CGMP For Aseptic

Federal Register / Vol. 73, No.
174 / Monday, September 8, 2008 / Rules and Regulations 51919
10. Order dated June 11, 2003, signed by direct effects on States, on the DEPARTMENT OF HEALTH AND
Julie Louise Gerberding, Director, Centers for relationship between the National HUMAN SERVICES
Disease Control and Prevention, and Mark B.
Government and the States, or on the
McClellan, Commissioner of Food and Drugs, Food and Drug Administration
titled ‘‘Joint Order of the Centers for Disease distribution of power and
Control and Prevention and the Food and responsibilities among the various
Drug Administration, Department of Health levels of government. Accordingly, we 21 CFR Parts 210 and 211
and Human Services.’’ have concluded that the rule does not [Docket No. FDA–2007–N–0379] (formerly
11. 68 FR 36566 (June 18, 2003). contain policies that have federalism Docket No. 2007N–0280)
12. Fleischauer, A. T., et al., ‘‘Evaluation of
Human-to-Human Transmission of
implications as defined in the Executive
Order, and, consequently, a federalism Amendments to the Current Good
Monkeypox from Infected Patients to Health
Care Workers,’’ Clinical Infectious Diseases, summary impact statement is not Manufacturing Practice Regulations for
40: 689–694 (2004). required. Finished Pharmaceuticals
13. Xiao, S.Y., et al., ‘‘Experimental
List of Subjects AGENCY: Food and Drug Administration,
Infection of Prairie Dogs with Monkeypox
Virus,’’ Emerging Infectious Diseases 11(4): HHS.
539–545 (2005). 21 CFR Part 16 ACTION: Final rule.
14. Likos, A.M., et al., ‘‘A Tale of Two
Administrative practice and SUMMARY: The Food and Drug
Clades: Monkeypox Viruses,’’ Journal of
General Virology 86: 2661–2672 (2005). procedure. Administration (FDA) is amending
15. Nalca, A., Rimoin, A.W., Bavari, S. and 21 CFR Part 1240 certain of its regulations on current good
Whitehouse, C.A., ‘‘Reemergence of manufacturing practice (CGMP)
Monkeypox: Prevalence, Diagnostics, and Communicable diseases, Public requirements for finished
Countermeasures,’’ Clinical Infectious
Diseases 41: 1765–1771 (2005).
health, Travel restrictions, Water pharmaceuticals as the culmination of
16. Kile, J.C., et al., ‘‘Transmission of supply. the first phase of an incremental
Monkeypox Among Persons Exposed to approach to modifying the CGMP
■ Therefore, under the Public Health regulations for these products. This rule
Infected Prairie Dogs in Indiana in 2003,’’
Archives of Pediatric Adolescent Medicine Service Act and under authority revises CGMP requirements primarily
159: 1022–1025 (2005). delegated to the Commissioner of Food concerning aseptic processing,
17. Guarner, J. et al., ‘‘Monkeypox and Drugs, 21 CFR 16 and 1240 are verification of performance of
Transmission and Pathogenesis in Prairie amended as follows: operations by a second individual, and
Dogs,’’ Emerging Infectious Diseases, 10:
426–431 (March 2004).
the use of asbestos filters. We are
PART 16—REGULATORY HEARING amending the regulations to modernize
18. Bernard, S., and Anderson, S., BEFORE THE FOOD AND DRUG
‘‘Qualitative Risk Assessment: Monkeypox in or clarify some of the requirements as
the United States Associated with Domestic
ADMINISTRATION well as to harmonize them with other
Trade in Certain Animal Species,’’ Emerging FDA regulations and international
Infectious Diseases, 12: 1827–1833 (2006). ■ 1. The authority citation for 21 CFR CGMP standards.
19. Anderson, M.G., et al., ‘‘A Case of part 16 continues to read as follows: DATES: This rule is effective December 8,
Severe Monkeypox Virus Disease in an
American Child: Emerging Infections and Authority: 15 U.S.C. 1451–1461; 21 U.S.C. 2008.
Changing Professional Values,’’ Pediatric 141–149, 321–394, 467f, 679, 821, 1034; 28 FOR FURTHER INFORMATION CONTACT:
Infectious Disease, 22: 1093–1096 (2003). U.S.C. 2112; 42 U.S.C. 201–262, 263b, 364. Mary Malarkey, Center for Biologics
20. Croft, D.R., et al., ‘‘Occupational Risks Evaluation and Research (HFM–600),
during a Monkeypox Outbreak, Wisconsin, § 16.1 [Amended]
Food and Drug Administration, 1401
2003,’’ Emerging Infectious Diseases, 13: Rockville Pike, Rockville, MD 20852–
1150–1157 (2007). ■ 2. Section 16.1 is amended in
21. Reynolds, M.G., et al., ‘‘Spectrum of paragraph (b)(2) by removing the entry 1448, 301–827–6190; or
Infection and Risk Factors for Human for ‘‘§ 1240.63(c)(3) ’’. Dennis Bensley, Center for Veterinary
Monkeypox, United States, 2003,’’ Emerging Medicine (HFV–140), Food and Drug
Infectious Diseases, 13: 1332–1339 (2007). PART 1240—CONTROL OF Administration, 7500 Standish Pl.,
22. Reed, K. D., Davis, J. P., and Damon, COMMUNICABLE DISEASES Rockville, MD 20855, 240–276–8268; or
I. K., ‘‘Monkeypox in the Western Brian Hasselbalch, Center for Drug
Hemisphere,’’ (Response to a Letter to the Evaluation and Research, Food and
Editor), New England Journal of Medicine, ■ 3. The authority citation for 21 CFR
part 1240 continues to read as follows: Drug Administration, 10903 New
350: 1791 (April 22, 2004).
23. Hutson, C.L., et al., ‘‘Monkeypox Hampshire Ave., rm. 4364, Silver
Authority: 42 U.S.C. 216, 243, 264, 271. Spring, MD 20993, 301–796–3279.
Zoonotic Associations: Insights from
Laboratory Evaluation of Animals Associated § 1240.63 [Removed] SUPPLEMENTARY INFORMATION:
with the Multi-State US Outbreak,’’
American Journal of Tropical Medicine and ■ 4. Remove § 1240.63. Table of Contents
Hygiene, 76: 757–767 (2007). I. Background
24. Centers for Disease Control and Dated: August 27, 2008.
II. Summary of the Final Rule
Prevention, ‘‘Multistate Outbreak of Jeffrey Shuren,
Monkeypox - Illinois, Indiana, and
A. Aseptic Processing
Associate Commissioner for Policy and B. Asbestos Filters
Wisconsin, 2003,’’ Morbidity and Mortality Planning.
Weekly Report, 52: 537–540 (June 13, 2003). C. Verification by a Second Individual
[FR Doc. E8–20779 Filed 9–5–08; 8:45 am] D. Other Minor Changes
VIII. Federalism BILLING CODE 4160–01–S III. Comments on the Proposed Rule and
pwalker on PROD1PC71 with RULES
FDA has analyzed this rule in FDA’s Response

accordance with the principles set forth A. General Comments
in Executive Order 13132. We have B. Plumbing
determined that the rule does not C. Aseptic Processing
contain policies that have substantial D. Asbestos Filters
VerDate Aug<31>2005 17:07 Sep 05, 2008 Jkt 214001 PO 00000 Frm 00021 Fmt 4700 Sfmt 4700 E:\FR\FM\08SER1.SGM 08SER1
51920 Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 / Rules and Regulations
E. Verification by a Second Individual rule (72 FR 68064) and companion testing of in-process materials, which
F. Miscellaneous Minor Changes proposed rule (72 FR 68113) to clarify again is consistent with industry
Based on 1996 Proposal and modernize certain provisions of the practice.
IV. Analysis of Impacts CGMP regulations. The comment period
V. Environmental Impact B. Asbestos Filters
for the direct final rule closed on
VI. Federalism February 19, 2008. On April 4, 2008, we We revised §§ 210.3(b)(6) and 211.72
VII. Paperwork Reduction Act of 1995 published a document withdrawing the to eliminate provisions permitting
I. Background direct final rule because we received limited use of asbestos-containing filters
significant adverse comments (73 FR used in processing injectable drug
Since the development of the CGMP products. We had proposed to simply
regulations for drug products in 1962, 18440). In the document withdrawing
the direct final rule, we explained that delete references to asbestos filters in
FDA has balanced the need for easily
the comments received would be these provisions. However, in response
understood minimum standards with
considered under our usual procedures to comments, we also added to § 211.72
the need to encourage innovation and
for notice and comment in connection the statement ‘‘The use of an asbestos-
the development of improved
with the notice of proposed rulemaking containing filter is prohibited.’’ Also in
manufacturing technologies. We strive
that was published as a companion to response to comments, we revised
to give manufacturers latitude to
the direct final rule. § 211.72 to reflect appropriate technical
determine how to achieve the level of
After careful consideration of all standards for nonfiber-releasing filters.
control necessary for CGMP compliance,
recognizing that, in some instances, comments received, we are now C. Verification by a Second Individual
more direction from FDA is necessary to publishing this final rule. The final rule
represents the culmination of the first The final rule makes several changes
provide a uniform standard to the entire to the regulations to acknowledge,
industry, minimize the potential for increment of modifications to parts 210
and 211. consistent with our longstanding
harm, or achieve some other CGMP interpretation, that certain operations
objective. We periodically reassess and II. Summary of the Final Rule may be performed by automated
revise the CGMP regulations to The final rule revises the drug CGMP equipment and verified by a person,
accommodate advances in technology regulations primarily in three areas: rather than one person performing an
and other scientific knowledge that Aseptic processing, use of asbestos operation and another person verifying
further safeguard the drug filters, and verification of operations by that the operation was correctly
manufacturing process and the public a second individual. performed. In particular, we added new
health. paragraph (c) to § 211.68 stating that
In 1996, as part of this reassessment A. Aseptic Processing
automated equipment used to perform
process, we proposed to: (1) Amend The final rule revises § 211.113(b) to operations addressed in §§ 211.101(c) or
certain requirements of the CGMP clarify that required written procedures (d), 211.103, 211.182, or 211.188(b)(11)
regulations for finished pharmaceuticals designed to prevent microbiological can satisfy the requirements in those
to clarify certain manufacturing, quality contamination of sterile drug products sections for the performance of an
control, and documentation must include procedures on the operation by one person and checking
requirements and (2) ensure that the validation of all aseptic processes in by another person if the equipment is
regulations more accurately addition to sterilization processes. Other used in conformity with § 211.68 and
encompassed current industry practice changes related to aseptic processing one person checks that the operations
(61 FR 20104, May 3, 1996) (1996 include the following: are properly performed. In response to
proposed rule). Subsequently, as a part • Revised § 211.67(a) requires that comments, we revised the paragraph to
of the risk-based Pharmaceutical CGMPs equipment and utensils be cleaned, minimize the possibility that the
for the 21st Century initiative, we maintained, and, as appropriate for the provision might be misinterpreted as
created a CGMP Harmonization nature of the drug, sanitized ‘‘and/or requiring a person to repeat by hand all
Analysis Working Group (CGMP sterilized’’ at appropriate intervals to calculations performed by automated
Working Group) to analyze related prevent malfunction or contamination. equipment.
CGMP requirements in effect in the This change recognizes that for sterile In accordance with the addition of
United States and internationally, drug products, sterilization (sometimes § 211.68(c), we are adopting
including those related to quality in addition to sanitization) is corresponding changes to the following
systems. The CGMP Working Group appropriate. provisions:
compared parts 210 and 211 (21 CFR • Revised § 211.84(d)(6) requires • Section 211.101(c) and (d)
parts 210 and 211) with the CGMPs of microbiological tests before use of each (concerning charge-in of components
the European Union (EU), as well as lot of a component, drug product and containers),
other FDA regulations (e.g., the Quality container, or closure ‘‘with potential for • Section 211.103 (calculation of
Systems Regulation, 21 CFR part 820) to microbiological contamination’’ that is yields),
identify the differences and consider the objectionable in view of its intended • Section 211.182 (equipment
value of supplementing or changing the use, consistent with longstanding cleaning and maintenance), and
current regulations. Based on the CGMP agency interpretation of this regulation. • Section 211.188(b)(11) (batch
Working Group’s analysis, we decided • Revised § 211.94(c) requires production and control records).
to take an incremental approach to validation of depyrogenation processes
modifying parts 210 and 211. for drug product containers and D. Other Minor Changes
Because of this change in approach, closures, consistent with longstanding In addition to the revisions to the
we decided not to finalize the 1996 industry practice and agency regulations previously noted, we have
proposed rule. On December 4, 2007, we interpretation of this regulation. made minor revisions to the following
published a document withdrawing the • Revised § 211.110(a) adds provisions to provide greater clarity
1996 proposed rule (72 FR 68111) (the bioburden testing to the list (which is without changing meaning or intent:
December 2007 proposed rule). On the not all-inclusive) of in-process control • Section 211.82(b) (storage of
same date, we published a direct final procedures relating to the sampling and components, containers, and closures),
Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 / Rules and Regulations 51921
• Section 211.84(c)(1) and (d)(3) to people working with biological drugs (particularly those of the EU and Japan)
(collection and testing of samples of and other products. Another comment and to make the U.S. regulation more
components, containers, and closures), stated that the December 2007 proposed consistent with the United States
and rule should have incorporated many of Pharmacopeia standard. In the preamble
• Section 211.160(b)(1) (laboratory the changes in the 1996 proposed rule of the direct final rule, we stated that
controls for determining conformity to regarding such matters as validation, the revised requirement could be met by
specifications). quality control unit responsibilities, compliance with the standards in the
III. Comments on the Proposed Rule batch failure investigations, and EPA regulations or in the current
and FDA’s Response stability samples because they involve regulations of the EU or Japan for
some of the most common CGMP potable water used to prepare water for
We received comments on the deficiencies. pharmaceutical purposes.
proposed rule from drug and biologic (Response) As we stated in the (Comment 4) Four comments objected
manufacturers, industry associations, December 4, 2007, document, we to the proposed change. Among other
consultants, and other interested withdrew the 1996 proposed rule things, the comments stated that the
persons. A summary of the comments because we concluded that, given our standard of ‘‘safe for human
received and our responses follow. We new approach to CGMP under the 21st consumption’’ is not sufficiently
first respond to comments of a general century initiative, it would be preferable prescriptive.
nature and then to comments on the five to revise the CGMP regulations (Response) Because of the comments
topics set forth in the preamble of the incrementally rather than in a one-time, received and other considerations, we
direct final rule. comprehensive fashion. Furthermore, have decided not to revise § 211.48(a) at
To make it easier to identify we believe that it is appropriate to this time. We will address the issue of
comments and our responses, the word reevaluate some of the matters standards for water used in a facility’s
‘‘Comment,’’ in parentheses, appears considered in the 1996 proposed rule in plumbing system when we consider
before the comment’s description, and light of recent scientific and proposing regulations for water used as
the word ‘‘Response,’’ in parentheses, technological advances. We appreciate a drug product component in the next
appears before our response. We have the comments’ interest in the specified phase of our CGMP initiative.
numbered each comment to help CGMP issues, and we will consider
distinguish between different C. Aseptic Processing
these issues in future phases of our
comments. Similar comments are CGMP modernization efforts. In the proposed rule, we sought to
grouped together under the same (Comment 3) One comment amend several regulations on aseptic
number if the same response would be encouraged FDA to consider other processing to reflect current industry
given for each. The number assigned to CGMP regulations that need standards and practices. Some of the
each comment is purely for modernization or clarification, or are no proposed revisions would also affect
organizational purposes and does not longer necessary due to technological other types of processes and operations.
signify the comment’s value or advances, such as aspects of 21 CFR We noted that the proposed changes
importance or the order in which it was 610.12 concerning the requirements for would not affect the applicability of the
received. bulk sterility testing and allowance for guidance for industry entitled ‘‘Sterile
sterility retesting for biological Drug Products Produced by Aseptic
A. General Comments products. Processing—Current Good
(Comment 1) One comment stated (Response) We appreciate the Manufacturing Practice’’ (Aseptic
that it will be very important for FDA comment’s interest in modernizing Processing Guidance), issued on
to ensure clarity and consistency in the CGMP regulations. As previously stated, October 4, 2004 (69 FR 59258).
understanding of the final rule among this final rule represents only our first
agency staff, including both product step in updating the drug CGMP 1. Equipment Cleaning and
reviewers and CGMP inspectors, to regulations to reflect current industry Maintenance (§ 211.67(a))
minimize different interpretations and practice and harmonize the regulations The version of § 211.67(a) amended
applications of these regulations. with international CGMP requirements. by this final rule stated: ‘‘Equipment
(Response) We agree that it is We will consider other aspects of CGMP and utensils shall be cleaned,
important that FDA employees who in future rulemaking proceedings. maintained, and sanitized at appropriate
perform application reviews, as well as intervals to prevent malfunctions or
conduct CGMP inspections and other B. Plumbing contamination that would alter the
compliance activities, understand these Section 211.48(a) requires that potable safety, identity, strength, quality, or
regulations and apply them in a water be supplied under continuous purity of the drug product beyond the
consistent manner in the performance of positive pressure in a plumbing system official or other established
their duties. Therefore, we will take free of defects that could contribute requirements.’’ We proposed to add the
appropriate steps to ensure that agency contamination to any drug product. It phrase ‘‘and/or sterilized’’ after the
staff receive adequate training regarding further requires that potable water meet word ‘‘sanitized’’ in § 211.67(a) to
the new regulations. the standards established by the U.S. reflect the fact that sterilization is
(Comment 2) One comment stated Environmental Protection Agency (EPA) appropriate for sterile drug products.
that we should not withdraw the 1996 for primary drinking water in 40 CFR On our own initiative, we have
proposed rule because it contained part 141. Proposed § 211.48(a) would revised § 211.67(a) to state that
many good features with respect to test have deleted the requirement that the equipment and utensils shall be
method validation and the out-of- potable water used in a plumbing cleaned, maintained, ‘‘and, as
specification test result problem. The system meet EPA’s standards for appropriate for the nature of the drug,
comment maintained that the guidance primary drinking water, and instead sanitized and/or sterilized at
for industry entitled ‘‘Investigating Out- required that the water be ‘‘safe for appropriate intervals * * *.’’ This
of-Specification (OOS) Test Results for human consumption.’’ This proposed revision does not alter the meaning of
Pharmaceutical Production’’ (71 FR revision was intended to improve the proposed rule change, but clarifies
60158, October 12, 2006) is not helpful harmonization with foreign regulations that for some equipment and utensils
used in the production of certain drug systems. We might consider in a future 3. Validation of Depyrogenation of Drug
products, sanitization is appropriate; for CGMP rulemaking whether it is Product Containers and Closures
other equipment and utensils, appropriate to revise § 211.67(a) to (§ 211.94(c))
sterilization is appropriate; and for still address its application to medical gases.
others, both sanitization and The version of § 211.94(c) amended
sterilization are appropriate. 2. Microbiological Testing of by this final rule stated: ‘‘Drug product
(Comment 5) One comment stated Objectionable Lots of Components, Drug containers and closures shall be clean
that it is not appropriate to address Product Containers, and Closures and, where indicated by the nature of
sterilization in § 211.67(a). Instead, the (§ 211.84(d)(6)) the drug, sterilized and processed to
comment recommended that a reference remove pyrogenic properties to assure
The version of § 211.84(d)(6) amended
to sterilization of equipment and that they are suitable for their intended
by this final rule stated: ‘‘Each lot of a
utensils be added to § 211.113(b), which use.’’ In the preamble to the direct final
requires the adoption of written component, drug product container, or
rule, we stated that it has been
procedures designed to prevent closure that is liable to microbiological
contamination that is objectionable in longstanding industry practice to
microbiological contamination of drug validate the sterilization and
products purporting to be sterile. view of its intended use shall be
subjected to microbiological tests before depyrogenation processes used for drug
(Response) We do not agree with the product containers and closures to
comment because, as previously noted, use.’’ We proposed to change the phrase
‘‘that is liable to microbiological ensure consistent removal of microbial
equipment and utensils used in the contamination and pyrogens or
production of sterile drug products must contamination’’ to ‘‘with potential for
microbiological contamination.’’ endotoxins. Therefore, we proposed to
be sterilized, not merely sanitized. In add a provision to § 211.94(c) requiring
addition, we have revised § 211.113(b) (Comment 8) One comment stated the validation of these depyrogenation
as discussed in section III.C.5 of this that the proposed change was processes.
final rule. unnecessarily restrictive and might lead
(Comment 6) One comment suggested to testing every lot when the risk of (Comment 9) One comment suggested
that we could simplify the language in microbial contamination is low and the that we require validation of
this regulation by changing the phrase impact on the intended use is ‘‘sterilization’’ as well as
‘‘beyond the official or other established insignificant. This comment suggested depyrogenation processes.
requirements’’ to ‘‘beyond the replacing ‘‘that is liable to microbial (Response) We do not believe that the
established (or other official) contamination’’ with ‘‘prone to suggested change is needed because
requirements.’’ microbial contamination.’’ One § 211.113(b) already requires validation
(Response) We do not believe that the
comment stated that the proposed of sterilization processes for the
suggested change simplifies the current
change could make it more difficult for prevention of microbiological
phrase, which we believe is clear.
drug manufacturers to replace a less contamination of drug products
Therefore, we do not believe that the
effective, quality control-based purporting to be sterile.
suggested change is necessary.
(Comment 7) One comment stated inspection and test method with a more (Comment 10) Four comments
that § 211.67(a) should not apply to the modern and effective quality audit objected to the requirement in existing
production of medical gases because method. The comment stated that § 211.94(c) because it requires
most medical gas manufacturing lines because the bioburden of dry items such
depyrogenation of components based on
are product-specific, closed systems that as vials and stoppers is often
the nature of the drug and does not take
are not subject to cleaning or sanitation heterogeneous, improved assurance of
into account the fact that some
as part of an established periodic cycle, this quality attribute is better achieved
containers and closures are inherently
but instead are specially cleaned to be through the audit, selection, and control
nonpyrogenic, have been qualified not
‘‘oxygen ready’’ and carefully handled by the manufacturers of these items.
This comment maintained that to require active depyrogenation, or do
in accordance with established not require depyrogenation because of
procedures. The comment maintained knowledge of and control over the
manufacturing processes for containers handling procedures. Three of the
that additional cleaning efforts beyond comments proposed that in addition to
the initial cleaning regimen and closures might fall short of
justifying that those products do not the nature of the drug, the drug’s
substantially increase the risk of manufacturing process be included as a
introducing contaminants into the have a ‘‘potential for contamination.’’
factor in determining when containers
system. Therefore, the comment stated, (Response) We decline to adopt the and closures must be sterilized and
it is not necessary to require cleaning of recommended change to § 211.84(d)(6) processed to remove pyrogenic
equipment at ‘‘appropriate intervals’’ for from ‘‘that is liable to microbial properties. Two of the comments
medical gas manufacturing. The contamination’’ to ‘‘prone to recommended that the requirement to
comment suggested that, alternatively, it microbiological contamination.’’ We
validate depyrogenation processes be
might be appropriate for the agency to believe that our proposed change to
limited to containers and closures that
state that medical gases may represent ‘‘with potential for microbiological
are made nonpyrogenic by a designated
unique circumstances that will be contamination’’ clarifies our
depyrogenation process (thus excluding
reflected in a separate guidance. longstanding interpretation of the
inherently nonpyrogenic containers and
(Response) We decline to exempt regulation that each lot of component,
medical gases from the requirements of drug product container, or closure that closures from the regulation).
§ 211.67(a) as recommended because is susceptible to contamination must (Response) We decline to adopt the
this would exceed the scope of our undergo microbiological testing before suggested revisions because they go
proposed change to clarify that use. Therefore, we have revised beyond the scope of our proposed
sterilization is appropriate for sterile § 211.84(d)(6) to refer to components, change to require validation of
drug products and would instead focus containers, or closures ‘‘with potential depyrogenation processes and instead
on whether there is any need for for microbiological contamination’’ as focus on the need for depyrogenation
periodic cleaning of medical gas proposed. itself.
4. Inclusion of Bioburden Testing in In- 5. Control of Microbiological systems normally associated with
Process Testing (§ 211.110(a)) Contamination (§ 211.113(b)) process validation. The comment
Section 211.113(b) states that further claimed that media fills do not
Section 211.110(a) requires that validate aseptic processing because they
appropriate written procedures,
written procedures be established and measure only detectable micro-
designed to prevent microbiological
followed that describe in-process organisms and do not verify that no
contamination of drug products
controls and tests or examinations to be micro-organisms exist. The comment
purporting to be sterile, must be
conducted on samples of in-process established and followed. The version of stated that although aseptic processing
materials of each batch of a drug § 211.113(b) amended by this final rule cannot be validated, a state of control
product. The regulation specifies five further stated: ‘‘Such procedures shall can be established, ensuring that the
control procedures that must be include validation of any sterilization aseptically produced drug consistently
established, where appropriate, to process.’’ We proposed to substitute ‘‘all meets its specifications and quality
monitor the output and to validate the aseptic and sterilization processes’’ for attributes. The comment recommended
performance of manufacturing processes ‘‘any sterilization process.’’ As noted in that rather than validation of aseptic
that may be responsible for causing the preamble of the direct final rule, processes, § 211.113(b) require ‘‘a
variation in the characteristics of in- even before we issued the now-replaced formalized quality risk management and
process material and the drug product. guidance on ‘‘Sterile Drug Products control strategy for aseptic processes to
We proposed to add bioburden testing Produced by Aseptic Processing’’ in provide assurance of requisite and
to this list (which is not all-inclusive) 1987, industry routinely conducted continued process capability and
because testing for bioburden is validation studies (often referred to as product quality.’’
standard industry practice for in-process media fills) that substituted One comment stated that although
materials and drug products that are microbiological media for the actual media fills can evaluate an aseptic
produced by aseptic processing. product to demonstrate that its aseptic process, they cannot be considered to
processes were validated (72 FR 68064 validate the process. The comment
(Comment 11) Three comments recommended that we either not adopt
objected to the addition of bioburden at 68066). The proposed change was
intended to clarify existing practice and the proposed requirement to validate
testing to § 211.110(a). One comment aseptic processes or provide more
objected to the inclusion of any specific to harmonize § 211.113 with Annex 1 of
the EU CGMPs. clarity on what is expected for
test and suggested that specific tests be validation of aseptic processes.
(Comment 12) Several comments
addressed in agency guidance. One Similarly, another comment
objected to the proposed change to
comment stated that bioburden testing § 211.113(b) on the basis that aseptic recommended that we not revise
is not conducted at the same time as processing cannot be validated. One § 211.113(b) as proposed unless we
other tests specified in § 211.110(a) and comment stated that validation of clarify that more than media fills are
is not an in-process test or control aseptic processing technically cannot be required to validate an aseptic process.
because it does not yield immediate done, although the manufacturer can The comment stated that a well-
results that allow for process ensure tight control over the process. controlled, robust process is required for
adjustment. The comment stated that it One comment stated that aseptic aseptic processes and that once a state
would be more appropriate to address processing simulations demonstrate the of control has been established for the
bioburden testing in § 211.84. One capability of a facility, equipment, and process, media fills can be useful in
comment suggested that because operational controls to provide a confirming the state of control.
§ 211.110 covers the sampling and minimal microbial contamination rate (Response) Although we acknowledge
testing of all in-process materials and in a single event, but they cannot that aseptic process validation does not
drug products, adding bioburden testing predict the outcome of a similar process provide absolute assurance of product
as a mandatory control procedure could performed at a different time. The sterility, we do not agree that aseptic
expand current industry validation comment maintained that to consider processes cannot be validated.
procedure and produce diversity among aseptic processing to be validated Validation of aseptic processes, which is
the industry and regulators on the overstates the ability to measure and a common practice throughout the
circumstances in which validation of control the process and could be pharmaceutical industry, means
bioburden testing is appropriate. interpreted as approval to relax the establishing documented evidence that
controls necessary for its success. The provides a high degree of assurance that
(Response) We do not agree with the a particular process will consistently
comment recommended that
comments. As stated in the direct final produce a product meeting its
§ 211.113(b) be revised to require
rule, testing for bioburden is an predetermined specifications and
validation of ‘‘all sterilization/
important in-process control, quality attributes. Media fills, together
depyrogenation processes’’ and to direct
particularly for drug products that are that aseptic processes ‘‘be subjected to with operational controls,
produced through aseptic processing. periodic assessment to demonstrate the environmental controls, and product
Section 211.110(a) provides flexibility capability of the control strategy to sterility testing, provide a sufficient
to manufacturers so that they need only adequately support end product level of assurance that drugs purported
conduct bioburden testing where the sterility.’’ to be sterile are in fact sterile.
testing is appropriate to assure batch One comment stated that there is (Comment 13) One comment
uniformity and drug product integrity. currently no means to comply with the suggested adding a definition of aseptic
We believe that manufacturers proposed requirement to validate processing to part 210.
understand for which types of drug aseptic processes. The comment (Response) We do not believe that it
products, and at what point in the maintained that the microbiological and is necessary to define aseptic processing
manufacturing process for these drugs, decontamination methods used in in the regulation. The Aseptic
bioburden testing is appropriate. aseptic processing lack the sensitivity, Processing Guidance makes it clear to
Accordingly, we have added bioburden recoverability, and accuracy of the manufacturers what aseptic processing
testing to § 211.110(a). physical and chemical measurement entails.
(Comment 14) One comment considered a good manufacturing E. Verification by a Second Individual
requested confirmation that it is practice. Therefore, we proposed to The current CGMP regulations
acceptable to follow the current FDA delete the reference to the use of include several provisions requiring that
guidance and use media fills to meet the asbestos-containing filters from § 211.72 certain activities be performed by one
requirement to validate aseptic and to delete the reference to asbestos person and checked as specified by a
processes. filters from the definition of ‘‘nonfiber- second person.
(Response) As stated in the preamble releasing filter’’ in § 210.3(b)(6). • Section 211.101(c) requires that: (1)
to the direct final rule and reiterated (Comment 16) Two comments stated Each container of component dispensed
previously in this document, that the regulations should state that the for use in manufacturing be examined
manufacturers can follow the use of asbestos filters is prohibited. One by a second person to assure that it was
recommendations in the Aseptic comment stated that if asbestos- released by the quality control unit, (2)
Processing Guidance to comply with containing filters are in fact available the weight or measure is correct as
CGMP requirements for aseptic and the proposed changes were
processing, including validation. stated in the batch production records,
interpreted as permitting their use, this and (3) the containers are properly
However, as with any guidance, the might pose a risk to patients.
Aseptic Processing Guidance is not identified.
(Response) We agree with the • Section 211.101(d) requires that
binding on industry or the agency, and comments. Therefore, in addition to
manufacturers may use an alternative each component be added to the batch
deleting the reference to asbestos- by one person and verified by a second
approach to achieve compliance if the containing filters in § 210.3(b)(6), we
approach meets the requirements of the person.
have revised the last sentence of • Section 211.103 requires that
act and FDA regulations. § 211.72 to state that the use of an
(Comment 15) One comment sought specified yield calculations be
asbestos-containing filter is prohibited. performed by one person and
clarification that the requirement to
(Comment 17) One comment independently verified by a second
validate aseptic processing would not
recommended that we clarify the second person.
inhibit implementation of novel
sentence in proposed § 211.72, which • Section 211.182 requires the
technologies recommended by the
stated: ‘‘Fiber-releasing filters may not persons performing and double-
International Conference on
be used in the manufacture, processing, checking the cleaning and maintenance
Harmonisation of Technical
or packing of these injectable drug of major equipment to date and sign or
Requirements for Registration of
products unless it is not possible to initial equipment logs indicating that
Pharmaceuticals for Human Use (ICH)
manufacture such drug products the work was performed.
in the ICH Q8, Q9, and Q10 guidances,
or other innovative approaches in these without the use of such filters.’’ The • Section 211.188(b)(11) requires that
areas. comment recommended that this batch production and control records
(Response) We do not believe that the sentence be revised to state as follows: include identification of the persons
requirement to validate aseptic ‘‘Fiber-releasing filters may be used performing and directly supervising or
processing will interfere with the when/where it is not possible to checking each significant step in the
implementation of new technologies manufacture such drug products operation.
either as part of following ICH without the use of such filters.’’ When we amended the CGMP
recommendations or as part of other (Response) We agree with this regulations in 1978, we established
efforts to meet CGMP requirements. As proposed change and have revised § 211.68, which provides that automatic,
stated in section I of this document, we § 211.72 accordingly. mechanical, or electronic equipment or
have always attempted to balance the (Comment 18) Four comments other types of equipment, including
need for easily understood minimum recommended revising the following computers, or related systems that will
CGMP standards with the desire to provision in proposed § 211.72: ‘‘If use perform a function satisfactorily, may be
encourage innovation and the of a fiber-releasing filter is necessary, an used in the manufacture, processing,
development of improved additional nonfiber-releasing filter of packing, and holding of a drug product,
manufacturing technologies. We are 0.22 micron maximum mean porosity subject to the following requirements:
confident that industry can meet the (0.45 micron if the manufacturing • Equipment is routinely checked
requirement to validate aseptic conditions so dictate) shall according to a program designed to
processing with no adverse impact on subsequently be used to reduce the assure proper performance,
technological innovation in drug content of particles in the injectable • Changes to records are made only
product manufacturing. drug product.’’ Each of these comments by authorized personnel,
stated that it is technically more • Input and output are checked for
D. Asbestos Filters accurate to describe a filter in terms of accuracy, and
As stated in the preamble to the direct its nominal pore size rating than its • Appropriate backup of data is
final rule, we need to update our mean porosity. One comment stated that maintained.
regulations on filters used in processing the filter pore size standard of 0.22 In the preamble to the 1978 final rule,
liquid injectable products. The version micron is outdated and should be we stated that the verification
of § 211.72 amended by this final rule changed to 0.2 micron. requirements in § 211.101 for charge-in
required manufacturers, before using an (Response) These suggested technical of components when automated systems
asbestos-containing filter, to submit changes are consistent with statements are used would be met if a person
proof to FDA that an alternative in our guidances for industry (e.g., the verified that the automated system was
nonfiber-releasing filter will, or is likely Aseptic Processing Guidance) working properly (43 FR 45014 at
to, compromise the safety or concerning filters. Therefore, we have 45051, September 29, 1978). Thus, in
effectiveness of the product. However, revised § 211.72 to require that if use of this situation, the first individual is
we are not aware that asbestos filters are a fiber-releasing filter is necessary, an replaced by a machine or other
currently commercially manufactured additional nonfiber-releasing filter automated process, and only one person
for pharmaceutical use or are used in having a maximum nominal pore size is necessary to verify that the automated
drug production, and their use is not rating of 0.2 micron be used. system is functioning as intended.
Because we have received questions revision. Two comments suggested that existing requirements in this regard, but
about the performance and checking the revised regulation did not only to clarify our longstanding
requirements in §§ 211.101(c) or (d), accommodate the accepted use of interpretation and policy for these
211.103, 211.182, or 211.188(b)(11) validated computerized drug production requirements. We note that the same
when the operations are performed by and control systems. We declined to basic considerations apply in this regard
automated equipment, such as the change the revision as proposed, stating today as we expressed in the 1995 final
widespread and increasing use of our belief that the wording in the rule. Although increasingly
computer-controlled operations, we revised rule adequately encompasses sophisticated controls and safeguards
proposed to revise these sections. We the use of these systems (60 FR 4087 at have been implemented for some
proposed to amend these regulations to 4089). automated systems, our policy has been
indicate that when automated Two comments on the 1991 proposal that some degree of human oversight,
equipment is used to perform certain questioned the need for human supervision, verification, monitoring, or
operations, only one person is needed to verification of operations that are checking is still necessary to verify
verify that the automated equipment is performed by validated computer proper performance as part of assuring
functioning adequately. systems. The comments listed other the identity, strength, quality, and
Correspondingly, proposed § 211.68(c) regulations that were not the subject of purity of drug products. For suitably
stated that automated equipment used the proposed rule that required more validated automated systems, even with
for performance of operations addressed than one person to verify certain real time alarms, it is still necessary for
by §§ 211.101(c) or (d), 211.103, manufacturing operations, apparently to a human to verify that the systems are
211.182, or 211.188(b)(11) can satisfy show that additional personnel would operating as planned and to monitor for
the requirements included in those be needed to comply with proposed abnormalities. We agree that the level,
sections for the performance of an § 211.68. We noted in the 1995 final rule nature, and frequency of such human
operation by one person and checking that the revisions to § 211.68 do not verification will vary depending on the
by another person if such equipment is impose any specific personnel level of automation used as well as the
used in conformity with § 211.68 and requirements. We also noted that the nature of the system and controls, and
one person verifies that the operations agency is aware that computers are the manufacturer has the flexibility and
addressed in those sections are subject to malfunctions, some of which responsibility to determine what is
performed accurately by such could possibly result in the loss of suitable and necessary. Contrary to the
equipment. We stated in the preamble of critical information regarding the comments, we believe that
the direct final rule that these revisions manufacturing process or a serious manufacturers can conduct human
would clarify our longstanding policy production error and the possible verification of automated operations in
that verification by a second individual distribution of an adulterated product. conjunction with the use of PAT in drug
may not be necessary when automatic Therefore, we stated that while production.
equipment is used under § 211.68. increasingly sophisticated system For these reasons, we continue to
safeguards and computerized believe that human verification is
1. General Comments on Verification monitoring of essential equipment and necessary to ensure that automated
(Comment 19) One comment stated programs help protect data, no systems are functioning properly.
that validated, automated systems automated system exists that can (Comment 20) One comment stated
equipped with real time alarms that do completely substitute for human that many current biotech processes
not require any human intervention oversight and supervision. We further include component additions and
should not require human verification. indicated that while the degree of deletions in a continuous or periodic
Another comment stated that such verification is left to the manufacturer’s manner over long periods of time. The
systems should not require human discretion, the exercise of such comment stated that there would be no
verification with each use and, when discretion under § 211.68 requires the added value in requiring a manual
human verification is needed, the level use of routine accuracy checks to verification of this component
of verification required should be provide a high degree of assurance that management scheme in a fully
consistent with the level of automation input to and output from a computer or automated scenario.
used. Both of these comments related system are reliable and accurate. (Response) For the reasons stated in
maintained that requiring operator We stated our intent that each our response to comment 19, we believe
verification of automated, validated manufacturer exercise reasonable that some degree of human oversight,
equipment under §§ 211.68(c), judgment based on a variety of factors, supervision, verification, monitoring, or
211.101(c)(3) and (d), 211.103, and including, but not limited to, the checking is a necessary part of CGMP
211.188(b)(11) might hinder the complexity of the computer or related for such processes and that there is
implementation of process analytical system, in developing a method to added value in having greater assurance
technology (PAT) in the drug industry. prevent inaccurate data input and that the automated systems are
(Response) In the Federal Register of output (60 FR 4087 at 4089). operating properly as intended. We do
February 12, 1991 (56 FR 5671) (the The December 4, 2007, direct final not expect that each individual
1991 proposal), we issued a proposed rule and companion proposed rule were component change must be witnessed in
rule in part to amend § 211.68 to add intended to amend the regulations person, but rather that a suitable system
what is now the third sentence of involving second-person checks only to of human oversight be established and
§ 211.68(b): ‘‘The degree and frequency clarify our longstanding policy that followed to effectively verify that the
of input/output verification shall be verification by a second individual may automated processes are indeed
based on the complexity and reliability not be necessary when automatic operating correctly in the performance
of the computer or related system.’’ This equipment is used under § 211.68, and of these operations.
revision was adopted as part of the final that in such situations only one person (Comment 21) One comment
rule issued on January 20, 1995 (60 FR is needed to verify that the automated maintained that our statement in the
4087) (the 1995 final rule). equipment is functioning adequately. preamble of the direct final rule that the
In the 1995 final rule, we responded The amendments were not intended to verifying individual may be, but is not
to several comments on the proposed either add to or detract from any required to be, the operator is a
contradiction of the CGMP regulations, automated equipment for a processing laboratory testing operations. However,
which require (in § 211.25(a)) that all step is functioning properly; we did not when automated equipment is used to
individuals have the education, propose deleting all human verification perform a laboratory test, typically a
training, and experience to enable them of the step. In addition, we disagree person initiates the test and ensures that
to perform their assigned functions. The with the comment’s apparent contention the correct equipment is used and that
comment asked why the agency would that no human signature would be it operates properly. In this situation,
allow an untrained operator to perform needed for issuance of electronic batch one person assists in or oversees the
a sole verification of a critical step if an production and control records. If such performance of the laboratory test and a
automated system is used and records are generated and issued second person reviews the records for
recommended that we retract the noted electronically as part of an automated accuracy, completeness, and
preamble statement. system, a person must verify that the compliance with established standards.
(Response) The comment incorrectly correct records were issued and that Thus, the use of equipment to perform
concluded that allowing the verifying they are still accurate and complete. We laboratory tests, though permissible, is
individual to be a person other than the believe it is clear that § 211.188(a) not a situation in which automated
operator would thereby allow an requires only one check for accuracy, equipment (rather than a person)
untrained individual to perform the with date and signature (which could be performs an operation and a person
function of verifying a critical step. electronic), and that it does not require verifies that performance, which is the
Section 211.25(a) requires each person a separate second check of this step. situation addressed in revised
performing an assigned function to have Therefore, no changes to § 211.188(a) § 211.68(c). Therefore, it would not be
the education, training, and experience, are necessary or appropriate. appropriate to include a reference to
or any combination thereof, to enable (Comment 23) Three comments § 211.194 (or to § 211.194(a)(8)
that person to perform the function. addressed second-person verification in specifically) in revised § 211.68(c).
Thus, any person, whether the operator § 211.194. Section 211.194(a) requires
or not, who performs such a verification that laboratory records include complete 2. Automatic, Mechanical, and
step would necessarily be required to data derived from all tests necessary to Electronic Equipment (§ 211.68)
have the knowledge, training, and assure compliance with established (Comment 24) One comment stated
experience needed to perform that specifications and standards as that § 211.68 is no longer in line with
function. Therefore, our preamble specified in that subsection. Section the technological improvements of the
statement does not conflict with the 211.194(a)(7) requires that laboratory past 30 years and with the increasing
regulations. records include the initials or signature knowledge of computer validation by
(Comment 22) One comment stated of the person who performs each test industry and regulators. The comment
that the proposed changes regarding and the date(s) the tests were performed. recommended that § 211.68 be aligned
second person verification should be Section 211.194(a)(8) requires the with 21 CFR 820.70(i), section 5.4 of the
extended to include § 211.188(a), which initials or signature of a second person ICH Q7A guidance entitled ‘‘Good
requires the preparation of batch showing that the original records have Manufacturing Practice Guidance for
production and control records that been reviewed for accuracy, Active Pharmaceutical Ingredients,’’ and
include an accurate reproduction of the completeness, and compliance with the Pharmaceutical Inspection
appropriate master production or established standards. Two of the Cooperation Scheme’s Annex 11 on
control record, checked for accuracy, comments stated that the principle computerized systems.
dated, and signed. The comment stated behind the proposed second-person (Response) We decline to adopt the
that when there is only one signature verification revisions should be suggested revisions because they exceed
needed, but the system is automated, it extended to § 211.194 to include the scope of our proposed revision of
would also follow that no human checking laboratory records involving § 211.68, which only addressed second-
signature or signature equivalent would automated laboratory equipment. The person verification of operations
be necessary, such as in issuance of a first comment recommended revising performed by automated equipment. We
batch record under § 211.188(a), when § 211.194 generally. The second might consider revising other provisions
the record is electronic. The comment comment specifically recommended of § 211.68 as part of a future
also stated that in this case, it is that § 211.194(a)(8) be revised to add rulemaking to update the CGMP
impossible to check the pages for a true that if laboratory tests have been regulations and make them consistent
and accurate copy. The comment performed by automated equipment with international CGMP provisions.
recommended revising § 211.68(c) to under § 211.68, the laboratory record (Comment 25) One comment
include § 211.188(a) in the listing of need only include the identification of recommended that instead of our
sections affected and to state that there one person conducting the review of the proposed changes to § 211.68(c) and
could be single performance verification tests performed by the automated other regulations concerning second-
under § 211.188(a). system. The comment also asked that person verification, we revise
(Response) We do not agree with the § 211.194(a)(8) be added to the list of § 211.68(a), which permits the use of
recommended changes to § 211.188(a), sections affected in § 211.68(c). The automatic, mechanical, or electronic
which would eliminate any human third comment stated that the failure to equipment in the manufacture,
verification of the records. As include § 211.194(a)(7) and (a)(8) in the processing, packing, and holding of
previously stated, we are clarifying in proposed revisions implies that the use drug products. The comment stated that
this rule that the checking of automated of automated systems to perform or the wording of our proposed changes
equipment by one person can satisfy the check testing is not allowed. only allows for actions to be performed
requirements of those regulations that (Response) We decline to include by automated equipment and checked
address the performance of a step by § 211.194 among the sections by a person, which would prevent the
one person and the verification of the enumerated in § 211.68(c) concerning introduction of automated systems to
step by a second person. Our proposal second-person verification of operations check operations performed by a person.
regarding verification of operations was performed by automated equipment. We The comment also stated that our
intended to make clear that only one acknowledge that automated equipment proposed changes would still require
person is needed to verify that may be used to conduct certain the involvement of at least one person
in each of these circumstances and (Comment 27) One comment supervised, or checked by a
prevent the use of a controlled system suggested revising § 211.68(c) to state computerized system, an acceptable
or systems that both perform and that automated equipment can satisfy means of complying with the
independently verify the relevant the requirements for verification of identification requirements in
operations. One comment suggested that operations addressed by the listed § 211.188(b)(11) would consist of
rather than our proposed revisions, the sections as follows: (1) If such unit conformance to certain requirements.
desired clarification concerning operation is fully automated, no manual The comment maintained that CPG
automated equipment and second- verification is necessary and (2) if there 425.500 gives companies the flexibility
person checks would be better achieved is an operator for the automated to automate not only the performance of
by adding to § 211.68(a) the following equipment, the verifying individual may critical actions but also the supervision
sentence: ‘‘Automated equipment can be, but is not required to be, the and checking of these actions if it is
satisfy the requirements for the operator. The comment gave several shown that the efficacy of these controls
performance of an operation by one reasons for this change: would be at least equivalent to the level
person and/or checking by another • Automated, validated systems of efficacy if the verification were done
person.’’ equipped with real-time alarms that do by a second person. The comment stated
(Response) We do not agree with the not require any human intervention that this flexibility should be extended
recommended change. The proposed should not require human verification to all CGMP sections in which a
rule simply clarified our longstanding because § 211.68(a) adequately verification is requested. The comment
position that only one human check is addresses the maintenance and therefore asked that § 211.68(c) be
necessary to verify a processing step verification of performance of these revised to state that automated
performed by automated equipment. systems. equipment used for performance of
The suggested revision of § 211.68(a), • The need and type of verification operations addressed by §§ 211.101(c) or
however, would allow manufacturers to required should be consistent with the (d), 211.103, 211.182, or 211.188(b)(11)
rely solely on automated equipment to level of automation used. For example, can satisfy the requirements included in
verify the human performance of certain operations that are not fully automated those sections for the performance of an
processing steps and allow automated and require operator participation may operation by one person and checking
equipment to both perform and check serve as verification of the operator’s by another person if such equipment is
operational steps, which would activities, while fully manual operations used in conformity with § 211.68 and
constitute a significant change from the would require a second human one person either performs the
current regulations. As stated in our verification. operations addressed in those sections
response to comment 19, we believe that • As proposed, § 211.68(c) might
under the control of the automated
human verification of certain processing hinder the adoption of PAT (e.g., there
equipment or verifies that these
steps, even when those steps are would be no value added by manual
operations are performed accurately by
performed by automated equipment, is verification when components are
such equipment.
still necessary. charged in a fully automated manner
(Comment 26) One comment stated according to a validated algorithm). (Response) We do not agree with the
that although proposed § 211.68(c) (Response) As stated in our response comment’s apparent interpretation of
implies that the automated equipment is to comment 19, we do not agree with CPG 425.500 that the CPG allows for
doing the work and a person can verify the contention that no human elimination of human oversight. The
that the work is done, there are cases in verification is necessary when fully purpose of the CPG is to explain what
which a person does the work and automated systems are used, and we constitutes ‘‘identification’’ of persons
automated equipment might be able to therefore decline to make these in batch records under § 211.188(b)(11)
verify the person’s work. The comment requested changes to § 211.68(c). We when automated systems are used for
cited as an example the case in which also do not believe that § 211.68(c) will various functions. The CPG states that
an automated system scans the bar hinder the adoption of PAT. As stated when an automated system is used to
codes of ingredients and equipment to in the preamble to the direct final rule, perform, directly supervise, or check
ensure that the ingredient is correct for we agree that if there is an operator for significant steps in the production of a
use with the equipment for that step in the automated equipment, the verifying drug, the identification requirements in
the process, but the physical addition of individual may be, but is not required § 211.188(b)(11) are met if there is
the ingredient is by the human operator to be, the operator. However, § 211.68(c) documentation that the system contains
(followed by the automated system does not require that the verifying adequate checks (and documentation of
scanning). The comment recommended, individual be the operator, and we do the performance of the system itself),
therefore, that § 211.68(c) be modified to not believe that it is necessary that the validation of the system’s performance,
allow both the automated system and provision explicitly state that the and recording of specific checks in
the person to do either the performance verifying individual need not be the batch records (including initial,
or the verification tasks for the operator. branching, and final steps). These
operations addressed by §§ 211.101(c) or (Comment 28) One comment stated conditions for applying the
(d), 211.103, 211.182, 211.188(b)(11), or that the proposed revision of identification requirements to steps
211.194(a)(8), or a single performance § 211.68(c), when applied to using automated equipment involve the
verification in the case of § 211.188(a). § 211.188(b), might be more restrictive responsibilities of persons. For example,
(Response) We acknowledge that it than FDA’s position in Compliance a person, rather than automated
might be possible to design an Policy Guide (CPG) Sec. 425.500, equipment, is needed to record these
automated system to verify operations Computerized Drug Processing; checks of production steps in batch
performed by humans, but as stated in Identification of ‘‘Persons’’ on Batch records. Therefore, contrary to the
our response to comment 19, we Production and Control Records comment’s implication, the CPG does
continue to believe that some human (formerly CPG 7132a.08). CPG 425.500 not state that human oversight is
verification of the processing steps states that when significant steps in the unnecessary when an automated system
performed by an automated system is manufacturing, processing, packing, or is involved in the performance,
necessary. holding of a batch are performed, supervision, or checking of production
steps. All automated systems require have revised § 211.68(c) to clarify that 4. Verification of Components Added to
some level (commensurate with the automated equipment can be used to the Batch (§ 211.101(d))
complexity and risk inherent in the perform an operation when the Proposed § 211.101(d) would have
system) of human oversight or checking performance is checked by a person required that each component be either
for expected performance at appropriate provided that ‘‘such equipment is used added to the batch by one person and
intervals. Therefore, we decline to in conformity with this section verified by a second person or, if the
revise § 211.68(c) as recommended. [§ 211.68] and one person checks that components are added by automated
(Comment 29) One comment, the equipment properly performed the equipment under § 211.68, only verified
although supportive of the proposal to operation.’’ by one person.
allow initial activities to be performed
3. Verification of Weighing, Measuring, (Comment 32) One comment stated
by automated equipment, objected to
or Subdividing Operations (§ 211.101(c)) that eliminating a double check for
requiring that the output of an
adding materials to a batch is
automated and adequately validated Section 211.101 concerns charge-in of problematic because an error in those
activity be checked for accuracy by a components. Proposed § 211.101(c) operations would be difficult to detect
person. The comment maintained that stated, in part, that if the weighing, and might not be discovered before the
the act of having validated software and measuring, or subdividing operations product is distributed, which could
its related processes itself constitutes an for components are performed by
independent check that operations are result in patient injury and product
automated equipment under § 211.68, recall. The comment recommended
being performed accurately and argued only one person is needed to ensure that
that this is more reliable than any deleting or modifying the ability to use
the requirements in § 211.101(c)(1), a sole verifier for operations involving
contemporaneous check by a person. (c)(2), and (c)(3) are met.
The comment therefore asked that addition of materials.
(Comment 30) One comment (Response) The comment appears to
§ 211.68(c) be changed to state that proposed broadening § 211.101(c) to
independent checks may consist of suggest that we proposed to eliminate
clarify that the weighing, measuring, the requirements concerning
contemporaneous analysis and and subdividing operations could be
verification by a second person verification that appropriate
either performed by automated components were added to a batch. The
following completion of the activity; or, equipment or checked by automated
where the automated process has been revisions we are adopting do not
equipment after being performed eliminate the requirement to verify
validated to a high degree of confidence, manually.
the prior validation can satisfy this performance in § 211.101(d); they
(Response) We decline to make this simply codify our longstanding policy
requirement and a second person’s suggested change for the reasons
check may then consist of verifying the that components may be added either by
provided in response to comments 19 a person or by suitable automated
validated status of the equipment and
and 25. Revised § 211.101(c) only equipment. The addition of components
processes.
(Response) We do not agree with the permits human checking of weighing, still must be checked by a person.
suggested change. Although we agree measuring, and subdividing operations (Comment 33) One comment stated
that it is an important part of process performed by automated equipment; we that under the proposed change to
controls to ensure the validated status of did not propose to allow automated § 211.101(d), if a validated system
equipment and processes even before checking of these operations. We performs a function, it is acceptable for
they are used, we do not believe that continue to believe that human one person to verify that action, but if
verifying this validated status can verification of these processing steps is an automated system prompts an
satisfy the requirement for checking the necessary. operator to perform a function, a second
actual performance of automated (Comment 31) One comment stated person would be required to confirm the
equipment. However, we believe that that with respect to medical gases, there proper execution of the action. The
the requirement in proposed § 211.68(c) is no measurement of components to be comment recommended changing
that one person ‘‘verifies that the dispensed for manufacturing that needs § 211.101(d) to state that each
operations * * * are performed to be double-checked to ensure that the component must be added to the batch
accurately’’ by automated equipment right quantity of the right component by one person and verified by a second
may have led some comments to believe was added, because transfers of pure person, ‘‘unless the components are
that we were requiring a more specific gases are within product-specific added by automated equipment under
and detailed repetitive type of check systems. However, the comment stated, § 211.68, in which case verification can
than we intended. When automated with respect to gas mixtures, it is be performed by one person.’’
equipment is used for operations appropriate to have a verification of (Response) We decline to accept the
addressed by revised § 211.68(c) in hook-ups as different components are suggested change because we do not
conformance with § 211.68, the person added unless there is subsequent purity believe that it constitutes a substantive
doing the checking must verify that the testing for each component. difference from the language of
automated equipment is functioning (Response) We decline to exempt proposed § 211.101(d). It is irrelevant
properly and that the operations are single gas filling operations from certain whether use of a particular automated
reliably performed in the intended requirements of § 211.101(c) as system for component charge-in
manner. As discussed in the response to recommended because such a change requires an operator to perform a related
comment 19, the nature and frequency would exceed the scope of our proposed function; in either case, verification of
necessary for such verification will vary change to § 211.101(c), which only the charge-in operation(s) must be
depending on the level of automation addressed human checking of weighing, performed by a person.
used as well as the nature of the system measuring, and subdividing operations (Comment 34) One comment
and controls. We do not expect that it performed by automated equipment. We recommended changing § 211.101(d) to
will normally be necessary, under might consider in a future rulemaking specify that the weighing, measuring, or
§ 211.68(c), for a person to repeat all of whether it is appropriate to exempt subdividing operations might be
the automatic calculations by hand to medical gases from certain requirements performed by automated equipment or
ensure their accuracy. Therefore, we of § 211.101(c). checked by automated equipment after
being performed manually. The but § 211.103 also permits the use of (Response) The comment appears to
comment also stated that in many other approaches, including verification suggest that we proposed to eliminate
instances, the verification by a person of that automated equipment functioned the requirements concerning
actions performed by automated properly while performing yield verification that equipment was
equipment can only be done on the calculations. appropriately cleaned and maintained.
basis of outputs from the equipment. As (Comment 36) One comment The revisions we are adopting do not
an example, the comment stated, when reiterated the views expressed in its eliminate the requirement to verify
the introduction of components in a comments on the CGMP for medical performance in § 211.182; they simply
liquid production line is fully gases draft guidance. Thus, the codify our longstanding policy that
automated, there is no possibility for the comment requested that the equipment may be cleaned and
operator to check that the correct requirements for yield calculation in maintained either by a person or by
amount of materials was incorporated § 211.103 not be applied to medical suitable automated equipment. Cleaning
into the batch other than by relying on gases because of the atmospheric-gas- and maintenance of equipment must
information given by the same separation and cylinder-filling processes still be checked by a person.
automated equipment. The comment associated with medical gases. In further (Comment 38) One comment stated
stated that in that case, the verification support of its position, the comment that operations addressed by §§ 211.182
would consist of confirming that the referred to an FDA publication (Human and 211.188(b)(11) are often performed
component’s incorporation process was Drug CGMP Notes, vol. 5, no. 2, June using semi-automated equipment that
completed without errors or alarms. 1997) in which the agency stated that it requires an operator to select the correct
(Response) We decline to make this would propose to revise the CGMP menu. The comment stated that major
suggested change for the reasons stated regulations to exempt medical gases pieces of equipment such as ‘‘Clean in
in response to comments 19 and 25. from the requirements for yield Place’’ (CIP) skids and vial washers
Revised § 211.101(d) only permits reconciliation. often require the operator to select the
human checking of component appropriate process menu before the
(Response) We decline to exempt
additions performed by automated execution of the actual automated cycle
medical gases from the requirements for
equipment; we did not propose to allow by the equipment’s controller. The
yield calculation in § 211.103 as
automated checking of component comment asked whether, when operator
recommended because this would
additions performed by humans. In the input is necessary to select but not
exceed the scope of our proposed
example given in the comment, human perform an operation, the signature of
change to § 211.103, which addressed
verification that components were the operator selecting the menu is
only human checking of yield
properly added to the liquid production required in cases when there is a second
calculations performed by automated
line by the automated equipment would signature that verifies the performance
equipment. We might consider in a
be needed to ensure that the equipment of the cycle. One comment requested
performed properly. We continue to future CGMP rulemaking whether it is that we verify in § 211.182 or the
believe that human verification of this appropriate to exempt medical gases preamble of the final rule that a single
processing step is necessary. from certain requirements of § 211.103. verification remains sufficient when
In addition, we might consider automated but portable cleaning skids
5. Calculation of Yield (§ 211.103) providing specific recommendations to are used.
We proposed, in § 211.103, to require medical gas manufacturers to help them (Response) We do not believe that
that calculations of actual yields and comply with the requirements for initiation of the automated cleaning
percentages of theoretical yields be calculating yields in the course of cycle by a human operator constitutes
performed by one person and finalizing the draft guidance on CGMP performance of the cleaning process for
independently verified by a second for medical gases. purposes of revised § 211.182. The
person or, if the yield is calculated by 6. Equipment Cleaning and Use Log revised regulation requires that after an
automated equipment under § 211.68, (§ 211.182) automated cleaning process (such as
be independently verified by one CIP) is completed, the human operator
person. We proposed, in § 211.182, to require must date and sign or initial the log
(Comment 35) One comment stated the persons performing and double- verifying that the equipment performed
that it is not necessary to have a person checking equipment cleaning and the automated cleaning process
recalculate a yield manually after a maintenance (or, if the cleaning and properly. The regulation does not
validated system does it automatically. maintenance is performed using require the operator to date and sign or
The comment asked that § 211.103 be automated equipment under § 211.68, initial the log simply for the initiation
revised to limit the human interaction to only the person verifying the cleaning of the automated cleaning cycle. This
data entry and data verification, but not and maintenance done by the automated approach applies to both portable
recalculation of yields if yields are equipment) to date and sign or initial equipment skids and fixed equipment.
calculated by a validated, automated the log indicating that the work was (Comment 39) One comment stated
system. A similar comment stated that performed. that in many instances, the human
§ 211.103 should be changed to state (Comment 37) One comment stated verification of an action performed by
that if the yield is calculated by that eliminating a double check for automated equipment can only be done
automated equipment, a person must cleaning equipment is problematic on the basis of outputs from the
verify the data entries, rather than because an error in those operations equipment. As an example, the
regenerate the calculations. would be difficult to detect and might comment stated, when equipment is
(Response) We do not believe that the not be discovered before the product is cleaned through CIP, the verification
recommended changes are needed or distributed, which could result in should consist of confirming that the
appropriate. Revised § 211.103 does not patient injury and product recall. The system reports the cleaning as
require that all yield calculations be comment recommended deleting or successfully completed without alarms.
repeated manually. Manual modifying the ability to use a sole (Response) What constitutes adequate
recalculation might be a suitable verifier for operations involving verification that equipment has been
approach to verifying yield calculations, equipment cleaning. properly cleaned or maintained using
automated equipment in accordance under § 211.68, the record would need meet the inspection criteria are moved
with revised § 211.182 depends on the to identify the person checking the to a quarantine area. The comment
particular circumstances. The outputs significant step performed by the stated that this practice satisfies the
from the automated equipment will automated equipment. intention that components, containers,
normally be key factors, but not (Comment 41) One comment stated and closures be inspected to ensure that
necessarily the only ones. The that § 211.188(b)(11) should be changed unacceptable assemblies are not used in
manufacturer should determine the to state that a significant manufacturing the manufacturing process.
reliability of the outputs and step could be either performed or (Response) Under revised § 211.82(b),
periodically check them. For example, it checked by automated equipment. The manufacturers of medical gases would
might be appropriate to verify that an comment stated that this approach is retain the ability to sequester and
alarm is working properly and is permitted by CPG 425.500. inspect returned valve/cylinder
successfully monitoring the equipment’s (Response) We decline to make this assemblies before refilling in accordance
critical functions. There might be other suggested change. As stated in our with the industry practice described by
ways of verifying the adequate response to comment 28, CPG 425.500 the comment. The practice described by
performance of cleaning and does not, as the comment implies, state the comment is to have the assembled
maintenance by automated equipment, that human oversight is unnecessary valve/cylinders placed in a segregated
such as by monitoring the usage of when an automated system is involved area (apparently not identified using the
cleaning supplies in a cleaning cycle or in the performance, supervision, or word ‘‘quarantine’’), examined for
conducting an independent check of the checking of production steps. To revise conformance to quality standards, and,
rinse. § 211.188(b)(11) as recommended by the if the criteria are met, immediately
(Comment 40) One comment stated comment might be interpreted as made available for refilling. This
that for most medical gas systems, permitting manufacturers to rely solely practice would meet the requirement for
routine or periodic cleaning is not on automated equipment to verify the a quarantine status if goods in such
performed because the industry is human performance of certain areas or under such a status are not
characterized by product-specific closed production steps. As stated in our acceptable for use as-is unless and until
systems that undergo an appropriate response to comments 19 and 25, we they are qualified to be suitable for use.
cleaning process before initial use. The believe that human verification of Therefore, we do not believe that the
comment stated that because of the high processing steps is still necessary. practice as described violates revised
number of batches produced on a § 211.82(b), and there is no need to
F. Miscellaneous Minor Changes Based
weekly/monthly basis in the medical exempt medical gas manufacturers from
on 1996 Proposal
gas industry, it is more appropriate to this requirement.
keep cleaning and maintenance records We proposed to make miscellaneous
minor changes to CGMP regulations to 2. Cleaning of Component Container
separate from batch records. The
clarify certain manufacturing, quality Samples (§ 211.84(c)(1))
comment maintained that although
requiring documentation of equipment control, and documentation The version of § 211.84(c)(1) amended
cleaning, maintenance, and use in requirements and to align the by this final rule stated: ‘‘The containers
individual equipment logs may be regulations with industry practice. of components selected [for sampling]
appropriate for traditional shall be cleaned where necessary, by
1. Storage of Untested Components, appropriate means.’’ We proposed to
pharmaceuticals (where key processing Drug Product Containers, and Closures
equipment may be used for multiple replace the phrase ‘‘where necessary, by
(§ 211.82(b)) appropriate means’’ with the phrase
products and lot numbers), applying
this requirement to medical gases would The version of § 211.82(b) amended ‘‘when necessary in a manner to prevent
make retrieval and management of by this final rule stated: ‘‘Components, introduction of contaminants into the
cleaning and maintenance records much drug product containers, and closures component.’’ This change was intended
more difficult. The comment added that shall be stored under quarantine until to clarify that the act of cleaning is done
use logs are not appropriate for medical they have been tested or examined, as for a particular purpose—to prevent the
gases because batch record appropriate, and released.’’ We introduction of contaminants—and
documentation provides a consecutive proposed to replace the phrase ‘‘as must be done unless cleaning is not
listing of products manufactured on appropriate’’ with the phrase necessary to prevent contamination.
each system. ‘‘whichever is appropriate’’ to eliminate (Comment 43) One comment
(Response) We decline to exempt any ambiguity in § 211.82(b) and to expressed concern that the proposed
medical gases from certain requirements emphasize that it is accepted industry change might be interpreted to require
of § 211.182 as recommended because practice to conduct some testing or validation of this prevention of
this would exceed the scope of our examination before components, drug contamination during sampling. The
proposed change to § 211.182, which product containers, or closures are comment requested that we confirm that
addressed human verification of released from quarantine. our intent is to place the contamination
cleaning steps performed by automated (Comment 42) One comment concern into the controls and
equipment. We might consider in a requested that medical gas container- procedures for sampling and into the
future CGMP rulemaking whether it is closure assemblies returned from training of staff who perform these
appropriate to exempt medical gases customers and reused be exempted from activities, rather than to require
from certain requirements of § 211.182. § 211.82(b). The comment stated that validation of the absence of
assembled cylinder/valve medical gas contamination.
7. Batch Production and Control combinations are reused and handled (Response) Revised § 211.84(c)(1)
Records (§ 211.188(b)(11)) differently than they would be at the does not require manufacturers to
Section 211.188 concerns batch time of initial receipt. The comment conduct validation studies to prove that
production and control records. stated that returned assemblies are the method of sampling prevents
Proposed 211.188(b)(11) specified that individually inspected for all critical contamination. When properly designed
when a significant step in the operation quality issues immediately before and followed, the cleaning procedures,
is performed by automated equipment filling; those assemblies that do not training, and facility and equipment
controls, along with supervisory and have a significant economic impact on of part 211 as well as § 210.3 (§ 210.3
quality unit oversight, should ensure a substantial number of small entities. does not contain information collection
compliance with § 211.84(c)(1). Section 202(a) of the Unfunded requirements). As concluded in section
Mandates Reform Act of 1995 requires IV of this document, ‘‘Analysis of
3. Editorial Changes (§§ 211.84(d)(3) and that agencies prepare a written Impacts,’’ the purpose of the final rule
211.160(b)(1)) statement, which includes an is to update the regulations to reflect
We proposed minor editorial changes assessment of anticipated costs and current practice and to harmonize
to two regulations, §§ 211.84(d)(3) and benefits, before proposing ‘‘any rule that requirements in the CGMP regulations
211.160(b)(1). The version of includes any Federal mandate that may with requirements in other regulations
§ 211.84(d)(3) amended by this final rule result in the expenditure by State, local, and with international CGMP standards.
stated: ‘‘Containers and closures shall be and tribal governments, in the aggregate, The final rule does not impose any
tested for conformance with all or by the private sector, of $100,000,000 additional requirements. Thus, because
appropriate written procedures.’’ We or more (adjusted annually for inflation) the final rule does not substantively
proposed to replace the word in any one year.’’ The current threshold revise the information collection
‘‘conformance’’ with ‘‘conformity’’ and after adjustment for inflation is $127 requirements in part 211 or add new
the word ‘‘procedures’’ with million, using the most current (2006) information collection requirements,
‘‘specifications.’’ The first sentence of Implicit Price Deflator for the Gross there is no need to conduct an analysis
the version of § 211.160(b)(1) amended Domestic Product. This rule does not under the PRA.
by this final rule stated: ‘‘Determination result in any 1-year expenditure that
would meet or exceed this amount. List of Subjects
of conformance to appropriate written
specifications for the acceptance of each The purpose of this final rule is to 21 CFR Part 210
lot within each shipment of update the codified language to reflect
current practice and to harmonize Drugs, Packaging and containers.
components, drug product containers,
closures, and labeling used in the requirements in the CGMP regulations 21 CFR Part 211
manufacture, processing, packing, or with requirements in other regulations Drugs, Labeling, Laboratories,
holding of drug products.’’ We proposed and with international CGMP standards. Packaging and containers, Prescription
to replace the word ‘‘conformance’’ with It does not impose any additional drugs, Reporting and recordkeeping
‘‘conformity’’ and the word requirements; therefore, industry will requirements, Warehouses.
‘‘appropriate’’ with ‘‘applicable.’’ We not incur incremental compliance costs
■ Therefore, under the Federal Food,
stated in the preamble to the direct final for these proposed changes.
Drug, and Cosmetic Act and under
rule that these revisions would provide V. Environmental Impact authority delegated to the Commissioner
clarity without changing the meaning or of Food and Drugs, 21 CFR parts 210
intent of these regulations. We received FDA concludes that issuing these
clarifying amendments to the CGMP and 211 are amended as follows:
no comments on these proposed
changes, and we have revised these regulations will not have a significant
impact on the human environment. PART 210—CURRENT GOOD
provisions as proposed. MANUFACTURING PRACTICE IN
Therefore, an environmental impact
IV. Analysis of Impacts statement is not required. MANUFACTURING, PROCESSING,
PACKING, OR HOLDING OF DRUGS;
FDA has examined the impacts of this VI. Federalism GENERAL
final rule under Executive Order 12866 FDA has analyzed this final rule in
and the Regulatory Flexibility Act (5 accordance with the principles set forth ■ 1. The authority citation for 21 CFR
U.S.C. 601–612), and the Unfunded in Executive Order 13132. We have part 210 continues to read as follows:
Mandates Reform Act of 1995 (Public determined that the rule does not Authority: 21 U.S.C. 321, 351, 352, 355,
Law 104–4). Executive Order 12866 contain policies that have substantial 360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264.
directs agencies to assess all costs and direct effects on the States, on the ■ 2. Section 210.3 is amended by
benefits of available regulatory relationship between the National revising paragraph (b)(6) to read as
alternatives and, when regulation is Government and the States, or on the follows:
necessary, to select regulatory distribution of power and
approaches that maximize net benefits § 210.3 Definitions.
responsibilities among the various
(including potential economic, levels of government. Accordingly, we (b) * * *
environmental, public health and safety, have concluded that the rule does not (6) Nonfiber releasing filter means any
and other advantages; distributive contain policies that have federalism filter, which after appropriate
impacts; and equity). The agency implications as defined in the Executive pretreatment such as washing or
believes that this final rule is not a order and, consequently, a federalism flushing, will not release fibers into the
significant regulatory action as defined summary impact statement is not component or drug product that is being
by the Executive order, because the rule required. filtered.
either clarifies the agency’s * * * * *
longstanding interpretation of, or VII. Paperwork Reduction Act of 1995
increases latitude for manufacturers in This final rule contains collections of PART 211—CURRENT GOOD
complying with, existing CGMP information that are subject to review by MANUFACTURING PRACTICE FOR
requirements. the Office of Management and Budget FINISHED PHARMACEUTICALS
The Regulatory Flexibility Act (OMB) under the Paperwork Reduction
requires agencies to analyze regulatory Act of 1995 (44 U.S.C. 3501–3520) (the ■ 3. The authority citation for 21 CFR
part 211 continues to read as follows:
options that would minimize any PRA). The collections of information

significant impact of a rule on small (recordkeeping requirements) in part Authority: 21 U.S.C. 321, 351, 352, 355,
entities. Because this final rule does not 211 have already been approved by 360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264.
impose any new regulatory obligations, OMB under control number 0910–0139. ■ 4. Section 211.67 is amended by
the agency believes that the rule will not The final rule amends certain sections revising paragraph (a) to read as follows:
§ 211.67 Equipment cleaning and § 211.84 Testing and approval or rejection or subdividing operations are performed
maintenance. of components, drug product containers, by automated equipment under
(a) Equipment and utensils shall be and closures. § 211.68, only one person is needed to
cleaned, maintained, and, as * * * * * assure paragraphs (c)(1), (c)(2), and
appropriate for the nature of the drug, (c) * * * (c)(3) of this section.
sanitized and/or sterilized at (1) The containers of components (d) Each component shall either be
appropriate intervals to prevent selected shall be cleaned when added to the batch by one person and
malfunctions or contamination that necessary in a manner to prevent verified by a second person or, if the
would alter the safety, identity, strength, introduction of contaminants into the components are added by automated
quality, or purity of the drug product component. equipment under § 211.68, only verified
beyond the official or other established * * * * * by one person.
requirements. (d) * * * ■ 11. Section 211.103 is revised to read
* * * * * (3) Containers and closures shall be as follows:
■ 5. Section 211.68 is amended by tested for conformity with all
§ 211.103 Calculation of yield.
adding paragraph (c) to read as follows: appropriate written specifications. In
lieu of such testing by the manufacturer, Actual yields and percentages of
§ 211.68 Automatic, mechanical, and a certificate of testing may be accepted theoretical yield shall be determined at
electronic equipment. from the supplier, provided that at least the conclusion of each appropriate
* * * * * a visual identification is conducted on phase of manufacturing, processing,
(c) Such automated equipment used such containers/closures by the packaging, or holding of the drug
for performance of operations addressed manufacturer and provided that the product. Such calculations shall either
by §§ 211.101(c) or (d), 211.103, manufacturer establishes the reliability be performed by one person and
211.182, or 211.188(b)(11) can satisfy of the supplier’s test results through independently verified by a second
the requirements included in those appropriate validation of the supplier’s person, or, if the yield is calculated by
sections relating to the performance of test results at appropriate intervals. automated equipment under § 211.68,
an operation by one person and be independently verified by one
* * * * * person.
checking by another person if such (6) Each lot of a component, drug
equipment is used in conformity with ■ 12. Section 211.110 is amended by
product container, or closure with
this section, and one person checks that revising paragraph (a) introductory text
potential for microbiological
the equipment properly performed the and by adding paragraph (a)(6) to read
contamination that is objectionable in
operation. as follows:
view of its intended use shall be
■ 6. Section 211.72 is revised to read as subjected to microbiological tests before § 211.110 Sampling and testing of in-
follows: use. process materials and drug products.
§ 211.72 Filters. * * * * * (a) To assure batch uniformity and
Filters for liquid filtration used in the ■ 9. Section 211.94 is amended by integrity of drug products, written
manufacture, processing, or packing of revising paragraph (c) as follows: procedures shall be established and
injectable drug products intended for followed that describe the in-process
human use shall not release fibers into § 211.94 Drug product containers and controls, and tests, or examinations to
closures. be conducted on appropriate samples of
such products. Fiber-releasing filters
may be used when it is not possible to * * * * * in-process materials of each batch. Such
manufacture such products without the (c) Drug product containers and control procedures shall be established
use of these filters. If use of a fiber- closures shall be clean and, where to monitor the output and to validate
releasing filter is necessary, an indicated by the nature of the drug, the performance of those manufacturing
additional nonfiber-releasing filter sterilized and processed to remove processes that may be responsible for
having a maximum nominal pore size pyrogenic properties to assure that they causing variability in the characteristics
rating of 0.2 micron (0.45 micron if the are suitable for their intended use. Such of in-process material and the drug
manufacturing conditions so dictate) depyrogenation processes shall be product. Such control procedures shall
shall subsequently be used to reduce the validated. include, but are not limited to, the
content of particles in the injectable * * * * * following, where appropriate:
drug product. The use of an asbestos- ■ 10. Section 211.101 is amended by * * * * *
containing filter is prohibited. revising paragraphs (c) and (d) to read (6) Bioburden testing.
■ 7. Section 211.82 is amended by as follows: * * * * *
revising paragraph (b) to read as follows: ■ 13. Section 211.113 is amended by
§ 211.101 Charge-in of components. revising paragraph (b) to read as follows:
§ 211.82 Receipt and storage of untested * * * * *
components, drug product containers, and (c) Weighing, measuring, or § 211.113 Control of microbiological
closures. subdividing operations for components contamination.
* * * * * shall be adequately supervised. Each * * * * *
(b) Components, drug product container of component dispensed to (b) Appropriate written procedures,
containers, and closures shall be stored manufacturing shall be examined by a designed to prevent microbiological
under quarantine until they have been second person to assure that: contamination of drug products
tested or examined, whichever is (1) The component was released by purporting to be sterile, shall be
appropriate, and released. Storage the quality control unit; established and followed. Such
within the area shall conform to the (2) The weight or measure is correct procedures shall include validation of
requirements of § 211.80. as stated in the batch production all aseptic and sterilization processes.
■ 8. Section 211.84 is amended by records; ■ 14. Section 211.160 is amended by
revising paragraphs (c)(1), (d)(3), and (3) The containers are properly revising paragraph (b)(1) to read as
(d)(6) to read as follows: identified. If the weighing, measuring, follows:
§ 211.160 General requirements. Dated: August 22, 2008. appears at the end of this document.
* * * * * Jeffrey Shuren, Comments received will be made
(b) * * * Associate Commissioner for Policy and available to the public via
(1) Determination of conformity to Planning. regulations.gov or upon request, without
applicable written specifications for the [FR Doc. E8–20709 Filed 9–5–08; 8:45 am] change and including any personal
acceptance of each lot within each BILLING CODE 4160–01–S information provided.
shipment of components, drug product FOR FURTHER INFORMATION CONTACT:
containers, closures, and labeling used Elton Ellison, Assistant Director, Civil
in the manufacture, processing, packing, DEPARTMENT OF THE TREASURY Penalties, (202) 622–6140 (not a toll-free
or holding of drug products. The call).
specifications shall include a Office of Foreign Assets Control SUPPLEMENTARY INFORMATION:
description of the sampling and testing
procedures used. Samples shall be 31 CFR Part 501 Electronic Availability
representative and adequately This document and additional
identified. Such procedures shall also Economic Sanctions Enforcement information concerning OFAC are
require appropriate retesting of any Guidelines available from OFAC’s Web site
component, drug product container, or AGENCY: Office of Foreign Assets (http://www.treas.gov/ofac) or via
closure that is subject to deterioration. Control, Treasury. facsimile through a 24-hour fax-on-
* * * * * ACTION: Interim final rule with request demand service, tel.: (202) 622–0077.
■ 15. Section 211.182 is revised to read for comments. Procedural Requirements
as follows: SUMMARY: The Office of Foreign Assets Because this interim final rule
§ 211.182 Equipment cleaning and use log. Control (OFAC) of the U.S. Department imposes no obligations on any person,
of the Treasury is issuing this interim but only explains OFAC’s enforcement
A written record of major equipment policy and procedures based on existing
final rule, ‘‘Economic Sanctions
cleaning, maintenance (except routine substantive rules, prior notice and
Enforcement Guidelines,’’ as
maintenance such as lubrication and public comment are not required
enforcement guidance for persons
adjustments), and use shall be included pursuant to 5 U.S.C. 553(b)(A). Because
subject to the requirements of U.S.
in individual equipment logs that show no notice of proposed rulemaking is
sanctions statutes, Executive orders and
the date, time, product, and lot number required, the provisions of the
regulations. This interim final rule
of each batch processed. If equipment is Regulatory Flexibility Act (5 U.S.C.
supersedes the Economic Sanctions
dedicated to manufacture of one chapter 6) do not apply. This interim
Enforcement Guidelines set forth in
product, then individual equipment logs final rule is not a significant regulatory
OFAC’s proposed rule of January 29,
are not required, provided that lots or action for purposes of Executive Order
2003 1 (with the exception of the
batches of such product follow in 12866.
proposed Appendix to the Cuban Assets
numerical order and are manufactured Although a prior notice of proposed
Control Regulations, 31 CFR Part 515,
in numerical sequence. In cases where rulemaking is not required, as discussed
set forth therein) and the Economic
dedicated equipment is employed, the in more detail below, OFAC is soliciting
Sanctions Enforcement Procedures for
records of cleaning, maintenance, and comments on this interim final rule in
Banking Institutions set forth in OFAC’s
use shall be part of the batch record. order to consider how it might make
interim final rule of January 12, 2006.2
The persons performing and double- improvements to these Guidelines.
These Enforcement Guidelines are
checking the cleaning and maintenance Comments must be submitted in
published as an appendix to the
(or, if the cleaning and maintenance is writing. The addresses and deadline for
Reporting, Procedures and Penalties
performed using automated equipment submitting comments appear near the
Regulations, 31 CFR Part 501.
under § 211.68, just the person verifying beginning of this notice. OFAC will not
the cleaning and maintenance done by DATES: The interim final rule is effective
September 8, 2008. Written comments accept comments accompanied by a
the automated equipment) shall date request that all or part of the submission
and sign or initial the log indicating that may be submitted on or before
November 7, 2008. be treated confidentially because of its
the work was performed. Entries in the business proprietary nature or for any
log shall be in chronological order. ADDRESSES: You may submit comments
by any of the following methods: other reason. All comments received by
■ 16. Section 211.188 is amended by the deadline will be a matter of public
Federal eRulemaking Portal: http://
revising paragraph (b)(11) to read as record and will be made available to the
www.regulations.gov.
follows: Follow the instructions for submitting public via regulations.gov.
comments. The collections of information related
§ 211.188 Batch production and control
records. Fax: Attn: Request for Comments to the Reporting, Procedures and
(Enforcement Guidelines) (202) 622– Penalties Regulations have been
* * * * * previously approved by the Office of
(b) * * * 1657.
Mail: Attn: Request for Comments Management and Budget (OMB) under
(11) Identification of the persons (Enforcement Guidelines), Office of control number 1505–0164. A small
performing and directly supervising or Foreign Assets Control, Department of adjustment to that collection has been
checking each significant step in the the Treasury, 1500 Pennsylvania submitted to OMB in order to take into
operation, or if a significant step in the Avenue, NW., Washington, DC 20220. account the voluntary self-disclosure
operation is performed by automated Instructions: All submissions received process set forth in these Guidelines. An
equipment under § 211.68, the
must include the agency name and the agency may not conduct or sponsor, and
identification of the person checking the Federal Register Doc. number that a person is not required to respond to,
significant step performed by the a collection of information unless it
automated equipment. 1 68 FR 4422–4429 (January 29, 2003). displays a valid control number
* * * * * 2 71 FR 1971–1976 (January 12, 2006). assigned by OMB. This collection of

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Federal Register / Vol. 73, No.

174 / Monday, September 8, 2008 / Rules and Regulations 51919

FDA has analyzed this rule in FDA’s Response

options that would minimize any PRA). The collections of information

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