Agency Information Collection Activities; Submission for OMB Review; 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; 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