[Federal Register: March 28, 2005 (Volume 70, Number 58)]
[Page 15628-15632]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]



Food and Drug Administration

[Docket No. 2005N-0100]

Agency Information Collection Activities; Proposed Collection; 
Comment Request; Current Good Manufacturing Practice Regulations for 
Finished Pharmaceuticals

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.


SUMMARY: The Food and Drug Administration (FDA) is announcing an 
opportunity for public comment on the proposed collection of certain 
information by the agency. Under the Paperwork Reduction Act of 1995 
(the PRA), Federal agencies are required to publish notice in the 
Federal Register concerning each proposed collection of information, 
including each proposed extension of an existing collection of 
information, and to allow 60 days for public comment in response to the 
notice. This notice solicits comments on the information collection 
provisions of FDA's current good manufacturing practice (CGMP) 
regulations for finished pharmaceuticals.

DATES: Submit written or electronic comments on the collection of 
information by May 27, 2005.

ADDRESSES: Submit electronic comments on the collection of information 
to: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments. Submit written comments on 

the collection of information to the Division of Dockets Management 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. All comments should be identified with the docket 
number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Karen Nelson, Office of Management 
Programs (HFA-250), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-1482.

SUPPLEMENTARY INFORMATION:  Under the PRA (44 U.S.C. 3501-3520), 
Federal agencies must obtain approval from the Office of Management and 
Budget (OMB) for each collection of information they conduct or 
sponsor. ``Collection of information'' is defined in 44 U.S.C. 3502(3) 
and 5 CFR 1320.3(c) and includes agency requests or requirements that 
members of the public submit reports, keep records, or provide 
information to a third party. Section 3506(c)(2)(A) of the PRA (44 
U.S.C. 3506(c)(2)(A)) requires Federal agencies to provide a 60-day 
notice in the Federal Register concerning each proposed collection of 
information, including each proposed extension of an existing 
collection of information, before submitting the collection to OMB for 
approval. To comply with this requirement, FDA is publishing notice of 
the proposed collection of information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on these topics: (1) Whether the proposed collection 
of information is necessary for the proper performance of FDA's 
functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    CGMP Regulations for Finished Pharmaceuticals--21 CFR Parts 210 and 
211 (OMB Control Number 0910-0139)--Extension

[[Page 15629]]

    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, 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 
    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; 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 Sec. Sec.  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 
     Section 211.137--Requirements regarding product expiration 
dating and compliance with 21 CFR 201.17 are set forth.
     Section 211.160(a)--The establishment of any 
specifications, standards, sampling plans, test procedures, or other 
laboratory control

[[Page 15630]]

mechanisms, including any change in such specifications, standards, 
sampling plans, test procedures, or other 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)--Homeopathic drug product requirements 
are set forth.
     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 part 211 
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--Specifies requirements for equipment 
cleaning records and the use log.
     Section 211.184--Specifies requirements for component, 
drug product container, closure, and labeling records.
     Section 211. 186--Specifies master production and control 
records requirements.
     Section 211.188--Specifies batch production and control 
records requirement.
     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 
     Section 211.194--Explains and describes 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 products and describes the procedures 
    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 for routine maintenance of SOPs is provided in table 1 of this 
document. The 25 SOP provisions under part 211 in the combined 
maintenance estimate include:
     Section 211.22(d)--Responsibilities and procedures of the 
quality control unit;
     Section 211.56(b)--Sanitation procedures;
     Section 211.56(c)--Use of suitable rodenticides, 
insecticides, fungicides, fumigating agents, and cleaning and 
sanitizing agents;
     Section 211.67(b)--Cleaning and maintenance of equipment;
     Section 211.68(a)--Proper performance of automatic, 
mechanical, and electronic equipment;
     Section 211.80(a)--Receipt, identification, storage, 
handling, sampling, testing, and approval or rejection of components 
and drug product containers or closures;
     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;
     Section 211.100(a)--Production and process control;
     Section 211.110(a)--Sampling and testing of in-process 
materials and drug products;
     Section 211.113(a)--Prevention of objectionable 
microorganisms in drug products not required to be sterile;
     Section 211.113(b)--Prevention of microbiological 
contamination of drug products purporting to be sterile, including 
validation of any sterilization process;
     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;
     Section 211.122(a)--Receipt, identification, storage, 
handling, sampling, examination, and/or testing of labeling and 
packaging materials;
     Section 211.125(f)--Control procedures for the issuance of 
     Section 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, and 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;
     Section 211.142--Warehousing;
     Section 211.150--Distribution of drug products;
     Section 211.160--Laboratory controls;
     Section 211.165(c)--Testing and release for distribution;
     Section 211.166(a)--Stability testing;
     Section 211.167--Special testing requirements;
     Section 211.180(f)--Notification of responsible officials 
of investigations, recalls, reports of inspectional observations, and 
any regulatory actions relating to good manufacturing practice;
     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 
     Section 211.204--Holding, testing, and reprocessing of 
returned drug products; and
     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,

[[Page 15631]]

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.
    The burden estimates for the recordkeeping requirements in table 1 
of this document are based on the following factors: (1) FDA's 
institutional experience regarding creation and review of such 
procedures and similar recordkeeping requirements, and (2) 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.
    FDA estimates the burden of this collection of information as 

                               Table 1.--Estimated Annual Recordkeeping Burden\1\
                       No. of        Annual Frequency      Total Annual         Hours per
 21 CFR Section    Recordkeepers     per Recordkeeping       Records          Recordkeeper        Total Hours
SOP Maintenance              4,184                1                 4,184               25               104,600
 (See list of
 25 SOPs in the
 section of
 this document)
New startup                    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

[[Page 15632]]

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
\1\ There are no capital costs or operating and maintenance costs associated with this collection of

    Dated: March 21, 2005.
Jeffrey Shuren,
Assistant Commisssioner for Policy.
[FR Doc. 05-5976 Filed 3-25-05; 8:45 am]