Amendment to the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, 68064-68070 [E7-23294]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 72, Number 232 (Tuesday, December 4, 2007)]
[Rules and Regulations]
[Pages 68064-68070]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E7-23294]


=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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revise outdated regulations without diminishing public health 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: https://www.regulation.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://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 https://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 https://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 https://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 https://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 (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 https://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