Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; Amendment of Certain Requirements for Finished Pharmaceuticals

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 211

[Docket No. 90N-0376]

RIN 0905-AA73

Current Good Manufacturing Practice in Manufacturing, Processing,

Packing, or Holding of Drugs; Amendment of Certain Requirements for

Finished Pharmaceuticals

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is revising certain

requirements of the current good manufacturing practice (CGMP)

regulations for finished human and veterinary pharmaceuticals. The

changes include clarifying the degree of discretion provided to

manufacturers to determine whether separate or defined areas of

production and storage are necessary, clarifying the standard used to

determine the degree of scrutiny necessary to check the accuracy of the

input to and output from computer systems, exempting investigational

new drug products from bearing an expiration date, permitting the use

of a representative sampling plan for the examination of reserve

samples, and clarifying the manufacturer's responsibilities regarding

batch records during the annual evaluation of drug product quality

standards. These revisions will reduce regulatory burdens.

EFFECTIVE DATE: February 21, 1995.

FOR FURTHER INFORMATION CONTACT:

Howard P. Muller, Jr., Center for Drug Evaluation and Research

(HFD-362), Food and Drug Administration, 7500 Standish Pl., Rockville,

MD 20855, 301-594-1046,

Paul J. Motise, Center for Drug Evaluation and Research (HFD-323),

Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855,

301-594-1089, or

William G. Marnane, Center for Veterinary Medicine (HFV-143), Food

and Drug Administration, 7500 Standish Pl., Rockville MD 20855, 301-

594-0678.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of July 14, 1981 (46 FR 36332), FDA

announced that it was undertaking a review of existing regulations with

the goal of minimizing regulatory burdens while maintaining an

acceptable level of consumer protection. The public was invited to

submit information to assist the agency in deciding the priority of

review. FDA invited data that would enable the agency to identify

specific existing regulations or groups of regulations perceived to be

unnecessarily costly, burdensome, or without public benefit, and on the

potential savings to be derived from revising or removing regulations.

In the Federal Register of July 2, 1982 (47 FR 29004), FDA

announced its review priorities based on comments from 125 individuals

and organizations. One area selected for regulatory review was part 211

(21 CFR part 211), the regulations that govern CGMP for finished

pharmaceuticals.

This, in turn, led to an internal retrospective review that

resulted in recommendations to the agency. As a result of the agency

review, in the Federal Register of February 12, 1991 (56 FR 5671), FDA

issued a proposed rule incorporating the recommendations resulting from

the review (hereinafter referred to as the proposed rule).

Consideration of these comments and any resulting revisions have been

incorporated into this final rule and are discussed in detail below.

The agency's review of CGMP regulations is ongoing and FDA

anticipates further revisions based on the agency's experience with the

regulations, enforcement efforts, and communications with industry and

the general public. [[Page 4088]]

II. The Agency's Retrospective Review

The agency conducted an internal retrospective review (the review)

of CGMP regulations to determine if any existing provisions should be

changed, modified, or removed. Based on that review, the agency

concluded that there was a continuing need for the CGMP regulations to

protect public health and safety. FDA's examination of individual CGMP

provisions revealed that most were necessary and effective in

addressing the underlying issues and concerns. The review did, however,

result in recommended changes in particular CGMP regulations. These

changes were intended to provide drug manufacturers with more

flexibility and discretion in manufacturing drug products while

maintaining the manufacturing control necessary to ensure drug product

quality. The proposed changes are discussed below.

Section 211.42(c) requires separate or defined areas for a firm's

operation to prevent contamination or a mixup of drug products or their

ingredients. Although the agency's review found that, in general, this

provision did not, with the exception of areas of aseptic processing or

penicillin production, require the construction of physical barriers,

FDA recognized that the word ``defined'' might be subject to differing

interpretations. FDA concluded that amending this provision would

clarify that, in most cases, manufacturers may exercise their judgment

to determine whether separate or defined areas of production and

storage are necessary. The agency is currently evaluating the matter of

separate or defined areas of production and storage and may, if

necessary, issue further clarification in the future.

Several CGMP regulations require that manufacturers take steps to

check the accuracy of equipment used in drug production. For example,

Sec. 211.68(b) addresses the accuracy of computerized records and data.

A number of comments opposed routine checking of the accuracy of input

to or output from a previously validated computer on the basis that it

was duplicative, redundant, and expensive. FDA reviewed these comments

and concluded that, although automated systems may be less prone to

error, such systems are not perfect and need to be monitored. Following

its review, however, FDA agreed that the degree of monitoring required

for computerized systems would differ from that required for manual

operations. FDA concluded that this provision of the CGMP regulations

should be revised to clarify that the degree and frequency of input/

output verification be based on the complexity and reliability of the

computer or related system.

Before its retrospective review of the CGMP regulations, FDA

declined to grant investigational drug products an unqualified

exemption from all or most of the CGMP requirements. Following the

retrospective review, however, FDA concluded that it was not always

possible to obtain expiration dates for investigational drug products

because relatively little stability data may be available at the

beginning of a clinical investigation. FDA concluded that the

expiration dating requirement should be eliminated for investigational

new drug application (IND) products so long as such products otherwise

meet the stability requirements provided in the regulation.

Section 211.170(b) requires that most reserve samples be examined

visually at least once a year for evidence of deterioration.

Manufacturers must keep reserve samples that are representative of each

lot or batch of finished drug product. The reserve sample is to consist

of at least twice the quantity necessary for all required tests.

Comments responding to the July 14, 1981, notice, as well as other

communications subsequently received by the agency, recommended

deleting this requirement because of the large cost to firms that

produce large numbers of lots (or batches) of a drug product. The

comments further asserted that this requirement was redundant given

other provisions of the regulations.

FDA declines to eliminate this requirement because suggested

alternatives do not provide effective surveillance of all lots of a

drug product. The agency believes the yearly inspection is necessary to

ensure the quality of the drug product. However, following the

retrospective review, FDA concluded that manufacturers could meet their

obligations under this regulation in a less burdensome way by

conducting an annual visual inspection of reserve samples from a

representative number of reserve sample lots. Therefore, FDA is

revising the regulation to permit the use of a representative sampling

plan for examination of reserve samples.

Section 211.180 provides general requirements for the retention,

treatment, and handling of CGMP records and reports. Section 211.180(e)

requires the evaluation, at least annually, of the quality standards of

each drug to determine the need for changes in drug product

specifications. Firms must establish and follow written procedures for

these annual evaluations, and Sec. 211.180(e)(1) and (e)(2) requires

that several specific items be included in such written procedures. For

example, Sec. 211.180(e)(1) requires these written procedures to

provide for ``[a] review of every batch, whether approved or rejected,

and, where applicable, records associated with the batch.''

Following the retrospective review, FDA concluded that some

manufacturers, rather than examining representative batch records for

each drug product manufactured during the year, construed this

provision to require that every batch record was to be reviewed

annually and evaluated according to written procedures. Following the

retrospective review, FDA decided to clarify Sec. 211.180(e)(1) on this

point.

III. Comments on the Proposed Rule

FDA received several comments on the proposed rule. These comments

came from pharmaceutical manufacturers, trade associations, and

consumers. In general, the comments supported the agency's efforts to

remove, where possible, regulatory requirements that could be

eliminated without adversely affecting drug product quality. A section-

by-section summary of the comments and the agency's response follow.

A. Design and Construction Features

Confusion about the interpretation of Sec. 211.42(c), which

requires separate or defined areas for a firm's operation to prevent

contamination or mixup, led to the proposed revision of this provision.

The proposed revision was intended to clarify that, in many situations,

other control systems may be used in lieu of complete physical

separation. The proposal would require separate or defined areas to

prevent contamination or mixup ``as necessary.''

1. Comments on proposed Sec. 211.42 generally supported the

revision. Three comments, however, recommended that the wording be

modified. One comment requested that the revision more explicitly

emphasize that the utilization of computer-controlled inventory systems

obviates the need for physical separation. Two comments suggested

removal of any reference to separate or defined areas.

The agency agrees in part and disagrees in part with these

comments. The preamble to the proposed rule noted that Sec. 211.42(c)

is intended to ensure that sufficient physical separation exists in

manufacturing operations to prevent contamination or mixups, and that

the degree of separation is dependent on the type of operation and its

proximity to other operations in the plant (56 FR 5671 at

[[Page 4089]] 5672). The proposed revision was intended to make it

clear that the regulation did not necessarily require a separate room

or partitioned area. The agency does not, however, intend to disallow

the possibility that, in certain instances, it may be necessary to

require physical separation to prevent contamination or mixups and, as

discussed above, is continuing to review this matter. Sophisticated

computer systems may provide more effective inventory control and help

reduce mixups, but certain substances, such as penicillin, may pose

such a high risk of contamination that a separate or defined area is

necessary to ensure the safety of drug products.

The agency has, therefore, retained the reference to separate or

defined areas but has revised the final rule to clarify that other

control systems may be used that are capable of preventing

contamination and mixups. The agency stated in the preamble to the CGMP

regulations published in the Federal Register of September 29, 1978 (43

FR 45014 at 45037), and reiterated in the proposed rule (56 FR 5671 at

5672 and 5673), and states again here that this provision is intended

to ensure that: ``enough physical separation be employed as is

necessary to prevent contamination or mixups. The degree of separation

will depend on the type of operation and its proximity to other

operations within the plant. The phrase `separate or defined' is not

intended necessarily to mean a separate room or partitioned area, if

other controls are adequate to prevent mixups and contamination.''

The agency, on its own initiative, has also revised Sec. 211.42 to

clarify that the procedures in paragraphs (c)(1) through (c)(10) of

that regulation should be protected from contamination or mixups.

B. Automatic, Mechanical, and Electronic Equipment

Section 211.68(b) deals with controls to be exercised over computer

operation, data, and records. The provision requires, in part, that

input to and output from a computer system or any related or similar

system of formulas or data shall be checked for accuracy. The proposal

would add a sentence stating that the degree and frequency of input/

output verification from a computer or related system of formulas or

other records or data are to be determined by the complexity and

reliability of such a computer or related system.

2. Although all comments supported the proposed change to

Sec. 211.68(b), three of them would modify the wording. The comments

suggested that the revised regulation does not accommodate the accepted

use of validated computerized drug production and control systems.

FDA declines to amend the rule as suggested by the comments. The

agency believes that the wording in the revised rule adequately

encompasses the use of validated computerized drug production and

control systems.

3. Two comments questioned the need for human verification of

operations that are performed by validated computer systems. Both

listed other regulations that were not the subject of the proposed rule

that required more than one person to verify certain manufacturing

operations, apparently in an effort to show that additional personnel

would be needed to comply with proposed Sec. 211.68.

FDA notes that the revisions to Sec. 211.68 do not impose any

specific personnel requirements. The agency, however, is aware that

computers are subject to malfunctions; for example, the abrupt loss of

data due to a computer ``crash'' can be a disruptive experience and

possibly result in the loss of crucial information regarding the

manufacturing process. Less dramatic events, such as faulty data entry

or programming, can also trigger a chain of events that result in a

serious production error and the possible distribution of an

adulterated product. Thus, while increasingly sophisticated system

safeguards and computerized monitoring of essential equipment and

programs help protect data, no automated system exists that can

completely substitute for human oversight and supervision.

The proposed rule stated (56 FR 5671 at 5673), and FDA reiterates

here, that while the degree of verification is left to the

manufacturer's discretion, the exercise of such discretion, under

Sec. 211.68, requires the use of routine accuracy checks to provide a

high degree of assurance that input to and output from a computer or

related system are reliable and accurate.

The agency intends that each manufacturer will exercise reasonable

judgment based on a variety of factors, including, but not limited to,

the complexity of the computer or related system, in developing a

method to prevent inaccurate data input and output.

C. Expiration Dating

Proposed Sec. 211.137(g) would exempt investigational drug products

from expiration dating requirements provided appropriate stability

studies demonstrate that such products meet appropriate standards or

specifications during their use in clinical investigations.

4. All comments supported the proposed revision of Sec. 211.137.

Two comments, however, recommended changes to clarify the labeling

requirements for new drug products for investigational use that are to

be reconstituted at the time of dispensing. One comment suggested

language specifying the requirement's application to new drug products

for investigational use to avoid confusion with Sec. 211.137(c), which

applies to all drug products that are to be reconstituted at the time

of dispensing.

The agency agrees with these comments and has revised the rule

accordingly.

5. Proposed Sec. 211.137(g) also deals with new drug products for

investigational use that are to be reconstituted at the time of

dispensing. The proposed regulation stated that labeling of such

products would be required to bear expiration ``dating'' for the

reconstituted drug product. One comment suggested changing the proposed

requirement instead to require the labeling to bear expiration

``information'' for reconstituted drug products.

The requirement that expiration ``information'' be placed in the

labeling of a drug product is found at Sec. 211.137(c), and FDA agrees

that this requirement should also apply to Sec. 211.137(g). The final

rule has been revised accordingly.

6. One comment recommended that the proposed exemption be extended

to other clinical supplies not subject to IND requirements that are

distributed for limited clinical testing, such as internal testing or

evaluation in laboratories or for market research. Examples cited

included drugs subject to over-the-counter drug monographs or Drug

Efficacy Study Implementation requirements.

The agency does not agree that clinical supplies not subject to IND

requirements should be exempt from expiration dating. The revision

recognizes that for IND products it is often difficult or impossible to

obtain the data upon which expiration dates are based. IND products

are, therefore, exempt from expiration dating requirements provided

that they meet appropriate standards or specifications as demonstrated

by stability studies during their use in clinical investigations.

D. Reserve Samples

As previously noted, proposed Sec. 211.170(b) would clarify FDA's

intent [[Page 4090]] that this provision requires visual examination of

reserve samples from representative sample lots or batches of a drug

product once a year for evidence of deterioration unless such

examination would affect the integrity of the reserve sample. The

representative sample lots or batches would be selected by acceptable

statistical procedures.

7. Although most comments agreed with the proposed change, several

questioned the value of the annual visual examination requirement given

other required procedures and programs such as stability testing,

production record reviews, and complaint investigations.

The agency has carefully considered these comments and has

concluded that the requirement for annual visual inspection should be

retained. A sufficient number of batches may not be examined during the

course of fulfilling the other required procedures and programs, or

batches examined may not be representative of annual batch production.

As a result, these other procedures and programs cannot replace the

annual visual examination, which provides both manufacturers and

consumers a greater degree of quality assurance.

8. Three comments requested clarification of the terms

``representative'' and ``acceptable statistical procedures.''

The agency does not believe that it is necessary or useful to

define these terms. The terms have been used in the CGMP regulations

for over a decade without apparent confusion due, in part, to a

widespread recognition that the meaning of the term ``representative''

may vary from one product to another as well as with respect to the

various manufacturing processes involved in producing a variety of

products. In addition, an incomplete definition might fail to encompass

the full variety of regulated products and processes, whereas a

complete and inclusive definition with regard to currently available

products and technology might not easily be adapted to new technology.

Similarly, with respect to the term ``acceptable statistical

procedures,'' a more detailed definition would not permit adaptation to

or evolution with advances in statistical analysis.

9. Another comment suggested that the phrase ``acceptable

statistical procedures'' could be interpreted to require FDA approval.

The comment suggested that the term be changed to ``appropriate

statistical procedures.''

As noted above, the agency does not believe that the suggested

change is necessary or useful. The agency emphasizes that the selection

of acceptable statistical procedures does not involve prior agency

approval. The choice of such procedures should, however, be based on a

knowledge of current statistical methodology and include consideration

of the application of such methodology to a particular drug product.

E. General Requirements

Section 211.180(e) requires that written records be maintained so

that the data contained therein are available at least annually for

evaluation of the quality standards for drug products. Proposed

Sec. 211.180(e)(1) was intended to correct the misinterpretation that

the regulation required the review of every batch record for every drug

product produced during the year. The proposed rule revised the

language to require at least annually a review of a representative

number of batch records.

10. One comment noted that current technology makes it possible to

use computer data to evaluate product quality data to detect adverse

trends. The comment asserted that such an approach permitted more

effective and frequent evaluation of such data.

The agency agrees that technological advances can produce gains in

both the accuracy of data evaluation and the speed at which the process

can be conducted, and FDA encourages the use of technology that helps

safeguard the integrity of the manufacturing process. However, such

computerized information must be used as a complement to, and not as a

substitute for, human judgment and intervention. Computerized

assessments must be monitored by qualified individuals to detect trends

that may provide an early indication of changes in drug product

specifications or manufacturing or control procedures that merit

attention and intervention. Moreover, other factors such as product

complaints and recall information may not be included in the computer

data.

11. Several comments requested clarification about the types of

records subject to the batch review requirement.

The proposed rule was not intended to change the types of records

subject to annual review, but instead to allow review of a

representative number of batches in lieu of examining all records from

every batch. FDA has, therefore, clarified the final rule to require a

review of a representative number of batches, whether approved or

rejected, and where applicable, records associated with those batches.

The overall intent of Sec. 211.180(e) is to provide manufacturers

with reliable procedures for reviewing the quality standards for each

drug product. Thus, FDA advises that, although this final rule does not

in all cases require an annual review of every batch record, adopting a

procedure to check every batch record would clearly be appropriate if,

for example, a representative review of batch records showed an adverse

trend in quality.

12. One comment advised that some firms may confuse the

requirements with regard to the annual review of representative batches

with the requirements for batch review prior to the release of a

product under Sec. 211.192.

FDA disagrees with the comment. The final rule amends

Sec. 211.180(e), which requires that written records be maintained so

that data can be used for evaluating, at least annually, the quality

standards of each drug product. Section 211.192, by contrast,

specifically requires a quality control unit to review drug product

production and control records to determine compliance with written

procedures prior to the release of a drug product batch. In brief,

Sec. 211.180(e) involves a retrospective overall evaluation of the

adequacy of the quality standards for drug products, while Sec. 211.192

involves a contemporaneous evaluation of a drug batch to determine its

conformity, at the time of marketing, with current quality standards.

13. One comment suggested allowing a biennial review to permit

trend analysis when three or fewer product batches are produced each

year.

FDA disagrees with this comment. The agency believes that a 2-year

interval between formal review of batches is inadequate. Potential

problems with product quality standards could go undetected and thereby

delay recognition of a need to revise specifications or manufacturing

or control procedures. If a serious error is not detected for a long

period, the resulting product could pose a threat to public health and

safety. Moreover, a trend analysis may be performed in situations where

only a few batches are produced annually by using batches produced in

preceding years.

14. One comment strongly opposed the proposed changes, stating that

every batch record must be reviewed to detect ``drift'' or changes in

specifications for components, manufacturing processes, or other

procedures. The comment asserted that, without reviewing every batch,

deleterious changes might be instituted by a firm employee or employees

without the full knowledge of their superiors, particularly the firm's

research and development group. [[Page 4091]]

The agency does not believe such additional measures are necessary.

This CGMP provision does not stand alone but must be read in context

with other CGMP regulations. Those regulations provide a variety of

safeguards for different stages and aspects of the drug manufacturing

process. It is the CGMP regulations, taken as a whole, that help ensure

drug quality. Moreover, the consequences of widespread disclosure of

problems with drug product quality resulting from a recall or other

ameliorative action are sufficiently severe to provide most firms with

a continuing incentive to maintain product quality. The agency has

carefully reviewed this issue and believes that the final rule will not

reduce drug product quality.

IV. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(10) that this

action is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required.

V. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive

Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). The agency believes that

this rule is consistent with the regulatory philosophy and principles

identified in the Executive Order. The amendments to the CGMP

regulations are intended to allow drug manufacturers more flexibility

and discretion in manufacturing drug products while maintaining those

CGMP requirements necessary to ensure drug product quality. Because

this may encourage innovation and the development of more efficient

manufacturing procedures that should lead to cost savings for drug

manufacturers. In addition, the rule is not a significant regulatory

action as defined by the Executive Order and so is not subject to

review under the Executive Order.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. The agency certifies that the final rule will not

have a significant economic impact on a substantial number of small

entities. Therefore, under the Regulatory Flexibility Act, no further

analysis is required.

List of Subjects in 21 CFR Part 211

Drugs, Labeling, Laboratories, Packaging and containers,

Prescription drugs, Reporting and recordkeeping requirements,

Warehouses.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, 21 CFR part

211 is amended as follows:

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED

PHARMACEUTICALS

1. The authority citation for 21 CFR part 211 continues to read as

follows:

Authority: Secs. 201, 501, 502, 505, 506, 507, 512, 701, 704 of

the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,

355, 356, 357, 360b, 371, 374).

2. Section 211.42 is amended in the introductory text of paragraph

(c) by revising the second sentence to read as follows:

Sec. 211.42 Design and construction features.

* * * * *

(c) * * * There shall be separate or defined areas or such other

control systems for the firm's operations as are necessary to prevent

contamination or mixups during the course of the following procedures:

* * * * *

3. Section 211.68 is amended by adding a new sentence after the

second sentence in paragraph (b) to read as follows:

Sec. 211.68 Automatic, mechanical, and electronic equipment.

* * * * *

(b) * * * The degree and frequency of input/output verification

shall be based on the complexity and reliability of the computer or

related system. * * *

4. Section 211.137 is amended by redesignating paragraph (g) as

paragraph (h), and by adding new paragraph (g) to read as follows:

Sec. 211.137 Expiration dating.

* * * * *

(g) New drug products for investigational use are exempt from the

requirements of this section, provided that they meet appropriate

standards or specifications as demonstrated by stability studies during

their use in clinical investigations. Where new drug products for

investigational use are to be reconstituted at the time of dispensing,

their labeling shall bear expiration information for the reconstituted

drug product.

* * * * *

5. Section 211.170 is amended by revising the fourth sentence in

the introductory text of paragraph (b) to read as follows:

Sec. 211.170 Reserve samples.

* * * * *

(b) * * * Except for those for drug products described in paragraph

(b)(2) of this section, reserve samples from representative sample lots

or batches selected by acceptable statistical procedures shall be

examined visually at least once a year for evidence of deterioration

unless visual examination would affect the integrity of the reserve

sample. * * *

* * * * *

6. Section 211.180 is amended by revising paragraph (e)(1) to read

as follows:

Sec. 211.180 General requirements.

* * * * *

(e) * * *

(1) A review of a representative number of batches, whether

approved or rejected, and, where applicable, records associated with

the batch.

* * * * *

Dated: January 11, 1995.

William K. Hubbard,

Interim Deputy Commissioner for Policy.

[FR Doc. 95-1361 Filed 1-19-95; 8:45 am]

BILLING CODE 4160-01-F