to a lack of uniform and enforceable standards in
HCT/P manufacturing. The costs of correcting these problems are
considered, to gauge the potential magnitude of the benefits associated
with improvements in manufacturing processes brought about through
implementation of CGTPs. The discussion is organized by type of HCT/P.
1. Eye Tissue
Primary corneal graft failure is a key adverse outcome of concern
following corneal tissue transplant. Such failures result in additional
graft attempts, and each attempt increases the risk of communicable
disease transmission by exposing the recipient to another HCT/P, and
another surgical procedure. Although primary corneal graft failure is
relatively uncommon, its occurrence has been attributed to several
factors related
[[Page 68668]]
to tissue collection, processing, and product distribution. These
factors include donor characteristics such as age (Ref. 5), donor
infectivity (e.g., with Herpes Simplex Virus and CJD) (Refs. 8 and 31),
length of product storage, type of storage medium, and shipping
distance from the eye bank to the recipient site. In an analysis of
factors contributing to primary corneal graft failure, Wilhelmus et al.
(Ref. 5) found that ``the duration of donor corneal preservation may
have a significant effect on endothelial vitality,'' citing studies
that demonstrate endothelial cell loss in chondroitin-supplemented
storage media after 7 to 10 days of storage. The authors suggest that,
even with modern eye bank screening and preservation procedures, a
donor corneal storage time greater than 1 week increases the risk of
primary corneal graft failure by more than two-fold.
Wilhelmus et al. include in their analysis a summary of selected
findings of studies published between 1971 and 1994 that report the
incidence of primary graft failure for corneal transplants using 4
degrees Celsius preservation, and a variety of preservation methods.
The rates of primary graft failure reported ranged from 0.9 percent to
3.1 percent, and a combined rate of 2.1 percent was estimated across
all preservation methods. In their analysis of factors associated with
corneal graft failures reported to the EBAA for 1991 to 1993, the
findings of Wilhelmus et al. illustrate the importance of verification
of quality and documentation of the receipt of supplies and reagents
used in HCT/P processing. The authors found that 86 cases
(approximately 59 percent of all cases studied) of primary corneal
graft failure shared preservation media from the same lots. These
findings underline the importance of the CGTP requirement for
verification of quality and documentation of receipt for each
particular lot of processing media used in the manufacture of uniquely
labeled and traceable products.
Primary corneal graft failure typically requires repeat surgery to
replace the failed graft. The Agency for Healthcare Research and
Quality (AHRQ), reports 598 total discharges for Principal Procedure
13, Corneal transplant, with a mean hospital length of stay (LOS) of
3.5 days and a mean hospital charge of $14,233 in 2000 (Ref.7). The
estimated rate of primary graft failure, which may result from one or
more aspects of cornea collection, processing, or distribution, ranges
from 0.1 percent (based on the number of cases voluntarily reported to
EBAA for the period 1991-1993, and again in 2001) to as much as 2.1
percent (combined failure rate reported in the literature, across the
range of preservation media currently used in eye tissue processing,
cited in Wilhelmus et al.). Based on 45,897 corneal transplants
reported by the EBAA in 1999, the estimated number of cases of primary
graft failure may range from 46 cases [0.001 x 45,897] to 413 cases
[0.009 x 45,897] per year. The lowest estimate of the incidence of
primary corneal graft failure reported by Wilhelmus et al. (0.9
percent) was used in this calculation to produce a conservative
estimate of the number of cases, and in response to public comments on
the proposed CGTP rule. The total cost of replacement of a failed
corneal graft is estimated to include $654 of physician services
(Ref.8), including an office visit to diagnose the graft failure before
hospitalization, and initial and followup physician visits during
patient hospitalization for the repeated corneal transplant. It also
includes one followup physician office visit to assess the outcome of
the second transplant. The patient is estimated to further incur at
least 1 week of time lost from work for doctor visits, hospitalization,
and recovery of visual function after surgery. The cost of this patient
time loss is estimated at $957.20, based on a 40-hour work week and
U.S. average employer costs for employee compensation of $23.93 (Ref.
32). Thus, the current annual cost impact of primary corneal graft
failure may range from $728,833 (46 x ($14,233 + $654 + $957.20)) to
$6,543,655 (413 x ($14,233 + $654 + $957.20)).
The risk, incidence, and cost of treating primary corneal graft
failure will be reduced through the implementation of CGTPs, due to
provisions requiring the validation of processing methods and process
quality controls, the verification of supplies and reagents, and
improved documentation. The total annualized cost to eye banks of
implementing the CGTP final rule is estimated to be $1.61 million to
$1.65 million, and the total cost of repeat surgery, hospitalization,
physician's services and work loss associated with primary corneal
graft failure is estimated to be $15,844.20 per occurrence ($14,233 +
$654 + $957.20). Based on these estimates, if implementation of the
CGTP final rule were to result in approximately 104 fewer cases ($1.65
million / $15,844 per case) of primary corneal graft failure per year,
the benefits realized (in the form of avoided health care costs and
income loss due to time away from work) would exceed the total
annualized cost to eye banks, thereby making the rule cost effective
for this sector of the HCT/P industry.
A reduction of 104 cases represents a 25 percent reduction (104
fewer cases / 413 total cases) in the risk of corneal graft failure
(from 0.9 percent to 0.675 percent) based on the lowest rate reported
by Wilhelmus et al. Due to uncertainty with respect to the actual risk
of primary corneal graft failure, and the degree to which CGTPs would
reduce this already uncertain risk, FDA is not able to determine
whether or not implementation of this final rule would generate this
level of risk reduction. No attempt was made to estimate the benefits
of any potential reduction in the risk of intraocular infection
(another HCT/P-related problem associated with eye tissue) resulting
from implementation of CGTPs due to a lack of data.
2. Conventional Tissue
Conventional tissue refers to a wide range of HCT/Ps including
pericardium, dura mater, heart valves, skin allograft, bone allograft,
fascia, tendons, and ligaments. FDA's survey of the clinical literature
indicates that bone, skin and heart valve allografts each present a
different potential for communicable disease transmission risk and
graft failure, and thus different levels of potential benefits from
improved processing procedures and quality assurance steps in HCT/P
manufacture. The discussion that follows considers these three distinct
conventional tissue products and thus areas of potential benefit.
a. Bone allograft. An analysis of the incidence, nature, and
treatment of infection associated with bone allograft by Lord et al.
(Ref.9), demonstrates the importance of quality standards and process
requirements to prevent tissue contamination. Of the 283 patients in
their analysis who had received a massive allograft of bone, infection
developed in 33 cases (11.7 percent). The final outcome for those 33
patients was poor compared to the 250 uninfected patients. About 82
percent (27 of the 33 patients) of the infected allografts were
considered failures of treatment because amputation or resection of the
graft was required to control the infection. Potential sources of
contamination cited in the study include donor infection or
contamination introduced during processing (estimated to occur in as
many as 7 percent of the infected grafts), highlighting the critical
need for HCT/Ps that are free from contamination by communicable
disease agents. Other factors cited include duration of the
[[Page 68669]]
operation, loss of blood, injury to soft tissue, and skin sloughing
during the operation.
The importance of process validation is also implied by Hardin
(Ref.10) in a review of banked bone allograft processes. In describing
methods for sterilization, Hardin identifies ethylene oxide as one of
the chemicals used, but indicates that its effectiveness may
nonetheless be questionable, because of reports of graft failures in
which residues of ethylene oxide have been implicated, and some
experimental evidence indicating toxicity of ethylene oxide in human
tissues.
Based on an average rate of 0.057 for bone allograft failure due to
contamination (based on an estimated allograft infection rate of 0.07 x
an estimated 0.82 failure rate for infected bone allograft), and the
conservative assumption that all graft failures would be treatable
through repeat surgery to replace the bone allograft, the associated
healthcare costs could be on the order of $60 million per year
($59,679,928 = 0.057 x 44,000 x ($22,497 + $1,133)). This figure is
based on a national level estimate of 44,000 bone allografts per year
(Ref.11), and a mean hospital charge of $22,497 for Principle Procedure
142, Partial excision of bone (Ref. 28). Physician costs per
hospitalization are estimated to be $1,133, based on submitted charges
per person served in the Orthopedic Surgery Physician Specialty
category (Ref. 8).
The reported average length of hospital stay for bone surgery is
approximately 6.3 days (Ref. 28). The estimated cost of patient time
lost assumes that repeat surgery would require at least 1 week of time
away from work, at an estimated value of $957.20, based on a 40-hour
work week and average hourly compensation of $23.93 (Ref.32). This
yields an estimated total patient time cost of $2,400,658 (0.057 x
44,000 x $9357.20). Thus, the total annual cost of bone allograft
failure due to contamination is estimated to be approximately $62
million ($62,080,586 = $59,679,928 + $2,400,658).
If bone allograft failures result in amputation, the direct and
indirect costs would be significantly higher. For example, the direct
cost per hospitalization for lower extremity amputation is estimated to
be $30,820 based on AHRQ Healthcare Cost and Utilization Project (HCUP)
data (Ref. 23). Moreover, permanent disability following amputation
imposes extremely high costs on the patient, the patient's family, and
on society as a whole. The AHRQ HCUP data also report 5,200 in-hospital
deaths and a 4.5 percent death rate associated with these amputation
procedures.
FDA is uncertain about the extent to which the estimated cost
impact will be reduced through implementation of the CGTP final rule
for two reasons. First, many graft failures result from transplantation
procedures and other factors not related to bone allograft manufacture,
or from a combination of factors. Second, some establishments may have
already developed new bone processing methods that may greatly reduce
infection risk. If as much as 90 percent of the estimated risk is
actually attributable to other factors, or has already been addressed
through better manufacturing processes, the benefit from CGTPs applied
to the remainder of bone tissue processes and establishments would be
on the order of $6.2 million ($62,080,586 x 0.10) per year. The total
annualized cost of the CGTP final rule for all conventional tissue
banks is estimated to be $2.03 million to 2.07 million, and the
estimated total cost of treatment for infected bone allograft,
including hospitalization, physician's office visits and work loss is
$24,587.20 per occurrence. If implementation of the CGTP final rule
resulted approximately 84 fewer cases of infected bone allograft
requiring repeat surgery ($2,073,547 / $24,587.2 = 84.3), the benefits
of CGTPs would exceed the estimated total annualized costs for all
conventional tissue banks. This reduction in the number of cases of
bone allograft infection corresponds to a 3.3 percent reduction (84.3
fewer cases / 2,525.6 potential cases) in risk based on the information
used as the basis for this analysis.
b. Skin allograft. Skin allografts represent another type of HCT/P
that is critically dependent on processing and quality controls to
prevent the manufacture, distribution and/or use of contaminated
products. The clinical literature reports cases of cytomegalovirus
(CMV) transmission due to skin donor infection (Ref.12), and HIV
contamination from infected donor skin tissue and subsequent tissue
processing (Ref.13). CMV infections are usually not life-threatening in
healthy individuals, but present grave risks to the types of patients
who typically require skin grafts. In general, patients who have
suffered severe burns and require skin grafts are immunosuppressed as a
result of their injuries and are therefore susceptible to potentially
life-threatening CMV infections. These include pneumonitis, retinitis,
gastroenteritis, hepatitis, and neurological complications (Ref. 12).
Contamination of skin allograft can also significantly affect burn
patient survival. Because the clinical literature does not provide
summary estimates of the risk of contamination associated with skin
allograft, the agency is unable to quantify the level of associated
risk. Although implementation of the CGTP final rule is expected to
reduce the risk of contaminated skin allograft, and thereby improve
burn patient outcomes, FDA could not quantify this source of expected
patient benefits due to a lack of necessary information.
c. Heart Valve Allografts. Heart valve allografts, another of the
many types of conventional tissue products, provides another compelling
case for HCT/P production process validation and quality control. Human
heart valve contaminants not effectively removed in tissue processing
have resulted in serious infections that, at a minimum, require valve
replacement and may also result in patient death. Sources of
contamination of a heart valve allograft include the donor, the
environment during harvesting and processing, and the operating room
during implantation. Microbial contamination of human heart valves is
common at tissue harvesting, with reports of over 50 percent
contamination among valves retrieved in open mortuary areas. According
to a study by Kuehnert et al. (Ref.14) common contaminants found before
disinfection consist of gastrointestinal and skin flora (including
coliforms), viridans group streptococci, Staphylococcus aureus, S.
epidermidis, and Bacillus species. In general, bacterial contamination
can be effectively removed through standard disinfection procedures
used in most accredited conventional tissue banks. However, tissue that
remains contaminated with these pathogens, particularly Staphylococcus
and Streptococcus species, can cause early onset allograft valve
endocarditis. In contrast to bacterial contamination, reported rates of
fungal contamination of heart valve allograft are relatively low.
However, Kuehnert et al. report that rates vary widely (1.7 percent to
28.0 percent), and that the inclusion of anti-fungal drugs in tissue
disinfection regimens is not effective in eradicating fungal
contamination.
Fungal endocarditis is a rare but potentially fatal complication of
allograft heart valve replacement. According to Kuehnert et al., the
incidence of fungal endocarditis following surgery for heart valve
replacement with allograft is estimated to range from 0.3 percent to
1.4 percent (midpoint estimate of 0.85 percent). In one reported case,
the infected patient needed subsequent surgery to replace
[[Page 68670]]
the valve and required treatment with intravenous amphotericin B for
the following 8 weeks. In many cases, treatment is not successful and
death results. In one review, cited by Kuehnert et al., over 40 percent
of patients who had acquired fungal endocarditis after heart valve
allograft implantation died within 2 weeks of diagnosis.
In their study, Kuehnert et al. describe the process controls used
by AATB-affiliated establishments including the establishment,
validation and documentation of decontamination protocols. Because
these regimens have not been found effective against fungal
contamination, AATB-affiliated establishments routinely discard tissue
with documented fungal contamination. However, according to Kuehnert et
al., the supplier of over 85 percent of all heart valve allografts
(approximately 41,000 since 1984) does not follow AATB standards, but
instead follows a decontamination protocol that is reported to be
proprietary. This protocol apparently includes efforts to disinfect
rather than discard tissue with fungal contamination. However, efforts
to eradicate fungal contamination identified in processing can be
unsuccessful, and in this case, a false-negative culture following
processing results in tissue being distributed for use in patients.
The CGTP final rule requires that all establishments use validated
procedures and that HCT/Ps meet all release criteria before they are
made available for distribution. Based on the rates of infection and
mortality risk reported by Kuehnert et al., and an estimated 5,000 to
6,000 human heart valve allografts per year (these figures were
reported to the agency by the largest supplier of this type of HCT/P in
their comment on the proposed rule), there may be an estimated 43
(0.0085 x 5,000) to 51 (0.0085 x 6,000) cases of fungal endocarditis
each year. These cases of fungal endocarditis may further cause an
estimated 17 (0.0085 x 0.40 x 5000) to 20 patient deaths per year
(0.0085 x 0.40 x 6,000). Fungal endocarditis may result from a variety
of peri- or post-operative factors including infection of the valve
allograft itself. While highly uncertain, one comment suggested that as
many as one-third of all cases of fungal endocarditis may be caused by
contaminated valve allografts. Based on this information, FDA expects
that there may be as many as 14 to 17 cases of heart valve
contamination causing fungal endocarditis along with 5 to 7 patient
deaths each year. Changes in processing procedures based on the CGTP
requirements will help to avoid cases of fungal endocarditis and,
perhaps, some of the resulting deaths. Substantial health care cost
savings will also be achieved through improved processing controls and
avoided adverse events due to implementation of the CGTP final rule.
AHRQ reports 82,874 total hospital discharges for Principle
Procedure 43, Heart Valve Procedures in 2000 with a mean LOS of 11.1
days and mean hospital charges of $78,494 (Ref. 24). The AHRQ also
reports 4,986 in-hospital deaths (and a 6.0 percent death rate)
associated with these procedures. If patients undergoing this procedure
were to lose 2 weeks of time away from work, the value of this work
loss, based on a 40-hour work week and an average hourly compensation
of $ 23.93 (Ref. 32), would be $1,914 per case. Based on reported
average charges of $78,494 per hospitalization for implantation of a
heart valve allograft (Ref. 24), estimated physician charges of $6,796
per case, including repeat surgery and patient care during the average
11.1-day hospital stay, and 2 weeks of patient work loss, the total
cost of treating cases of heart valve contamination causing fungal
endocarditis would be between $1,220,862 (14 x ($78,494 + $6,796 +
$1,914.4)) and $1,482,475 (17 x ($78,494 + $6,796 + $1,914.4)). These
estimates should be viewed as conservative because they reflect only
the costs associated with contaminated heart valve allografts causing
fungal endocarditis, and do not consider the costs associated with the
more common bacteria-induced early onset allograft valve endocarditis.
No estimate of the potential benefit of CGTPs in reducing the cost of
treating early onset allograft valve endocarditis was generated due to
a lack of necessary information.
The total annualized costs of the CGTP final rule for conventional
tissue banks are estimated to be $2.03 million to $2.07 million. The
total costs associated with infected bone allografts and contaminated
heart valve allografts causing fungal endocarditis are estimated to be
between $61.3 million ($60.1 million + $1.2 million) and $61.6 million
($60.1 million + $1.5 million). If implementation of the CGTP final
rule were to reduce these estimated costs by 3.3 percent, the estimated
annual cost savings, or benefit, would exceed the estimated compliance
costs. Thus, a 3.3 percent reduction in the cost associated with only
two HCT/P-related problems would make the CGTP final rule cost
effective for the conventional tissue industry.
3. Hematopoietic Stem/Progenitor Cells
Promising outcomes from use of peripheral blood stem/progenitor
cells (PBSC) and cord blood-derived stem/progenitor cells (CBSC) in
lieu of bone marrow have resulted in increased collection and use of
these products in hematopoietic stem/progenitor cell transplants. For
example, recent studies have reported the use of PBSC (rather than bone
marrow) in 54 percent (Ref. 15) and 62 percent of cases, respectively
(Ref. 16). However, studies of hematopoietic stem/progenitor cell
products indicate that products manufactured by this industry may
become contaminated during collection and processing. Moreover, the
therapy-induced immunosuppression of the oncology patients who receive
these products places them at particularly high risk for serious
infection and subsequent mortality. Manufacturing methods conforming to
CGTP are necessary to prevent this threat to the safety and
effectiveness of hematopoietic stem/progenitor cell therapies. For
example, investigations of PBSC have reported that the large quantity
of blood that must be processed to obtain adequate numbers of
hematopoietic stem/progenitor cells resulted in large volumes of
cryopreserved cells received by patients. This process posed the risk
of increased toxicity, because of the amount of dimethyl sulfoxide used
for cryopreservation (Ref. 20).
Another quality concern with PBSC involves the maintenance of the
sterile integrity of the apheresis catheter and component throughout
the period of leukapheresis, cryopreservation, thawing, and transfusion
(Espinosa et al., 1996) (Ref. 17). Webb et al. (Ref. 18) reported a
2.41 percent rate of bacterial contamination in PBSC products, and a
13.7 percent rate of infection of patients receiving contaminated
products.
Although bacteremia-induced fever and other clinical sequelae are
generally considered reversible, infections present more serious risks
for hematopoietic stem/progenitor cell recipients than for the overall
population. Survival rates for hematopoietic stem/progenitor cell
transplantation are significantly reduced for patients who become
critically ill. In a study of survival rates among hematopoietic stem/
progenitor cell recipients admitted to an intensive care unit, Price et
al. (Ref. 16) found that patients with probable infection had a
significantly higher death rate (57 percent) compared to patients with
no probable infection (13 percent). Multiple regression analyses by
Price et al., controlling for other risk factors such as patient
intubation, type of transplant, source of hematopoietic stem/progenitor
cells, human leukocyte antigen compatibility, type of
[[Page 68671]]
malignancy and patient age, also found infection to be a significant
predictor of mortality.
Based on reported blood collection and transfusion statistics (Ref.
25), a total of 32,291 units of PBSCs were collected, and 18,123 units
transfused, in the United States in 1997 (the use of PBSCs has been
increasing steadily since that time). Thus, an estimated 60 patients
per year (18,123 PBSC transfusions x 0.024 x 0.137) could suffer
infection following receipt of contaminated PBSC, based on the reported
rates of 2.4 percent of patients receiving contaminated PBSC, 13.7
percent of those patients subsequently developing infection (Ref. 15),
and 18,123 hematopoietic stem/progenitor cell transplants performed in
1997. Costs of treating patients who become infected after receiving
contaminated hematopoietic stem/progenitor cell products are estimated
based on 8,985 AHRQ-reported total discharges for Principle Procedure
3, Bacterial Infection, Unspecified Site, with average hospital charges
of $21,221 per 6.9-day patient stay (Ref. 26). Estimated total health
care costs also include physician costs of $918 assuming one initial
in-hospital visit, and daily followup visits during the patient stay
(Ref. 8). Patient income loss is valued at $1,914 based on estimated
hourly compensation of $23.93 (Ref. 32) and an estimated 2 weeks away
from work. Thus, the total annual cost impact of infection following
transplant of contaminated PBSC products is estimated to be $1,443,180
(60 x ($21,221 + $918 + $1,914)).
In addition to health care and time away from work costs, reducing
the risk of contaminated PBSC products could result in avoiding 26
excess hematopoietic stem/progenitor cell patient deaths per year, due
to infection. This number reflects the excess mortality risk reported
for hematopoietic stem/progenitor cell recipients with infection versus
those without infection. It is based on the following: (18,123
transplant procedures per year) x (2.41 percent PBSC patients receiving
contaminated product) x (13.7 percent patients receiving contaminated
product develop infection) x (44 percent excess mortality risk for
hematopoietic stem/progenitor cell recipients with a probable
infection). This estimate suggests a risk of death due to infection
resulting from a contaminated hematopoietic stem/progenitor cell
transplant of approximately 0.14 percent (26 deaths / 18,123
hematopoietic stem/progenitor cell transplants). FDA currently has no
basis for predicting how many of these deaths might be avoided through
implementation of the CGTP final rule.
As bacterial contamination has also been documented in studies of
cord blood processing, the CGTP requirements for staff training and
process validation will likely support risk and cost reduction efforts
across the 25 CBSC establishments. For example, a study by Kogler et
al. (Ref. 18) found that, during the initial 6 months of a CB
collection program, the median bacterial contamination rate was 18
percent. After extensive training in sterile procedures for the staff
who collect cord blood, the contamination rate was reduced to 1
percent. Due to a lack of data regarding the incidence and risks
associated with CBSC procedures, FDA currently has no basis for
predicting the magnitude of benefits that might be realized from
implementation of the CGTP final rule in this HCT/P industry sector.
D. Summary of cGTP Benefits
This analysis of the potential benefits of the CGTP final rule has
considered its impact on major sectors of the HCT/P industry by
focusing on problems associated with HCT/Ps cited in the literature,
and the costs of correcting those problems. This review suggests that
current industry voluntary standards are not followed uniformly, and
that implementation of the CGTP final rule has the potential to
generate economic benefits by reducing communicable disease
transmission risks, improving product safety, and by reducing the costs
associated with correcting HCT/P related problems.
Table 13 of this document provides a summary of the particular
products, problems identified and their associated costs based on the
agency's survey of the literature. FDA estimated the associated health
care costs based on reported risks, national level database estimates
of the numbers of patients undergoing related procedures, and estimates
of the direct medical costs associated with those procedures. These
estimates also reflect the cost of work loss experienced by patients
undergoing treatment to correct HCT/P related problems.
Rather than attempting to generate point estimates of the benefits
of the CGTP rule, the agency has chosen to present the results of this
analysis of potential benefits in cost-effectiveness or break-even
terms. There are several reasons for this. First, the current or
baseline risks associated with the various types of HCT/Ps are unknown
because the data required to establish these risks is either not
readily available or is not currently collected by any entity. The lack
of comprehensive risk data for the HCT/P industry is due primarily to a
lack of mandatory reporting requirements for adverse health events
associated with human tissues, a situation that is addressed by the
reporting requirements of the CGTP final rule. Second, given that the
current baseline risks associated with various types of HCT/Ps are
uncertain, FDA has no basis for determining defensible estimates of the
degree to which implementation of the CGTP final rule might be expected
to reduce these already uncertain risks. Finally, while limited data
with which to characterize a few of the risks associated with a select
few of the many and diverse HCT/Ps, it is not possible to fully
characterize all of the potential problems associated with all of the
HCT/Ps that would be affected by this rule. Thus, it is not possible to
develop comprehensive estimates of the aggregate benefits of the CGTP
final rule.
Table 13.--Summary of CGTP Benefits
----------------------------------------------------------------------------------------------------------------
Cost-Effective
HCT/P Industry Sector HCT/P-Related Problem Avoided Treatment Estimated Cost of Percent Reduction
Outcome Treatment in Cost/Risk
----------------------------------------------------------------------------------------------------------------
Eye Tissue Primary Corneal Graft Repeat Surgery $.729 to $6.5 25%
Failure million
$15,844 per case
----------------------------------------------------------------------------------------------------------------
Conventional Tissue Bone Allograft Repeat Surgery/ $62 million 3.2%
Infection/Graft Amputation $24,587 per case
Failure
----------------------------------------------------------------------------------------------------------------
[[Page 68672]]
Conventional Tissue Heart Valve Fungal Repeat Surgery (Death) $1.2 to $1.5 3.3%
Endocarditis million
$87,204 per case
----------------------------------------------------------------------------------------------------------------
Hematopoietic Stem/ PBSC Transplant Hospitalization $1.4 million Unable to
Progenitor Cells Infection (Death) $24,053 per case Determine
26 deaths
----------------------------------------------------------------------------------------------------------------
Additional uncertainties associated with estimating the benefits of
the CGTP final rule include: The actual extent of current compliance in
each of the affected industry sectors, the direct impact of HCT/P
related problems on patient outcomes, and the precise size of the
affected patient populations. Because of the limits of available data,
the forgoing analysis has focused on a limited set of HCT/Ps. It is not
certain how well these data represent the most critical areas, or
actual levels of risk, associated with the many and varied products
produced by the HCT/P industry. For some products, such as
demineralized bone, the industry has achieved important advances in
processing that have improved the safety and effectiveness of products.
Thus, the analysis of benefits based on problem reports from several
years ago, may overstate the potential for improvements in the current
industry practice. In other cases, the publication of the recent
reports suggests that deficiencies still exist within current
practices. These areas present important opportunities to avoid product
failures due to HCT/P-related problems, which lead to unnecessary
communicable disease transmission risks and greater health care costs.
E. Small Entity Impacts
The Regulatory Flexibility Act requires agencies to assess whether
a rule may have a significant economic impact on a substantial number
of small entities. Based on size standards established by the SBA, a
small establishment in this industry sector (NAICS code 621991, Blood
and Organ Banks) has annual receipts of less than $8.5 million (Refs.
21 and 22). In every sector of the HCT/P industry, the majority of
establishments are estimated to be classified as small entities.
However, because of the large number of entities currently following
industry voluntary standards, the increase in costs is expected to be
limited primarily to establishments that do not follow those existing
standards. To assess the impact of the CGTP rule on small businesses,
FDA first calculated the ratio of average compliance costs to average
annual revenues, assuming that all establishments will incur similar
costs. The small entity impacts estimated below also focus on
establishments that will be newly compliant under the CGTP final rule,
and thus will experience the greatest potential new cost burden.
Although current quality management practices at nonaccredited
establishments may vary, and not every facility will incur every new
cost estimated in table 4 of this document, the analysis that follows
also considers a worst-case scenario in which every estimated cost is
incurred by an establishment, to provide additional insight as to the
maximum potential impact on small entities. While some firms may have
lower than estimated average revenues, making them potentially more
sensitive to cost increases, FDA does not know the distribution of
firms by revenues because this information is not readily available.
Therefore, the agency requested detailed industry comment regarding our
average annual revenue assumptions in the CGTP proposed rule. To the
extent possible, information obtained during the comment period has
been incorporated into this analysis of the small entity impacts of the
CGTP final rule. The results of this analysis are summarized in table
14 of this document.
A 1995 study of conventional tissue banks (Ref. 19) reports average
annual revenues of $1.23 million per establishment, which translates
into $1.45 million per establishment (in the year 2002 dollars) based
on inflation data reported by the Bureau of Labor Statistics (Ref. 27).
Most eye banks, conventional tissue banks and hematopoietic stem/
progenitor cell establishments were assumed to have a comparable level
of average revenues in the proposed rule, and that assumption is
retained here.
Within the eye banking industry, experts estimate that virtually
all of the 134 establishments would be classified as small, and all are
believed to follow the current industry (EBAA) standards. The average
annual revenue per eye bank is estimated at $1.45 million. If an eye
bank were to incur every new cost estimated for establishments in that
industry sector, the total cost impact, including total one-time and
annual costs, would be $39,750, which represents 2.7 percent ($39,750 /
$1.45 million) of estimated annual revenues. Average annualized
compliance costs are estimated to be $12,087 ($1,619,659 total
annualized costs / 134 small eye banks), and represents 0.83 percent
($12,087 / $1.45 million) of average annual revenues per firm.
In the conventional tissue banking industry, an estimated 75 to 80
percent of the total of 166 establishments may be classified as small
entities. Industry experts also estimate that 75 to 80 percent of those
establishments currently follow AATB standards, which generally meet or
exceed the requirements of the CGTP final rule. Based on the assumed
levels of increased effort and costs shown in table 4 of this document,
the remaining 20 to 25 percent of small establishments that do not
follow current AATB standards could incur up to $66,621 in total
incremental costs, including both one-time and annual costs, assuming
that every potential area of new quality management effort will be
needed under the worst-case scenario. The average annual revenue per
small conventional tissue bank is estimated at $1.45 million. Thus, the
estimated maximum potential new costs would represent approximately 4.6
percent ($66,621 / $1.45 million) of this average annual revenue
figure. The average total annualized cost for a small conventional
tissue bank is estimated to be $11,678 ($1,506,433 total annualized
costs / 129 small conventional tissue banks), and represents 0.8
percent ($11,678 / $1.45 million) of average annual revenues.
The agency estimates that approximately 250 hematopoietic stem/
progenitor cell establishments may be classified as small entities, and
that these establishments have average annual revenues of $1.45
million. An
[[Page 68673]]
estimated 200 (or 80 percent) of these small establishments follow the
current FACT or AABB standards but will incur some additional costs. If
one of these establishments were to incur new costs for each of the
relevant provisions identified in table 4 of this document, the total
incremental cost per establishment, including total one-time and annual
costs, would be approximately $21,602. This figure represents
approximately 1.5 percent ($21,602 / $1.45 million) of estimated annual
revenues. The estimated 50 (or 20 percent of) small hematopoietic stem/
progenitor cell establishments that do not currently comply with AABB
or FACT standards will incur greater costs, as shown in table 4 of this
document. If one of these establishments were assumed to incur every
new cost identified in the cost analysis, the total one-time and annual
costs would be approximately $83,483. This represents approximately 5.8
percent ($83,483 / $1.45 million) of average annual revenues.
The average annualized costs incurred by small hematopoietic stem/
progenitor cell establishments would also vary depending on current
practices and the degree to which establishments follow AABB or FACT
standards. If a small hematopoietic stem/progenitor cell establishment
is currently following industry standards, the average annualized cost
associated with the CGTP final rule is estimated to be $8,367
($1,673,301 total annualized costs / 200 small hematopoietic stem/
progenitor cell establishments), and represents approximately 0.58
percent ($8,367 / $1.45 million) of the average annual revenue of these
firms. However, if a small establishment is not following the current
industry standards, a greater level of new effort will be required for
quality assurance and quality management. The average annualized cost
per small establishment not following current industry standards is
estimated to be $43,207 ($2,160,341 total annualized costs / 50 small
hematopoietic stem/progenitor cell establishments), and represents
about 3 percent ($43,207 / $1.45 million) of average annual revenue.
Consultants estimate that two-thirds of all ART establishments
could be classified as small entities, and have average annual revenues
of approximately $2.1 million. A typical ART establishment is expected
to incur average annual and annualized costs of $768. This figure
represents approximately 0.04 percent ($768 / $2.1 million) of average
annual revenues.
According to estimates by a semen banking industry expert,
approximately 100,000 total daily intake (TDI) units are produced each
year from collected and processed semen donations. An estimated 95
percent of that total production is handled by the largest 20
commercial establishments. Nineteen of these largest 20 establishments
are estimated to have average annual revenues of approximately $2.4
million, and only 1 establishment is estimated to have revenues greater
than $8.5 million per year. The remaining 5 percent of industry
production, or 5,000 TDI units, are processed by very small semen banks
that typically function within a physician office practice (e.g., that
of an obstetrician/gynecologist (Ob/Gyn)). Semen banking in these
establishments is generally offered as an additional service to
patients receiving fertility treatment, and is not a primary line of
business.
The annual revenue for these individual physician practices is
estimated to be $692,000 per year, based on the average annual practice
revenue per self-employed physician in the Ob/Gyn specialty category
reported as $627,000 in 1998 (Ref. 20), adjusted to year 2002 dollars
based on inflation data reported by the Bureau of Labor Statistics
(Ref. 27). Thus the majority of semen banks would be considered small
entities.
The average annual and annualized costs associated with the
inspection and enforcement provisions are estimated to be $768 per
affected ART establishment and semen bank. This figure represents
approximately 0.03 percent ($768 / $2.4 million) of average annual
revenues for the 19 small commercial semen banks, and about 0.11
percent ($768 / $692,000) for individual Ob/Gyn ART establishments and
small physician practice-based semen banks.
Although these cost figures account for a much larger percentage of
individual physician practice income, the semen banking provided by
these establishments is considered to represent a small part of their
overall business. For the smallest banks, the estimated 5,000 TDI units
supplied by the estimated 90 establishments in this category translate
to an average volume of 55 units per establishment per year. With an
estimated price of $95 to $145 per TDI unit (Ref. 30) and an estimated
profit of 15 percent, these banks would realize, on average, a net
income of $12.40 to $19.00 per unit, or a total net income of $682 to
$1,045 for 55 units. This income would represent only 0.1 percent ($682
/ $692,000) to 0.15 percent ($1,045 / $692,000) of the estimated annual
practice revenue per self-employed physician in the Ob/Gyn specialty
category.
In summary, the majority of establishments within each sector of
the HCT/P industry are expected to qualify as small business entities.
The actual cost impact on these entities is uncertain, because of the
limited information available with which to describe current practices
and the degree to which individual establishments follow voluntary
industry standards within each HCT/P industry sector. Based on the
limited available data and industry expert opinions, the agency
estimates impacts that would result in an average annualized cost per
small establishment subject to CGTPs in their entirety ranging from
$8,367 to $12,087 for establishments that currently follow industry
standards, and $43,207 for establishments that do not currently follow
industry quality standards. These annualized costs represent 0.6
percent to 0.83 percent of estimated average annual revenues for firms
currently following industry standards, and 3 percent of average annual
revenues for firms not following industry standards.
The worst-case analysis assumes that an affected small entity will
incur new costs for every provision of the CGTP final rule. While this
represents a highly unlikely scenario for nearly all firms in the HCT/P
industry sectors subject to CGTPs in their entirety, this analysis does
provide a useful illustration of the maximum potential burden of the
CGTP final rule. The agency estimates worst-case average annualized
costs per small establishment ranging from $21,602 to $66,621 for
establishments that currently follow industry standards, and $83,483
for establishments that do not currently follow industry quality
standards. These worst-case annualized costs for small entities,
expressed as a percentage of estimated average annual revenue, range
from 1.5 percent to 4.6 percent for firms currently following industry
standards, and represent 5.8 percent of estimated average annual
revenues for firms not following industry standards.
Establishments handling reproductive tissue are subject only to the
inspection and enforcement provisions of the CGTP final rule as they
apply to donor eligibility requirements under subpart C of part 1271.
Small ART establishments and semen banks are expected to incur average
annualized costs of $768, which represent between 0.03 and 0.11 percent
of average annual revenues. The results of FDA's analysis of small
entity impacts are summarized in table 14 of this document.
[[Page 68674]]
Table 14.--Summary of Small Business Impacts
----------------------------------------------------------------------------------------------------------------
Average
No. of Small Average Annual Average Annualized Cost Worst-Case Costs Worst-Case Costs
Establishments by Revenue per Small Annualized Cost as a Percentage for an affected as a Percentage
Industry Sector Establishment per Small of Average Small of Average
(in millions) Establishment Revenue Establishment Revenue
----------------------------------------------------------------------------------------------------------------
Eye Banks (134 $1.45 $12,087 0.83% $39,750 2.7%
Establishments)
----------------------------------------------------------------------------------------------------------------
Conventional $1.45 $11,678 0.8% $66,621 4.6%
Tissue (129
Establishments)
----------------------------------------------------------------------------------------------------------------
Stem/Progenitor $1.45 $8,367 0.6% $21,602 1.5%
Cell
Establishments
Following
Industry
Standards (200
Establishments)
----------------------------------------------------------------------------------------------------------------
Stem/Progenitor $1.45 $43,207 3% $83,483 5.8%
Cell
Establishments
Not Following
Industry
Standards (50
Establishments)
----------------------------------------------------------------------------------------------------------------
ART $2.1 $768 0.04% $768 0.04%
Establishments
(260
Establishments)
----------------------------------------------------------------------------------------------------------------
Ob/Gyn and small $0.692 $768 0.11 $768 0.11
physician based
practices
----------------------------------------------------------------------------------------------------------------
Semen Banks (19 $2.4 $768 0.03% $768 0.03%
Establishments)
----------------------------------------------------------------------------------------------------------------
The agency is uncertain about the accuracy of these estimates,
however, because of the lack of revenue data for individual
establishments. Because of the importance of this information in
accurately assessing the impact on small entities, the agency requested
detailed industry comment on individual firm revenues, the percentage
of establishments that qualify as small entities, the percentage of
those establishments that comply with current industry quality
standards and the extent of their compliance, and the specific areas
where industry anticipates substantial differences between current
manufacturing practices and the quality assurance elements specified
under the CGTP final rule. For those areas of identified difference,
the agency further requested estimates of the resources and costs
required for establishment compliance. This analysis has incorporated
information received during the comment period to the extent possible.
Please see our responses to comments 172 through 197 at section III.F.
of this document for details.
Although the CGTP final rule will impose some costs on small
entities involved in the manufacture of HCT/Ps, the agency believes
that this approach represents an effective means of protecting patient
safety and public health. The less burdensome alternatives to the CGTP
final rule involve fewer requirements for small entities (the vast
majority of entities in this industry), but fail to provide fundamental
assurances of product quality and safety. Reliance on industry
professional organization voluntary standards or published FDA guidance
for good tissue practice, rather that establishing a regulatory
requirement, would not ensure uniform or consistent compliance and
would preclude the agency's ability to effectively monitor HCT/Ps to
ensure public health and safety. Given that each trade organization
varies in their standards or guidelines, regulatory requirements for
good tissue practice would help to ensure consistency among
manufacturers and across the various sectors of the HCT/P industry.
Further, the adverse reaction reporting requirements of the CGTP final
rule will provide valuable information that will allow the agency to
identify and respond to emerging public health and safety risks
associated with HCT/Ps. FDA finds that the CGTP final rule will enhance
both public health and public confidence in the safety and quality of
the nation's supply of HCT/Ps, while imposing only a minimum burden on
the affected entities.
Another alternative would involve waiving some of the requirements
for small establishments. However, as noted previously, nearly all
establishments in this industry are small. Moreover, this alternative
would increase HCT/P safety risks if small establishments that
currently follow voluntary industry standards for good tissue practice
choose to discontinue this practice due to an FDA-granted waiver.
Furthermore, documentation and record retention provisions ensure that
HCT/Ps can be tracked to their source in the event of infection or
other adverse reactions that result from donor tissue characteristics.
In summary, the agency believes that abridged requirements for
CGTP, based on voluntary standards or facility size criteria, would
provide inadequate protection against the risk of communicable disease
transmission. Most notably, the current absence of regulation allows
some establishments handling human tissues to ignore the standards
established by industry professional associations and followed by a
majority of entities in all sectors of the HCT/P industry.
FDA has made a number of revisions to this final rule, many in
response to public comments on the proposed CGTP rule, that are
expected to reduce the overall compliance burden on affected entities.
Provisions under Sec. 1271.160(c) have been revised to require
audits periodically rather than annually as stipulated under the CGTP
proposed rule. However, the cost estimates presented in this analysis
of economic impacts retain the assumption that audits will impose an
annual burden so as to generate conservative estimates of overall
compliance costs. The provisions proposed under Sec. 1271.160(f),
requiring complete validation of custom computer software used for
making HCT/P-related decisions or determinations, have been changed to
a requirement for validation or verification as appropriate.
[[Page 68675]]
Verification is a less burdensome alternative that would apply to
software not relied upon for making donor eligibility or HCT/P
suitability decisions or determinations (e.g., inventory).
The proposed requirement under Sec. 1271.180 for an annual review
of all procedures has been removed, as has the requirement for prior
authorization of any deviation from an established procedure.
Provisions proposed under Sec. 1271.220(b) (process controls)
requiring procedures for the use and removal of processing material
have been deleted in response to comments. Proposed provisions under
Sec. 1271.230(e) requiring validation of all process changes and
process deviations now require validation only of process changes.
Requirements proposed under Sec. 1271.265(e) for HCT/P packaging
validation now allow for packaging validation or verification (a less
burdensome alternative) as appropriate.
Provisions proposed under Sec. 1271.290(d) and (e) requiring
establishments to ensure each HCT/P is tracked from donor to recipient
and from recipient to donor, now only require that establishments have
a method of tracking in place. This will reduce the burden on affected
entities because they no longer bear the responsibility of ensuring
tracking with respect to their consignees. The proposed requirement for
the reporting of all HCT/P deviations under Sec. 1271.350(b) now only
applies to distributed HCT/Ps and not to those still in inventory.
Finally, language has been added to Sec. 1271.420(b) to allow
transportation to the consignee under quarantine of HCT/Ps offered for
import to facilitate more rapid release of imported tissue products.
As part of the development process for this final rule, FDA
conducted an extensive outreach program in an effort to inform affected
small entities and to request input regarding the potential economic
impact. Representatives from CBER have given presentations on good
tissue practice related issues at the annual conferences of many of the
professional associations representing affected entities including
ASRM, AATB, EBAA, and others. The agency has also engaged in outreach
activities directed toward interested consumer groups such as RESOLVE
and the American Infertility Association. At their request, FDA also
held individual meetings with ASRM, EBAA, and AATB to discuss specific
concerns regarding the impact of the CGTP rule. Some of these
presentation materials and meeting minutes are available on the CBER
Web page at http://www.fda.gov/cber/tissue/min.htm. Additional
materials associated with the CGTP rule are available online at http://www.fda.gov/cber/tissue/docs.htm. Finally, in the proposed rule, FDA
requested industry comment regarding the many assumptions upon which
this analysis of economic impacts was based. In particular, we
requested detailed industry comment regarding our estimates of: The
number and type of entities affected, the extent of CGTP, compliance
rates for firms in various sectors of the HCT/P industry, and the level
of compliance costs. To the extent possible, we have incorporated these
comments and our responses into the preamble and analysis of economic
impacts of this final rule.
The specific requirements for good tissue practice, the required
recordkeeping, and the required types of professional skills are
described in the economic analysis provided previously. This analysis
includes an accounting of all major cost factors, with the exception of
the reduced potential liability currently encountered by those marginal
tissue establishments that fail to provide the level of protection from
infectious disease that is considered a standard of good practice in
other sectors of the tissue-based product industry. The relevant
Federal rules that are related to this final rule are discussed in
section II of this document. This economic analysis provides a summary
of the private industry standards that overlap this final Federal
standard, but as discussed, there is no current regulation of tissue
that will duplicate this final rule. Consequently, FDA finds that this
final rule will enhance both public health and public confidence in the
safety and utility of HCT/Ps, while imposing only a minimum burden on
the affected industry sectors.
VI. Environmental Impact
The agency has determined under 21 CFR 25.30(h) and (j) that this
action is of a type that is categorically excluded from the preparation
of an environmental assessment because these actions, as a class, will
not result in the production or distribution of any substance and
therefore will not result in the production of any substance into the
environment.
VII. Federalism Assessment
Executive Order 13132, dated August 4, 1999, establishes the
procedure that Federal agencies must follow when formulating and
implementing policies that have federalism implications. The Executive
order described nine fundamental federalism principles, stressing the
importance and sovereignty of State and local governments, and the
contributions of individual states and communities to the development
of enlightened public policy. Principles of federalism are inherent in
the very structure of the Constitution and formalized in and protected
by the tenth amendment. Regulations have federalism implications
whenever they have a substantial direct effect on the States, on the
relationship between the National Government and the States, or on the
distribution of power and responsibilities among the various levels of
government. Whenever a regulation has this result, the agency must
prepare a federalism assessment.
The Executive order directs Federal agencies to:
Encourage States to develop their own policies to achieve
program objectives and to work with appropriate officials in other
States;
Where possible, defer to the States to establish
standards;
In determining whether to establish uniform national
standards, consult with appropriate State and local officials as to the
need for national standards and any alternatives that would limit the
scope of national standards or otherwise preserve State prerogatives
and authority; and
Where national standards are required by Federal statutes,
consult with appropriate State and local officials in developing those
standards.
In the proposed rule (66 FR 1508 at 1551), we made the statement
that we had analyzed the proposed rule in accordance with the
principles set forth in Executive Order 13132, and that the proposed
rule may raise federalism implications because it could preempt States'
laws regarding donated human cells and tissues. We then invited
comments from elected State and local government officials on:
The need for the proposed CGTP to prevent communicable
disease transmission through HCT/Ps;
Alternatives that would limit the scope of such national
requirements or otherwise preserve State prerogatives and authority;
The proposed CGTP provisions; and
Any other issues raised by the proposed rule that could
affect State laws and authorities.
We received no comments from State officials on federalism issues.
This final rule represents the exercise of a core Federal function:
``prevent[ing] the introduction, transmission, or spread of
communicable diseases from foreign countries into the States or
possessions, or from one State or possession into any other State or
possession'' (section 361(a) of the PHS
[[Page 68676]]
Act; 42 U.S.C. 264). To prevent the transmission of communicable
disease in the United States, including the interstate transmission of
disease, uniform national standards for HCT/Ps are necessary. No State
official commented otherwise. For these reasons, this rule is
consistent with the federalism principles expressed in Executive Order
13132.
However, we received two comments requesting that we clearly state
that this rulemaking's provisions preempt state tissue regulations.
We decline to make this statement. Section 361 was recently amended
to provide,
Nothing in this section or section 363 [42 U.S.C. 266], or the
regulations promulgated under such sections, may be construed as
superseding any provision under State law (including regulations and
including provisions established by political subdivisions of
States), except to the extent that such a provision conflicts with
an exercise of Federal authority under this section or section 363.
(section 361(e); 42 U.S.C. 264(e)).
Accordingly, consistent with this provision, establishments must
comply with applicable State law and regulations, unless the State
provisions conflict with this exercise of Federal authority under
section 361. In the event of such a conflict, these regulations would
preempt the State provisions under ordinary principles of preemption.
(Geier v. Honda, 529 U.S. 861 (2000).)
VIII. The Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-3520). A
description of these provisions is shown as follows with an estimate of
the annual reporting and recordkeeping burden. Included in the estimate
is the time for reviewing the instructions, searching existing data
sources, gathering and maintaining the data needed, and completing and
reviewing each collection of information.
Title: Current Good Tissue Practice for Human Cell, Tissue, and
Cellular and Tissue-Based Product Establishments; Inspection and
Enforcement.
Description: Under the authority of section 361 of the PHS Act, FDA
is requiring certain HCT/P establishments to follow CGTP, which
includes information collection provisions such as the establishment
and maintenance of SOPs, recordkeeping, reporting, and labeling of the
HCT/Ps. The CGTP information collection provisions in this rulemaking
provide: (1) Additional measures for preventing the introduction,
transmission, or spread of communicable diseases; (2) step-by-step
consistency in the manufacturing of the HCT/P; (3) necessary
information to FDA for the purpose of protecting public health and
safety; (4) accountability in the manufacturing of HCT/Ps; and (5)
information facilitating the tracking of an HCT/P back to its original
source or to a consignee.
Table 15 lists provisions that require reporting or disclosure of
information to third parties, the Federal Government, or the public.
Section 1271.155(a) permits the submission of a request for FDA
approval of an exemption or an alternative from any requirement in
subpart C or D of part 1271. Section 1271.290(c) requires the
establishment to affix a distinct identification code to each HCT/P
relating the HCT/P to the donor and all records pertaining to the HCT/
P. Whenever an establishment initially distributes an HCT/P to a
consignee, Sec. 1271.290(f) requires the establishment to inform the
consignee, in writing, of the product tracking requirements and the
methods the establishment uses to fulfill the requirements. Non-
reproductive HCT/P establishments described in Sec. 1271.10 are
required under Sec. 1271.350(a)(1) and (b)(1) to report to FDA adverse
reactions (defined in Sec. 1271.3(y)) and HCT/P deviations (defined in
Sec. 1271.3(dd)). Section 1271.370(b) and (c) requires establishments
to include specific information either on the HCT/P label or in the
package insert.
Table 16 lists recordkeeping provisions under this final rule.
Nonreproductive HCT/P establishments are required to prepare and
maintain written SOPs to meet the core CGTP requirements for all steps
performed in the manufacturing of HCT/Ps. As calculated in table 16 of
this document, the preparation of the SOPs would result in a one-time
impact on establishments and, once composed and/or reviewed for
compliance, SOPs would only be updated as necessary.
The requirement for reporting, SOPs, and recordkeeping in proposed
Sec. Sec. 1271.160(d)(3), 1271.160(f), 1271.170(d), 1271.195(a),
1271.210(a) and (b), 1271.220(b), 1271.225(b), 1271.230(b) and (d),
1271.270(c), 1271.290(f), and 1271.350(c) are not included in the final
rule.
The SOP provisions under part 1271 include: (1) Sec.
1271.160(b)(2) (receiving, investigation, evaluating, and documenting
information relating to core CGTP requirements received from other
sources and for sharing information with consignees and other
establishments); (2) Sec. 1271.180(a) (to meet core CGTP requirements
for all steps performed in the manufacture of HCT/Ps); (3) Sec.
1271.190(d)(1) (facility cleaning and sanitization); (4) Sec.
1271.200(b) (cleaning, sanitizing, and maintenance of equipment); (5)
Sec. 1271.200(c) (calibration of equipment); (6) Sec. 1271.230(a)
(verification or validation of changes to a process); (7) Sec.
1271.250(a) (controls for labeling HCT/Ps); (8) Sec. 1271.265(e)
(receipt, pre-distribution shipment, availability for distribution, and
packaging and shipping of HCT/Ps); (9) Sec. 1271.265(f) (suitable for
return to inventory); (10) Sec. 1271.270(b) (records management
system); (11) Sec. 1271.290(b)(1) (system of HCT/P tracking); and,
(12) Sec. 1271.320(a) (review, evaluation, and documentation of all
complaints).
Part 1271 requires the following additional recordkeeping
provisions listed under Table 16. Section 1271.155(f) requires an
establishment operating under the terms of an exemption or alternative
to maintain documentation of the terms and date of FDA approval.
Section 1271.160(b)(3) requires documentation of corrective actions
taken as a result of an audit of the quality program. Section
1271.160(b)(6) requires documentation of HCT/P deviations. Section
1271.160(d) requires documentation of computer validation or
verification activities and results when computers are used to comply
with the core CGTP requirements for its intended use. Section
1271.190(d)(2) requires documentation of all significant facility
cleaning and sanitation. Section 1271.195(d) requires documentation of
environmental control and monitoring activities. Section 1271.200(e)
requires documentation of all equipment maintenance, cleaning,
sanitizing, calibration, and other activities. Section 1271.210(d)
requires documentation of the receipt, verification, and use of each
supply or reagent. Section 1271.230(a) requires documentation of
validation activities when the results of a process cannot be fully
verified by subsequent inspection and tests. Section 1271.230(c)
requires documentation of the review and evaluation of a process and
revalidation of the process, if necessary, when any changes to a
validated process occur. Sections 1271.260(d) and (e) require
documentation of the storage temperature of HCT/Ps and any corrective
action taken when acceptable storage conditions are not met. Section
1271.265(c)(1) requires documentation that all release criteria are met
before distribution of an HCT/P. Section
[[Page 68677]]
1271.265(c)(3) requires documentation of any departure from a procedure
at the time of occurrence. Section 1271.265(e) requires documentation
of the receipt, pre-distribution shipment, distribution, and packaging
and shipping of HCT/Ps. Section 1271.270(a) requires documentation of
each step in manufacturing required in subparts C and D.
Section 1271.270(e) requires documentation of the name and address,
and a list of responsibilities of any establishment that performs a
manufacturing step for you. Sections 1271.290(d) and (e) require
documentation of the disposition of each non-reproductive HCT/P as part
of its tracking method. Section 1271.320(b) requires an establishment
to maintain a record of each complaint that it receives, including a
review and evaluation.
Section 1271.270(d) requires the retention of all records for a
period of 10 years after their creation. Records pertaining to a
particular nonreproductive HCT/P are required to be retained at least
10 years after the date of administration. If the date of
administration is not known, then records are required to be retained
at least 10 years after the date of the HCT/P's distribution,
disposition, or expiration, whichever is latest. This retention time is
necessary because certain nonreproductive HCT/Ps have long storage
periods. In addition, advances in medical technology have created
opportunities for diagnosis and therapy for up to 10 years after
recipient exposure to an HCT/P from a donor later determined to be at
risk for communicable disease agents or diseases.
Description of Respondents: For-profit and not-for-profit
institutions.
As required by section 3506(c)(2)(B) of the PRA, we provided an
opportunity for public comment on the information collection
requirements of the proposed rule (66 FR 1508 at 1548). No comments on
the information collection burden estimate were submitted to the
docket. However, we respond to comments on the utility of the
information collection in section III of this document, e.g., response
to comment 68 addresses the utility and burden of retaining facility
cleaning and sanitation records for 10 years.
FDA estimates the burden of this collection of information as
follows:
Table 15.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
21 CFR Section Respondents per Response Responses Response Total Hours
----------------------------------------------------------------------------------------------------------------
1271.155(a) 1,302 1 1,302 3 3,906
----------------------------------------------------------------------------------------------------------------
1271.290(c) 93 52.2 4,855 0.08 388
----------------------------------------------------------------------------------------------------------------
1271.290(f) 227 1 227 1 227
----------------------------------------------------------------------------------------------------------------
1271.350(a)(1) 792 6 4,752 1 4,752
----------------------------------------------------------------------------------------------------------------
1271.350(b)(1) 792 2 1,584 1 1,584
----------------------------------------------------------------------------------------------------------------
1271.370(b) and 93 52.2 4,855 0.25 1,214
(c)
----------------------------------------------------------------------------------------------------------------
Total 12,071
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Table 16.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Recordkeepers Recordkeeping Records Record
----------------------------------------------------------------------------------------------------------------
One-time Burden (Creation of SOPs) 93 12 1,116 16 17,856
--------------------------------------------------------------------------
134 3 402 16 6,432
----------------------------------------------------------------------------------------------------------------
One-time Burden (Review of existing 699 12 8,388 8 67,104
SOPs for compliance)
--------------------------------------------------------------------------
134 9 1,206 8 9,648
----------------------------------------------------------------------------------------------------------------
SOP Maintenance (See previous list of 792 12 9,504 2 19,008
12 SOPs)
----------------------------------------------------------------------------------------------------------------
1271.155(f) 792 1 792 0.25 198
----------------------------------------------------------------------------------------------------------------
1271.160(b)(3) 93 12 1,116 1 1,116
----------------------------------------------------------------------------------------------------------------
1271.160(b)(6) 227 12 2,724 1 2,724
----------------------------------------------------------------------------------------------------------------
1271.160(d) 227 12 2,724 1 2,724
----------------------------------------------------------------------------------------------------------------
1271.190(d)(2) 93 12 1,116 1 1,116
----------------------------------------------------------------------------------------------------------------
1271.195(d) 227 12 2,724 1 2,724
----------------------------------------------------------------------------------------------------------------
1271.200(e) 93 12 1,116 1 1,116
----------------------------------------------------------------------------------------------------------------
[[Page 68678]]
1271.210(d) 93 12 1,116 1 1,116
----------------------------------------------------------------------------------------------------------------
1271.230(a) 227 12 2,724 1 2,724
----------------------------------------------------------------------------------------------------------------
1271.230(c) 360 1 360 1 360
----------------------------------------------------------------------------------------------------------------
1271.260(d) 227 12 2,724 0.25 681
----------------------------------------------------------------------------------------------------------------
1271.260(e) 93 365 33,945 0.08 2,716
----------------------------------------------------------------------------------------------------------------
1271.265(c)(1) 227 1,079.8 245,105 0.08 19,608
----------------------------------------------------------------------------------------------------------------
1271.265(c)(3) 592 1 592 1 592
----------------------------------------------------------------------------------------------------------------
1271.265(e) 93 1,622.6 150,905 0.08 12,072
----------------------------------------------------------------------------------------------------------------
1271.270(a) 227 1,079.8 245,105 0.25 61,276
----------------------------------------------------------------------------------------------------------------
1271.270(e) 227 2 454 0.5 227
----------------------------------------------------------------------------------------------------------------
1271.290(d) and (e) 93 1,622.6 150,905 0.25 37,726
----------------------------------------------------------------------------------------------------------------
1271.320(b) 93 5 465 1 465
----------------------------------------------------------------------------------------------------------------
Total 271,329
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Under this final rule, 12 SOPs are required as previously
described. FDA is assuming that approximately 93 nonreproductive HCT/P
establishments would create all 12 SOPs, and 134 nonreproductive HCT/P
establishments would create 3 SOPs, for a total of 1,518 records; and
we estimate that it would take 16 hours per new SOP for a total of
24,288 hours as a one-time burden. We estimate that up to 12 SOPs would
already exist for each nonreproductive HCT/P establishment as a result
of complying with current applicable regulations or following industry
organizational standards. We estimate that approximately 699
nonreproductive HCT/P establishments would review all 12 SOPs, and 134
nonreproductive HCT/P establishments would revise 9 SOPs. Each review
would take approximately 8 hours per SOP for a total one-time burden of
76,752 hours.
Once the SOPs are created, annual SOP maintenance of existing SOPs
is estimated to involve 2 hours annually per SOP. An additional hour
for clerical time is added to the 1 hour per SOP stated in the proposed
rule. Annual total hours for maintaining the SOPs is estimated at
19,008 hours.
In some cases, the estimated burden may appear to be lower or
higher than the burden experienced by individual establishments. The
estimated burden in these charts is an estimated average burden, taking
into account the range of impact each regulation may have. In
estimating the burden, FDA compared the regulations with the current
voluntary standards of a number of industry organizations, such as,
AATB, EBAA, AABB, FACT, NMDP, and CAP. In those cases where a voluntary
industry standard appears to be equivalent to a regulation, FDA has
assumed that any reporting or recordkeeping burden is a customary and
usual business practice of establishments who are members of those
organizations and no additional burden is calculated here. In some
cases establishments affected by this rule may already be required to
comply with regulations for manufacturers of human drugs or biological
products, e.g., 21 CFR parts 210, 211, 312, 314, 600, and 606. FDA
attributes the decrease in total burden hours in the final rule
(283,400 hours) from the total burden hours in the proposed rule
(621,573 hours) to:
Not including certain proposed information collection
burden in the final rule;
Not applying the information collection burden to
reproductive HCT/P establishments; and
Industry strengthening their current standards.
FDA has estimated the reporting (table 15 of this document) and
recordkeeping (table 16 of this document) burdens based upon our
institutional experience with comparable recordkeeping and reporting
provisions applicable to the human drug and biological product
industries, recent information from trade organizations related to the
manufacturing of non-reproductive HCT/Ps utilizing cells and tissues,
and data provided by the Eastern Research Group (ERG), a consulting
firm hired by FDA to prepare an economic analysis of the potential
economic impact on semen banks and ART facilities.
We have estimated that there are approximately 792 nonreproductive
HCT/P manufacturers (approximately 166 conventional tissue
establishments, 134 eye tissue establishments, 425 peripheral and cord
blood stem/progenitor cells, and 67 manufacturers of licensed
biological products or devices). For the number of respondents for
requesting a variance under Sec. 1271.155(a) in table 15 of this
document, we added 510 reproductive HCT/P establishments. FDA obtained
these estimates of manufacturers (including percentage of members and
nonmembers) from the various trade organizations and our registration
systems for HCT/P, biological product, and device manufacturers. The
total number of respondents and recordkeepers, 1,302, in the tables is
decreased for each provision by the estimated number of establishments
that follow, as usual and customary practice, the applicable
established trade
[[Page 68679]]
organizational standards comparable to the GTP requirements, i.e.,
AATB, EBAA, FACT, AABB, NMDP, or CAP. FDA based the estimated numbers
for ``Number of Respondents'' and ``Number of Recordkeepers'' on
information provided by the trade organizations and FDA registration
databases.
FDA based the estimated numbers for ``Annual Frequency per
Response,'' ``Total Annual Responses,'' ``Annual Frequency per
Recordkeeping,'' and ``Total Annual Records'' on information received
from the trade organizations, institutional experience with similar
requirements (Good Manufacturing Practice), general information
provided to FDA during inspections of manufacturers of human tissue
intended for transplantation, and information gathered by ERG.
The estimates for ``Hours per Response'' or ``Hours per Record''
were calculated using comparable burdens under drug GMP regulations (21
CFR part 211) and GMP for blood and blood components (21 Part 606) or
by using the information provided by ERG, e.g., time spent on
Sec. Sec. 1271.190(c)(4) (documentation of cleaning and sanitation)
and 1271.195(c) (documentation of environmental control and monitoring
activities) was an estimate provided by ERG.
The information collection requirements of this final rule have
been approved by OMB. The OMB control number is 0910-0559; it expires
11/30/07. An agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless it displays
a currently valid OMB control number.
IX. References
The following references have been placed on display in the Dockets
Management Branch (see ADDRESSES) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday. (FDA has verified the
Web site addresses, but we are not responsible for subsequent changes
to the Web site after this document publishes in the Federal Register.)
1. U.S. Department of Health and Human Services, Center for
Disease Control and Prevention, ``Update: Allograft-Associated
Bacterial Infections--United States,'' Morbidity and Mortality
Weekly Report, vol. 51, no. 10, pp. 207-210, March 15, 2002.
2. Diringer, H. and H.R. Braig, ``Infectivity of Unconventional
Viruses in Dura Mater,'' Lancet, pp. 439-440, 1989.
3. U.S. Department of Health and Human Services, Food and Drug
Administration, Center for Devices and Radiological Health, ``Class
II Special Controls Guidance Document: Human Dura Mater; Draft
Guidance for Industry and FDA,'' October 2002.
4. U.S. Department of Health and Human Services, Food and Drug
Administration, Transmissible Spongiform Encephalopathies Advisory
Committee Meeting Transcript, pp. 1-100, June 26, 2002.
5. Wilhelmus, K. R., R. D. Stulting, J. Sugar, and M. M. Khan,
``Primary Corneal Graft Failure,'' Archives of Ophthalmology, vol.
113, pp. 1497-1502, December 1995.
6. Remeijer, L., P. Doornenbal, A. J. M. Geerards, W. A.
Rijneveld, and W. H. Beekhuis, ``Newly Acquired Herpes Simplex Virus
Keratitis After Penetrating Keratoplasty,'' Ophthalmology, vol. 104,
No. 4, pp. 648-652, April 1997.
7. Health Care Utilization Project (HCUP), Nationwide Inpatient
Sample (NIS) for 2000, Outcomes for Principle Procedure 13, Corneal
transplant, Available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
8. Health Care Financing Review, 2000 Statistical Supplement,
Submitted Charges per Person Served, Calendar Year 1998, U.S.
Department of Health and Human Services, Center for Medicare and
Medicaid Services, Table 59, pp. 226-227.
9. Lord, C. F., M. C. Gebhardt, W. W. Tomford, and H. J. Mankin,
``Infection in Bone Allograft: Incidence, Nature and Treatment,''
The Journal of Bone and Joint Surgery, vol. 70-A, No. 3, pp. 369-
376, March 1988.
10. Hardin, C. K., ``Banked Bone,'' Otolaryngologic Clinics of
North America, vol. 27, No. 5, pp. 911-925, October 1994.
11. Detailed Diagnoses and Procedures Data, National Hospital
Discharge Survey 2000, Series 13, No. 153, Table 46, p. 153,
November 2002.
12. Abecassis, M. M., ``Transmission of Cytomegalovirus by Skin
Allograft,'' Tissue and Cell Report, vol. 2, No. 1, pp. 14-17, 1995.
13. Gala, J., A. Vandenbroucke, B. Vandercam, J. Pirnay, N.
Delferriere, and G. Burronboy, ``Human Immunodeficiency Virus in
Fresh or Cryopreserved Postmortem Skin: Potential Implications for
Skin Handling and Allografting,'' Journal of Clinical Pathology,
vol. 50, pp. 481-484, 1997.
14. Kuehnert, M. J., E. Clark, S. R. Lockhart, D. R. Soll, J.
Chia, and W. R. Jarvis, ``Candida Albicans Endocarditis Associated
with a Contaminated Aortic Valve Allograft: Implications for
Regulation of Allograft Processing,'' Clinical Infectious Diseases,
vol. 27, pp. 688-91, October 1998.
15. Webb, I. J., F. S. Coral, J. W. Andersen, A. D. Elias, R. W.
Finberg, L. M. Nadler, J. Ritz, and K. C. Anderson, ``Sources and
Sequelae of Bacterial Contamination of Hematopoietic Stem Cell
Components: Implications for the Safety of Hematotherapy and Graft
Engineering,'' Transfusion, vol. 36, pp. 782-788, 1996.
16. Price, K. J., P. F. Thall, S. K. Kish, V. R. Shannon, and B.
S. Andersson, ``Prognostic Indicators for Blood and Marrow
Transplant Patients Admitted to an Intensive Care Unit,'' American
Journal of Respiratory Critical Care Medicine, vol. 158, pp. 876-
884, 1998.
17. Espinosa, M. T. F., R. Fox, R. J. Creger, and H. M. Lazarus,
``Microbiologic Contamination of Peripheral Blood Progenitor Cells
Collected for Hematopoietic Cell Transplantation,'' Transfusion,
vol. 36, pp. 789-793, 1996.
18. Kogler, G., J. Callejas, P. Hakenberg, J. Enczmann, O.
Adams, W. Daubener, C. Krempe, U. Gobel, T. Somville, and P. Wernet,
``Hematopoietic Transplant Potential of Unrelated Cord Blood:
Critical Issues,'' Journal of Hematotherapy, vol. 5, pp. 105-116,
1996.
19. Prottas, Jeffrey, ``A Study of the Tissue Procurement and
Distribution System of the United States,'' Brandeis University,
FDA/HRSA Contract No. 240-090-0048, October 1995.
20. American Medical Association, Center for Health Policy
Research, Physician Socioeconomic Statistics, 2002 Edition, Table
41, p. 83, 2002.
21. North American Industry Classification System (NAICS),
available online at http://www.naics.com.
22. U.S. Small Business Administration, Office of Size
Standards, Table of Size Standards, Sector 62, Health Care and
Social Assistance, 2002.
23. HCUP, NIS for 2000, Outcomes for Principle Procedure 157,
Amputation of Lower Extremity, available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
24. AHRQ, HCUP, NIS for 2000, Outcomes for Principle Procedure
43, Heart Valve Procedures, available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
25. ``Blood Collection and Transfusion in the United States in
1997,'' Transfusion, vol. 42, pp. 1253-1300, 2002.
26. AHRQ, HCUP, NIS for 2000, Outcomes for Principle Procedure
3, Bacterial Infection, Unspecified Site, available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
27. U.S. Department of Labor, Bureau of Labor Statistics,
Available online at http://www.bls.gov/cpi.
28. AHRQ, HCUP, NIS for 2001, Outcomes for Principle Procedure
142, Partial Excision of Bone, available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
29. U.S. Department of Health and Human Services, Centers for
Disease Control and Prevention, American Society for Reproductive
Medicine and RESOLVE, 1999 Assisted Reproductive Technology Success
Rates: National Summary and Fertility Clinic Reports, 2000.
30. Fee Schedule 1/98, Donor Semen 0.5cc and Donor Semen 0.8cc-
1.0cc, The Sperm Bank of California, at http://www.thespermbankofca.org/fees.html.
31. Hogan, R. N., P. Brown, and E. Heck, ``Risk of Prion Disease
Transmission From Ocular Donor Tissue Transplantation,'' Cornea,
vol. 18, No. 1, 1999, pp. 2-11.
32. U.S. Department of Labor, Bureau of Labor Statistics,
``Employer Costs for Employee Compensation per hour worked for
Civilian Workers in Private Industry and State and local
Governments, March 2003, available online at http://www.bls.gov.
List of Subjects
21 CFR part 16
Administrative practice and procedure.
[[Page 68680]]
21 CFR part 1270
Communicable diseases, HIV/AIDS, Reporting and recordkeeping
requirements.
21 CFR part 1271
Communicable diseases, HIV/AIDS, Human cells, tissues, and cellular
and tissue-based products, Reporting and recordkeeping requirements.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, Chapter I of title 21 of the Code of
Federal Regulations is amended as follows:
0
1. The authority citation for 21 CFR part 16 continues to read as
follows:
Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 141-149, 321-394,
467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201-262, 263b, 364.
0
2. Section 16.1 is amended in paragraph (b)(2) by numerically adding an
entry for Sec. 1271.440(e) to read as follows:
Sec. 16.1 Scope.
* * * * *
(b) * * *
(2) * * *
Sec. 1271.440(e) relating to the retention, recall, and
destruction of human cells, tissues, and cellular and tissue-based
products (HCT/Ps), and/or the cessation of manufacturing HCT/Ps.
PART 1270--HUMAN TISSUE INTENDED FOR TRANSPLANTATION
0
3. The authority citation for 21 CFR part 1270 continues to read as
follows:
Authority: 42 U.S.C. 216, 243, 264, 271.
0
4. Section 1270.3 is amended by revising paragraph (j) introductory
text to read as follows:
Sec. 1270.3 Definitions
* * * * *
(j) Human tissue, for the purpose of this part means any tissue
derived from a human body and recovered before May 25, 2005, which:
* * * * *
PART 1271--HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED
PRODUCTS
0
5. The authority citation for 21 CFR part 1271 continues to read as
follows:
Authority: 42 U.S.C. 216, 243, 263a, 264, 271.
0
6. Section 1271.3 is amended by revising paragraphs (c) and (d) and by
adding paragraphs (y) through (ll) to read as follows:
Sec. 1271.3 How does FDA define important terms in this part?
* * * * *
(c) Homologous use means the repair, reconstruction, replacement,
or supplementation of a recipient's cells or tissues with an HCT/P that
performs the same basic function or functions in the recipient as in
the donor.
(d) Human cells, tissues, or cellular or tissue-based products
(HCT/Ps) means articles containing or consisting of human cells or
tissues that are intended for implantation, transplantation, infusion,
or transfer into a human recipient. Examples of HCT/Ps include, but are
not limited to, bone, ligament, skin, dura mater, heart valve, cornea,
hematopoietic stem/progenitor cells derived from peripheral and cord
blood, manipulated autologous chondrocytes, epithelial cells on a
synthetic matrix, and semen or other reproductive tissue. The following
articles are not considered HCT/Ps:
(1) Vascularized human organs for transplantation;
(2) Whole blood or blood components or blood derivative products
subject to listing under parts 607 and 207 of this chapter,
respectively;
(3) Secreted or extracted human products, such as milk, collagen,
and cell factors; except that semen is considered an HCT/P;
(4) Minimally manipulated bone marrow for homologous use and not
combined with another article (except for water, crystalloids, or a
sterilizing, preserving, or storage agent, if the addition of the agent
does not raise new clinical safety concerns with respect to the bone
marrow);
(5) Ancillary products used in the manufacture of HCT/P;
(6) Cells, tissues, and organs derived from animals other than
humans; and
(7) In vitro diagnostic products as defined in Sec. 809.3(a) of
this chapter.
* * * * *
(y) Adverse reaction means a noxious and unintended response to any
HCT/P for which there is a reasonable possibility that the HCT/P caused
the response.
(z) Available for distribution means that the HCT/P has been
determined to meet all release criteria.
(aa) Complaint means any written, oral, or electronic communication
about a distributed HCT/P that alleges:
(1) That an HCT/P has transmitted or may have transmitted a
communicable disease to the recipient of the HCT/P; or
(2) Any other problem with an HCT/P relating to the potential for
transmission of communicable disease, such as the failure to comply
with current good tissue practice.
(bb) Distribution means any conveyance or shipment (including
importation and exportation) of an HCT/P that has been determined to
meet all release criteria, whether or not such conveyance or shipment
is entirely intrastate. If an entity does not take physical possession
of an HCT/P, the entity is not considered a distributor.
(cc) Establish and maintain means define, document (in writing or
electronically), and implement; then follow, review, and, as needed,
revise on an ongoing basis.
(dd) HCT/P deviation means an event:
(1) That represents a deviation from applicable regulations in this
part or from applicable standards or established specifications that
relate to the prevention of communicable disease transmission or HCT/P
contamination; or
(2) That is an unexpected or unforeseeable event that may relate to
the transmission or potential transmission of a communicable disease or
may lead to HCT/P contamination.
(ee) Importer of record means the person, establishment, or its
representative responsible for making entry of imported goods in
accordance with all laws affecting such importation.
(ff) Processing means any activity performed on an HCT/P, other
than recovery, donor screening, donor testing, storage, labeling,
packaging, or distribution, such as testing for microorganisms,
preparation, sterilization, steps to inactivate or remove adventitious
agents, preservation for storage, and removal from storage.
(gg) Quality audit means a documented, independent inspection and
review of an establishment's activities related to core CGTP
requirements. The purpose of a quality audit is to verify, by
examination and evaluation of objective evidence, the degree of
compliance with those aspects of the quality program under review.
(hh) Quality program means an organization's comprehensive system
for manufacturing and tracking HCT/Ps in accordance with this part. A
quality program is designed to prevent, detect, and correct
deficiencies that may lead to circumstances that increase the risk of
introduction, transmission, or spread of communicable diseases.
(ii) Recovery means obtaining from a human donor cells or tissues
that are intended for use in human implantation, transplantation,
infusion, or transfer.
(jj) Storage means holding HCT/Ps for future processing and/or
distribution.
(kk) Validation means confirmation by examination and provision of
[[Page 68681]]
objective evidence that particular requirements can consistently be
fulfilled. Validation of a process, or process validation, means
establishing by objective evidence that a process consistently produces
a result or HCT/P meeting its predetermined specifications.
(ll) Verification means confirmation by examination and provision
of objective evidence that specified requirements have been fulfilled.
0
7. Section 1271.10 is amended by revising paragraph (a)(3) to read as
follows:
Sec. 1271.10 Are my HCT/Ps regulated solely under section 361 of the
PHS Act and the regulations in this part, and if so what must I do?
(a) * * *
(3) The manufacture of the HCT/P does not involve the combination
of the cells or tissues with another article, except for water,
crystalloids, or a sterilizing, preserving, or storage agent, provided
that the addition of water, crystalloids, or the sterilizing,
preserving, or storage agent does not raise new clinical safety
concerns with respect to the HCT/P; and
* * * * *
0
8. Section 1271.22 is revised to read as follows:
Sec. 1271.22 How and where do I register and submit an HCT/P list?
(a) You must use Form FDA 3356 for:
(1) Establishment registration,
(2) HCT/P listings, and
(3) Updates of registration and HCT/P listing.
(b) You may obtain Form FDA 3356:
(1) By writing to the Center for Biologics Evaluation and Research
(HFM-775), Food and Drug Administration, 1401 Rockville Pike,
Rockville, MD 20852-1448, Attention: Tissue Establishment Registration
Coordinator;
(2) By contacting any Food and Drug Administration district office;
(3) By calling the CBER Voice Information System at 1-800-835-4709
or 301-827-1800; or
(4) By connecting to http://www.fda.gov/opacom/morechoices/fdaforms/cber.html on the Internet.
(c)(1) You may submit Form FDA 3356 to the Center for Biologics
Evaluation and Research (HFM-775), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852-1448, Attention: Tissue
Establishment Registration Coordinator; or
(2) You may submit Form FDA 3356 electronically through a secure
web server at http://www.fda.gov/cber/tissue/tisreg.htm.
0
9. Section 1271.45 is amended in paragraph (a), after the second
sentence, by adding a sentence to read as follows:
Sec. 1271.45 What requirements does this subpart contain?
(a) * * * Other CGTP requirements are set out in subpart D of this
part.
* * * * *
0
10. Part 1271 is amended by adding subpart D, consisting of Sec. Sec.
1271.145 through 1271.320, to read as follows:
Subpart D--Current Good Tissue Practice
Sec.
1271.145 Prevention of the introduction, transmission, or spread of
communicable diseases.
1271.150 Current good tissue practice requirements.
1271.155 Exemptions and alternatives.
1271.160 Establishment and maintenance of a quality program.
1271.170 Personnel.
1271.180 Procedures.
1271.190 Facilities.
1271.195 Environmental control and monitoring.
1271.200 Equipment.
1271.210 Supplies and reagents.
1271.215 Recovery.
1271.220 Processing and process controls.
1271.225 Process changes.
1271.230 Process validation.
1271.250 Labeling controls.
1271.260 Storage.
1271.265 Receipt, predistribution shipment, and distribution of an
HCT/P.
1271.270 Records.
1271.290 Tracking.
1271.320 Complaint file.
Subpart D--Current Good Tissue Practice
Sec. 1271.145 Prevention of the introduction, transmission, or spread
of communicable diseases.
You must recover, process, store, label, package, and distribute
HCT/Ps, and screen and test cell and tissue donors, in a way that
prevents the introduction, transmission, or spread of communicable
diseases.
Sec. 1271.150 Current good tissue practice requirements.
(a) General. This subpart D and subpart C of this part set forth
current good tissue practice (CGTP) requirements. You must follow CGTP
requirements to prevent the introduction, transmission, or spread of
communicable diseases by HCT/Ps (e.g., by ensuring that the HCT/Ps do
not contain communicable disease agents, that they are not
contaminated, and that they do not become contaminated during
manufacturing). Communicable diseases include, but are not limited to,
those transmitted by viruses, bacteria, fungi, parasites, and
transmissible spongiform encephalopathy agents. CGTP requirements
govern the methods used in, and the facilities and controls used for,
the manufacture of HCT/Ps, including but not limited to all steps in
recovery, donor screening, donor testing, processing, storage,
labeling, packaging, and distribution. The CGTP provisions specifically
governing determinations of donor eligibility, including donor
screening and testing, are set out separately in subpart C of this
part.
(b) Core CGTP requirements. The following are core CGTP
requirements:
(1) Requirements relating to facilities in Sec. 1271.190(a) and
(b);
(2) Requirements relating to environmental control in Sec.
1271.195(a);
(3) Requirements relating to equipment in Sec. 1271.200(a);
(4) Requirements relating to supplies and reagents in Sec.
1271.210(a) and (b);
(5) Requirements relating to recovery in Sec. 1271.215;
(6) Requirements relating to processing and process controls in
Sec. 1271.220;
(7) Requirements relating to labeling controls in Sec. 1271.250(a)
and (b);
(8) Requirements relating to storage in Sec. 1271.260 (a) through
(d);
(9) Requirements relating to receipt, predistribution shipment, and
distribution of an HCT/P in Sec. 1271.265(a) through (d); and
(10) Requirements relating to donor eligibility determinations,
donor screening, and donor testing in Sec. Sec. 1271.50, 1271.75,
1271.80, and 1271.85.
(c) Compliance with applicable requirements--(1) Manufacturing
arrangements (i) If you are an establishment that engages in only some
operations subject to the regulations in this subpart and subpart C of
this part, and not others, then you need only comply with those
requirements applicable to the operations that you perform.
(ii) If you engage another establishment (e.g., a laboratory to
perform communicable disease testing, or an irradiation facility to
perform terminal sterilization), under a contract, agreement, or other
arrangement, to perform any step in manufacture for you, that
establishment is responsible for complying with requirements applicable
to that manufacturing step.
(iii) Before entering into a contract, agreement, or other
arrangement with another establishment to perform any step in
manufacture for you, you must ensure that the establishment complies
with applicable CGTP requirements. If, during the course of this
contract, agreement, or other arrangement, you
[[Page 68682]]
become aware of information suggesting that the establishment may no
longer be in compliance with such requirements, you must take
reasonable steps to ensure the establishment complies with those
requirements. If you determine that the establishment is not in
compliance with those requirements, you must terminate your contract,
agreement, or other arrangement with the establishment.
(2) If you are the establishment that determines that an HCT/P
meets all release criteria and makes the HCT/P available for
distribution, whether or not you are the actual distributor, you are
responsible for reviewing manufacturing and tracking records to
determine that the HCT/P has been manufactured and tracked in
compliance with the requirements of this subpart and subpart C of this
part and any other applicable requirements.
(3) With the exception of Sec. Sec. 1271.150(c) and 1271.155 of
this subpart, the regulations in this subpart are not being implemented
for reproductive HCT/Ps described in Sec. 1271.10 and regulated solely
under section 361 of the Public Health Service Act and the regulations
in this part, or for the establishments that manufacture them.
(d) Compliance with parts 210, 211, and 820 of this chapter. With
respect to HCT/Ps that are drugs (subject to review under an
application submitted under section 505 of the Federal Food, Drug, and
Cosmetic Act or under a biological product license application under
section 351 of the Public Health Service Act) or that are devices
(subject to premarket review or notification under the device
provisions of the act or under a biological product license application
under section 351 of the Public Health Service Act), the procedures
contained in this subpart and in subpart C of this part and the current
good manufacturing practice regulations in parts 210 and 211 of this
chapter and the quality system regulations in part 820 of this chapter
supplement, and do not supersede, each other unless the regulations
explicitly provide otherwise. In the event that a regulation in part
1271 of this chapter is in conflict with a requirement in parts 210,
211, or 820 of this chapter, the regulations more specifically
applicable to the product in question will supersede the more general.
(e) Where appropriate. When a requirement is qualified by ``where
appropriate,'' it is deemed to be ``appropriate'' unless you can
document justification otherwise. A requirement is ``appropriate'' if
nonimplementation of the requirement could reasonably be expected to
result in the HCT/P not meeting its specified requirements related to
prevention of introduction, transmission, or spread of communicable
diseases, or in your inability to carry out any necessary corrective
action.
Sec. 1271.155 Exemptions and alternatives.
(a) General. You may request an exemption from or alternative to
any requirement in subpart C or D of this part.
(b) Request for exemption or alternative. Submit your request under
this section to the Director of the appropriate Center (the Director),
e.g., the Center for Biologics Evaluation and Research or the Center
for Devices and Radiological Health. The request must be accompanied by
supporting documentation, including all relevant valid scientific data,
and must contain either:
(1) Information justifying the requested exemption from the
requirement, or
(2) A description of a proposed alternative method of meeting the
requirement.
(c) Criteria for granting an exemption or alternative. The Director
may grant an exemption or alternative if he or she finds that such
action is consistent with the goals of protecting the public health
and/or preventing the introduction, transmission, or spread of
communicable diseases and that:
(1) The information submitted justifies an exemption; or
(2) The proposed alternative satisfies the purpose of the
requirement.
(d) Form of request. You must ordinarily make your request for an
exemption or alternative in writing (hard copy or electronically).
However, if circumstances make it difficult (e.g., there is inadequate
time) to submit your request in writing, you may make the request
orally, and the Director may orally grant an exemption or alternative.
You must follow your oral request with an immediate written request, to
which the Director will respond in writing.
(e) Operation under exemption or alternative. You must not begin
operating under the terms of a requested exemption or alternative until
the exemption or alternative has been granted. You may apply for an
extension of an exemption or alternative beyond its expiration date, if
any.
(f) Documentation. If you operate under the terms of an exemption
or alternative, you must maintain documentation of:
(1) FDA's grant of the exemption or alternative, and
(2) The date on which you began operating under the terms of the
exemption or alternative.
(g) Issuance of an exemption or alternative by the Director. In a
public health emergency, the Director may issue an exemption from, or
alternative to, any requirement in part 1271. The Director may issue an
exemption or alternative under this section if the exemption or
alternative is necessary to assure that certain HCT/Ps will be
available in a specified location to respond to an unanticipated
immediate need for those HCT/Ps.
Sec. 1271.160 Establishment and maintenance of a quality program.
(a) General. If you are an establishment that performs any step in
the manufacture of HCT/Ps, you must establish and maintain a quality
program intended to prevent the introduction, transmission, or spread
of communicable diseases through the manufacture and use of HCT/Ps. The
quality program must be appropriate for the specific HCT/Ps
manufactured and the manufacturing steps performed. The quality program
must address all core CGTP requirements listed in Sec. 1271.150(b).
(b) Functions. Functions of the quality program must include:
(1) Establishing and maintaining appropriate procedures relating to
core CGTP requirements, and ensuring compliance with the requirements
of Sec. 1271.180 with respect to such procedures, including review,
approval, and revision;
(2) Ensuring that procedures exist for receiving, investigating,
evaluating, and documenting information relating to core CGTP
requirements, including complaints, and for sharing any information
pertaining to the possible contamination of the HCT/P or the potential
for transmission of a communicable disease by the HCT/P with the
following:
(i) Other establishments that are known to have recovered HCT/Ps
from the same donor;
(ii) Other establishments that are known to have performed
manufacturing steps with respect to the same HCT/P; and
(iii) Relating to consignees, in the case of such information
received after the HCT/P is made available for distribution, shipped to
the consignee, or administered to the recipient, procedures must
include provisions for assessing risk and appropriate followup, and
evaluating the effect this information has on the HCT/P and for the
notification of all entities to whom the affected HCT/P was
distributed, the
[[Page 68683]]
quarantine and recall of the HCT/P, and/or reporting to FDA, as
necessary.
(3) Ensuring that appropriate corrective actions relating to core
CGTP requirements, including reaudits of deficiencies, are taken and
documented, as necessary. You must verify corrective actions to ensure
that such actions are effective and are in compliance with CGTP. Where
appropriate, corrective actions must include both short-term action to
address the immediate problem and long-term action to prevent the
problem's recurrence. Documentation of corrective actions must include,
where appropriate:
(i) Identification of the HCT/P affected and a description of its
disposition;
(ii) The nature of the problem requiring corrective action;
(iii) A description of the corrective action taken; and
(iv) The date(s) of the corrective action.
(4) Ensuring the proper training and education of personnel
involved in activities related to core CGTP requirements;
(5) Establishing and maintaining appropriate monitoring systems as
necessary to comply with the requirements of this subpart (e.g.,
environmental monitoring);
(6) Investigating and documenting HCT/P deviations and trends of
HCT/P deviations relating to core CGTP requirements and making reports
if required under Sec. 1271.350(b) or other applicable regulations.
Each investigation must include a review and evaluation of the HCT/P
deviation, the efforts made to determine the cause, and the
implementation of corrective action(s) to address the HCT/P deviation
and prevent recurrence.
(c) Audits. You must periodically perform for management review a
quality audit, as defined in Sec. 1271.3(gg), of activities related to
core CGTP requirements.
(d) Computers. You must validate the performance of computer
software for the intended use, and the performance of any changes to
that software for the intended use, if you rely upon the software to
comply with core CGTP requirements and if the software either is custom
software or is commercially available software that has been customized
or programmed (including software programmed to perform a user defined
calculation or table) to perform a function related to core CGTP
requirements. You must verify the performance of all other software for
the intended use if you rely upon it to comply with core CGTP
requirements. You must approve and document these activities and
results before implementation.
Sec. 1271.170 Personnel.
(a) General. You must have personnel sufficient to ensure
compliance with the requirements of this part.
(b) Competent performance of functions. You must have personnel
with the necessary education, experience, and training to ensure
competent performance of their assigned functions. Personnel must
perform only those activities for which they are qualified and
authorized.
(c) Training. You must train all personnel, and retrain as
necessary, to perform their assigned responsibilities adequately.
Sec. 1271.180 Procedures.
(a) General. You must establish and maintain procedures appropriate
to meet core CGTP requirements for all steps that you perform in the
manufacture of HCT/Ps. You must design these procedures to prevent
circumstances that increase the risk of the introduction, transmission,
or spread of communicable diseases through the use of HCT/Ps.
(b) Review and approval. Before implementation, a responsible
person must review and approve these procedures.
(c) Availability. These procedures must be readily available to the
personnel in the area where the operations to which they relate are
performed, or in a nearby area if such availability is impractical.
(d) Standard procedures. If you adopt current standard procedures
from another organization, you must verify that the procedures meet the
requirements of this part and are appropriate for your operations.
Sec. 1271.190 Facilities.
(a) General. Any facility used in the manufacture of HCT/Ps must be
of suitable size, construction, and location to prevent contamination
of HCT/Ps with communicable disease agents and to ensure orderly
handling of HCT/Ps without mix-ups. You must maintain the facility in a
good state of repair. You must provide lighting, ventilation, plumbing,
drainage, and access to sinks and toilets that are adequate to prevent
the introduction, transmission, or spread of communicable disease.
(b) Facility cleaning and sanitation. (1) You must maintain any
facility used in the manufacture of HCT/Ps in a clean, sanitary, and
orderly manner, to prevent the introduction, transmission, or spread of
communicable disease.
(2) You must dispose of sewage, trash, and other refuse in a
timely, safe, and sanitary manner.
(c) Operations. You must divide a facility used in the manufacture
of HCT/Ps into separate or defined areas of adequate size for each
operation that takes place in the facility, or you must establish and
maintain other control systems to prevent improper labeling, mix-ups,
contamination, cross-contamination, and accidental exposure of HCT/Ps
to communicable disease agents.
(d) Procedures and records. (1) You must establish and maintain
procedures for facility cleaning and sanitation for the purpose of
preventing the introduction, transmission, or spread of communicable
disease. These procedures must assign responsibility for sanitation and
must describe in sufficient detail the cleaning methods to be used and
the schedule for cleaning the facility.
(2) You must document, and maintain records of, all cleaning and
sanitation activities performed to prevent contamination of HCT/Ps. You
must retain such records 3 years after their creation.
Sec. 1271.195 Environmental control and monitoring.
(a) Environmental control. Where environmental conditions could
reasonably be expected to cause contamination or cross-contamination of
HCT/Ps or equipment, or accidental exposure of HCT/Ps to communicable
disease agents, you must adequately control environmental conditions
and provide proper conditions for operations. Where appropriate, you
must provide for the following control activities or systems:
(1) Temperature and humidity controls;
(2) Ventilation and air filtration;
(3) Cleaning and disinfecting of rooms and equipment to ensure
aseptic processing operations; and
(4) Maintenance of equipment used to control conditions necessary
for aseptic processing operations.
(b) Inspections. You must inspect each environmental control system
periodically to verify that the system, including necessary equipment,
is adequate and functioning properly. You must take appropriate
corrective action as necessary.
(c) Environmental monitoring. You must monitor environmental
conditions where environmental conditions could reasonably be expected
to cause contamination or cross-contamination of HCT/Ps or equipment,
or accidental exposure of HCT/Ps to communicable
[[Page 68684]]
disease agents. Where appropriate, you must provide environmental
monitoring for microorganisms.
(d) Records. You must document, and maintain records of,
environmental control and monitoring activities.
Sec. 1271.200 Equipment.
(a) General. To prevent the introduction, transmission, or spread
of communicable diseases, equipment used in the manufacture of HCT/Ps
must be of appropriate design for its use and must be suitably located
and installed to facilitate operations, including cleaning and
maintenance. Any automated, mechanical, electronic, or other equipment
used for inspection, measuring, or testing in accordance with this part
must be capable of producing valid results. You must clean, sanitize,
and maintain equipment according to established schedules.
(b) Procedures and schedules. You must establish and maintain
procedures for cleaning, sanitizing, and maintaining equipment to
prevent malfunctions, contamination or cross-contamination, accidental
exposure of HCT/Ps to communicable disease agents, and other events
that could reasonably be expected to result in the introduction,
transmission, or spread of communicable diseases.
(c) Calibration of equipment. Where appropriate, you must routinely
calibrate according to established procedures and schedules all
automated, mechanical, electronic, or other equipment used for
inspection, measuring, and testing in accordance with this part.
(d) Inspections. You must routinely inspect equipment for
cleanliness, sanitation, and calibration, and to ensure adherence to
applicable equipment maintenance schedules.
(e) Records. You must document and maintain records of all
equipment maintenance, cleaning, sanitizing, calibration, and other
activities performed in accordance with this section. You must display
records of recent maintenance, cleaning, sanitizing, calibration, and
other activities on or near each piece of equipment, or make the
records readily available to the individuals responsible for performing
these activities and to the personnel using the equipment. You must
maintain records of the use of each piece of equipment, including the
identification of each HCT/P manufactured with that equipment.
Sec. 1271.210 Supplies and reagents.
(a) Verification. You must not use supplies and reagents until they
have been verified to meet specifications designed to prevent
circumstances that increase the risk of the introduction, transmission,
or spread of communicable diseases. Verification may be accomplished by
the establishment that uses the supply or reagent, or by the vendor of
the supply or reagent.
(b) Reagents. Reagents used in processing and preservation of HCT/
Ps must be sterile, where appropriate.
(c) In-house reagents. You must validate and/or verify the
processes used for production of in-house reagents.
(d) Records. You must maintain the following records pertaining to
supplies and reagents:
(1) Records of the receipt of each supply or reagent, including the
type, quantity, manufacturer, lot number, date of receipt, and
expiration date;
(2) Records of the verification of each supply or reagent,
including test results or, in the case of vendor verification, a
certificate of analysis from the vendor; and
(3) Records of the lot of supply or reagent used in the manufacture
of each HCT/P.
Sec. 1271.215 Recovery.
If you are an establishment that recovers HCT/Ps, you must recover
each HCT/P in a way that does not cause contamination or cross-
contamination during recovery, or otherwise increase the risk of the
introduction, transmission, or spread of communicable disease through
the use of the HCT/P.
Sec. 1271.220 Processing and process controls.
(a) General. If you are an establishment that processes HCT/Ps, you
must process each HCT/P in a way that does not cause contamination or
cross-contamination during processing, and that prevents the
introduction, transmission, or spread of communicable disease through
the use of the HCT/P.
(b) Pooling. Human cells or tissue from two or more donors must not
be pooled (placed in physical contact or mixed in a single receptacle)
during manufacturing.
(c) In-process control and testing. You must ensure that specified
requirements, consistent with paragraph (a) of this section, for in-
process controls are met, and that each in-process HCT/P is controlled
until the required inspection and tests or other verification
activities have been completed, or necessary approvals are received and
documented. Sampling of in-process HCT/Ps must be representative of the
material to be evaluated.
(d) Dura mater. (1) When there is a published validated process
that reduces the risk of transmissible spongiform encephalopathy, you
must use this process for dura mater (or an equivalent process that you
have validated), unless following this process adversely affects the
clinical utility of the dura mater.
(2) When you use a published validated process, you must verify
such a process in your establishment.
Sec. 1271.225 Process changes.
Any change to a process must be verified or validated in accordance
with Sec. 1271.230, to ensure that the change does not create an
adverse impact elsewhere in the operation, and must be approved before
implementation by a responsible person with appropriate knowledge and
background. You must communicate approved changes to the appropriate
personnel in a timely manner.
Sec. 1271.230 Process validation.
(a) General. Where the results of processing described in Sec.
1271.220 cannot be fully verified by subsequent inspection and tests,
you must validate and approve the process according to established
procedures. The validation activities and results must be documented,
including the date and signature of the individual(s) approving the
validation.
(b) Written representation. Any written representation that your
processing methods reduce the risk of transmission of communicable
disease by an HCT/P, including but not limited to, a representation of
sterility or pathogen inactivation of an HCT/P, must be based on a
fully verified or validated process.
(c) Changes. When changes to a validated process subject to
paragraph (a) of this section occur, you must review and evaluate the
process and perform revalidation where appropriate. You must document
these activities.
Sec. 1271.250 Labeling controls.
(a) General. You must establish and maintain procedures to control
the labeling of HCT/Ps. You must design these procedures to ensure
proper HCT/P identification and to prevent mix-ups.
(b) Verification. Procedures must include verification of label
accuracy, legibility, and integrity.
(c) Labeling requirements. Procedures must ensure that each HCT/P
is labeled in accordance with all applicable labeling requirements,
including those in Sec. Sec. 1271.55, 1271.60, 1271.65,
[[Page 68685]]
1271.90, 1271.290, and 1271.370, and that each HCT/P made available for
distribution is accompanied by documentation of the donor eligibility
determination as required under Sec. 1271.55.
Sec. 1271.260 Storage.
(a) Control of storage areas. You must control your storage areas
and stock rooms to prevent:
(1) Mix-ups, contamination, and cross-contamination of HCT/Ps,
supplies, and reagents, and
(2) An HCT/P from being improperly made available for distribution.
(b) Temperature. You must store HCT/Ps at an appropriate
temperature.
(c) Expiration date. Where appropriate, you must assign an
expiration date to each HCT/P based on the following factors:
(1) HCT/P type;
(2) Processing, including the method of preservation;
(3) Storage conditions; and
(4) Packaging.
(d) Corrective action. You must take and document corrective action
whenever proper storage conditions are not met.
(e) Acceptable temperature limits. You must establish acceptable
temperature limits for storage of HCT/Ps at each step of the
manufacturing process to inhibit the growth of infectious agents. You
must maintain and record storage temperatures for HCT/Ps. You must
periodically review recorded temperatures to ensure that temperatures
have been within acceptable limits.
Sec. 1271.265 Receipt, predistribution shipment, and distribution of
an HCT/P.
(a) Receipt. You must evaluate each incoming HCT/P for the presence
and significance of microorganisms and inspect for damage and
contamination. You must determine whether to accept, reject, or place
in quarantine each incoming HCT/P, based upon pre-established criteria
designed to prevent communicable disease transmission.
(b) Predistribution shipment. If you ship an HCT/P within your
establishment or between establishments (e.g., procurer to processor)
and the HCT/P is not available for distribution as described in
paragraph (c) of this section, you must first determine and document
whether pre-established criteria designed to prevent communicable
disease transmission have been met, and you must ship the HCT/P in
quarantine.
(c) Availability for distribution. (1) Before making an HCT/P
available for distribution, you must review manufacturing and tracking
records pertaining to the HCT/P, and, on the basis of that record
review, you must verify and document that the release criteria have
been met. A responsible person must document and date the determination
that an HCT/P is available for distribution.
(2) You must not make available for distribution an HCT/P that is
in quarantine, is contaminated, is recovered from a donor who has been
determined to be ineligible or for whom a donor-eligibility
determination has not been completed (except as provided under
Sec. Sec. 1271.60, 1271.65, and 1271.90), or that otherwise does not
meet release criteria designed to prevent communicable disease
transmission.
(3) You must not make available for distribution any HCT/P
manufactured under a departure from a procedure relevant to preventing
risks of communicable disease transmission, unless a responsible person
has determined that the departure does not increase the risk of
communicable disease through the use of the HCT/P. You must record and
justify any departure from a procedure at the time of its occurrence.
(d) Packaging and shipping. Packaging and shipping containers must
be designed and constructed to protect the HCT/P from contamination.
For each type of HCT/P, you must establish appropriate shipping
conditions to be maintained during transit.
(e) Procedures. You must establish and maintain procedures,
including release criteria, for the activities in paragraphs (a)
through (d) of this section. You must document these activities.
Documentation must include:
(1) Identification of the HCT/P and the establishment that supplied
the HCT/P;
(2) Activities performed and the results of each activity;
(3) Date(s) of activity;
(4) Quantity of HCT/P subject to the activity; and
(5) Disposition of the HCT/P (e.g., identity of consignee).
(f) Return to inventory. You must establish and maintain procedures
to determine if an HCT/P that is returned to your establishment is
suitable to be returned to inventory.
Sec. 1271.270 Records.
(a) General. You must maintain records concurrently with the
performance of each step required in this subpart and subpart C of this
part. Any requirement in this part that an action be documented
involves the creation of a record, which is subject to the requirements
of this section. All records must be accurate, indelible, and legible.
The records must identify the person performing the work and the dates
of the various entries, and must be as detailed as necessary to provide
a complete history of the work performed and to relate the records to
the particular HCT/P involved.
(b) Records management system. You must establish and maintain a
records management system relating to core CGTP requirements. Under
this system, records pertaining to a particular HCT/P must be
maintained in such a way as to facilitate review of the HCT/Ps history
before making it available for distribution and, if necessary,
subsequent to the HCT/Ps release as part of a followup evaluation or
investigation. Records pertinent to the manufacture of HCT/Ps (e.g.,
labeling and packaging procedures, and equipment logs) must also be
maintained and organized under the records management system. If
records are maintained in more than one location, then the records
management system must be designed to ensure prompt identification,
location, and retrieval of all records.
(c) Methods of retention. You may maintain records required under
this subpart electronically, as original paper records, or as true
copies such as photocopies, microfiche, or microfilm. Equipment that is
necessary to make the records available and legible, such as computer
and reader equipment, must be readily available. Records stored in
electronic systems must be backed up.
(d) Length of retention. You must retain all records for 10 years
after their creation, unless stated otherwise in this part. However,
you must retain the records pertaining to a particular HCT/P at least
10 years after the date of its administration, or if the date of
administration is not known, then at least 10 years after the date of
the HCT/Ps distribution, disposition, or expiration, whichever is
latest. You must retain records for archived specimens of dura mater
for 10 years after the appropriate disposition of the specimens.
(e) Contracts and agreements. You must maintain the name and
address and a list of the responsibilities of any establishment that
performs a manufacturing step for you. This information must be
available during an inspection conducted under Sec. 1271.400.
Sec. 1271.290 Tracking.
(a) General. If you perform any step in the manufacture of an HCT/P
in which you handle the HCT/P, you must track each such HCT/P in
accordance with this section, to facilitate the
[[Page 68686]]
investigation of actual or suspected transmission of communicable
disease and take appropriate and timely corrective action.
(b) System of HCT/P tracking. (1) You must establish and maintain a
system of HCT/P tracking that enables the tracking of all HCT/Ps from:
(i) The donor to the consignee or final disposition; and
(ii) The consignee or final disposition to the donor.
(2) Alternatively, if you are an establishment that performs some
but not all of the steps in the manufacture of an HCT/P in which you
handle the HCT/P, you may participate in a system of HCT/P tracking
established and maintained by another establishment responsible for
other steps in the manufacture of the same HCT/P, provided that the
tracking system complies with all the requirements of this section.
(c) Distinct identification code. As part of your tracking system,
you must ensure: That each HCT/P that you manufacture is assigned and
labeled with a distinct identification code, e.g., alphanumeric, that
relates the HCT/P to the donor and to all records pertaining to the
HCT/P; and that labeling includes information designed to facilitate
effective tracking, using the distinct identification code, from the
donor to the recipient and from the recipient to the donor. Except in
the case of autologous or directed donations, you must create such a
code specifically for tracking, and it may not include an individual's
name, social security number, or medical record number. You may adopt a
distinct identification code assigned by another establishment engaged
in the manufacturing process, or you may assign a new code. If you
assign a new code to an HCT/P, you must establish and maintain
procedures for relating the new code to the old code.
(d) Tracking from consignee to donor. As part of your tracking
system, you must establish and maintain a method for recording the
distinct identification code and type of each HCT/P distributed to a
consignee to enable tracking from the consignee to the donor.
(e) Tracking from donor to consignee or final disposition. As part
of your tracking system, you must establish and maintain a method for
documenting the disposition of each of your HCT/Ps, to enable tracking
from the donor to the consignee or final disposition. The information
you maintain must permit the prompt identification of the consignee of
the HCT/P, if any.
(f) Consignees. At or before the time of distribution of an HCT/P
to a consignee, you must inform the consignee in writing of the
requirements in this section and of the tracking system that you have
established and are maintaining to comply with these requirements.
(g) Requirements specific to dura mater donors. You must archive
appropriate specimens from each donor of dura mater, under appropriate
storage conditions, and for the appropriate duration, to enable testing
of the archived material for evidence of transmissible spongiform
encephalopathy, and to enable appropriate disposition of any affected
nonadministered dura mater tissue, if necessary.
Sec. 1271.320 Complaint file.
(a) Procedures. You must establish and maintain procedures for the
review, evaluation, and documentation of complaints as defined in
Sec. 1271.3(aa), relating to core current good tissue practice (CGTP)
requirements, and the investigation of complaints as appropriate.
(b) Complaint file. You must maintain a record of complaints that
you receive in a file designated for complaints. The complaint file
must contain sufficient information about each complaint for proper
review and evaluation of the complaint (including the distinct
identification code of the HCT/P that is the subject of the complaint)
and for determining whether the complaint is an isolated event or
represents a trend. You must make the complaint file available for
review and copying upon request from FDA.
(c) Review and evaluation of complaints. You must review and
evaluate each complaint relating to core CGTP requirements to determine
if the complaint is related to an HCT/P deviation or to a adverse
reaction, and to determine if a report under Sec. 1271.350 or another
applicable regulation is required. As soon as practical, you must
review, evaluate, and investigate each complaint that represents an
event required to be reported to FDA, as described in Sec. 1271.350.
You must review and evaluate a complaint relating to core CGTP
requirements that does not represent an event required to be reported
to determine whether an investigation is necessary; an investigation
may include referring a copy of the complaint to another establishment
that performed manufacturing steps pertinent to the complaint. When no
investigation is made, you must maintain a record that includes the
reason no investigation was made, and the name of the individual(s)
responsible for the decision not to investigate.
0
11. Part 1271 is amended by adding subpart E, consisting of Sec. Sec.
1271.330 through 1271.370, to read as follows:
Subpart E--Additional Requirements for Establishments Described in
Sec. 1271.10
Sec.
1271.330 Applicability.
1271.350 Reporting.
1271.370 Labeling.
Subpart E--Additional Requirements for Establishments Described in
Sec. 1271.10
Sec. 1271.330 Applicability.
The provisions set forth in this subpart are being implemented for
nonreproductive HCT/Ps described in Sec. 1271.10 and regulated solely
under section 361 of the Public Health Service Act and the regulations
in this part, and for the establishments that manufacture those HCT/Ps.
HCT/Ps that are drugs or devices regulated under the act, or are
biological products regulated under section 351 of the Public Health
Service Act, are not subject to the regulations set forth in this
subpart.
Sec. 1271.350 Reporting.
(a) Adverse reaction reports. (1) You must investigate any adverse
reaction involving a communicable disease related to an HCT/P that you
made available for distribution. You must report to FDA an adverse
reaction involving a communicable disease if it:
(i) Is fatal;
(ii) Is life-threatening;
(iii) Results in permanent impairment of a body function or
permanent damage to body structure; or
(iv) Necessitates medical or surgical intervention, including
hospitalization.
(2) You must submit each report on a Form FDA-3500A to the address
in paragraph (a)(5) of this section within 15 calendar days of initial
receipt of the information.
(3) You must, as soon as practical, investigate all adverse
reactions that are the subject of these 15-day reports and must submit
followup reports within 15 calendar days of the receipt of new
information or as requested by FDA. If additional information is not
obtainable, a followup report may be required that describes briefly
the steps taken to seek additional information and the reasons why it
could not be obtained.
(4) You may obtain copies of the reporting form (FDA-3500A) from
the Center for Biologics Evaluation and Research (see address in
paragraph (a)(5) of this section). Electronic Form
[[Page 68687]]
FDA-3500A may be obtained at http://www.fda.gov/medwatch or at http://www.hhs.gov/forms.
(5) You must submit two copies of each report described in this
paragraph to the Center for Biologics Evaluation and Research (HFM-
210), Food and Drug Administration, 1401 Rockville Pike, suite 200N,
Rockville, MD 20852-1448. FDA may waive the requirement for the second
copy in appropriate circumstances.
(b) Reports of HCT/P deviations. (1) You must investigate all HCT/P
deviations related to a distributed HCT/P for which you performed a
manufacturing step.
(2) You must report any such HCT/P deviation relating to the core
CGTP requirements, if the HCT/P deviation occurred in your facility or
in a facility that performed a manufacturing step for you under
contract, agreement, or other arrangement. Each report must contain a
description of the HCT/P deviation, information relevant to the event
and the manufacture of the HCT/P involved, and information on all
follow-up actions that have been or will be taken in response to the
HCT/P deviation (e.g., recalls).
(3) You must report each such HCT/P deviation that relates to a
core CGTP requirement on Form FDA-3486 available at http://www.fda.gov/cber/biodev/bpdrform.pdf, within 45 days of the discovery of the event
either electronically at http://www.fda.gov/cber/biodev/biodevsub.htm
or by mail to the Director, Office of Compliance and Biologics Quality,
Center for Biologics Evaluation and Research (HFM-600), 1401 Rockville
Pike, suite 200N, Rockville, MD 20852-1448.
Sec. 1271.370 Labeling.
The following requirements apply in addition to Sec. Sec. 1271.55,
1271.60, 1271.65, and 1271.90:
(a) You must label each HCT/P made available for distribution
clearly and accurately.
(b) The following information must appear on the HCT/P label:
(1) Distinct identification code affixed to the HCT/P container,
and assigned in accordance with Sec. 1271.290(c);
(2) Description of the type of HCT/P;
(3) Expiration date, if any; and
(4) Warnings required under Sec. Sec. 1271.60(d)(2),
1271,65(b)(2), or 1271.90(b), if applicable.
(c) The following information must either appear on the HCT/P label
or accompany the HCT/P:
(1) Name and address of the establishment that determines that the
HCT/P meets release criteria and makes the HCT/P available for
distribution;
(2) Storage temperature;
(3) Other warnings, where appropriate; and
(4) Instructions for use when related to the prevention of the
introduction, transmission, or spread of communicable diseases.
0
12. Part 1271 is amended by adding subpart F, consisting of Sec. Sec.
1271.390 through 1271.440, to read as follows:
Subpart F--Inspection and Enforcement of Establishments Described in
Sec. 1271.10
Sec.
1271.390 Applicability.
1271.400 Inspections.
1271.420 HCT/Ps offered for import.
1271.440 Orders of retention, recall, destruction, and cessation of
manufacturing.
Subpart F--Inspection and Enforcement of Establishments Described
in Sec. 1271.10
Sec. 1271.390 Applicability.
The provisions set forth in this subpart are applicable only to
HCT/Ps described in Sec. 1271.10 and regulated solely under section
361 of the Public Health Service Act and the regulations in this part,
and to the establishments that manufacture those HCT/Ps. HCT/Ps that
are drugs or devices regulated under the act, or are biological
products regulated under section 351 of the Public Health Service Act,
are not subject to the regulations set forth in this subpart.
Sec. 1271.400 Inspections.
(a) If you are an establishment that manufactures HCT/Ps described
in Sec. 1271.10, whether or not under contract, you must permit the
Food and Drug Administration (FDA) to inspect any manufacturing
location at any reasonable time and in a reasonable manner to determine
compliance with applicable provisions of this part. The inspection will
be conducted as necessary in the judgment of the FDA and may include
your establishment, facilities, equipment, finished and unfinished
materials, containers, processes, HCT/Ps, procedures, labeling,
records, files, papers, and controls required to be maintained under
the part. The inspection may be made with or without prior notification
and will ordinarily be made during regular business hours.
(b) The frequency of inspection will be at the agency's discretion.
(c) FDA will call upon the most responsible person available at the
time of the inspection of the establishment and may question the
personnel of the establishment as necessary to determine compliance
with the provisions of this part.
(d) FDA's representatives may take samples, may review and copy any
records required to be kept under this part, and may use other
appropriate means to record evidence of observations during inspections
conducted under this subpart.
(e) The public disclosure of records containing the name or other
positive identification of donors or recipients of HCT/Ps will be
handled in accordance with FDA's procedures on disclosure of
information as set forth in parts 20 and 21 of this chapter.
Sec. 1271.420 HCT/Ps offered for import.
(a) Except as provided in paragraphs (c) and (d) of this section,
when an HCT/P is offered for import, the importer of record must
notify, either before or at the time of importation, the director of
the district of the Food and Drug Administration (FDA) having
jurisdiction over the port of entry through which the HCT/P is imported
or offered for import, or such officer of the district as the director
may designate to act in his or her behalf in administering and
enforcing this part, and must provide sufficient information for FDA to
make an admissibility decision.
(b) Except as provided in paragraphs (c) and (d) of this section,
an HCT/P offered for import must be held intact by the importer or
consignee, under conditions necessary to prevent transmission of
communicable disease, until an admissibility decision is made by FDA.
The HCT/P may be transported under quarantine to the consignee, while
the FDA district reviews the documentation accompanying the HCT/P. When
FDA makes a decision regarding the admissibility of the HCT/P, FDA will
notify the importer of record.
(c) This section does not apply to reproductive HCT/Ps regulated
solely under section 361 of the Public Health Service Act and the
regulations in this part, and donated by a sexually intimate partner of
the recipient for reproductive use.
(d) This section does not apply to peripheral blood stem/progenitor
cells regulated solely under section 361 of the Public Health Service
Act and the regulations in this part, except that paragraphs (a) and
(b) of this section apply when circumstances occur under which such
imported peripheral blood stem/progenitor cells may present an
unreasonable risk of communicable disease transmission which indicates
the need to review the information referenced in paragraph (a) of this
section.
[[Page 68688]]
Sec. 1271.440 Orders of retention, recall, destruction, and cessation
of manufacturing.
(a) Upon an agency finding that there are reasonable grounds to
believe that an HCT/P is a violative HCT/P because it was manufactured
in violation of the regulations in this part and, therefore, the
conditions of manufacture of the HCT/P do not provide adequate
protections against risks of communicable disease transmission; or the
HCT/P is infected or contaminated so as to be a source of dangerous
infection to humans; or an establishment is in violation of the
regulations in this part and, therefore, does not provide adequate
protections against the risks of communicable disease transmission, the
Food and Drug Administration (FDA) may take one or more of the
following actions:
(1) Serve upon the person who distributed the HCT/P a written order
that the HCT/P be recalled and/or destroyed, as appropriate, and upon
persons in possession of the HCT/P that the HCT/P must be retained
until it is recalled by the distributor, destroyed, or disposed of as
agreed by FDA, or the safety of the HCT/P is confirmed;
(2) Take possession of and/or destroy the violative HCT/P; or
(3) Serve upon the establishment an order to cease manufacturing
until compliance with the regulations of this part has been achieved.
When FDA determines there are reasonable grounds to believe there is a
danger to health, such order will be effective immediately. In other
situations, such order will be effective after one of the following
events, whichever is later:
(i) Passage of 5 working days from the establishment's receipt of
the order; or
(ii) If the establishment requests a hearing in accordance with
paragraph (e) of this section and part 16 of this chapter, a decision
in, and in accordance with, those proceedings.
(b) A written order issued under paragraph (a) of this section will
state with particularity the facts that justify the order.
(c)(1) A written order issued under paragraph (a)(1) of this
section will ordinarily provide that the HCT/P be recalled and/or
destroyed within 5 working days from the date of receipt of the order.
After receipt of an order issued under paragraph (a)(1) of this
section, the establishment in possession of the HCT/P must not
distribute or dispose of the HCT/P in any manner except to recall and/
or destroy the HCT/P consistent with the provisions of the order, under
the supervision of FDA.
(2) In lieu of paragraph (c)(1) of this section, other arrangements
for assuring the proper disposition of the HCT/P may be agreed upon by
the person receiving the written order and FDA. Such arrangements may
include, among others, providing FDA with records or other written
information that adequately ensure that the HCT/P has been recovered,
processed, stored, and distributed in conformance with this part, and
that, except as provided under Sec. Sec. 1271.60, 1271.65, and
1271.90, the donor of the cells or tissue for the HCT/P has been
determined to be eligible.
(d) A written order issued under paragraph (a)(3) of this section
will specify the regulations with which you must achieve compliance and
will ordinarily specify the particular operations covered by the order.
After receipt of an order that is in effect and issued under paragraph
(a)(3) of this section, you must not resume operations without prior
written authorization of FDA.
(e) The recipient of an order issued under this section may request
a hearing in accordance with part 16 of this chapter. To request a
hearing, the recipient of the written order or prior possessor of such
HCT/P must make the request within 5 working days of receipt of a
written order for retention, recall, destruction, and/or cessation (or
within 5 working days of the agency's possession of an HCT/P under
paragraph (a)(2) of this section), in accordance with part 16 of this
chapter. An order of destruction will be held in abeyance pending
resolution of the hearing request. Upon request under part 16 of this
chapter, FDA will provide an opportunity for an expedited hearing for
an order of cessation that is not stayed by the Commissioner of Food
and Drugs.
(f) FDA will not issue an order for the destruction of reproductive
tissue under paragraph (a)(1) of this section, nor will it carry out
such destruction itself under paragraph (a)(2) of this section.
Dated: June 17, 2004.
Lester Crawford,
Acting Commissioner of Food and Drugs.
Dated: September 16, 2004.
Tommy G. Thompson,
Secretary of Health and Human Services.
[FR Doc. 04-25798 Filed 11-18-04; 12:30 pm]
BILLING CODE 4160-01-S