[Federal Register Volume 67, Number 95 (Thursday, May 16, 2002)]
[Notices]
[Pages 34939-34942]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-12263]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 02N-0007]


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 has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995.

DATES:  Submit written comments on the collection of information by 
June 17, 2002.

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: 
Stuart Shapiro, 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 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)--Extension

    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

[[Page 34940]]

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 
(CGMPs) 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 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. 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 CGMP 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 CFR 
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 over-the-
counter (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.
    The specific recordkeeping requirements provided in table 1 of this 
document are as follows:
    Section 211.34--Consultants advising on the manufacture, 
processing, packing, or holding of drug products must have sufficient 
education, training, and experience to advise on the subject for which 
they are retained. Records must be maintained stating the name, 
address, and qualifications of any consultants and the type of service 
they provide.
    Section 211.67(c)--Records must be kept of maintenance, cleaning, 
sanitizing, and inspection as specified in Secs. 211.180 and 211.182.
    Section 211.68--Appropriate controls must be exercised over 
computer or related systems to assure that changes in master production 
and control records or other records are instituted only by authorized 
personnel.
    Section 211.68(a)--Records must be maintained of calibration 
checks, inspections, and computer or related system programs for 
automatic, mechanical, and electronic equipment.
     Section 211.68(b)--All appropriate controls must be exercised over 
all computers or related systems and control data systems to assure 
that changes in master production and controls records or other records 
are instituted only by authorized persons.
    Section 211.72--Filters for liquid filtration used in the 
manufacture, processing, or packing of injectable drug products 
intended for human use must not release fibers into such products.
    Section 211.80(d)--Each container or grouping of containers for 
components or drug product containers or closures must be identified 
with a distinctive code for each lot in each shipment received. This 
code must be used in recording the disposition of each lot. Each lot 
must be appropriately identified as to its status.
    Section 211.100(b)--Written production and process control 
procedures must be followed in the execution of the various production 
and process control functions and must be documented at the time of 
performance. Any deviation from the written procedures must be recorded 
and justified.
    Section 211.105(b)--Major equipment must be identified by a 
distinctive identification number or code that must be recorded in the 
batch production record to show the specific equipment used in the 
manufacture of each batch of a drug product. In cases where only one of 
a particular type of equipment exists in a manufacturing facility, the 
name of the equipment may be used in lieu of a distinctive 
identification number or code.
     Section 211.122(c)--Records must be maintained for each shipment 
received of each different labeling and packaging material indicating 
receipt, examination, or testing.
    Section 211.130(e)--Inspection of packaging and labeling facilities 
must be made immediately before use to assure that all drug products 
have been removed from previous operations. Inspection must also be 
made to assure that packaging and labeling materials not suitable for 
subsequent operations have been removed. Results of inspection must be 
documented in the batch production records.
    Section 211.132(c)--Certain retail packages of OTC drug products 
must bear a statement that is prominently placed so consumers are 
alerted to the specific tamper-evident feature of the package. The 
labeling statement is required to be so placed that it will be 
unaffected if the tamper-resistant feature of the package is breached 
or missing. If the tamper-evident feature chosen is one that uses an 
identifying characteristic, that characteristic is required to be 
referred to in the labeling statement.
    Section 211.132(d)--A request for an exemption from packaging and 
labeling requirements by a manufacturer or packer is required to be 
submitted in the form of a citizen petition under 21 CFR 10.30.
    Section 211.137--Requirements regarding product expiration dating 
and compliance with 21 CFR 201.17.
    Section 211.160(a)--The establishment of any specifications, 
standards, sampling plans, test procedures, or other laboratory control 
mechanisms, including any change in such specifications, standards, 
sampling plans, test procedures, or other

[[Page 34941]]

laboratory control mechanism, must be drafted by the appropriate 
organizational unit and reviewed and approved by the quality control 
unit. These requirements must be followed and documented at the time of 
performance. Any deviation from the written specifications, standards, 
sampling plans, test procedures, or other laboratory control mechanisms 
must be recorded and justified.
    Section 211.165(e)--The accuracy, sensitivity, specificity, and 
reproducibility of test methods employed by a firm must be established 
and documented. Such validation and documentation may be accomplished 
in accordance with Sec. 211.194(a)(2).
    Section 211.166(c)--Specifies homeopathic drug product 
requirements.
    Section 211.173--Animals used in testing components, in-process 
materials, or drug products for compliance with established 
specifications must be maintained and controlled in a manner that 
assures their suitability for their intended use. They must be 
identified, and adequate records must be maintained showing the history 
of their use.
    Section 211.180(e)--Written records required by this part 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. Written procedures must be established and followed for 
such evaluations and must include provisions for a representative 
number of batches, whether approved or unapproved or rejected, and a 
review of complaints, recalls, returned or salvaged drug products, and 
investigations conducted under Sec. 211.192 for each drug product.
    Section 211.180(f)--Procedures must be established to assure that 
the responsible officials of the firm, if they are not personally 
involved in or immediately aware of such actions, are notified in 
writing of any investigations, conducted under Sec. 211.198, 
Sec. 211.204, or Sec. 211.208, any recalls, reports of inspectional 
observations issued, or any regulatory actions relating to good 
manufacturing practices brought by FDA.
    Section 211.182--Specifically explains equipment cleaning and the 
use log.
    Section 211.184--Specifies component, drug product container, 
closure, and labeling records.
    Section 211.186--Specifies master production and control records.
    Section 211.188--Specifies batch production and control records.
    Section 211.192--Specifies the information that must be maintained 
on the investigation of discrepancies found in the review of all drug 
product production and control records by the quality control staff.
    Section 211.194--Explanation and description of laboratory records 
that must be retained.
    Section 211.196--Specifies the information that must be included in 
records on the distribution of the drug.
    Section 211.198--Specifies and describes the handling of all 
complaint files received by the applicant.
    Section 211.204--Specifies that records be maintained of returned 
and salvaged drug product and describes the procedures involved.
    Written procedures, referred to here as standard operating 
procedures (SOPs), 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 information collection impact of SOPs results from their 
creation. Thereafter, SOPs need to be periodically updated. A combined 
estimate is provided in table 1 of this document for routine 
maintenance of SOPs. The 25 SOP provisions under part 211 in the 
combined maintenance estimate include:
    (1) Section 211.22(d)--Responsibilities and procedures of the 
quality control unit;
    (2) Section 211.56(b)--Sanitation procedures;
    (3) Section 211.56(c)--Use of suitable rodenticides, insecticides, 
fungicides, fumigating agents, and cleaning and sanitizing agents;
    (4) Section 211.67(b)--Cleaning and maintenance of equipment;
    (5) Section 211.68(a)--Proper performance of automatic, mechanical, 
and electronic equipment;
    (6) Section 211.80(a)--Receipt, identification, storage, handling, 
sampling, testing, approval, or rejection of components and drug 
product containers or closures;
    (7) Section 211.94(d)--Standards or specifications, methods of 
testing, and methods of cleaning, sterilizing, and processing to remove 
pyrogenic properties for drug product containers and closures;
    (8) Section 211.100(a)--Production and process control;
    (9) Section 211.110(a)--Sampling and testing of in-process 
materials and drug products;
    (10) Section 211.113(a)--Prevention of objectionable microorganisms 
in drug products not required to be sterile;
    (11) Section 211.113(b)--Prevention of microbiological 
contamination of drug products purporting to be sterile, including 
validation of any sterilization process;
     (12) Section 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) Section 211.122(a)--Receipt, identification, storage, 
handling, sampling, examination and/or testing of labeling and 
packaging materials;
    (14) Section 211.125(f)--Control procedures for the issuance of 
labeling;
    (15) Section 211.130--Packaging and label operations, prevention of 
mix-up 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) Section 211.142--Warehousing;
    (17) Section 211.150--Distribution of drug products;
    (18) Section 211.160--Laboratory controls;
    (19) Section 211.165(c)--Testing and release for distribution;
    (20) Section 211.166(a)--Stability testing;
    (21) Section 211.167--Special testing requirements;
    (22) Section 211.180(f)--Notification of responsible officials of 
investigations, recalls, reports of inspectional observations, and any 
regulatory actions relating to good manufacturing practice;
     (23) Section 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) Section 211.204--Holding, testing, and reprocessing of 
returned drug products; and
    (25) Section 211.208--Drug product salvaging.
    Although 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 startup firms that will need to create 
SOPs. As provided in table 1 of this document, FDA is assuming that 
approximately 100 firms will have to create up to 25 SOPs for a total 
of 2,500 records, and the agency estimates that it will take 20 hours 
per recordkeeper to create 25 new SOPs for a total of 50,000 hours.

[[Page 34942]]

    The burden estimates for the recordkeeping requirements in table 1 
of this document are based on FDA's institutional experience regarding 
creation and review of such procedures and similar recordkeeping 
requirements, and data provided to FDA to prepare an economic analysis 
of the potential economic impact of the May 3, 1996, proposed rule 
entitled ``Current Good Manufacturing Practice: Proposed Amendment of 
Certain Requirements for Finished Pharmaceuticals'' (61 FR 20104). 
Annual SOP maintenance is estimated to involve 1 hour annually per SOP, 
totaling 25 hours annually per recordkeeper.
    The May 3, 1996, proposed rule revising part 211 CGMP requirements 
would require additional SOPs. Cost estimates for those additional SOPs 
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 February 7, 2002 (67 FR 5825), the 
agency requested comments on the proposed collection of information. 
There were no comments received.
    FDA estimates the burden of this collection of information as 
follows:

                                                   Table 1.--Estimated Annual Recordkeeping Burden\1\
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                                                                Annual Frequency per                               Hours per
             21 CFR Section               No. of Recordkeepers      Recordkeeping      Total Annual Records      Recordkeeper           Total Hours
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SOP Maintenance (See previous list of            4,184                    1                    4,184                  25                  104,600
 25 SOPs)
New startup SOPs                                   100                   25                    2,500                  20                   50,000
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
211.160(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.


    Dated: May 8, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-12263 Filed 5-15-02; 8:45 am]
BILLING CODE 4160-01-S