Agency Information Collection Activities: Proposed Collection; Comment Request; CGMP Regulations for Finished Pharmaceuticals

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 98N-1110]

Agency Information Collection Activities: Proposed Collection;

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 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 reinstatement of an existing collection of

information, and to allow 60 days for public comment in response to the

notice. This notice solicits comments on information collection

provisions relating to the regulation of FDA's current good

manufacturing practices (CGMP's) and related regulations for finished

pharmaceuticals.

DATES: Submit written comments on the collection of information by

February 22, 1999.

ADDRESSES: Submit written comments on the collection of information to

the Dockets Management Branch (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 L. Nelson, Office of

Information Resources Management (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 reinstatement 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 listed below.

With respect to the following collection of information, FDA

invites comments on: (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.

[[Page 71292]]

CGMP Regulations for Finished Pharmaceuticals--Parts 210 and 211

(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 deemed to be

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 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 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 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 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 below for routine maintenance of SOP's. Estimates for

specific recordkeeping requirements are listed individually.

The 25 SOP 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 cleaning, sterilizing, and processing to remove pyrogenic

properties for drug product containers 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 the FDA economics

staff to prepare an economic

[[Page 71293]]

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: Amendment of Certain Requirements for Finished

Pharmaceuticals'' (61 FR 20104). This report provided information on

the current number of establishments affected by FDA recordkeeping

requirements and FDA 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 registration files. The ERG report is available at the Dockets

Management Branch (address above) 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

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.

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

previous list of 25 SOP's) 4,184 1 4,184 25 104,600

One-time Burden (New Start-

up SOP's)2 100 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 2,0920 .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

211.188 4,184 25 104,600 2 209,200

211.186 4,184 10 41,840 2 83,680

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.

[[Page 71294]]

Dated: December 15, 1998

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 98-34114 Filed 12-23-98; 8:45 am]

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