[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