Amendment to the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals; Companion Document to the Direct Final Rule, 68113-68116 [E7-23292]

Agencies

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

[Federal Register Volume 72, Number 232 (Tuesday, December 4, 2007)]
[Proposed Rules]
[Pages 68113-68116]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E7-23292]


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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; Companion Document to the Direct Final 
Rule

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is publishing this 
companion proposed rule to the direct final rule, published elsewhere 
in this issue of the Federal Register, which is intended to amend 
certain sections of the regulations as the first phase of an 
incremental approach to modifying the current good manufacturing 
practice (CGMP) regulations for finished pharmaceuticals.

DATES: Submit written or electronic comments on or before February 19, 
2008.

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.regulations.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 to 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 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 to 
amend certain requirements of 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 amd 211 (21 CFR parts 210 and 211) 
with 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

[[Page 68114]]

proposed rule. Therefore, elsewhere in this issue of the Federal 
Register, we are publishing a notice withdrawing the 1996 proposed 
rule.
    The amendments being proposed in this rule are intended to clarify 
and modernize the CGMP regulations, as well as harmonize the 
regulations with international GMP requirements and other FDA 
regulations. This proposed rule represents the first increment of 
modifications to parts 210 and 211.

II. Additional Information

    This proposed rule is a companion to the direct final rule 
published in the final rule section of this issue of the Federal 
Register. The proposed rule and the direct final rule are substantively 
identical. This companion proposed rule provides the procedural 
framework to proceed with standard notice-and-comment rulemaking if the 
direct final rule receives significant adverse comment and is 
withdrawn. A significant adverse comment is one 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. The comment period for the companion proposed rule 
runs concurrently with the comment period of the direct final rule. Any 
comments received on this companion proposed rule will also be treated 
as comments on the direct final rule and vice versa.
    For additional information, see the corresponding direct final rule 
published in the final rules section of this issue of the Federal 
Register. All persons who may wish to comment should review the 
rationale for these amendments set out in the preamble discussion of 
the direct final rule. A comment recommending a rule change in addition 
to this rule will not be considered a significant adverse comment 
unless the comment states why this rule would be ineffective without 
the additional change. If no significant adverse comment is received in 
response to the direct final rule, no further action will be taken 
related to this companion proposed rule. Instead, we will publish a 
confirmation notice within 30 days after the comment period ends, and 
we intend the direct final rule to become effective 30 days after 
publication of the confirmation notice. If we receive significant 
adverse comments, we will withdraw the direct final rule. We will 
proceed to respond to all of the comments received regarding the direct 
final rule, treating those comments as comments to this proposed rule. 
The agency will address the comments in a subsequent final rule. We 
will not provide additional opportunity for comment.

III. 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 proposed 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 impacts; and equity). The agency believes that 
this proposed rule is not a significant regulatory action as defined by 
the Executive order, because the rule, if finalized, would generally 
either clarify the agency's longstanding interpretation of, or increase 
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 proposed rule, if finalized, would not 
impose any new regulatory obligations, the agency tentatively 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 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The purpose of this proposed rule is to update the codified 
language to reflect current practice and to harmonize requirements in 
the CGMP regulations with requirements in other regulations. It would 
not impose any additional requirements; therefore, industry would not 
incur incremental compliance costs for these proposed changes.

B. Environmental Impact

    It is FDA's tentative conclusion that issuing these clarifying 
amendments to the CGMP regulations would not have a significant impact 
on the human environment. Therefore, FDA believes that an environmental 
impact statement is not required.

C. Federalism

    FDA has analyzed this proposed 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 
tentatively 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.

IV. Paperwork Reduction Act of 1995

    The provisions of this proposed 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.

V. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
This comment period runs concurrently with the comment period for the 
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

[[Page 68115]]

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, it is 
proposed that 21 CFR parts 210 and 211 be amended as follows:

PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, 
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL

    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.
    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

    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.
    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.
* * * * *
    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.
* * * * *
    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 
relating to 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.
    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 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.
    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.
    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.
* * * * *
    10. Section 211.94 is amended by revising paragraph (c) 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.
* * * * *
    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 
paragraphs (c)(1), (c)(2), and (c)(3) of this section.
    (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.
    12. Section 211.103 is revised to read as follows:

[[Page 68116]]

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.
    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.
* * * * *
    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.
    15. Section 211.160 is amended by revising paragraph (b)(1) to read 
as follows:


Sec.  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.
* * * * *
    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 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, just 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.
    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. E7-23292 Filed 12-3-07; 8:45 am]
BILLING CODE 4160-01-S