[Federal Register Volume 73, Number 174 (Monday, September 8, 2008)]
[Rules and Regulations]
[Pages 51919-51933]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-20709]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 210 and 211

[Docket No. FDA-2007-N-0379] (formerly Docket No. 2007N-0280)


Amendments to the Current Good Manufacturing Practice Regulations 
for Finished Pharmaceuticals

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending certain of 
its regulations on current good manufacturing practice (CGMP) 
requirements for finished pharmaceuticals as the culmination of the 
first phase of an incremental approach to modifying the CGMP 
regulations for these products. This rule revises CGMP requirements 
primarily concerning aseptic processing, verification of performance of 
operations by a second individual, and the use of asbestos filters. We 
are amending the regulations to modernize or clarify some of the 
requirements as well as to harmonize them with other FDA regulations 
and international CGMP standards.

DATES: This rule is effective December 8, 2008.

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, 240-276-
8268; or
    Brian Hasselbalch, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., rm. 4364, Silver 
Spring, MD 20993, 301-796-3279.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Summary of the Final Rule
    A. Aseptic Processing
    B. Asbestos Filters
    C. Verification by a Second Individual
    D. Other Minor Changes
III. Comments on the Proposed Rule and FDA's Response
    A. General Comments
    B. Plumbing
    C. Aseptic Processing
    D. Asbestos Filters

[[Page 51920]]

    E. Verification by a Second Individual
    F. Miscellaneous Minor Changes Based on 1996 Proposal
IV. Analysis of Impacts
V. Environmental Impact
VI. Federalism
VII. Paperwork Reduction Act of 1995

I. Background

    Since the development of the CGMP regulations for drug products 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, 
minimize the potential for harm, or achieve some other CGMP objective. 
We periodically reassess and revise the CGMP regulations to accommodate 
advances in technology and other scientific knowledge that further 
safeguard the drug manufacturing process and the public health.
    In 1996, as part of this reassessment process, we proposed to: (1) 
Amend certain requirements of the CGMP regulations for finished 
pharmaceuticals to clarify certain manufacturing, quality control, and 
documentation requirements and (2) ensure that the regulations more 
accurately encompassed current industry practice (61 FR 20104, May 3, 
1996) (1996 proposed rule). Subsequently, as a part of the risk-based 
Pharmaceutical CGMPs for the 21st Century initiative, we 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) 
with the CGMPs 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.
    Because of this change in approach, we decided not to finalize the 
1996 proposed rule. On December 4, 2007, we published a document 
withdrawing the 1996 proposed rule (72 FR 68111) (the December 2007 
proposed rule). On the same date, we published a direct final rule (72 
FR 68064) and companion proposed rule (72 FR 68113) to clarify and 
modernize certain provisions of the CGMP regulations. The comment 
period for the direct final rule closed on February 19, 2008. On April 
4, 2008, we published a document withdrawing the direct final rule 
because we received significant adverse comments (73 FR 18440). In the 
document withdrawing the direct final rule, we explained that the 
comments received would be considered under our usual procedures for 
notice and comment in connection with the notice of proposed rulemaking 
that was published as a companion to the direct final rule.
    After careful consideration of all comments received, we are now 
publishing this final rule. The final rule represents the culmination 
of the first increment of modifications to parts 210 and 211.

II. Summary of the Final Rule

    The final rule revises the drug CGMP regulations primarily in three 
areas: Aseptic processing, use of asbestos filters, and verification of 
operations by a second individual.

A. Aseptic Processing

    The final rule revises Sec.  211.113(b) to clarify that required 
written procedures designed to prevent microbiological contamination of 
sterile drug products must include procedures on the validation of all 
aseptic processes in addition to sterilization processes. Other changes 
related to aseptic processing include the following:
     Revised Sec.  211.67(a) requires that equipment and 
utensils be cleaned, maintained, and, as appropriate for the nature of 
the drug, sanitized ``and/or sterilized'' at appropriate intervals to 
prevent malfunction or contamination. This change recognizes that for 
sterile drug products, sterilization (sometimes in addition to 
sanitization) is appropriate.
     Revised Sec.  211.84(d)(6) requires microbiological tests 
before use of each lot of a component, drug product container, or 
closure ``with potential for microbiological contamination'' that is 
objectionable in view of its intended use, consistent with longstanding 
agency interpretation of this regulation.
     Revised Sec.  211.94(c) requires validation of 
depyrogenation processes for drug product containers and closures, 
consistent with longstanding industry practice and agency 
interpretation of this regulation.
     Revised Sec.  211.110(a) adds bioburden testing to the 
list (which is not all-inclusive) of in-process control procedures 
relating to the sampling and testing of in-process materials, which 
again is consistent with industry practice.

B. Asbestos Filters

    We revised Sec. Sec.  210.3(b)(6) and 211.72 to eliminate 
provisions permitting limited use of asbestos-containing filters used 
in processing injectable drug products. We had proposed to simply 
delete references to asbestos filters in these provisions. However, in 
response to comments, we also added to Sec.  211.72 the statement ``The 
use of an asbestos-containing filter is prohibited.'' Also in response 
to comments, we revised Sec.  211.72 to reflect appropriate technical 
standards for nonfiber-releasing filters.

C. Verification by a Second Individual

    The final rule makes several changes to the regulations to 
acknowledge, consistent with our longstanding interpretation, that 
certain operations may be performed by automated equipment and verified 
by a person, rather than one person performing an operation and another 
person verifying that the operation was correctly performed. In 
particular, we added new paragraph (c) to Sec.  211.68 stating that 
automated equipment used to perform operations addressed in Sec. Sec.  
211.101(c) or (d), 211.103, 211.182, or 211.188(b)(11) can satisfy the 
requirements in those sections for the performance of an operation by 
one person and checking by another person if the equipment is used in 
conformity with Sec.  211.68 and one person checks that the operations 
are properly performed. In response to comments, we revised the 
paragraph to minimize the possibility that the provision might be 
misinterpreted as requiring a person to repeat by hand all calculations 
performed by automated equipment.
    In accordance with the addition of Sec.  211.68(c), we are adopting 
corresponding changes to the following provisions:
     Section 211.101(c) and (d) (concerning charge-in of 
components and containers),
     Section 211.103 (calculation of yields),
     Section 211.182 (equipment cleaning and maintenance), and
     Section 211.188(b)(11) (batch production and control 
records).

D. Other Minor Changes

    In addition to the revisions to the regulations previously noted, 
we have made minor revisions to the following provisions to provide 
greater clarity without changing meaning or intent:
     Section 211.82(b) (storage of components, containers, and 
closures),

[[Page 51921]]

     Section 211.84(c)(1) and (d)(3) (collection and testing of 
samples of components, containers, and closures), and
     Section 211.160(b)(1) (laboratory controls for determining 
conformity to specifications).

III. Comments on the Proposed Rule and FDA's Response

    We received comments on the proposed rule from drug and biologic 
manufacturers, industry associations, consultants, and other interested 
persons. A summary of the comments received and our responses follow. 
We first respond to comments of a general nature and then to comments 
on the five topics set forth in the preamble of the direct final rule.
    To make it easier to identify comments and our responses, the word 
``Comment,'' in parentheses, appears before the comment's description, 
and the word ``Response,'' in parentheses, appears before our response. 
We have numbered each comment to help distinguish between different 
comments. Similar comments are grouped together under the same number 
if the same response would be given for each. The number assigned to 
each comment is purely for organizational purposes and does not signify 
the comment's value or importance or the order in which it was 
received.

A. General Comments

    (Comment 1) One comment stated that it will be very important for 
FDA to ensure clarity and consistency in the understanding of the final 
rule among agency staff, including both product reviewers and CGMP 
inspectors, to minimize different interpretations and applications of 
these regulations.
    (Response) We agree that it is important that FDA employees who 
perform application reviews, as well as conduct CGMP inspections and 
other compliance activities, understand these regulations and apply 
them in a consistent manner in the performance of their duties. 
Therefore, we will take appropriate steps to ensure that agency staff 
receive adequate training regarding the new regulations.
    (Comment 2) One comment stated that we should not withdraw the 1996 
proposed rule because it contained many good features with respect to 
test method validation and the out-of-specification test result 
problem. The comment maintained that the guidance for industry entitled 
``Investigating Out-of-Specification (OOS) Test Results for 
Pharmaceutical Production'' (71 FR 60158, October 12, 2006) is not 
helpful to people working with biological drugs and other products. 
Another comment stated that the December 2007 proposed rule should have 
incorporated many of the changes in the 1996 proposed rule regarding 
such matters as validation, quality control unit responsibilities, 
batch failure investigations, and stability samples because they 
involve some of the most common CGMP deficiencies.
    (Response) As we stated in the December 4, 2007, document, we 
withdrew the 1996 proposed rule because we concluded that, given our 
new approach to CGMP under the 21st century initiative, it would be 
preferable to revise the CGMP regulations incrementally rather than in 
a one-time, comprehensive fashion. Furthermore, we believe that it is 
appropriate to reevaluate some of the matters considered in the 1996 
proposed rule in light of recent scientific and technological advances. 
We appreciate the comments' interest in the specified CGMP issues, and 
we will consider these issues in future phases of our CGMP 
modernization efforts.
    (Comment 3) One comment encouraged FDA to consider other CGMP 
regulations that need modernization or clarification, or are no longer 
necessary due to technological advances, such as aspects of 21 CFR 
610.12 concerning the requirements for bulk sterility testing and 
allowance for sterility retesting for biological products.
    (Response) We appreciate the comment's interest in modernizing CGMP 
regulations. As previously stated, this final rule represents only our 
first step in updating the drug CGMP regulations to reflect current 
industry practice and harmonize the regulations with international CGMP 
requirements. We will consider other aspects of CGMP in future 
rulemaking proceedings.

B. Plumbing

    Section 211.48(a) requires that potable water be supplied under 
continuous positive pressure in a plumbing system free of defects that 
could contribute contamination to any drug product. It further requires 
that potable water meet the standards established by the U.S. 
Environmental Protection Agency (EPA) for primary drinking water in 40 
CFR part 141. Proposed Sec.  211.48(a) would have deleted the 
requirement that the potable water used in a plumbing system meet EPA's 
standards for primary drinking water, and instead required that the 
water be ``safe for human consumption.'' This proposed revision was 
intended to improve harmonization with foreign regulations 
(particularly those of the EU and Japan) and to make the U.S. 
regulation more consistent with the United States Pharmacopeia 
standard. In the preamble of the direct final rule, we stated that the 
revised requirement could be met by compliance with the standards in 
the EPA regulations or in the current regulations of the EU or Japan 
for potable water used to prepare water for pharmaceutical purposes.
    (Comment 4) Four comments objected to the proposed change. Among 
other things, the comments stated that the standard of ``safe for human 
consumption'' is not sufficiently prescriptive.
    (Response) Because of the comments received and other 
considerations, we have decided not to revise Sec.  211.48(a) at this 
time. We will address the issue of standards for water used in a 
facility's plumbing system when we consider proposing regulations for 
water used as a drug product component in the next phase of our CGMP 
initiative.

C. Aseptic Processing

    In the proposed rule, we sought to amend several regulations on 
aseptic processing to reflect current industry standards and practices. 
Some of the proposed revisions would also affect other types of 
processes and operations. We noted that the proposed changes would not 
affect the applicability of the guidance for industry entitled 
``Sterile Drug Products Produced by Aseptic Processing--Current Good 
Manufacturing Practice'' (Aseptic Processing Guidance), issued on 
October 4, 2004 (69 FR 59258).
1. Equipment Cleaning and Maintenance (Sec.  211.67(a))
    The version of Sec.  211.67(a) amended by this final rule stated: 
``Equipment and utensils shall be cleaned, maintained, and sanitized 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.'' 
We proposed to add the phrase ``and/or sterilized'' after the word 
``sanitized'' in Sec.  211.67(a) to reflect the fact that sterilization 
is appropriate for sterile drug products.
    On our own initiative, we have revised Sec.  211.67(a) to state 
that equipment and utensils shall be cleaned, maintained, ``and, as 
appropriate for the nature of the drug, sanitized and/or sterilized at 
appropriate intervals * * *.'' This revision does not alter the meaning 
of the proposed rule change, but clarifies that for some equipment and 
utensils

[[Page 51922]]

used in the production of certain drug products, sanitization is 
appropriate; for other equipment and utensils, sterilization is 
appropriate; and for still others, both sanitization and sterilization 
are appropriate.
    (Comment 5) One comment stated that it is not appropriate to 
address sterilization in Sec.  211.67(a). Instead, the comment 
recommended that a reference to sterilization of equipment and utensils 
be added to Sec.  211.113(b), which requires the adoption of written 
procedures designed to prevent microbiological contamination of drug 
products purporting to be sterile.
    (Response) We do not agree with the comment because, as previously 
noted, equipment and utensils used in the production of sterile drug 
products must be sterilized, not merely sanitized. In addition, we have 
revised Sec.  211.113(b) as discussed in section III.C.5 of this final 
rule.
    (Comment 6) One comment suggested that we could simplify the 
language in this regulation by changing the phrase ``beyond the 
official or other established requirements'' to ``beyond the 
established (or other official) requirements.''
    (Response) We do not believe that the suggested change simplifies 
the current phrase, which we believe is clear. Therefore, we do not 
believe that the suggested change is necessary.
    (Comment 7) One comment stated that Sec.  211.67(a) should not 
apply to the production of medical gases because most medical gas 
manufacturing lines are product-specific, closed systems that are not 
subject to cleaning or sanitation as part of an established periodic 
cycle, but instead are specially cleaned to be ``oxygen ready'' and 
carefully handled in accordance with established procedures. The 
comment maintained that additional cleaning efforts beyond the initial 
cleaning regimen substantially increase the risk of introducing 
contaminants into the system. Therefore, the comment stated, it is not 
necessary to require cleaning of equipment at ``appropriate intervals'' 
for medical gas manufacturing. The comment suggested that, 
alternatively, it might be appropriate for the agency to state that 
medical gases may represent unique circumstances that will be reflected 
in a separate guidance.
    (Response) We decline to exempt medical gases from the requirements 
of Sec.  211.67(a) as recommended because this would exceed the scope 
of our proposed change to clarify that sterilization is appropriate for 
sterile drug products and would instead focus on whether there is any 
need for periodic cleaning of medical gas systems. We might consider in 
a future CGMP rulemaking whether it is appropriate to revise Sec.  
211.67(a) to address its application to medical gases.
2. Microbiological Testing of Objectionable Lots of Components, Drug 
Product Containers, and Closures (Sec.  211.84(d)(6))
    The version of Sec.  211.84(d)(6) amended by this final rule 
stated: ``Each lot of a component, drug product container, or closure 
that is liable to microbiological contamination that is objectionable 
in view of its intended use shall be subjected to microbiological tests 
before use.'' We proposed to change the phrase ``that is liable to 
microbiological contamination'' to ``with potential for microbiological 
contamination.''
    (Comment 8) One comment stated that the proposed change was 
unnecessarily restrictive and might lead to testing every lot when the 
risk of microbial contamination is low and the impact on the intended 
use is insignificant. This comment suggested replacing ``that is liable 
to microbial contamination'' with ``prone to microbial contamination.'' 
One comment stated that the proposed change could make it more 
difficult for drug manufacturers to replace a less effective, quality 
control-based inspection and test method with a more modern and 
effective quality audit method. The comment stated that because the 
bioburden of dry items such as vials and stoppers is often 
heterogeneous, improved assurance of this quality attribute is better 
achieved through the audit, selection, and control by the manufacturers 
of these items. This comment maintained that knowledge of and control 
over the manufacturing processes for containers and closures might fall 
short of justifying that those products do not have a ``potential for 
contamination.''
    (Response) We decline to adopt the recommended change to Sec.  
211.84(d)(6) from ``that is liable to microbial contamination'' to 
``prone to microbiological contamination.'' We believe that our 
proposed change to ``with potential for microbiological contamination'' 
clarifies our longstanding interpretation of the regulation that each 
lot of component, drug product container, or closure that is 
susceptible to contamination must undergo microbiological testing 
before use. Therefore, we have revised Sec.  211.84(d)(6) to refer to 
components, containers, or closures ``with potential for 
microbiological contamination'' as proposed.
3. Validation of Depyrogenation of Drug Product Containers and Closures 
(Sec.  211.94(c))
    The version of Sec.  211.94(c) amended by this final rule stated: 
``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.'' In the preamble to the direct final rule, we stated 
that it has been longstanding industry practice to validate the 
sterilization and depyrogenation processes used for drug product 
containers and closures to ensure consistent removal of microbial 
contamination and pyrogens or endotoxins. Therefore, we proposed to add 
a provision to Sec.  211.94(c) requiring the validation of these 
depyrogenation processes.
    (Comment 9) One comment suggested that we require validation of 
``sterilization'' as well as depyrogenation processes.
    (Response) We do not believe that the suggested change is needed 
because Sec.  211.113(b) already requires validation of sterilization 
processes for the prevention of microbiological contamination of drug 
products purporting to be sterile.
    (Comment 10) Four comments objected to the requirement in existing 
Sec.  211.94(c) because it requires depyrogenation of components based 
on the nature of the drug and does not take into account the fact that 
some containers and closures are inherently nonpyrogenic, have been 
qualified not to require active depyrogenation, or do not require 
depyrogenation because of handling procedures. Three of the comments 
proposed that in addition to the nature of the drug, the drug's 
manufacturing process be included as a factor in determining when 
containers and closures must be sterilized and processed to remove 
pyrogenic properties. Two of the comments recommended that the 
requirement to validate depyrogenation processes be limited to 
containers and closures that are made nonpyrogenic by a designated 
depyrogenation process (thus excluding inherently nonpyrogenic 
containers and closures from the regulation).
    (Response) We decline to adopt the suggested revisions because they 
go beyond the scope of our proposed change to require validation of 
depyrogenation processes and instead focus on the need for 
depyrogenation itself.

[[Page 51923]]

4. Inclusion of Bioburden Testing in In-Process Testing (Sec.  
211.110(a))
    Section 211.110(a) requires that written procedures be established 
and followed that describe in-process controls and tests or 
examinations to be conducted on samples of in-process materials of each 
batch of a drug product. The regulation specifies five control 
procedures that must be established, 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 the drug product. We proposed to add bioburden 
testing to this list (which is not all-inclusive) because testing for 
bioburden is standard industry practice for in-process materials and 
drug products that are produced by aseptic processing.
    (Comment 11) Three comments objected to the addition of bioburden 
testing to Sec.  211.110(a). One comment objected to the inclusion of 
any specific test and suggested that specific tests be addressed in 
agency guidance. One comment stated that bioburden testing is not 
conducted at the same time as other tests specified in Sec.  211.110(a) 
and is not an in-process test or control because it does not yield 
immediate results that allow for process adjustment. The comment stated 
that it would be more appropriate to address bioburden testing in Sec.  
211.84. One comment suggested that because Sec.  211.110 covers the 
sampling and testing of all in-process materials and drug products, 
adding bioburden testing as a mandatory control procedure could expand 
current industry validation procedure and produce diversity among the 
industry and regulators on the circumstances in which validation of 
bioburden testing is appropriate.
    (Response) We do not agree with the comments. As stated in the 
direct final rule, testing for bioburden is an important in-process 
control, particularly for drug products that are produced through 
aseptic processing. Section 211.110(a) provides flexibility to 
manufacturers so that they need only conduct bioburden testing where 
the testing is appropriate to assure batch uniformity and drug product 
integrity. We believe that manufacturers understand for which types of 
drug products, and at what point in the manufacturing process for these 
drugs, bioburden testing is appropriate. Accordingly, we have added 
bioburden testing to Sec.  211.110(a).
5. Control of Microbiological Contamination (Sec.  211.113(b))
    Section 211.113(b) states that appropriate written procedures, 
designed to prevent microbiological contamination of drug products 
purporting to be sterile, must be established and followed. The version 
of Sec.  211.113(b) amended by this final rule further stated: ``Such 
procedures shall include validation of any sterilization process.'' We 
proposed to substitute ``all aseptic and sterilization processes'' for 
``any sterilization process.'' As noted in the preamble of the direct 
final rule, even before we issued the now-replaced guidance on 
``Sterile Drug Products Produced by Aseptic Processing'' in 1987, 
industry routinely conducted validation studies (often referred to as 
media fills) that substituted microbiological media for the actual 
product to demonstrate that its aseptic processes were validated (72 FR 
68064 at 68066). The proposed change was intended to clarify existing 
practice and to harmonize Sec.  211.113 with Annex 1 of the EU CGMPs.
    (Comment 12) Several comments objected to the proposed change to 
Sec.  211.113(b) on the basis that aseptic processing cannot be 
validated. One comment stated that validation of aseptic processing 
technically cannot be done, although the manufacturer can ensure tight 
control over the process. One comment stated that aseptic processing 
simulations demonstrate the capability of a facility, equipment, and 
operational controls to provide a minimal microbial contamination rate 
in a single event, but they cannot predict the outcome of a similar 
process performed at a different time. The comment maintained that to 
consider aseptic processing to be validated overstates the ability to 
measure and control the process and could be interpreted as approval to 
relax the controls necessary for its success. The comment recommended 
that Sec.  211.113(b) be revised to require validation of ``all 
sterilization/depyrogenation processes'' and to direct that aseptic 
processes ``be subjected to periodic assessment to demonstrate the 
capability of the control strategy to adequately support end product 
sterility.''
    One comment stated that there is currently no means to comply with 
the proposed requirement to validate aseptic processes. The comment 
maintained that the microbiological and decontamination methods used in 
aseptic processing lack the sensitivity, recoverability, and accuracy 
of the physical and chemical measurement systems normally associated 
with process validation. The comment further claimed that media fills 
do not validate aseptic processing because they measure only detectable 
micro-organisms and do not verify that no micro-organisms exist. The 
comment stated that although aseptic processing cannot be validated, a 
state of control can be established, ensuring that the aseptically 
produced drug consistently meets its specifications and quality 
attributes. The comment recommended that rather than validation of 
aseptic processes, Sec.  211.113(b) require ``a formalized quality risk 
management and control strategy for aseptic processes to provide 
assurance of requisite and continued process capability and product 
quality.''
    One comment stated that although media fills can evaluate an 
aseptic process, they cannot be considered to validate the process. The 
comment recommended that we either not adopt the proposed requirement 
to validate aseptic processes or provide more clarity on what is 
expected for validation of aseptic processes. Similarly, another 
comment recommended that we not revise Sec.  211.113(b) as proposed 
unless we clarify that more than media fills are required to validate 
an aseptic process. The comment stated that a well-controlled, robust 
process is required for aseptic processes and that once a state of 
control has been established for the process, media fills can be useful 
in confirming the state of control.
    (Response) Although we acknowledge that aseptic process validation 
does not provide absolute assurance of product sterility, we do not 
agree that aseptic processes cannot be validated. Validation of aseptic 
processes, which is a common practice throughout the pharmaceutical 
industry, means establishing documented evidence that provides a high 
degree of assurance that a particular process will consistently produce 
a product meeting its predetermined specifications and quality 
attributes. Media fills, together with operational controls, 
environmental controls, and product sterility testing, provide a 
sufficient level of assurance that drugs purported to be sterile are in 
fact sterile.
    (Comment 13) One comment suggested adding a definition of aseptic 
processing to part 210.
    (Response) We do not believe that it is necessary to define aseptic 
processing in the regulation. The Aseptic Processing Guidance makes it 
clear to manufacturers what aseptic processing entails.

[[Page 51924]]

    (Comment 14) One comment requested confirmation that it is 
acceptable to follow the current FDA guidance and use media fills to 
meet the requirement to validate aseptic processes.
    (Response) As stated in the preamble to the direct final rule and 
reiterated previously in this document, manufacturers can follow the 
recommendations in the Aseptic Processing Guidance to comply with CGMP 
requirements for aseptic processing, including validation. However, as 
with any guidance, the Aseptic Processing Guidance is not binding on 
industry or the agency, and manufacturers may use an alternative 
approach to achieve compliance if the approach meets the requirements 
of the act and FDA regulations.
    (Comment 15) One comment sought clarification that the requirement 
to validate aseptic processing would not inhibit implementation of 
novel technologies recommended by the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) in the ICH Q8, Q9, and Q10 
guidances, or other innovative approaches in these areas.
    (Response) We do not believe that the requirement to validate 
aseptic processing will interfere with the implementation of new 
technologies either as part of following ICH recommendations or as part 
of other efforts to meet CGMP requirements. As stated in section I of 
this document, we have always attempted to balance the need for easily 
understood minimum CGMP standards with the desire to encourage 
innovation and the development of improved manufacturing technologies. 
We are confident that industry can meet the requirement to validate 
aseptic processing with no adverse impact on technological innovation 
in drug product manufacturing.

D. Asbestos Filters

    As stated in the preamble to the direct final rule, we need to 
update our regulations on filters used in processing liquid injectable 
products. The version of Sec.  211.72 amended by this final rule 
required manufacturers, before using an asbestos-containing filter, to 
submit proof to FDA that an alternative nonfiber-releasing filter will, 
or is likely to, compromise the safety or effectiveness of the product. 
However, we are not aware that asbestos filters are currently 
commercially manufactured for pharmaceutical use or are used in drug 
production, and their use is not considered a good manufacturing 
practice. Therefore, we proposed to delete the reference to the use of 
asbestos-containing filters from Sec.  211.72 and to delete the 
reference to asbestos filters from the definition of ``nonfiber-
releasing filter'' in Sec.  210.3(b)(6).
    (Comment 16) Two comments stated that the regulations should state 
that the use of asbestos filters is prohibited. One comment stated that 
if asbestos-containing filters are in fact available and the proposed 
changes were interpreted as permitting their use, this might pose a 
risk to patients.
    (Response) We agree with the comments. Therefore, in addition to 
deleting the reference to asbestos-containing filters in Sec.  
210.3(b)(6), we have revised the last sentence of Sec.  211.72 to state 
that the use of an asbestos-containing filter is prohibited.
    (Comment 17) One comment recommended that we clarify the second 
sentence in proposed Sec.  211.72, which stated: ``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.'' The comment 
recommended that this sentence be revised to state as follows: ``Fiber-
releasing filters may be used when/where it is not possible to 
manufacture such drug products without the use of such filters.''
    (Response) We agree with this proposed change and have revised 
Sec.  211.72 accordingly.
    (Comment 18) Four comments recommended revising the following 
provision in proposed Sec.  211.72: ``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.'' Each of these comments 
stated that it is technically more accurate to describe a filter in 
terms of its nominal pore size rating than its mean porosity. One 
comment stated that the filter pore size standard of 0.22 micron is 
outdated and should be changed to 0.2 micron.
    (Response) These suggested technical changes are consistent with 
statements in our guidances for industry (e.g., the Aseptic Processing 
Guidance) concerning filters. Therefore, we have revised Sec.  211.72 
to require that if use of a fiber-releasing filter is necessary, an 
additional nonfiber-releasing filter having a maximum nominal pore size 
rating of 0.2 micron be used.

E. Verification by a Second Individual

    The current CGMP regulations include several provisions requiring 
that certain activities be performed by one person and checked as 
specified by a second person.
     Section 211.101(c) requires that: (1) 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, (2) 
the weight or measure is correct as stated in the batch production 
records, and (3) the containers are properly identified.
     Section 211.101(d) requires that each component be added 
to the batch by one person and verified by a second person.
     Section 211.103 requires that specified yield calculations 
be performed by one person and independently verified by a second 
person.
     Section 211.182 requires the persons performing and 
double-checking the cleaning and maintenance of major equipment to date 
and sign or initial equipment logs indicating that the work was 
performed.
     Section 211.188(b)(11) requires that batch production and 
control records include identification of the persons performing and 
directly supervising or checking each significant step in the 
operation.
    When we amended the CGMP regulations in 1978, we established 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 the following requirements:
     Equipment is routinely checked according to a program 
designed to assure proper performance,
     Changes to records are made only by authorized personnel,
     Input and output are checked for accuracy, and
     Appropriate backup of data is maintained.
    In the preamble to the 1978 final rule, we stated that the 
verification requirements in Sec.  211.101 for charge-in of components 
when automated systems are used would be met if a person verified that 
the automated system was working properly (43 FR 45014 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.

[[Page 51925]]

    Because we have received questions about the performance and 
checking requirements in Sec. Sec.  211.101(c) or (d), 211.103, 
211.182, or 211.188(b)(11) when the operations are performed by 
automated equipment, such as the widespread and increasing use of 
computer-controlled operations, we proposed to revise these sections. 
We proposed to amend these regulations to indicate that when automated 
equipment is used to perform certain operations, only one person is 
needed to verify that the automated equipment is functioning 
adequately. Correspondingly, proposed Sec.  211.68(c) stated that 
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 Sec.  211.68 and one person 
verifies that the operations addressed in those sections are performed 
accurately by such equipment. We stated in the preamble of the direct 
final rule that these revisions would clarify our longstanding policy 
that verification by a second individual may not be necessary when 
automatic equipment is used under Sec.  211.68.
1. General Comments on Verification
    (Comment 19) One comment stated that validated, automated systems 
equipped with real time alarms that do not require any human 
intervention should not require human verification. Another comment 
stated that such systems should not require human verification with 
each use and, when human verification is needed, the level of 
verification required should be consistent with the level of automation 
used. Both of these comments maintained that requiring operator 
verification of automated, validated equipment under Sec. Sec.  
211.68(c), 211.101(c)(3) and (d), 211.103, and 211.188(b)(11) might 
hinder the implementation of process analytical technology (PAT) in the 
drug industry.
    (Response) In the Federal Register of February 12, 1991 (56 FR 
5671) (the 1991 proposal), we issued a proposed rule in part to amend 
Sec.  211.68 to add what is now the third sentence of Sec.  211.68(b): 
``The degree and frequency of input/output verification shall be based 
on the complexity and reliability of the computer or related system.'' 
This revision was adopted as part of the final rule issued on January 
20, 1995 (60 FR 4087) (the 1995 final rule).
    In the 1995 final rule, we responded to several comments on the 
proposed revision. Two comments suggested that the revised regulation 
did not accommodate the accepted use of validated computerized drug 
production and control systems. We declined to change the revision as 
proposed, stating our belief that the wording in the revised rule 
adequately encompasses the use of these systems (60 FR 4087 at 4089).
    Two comments on the 1991 proposal questioned the need for human 
verification of operations that are performed by validated computer 
systems. The comments listed other regulations that were not the 
subject of the proposed rule that required more than one person to 
verify certain manufacturing operations, apparently to show that 
additional personnel would be needed to comply with proposed Sec.  
211.68. We noted in the 1995 final rule that the revisions to Sec.  
211.68 do not impose any specific personnel requirements. We also noted 
that the agency is aware that computers are subject to malfunctions, 
some of which could possibly result in the loss of critical information 
regarding the manufacturing process or a serious production error and 
the possible distribution of an adulterated product. Therefore, we 
stated that while increasingly sophisticated system safeguards and 
computerized monitoring of essential equipment and programs help 
protect data, no automated system exists that can completely substitute 
for human oversight and supervision. We further indicated that while 
the degree of verification is left to the manufacturer's discretion, 
the exercise of such discretion under Sec.  211.68 requires the use of 
routine accuracy checks to provide a high degree of assurance that 
input to and output from a computer or related system are reliable and 
accurate. We stated our intent that each manufacturer exercise 
reasonable judgment based on a variety of factors, including, but not 
limited to, the complexity of the computer or related system, in 
developing a method to prevent inaccurate data input and output (60 FR 
4087 at 4089).
    The December 4, 2007, direct final rule and companion proposed rule 
were intended to amend the regulations involving second-person checks 
only to clarify our longstanding policy that verification by a second 
individual may not be necessary when automatic equipment is used under 
Sec.  211.68, and that in such situations only one person is needed to 
verify that the automated equipment is functioning adequately. The 
amendments were not intended to either add to or detract from any 
existing requirements in this regard, but only to clarify our 
longstanding interpretation and policy for these requirements. We note 
that the same basic considerations apply in this regard today as we 
expressed in the 1995 final rule. Although increasingly sophisticated 
controls and safeguards have been implemented for some automated 
systems, our policy has been that some degree of human oversight, 
supervision, verification, monitoring, or checking is still necessary 
to verify proper performance as part of assuring the identity, 
strength, quality, and purity of drug products. For suitably validated 
automated systems, even with real time alarms, it is still necessary 
for a human to verify that the systems are operating as planned and to 
monitor for abnormalities. We agree that the level, nature, and 
frequency of such human verification will vary depending on the level 
of automation used as well as the nature of the system and controls, 
and the manufacturer has the flexibility and responsibility to 
determine what is suitable and necessary. Contrary to the comments, we 
believe that manufacturers can conduct human verification of automated 
operations in conjunction with the use of PAT in drug production.
    For these reasons, we continue to believe that human verification 
is necessary to ensure that automated systems are functioning properly.
    (Comment 20) One comment stated that many current biotech processes 
include component additions and deletions in a continuous or periodic 
manner over long periods of time. The comment stated that there would 
be no added value in requiring a manual verification of this component 
management scheme in a fully automated scenario.
    (Response) For the reasons stated in our response to comment 19, we 
believe that some degree of human oversight, supervision, verification, 
monitoring, or checking is a necessary part of CGMP for such processes 
and that there is added value in having greater assurance that the 
automated systems are operating properly as intended. We do not expect 
that each individual component change must be witnessed in person, but 
rather that a suitable system of human oversight be established and 
followed to effectively verify that the automated processes are indeed 
operating correctly in the performance of these operations.
    (Comment 21) One comment maintained that our statement in the 
preamble of the direct final rule that the verifying individual may be, 
but is not required to be, the operator is a

[[Page 51926]]

contradiction of the CGMP regulations, which require (in Sec.  
211.25(a)) that all individuals have the education, training, and 
experience to enable them to perform their assigned functions. The 
comment asked why the agency would allow an untrained operator to 
perform a sole verification of a critical step if an automated system 
is used and recommended that we retract the noted preamble statement.
    (Response) The comment incorrectly concluded that allowing the 
verifying individual to be a person other than the operator would 
thereby allow an untrained individual to perform the function of 
verifying a critical step. Section 211.25(a) requires each person 
performing an assigned function to have the education, training, and 
experience, or any combination thereof, to enable that person to 
perform the function. Thus, any person, whether the operator or not, 
who performs such a verification step would necessarily be required to 
have the knowledge, training, and experience needed to perform that 
function. Therefore, our preamble statement does not conflict with the 
regulations.
    (Comment 22) One comment stated that the proposed changes regarding 
second person verification should be extended to include Sec.  
211.188(a), which requires the preparation of batch production and 
control records that include an accurate reproduction of the 
appropriate master production or control record, checked for accuracy, 
dated, and signed. The comment stated that when there is only one 
signature needed, but the system is automated, it would also follow 
that no human signature or signature equivalent would be necessary, 
such as in issuance of a batch record under Sec.  211.188(a), when the 
record is electronic. The comment also stated that in this case, it is 
impossible to check the pages for a true and accurate copy. The comment 
recommended revising Sec.  211.68(c) to include Sec.  211.188(a) in the 
listing of sections affected and to state that there could be single 
performance verification under Sec.  211.188(a).
    (Response) We do not agree with the recommended changes to Sec.  
211.188(a), which would eliminate any human verification of the 
records. As previously stated, we are clarifying in this rule that the 
checking of automated equipment by one person can satisfy the 
requirements of those regulations that address the performance of a 
step by one person and the verification of the step by a second person. 
Our proposal regarding verification of operations was intended to make 
clear that only one person is needed to verify that automated equipment 
for a processing step is functioning properly; we did not propose 
deleting all human verification of the step. In addition, we disagree 
with the comment's apparent contention that no human signature would be 
needed for issuance of electronic batch production and control records. 
If such records are generated and issued electronically as part of an 
automated system, a person must verify that the correct records were 
issued and that they are still accurate and complete. We believe it is 
clear that Sec.  211.188(a) requires only one check for accuracy, with 
date and signature (which could be electronic), and that it does not 
require a separate second check of this step. Therefore, no changes to 
Sec.  211.188(a) are necessary or appropriate.
    (Comment 23) Three comments addressed second-person verification in 
Sec.  211.194. Section 211.194(a) requires that laboratory records 
include complete data derived from all tests necessary to assure 
compliance with established specifications and standards as specified 
in that subsection. Section 211.194(a)(7) requires that laboratory 
records include the initials or signature of the person who performs 
each test and the date(s) the tests were performed. Section 
211.194(a)(8) requires the initials or signature of a second person 
showing that the original records have been reviewed for accuracy, 
completeness, and compliance with established standards. Two of the 
comments stated that the principle behind the proposed second-person 
verification revisions should be extended to Sec.  211.194 to include 
checking laboratory records involving automated laboratory equipment. 
The first comment recommended revising Sec.  211.194 generally. The 
second comment specifically recommended that Sec.  211.194(a)(8) be 
revised to add that if laboratory tests have been performed by 
automated equipment under Sec.  211.68, the laboratory record need only 
include the identification of one person conducting the review of the 
tests performed by the automated system. The comment also asked that 
Sec.  211.194(a)(8) be added to the list of sections affected in Sec.  
211.68(c). The third comment stated that the failure to include Sec.  
211.194(a)(7) and (a)(8) in the proposed revisions implies that the use 
of automated systems to perform or check testing is not allowed.
    (Response) We decline to include Sec.  211.194 among the sections 
enumerated in Sec.  211.68(c) concerning second-person verification of 
operations performed by automated equipment. We acknowledge that 
automated equipment may be used to conduct certain laboratory testing 
operations. However, when automated equipment is used to perform a 
laboratory test, typically a person initiates the test and ensures that 
the correct equipment is used and that it operates properly. In this 
situation, one person assists in or oversees the performance of the 
laboratory test and a second person reviews the records for accuracy, 
completeness, and compliance with established standards. Thus, the use 
of equipment to perform laboratory tests, though permissible, is not a 
situation in which automated equipment (rather than a person) performs 
an operation and a person verifies that performance, which is the 
situation addressed in revised Sec.  211.68(c). Therefore, it would not 
be appropriate to include a reference to Sec.  211.194 (or to Sec.  
211.194(a)(8) specifically) in revised Sec.  211.68(c).
2. Automatic, Mechanical, and Electronic Equipment (Sec.  211.68)
    (Comment 24) One comment stated that Sec.  211.68 is no longer in 
line with the technological improvements of the past 30 years and with 
the increasing knowledge of computer validation by industry and 
regulators. The comment recommended that Sec.  211.68 be aligned with 
21 CFR 820.70(i), section 5.4 of the ICH Q7A guidance entitled ``Good 
Manufacturing Practice Guidance for Active Pharmaceutical 
Ingredients,'' and the Pharmaceutical Inspection Cooperation Scheme's 
Annex 11 on computerized systems.
    (Response) We decline to adopt the suggested revisions because they 
exceed the scope of our proposed revision of Sec.  211.68, which only 
addressed second-person verification of operations performed by 
automated equipment. We might consider revising other provisions of 
Sec.  211.68 as part of a future rulemaking to update the CGMP 
regulations and make them consistent with international CGMP 
provisions.
    (Comment 25) One comment recommended that instead of our proposed 
changes to Sec.  211.68(c) and other regulations concerning second-
person verification, we revise Sec.  211.68(a), which permits the use 
of automatic, mechanical, or electronic equipment in the manufacture, 
processing, packing, and holding of drug products. The comment stated 
that the wording of our proposed changes only allows for actions to be 
performed by automated equipment and checked by a person, which would 
prevent the introduction of automated systems to check operations 
performed by a person. The comment also stated that our proposed 
changes would still require the involvement of at least one person

[[Page 51927]]

in each of these circumstances and prevent the use of a controlled 
system or systems that both perform and independently verify the 
relevant operations. One comment suggested that rather than our 
proposed revisions, the desired clarification concerning automated 
equipment and second-person checks would be better achieved by adding 
to Sec.  211.68(a) the following sentence: ``Automated equipment can 
satisfy the requirements for the performance of an operation by one 
person and/or checking by another person.''
    (Response) We do not agree with the recommended change. The 
proposed rule simply clarified our longstanding position that only one 
human check is necessary to verify a processing step performed by 
automated equipment. The suggested revision of Sec.  211.68(a), 
however, would allow manufacturers to rely solely on automated 
equipment to verify the human performance of certain processing steps 
and allow automated equipment to both perform and check operational 
steps, which would constitute a significant change from the current 
regulations. As stated in our response to comment 19, we believe that 
human verification of certain processing steps, even when those steps 
are performed by automated equipment, is still necessary.
    (Comment 26) One comment stated that although proposed Sec.  
211.68(c) implies that the automated equipment is doing the work and a 
person can verify that the work is done, there are cases in which a 
person does the work and automated equipment might be able to verify 
the person's work. The comment cited as an example the case in which an 
automated system scans the bar codes of ingredients and equipment to 
ensure that the ingredient is correct for use with the equipment for 
that step in the process, but the physical addition of the ingredient 
is by the human operator (followed by the automated system scanning). 
The comment recommended, therefore, that Sec.  211.68(c) be modified to 
allow both the automated system and the person to do either the 
performance or the verification tasks for the operations addressed by 
Sec. Sec.  211.101(c) or (d), 211.103, 211.182, 211.188(b)(11), or 
211.194(a)(8), or a single performance verification in the case of 
Sec.  211.188(a).
    (Response) We acknowledge that it might be possible to design an 
automated system to verify operations performed by humans, but as 
stated in our response to comment 19, we continue to believe that some 
human verification of the processing steps performed by an automated 
system is necessary.
    (Comment 27) One comment suggested revising Sec.  211.68(c) to 
state that automated equipment can satisfy the requirements for 
verification of operations addressed by the listed sections as follows: 
(1) If such unit operation is fully automated, no manual verification 
is necessary and (2) if there is an operator for the automated 
equipment, the verifying individual may be, but is not required to be, 
the operator. The comment gave several reasons for this change:
     Automated, validated systems equipped with real-time 
alarms that do not require any human intervention should not require 
human verification because Sec.  211.68(a) adequately addresses the 
maintenance and verification of performance of these systems.
     The need and type of verification required should be 
consistent with the level of automation used. For example, operations 
that are not fully automated and require operator participation may 
serve as verification of the operator's activities, while fully manual 
operations would require a second human verification.
     As proposed, Sec.  211.68(c) might hinder the adoption of 
PAT (e.g., there would be no value added by manual verification when 
components are charged in a fully automated manner according to a 
validated algorithm).
    (Response) As stated in our response to comment 19, we do not agree 
with the contention that no human verification is necessary when fully 
automated systems are used, and we therefore decline to make these 
requested changes to Sec.  211.68(c). We also do not believe that Sec.  
211.68(c) will hinder the adoption of PAT. As stated in the preamble to 
the direct final rule, we agree that if there is an operator for the 
automated equipment, the verifying individual may be, but is not 
required to be, the operator. However, Sec.  211.68(c) does not require 
that the verifying individual be the operator, and we do not believe 
that it is necessary that the provision explicitly state that the 
verifying individual need not be the operator.
    (Comment 28) One comment stated that the proposed revision of Sec.  
211.68(c), when applied to Sec.  211.188(b), might be more restrictive 
than FDA's position in Compliance Policy Guide (CPG) Sec. 425.500, 
Computerized Drug Processing; Identification of ``Persons'' on Batch 
Production and Control Records (formerly CPG 7132a.08). CPG 425.500 
states that when significant steps in the manufacturing, processing, 
packing, or holding of a batch are performed, supervised, or checked by 
a computerized system, an acceptable means of complying with the 
identification requirements in Sec.  211.188(b)(11) would consist of 
conformance to certain requirements. The comment maintained that CPG 
425.500 gives companies the flexibility to automate not only the 
performance of critical actions but also the supervision and checking 
of these actions if it is shown that the efficacy of these controls 
would be at least equivalent to the level of efficacy if the 
verification were done by a second person. The comment stated that this 
flexibility should be extended to all CGMP sections in which a 
verification is requested. The comment therefore asked that Sec.  
211.68(c) be revised to state that 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 Sec.  211.68 and one person either performs the 
operations addressed in those sections under the control of the 
automated equipment or verifies that these operations are performed 
accurately by such equipment.
    (Response) We do not agree with the comment's apparent 
interpretation of CPG 425.500 that the CPG allows for elimination of 
human oversight. The purpose of the CPG is to explain what constitutes 
``identification'' of persons in batch records under Sec.  
211.188(b)(11) when automated systems are used for various functions. 
The CPG states that when an automated system is used to perform, 
directly supervise, or check significant steps in the production of a 
drug, the identification requirements in Sec.  211.188(b)(11) are met 
if there is documentation that the system contains adequate checks (and 
documentation of the performance of the system itself), validation of 
the system's performance, and recording of specific checks in batch 
records (including initial, branching, and final steps). These 
conditions for applying the identification requirements to steps using 
automated equipment involve the responsibilities of persons. For 
example, a person, rather than automated equipment, is needed to record 
these checks of production steps in batch records. Therefore, contrary 
to the comment's implication, the CPG does not state that human 
oversight is unnecessary when an automated system is involved in the 
performance, supervision, or checking of production

[[Page 51928]]

steps. All automated systems require some level (commensurate with the 
complexity and risk inherent in the system) of human oversight or 
checking for expected performance at appropriate intervals. Therefore, 
we decline to revise Sec.  211.68(c) as recommended.
    (Comment 29) One comment, although supportive of the proposal to 
allow initial activities to be performed by automated equipment, 
objected to requiring that the output of an automated and adequately 
validated activity be checked for accuracy by a person. The comment 
maintained that the act of having validated software and its related 
processes itself constitutes an independent check that operations are 
being performed accurately and argued that this is more reliable than 
any contemporaneous check by a person. The comment therefore asked that 
Sec.  211.68(c) be changed to state that independent checks may consist 
of contemporaneous analysis and verification by a second person 
following completion of the activity; or, where the automated process 
has been validated to a high degree of confidence, the prior validation 
can satisfy this requirement and a second person's check may then 
consist of verifying the validated status of the equipment and 
processes.
    (Response) We do not agree with the suggested change. Although we 
agree that it is an important part of process controls to ensure the 
validated status of equipment and processes even before they are used, 
we do not believe that verifying this validated status can satisfy the 
requirement for checking the actual performance of automated equipment. 
However, we believe that the requirement in proposed Sec.  211.68(c) 
that one person ``verifies that the operations * * * are performed 
accurately'' by automated equipment may have led some comments to 
believe that we were requiring a more specific and detailed repetitive 
type of check than we intended. When automated equipment is used for 
operations addressed by revised Sec.  211.68(c) in conformance with 
Sec.  211.68, the person doing the checking must verify that the 
automated equipment is functioning properly and that the operations are 
reliably performed in the intended manner. As discussed in the response 
to comment 19, the nature and frequency necessary for such verification 
will vary depending on the level of automation used as well as the 
nature of the system and controls. We do not expect that it will 
normally be necessary, under Sec.  211.68(c), for a person to repeat 
all of the automatic calculations by hand to ensure their accuracy. 
Therefore, we have revised Sec.  211.68(c) to clarify that automated 
equipment can be used to perform an operation when the performance is 
checked by a person provided that ``such equipment is used in 
conformity with this section [Sec.  211.68] and one person checks that 
the equipment properly performed the operation.''
3. Verification of Weighing, Measuring, or Subdividing Operations 
(Sec.  211.101(c))
    Section 211.101 concerns charge-in of components. Proposed Sec.  
211.101(c) stated, in part, that if the weighing, measuring, or 
subdividing operations for components are performed by automated 
equipment under Sec.  211.68, only one person is needed to ensure that 
the requirements in Sec.  211.101(c)(1), (c)(2), and (c)(3) are met.
    (Comment 30) One comment proposed broadening Sec.  211.101(c) to 
clarify that the weighing, measuring, and subdividing operations could 
be either performed by automated equipment or checked by automated 
equipment after being performed manually.
    (Response) We decline to make this suggested change for the reasons 
provided in response to comments 19 and 25. Revised Sec.  211.101(c) 
only permits human checking of weighing, measuring, and subdividing 
operations performed by automated equipment; we did not propose to 
allow automated checking of these operations. We continue to believe 
that human verification of these processing steps is necessary.
    (Comment 31) One comment stated that with respect to medical gases, 
there is no measurement of components to be dispensed for manufacturing 
that needs to be double-checked to ensure that the right quantity of 
the right component was added, because transfers of pure gases are 
within product-specific systems. However, the comment stated, with 
respect to gas mixtures, it is appropriate to have a verification of 
hook-ups as different components are added unless there is subsequent 
purity testing for each component.
    (Response) We decline to exempt single gas filling operations from 
certain requirements of Sec.  211.101(c) as recommended because such a 
change would exceed the scope of our proposed change to Sec.  
211.101(c), which only addressed human checking of weighing, measuring, 
and subdividing operations performed by automated equipment. We might 
consider in a future rulemaking whether it is appropriate to exempt 
medical gases from certain requirements of Sec.  211.101(c).
4. Verification of Components Added to the Batch (Sec.  211.101(d))
    Proposed Sec.  211.101(d) would have required that each component 
be either 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.
    (Comment 32) One comment stated that eliminating a double check for 
adding materials to a batch is problematic because an error in those 
operations would be difficult to detect and might not be discovered 
before the product is distributed, which could result in patient injury 
and product recall. The comment recommended deleting or modifying the 
ability to use a sole verifier for operations involving addition of 
materials.
    (Response) The comment appears to suggest that we proposed to 
eliminate the requirements concerning verification that appropriate 
components were added to a batch. The revisions we are adopting do not 
eliminate the requirement to verify performance in Sec.  211.101(d); 
they simply codify our longstanding policy that components may be added 
either by a person or by suitable automated equipment. The addition of 
components still must be checked by a person.
    (Comment 33) One comment stated that under the proposed change to 
Sec.  211.101(d), if a validated system performs a function, it is 
acceptable for one person to verify that action, but if an automated 
system prompts an operator to perform a function, a second person would 
be required to confirm the proper execution of the action. The comment 
recommended changing Sec.  211.101(d) to state that each component must 
be added to the batch by one person and verified by a second person, 
``unless the components are added by automated equipment under Sec.  
211.68, in which case verification can be performed by one person.''
    (Response) We decline to accept the suggested change because we do 
not believe that it constitutes a substantive difference from the 
language of proposed Sec.  211.101(d). It is irrelevant whether use of 
a particular automated system for component charge-in requires an 
operator to perform a related function; in either case, verification of 
the charge-in operation(s) must be performed by a person.
    (Comment 34) One comment recommended changing Sec.  211.101(d) to 
specify that the weighing, measuring, or subdividing operations might 
be performed by automated equipment or checked by automated equipment 
after

[[Page 51929]]

being performed manually. The comment also stated that in many 
instances, the verification by a person of actions performed by 
automated equipment can only be done on the basis of outputs from the 
equipment. As an example, the comment stated, when the introduction of 
components in a liquid production line is fully automated, there is no 
possibility for the operator to check that the correct amount of 
materials was incorporated into the batch other than by relying on 
information given by the same automated equipment. The comment stated 
that in that case, the verification would consist of confirming that 
the component's incorporation process was completed without errors or 
alarms.
    (Response) We decline to make this suggested change for the reasons 
stated in response to comments 19 and 25. Revised Sec.  211.101(d) only 
permits human checking of component additions performed by automated 
equipment; we did not propose to allow automated checking of component 
additions performed by humans. In the example given in the comment, 
human verification that components were properly added to the liquid 
production line by the automated equipment would be needed to ensure 
that the equipment performed properly. We continue to believe that 
human verification of this processing step is necessary.
5. Calculation of Yield (Sec.  211.103)
    We proposed, in Sec.  211.103, to require that calculations of 
actual yields and percentages of theoretical yields 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.
    (Comment 35) One comment stated that it is not necessary to have a 
person recalculate a yield manually after a validated system does it 
automatically. The comment asked that Sec.  211.103 be revised to limit 
the human interaction to data entry and data verification, but not 
recalculation of yields if yields are calculated by a validated, 
automated system. A similar comment stated that Sec.  211.103 should be 
changed to state that if the yield is calculated by automated 
equipment, a person must verify the data entries, rather than 
regenerate the calculations.
    (Response) We do not believe that the recommended changes are 
needed or appropriate. Revised Sec.  211.103 does not require that all 
yield calculations be repeated manually. Manual recalculation might be 
a suitable approach to verifying yield calculations, but Sec.  211.103 
also permits the use of other approaches, including verification that 
automated equipment functioned properly while performing yield 
calculations.
    (Comment 36) One comment reiterated the views expressed in its 
comments on the CGMP for medical gases draft guidance. Thus, the 
comment requested that the requirements for yield calculation in Sec.  
211.103 not be applied to medical gases because of the atmospheric-gas-
separation and cylinder-filling processes associated with medical 
gases. In further support of its position, the comment referred to an 
FDA publication (Human Drug CGMP Notes, vol. 5, no. 2, June 1997) in 
which the agency stated that it would propose to revise the CGMP 
regulations to exempt medical gases from the requirements for yield 
reconciliation.
    (Response) We decline to exempt medical gases from the requirements 
for yield calculation in Sec.  211.103 as recommended because this 
would exceed the scope of our proposed change to Sec.  211.103, which 
addressed only human checking of yield calculations performed by 
automated equipment. We might consider in a future CGMP rulemaking 
whether it is appropriate to exempt medical gases from certain 
requirements of Sec.  211.103. In addition, we might consider providing 
specific recommendations to medical gas manufacturers to help them 
comply with the requirements for calculating yields in the course of 
finalizing the draft guidance on CGMP for medical gases.
6. Equipment Cleaning and Use Log (Sec.  211.182)
    We proposed, in Sec.  211.182, to require the persons performing 
and double-checking equipment 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) to date and sign or initial the log 
indicating that the work was performed.
    (Comment 37) One comment stated that eliminating a double check for 
cleaning equipment is problematic because an error in those operations 
would be difficult to detect and might not be discovered before the 
product is distributed, which could result in patient injury and 
product recall. The comment recommended deleting or modifying the 
ability to use a sole verifier for operations involving equipment 
cleaning.
    (Response) The comment appears to suggest that we proposed to 
eliminate the requirements concerning verification that equipment was 
appropriately cleaned and maintained. The revisions we are adopting do 
not eliminate the requirement to verify performance in Sec.  211.182; 
they simply codify our longstanding policy that equipment may be 
cleaned and maintained either by a person or by suitable automated 
equipment. Cleaning and maintenance of equipment must still be checked 
by a person.
    (Comment 38) One comment stated that operations addressed by 
Sec. Sec.  211.182 and 211.188(b)(11) are often performed using semi-
automated equipment that requires an operator to select the correct 
menu. The comment stated that major pieces of equipment such as ``Clean 
in Place'' (CIP) skids and vial washers often require the operator to 
select the appropriate process menu before the execution of the actual 
automated cycle by the equipment's controller. The comment asked 
whether, when operator input is necessary to select but not perform an 
operation, the signature of the operator selecting the menu is required 
in cases when there is a second signature that verifies the performance 
of the cycle. One comment requested that we verify in Sec.  211.182 or 
the preamble of the final rule that a single verification remains 
sufficient when automated but portable cleaning skids are used.
    (Response) We do not believe that initiation of the automated 
cleaning cycle by a human operator constitutes performance of the 
cleaning process for purposes of revised Sec.  211.182. The revised 
regulation requires that after an automated cleaning process (such as 
CIP) is completed, the human operator must date and sign or initial the 
log verifying that the equipment performed the automated cleaning 
process properly. The regulation does not require the operator to date 
and sign or initial the log simply for the initiation of the automated 
cleaning cycle. This approach applies to both portable equipment skids 
and fixed equipment.
    (Comment 39) One comment stated that in many instances, the human 
verification of an action performed by automated equipment can only be 
done on the basis of outputs from the equipment. As an example, the 
comment stated, when equipment is cleaned through CIP, the verification 
should consist of confirming that the system reports the cleaning as 
successfully completed without alarms.
    (Response) What constitutes adequate verification that equipment 
has been properly cleaned or maintained using

[[Page 51930]]

automated equipment in accordance with revised Sec.  211.182 depends on 
the particular circumstances. The outputs from the automated equipment 
will normally be key factors, but not necessarily the only ones. The 
manufacturer should determine the reliability of the outputs and 
periodically check them. For example, it might be appropriate to verify 
that an alarm is working properly and is successfully monitoring the 
equipment's critical functions. There might be other ways of verifying 
the adequate performance of cleaning and maintenance by automated 
equipment, such as by monitoring the usage of cleaning supplies in a 
cleaning cycle or conducting an independent check of the rinse.
    (Comment 40) One comment stated that for most medical gas systems, 
routine or periodic cleaning is not performed because the industry is 
characterized by product-specific closed systems that undergo an 
appropriate cleaning process before initial use. The comment stated 
that because of the high number of batches produced on a weekly/monthly 
basis in the medical gas industry, it is more appropriate to keep 
cleaning and maintenance records separate from batch records. The 
comment maintained that although requiring documentation of equipment 
cleaning, maintenance, and use in individual equipment logs may be 
appropriate for traditional pharmaceuticals (where key processing 
equipment may be used for multiple products and lot numbers), applying 
this requirement to medical gases would make retrieval and management 
of cleaning and maintenance records much more difficult. The comment 
added that use logs are not appropriate for medical gases because batch 
record documentation provides a consecutive listing of products 
manufactured on each system.
    (Response) We decline to exempt medical gases from certain 
requirements of Sec.  211.182 as recommended because this would exceed 
the scope of our proposed change to Sec.  211.182, which addressed 
human verification of cleaning steps performed by automated equipment. 
We might consider in a future CGMP rulemaking whether it is appropriate 
to exempt medical gases from certain requirements of Sec.  211.182.
7. Batch Production and Control Records (Sec.  211.188(b)(11))
    Section 211.188 concerns batch production and control records. 
Proposed 211.188(b)(11) specified that when a significant step in the 
operation is performed by automated equipment under Sec.  211.68, the 
record would need to identify the person checking the significant step 
performed by the automated equipment.
    (Comment 41) One comment stated that Sec.  211.188(b)(11) should be 
changed to state that a significant manufacturing step could be either 
performed or checked by automated equipment. The comment stated that 
this approach is permitted by CPG 425.500.
    (Response) We decline to make this suggested change. As stated in 
our response to comment 28, CPG 425.500 does not, as the comment 
implies, state that human oversight is unnecessary when an automated 
system is involved in the performance, supervision, or checking of 
production steps. To revise Sec.  211.188(b)(11) as recommended by the 
comment might be interpreted as permitting manufacturers to rely solely 
on automated equipment to verify the human performance of certain 
production steps. As stated in our response to comments 19 and 25, we 
believe that human verification of processing steps is still necessary.

F. Miscellaneous Minor Changes Based on 1996 Proposal

    We proposed to make miscellaneous minor changes to CGMP regulations 
to clarify certain manufacturing, quality control, and documentation 
requirements and to align the regulations with industry practice.
1. Storage of Untested Components, Drug Product Containers, and 
Closures (Sec.  211.82(b))
    The version of Sec.  211.82(b) amended by this final rule stated: 
``Components, drug product containers, and closures shall be stored 
under quarantine until they have been tested or examined, as 
appropriate, and released.'' We proposed to replace the phrase ``as 
appropriate'' with the phrase ``whichever is appropriate'' to eliminate 
any ambiguity in Sec.  211.82(b) and to emphasize that it is accepted 
industry practice to conduct some testing or examination before 
components, drug product containers, or closures are released from 
quarantine.
    (Comment 42) One comment requested that medical gas container-
closure assemblies returned from customers and reused be exempted from 
Sec.  211.82(b). The comment stated that assembled cylinder/valve 
medical gas combinations are reused and handled differently than they 
would be at the time of initial receipt. The comment stated that 
returned assemblies are individually inspected for all critical quality 
issues immediately before filling; those assemblies that do not meet 
the inspection criteria are moved to a quarantine area. The comment 
stated that this practice satisfies the intention that components, 
containers, and closures be inspected to ensure that unacceptable 
assemblies are not used in the manufacturing process.
    (Response) Under revised Sec.  211.82(b), manufacturers of medical 
gases would retain the ability to sequester and inspect returned valve/
cylinder assemblies before refilling in accordance with the industry 
practice described by the comment. The practice described by the 
comment is to have the assembled valve/cylinders placed in a segregated 
area (apparently not identified using the word ``quarantine''), 
examined for conformance to quality standards, and, if the criteria are 
met, immediately made available for refilling. This practice would meet 
the requirement for a quarantine status if goods in such areas or under 
such a status are not acceptable for use as-is unless and until they 
are qualified to be suitable for use. Therefore, we do not believe that 
the practice as described violates revised Sec.  211.82(b), and there 
is no need to exempt medical gas manufacturers from this requirement.
2. Cleaning of Component Container Samples (Sec.  211.84(c)(1))
    The version of Sec.  211.84(c)(1) amended by this final rule 
stated: ``The containers of components selected [for sampling] shall be 
cleaned where necessary, by appropriate means.'' We proposed to replace 
the phrase ``where necessary, by appropriate means'' with the phrase 
``when necessary in a manner to prevent introduction of contaminants 
into the component.'' This change was intended to clarify that the act 
of cleaning is done for a particular purpose--to prevent the 
introduction of contaminants--and must be done unless cleaning is not 
necessary to prevent contamination.
    (Comment 43) One comment expressed concern that the proposed change 
might be interpreted to require validation of this prevention of 
contamination during sampling. The comment requested that we confirm 
that our intent is to place the contamination concern into the controls 
and procedures for sampling and into the training of staff who perform 
these activities, rather than to require validation of the absence of 
contamination.
    (Response) Revised Sec.  211.84(c)(1) does not require 
manufacturers to conduct validation studies to prove that the method of 
sampling prevents contamination. When properly designed and followed, 
the cleaning procedures, training, and facility and equipment

[[Page 51931]]

controls, along with supervisory and quality unit oversight, should 
ensure compliance with Sec.  211.84(c)(1).
3. Editorial Changes (Sec. Sec.  211.84(d)(3) and 211.160(b)(1))
    We proposed minor editorial changes to two regulations, Sec. Sec.  
211.84(d)(3) and 211.160(b)(1). The version of Sec.  211.84(d)(3) 
amended by this final rule stated: ``Containers and closures shall be 
tested for conformance with all appropriate written procedures.'' We 
proposed to replace the word ``conformance'' with ``conformity'' and 
the word ``procedures'' with ``specifications.'' The first sentence of 
the version of Sec.  211.160(b)(1) amended by this final rule stated: 
``Determination of conformance to appropriate 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.'' We proposed to 
replace the word ``conformance'' with ``conformity'' and the word 
``appropriate'' with ``applicable.'' We stated in the preamble to the 
direct final rule that these revisions would provide clarity without 
changing the meaning or intent of these regulations. We received no 
comments on these proposed changes, and we have revised these 
provisions as proposed.

IV. Analysis of Impacts

    FDA has examined the impacts of this 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 impacts; and equity). The agency believes that 
this final rule is not a significant regulatory action as defined by 
the Executive order, because the rule either clarifies the agency's 
longstanding interpretation of, or increases latitude for manufacturers 
in complying with, existing 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 final rule does not impose any new 
regulatory obligations, the agency believes that the rule will 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 $127 million, using the most current (2006) Implicit 
Price Deflator for the Gross Domestic Product. This rule does not 
result in any 1-year expenditure that would meet or exceed this amount.
    The purpose of this final rule is to update the codified language 
to reflect current practice and to harmonize requirements in the CGMP 
regulations with requirements in other regulations and with 
international CGMP standards. It does not impose any additional 
requirements; therefore, industry will not incur incremental compliance 
costs for these proposed changes.

V. Environmental Impact

    FDA concludes that 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.

VI. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. We have 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, we have 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.

VII. Paperwork Reduction Act of 1995

    This final rule contains collections of information that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520) (the PRA). 
The collections of information (recordkeeping requirements) in part 211 
have already been approved by OMB under control number 0910-0139. The 
final rule amends certain sections of part 211 as well as Sec.  210.3 
(Sec.  210.3 does not contain information collection requirements). As 
concluded in section IV of this document, ``Analysis of Impacts,'' the 
purpose of the final rule is to update the regulations to reflect 
current practice and to harmonize requirements in the CGMP regulations 
with requirements in other regulations and with international CGMP 
standards. The final rule does not impose any additional requirements. 
Thus, because the final rule does not substantively revise the 
information collection requirements in part 211 or add new information 
collection requirements, there is no need to conduct an analysis under 
the PRA.

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 211.67 is amended by revising paragraph (a) to read as 
follows:

[[Page 51932]]

Sec.  211.67  Equipment cleaning and maintenance.

    (a) Equipment and utensils shall be cleaned, maintained, and, as 
appropriate for the nature of the drug, 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
5. 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 checks that the equipment properly performed 
the operation.

0
6. 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 be used 
when it is not possible to manufacture such products without the use of 
these filters. If use of a fiber-releasing filter is necessary, an 
additional nonfiber-releasing filter having a maximum nominal pore size 
rating of 0.2 micron (0.45 micron if the manufacturing conditions so 
dictate) shall subsequently be used to reduce the content of particles 
in the injectable drug product. The use of an asbestos-containing 
filter is prohibited.

0
7. 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
8. 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
9. 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.
* * * * *

0
10. 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.

0
11. 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
12. 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
13. 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
14. Section 211.160 is amended by revising paragraph (b)(1) to read as 
follows:

[[Page 51933]]

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.
* * * * *

0
15. 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.

0
16. 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: August 22, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-20709 Filed 9-5-08; 8:45 am]
BILLING CODE 4160-01-S