[Federal Register Volume 60, Number 13 (Friday, January 20, 1995)]
[Rules and Regulations]
[Pages 4087-4091]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-1361]
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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