[Federal Register Volume 64, Number 74 (Monday, April 19, 1999)]
[Notices]
[Pages 19180-19182]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-9636]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 98N-1110]
Agency Information Collection Activities; Submission for OMB
Review; Comment Request; CGMP Regulations for Finished Pharmaceuticals
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing that the
proposed collection of information listed below has been submitted to
the Office of Management and Budget (OMB) for review and clearance
under the Paperwork Reduction Act of 1995 (the PRA).
DATES: Submit written comments on the collection of information by May
19, 1999.
ADDRESSES: Submit written comments on the collection of information to
the Office of Information and Regulatory Affairs, OMB, New Executive
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn:
Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information
Resources Management (HFA-250), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-1482.
SUPPLEMENTARY INFORMATION: In compliance with section 3507 of the PRA
(44 U.S.C. 3507), FDA has submitted the following proposed collection
of information to OMB for review and clearance.
CGMP Regulations for Finished Pharmaceuticals--21 CFR Parts 210 and
211 (OMB Control Number 0910-0139)--Reinstatement
Under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic
Act (the act) (21 U.S.C. 351(a)(2)(B)), a drug is adulterated if the
methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding do not conform to or are
not operated or administered in conformity with current good
manufacturing practices (CGMP's) to ensure that such drug meets the
requirements of the act as to safety and has the identity and strength,
and meets the quality and purity characteristics, which it purports or
is represented to possess.
FDA has the authority under section 701(a) of the act (21 U.S.C.
371(a)) to issue regulations for the efficient enforcement of the act
regarding CGMP procedures for manufacturing, processing, and holding
drugs and drug products. The CGMP regulations help ensure that drug
products meet the statutory requirements for safety and have their
purported or represented their purported or represented identity,
strength, quality, and purity characteristics. The information
collection requirements in the CGMP regulations provide FDA with the
necessary information to perform its duty to protect public health and
safety.
Although CGMP must be current in the industry, a practice need not
be widely prevalent providing such practice is both feasible and
valuable in ensuring drug quality. CGMP requirements establish
accountability in the manufacturing and processing of drug products,
provide for meaningful FDA inspections, and enable manufacturers to
improve the quality of drug products over time. The recordkeeping
requirements also serve preventive and remedial purposes and provide
crucial information if it is necessary to recall a drug product.
The general requirements for recordkeeping under part 211 (21 part
211) are set forth in Sec. 211.180. Any production, control, or
distribution record associated with a batch and required to be
maintained in compliance with part 211 must be retained for at least 1
year after the expiration date of the batch and, for certain OTC drugs,
3 years after distribution of the batch (Sec. 211.180(a)). Records for
all components, drug product containers, closures, and labeling are
required to be maintained for at least 1 year after the expiration date
and 3 years for certain OTC products (Sec. 211.180(b)).
All part 211 records must be readily available for authorized
inspections during the retention period (Sec. 211.180(c)), and such
records may be retained either as original records or as true copies
(Sec. 211.180(d)). In addition, 21 CFR 11.2(a) provides that ``For
records required to be maintained but not submitted to the agency,
persons may use electronic records in lieu of paper records or
electronic signatures in lieu of traditional signatures, in whole or in
part, provided that the requirements of this part are met.'' To the
extent this electronic option is used, the burden of maintaining paper
records should be substantially reduced as should any review of such
records.
In order to facilitate improvements and corrective actions, records
must be maintained so that data can be used for evaluating, at least
annually, the quality standards of each drug product to determine the
need for changes in drug product specifications or manufacturing or
control procedures (Sec. 211.180(e)). Written procedures for these
evaluations are to be established and include provisions for a review
of a representative number of batches and, where applicable, records
associated with the batch, and provisions for a review of complaints,
recalls, returned or salvaged drug products, and investigations
conducted under Sec. 211.192 for each drug product.
Written procedures, referred to here as standard operating
procedures (SOP's), are required for many part 211 records. The current
SOP requirements were initially provided in a final rule published in
the Federal Register of September 29, 1978 (43 FR 45014), and are now
an integral and familiar part of the drug manufacturing process. The
major paperwork impact of SOP's results from their creation.
Thereafter, SOP's need to be periodically updated. A combined estimate
is provided in
[[Page 19181]]
Table 1 of this document for routine maintenance of SOP's. Estimates
for specific recordkeeping requirements are listed individually.
The 25 SOP's provisions under part 211 in the combined maintenance
estimate include: (1) Sec. 211.22(d) (responsibilities and procedures
of the quality control unit); (2) Sec. 211.56(b) (sanitation
procedures); (3) Sec. 211.56(c) (use of suitable rodenticides,
insecticides, fungicides, fumigating agents, and cleaning and
sanitizing agents; (4) Sec. 211.67(b) (cleaning and maintenance of
equipment); (5) Sec. 211.68(a) (proper performance of automatic,
mechanical, and electronic equipment); (6) Sec. 211.80(a) (receipt,
identification, storage, handling, sampling, testing, approval or
rejection of components and drug product containers or closures); (7)
Sec. 211.94(d) (standards or specifications, methods of testing, and
methods of remove pyrogenic properties for drug product container and
closures); (8) Sec. 211.100(a) (production and process control; (9)
Sec. 211.110(a) (sampling and testing of in-process materials and drug
products); (10) Sec. 211.113(a)(prevention of objectionable
microorganisms in drug products not required to be sterile); (11)
Sec. 211.113(b) (prevention of microbiological contamination of drug
products purporting to be sterile, including validation of any
sterilization process); (12) Sec. 211.115(a) (system for reprocessing
batches that do not conform to standards or specifications, to insure
that reprocessed batches conform with all established standards,
specifications, and characteristics); (13) Sec. 211.122(a) (receipt,
identification, storage, handling, sampling, examination and/or testing
of labeling and packaging materials); (14) Sec. 211.125(f) (control
procedures for the issuance of labeling); (15) Sec. 211.130 (packaging
and label operations, prevention of mixup and cross contamination,
identification and handling of filed drug product containers that are
set aside and held in unlabeled condition, identification of the drug
product with a lot or control number that permits determination of the
history of the manufacture and control of the batch); (16) Sec. 211.142
(warehousing); (17) Sec. 211.150 (distribution of drug products); (18)
Sec. 211.160 (laboratory controls); (19) Sec. 211.165(c) (testing and
release for distribution); (20) Sec. 211.166(a) (stability testing);
(21) Sec. 211.167 (special testing requirements); (22) Sec. 211.180(f)
(notification of responsible officials of investigations, recalls,
reports of inspectional observations, and any regulatory actions
relating to good manufacturing practice); (23) Sec. 211.198(a) (written
and oral complaint procedures, including quality control unit review of
any complaint involving specifications failures, and serious and
unexpected adverse drug experiences); (24) Sec. 211.204 (holding,
testing, and reprocessing of returned drug products); and (25)
Sec. 211.208 (drug product salvaging).
The following burden estimates for routine maintenance and for
specific recordkeeping requirements are based on FDA's institutional
experience regarding creation and review of such procedures and similar
recordkeeping requirements, and data provided by the Eastern Research
Group (ERG), which is a consulting group hired by FDA's economics staff
to prepare an economic analysis of the potential economic impact of the
May 3, 1996 (61 FR 20104), proposed rule. ERG prepared a report for FDA
that estimated the recordkeeping burden for the proposed rule entitled
``Current Good Manufacturing Practice; Proposed Amendment of Certain
Requirements for Finished Pharmaceuticals'' (61 FR 20104). This report
provided information on the current number of establishments affected
by FDA's recordkeeping requirements and the agency has relied on these
figures to estimate the number of establishments affected by part 211
recordkeeping provisions. ERG estimated that there are 1,077
establishments involved in pharmaceutical preparations, diagnostic
substances, and biological products; 948 repackers or relabelers; and
2,159 medical gas establishments for a total estimate of 4,184
recordkeepers subject to CGMP recordkeeping requirements. ERG used a
variety of sources to obtain its estimates including reports from the
Department of Commerce and FDA's registration files. The ERG report is
available at the Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, under
Docket No. 95N-0362.
ERG also provided estimates on the burden involved in creating
SOP's. While most of the CGMP provisions covered in this document were
created many years ago, there will be some existing firms expanding
into new manufacturing areas and start-up firms that will need to
create SOP's. FDA is assuming that approximately 100 firms will have to
create up to 25 SOP's for a total of 2,500 records, and the agency
estimates that it will take 20 hours per recordkeeper to create 25 new
SOP's for a total of 50,000 hours as a one-time burden. Annual SOP's
maintenance is estimated to involve 1 hour annually per SOP, totaling
25 hours annually per recordkeeper.
The proposed rule revising part 211 CGMP requirements of May 3,
1996, would require additional SOP's. Cost estimates for those
additional SOP's were included in the proposed rule, but are not
included here. Any comments on those estimates will be evaluated in any
final rule based on that proposal.
In the Federal Register of December 24, 1998 (63 FR 71291), the
agency requested comments on the proposed collections of information.
One comment was received from a pharmaceutical trade association. The
comment said that the agency's estimates of paperwork needed to comply
with the CGMP regulations were far too low. The comment based its
conclusion on : (1) An informal poll of seven pharmaceutical firms; (2)
the assertion that the agency had not considered the records that are
required by several specific sections of the regulations; (3) the added
recordkeeping attendant to agency guidances; and (4) the premise that
part 11 (21 CFR part 11) (electronic records; electronic signatures)
imposed costs that do not offset savings of electronic recordkeeping.
The agency has carefully considered the comment and concludes that
the agency's estimates of the CGMP paperwork are reasonable and
correct. The agency's estimates are based upon not only the ERG report,
but its extensive experience with a broad spectrum of industry,
including small and large firms, makers of generic and innovator drug
products, and repackers. FDA believes these estimates reflect a more
accurate characterization of the industry than the comment suggests.
FDA's estimates are based on information received from large and small
pharmaceutical firms. The numbers in the burden chart reflect an
average of all firms involved in the review process.
With respect to the comment that FDA had not considered several
sections of the regulations, the agency believes there may have been
some misunderstanding on the part of comments. In fact, all sections of
the regulations were considered, including those which the comments
stated ``were ignored.'' Part of the misunderstanding is likely due to
the fact that sections the comments considered to be ``ignored'' were
those that contained no paperwork and therefore were not factored into
the final analysis.
With respect to recordkeeping that is referenced in agency guidance
documents, where a guidance document
[[Page 19182]]
addresses recordkeeping requirements that are already codified, the
guidance documents themselves create no new paperwork burdens. However,
the agency acknowledges that, on occasion, the information collection
contained in guidance documents is beyond the scope of the regulation.
FDA recognizes the need to ensure all potentially new paperwork burdens
are identified, and that public comment is sought accordingly.
Regarding electronic recordkeeping, the agency fully met its
obligations under the paperwork reduction act in developing and issuing
part 11 and received no objections to the rule with respect to
paperwork reduction. In fact, extensive discussions were held with
industry throughout the development of the rule. FDA believes that the
benefits of electronic recordkeeping, especially with regard to
paperwork reduction, far outweigh the costs of compliance with part 11
to ensure that the electronic records are trustworthy, reliable, and
compatible with FDA's mandate to protect and promote public health.
FDA estimates the burden of this collection of information as
follows:
Table 1.--Estimated Annual Recordkeeping Burden1
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Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Recordkeepers Recordkeeping Records Recordkeeper
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SOP Maintenance (See 4,184 1 4,184 25 104,600
previous list of 25
SOP's)
One-time Burden (New 100 25 2,500 20 50,000
Start-up SOP's)\2\
211.34 4,184 .25 1,046 .5 523
211.67(c) 4,184 50 209,200 .25 52,300
211.68 4,184 2 8,368 1 8,368
211.68(a) 4,184 10 41,840 .5 20,920
211.68(b) 4,184 5 20,920 .25 5,230
211.72 4,184 .25 1,046 1 1,046
211.80(d) 4,184 .25 1,046 .1 105
211.100(b) 4,184 3 12,552 2 25,104
211.105(b) 4,184 .25 1,046 .25 262
211.122(c) 4,184 50 209,200 .25 52,300
211.130(e) 4,184 50 209,200 .25 52,300
211.132(c) 1,698 20 33,960 .5 16,980
211.132(d) 1,698 .2 340 .5 170
211.137 4,184 5 20,920 .5 10,460
2111.160(a) 4,184 2 8,368 1 8,368
211.165(e) 4,184 1 4,184 1 4,184
211.166(c) 4,184 2 8,368 .5 4,184
211.173 1,077 1 1,077 .25 269
211.180(e) 4,184 .2 837 .25 209
211.180(f) 4,184 .2 837 1 837
211.182 4,184 2 8,368 .25 2,092
211.184 4,184 3 12,552 .5 6,276
211.186 4,184 10 41,840 2 83,680
211.188 4,184 25 104,600 2 209,200
211.192 4,184 2 8,368 1 8,368
211.194 4,184 25 104,600 .5 52,300
211.196 4,184 25 104,600 .25 26,150
211.198 4,184 5 20,920 1 20,920
211.204 4,184 10 41,840 .5 20,920
Total 848,625
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
\2\ This is a one-time burden.
Dated: April 12, 1999.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 99-9636 Filed 4-16-99; 8:45 am]
BILLING CODE 4160-01-F