[Federal Register: December 4, 2007 (Volume 72, Number 232)]
[Rules and Regulations]
[Page 68064-68070]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr04de07-5]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 210 and 211
[Docket No. 2007N-0280]
Amendment to the Current Good Manufacturing Practice Regulations
for Finished Pharmaceuticals
AGENCY: Food and Drug Administration, HHS.
ACTION: Direct final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending certain
regulations as the first phase of an incremental approach to modifying
the current good manufacturing practice (CGMP) regulations for finished
pharmaceuticals. We are amending the regulations to modernize or
clarify some of the CGMP requirements, as well as harmonize some of the
CGMP requirements with those of other foreign regulators and other FDA
regulations. These amendments are also consistent with current industry
practice. We are taking this action as part of our continuing effort to
revise outdated regulations without diminishing public health
protection. We are issuing a direct final rule for this action because
FDA expects there will be no significant adverse comments on these
amendments. Elsewhere in this issue of the Federal Register, we are
publishing a companion proposed rule, under our usual notice-and-
comment rulemaking procedures, to provide a procedural framework to
finalize the rule in the event the agency receives any significant
adverse comments and withdraws this direct final rule. The companion
proposed rule and direct final rule are substantively identical.
DATES: This rule is effective April 17, 2008. Submit written or
electronic comments on or before February 19, 2008. If we receive no
significant adverse comments during the specified comment period, we
intend to publish a notice in the Federal Register no later than March
18, 2008, confirming the effective date of the direct final rule. If we
receive any timely significant adverse comments during the comment
period, we will publish a notice of significant adverse comment in the
Federal Register withdrawing this direct final rule before its
effective date.
ADDRESSES: You may submit comments, identified by Docket No. 2007N-
0280, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://www.regulation.gov.
Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described previously, in
the ADDRESSES portion of this document under Electronic Submissions.
Instructions: All submissions received must include the agency name
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN
number has been assigned) for this rulemaking. All comments received
may be posted without change to http://www.fda.gov/ohrms/dockets/default.htm
, including any personal information provided.
For additional information on submitting comments, see the
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number(s), found in brackets in the heading of
this document, into the ``Search'' box and follow the prompts and/or go
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Mary Malarkey, Center for Biologics Evaluation and Research (HFM-
600), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD
20852-1448, 301-827-6190, or
Dennis Bensley, Center for Veterinary Medicine (HFV-140), Food and
Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-827-
6956, or
Frederick Blumenschein, Center for Drug Evaluation and Research
(HFD-326), Food and Drug Administration, 11919 Rockville Pike,
Rockville, MD 20852, 301-827-9022.
SUPPLEMENTARY INFORMATION:
I. Background
Since the development of the CGMP regulations in 1962, FDA has
balanced the need for easily understood minimum standards with the need
to encourage innovation and the development of improved manufacturing
technologies. We strive to give manufacturers latitude to determine how
to achieve the level of control necessary for CGMP compliance,
recognizing that, in some instances, more direction from FDA is
necessary to provide a uniform standard for the entire industry or
because of the potential for harm, or the narrow range of acceptable
means to accomplish a particular CGMP objective. FDA periodically
reassesses and revises the CGMP regulations to accommodate advances in
technology that further safeguard the drug manufacturing process and
the public health. As technology and scientific knowledge related to
CGMP evolve, so does
[[Page 68065]]
understanding of the material, equipment, and process variables, as
well as the operational procedures and oversight methods that must be
defined and controlled to achieve assurance of drug product quality.
In 1996, as part of this reassessment process, FDA proposed a
significant revision to the CGMP regulations for finished
pharmaceuticals to clarify certain manufacturing, quality control, and
documentation requirements, and to ensure that the regulations more
accurately encompass current industry practice (61 FR 20103, May 3,
1996) (1996 proposed rule). Subsequently, as a part of the risk-based
pharmaceutical CGMPs for the 21st century initiative, FDA created a
CGMP Harmonization Analysis Working Group (CGMP Working Group) to
analyze related CGMP requirements in effect in the United States and
internationally, including those related to quality systems. The CGMP
Working Group compared parts 210 and 211 (21 CFR parts 210 and 211) to
the GMPs of the European Union (EU), as well as other FDA regulations
(e.g., the Quality Systems Regulation, 21 CFR part 820) to identify the
differences and consider the value of supplementing or changing the
current regulations. Based on the CGMP Working Group's analysis, we
decided to take an incremental approach to modifying parts 210 and 211
(see http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm#_Toc84065744
).
Because of this change in approach, FDA decided not to finalize the
1996 proposed rule. Therefore, elsewhere in this issue of the Federal
Register, we are publishing a notice withdrawing the 1996 proposed
rule.
This direct final rule is intended to clarify and modernize the
CGMP regulations, as well as harmonize the regulations with
international GMP requirements and other FDA regulations. This direct
final rule represents the first increment of modifications to parts 210
and 211. We believe that these updating changes are noncontroversial.
II. Description of the Direct Final Rule
A. Plumbing
This rule deletes from Sec. 211.48(a) the current requirement of
adherence to a specific U.S. Environmental Protection Agency (EPA)
water standard and instead simply requires that the plumbing system
contain water that is ``safe for human consumption.'' In an effort to
improve harmonization with foreign regulations (particularly the
European Union and Japan) and to make the U.S. regulation more
consistent with that of the United States Pharmacopeia standard, which
is satisfied by compliance with the regulations of the European Union
(EU) and Japan, this revision requires that water supplied by the
plumbing system and used to prepare water for pharmaceutical purposes
be ``safe for human consumption,'' and continues the requirement that
it ``be supplied under continuous positive pressure in a plumbing
system free of defects that could contribute contamination to any drug
product.'' Compliance with the standards set forth in the regulations
currently prescribed by the EPA would be acceptable under this
revision, as would compliance with the standards set forth in the
current regulations of the EU or Japan for potable water used to
prepare water for pharmaceutical purposes.
B. Aseptic Processing
The current regulations related to aseptic processing have not been
updated to reflect current industry standards and practices. In
September 2004, we issued ``Guidance for Industry: Sterile Drug
Products Produced by Aseptic Processing--Current Good Manufacturing
Practice'' (see http://www.fda.gov/cder/guidance/5882.fnl.htm''). The
issuance of this document was the culmination of several years of work,
including soliciting input from external stakeholders, such as
described below.
In 2002, we began work on a draft guidance that was intended to
replace the 1987 Guideline on Sterile Drug Products Produced by Aseptic
Processing. A concept paper was presented to FDA's Advisory Committee
on Pharmaceutical Science on October 22, 2002, for comment. Among other
things, the Committee recommended that we work with the Pharmaceutical
Quality Research Institute (PQRI) for resolution of major issues. The
PQRI Aseptic Processing Working Group (Aseptic Processing Working
Group), composed of members from FDA, industry, and academia, was
formed to provide scientifically based input targeting specific aseptic
processing topics (e.g., media fills). PQRI performed a survey of the
industry on these topics, the results of which were presented to the
Aseptic Processing Working Group for consideration. The Aseptic
Processing Working Group also considered scientific publications and
other regulatory documents in preparing recommendations concerning
specific aseptic processing topics. These recommendations were
discussed by the Aseptic Processing Working Group on February 27 and
28, 2003 (http://www.pqri.org/commworking/minutes/mtc.asp) and presented to
the Manufacturing Subcommittee of FDA's Advisory Committee on
Pharmaceutical Science on May 22, 2003.
In its September 2003, ``Pharmaceutical CGMPs for the 21st
Century--A Risk-Based Approach: Second Progress Report and
Implementation Plan,'' FDA announced the issuance of the draft
guidance. See http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm. At
the time, the agency noted that the guidance was intended to clarify
regulatory expectations, including relevant regulatory standards for
sterile drug products. FDA believed the guidance would help reduce the
incidence of manufacturing problems with sterile drug products and
related drug shortages. The guidance was also consistent with agency
efforts to harmonize with international regulatory standards and
develop more science-based guidance documents. As noted previously, FDA
issued the final guidance in September 2004.
After the GMP Harmonization Analysis Working Group completed its
formal analysis comparing parts 210 and 211 with the GMPs of the EU as
well as with other FDA current good manufacturing practice regulations,
it recommended that part 211 be modernized by adding more clarification
about aseptic processing in an effort to harmonize with current
industry standards and practices. Therefore, we are now amending
several regulations related to aseptic processing to clarify the
regulatory requirements to reflect currently accepted industry practice
as well as, in some cases, to harmonize with international regulatory
standards. The revision to Sec. 211.113(b) applies specifically to
validation of aseptic processes, but the revisions to the other four
sections discussed below apply, as appropriate, to both aseptic and
other types of processes and operations. These revisions clarify and
reflect longstanding agency interpretation of these regulations and
industry practices. The agency notes that these clarifications of the
regulations with respect to aseptic processing do not affect the
applicability of the final guidance issued in September 2004. The
guidance's recommendations on the ways in which manufacturers can
satisfy certain aseptic processing regulatory requirements still apply.
Section 211.67(a) Equipment cleaning and maintenance is being
revised to add the phrase ``and/or sterilized'' after the word
``sanitized'' in the current
[[Page 68066]]
regulation. This change updates the terminology to reflect the fact
that, in the context of sterile drug products, the appropriate form of
sanitization would be sterilization. This is consistent with our
interpretation of this regulation for more than 20 years and reflects
the currently accepted industry practice.
Section 211.84(d)(6) Testing and approval or rejection of
components drug product containers, and closures, is being revised to
change the phrase ``that is liable to microbiological contamination,''
to ``with potential for microbiological contamination.'' We believe
this revision provides additional clarity without changing the meaning
or intent of the regulation.
Section 211.94(c) Drug product containers and closures is being
revised to clarify that validation is required for the processes used
to remove pyrogenic properties (depyrogenation processes). The revision
reflects currently accepted industry practice and the agency's
longstanding interpretation of this regulation. To assure that certain
drug products are suitable for their intended use, drug product
containers and closures are required to be sterilized and depyrogenated
to remove microbial contamination and pyrogens or endotoxin. It has
been longstanding industry practice to validate the sterilization and
depyrogenation processes used for drug product containers and closures
to assure consistent removal of microbial contamination and pyrogens or
endotoxin. Lack of evidence of such validation and inadequacies in the
validation studies have been cited in FDA actions throughout the years
based on this regulation. Accordingly, this rule simply clarifies Sec.
211.94(c) by adding a new sentence at the end which states; ``Such
depyrogenation processes shall be validated.''
Paragraph (a) of Sec. 211.110 Sampling and testing of in-process
materials and drug products is being revised to include bioburden
process control procedures and tests, where appropriate. The existing
regulation provides five examples of control procedures and tests that
must be addressed, where appropriate, to monitor the output and to
validate the performance of manufacturing processes that may be
responsible for causing variation in the characteristics of in-process
material and drug product. The existing regulation also acknowledges
that the examples are not an all inclusive list of necessary process
control procedures and tests. For in-process materials and drug
products that are produced by aseptic processing, testing for bioburden
is a well established industry standard to ensure that the finished
dosage form will be sterile and that the process is not shifting from
established limits that may affect control. The revised regulation will
add bioburden testing as the sixth example of process control
procedures.
Paragraph (b) of Sec. 211.113 Control of microbiological
contamination is being revised to include validation of aseptic
processes for drug products that are purported to be sterile. The
current regulation mentions only validation of sterilization processes,
not aseptic processes. Even before 1987, when the Guideline for Sterile
Drug Products Produced by Aseptic Processing was issued, industry
routinely conducted validation studies that substituted microbiological
media for the actual product to demonstrate that its aseptic processes
were validated. These parts of validation studies are often referred to
as media fills. We believe that this revision clarifies existing
practices and serves to harmonize the CGMP requirements with Annex 1 of
the EU GMPs, which requires such validation.
C. Asbestos Filters
Our current regulations for filters used in processing liquid
injectable products need to be updated. The current regulations require
manufacturers, before using asbestos-containing filters, to submit
proof to FDA that an alternative filter will or is more likely to
result in product contamination. However, we are not aware that
asbestos filters are currently commercially manufactured for
pharmaceutical use or that they are currently used in the production of
pharmaceuticals. Indeed, their use would no longer be considered a good
manufacturing practice. Therefore, we are revising Sec. Sec.
210.3(b)(6) and 211.72 to remove an outdated regulation permitting
limited use of asbestos-containing filters. This revision also provides
consistency with international standards.
We removed from the definition of ``non-fiber releasing filter,''
the statement that ``All filters composed of asbestos are deemed to be
fiber-releasing filters''; because the revised regulation does not
permit any use of asbestos-containing filters. Thus, this sentence is
no longer necessary. Because other nonasbestos, fiber-releasing filters
may still be used, the revised regulation retains the current
requirement that allows the use of fiber-releasing filters only when
necessary, and only if another filter is also used specifically to
reduce the amount of shed fibers in the finished pharmaceutical.
It is noteworthy that the current CGMP regulation at paragraph (a)
of Sec. 211.65 Equipment construction, requires equipment, including
filters, to be constructed so that ``surfaces that contact components,
in-process materials, or drug products shall not be reactive, additive,
or absorptive so as to alter the safety, identity, strength, quality,
or purity of the drug product beyond the official or other established
requirements.'' We are not changing this requirement, which also
restricts the amount and type of objectionable particulates in drug
products resulting from contact with equipment.
D. Verification by Second Individual
Under the current CGMP regulations, several regulations include
requirements that certain activities be performed by one person and
checked as specified by a second person. Section 211.101(c) requires
that each container of component dispensed for use in manufacturing be
examined by a second person to assure that it was released by the
quality control unit, that the weight or measure is correct as stated
in the batch production records, and that the containers are properly
identified. Section 211.101(d) requires that each component shall be
added to the batch by one person and verified by a second person.
Section 211.103 requires that specified yield calculations shall be
performed by one person and independently verified by a second person.
Section 211.182 requires that the persons performing and double-
checking the cleaning and maintenance of major equipment shall date and
sign or initial equipment logs indicating that the work was performed.
Finally, Sec. 211.188(b)(11) requires that batch production and
control records shall include identification of the persons performing
and directly supervising or checking each significant step in the
operation.
When the CGMP regulations were amended in 1978, FDA issued Sec.
211.68, which provides that automatic, mechanical, or electronic
equipment or other types of equipment, including computers, or related
systems that will perform a function satisfactorily, may be used in the
manufacture, processing, packing, and holding of a drug product,
subject to certain requirements that the controls used are designed to
assure proper performance of such equipment, to assure that changes to
records are made only by authorized personnel, to check the input and
output for accuracy, and to provide for appropriate backup of data.
FDA has periodically been asked whether the requirements for
[[Page 68067]]
verification by a second individual in Sec. Sec. 211.101(c) and (d),
211.103, 211.182, and 211.188(b)(11) are applicable in situations where
operations are performed by various types of automated equipment rather
than by an individual. When these regulations were adopted in 1978, the
preamble addressed this issue in response to several comments about the
second checking requirements of Sec. 211.101 for charge-in of
components when automated systems are used. We specifically noted that
the use of automated systems is permitted under section 211.68 and that
the requirement of 211.101 would be met if the second individual
verifies that the automated system is working properly (43 FR 45013 to
45087 at 45051, September 29, 1978). Thus, in this situation, the first
individual is replaced by a machine or other automated process, and
only one person is necessary to verify that the automated system is
functioning as intended.
Due to periodic questions received by FDA about the performance and
checking requirements required by Sec. Sec. 211.101(c) and (d),
211.103, 211.182, and 211.188(b)(11) when the operations are performed
by automated equipment, such as the widespread and increasing use of
computer-controlled operations, we are revising these sections. The
revisions will clarify our long-standing interpretation and policy that
verification by a second individual may not be necessary when automatic
equipment is used under Sec. 211.68. Rather, in these situations, only
one person is needed to verify that the automated equipment is
functioning adequately. In cases where there is an operator for the
automated equipment, the verifying individual may be, but is not
required to be, the operator.
Thus, we are amending Sec. Sec. 211.101(c) and (d), 211.103,
211.182, and 211.188(b)(11) to indicate that the use of automated
equipment under Sec. 211.68 may eliminate the need for verification by
a second individual and that in those situations only one person is
needed to verify that the automated equipment is functioning properly.
In addition, we are amending section 211.68 to provide a consistent
clarification of this point.
E. Miscellaneous Minor Changes Based on 1996 Proposal
We are revising Sec. 211.82(b) by replacing the phrase ``as
appropriate'' by the phrase ``whichever is appropriate'' to eliminate
any ambiguity in the regulation and to emphasize that it is, in fact,
accepted industry practice to conduct some testing or examination
before the components, drug product containers, or closures are
released from quarantine.
We are revising Sec. 211.84(c)(1) by replacing the phrases ``where
necessary, by appropriate means'' with ``when necessary in a manner to
prevent introduction of contaminants into the component.'' This change
will clarify that the act of cleaning is done for a particular purpose,
to prevent the introduction of contaminants, and must be done unless
such cleaning is not necessary to prevent such an introduction of
contaminants.
In addition, two editorial changes are being made to Sec.
211.84(d)(3) by replacing the word ``conformance'' with ``conformity''
and ``procedure'' with ``specifications.'' Similarly, two minor
editorial changes are being made to the first sentence of Sec.
211.160(b)(1) by replacing the word ``conformance'' with ``conformity''
and ``appropriate'' with ``applicable.'' We believe that these
revisions provide clarity without changing the meaning or intent of the
regulations.
III. Direct Final Rulemaking
In the Federal Register of November 21, 1997 (62 FR 62466), FDA
published a notice of availability of a guidance document that explains
when and how we intend to employ direct final rulemaking. We have
determined that this rule is appropriate for direct final rulemaking
because we believe that it includes only noncontroversial amendments
and we anticipate no significant adverse comments. Consistent with our
procedures on direct final rulemaking, FDA is publishing elsewhere in
this issue of the Federal Register a companion proposed rule to revise
the CGMP regulations for finished pharmaceuticals. The companion
proposed rule provides a procedural framework within which the rule may
be finalized in the event that the direct final rule is withdrawn as a
result of any significant adverse comments. The comment period for the
direct final rule runs concurrently with the companion proposed rule.
Any comments received in response to either of these rules will be
considered as comments to the other.
We are providing a comment period on the direct final rule of 75
days after the date of the publication in the Federal Register. If we
receive any significant adverse comments, we intend to withdraw this
direct final rule before its effective date by publication of a notice
in the Federal Register. A significant adverse comment is defined as a
comment that explains why the rule would be inappropriate, including
challenges to the rule's underlying premise or approach, or would be
ineffective or unacceptable without a change. In determining whether an
adverse comment is significant and warrants terminating a direct final
rulemaking, we will consider whether the comment raises an issue
serious enough to warrant a substantive response in a notice-and-
comment process in accordance with section 553 of the Administrative
Procedure Act (5 U.S.C. 553). Comments that are frivolous,
insubstantial, or outside the scope of the rule will not be considered
significant or adverse under this procedure. A comment recommending a
regulation change in addition to those in the rule would not be
considered a significant adverse comment unless the comment states why
the rule would be ineffective without the additional change. In
addition, if a significant adverse comment applies to an amendment,
paragraph, or section of this rule and that provision can be severed
from the remainder of the rule, we may adopt as final those provisions
of the rule that are not the subjects of a significant adverse comment.
If any significant adverse comments are received during the comment
period, FDA will publish, within 30 days after the close of the comment
period, a notice of significant adverse comment and will withdraw the
direct final rule. If we withdraw the direct final rule, any comments
received will be applied to the proposed rule and will be considered in
developing a final rule using the usual notice-and-comment procedures.
If FDA receives no significant adverse comments during the
specified comment period, FDA intends to publish a document confirming
the effective date of the direct final rule within 30 days after the
comment period ends.
IV. Analysis of Impacts
A. Review Under Executive Order 12866, the Regulatory Flexibility Act,
and the Unfunded Mandates Reform Act of 1995
FDA has examined the impacts of this direct final rule under
Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-
612), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-4).
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
[[Page 68068]]
impacts; and equity). The agency believes that this direct final rule
is not a significant regulatory action as defined by the Executive
order, because the rule generally either clarifies the agency's
longstanding interpretation of, or increases latitude for manufacturers
in complying with, preexisting CGMP requirements. The Regulatory
Flexibility Act requires agencies to analyze regulatory options that
would minimize any significant impact of a rule on small entities.
Because this direct final rule does not impose any new regulatory
obligations, the agency certifies that it would not have a significant
economic impact on a substantial number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $122 million, using the most current (2005) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
direct final rule to result in any 1-year expenditure that would meet
or exceed this amount.
The purpose of this direct final rule is to update the codified
language to reflect current practice and to harmonize requirements in
the CGMP regulations with international GMP requirements and other FDA
regulations. It would not impose any additional requirements;
therefore, industry would not incur incremental compliance costs for
these changes.
B. Environmental Impact
Issuing these clarifying amendments to the CGMP regulations will
not have a significant impact on the human environment. Therefore, an
environmental impact statement is not required.
C. Federalism
FDA has analyzed this direct final rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the rule does not contain policies that have substantial direct effects
on the States, on the relationship between the National Government and
the States, or on the distribution of power and responsibilities among
the various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive Order and, consequently, a
federalism summary impact statement is not required.
V. Paperwork Reduction Act of 1995
The provisions of this direct final rule contain requirements that
were submitted for review and approval to the Director of the Office of
Management and Budget (OMB), as required by section 3507(d) of the
Paperwork Reduction Act of 1995. The requirements were approved and
assigned OMB control number 0910-0139.
VI. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this direct
final rule. Submit a single copy of electronic comments or two paper
copies of any mailed comments, except that any individuals may submit
one paper copy. Comments are to be identified with the docket number
found in brackets in the heading of this document. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday.
List of Subjects
21 CFR Part 210
Drugs, Packaging and containers.
21 CFR Part 211
Drugs, Labeling, Laboratories, Packaging and Containers,
Prescription drugs, Reporting and recordkeeping requirements,
Warehouses.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
210 and 211 are amended as follows:
PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING,
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL
0
1. The authority citation for 21 CFR part 210 continues to read as
follows;
Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42
U.S.C. 216, 262, 263a, 264.
0
2. Section 210.3 is amended by revising paragraph (b)(6) to read as
follows:
Sec. 210.3 Definitions.
(b) * * *
(6) Nonfiber releasing filter means any filter, which after
appropriate pretreatment such as washing or flushing, will not release
fibers into the component or drug product that is being filtered.
* * * * *
PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS
0
3. The authority citation for 21 CFR part 211 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42
U.S.C. 216, 262, 263a, 264.
0
4. Section 211.48 is amended by revising paragraph (a) to read as
follows:
Sec. 211.48 Plumbing.
(a) Water supplied by the plumbing system of the facility must be
safe for human consumption. This water shall be supplied under
continuous positive pressure in a plumbing system free of defects that
could contribute contamination to any drug product.
* * * * *
0
5. Section 211.67 is amended by revising paragraph (a) to read as
follows:
Sec. 211.67 Equipment cleaning and maintenance.
(a) Equipment and utensils shall be cleaned, maintained, and
sanitized and/or sterilized at appropriate intervals to prevent
malfunctions or contamination that would alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or
other established requirements.
* * * * *
0
6. Section 211.68 is amended by adding paragraph (c) to read as
follows:
Sec. 211.68 Automatic, mechanical, and electronic equipment.
* * * * *
(c) Such automated equipment used for performance of operations
addressed by Sec. Sec. 211.101(c) or (d), 211.103, 211.182, or
211.188(b)(11) can satisfy the requirements included in those sections
for the performance of an operation by one person and checking by
another person if such equipment is used in conformity with this
section and one person verifies that the operations addressed in those
sections are performed accurately by such equipment.
0
7. Section 211.72 is revised to read as follows:
Sec. 211.72 Filters.
Filters for liquid filtration used in the manufacture, processing,
or packing of injectable drug products intended for human use shall not
release fibers into such products. Fiber-releasing filters may not be
used in the manufacture, processing, or packing of these
[[Page 68069]]
injectable drug products unless it is not possible to manufacture such
drug products without the use of such filters. If use of a fiber-
releasing filter is necessary, an additional nonfiber-releasing filter
of 0.22 micron maximum mean porosity (0.45 micron if the manufacturing
conditions so dictate) shall subsequently be used to reduce the content
of particles in the injectable drug product.
0
8. Section 211.82 is amended by revising paragraph (b) to read as
follows:
Sec. 211.82 Receipt and storage of untested components, drug product
containers, and closures.
* * * * *
(b) Components, drug product containers, and closures shall be
stored under quarantine until they have been tested or examined,
whichever is appropriate, and released. Storage within the area shall
conform to the requirements of Sec. 211.80.
0
9. Section 211.84 is amended by revising paragraphs (c)(1), (d)(3), and
(d)(6) to read as follows:
Sec. 211.84 Testing and approval or rejection of components, drug
product containers, and closures.
* * * * *
(c) * * *
(1) The containers of components selected shall be cleaned when
necessary in a manner to prevent introduction of contaminants into the
component.
* * * * *
(d) * * *
(3) Containers and closures shall be tested for conformity with all
appropriate written specifications. In lieu of such testing by the
manufacturer, a certificate of testing may be accepted from the
supplier, provided that at least a visual identification is conducted
on such containers/closures by the manufacturer and provided that the
manufacturer establishes the reliability of the supplier's test results
through appropriate validation of the supplier's test results at
appropriate intervals.
* * * * *
(6) Each lot of a component, drug product container, or closure
with potential for microbiological contamination that is objectionable
in view of its intended use shall be subjected to microbiological tests
before use.
* * * * *
0
10. Section 211.94 is amended by revising paragraph (c) to read as
follows:
Sec. 211.94 Drug product containers and closures.
* * * * *
(c) Drug product containers and closures shall be clean and, where
indicated by the nature of the drug, sterilized and processed to remove
pyrogenic properties to assure that they are suitable for their
intended use. Such depyrogenation processes shall be validated.
* * * * *
0
11. Section 211.101 is amended by revising paragraphs (c) and (d) to
read as follows:
Sec. 211.101 Charge-in of components.
* * * * *
(c) Weighing, measuring, or subdividing operations for components
shall be adequately supervised. Each container of component dispensed
to manufacturing shall be examined by a second person to assure that:
(1) The component was released by the quality control unit;
(2) The weight or measure is correct as stated in the batch
production records;
(3) The containers are properly identified. If the weighing,
measuring, or subdividing operations are performed by automated
equipment under Sec. 211.68, only one person is needed to assure
conditions of paragraphs (c)(1), (c)(2), and (c)(3) of this section
have been met.
(d) Each component shall either be added to the batch by one person
and verified by a second person or, if the components are added by
automated equipment under Sec. 211.68, only verified by one person.
0
12. Section 211.103 is revised to read as follows:
Sec. 211.103 Calculation of yield.
Actual yields and percentages of theoretical yield shall be
determined at the conclusion of each appropriate phase of
manufacturing, processing, packaging, or holding of the drug product.
Such calculations shall either be performed by one person and
independently verified by a second person, or, if the yield is
calculated by automated equipment under Sec. 211.68, be independently
verified by one person.
0
13. Section 211.110 is amended by revising paragraph (a) introductory
text and by adding paragraph (a)(6) to read as follows:
Sec. 211.110 Sampling and testing of in-process materials and drug
products.
(a) To assure batch uniformity and integrity of drug products,
written procedures shall be established and followed that describe the
in-process controls, and tests, or examinations to be conducted on
appropriate samples of in-process materials of each batch. Such control
procedures shall be established to monitor the output and to validate
the performance of those manufacturing processes that may be
responsible for causing variability in the characteristics of in-
process material and the drug product. Such control procedures shall
include, but are not limited to, the following, where appropriate:
* * * * *
(6) Bioburden testing.
* * * * *
0
14. Section 211.113 is amended by revising paragraph (b) to read as
follows:
Sec. 211.113 Control of microbiological contamination.
* * * * *
(b) Appropriate written procedures, designed to prevent
microbiological contamination of drug products purporting to be
sterile, shall be established and followed. Such procedures shall
include validation of all aseptic and sterilization processes.
0
15. Section 211.160 is amended by revising paragraph (b)(1) to read as
follows:
211.160 General requirements.
* * * * *
(b) * * *
(1) Determination of conformity to applicable written
specifications for the acceptance of each lot within each shipment of
components, drug product containers, closures, and labeling used in the
manufacture, processing, packing, or holding of drug products. The
specifications shall include a description of the sampling and testing
procedures used. Samples shall be representative and adequately
identified. Such procedures shall also require appropriate retesting of
any component, drug product container, or closure that is subject to
deterioration.
* * * * *
0
16. Section 211.182 is revised to read as follows:
Sec. 211.182 Equipment cleaning and use log.
A written record of major equipment cleaning, maintenance (except
routine maintenance such as lubrication and adjustments), and use shall
be included in individual equipment logs that show the date, time,
product, and lot number of each batch processed. If equipment is
dedicated to manufacture of one product, then individual equipment logs
are not required, provided that lots or batches of such product follow
in numerical order and are manufactured in numerical sequence. In cases
where dedicated equipment is employed, the records of cleaning,
maintenance, and
[[Page 68070]]
use shall be part of the batch record. The persons performing and
double-checking the cleaning and maintenance (or, if the cleaning and
maintenance is performed using automated equipment under Sec. 211.68,
only the person verifying the cleaning and maintenance done by the
automated equipment) shall date and sign or initial the log indicating
that the work was performed. Entries in the log shall be in
chronological order.
0
17. Section 211.188 is amended by revising paragraph (b)(11) to read as
follows:
Sec. 211.188 Batch production and control records.
* * * * *
(b) * * *
(11) Identification of the persons performing and directly
supervising or checking each significant step in the operation, or if a
significant step in the operation is performed by automated equipment
under Sec. 211.68, the identification of the person checking the
significant step performed by the automated equipment.
* * * * *
Dated: November 26, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-23294 Filed 12-3-07; 8:45 am]
BILLING CODE 4160-01-S