Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 / Rules and Regulations 51919 

10. Order dated June 11, 2003, signed by 

Julie Louise Gerberding, Director, Centers for 

Disease Control and Prevention, and Mark B. 

McClellan, Commissioner of Food and Drugs, 

titled ‘‘Joint Order of the Centers for Disease 

Control and Prevention and the Food and 

Drug Administration, Department of Health 

and Human Services.’’

11. 68 FR 36566 (June 18, 2003). 

12. Fleischauer, A. T., et al., ‘‘Evaluation of 

Human-to-Human Transmission of 

Monkeypox from Infected Patients to Health 

Care Workers,’’ Clinical Infectious Diseases, 

40: 689–694 (2004). 

13. Xiao, S.Y., et al., ‘‘Experimental 

Infection of Prairie Dogs with Monkeypox 

Virus,’’ Emerging Infectious Diseases 11(4): 

539–545 (2005). 

14. Likos, A.M., et al., ‘‘A Tale of Two 

Clades: Monkeypox Viruses,’’ Journal of 

General Virology 86: 2661–2672 (2005). 

15. Nalca, A., Rimoin, A.W., Bavari, S. and 

Whitehouse, C.A., ‘‘Reemergence of 

Monkeypox: Prevalence, Diagnostics, and 

Countermeasures,’’ Clinical Infectious 

Diseases 41: 1765–1771 (2005). 

16. Kile, J.C., et al., ‘‘Transmission of 

Monkeypox Among Persons Exposed to 

Infected Prairie Dogs in Indiana in 2003,’’

Archives of Pediatric Adolescent Medicine 

159: 1022–1025 (2005). 

17. Guarner, J. et al., ‘‘Monkeypox 

Transmission and Pathogenesis in Prairie 

Dogs,’’ Emerging Infectious Diseases, 10: 

426–431 (March 2004). 

18. Bernard, S., and Anderson, S., 

‘‘Qualitative Risk Assessment: Monkeypox in 

the United States Associated with Domestic 

Trade in Certain Animal Species,’’ Emerging 

Infectious Diseases, 12: 1827–1833 (2006). 

19. Anderson, M.G., et al., ‘‘A Case of 

Severe Monkeypox Virus Disease in an 

American Child: Emerging Infections and 

Changing Professional Values,’’ Pediatric 

Infectious Disease, 22: 1093–1096 (2003). 

20. Croft, D.R., et al., ‘‘Occupational Risks 

during a Monkeypox Outbreak, Wisconsin, 

2003,’’ Emerging Infectious Diseases, 13: 

1150–1157 (2007). 

21. Reynolds, M.G., et al., ‘‘Spectrum of 

Infection and Risk Factors for Human 

Monkeypox, United States, 2003,’’ Emerging 

Infectious Diseases, 13: 1332–1339 (2007). 

22. Reed, K. D., Davis, J. P., and Damon, 

I. K., ‘‘Monkeypox in the Western 

Hemisphere,’’ (Response to a Letter to the 

Editor), New England Journal of Medicine, 

350: 1791 (April 22, 2004). 

23. Hutson, C.L., et al., ‘‘Monkeypox 

Zoonotic Associations: Insights from 

Laboratory Evaluation of Animals Associated 

with the Multi-State US Outbreak,’’

American Journal of Tropical Medicine and 

Hygiene, 76: 757–767 (2007). 

24. Centers for Disease Control and 

Prevention, ‘‘Multistate Outbreak of 

Monkeypox - Illinois, Indiana, and 

Wisconsin, 2003,’’ Morbidity and Mortality 

Weekly Report, 52: 537–540 (June 13, 2003). 

VIII. Federalism 

FDA has analyzed this rule in 

accordance with the principles set forth 

in Executive Order 13132. We have 

determined that the rule does not 

contain policies that have substantial 

direct effects on States, on the 

relationship between the National 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. Accordingly, we 

have concluded that the rule does not 

contain policies that have federalism 

implications as defined in the Executive 

Order, and, consequently, a federalism 

summary impact statement is not 

required. 

List of Subjects 

21 CFR Part 16 

Administrative practice and 

procedure. 

21 CFR Part 1240 

Communicable diseases, Public 

health, Travel restrictions, Water 

supply. 

■ Therefore, under the Public Health 

Service Act and under authority 

delegated to the Commissioner of Food 

and Drugs, 21 CFR 16 and 1240 are 

amended as follows: 

PART 16—REGULATORY HEARING 

BEFORE THE FOOD AND DRUG 

ADMINISTRATION 

■ 1. The authority citation for 21 CFR 

part 16 continues to read as follows: 

Authority: 15 U.S.C. 1451–1461; 21 U.S.C. 

141–149, 321–394, 467f, 679, 821, 1034; 28 

U.S.C. 2112; 42 U.S.C. 201–262, 263b, 364. 

§ 16.1 [Amended] 

■ 2. Section 16.1 is amended in 

paragraph (b)(2) by removing the entry 

for ‘‘§ 1240.63(c)(3) ’’. 

PART 1240—CONTROL OF 

COMMUNICABLE DISEASES 

■ 3. The authority citation for 21 CFR 

part 1240 continues to read as follows: 

Authority: 42 U.S.C. 216, 243, 264, 271. 

§ 1240.63 [Removed] 

■ 4. Remove § 1240.63. 

Dated: August 27, 2008. 

Jeffrey Shuren, 

Associate Commissioner for Policy and 

Planning. 

[FR Doc. E8–20779 Filed 9–5–08; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 210 and 211 

[Docket No. FDA–2007–N–0379] (formerly 

Docket No. 2007N–0280) 

Amendments to the Current Good 

Manufacturing Practice Regulations for 

Finished Pharmaceuticals 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is amending 

certain of its regulations on current good 

manufacturing practice (CGMP) 

requirements for finished 

pharmaceuticals as the culmination of 

the first phase of an incremental 

approach to modifying the CGMP 

regulations for these products. This rule 

revises CGMP requirements primarily 

concerning aseptic processing, 

verification of performance of 

operations by a second individual, and 

the use of asbestos filters. We are 

amending the regulations to modernize 

or clarify some of the requirements as 

well as to harmonize them with other 

FDA regulations and international 

CGMP standards. 

DATES: This rule is effective December 8, 

2008. 

FOR FURTHER INFORMATION CONTACT: 

Mary Malarkey, Center for Biologics 

Evaluation and Research (HFM–600), 

Food and Drug Administration, 1401 

Rockville Pike, Rockville, MD 20852–

1448, 301–827–6190; or 

Dennis Bensley, Center for Veterinary 

Medicine (HFV–140), Food and Drug 

Administration, 7500 Standish Pl., 

Rockville, MD 20855, 240–276–8268; or 

Brian Hasselbalch, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., rm. 4364, Silver 

Spring, MD 20993, 301–796–3279. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Background 

II. Summary of the Final Rule 

A. Aseptic Processing 

B. Asbestos Filters 

C. Verification by a Second Individual 

D. Other Minor Changes 

III. Comments on the Proposed Rule and 

FDA’s Response 

A. General Comments 

B. Plumbing 

C. Aseptic Processing 

D. Asbestos Filters 


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E. Verification by a Second Individual 

F. Miscellaneous Minor Changes 

Based on 1996 Proposal 

IV. Analysis of Impacts 

V. Environmental Impact 

VI. Federalism 

VII. Paperwork Reduction Act of 1995 

I. Background 

Since the development of the CGMP 

regulations for drug products in 1962, 

FDA has balanced the need for easily 

understood minimum standards with 

the need to encourage innovation and 

the development of improved 

manufacturing technologies. We strive 

to give manufacturers latitude to 

determine how to achieve the level of 

control necessary for CGMP compliance, 

recognizing that, in some instances, 

more direction from FDA is necessary to 

provide a uniform standard to the entire 

industry, minimize the potential for 

harm, or achieve some other CGMP 

objective. We periodically reassess and 

revise the CGMP regulations to 

accommodate advances in technology 

and other scientific knowledge that 

further safeguard the drug 

manufacturing process and the public 

health. 

In 1996, as part of this reassessment 

process, we proposed to: (1) Amend 

certain requirements of the CGMP 

regulations for finished pharmaceuticals 

to clarify certain manufacturing, quality 

control, and documentation 

requirements and (2) ensure that the 

regulations more accurately 

encompassed current industry practice 

(61 FR 20104, May 3, 1996) (1996 

proposed rule). Subsequently, as a part 

of the risk-based Pharmaceutical CGMPs 

for the 21st Century initiative, we 

created a CGMP Harmonization 

Analysis Working Group (CGMP 

Working Group) to analyze related 

CGMP requirements in effect in the 

United States and internationally, 

including those related to quality 

systems. The CGMP Working Group 

compared parts 210 and 211 (21 CFR 

parts 210 and 211) with the CGMPs of 

the European Union (EU), as well as 

other FDA regulations (e.g., the Quality 

Systems Regulation, 21 CFR part 820) to 

identify the differences and consider the 

value of supplementing or changing the 

current regulations. Based on the CGMP 

Working Group’s analysis, we decided 

to take an incremental approach to 

modifying parts 210 and 211. 

Because of this change in approach, 

we decided not to finalize the 1996 

proposed rule. On December 4, 2007, we 

published a document withdrawing the 

1996 proposed rule (72 FR 68111) (the 

December 2007 proposed rule). On the 

same date, we published a direct final 

rule (72 FR 68064) and companion 

proposed rule (72 FR 68113) to clarify 

and modernize certain provisions of the 

CGMP regulations. The comment period 

for the direct final rule closed on 

February 19, 2008. On April 4, 2008, we 

published a document withdrawing the 

direct final rule because we received 

significant adverse comments (73 FR 

18440). In the document withdrawing 

the direct final rule, we explained that 

the comments received would be 

considered under our usual procedures 

for notice and comment in connection 

with the notice of proposed rulemaking 

that was published as a companion to 

the direct final rule. 

After careful consideration of all 

comments received, we are now 

publishing this final rule. The final rule 

represents the culmination of the first 

increment of modifications to parts 210 

and 211. 

II. Summary of the Final Rule 

The final rule revises the drug CGMP 

regulations primarily in three areas: 

Aseptic processing, use of asbestos 

filters, and verification of operations by 

a second individual. 

A. Aseptic Processing 

The final rule revises § 211.113(b) to 

clarify that required written procedures 

designed to prevent microbiological 

contamination of sterile drug products 

must include procedures on the 

validation of all aseptic processes in 

addition to sterilization processes. Other 

changes related to aseptic processing 

include the following: 

• Revised § 211.67(a) requires that 

equipment and utensils be cleaned, 

maintained, and, as appropriate for the 

nature of the drug, sanitized ‘‘and/or 

sterilized’’ at appropriate intervals to 

prevent malfunction or contamination. 

This change recognizes that for sterile 

drug products, sterilization (sometimes 

in addition to sanitization) is 

appropriate. 

• Revised § 211.84(d)(6) requires 

microbiological tests before use of each 

lot of a component, drug product 

container, or closure ‘‘with potential for 

microbiological contamination’’ that is 

objectionable in view of its intended 

use, consistent with longstanding 

agency interpretation of this regulation. 

• Revised § 211.94(c) requires 

validation of depyrogenation processes 

for drug product containers and 

closures, consistent with longstanding 

industry practice and agency 

interpretation of this regulation. 

• Revised § 211.110(a) adds 

bioburden testing to the list (which is 

not all-inclusive) of in-process control 

procedures relating to the sampling and 

testing of in-process materials, which 

again is consistent with industry 

practice. 

B. Asbestos Filters 

We revised §§ 210.3(b)(6) and 211.72 

to eliminate provisions permitting 

limited use of asbestos-containing filters 

used in processing injectable drug 

products. We had proposed to simply 

delete references to asbestos filters in 

these provisions. However, in response 

to comments, we also added to § 211.72 

the statement ‘‘The use of an asbestoscontaining filter is prohibited.’’ Also in 

response to comments, we revised 

§ 211.72 to reflect appropriate technical 

standards for nonfiber-releasing filters. 

C. Verification by a Second Individual 

The final rule makes several changes 

to the regulations to acknowledge, 

consistent with our longstanding 

interpretation, that certain operations 

may be performed by automated 

equipment and verified by a person, 

rather than one person performing an 

operation and another person verifying 

that the operation was correctly 

performed. In particular, we added new 

paragraph (c) to § 211.68 stating that 

automated equipment used to perform 

operations addressed in §§ 211.101(c) or 

(d), 211.103, 211.182, or 211.188(b)(11) 

can satisfy the requirements in those 

sections for the performance of an 

operation by one person and checking 

by another person if the equipment is 

used in conformity with § 211.68 and 

one person checks that the operations 

are properly performed. In response to 

comments, we revised the paragraph to 

minimize the possibility that the 

provision might be misinterpreted as 

requiring a person to repeat by hand all 

calculations performed by automated 

equipment. 

In accordance with the addition of 

§ 211.68(c), we are adopting 

corresponding changes to the following 

provisions: 

• Section 211.101(c) and (d) 

(concerning charge-in of components 

and containers), 

• Section 211.103 (calculation of 

yields), 

• Section 211.182 (equipment 

cleaning and maintenance), and 

• Section 211.188(b)(11) (batch 

production and control records). 

D. Other Minor Changes 

In addition to the revisions to the 

regulations previously noted, we have 

made minor revisions to the following 

provisions to provide greater clarity 

without changing meaning or intent: 

• Section 211.82(b) (storage of 

components, containers, and closures), 


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• Section 211.84(c)(1) and (d)(3) 

(collection and testing of samples of 

components, containers, and closures), 

and 

• Section 211.160(b)(1) (laboratory 

controls for determining conformity to 

specifications). 

III. Comments on the Proposed Rule 

and FDA’s Response 

We received comments on the 

proposed rule from drug and biologic 

manufacturers, industry associations, 

consultants, and other interested 

persons. A summary of the comments 

received and our responses follow. We 

first respond to comments of a general 

nature and then to comments on the five 

topics set forth in the preamble of the 

direct final rule. 

To make it easier to identify 

comments and our responses, the word 

‘‘Comment,’’ in parentheses, appears 

before the comment’s description, and 

the word ‘‘Response,’’ in parentheses, 

appears before our response. We have 

numbered each comment to help 

distinguish between different 

comments. Similar comments are 

grouped together under the same 

number if the same response would be 

given for each. The number assigned to 

each comment is purely for 

organizational purposes and does not 

signify the comment’s value or 

importance or the order in which it was 

received. 

A. General Comments 

(Comment 1) One comment stated 

that it will be very important for FDA 

to ensure clarity and consistency in the 

understanding of the final rule among 

agency staff, including both product 

reviewers and CGMP inspectors, to 

minimize different interpretations and 

applications of these regulations. 

(Response) We agree that it is 

important that FDA employees who 

perform application reviews, as well as 

conduct CGMP inspections and other 

compliance activities, understand these 

regulations and apply them in a 

consistent manner in the performance of 

their duties. Therefore, we will take 

appropriate steps to ensure that agency 

staff receive adequate training regarding 

the new regulations. 

(Comment 2) One comment stated 

that we should not withdraw the 1996 

proposed rule because it contained 

many good features with respect to test 

method validation and the out-ofspecification test result problem. The 

comment maintained that the guidance 

for industry entitled ‘‘Investigating Outof-Specification (OOS) Test Results for 

Pharmaceutical Production’’ (71 FR 

60158, October 12, 2006) is not helpful 

to people working with biological drugs 

and other products. Another comment 

stated that the December 2007 proposed 

rule should have incorporated many of 

the changes in the 1996 proposed rule 

regarding such matters as validation, 

quality control unit responsibilities, 

batch failure investigations, and 

stability samples because they involve 

some of the most common CGMP 

deficiencies. 

(Response) As we stated in the 

December 4, 2007, document, we 

withdrew the 1996 proposed rule 

because we concluded that, given our 

new approach to CGMP under the 21st 

century initiative, it would be preferable 

to revise the CGMP regulations 

incrementally rather than in a one-time, 

comprehensive fashion. Furthermore, 

we believe that it is appropriate to 

reevaluate some of the matters 

considered in the 1996 proposed rule in 

light of recent scientific and 

technological advances. We appreciate 

the comments’ interest in the specified 

CGMP issues, and we will consider 

these issues in future phases of our 

CGMP modernization efforts. 

(Comment 3) One comment 

encouraged FDA to consider other 

CGMP regulations that need 

modernization or clarification, or are no 

longer necessary due to technological 

advances, such as aspects of 21 CFR 

610.12 concerning the requirements for 

bulk sterility testing and allowance for 

sterility retesting for biological 

products. 

(Response) We appreciate the 

comment’s interest in modernizing 

CGMP regulations. As previously stated, 

this final rule represents only our first 

step in updating the drug CGMP 

regulations to reflect current industry 

practice and harmonize the regulations 

with international CGMP requirements. 

We will consider other aspects of CGMP 

in future rulemaking proceedings. 

B. Plumbing 

Section 211.48(a) requires that potable 

water be supplied under continuous 

positive pressure in a plumbing system 

free of defects that could contribute 

contamination to any drug product. It 

further requires that potable water meet 

the standards established by the U.S. 

Environmental Protection Agency (EPA) 

for primary drinking water in 40 CFR 

part 141. Proposed § 211.48(a) would 

have deleted the requirement that the 

potable water used in a plumbing 

system meet EPA’s standards for 

primary drinking water, and instead 

required that the water be ‘‘safe for 

human consumption.’’ This proposed 

revision was intended to improve 

harmonization with foreign regulations 

(particularly those of the EU and Japan) 

and to make the U.S. regulation more 

consistent with the United States 

Pharmacopeia standard. In the preamble 

of the direct final rule, we stated that 

the revised requirement could be met by 

compliance with the standards in the 

EPA regulations or in the current 

regulations of the EU or Japan for 

potable water used to prepare water for 

pharmaceutical purposes. 

(Comment 4) Four comments objected 

to the proposed change. Among other 

things, the comments stated that the 

standard of ‘‘safe for human 

consumption’’ is not sufficiently 

prescriptive. 

(Response) Because of the comments 

received and other considerations, we 

have decided not to revise § 211.48(a) at 

this time. We will address the issue of 

standards for water used in a facility’s 

plumbing system when we consider 

proposing regulations for water used as 

a drug product component in the next 

phase of our CGMP initiative. 

C. Aseptic Processing 

In the proposed rule, we sought to 

amend several regulations on aseptic 

processing to reflect current industry 

standards and practices. Some of the 

proposed revisions would also affect 

other types of processes and operations. 

We noted that the proposed changes 

would not affect the applicability of the 

guidance for industry entitled ‘‘Sterile 

Drug Products Produced by Aseptic 

Processing—Current Good 

Manufacturing Practice’’ (Aseptic 

Processing Guidance), issued on 

October 4, 2004 (69 FR 59258). 

1. Equipment Cleaning and 

Maintenance (§ 211.67(a)) 

The version of § 211.67(a) amended 

by this final rule stated: ‘‘Equipment 

and utensils shall be cleaned, 

maintained, and sanitized at appropriate 

intervals to prevent malfunctions or 

contamination that would alter the 

safety, identity, strength, quality, or 

purity of the drug product beyond the 

official or other established 

requirements.’’ We proposed to add the 

phrase ‘‘and/or sterilized’’ after the 

word ‘‘sanitized’’ in § 211.67(a) to 

reflect the fact that sterilization is 

appropriate for sterile drug products. 

On our own initiative, we have 

revised § 211.67(a) to state that 

equipment and utensils shall be 

cleaned, maintained, ‘‘and, as 

appropriate for the nature of the drug, 

sanitized and/or sterilized at 

appropriate intervals * * *.’’ This 

revision does not alter the meaning of 

the proposed rule change, but clarifies 

that for some equipment and utensils 


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used in the production of certain drug 

products, sanitization is appropriate; for 

other equipment and utensils, 

sterilization is appropriate; and for still 

others, both sanitization and 

sterilization are appropriate. 

(Comment 5) One comment stated 

that it is not appropriate to address 

sterilization in § 211.67(a). Instead, the 

comment recommended that a reference 

to sterilization of equipment and 

utensils be added to § 211.113(b), which 

requires the adoption of written 

procedures designed to prevent 

microbiological contamination of drug 

products purporting to be sterile. 

(Response) We do not agree with the 

comment because, as previously noted, 

equipment and utensils used in the 

production of sterile drug products must 

be sterilized, not merely sanitized. In 

addition, we have revised § 211.113(b) 

as discussed in section III.C.5 of this 

final rule. 

(Comment 6) One comment suggested 

that we could simplify the language in 

this regulation by changing the phrase 

‘‘beyond the official or other established 

requirements’’ to ‘‘beyond the 

established (or other official) 

requirements.’’

(Response) We do not believe that the 

suggested change simplifies the current 

phrase, which we believe is clear. 

Therefore, we do not believe that the 

suggested change is necessary. 

(Comment 7) One comment stated 

that § 211.67(a) should not apply to the 

production of medical gases because 

most medical gas manufacturing lines 

are product-specific, closed systems that 

are not subject to cleaning or sanitation 

as part of an established periodic cycle, 

but instead are specially cleaned to be 

‘‘oxygen ready’’ and carefully handled 

in accordance with established 

procedures. The comment maintained 

that additional cleaning efforts beyond 

the initial cleaning regimen 

substantially increase the risk of 

introducing contaminants into the 

system. Therefore, the comment stated, 

it is not necessary to require cleaning of 

equipment at ‘‘appropriate intervals’’ for 

medical gas manufacturing. The 

comment suggested that, alternatively, it 

might be appropriate for the agency to 

state that medical gases may represent 

unique circumstances that will be 

reflected in a separate guidance. 

(Response) We decline to exempt 

medical gases from the requirements of 

§ 211.67(a) as recommended because 

this would exceed the scope of our 

proposed change to clarify that 

sterilization is appropriate for sterile 

drug products and would instead focus 

on whether there is any need for 

periodic cleaning of medical gas 

systems. We might consider in a future 

CGMP rulemaking whether it is 

appropriate to revise § 211.67(a) to 

address its application to medical gases. 

2. Microbiological Testing of 

Objectionable Lots of Components, Drug 

Product Containers, and Closures 

(§ 211.84(d)(6)) 

The version of § 211.84(d)(6) amended 

by this final rule stated: ‘‘Each lot of a 

component, drug product container, or 

closure that is liable to microbiological 

contamination that is objectionable in 

view of its intended use shall be 

subjected to microbiological tests before 

use.’’ We proposed to change the phrase 

‘‘that is liable to microbiological 

contamination’’ to ‘‘with potential for 

microbiological contamination.’’

(Comment 8) One comment stated 

that the proposed change was 

unnecessarily restrictive and might lead 

to testing every lot when the risk of 

microbial contamination is low and the 

impact on the intended use is 

insignificant. This comment suggested 

replacing ‘‘that is liable to microbial 

contamination’’ with ‘‘prone to 

microbial contamination.’’ One 

comment stated that the proposed 

change could make it more difficult for 

drug manufacturers to replace a less 

effective, quality control-based 

inspection and test method with a more 

modern and effective quality audit 

method. The comment stated that 

because the bioburden of dry items such 

as vials and stoppers is often 

heterogeneous, improved assurance of 

this quality attribute is better achieved 

through the audit, selection, and control 

by the manufacturers of these items. 

This comment maintained that 

knowledge of and control over the 

manufacturing processes for containers 

and closures might fall short of 

justifying that those products do not 

have a ‘‘potential for contamination.’’

(Response) We decline to adopt the 

recommended change to § 211.84(d)(6) 

from ‘‘that is liable to microbial 

contamination’’ to ‘‘prone to 

microbiological contamination.’’ We 

believe that our proposed change to 

‘‘with potential for microbiological 

contamination’’ clarifies our 

longstanding interpretation of the 

regulation that each lot of component, 

drug product container, or closure that 

is susceptible to contamination must 

undergo microbiological testing before 

use. Therefore, we have revised 

§ 211.84(d)(6) to refer to components, 

containers, or closures ‘‘with potential 

for microbiological contamination’’ as 

proposed. 

3. Validation of Depyrogenation of Drug 

Product Containers and Closures 

(§ 211.94(c)) 

The version of § 211.94(c) amended 

by this final rule stated: ‘‘Drug product 

containers and closures shall be clean 

and, where indicated by the nature of 

the drug, sterilized and processed to 

remove pyrogenic properties to assure 

that they are suitable for their intended 

use.’’ In the preamble to the direct final 

rule, we stated that it has been 

longstanding industry practice to 

validate the sterilization and 

depyrogenation processes used for drug 

product containers and closures to 

ensure consistent removal of microbial 

contamination and pyrogens or 

endotoxins. Therefore, we proposed to 

add a provision to § 211.94(c) requiring 

the validation of these depyrogenation 

processes. 

(Comment 9) One comment suggested 

that we require validation of 

‘‘sterilization’’ as well as 

depyrogenation processes. 

(Response) We do not believe that the 

suggested change is needed because 

§ 211.113(b) already requires validation 

of sterilization processes for the 

prevention of microbiological 

contamination of drug products 

purporting to be sterile. 

(Comment 10) Four comments 

objected to the requirement in existing 

§ 211.94(c) because it requires 

depyrogenation of components based on 

the nature of the drug and does not take 

into account the fact that some 

containers and closures are inherently 

nonpyrogenic, have been qualified not 

to require active depyrogenation, or do 

not require depyrogenation because of 

handling procedures. Three of the 

comments proposed that in addition to 

the nature of the drug, the drug’s 

manufacturing process be included as a 

factor in determining when containers 

and closures must be sterilized and 

processed to remove pyrogenic 

properties. Two of the comments 

recommended that the requirement to 

validate depyrogenation processes be 

limited to containers and closures that 

are made nonpyrogenic by a designated 

depyrogenation process (thus excluding 

inherently nonpyrogenic containers and 

closures from the regulation). 

(Response) We decline to adopt the 

suggested revisions because they go 

beyond the scope of our proposed 

change to require validation of 

depyrogenation processes and instead 

focus on the need for depyrogenation 

itself. 


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4. Inclusion of Bioburden Testing in InProcess Testing (§ 211.110(a)) 

Section 211.110(a) requires that 

written procedures be established and 

followed that describe in-process 

controls and tests or examinations to be 

conducted on samples of in-process 

materials of each batch of a drug 

product. The regulation specifies five 

control procedures that must be 

established, where appropriate, to 

monitor the output and to validate the 

performance of manufacturing processes 

that may be responsible for causing 

variation in the characteristics of inprocess material and the drug product. 

We proposed to add bioburden testing 

to this list (which is not all-inclusive) 

because testing for bioburden is 

standard industry practice for in-process 

materials and drug products that are 

produced by aseptic processing. 

(Comment 11) Three comments 

objected to the addition of bioburden 

testing to § 211.110(a). One comment 

objected to the inclusion of any specific 

test and suggested that specific tests be 

addressed in agency guidance. One 

comment stated that bioburden testing 

is not conducted at the same time as 

other tests specified in § 211.110(a) and 

is not an in-process test or control 

because it does not yield immediate 

results that allow for process 

adjustment. The comment stated that it 

would be more appropriate to address 

bioburden testing in § 211.84. One 

comment suggested that because 

§ 211.110 covers the sampling and 

testing of all in-process materials and 

drug products, adding bioburden testing 

as a mandatory control procedure could 

expand current industry validation 

procedure and produce diversity among 

the industry and regulators on the 

circumstances in which validation of 

bioburden testing is appropriate. 

(Response) We do not agree with the 

comments. As stated in the direct final 

rule, testing for bioburden is an 

important in-process control, 

particularly for drug products that are 

produced through aseptic processing. 

Section 211.110(a) provides flexibility 

to manufacturers so that they need only 

conduct bioburden testing where the 

testing is appropriate to assure batch 

uniformity and drug product integrity. 

We believe that manufacturers 

understand for which types of drug 

products, and at what point in the 

manufacturing process for these drugs, 

bioburden testing is appropriate. 

Accordingly, we have added bioburden 

testing to § 211.110(a). 

5. Control of Microbiological 

Contamination (§ 211.113(b)) 

Section 211.113(b) states that 

appropriate written procedures, 

designed to prevent microbiological 

contamination of drug products 

purporting to be sterile, must be 

established and followed. The version of 

§ 211.113(b) amended by this final rule 

further stated: ‘‘Such procedures shall 

include validation of any sterilization 

process.’’ We proposed to substitute ‘‘all 

aseptic and sterilization processes’’ for 

‘‘any sterilization process.’’ As noted in 

the preamble of the direct final rule, 

even before we issued the now-replaced 

guidance on ‘‘Sterile Drug Products 

Produced by Aseptic Processing’’ in 

1987, industry routinely conducted 

validation studies (often referred to as 

media fills) that substituted 

microbiological media for the actual 

product to demonstrate that its aseptic 

processes were validated (72 FR 68064 

at 68066). The proposed change was 

intended to clarify existing practice and 

to harmonize § 211.113 with Annex 1 of 

the EU CGMPs. 

(Comment 12) Several comments 

objected to the proposed change to 

§ 211.113(b) on the basis that aseptic 

processing cannot be validated. One 

comment stated that validation of 

aseptic processing technically cannot be 

done, although the manufacturer can 

ensure tight control over the process. 

One comment stated that aseptic 

processing simulations demonstrate the 

capability of a facility, equipment, and 

operational controls to provide a 

minimal microbial contamination rate 

in a single event, but they cannot 

predict the outcome of a similar process 

performed at a different time. The 

comment maintained that to consider 

aseptic processing to be validated 

overstates the ability to measure and 

control the process and could be 

interpreted as approval to relax the 

controls necessary for its success. The 

comment recommended that 

§ 211.113(b) be revised to require 

validation of ‘‘all sterilization/ 

depyrogenation processes’’ and to direct 

that aseptic processes ‘‘be subjected to 

periodic assessment to demonstrate the 

capability of the control strategy to 

adequately support end product 

sterility.’’

One comment stated that there is 

currently no means to comply with the 

proposed requirement to validate 

aseptic processes. The comment 

maintained that the microbiological and 

decontamination methods used in 

aseptic processing lack the sensitivity, 

recoverability, and accuracy of the 

physical and chemical measurement 

systems normally associated with 

process validation. The comment 

further claimed that media fills do not 

validate aseptic processing because they 

measure only detectable microorganisms and do not verify that no 

micro-organisms exist. The comment 

stated that although aseptic processing 

cannot be validated, a state of control 

can be established, ensuring that the 

aseptically produced drug consistently 

meets its specifications and quality 

attributes. The comment recommended 

that rather than validation of aseptic 

processes, § 211.113(b) require ‘‘a 

formalized quality risk management and 

control strategy for aseptic processes to 

provide assurance of requisite and 

continued process capability and 

product quality.’’

One comment stated that although 

media fills can evaluate an aseptic 

process, they cannot be considered to 

validate the process. The comment 

recommended that we either not adopt 

the proposed requirement to validate 

aseptic processes or provide more 

clarity on what is expected for 

validation of aseptic processes. 

Similarly, another comment 

recommended that we not revise 

§ 211.113(b) as proposed unless we 

clarify that more than media fills are 

required to validate an aseptic process. 

The comment stated that a wellcontrolled, robust process is required for 

aseptic processes and that once a state 

of control has been established for the 

process, media fills can be useful in 

confirming the state of control. 

(Response) Although we acknowledge 

that aseptic process validation does not 

provide absolute assurance of product 

sterility, we do not agree that aseptic 

processes cannot be validated. 

Validation of aseptic processes, which is 

a common practice throughout the 

pharmaceutical industry, means 

establishing documented evidence that 

provides a high degree of assurance that 

a particular process will consistently 

produce a product meeting its 

predetermined specifications and 

quality attributes. Media fills, together 

with operational controls, 

environmental controls, and product 

sterility testing, provide a sufficient 

level of assurance that drugs purported 

to be sterile are in fact sterile. 

(Comment 13) One comment 

suggested adding a definition of aseptic 

processing to part 210. 

(Response) We do not believe that it 

is necessary to define aseptic processing 

in the regulation. The Aseptic 

Processing Guidance makes it clear to 

manufacturers what aseptic processing 

entails. 


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(Comment 14) One comment 

requested confirmation that it is 

acceptable to follow the current FDA 

guidance and use media fills to meet the 

requirement to validate aseptic 

processes. 

(Response) As stated in the preamble 

to the direct final rule and reiterated 

previously in this document, 

manufacturers can follow the 

recommendations in the Aseptic 

Processing Guidance to comply with 

CGMP requirements for aseptic 

processing, including validation. 

However, as with any guidance, the 

Aseptic Processing Guidance is not 

binding on industry or the agency, and 

manufacturers may use an alternative 

approach to achieve compliance if the 

approach meets the requirements of the 

act and FDA regulations. 

(Comment 15) One comment sought 

clarification that the requirement to 

validate aseptic processing would not 

inhibit implementation of novel 

technologies recommended by the 

International Conference on 

Harmonisation of Technical 

Requirements for Registration of 

Pharmaceuticals for Human Use (ICH) 

in the ICH Q8, Q9, and Q10 guidances, 

or other innovative approaches in these 

areas. 

(Response) We do not believe that the 

requirement to validate aseptic 

processing will interfere with the 

implementation of new technologies 

either as part of following ICH 

recommendations or as part of other 

efforts to meet CGMP requirements. As 

stated in section I of this document, we 

have always attempted to balance the 

need for easily understood minimum 

CGMP standards with the desire to 

encourage innovation and the 

development of improved 

manufacturing technologies. We are 

confident that industry can meet the 

requirement to validate aseptic 

processing with no adverse impact on 

technological innovation in drug 

product manufacturing. 

D. Asbestos Filters 

As stated in the preamble to the direct 

final rule, we need to update our 

regulations on filters used in processing 

liquid injectable products. The version 

of § 211.72 amended by this final rule 

required manufacturers, before using an 

asbestos-containing filter, to submit 

proof to FDA that an alternative 

nonfiber-releasing filter will, or is likely 

to, compromise the safety or 

effectiveness of the product. However, 

we are not aware that asbestos filters are 

currently commercially manufactured 

for pharmaceutical use or are used in 

drug production, and their use is not 

considered a good manufacturing 

practice. Therefore, we proposed to 

delete the reference to the use of 

asbestos-containing filters from § 211.72 

and to delete the reference to asbestos 

filters from the definition of ‘‘nonfiberreleasing filter’’ in § 210.3(b)(6). 

(Comment 16) Two comments stated 

that the regulations should state that the 

use of asbestos filters is prohibited. One 

comment stated that if asbestoscontaining filters are in fact available 

and the proposed changes were 

interpreted as permitting their use, this 

might pose a risk to patients. 

(Response) We agree with the 

comments. Therefore, in addition to 

deleting the reference to asbestoscontaining filters in § 210.3(b)(6), we 

have revised the last sentence of 

§ 211.72 to state that the use of an 

asbestos-containing filter is prohibited. 

(Comment 17) One comment 

recommended that we clarify the second 

sentence in proposed § 211.72, which 

stated: ‘‘Fiber-releasing filters may not 

be used in the manufacture, processing, 

or packing of these injectable drug 

products unless it is not possible to 

manufacture such drug products 

without the use of such filters.’’ The 

comment recommended that this 

sentence be revised to state as follows: 

‘‘Fiber-releasing filters may be used 

when/where it is not possible to 

manufacture such drug products 

without the use of such filters.’’

(Response) We agree with this 

proposed change and have revised 

§ 211.72 accordingly. 

(Comment 18) Four comments 

recommended revising the following 

provision in proposed § 211.72: ‘‘If use 

of a fiber-releasing filter is necessary, an 

additional nonfiber-releasing filter of 

0.22 micron maximum mean porosity 

(0.45 micron if the manufacturing 

conditions so dictate) shall 

subsequently be used to reduce the 

content of particles in the injectable 

drug product.’’ Each of these comments 

stated that it is technically more 

accurate to describe a filter in terms of 

its nominal pore size rating than its 

mean porosity. One comment stated that 

the filter pore size standard of 0.22 

micron is outdated and should be 

changed to 0.2 micron. 

(Response) These suggested technical 

changes are consistent with statements 

in our guidances for industry (e.g., the 

Aseptic Processing Guidance) 

concerning filters. Therefore, we have 

revised § 211.72 to require that if use of 

a fiber-releasing filter is necessary, an 

additional nonfiber-releasing filter 

having a maximum nominal pore size 

rating of 0.2 micron be used. 

E. Verification by a Second Individual 

The current CGMP regulations 

include several provisions requiring that 

certain activities be performed by one 

person and checked as specified by a 

second person. 

• Section 211.101(c) requires that: (1) 

Each container of component dispensed 

for use in manufacturing be examined 

by a second person to assure that it was 

released by the quality control unit, (2) 

the weight or measure is correct as 

stated in the batch production records, 

and (3) the containers are properly 

identified. 

• Section 211.101(d) requires that 

each component be added to the batch 

by one person and verified by a second 

person. 

• Section 211.103 requires that 

specified yield calculations be 

performed by one person and 

independently verified by a second 

person. 

• Section 211.182 requires the 

persons performing and doublechecking the cleaning and maintenance 

of major equipment to date and sign or 

initial equipment logs indicating that 

the work was performed. 

• Section 211.188(b)(11) requires that 

batch production and control records 

include identification of the persons 

performing and directly supervising or 

checking each significant step in the 

operation. 

When we amended the CGMP 

regulations in 1978, we established 

§ 211.68, which provides that automatic, 

mechanical, or electronic equipment or 

other types of equipment, including 

computers, or related systems that will 

perform a function satisfactorily, may be 

used in the manufacture, processing, 

packing, and holding of a drug product, 

subject to the following requirements: 

• Equipment is routinely checked 

according to a program designed to 

assure proper performance, 

• Changes to records are made only 

by authorized personnel, 

• Input and output are checked for 

accuracy, and 

• Appropriate backup of data is 

maintained. 

In the preamble to the 1978 final rule, 

we stated that the verification 

requirements in § 211.101 for charge-in 

of components when automated systems 

are used would be met if a person 

verified that the automated system was 

working properly (43 FR 45014 at 

45051, September 29, 1978). Thus, in 

this situation, the first individual is 

replaced by a machine or other 

automated process, and only one person 

is necessary to verify that the automated 

system is functioning as intended. 


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Because we have received questions 

about the performance and checking 

requirements in §§ 211.101(c) or (d), 

211.103, 211.182, or 211.188(b)(11) 

when the operations are performed by 

automated equipment, such as the 

widespread and increasing use of 

computer-controlled operations, we 

proposed to revise these sections. We 

proposed to amend these regulations to 

indicate that when automated 

equipment is used to perform certain 

operations, only one person is needed to 

verify that the automated equipment is 

functioning adequately. 

Correspondingly, proposed § 211.68(c) 

stated that automated equipment used 

for performance of operations addressed 

by §§ 211.101(c) or (d), 211.103, 

211.182, or 211.188(b)(11) can satisfy 

the requirements included in those 

sections for the performance of an 

operation by one person and checking 

by another person if such equipment is 

used in conformity with § 211.68 and 

one person verifies that the operations 

addressed in those sections are 

performed accurately by such 

equipment. We stated in the preamble of 

the direct final rule that these revisions 

would clarify our longstanding policy 

that verification by a second individual 

may not be necessary when automatic 

equipment is used under § 211.68. 

1. General Comments on Verification 

(Comment 19) One comment stated 

that validated, automated systems 

equipped with real time alarms that do 

not require any human intervention 

should not require human verification. 

Another comment stated that such 

systems should not require human 

verification with each use and, when 

human verification is needed, the level 

of verification required should be 

consistent with the level of automation 

used. Both of these comments 

maintained that requiring operator 

verification of automated, validated 

equipment under §§ 211.68(c), 

211.101(c)(3) and (d), 211.103, and 

211.188(b)(11) might hinder the 

implementation of process analytical 

technology (PAT) in the drug industry. 

(Response) In the Federal Register of 

February 12, 1991 (56 FR 5671) (the 

1991 proposal), we issued a proposed 

rule in part to amend § 211.68 to add 

what is now the third sentence of 

§ 211.68(b): ‘‘The degree and frequency 

of input/output verification shall be 

based on the complexity and reliability 

of the computer or related system.’’ This 

revision was adopted as part of the final 

rule issued on January 20, 1995 (60 FR 

4087) (the 1995 final rule). 

In the 1995 final rule, we responded 

to several comments on the proposed 

revision. Two comments suggested that 

the revised regulation did not 

accommodate the accepted use of 

validated computerized drug production 

and control systems. We declined to 

change the revision as proposed, stating 

our belief that the wording in the 

revised rule adequately encompasses 

the use of these systems (60 FR 4087 at 

4089). 

Two comments on the 1991 proposal 

questioned the need for human 

verification of operations that are 

performed by validated computer 

systems. The comments listed other 

regulations that were not the subject of 

the proposed rule that required more 

than one person to verify certain 

manufacturing operations, apparently to 

show that additional personnel would 

be needed to comply with proposed 

§ 211.68. We noted in the 1995 final rule 

that the revisions to § 211.68 do not 

impose any specific personnel 

requirements. We also noted that the 

agency is aware that computers are 

subject to malfunctions, some of which 

could possibly result in the loss of 

critical information regarding the 

manufacturing process or a serious 

production error and the possible 

distribution of an adulterated product. 

Therefore, we stated that while 

increasingly sophisticated system 

safeguards and computerized 

monitoring of essential equipment and 

programs help protect data, no 

automated system exists that can 

completely substitute for human 

oversight and supervision. We further 

indicated that while the degree of 

verification is left to the manufacturer’s 

discretion, the exercise of such 

discretion under § 211.68 requires the 

use of routine accuracy checks to 

provide a high degree of assurance that 

input to and output from a computer or 

related system are reliable and accurate. 

We stated our intent that each 

manufacturer exercise reasonable 

judgment based on a variety of factors, 

including, but not limited to, the 

complexity of the computer or related 

system, in developing a method to 

prevent inaccurate data input and 

output (60 FR 4087 at 4089). 

The December 4, 2007, direct final 

rule and companion proposed rule were 

intended to amend the regulations 

involving second-person checks only to 

clarify our longstanding policy that 

verification by a second individual may 

not be necessary when automatic 

equipment is used under § 211.68, and 

that in such situations only one person 

is needed to verify that the automated 

equipment is functioning adequately. 

The amendments were not intended to 

either add to or detract from any 

existing requirements in this regard, but 

only to clarify our longstanding 

interpretation and policy for these 

requirements. We note that the same 

basic considerations apply in this regard 

today as we expressed in the 1995 final 

rule. Although increasingly 

sophisticated controls and safeguards 

have been implemented for some 

automated systems, our policy has been 

that some degree of human oversight, 

supervision, verification, monitoring, or 

checking is still necessary to verify 

proper performance as part of assuring 

the identity, strength, quality, and 

purity of drug products. For suitably 

validated automated systems, even with 

real time alarms, it is still necessary for 

a human to verify that the systems are 

operating as planned and to monitor for 

abnormalities. We agree that the level, 

nature, and frequency of such human 

verification will vary depending on the 

level of automation used as well as the 

nature of the system and controls, and 

the manufacturer has the flexibility and 

responsibility to determine what is 

suitable and necessary. Contrary to the 

comments, we believe that 

manufacturers can conduct human 

verification of automated operations in 

conjunction with the use of PAT in drug 

production. 

For these reasons, we continue to 

believe that human verification is 

necessary to ensure that automated 

systems are functioning properly. 

(Comment 20) One comment stated 

that many current biotech processes 

include component additions and 

deletions in a continuous or periodic 

manner over long periods of time. The 

comment stated that there would be no 

added value in requiring a manual 

verification of this component 

management scheme in a fully 

automated scenario. 

(Response) For the reasons stated in 

our response to comment 19, we believe 

that some degree of human oversight, 

supervision, verification, monitoring, or 

checking is a necessary part of CGMP 

for such processes and that there is 

added value in having greater assurance 

that the automated systems are 

operating properly as intended. We do 

not expect that each individual 

component change must be witnessed in 

person, but rather that a suitable system 

of human oversight be established and 

followed to effectively verify that the 

automated processes are indeed 

operating correctly in the performance 

of these operations. 

(Comment 21) One comment 

maintained that our statement in the 

preamble of the direct final rule that the 

verifying individual may be, but is not 

required to be, the operator is a 


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contradiction of the CGMP regulations, 

which require (in § 211.25(a)) that all 

individuals have the education, 

training, and experience to enable them 

to perform their assigned functions. The 

comment asked why the agency would 

allow an untrained operator to perform 

a sole verification of a critical step if an 

automated system is used and 

recommended that we retract the noted 

preamble statement. 

(Response) The comment incorrectly 

concluded that allowing the verifying 

individual to be a person other than the 

operator would thereby allow an 

untrained individual to perform the 

function of verifying a critical step. 

Section 211.25(a) requires each person 

performing an assigned function to have 

the education, training, and experience, 

or any combination thereof, to enable 

that person to perform the function. 

Thus, any person, whether the operator 

or not, who performs such a verification 

step would necessarily be required to 

have the knowledge, training, and 

experience needed to perform that 

function. Therefore, our preamble 

statement does not conflict with the 

regulations. 

(Comment 22) One comment stated 

that the proposed changes regarding 

second person verification should be 

extended to include § 211.188(a), which 

requires the preparation of batch 

production and control records that 

include an accurate reproduction of the 

appropriate master production or 

control record, checked for accuracy, 

dated, and signed. The comment stated 

that when there is only one signature 

needed, but the system is automated, it 

would also follow that no human 

signature or signature equivalent would 

be necessary, such as in issuance of a 

batch record under § 211.188(a), when 

the record is electronic. The comment 

also stated that in this case, it is 

impossible to check the pages for a true 

and accurate copy. The comment 

recommended revising § 211.68(c) to 

include § 211.188(a) in the listing of 

sections affected and to state that there 

could be single performance verification 

under § 211.188(a). 

(Response) We do not agree with the 

recommended changes to § 211.188(a), 

which would eliminate any human 

verification of the records. As 

previously stated, we are clarifying in 

this rule that the checking of automated 

equipment by one person can satisfy the 

requirements of those regulations that 

address the performance of a step by 

one person and the verification of the 

step by a second person. Our proposal 

regarding verification of operations was 

intended to make clear that only one 

person is needed to verify that 

automated equipment for a processing 

step is functioning properly; we did not 

propose deleting all human verification 

of the step. In addition, we disagree 

with the comment’s apparent contention 

that no human signature would be 

needed for issuance of electronic batch 

production and control records. If such 

records are generated and issued 

electronically as part of an automated 

system, a person must verify that the 

correct records were issued and that 

they are still accurate and complete. We 

believe it is clear that § 211.188(a) 

requires only one check for accuracy, 

with date and signature (which could be 

electronic), and that it does not require 

a separate second check of this step. 

Therefore, no changes to § 211.188(a) 

are necessary or appropriate. 

(Comment 23) Three comments 

addressed second-person verification in 

§ 211.194. Section 211.194(a) requires 

that laboratory records include complete 

data derived from all tests necessary to 

assure compliance with established 

specifications and standards as 

specified in that subsection. Section 

211.194(a)(7) requires that laboratory 

records include the initials or signature 

of the person who performs each test 

and the date(s) the tests were performed. 

Section 211.194(a)(8) requires the 

initials or signature of a second person 

showing that the original records have 

been reviewed for accuracy, 

completeness, and compliance with 

established standards. Two of the 

comments stated that the principle 

behind the proposed second-person 

verification revisions should be 

extended to § 211.194 to include 

checking laboratory records involving 

automated laboratory equipment. The 

first comment recommended revising 

§ 211.194 generally. The second 

comment specifically recommended 

that § 211.194(a)(8) be revised to add 

that if laboratory tests have been 

performed by automated equipment 

under § 211.68, the laboratory record 

need only include the identification of 

one person conducting the review of the 

tests performed by the automated 

system. The comment also asked that 

§ 211.194(a)(8) be added to the list of 

sections affected in § 211.68(c). The 

third comment stated that the failure to 

include § 211.194(a)(7) and (a)(8) in the 

proposed revisions implies that the use 

of automated systems to perform or 

check testing is not allowed. 

(Response) We decline to include 

§ 211.194 among the sections 

enumerated in § 211.68(c) concerning 

second-person verification of operations 

performed by automated equipment. We 

acknowledge that automated equipment 

may be used to conduct certain 

laboratory testing operations. However, 

when automated equipment is used to 

perform a laboratory test, typically a 

person initiates the test and ensures that 

the correct equipment is used and that 

it operates properly. In this situation, 

one person assists in or oversees the 

performance of the laboratory test and a 

second person reviews the records for 

accuracy, completeness, and 

compliance with established standards. 

Thus, the use of equipment to perform 

laboratory tests, though permissible, is 

not a situation in which automated 

equipment (rather than a person) 

performs an operation and a person 

verifies that performance, which is the 

situation addressed in revised 

§ 211.68(c). Therefore, it would not be 

appropriate to include a reference to 

§ 211.194 (or to § 211.194(a)(8) 

specifically) in revised § 211.68(c). 

2. Automatic, Mechanical, and 

Electronic Equipment (§ 211.68) 

(Comment 24) One comment stated 

that § 211.68 is no longer in line with 

the technological improvements of the 

past 30 years and with the increasing 

knowledge of computer validation by 

industry and regulators. The comment 

recommended that § 211.68 be aligned 

with 21 CFR 820.70(i), section 5.4 of the 

ICH Q7A guidance entitled ‘‘Good 

Manufacturing Practice Guidance for 

Active Pharmaceutical Ingredients,’’ and 

the Pharmaceutical Inspection 

Cooperation Scheme’s Annex 11 on 

computerized systems. 

(Response) We decline to adopt the 

suggested revisions because they exceed 

the scope of our proposed revision of 

§ 211.68, which only addressed secondperson verification of operations 

performed by automated equipment. We 

might consider revising other provisions 

of § 211.68 as part of a future 

rulemaking to update the CGMP 

regulations and make them consistent 

with international CGMP provisions. 

(Comment 25) One comment 

recommended that instead of our 

proposed changes to § 211.68(c) and 

other regulations concerning secondperson verification, we revise 

§ 211.68(a), which permits the use of 

automatic, mechanical, or electronic 

equipment in the manufacture, 

processing, packing, and holding of 

drug products. The comment stated that 

the wording of our proposed changes 

only allows for actions to be performed 

by automated equipment and checked 

by a person, which would prevent the 

introduction of automated systems to 

check operations performed by a person. 

The comment also stated that our 

proposed changes would still require 

the involvement of at least one person 


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in each of these circumstances and 

prevent the use of a controlled system 

or systems that both perform and 

independently verify the relevant 

operations. One comment suggested that 

rather than our proposed revisions, the 

desired clarification concerning 

automated equipment and secondperson checks would be better achieved 

by adding to § 211.68(a) the following 

sentence: ‘‘Automated equipment can 

satisfy the requirements for the 

performance of an operation by one 

person and/or checking by another 

person.’’

(Response) We do not agree with the 

recommended change. The proposed 

rule simply clarified our longstanding 

position that only one human check is 

necessary to verify a processing step 

performed by automated equipment. 

The suggested revision of § 211.68(a), 

however, would allow manufacturers to 

rely solely on automated equipment to 

verify the human performance of certain 

processing steps and allow automated 

equipment to both perform and check 

operational steps, which would 

constitute a significant change from the 

current regulations. As stated in our 

response to comment 19, we believe that 

human verification of certain processing 

steps, even when those steps are 

performed by automated equipment, is 

still necessary. 

(Comment 26) One comment stated 

that although proposed § 211.68(c) 

implies that the automated equipment is 

doing the work and a person can verify 

that the work is done, there are cases in 

which a person does the work and 

automated equipment might be able to 

verify the person’s work. The comment 

cited as an example the case in which 

an automated system scans the bar 

codes of ingredients and equipment to 

ensure that the ingredient is correct for 

use with the equipment for that step in 

the process, but the physical addition of 

the ingredient is by the human operator 

(followed by the automated system 

scanning). The comment recommended, 

therefore, that § 211.68(c) be modified to 

allow both the automated system and 

the person to do either the performance 

or the verification tasks for the 

operations addressed by §§ 211.101(c) or 

(d), 211.103, 211.182, 211.188(b)(11), or 

211.194(a)(8), or a single performance 

verification in the case of § 211.188(a). 

(Response) We acknowledge that it 

might be possible to design an 

automated system to verify operations 

performed by humans, but as stated in 

our response to comment 19, we 

continue to believe that some human 

verification of the processing steps 

performed by an automated system is 

necessary. 

(Comment 27) One comment 

suggested revising § 211.68(c) to state 

that automated equipment can satisfy 

the requirements for verification of 

operations addressed by the listed 

sections as follows: (1) If such unit 

operation is fully automated, no manual 

verification is necessary and (2) if there 

is an operator for the automated 

equipment, the verifying individual may 

be, but is not required to be, the 

operator. The comment gave several 

reasons for this change: 

• Automated, validated systems 

equipped with real-time alarms that do 

not require any human intervention 

should not require human verification 

because § 211.68(a) adequately 

addresses the maintenance and 

verification of performance of these 

systems. 

• The need and type of verification 

required should be consistent with the 

level of automation used. For example, 

operations that are not fully automated 

and require operator participation may 

serve as verification of the operator’s 

activities, while fully manual operations 

would require a second human 

verification. 

• As proposed, § 211.68(c) might 

hinder the adoption of PAT (e.g., there 

would be no value added by manual 

verification when components are 

charged in a fully automated manner 

according to a validated algorithm). 

(Response) As stated in our response 

to comment 19, we do not agree with 

the contention that no human 

verification is necessary when fully 

automated systems are used, and we 

therefore decline to make these 

requested changes to § 211.68(c). We 

also do not believe that § 211.68(c) will 

hinder the adoption of PAT. As stated 

in the preamble to the direct final rule, 

we agree that if there is an operator for 

the automated equipment, the verifying 

individual may be, but is not required 

to be, the operator. However, § 211.68(c) 

does not require that the verifying 

individual be the operator, and we do 

not believe that it is necessary that the 

provision explicitly state that the 

verifying individual need not be the 

operator. 

(Comment 28) One comment stated 

that the proposed revision of 

§ 211.68(c), when applied to 

§ 211.188(b), might be more restrictive 

than FDA’s position in Compliance 

Policy Guide (CPG) Sec. 425.500, 

Computerized Drug Processing; 

Identification of ‘‘Persons’’ on Batch 

Production and Control Records 

(formerly CPG 7132a.08). CPG 425.500 

states that when significant steps in the 

manufacturing, processing, packing, or 

holding of a batch are performed, 

supervised, or checked by a 

computerized system, an acceptable 

means of complying with the 

identification requirements in 

§ 211.188(b)(11) would consist of 

conformance to certain requirements. 

The comment maintained that CPG 

425.500 gives companies the flexibility 

to automate not only the performance of 

critical actions but also the supervision 

and checking of these actions if it is 

shown that the efficacy of these controls 

would be at least equivalent to the level 

of efficacy if the verification were done 

by a second person. The comment stated 

that this flexibility should be extended 

to all CGMP sections in which a 

verification is requested. The comment 

therefore asked that § 211.68(c) be 

revised to state that automated 

equipment used for performance of 

operations addressed by §§ 211.101(c) or 

(d), 211.103, 211.182, or 211.188(b)(11) 

can satisfy the requirements included in 

those sections for the performance of an 

operation by one person and checking 

by another person if such equipment is 

used in conformity with § 211.68 and 

one person either performs the 

operations addressed in those sections 

under the control of the automated 

equipment or verifies that these 

operations are performed accurately by 

such equipment. 

(Response) We do not agree with the 

comment’s apparent interpretation of 

CPG 425.500 that the CPG allows for 

elimination of human oversight. The 

purpose of the CPG is to explain what 

constitutes ‘‘identification’’ of persons 

in batch records under § 211.188(b)(11) 

when automated systems are used for 

various functions. The CPG states that 

when an automated system is used to 

perform, directly supervise, or check 

significant steps in the production of a 

drug, the identification requirements in 

§ 211.188(b)(11) are met if there is 

documentation that the system contains 

adequate checks (and documentation of 

the performance of the system itself), 

validation of the system’s performance, 

and recording of specific checks in 

batch records (including initial, 

branching, and final steps). These 

conditions for applying the 

identification requirements to steps 

using automated equipment involve the 

responsibilities of persons. For example, 

a person, rather than automated 

equipment, is needed to record these 

checks of production steps in batch 

records. Therefore, contrary to the 

comment’s implication, the CPG does 

not state that human oversight is 

unnecessary when an automated system 

is involved in the performance, 

supervision, or checking of production 


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steps. All automated systems require 

some level (commensurate with the 

complexity and risk inherent in the 

system) of human oversight or checking 

for expected performance at appropriate 

intervals. Therefore, we decline to 

revise § 211.68(c) as recommended. 

(Comment 29) One comment, 

although supportive of the proposal to 

allow initial activities to be performed 

by automated equipment, objected to 

requiring that the output of an 

automated and adequately validated 

activity be checked for accuracy by a 

person. The comment maintained that 

the act of having validated software and 

its related processes itself constitutes an 

independent check that operations are 

being performed accurately and argued 

that this is more reliable than any 

contemporaneous check by a person. 

The comment therefore asked that 

§ 211.68(c) be changed to state that 

independent checks may consist of 

contemporaneous analysis and 

verification by a second person 

following completion of the activity; or, 

where the automated process has been 

validated to a high degree of confidence, 

the prior validation can satisfy this 

requirement and a second person’s 

check may then consist of verifying the 

validated status of the equipment and 

processes. 

(Response) We do not agree with the 

suggested change. Although we agree 

that it is an important part of process 

controls to ensure the validated status of 

equipment and processes even before 

they are used, we do not believe that 

verifying this validated status can 

satisfy the requirement for checking the 

actual performance of automated 

equipment. However, we believe that 

the requirement in proposed § 211.68(c) 

that one person ‘‘verifies that the 

operations * * * are performed 

accurately’’ by automated equipment 

may have led some comments to believe 

that we were requiring a more specific 

and detailed repetitive type of check 

than we intended. When automated 

equipment is used for operations 

addressed by revised § 211.68(c) in 

conformance with § 211.68, the person 

doing the checking must verify that the 

automated equipment is functioning 

properly and that the operations are 

reliably performed in the intended 

manner. As discussed in the response to 

comment 19, the nature and frequency 

necessary for such verification will vary 

depending on the level of automation 

used as well as the nature of the system 

and controls. We do not expect that it 

will normally be necessary, under 

§ 211.68(c), for a person to repeat all of 

the automatic calculations by hand to 

ensure their accuracy. Therefore, we 

have revised § 211.68(c) to clarify that 

automated equipment can be used to 

perform an operation when the 

performance is checked by a person 

provided that ‘‘such equipment is used 

in conformity with this section 

[§ 211.68] and one person checks that 

the equipment properly performed the 

operation.’’

3. Verification of Weighing, Measuring, 

or Subdividing Operations (§ 211.101(c)) 

Section 211.101 concerns charge-in of 

components. Proposed § 211.101(c) 

stated, in part, that if the weighing, 

measuring, or subdividing operations 

for components are performed by 

automated equipment under § 211.68, 

only one person is needed to ensure that 

the requirements in § 211.101(c)(1), 

(c)(2), and (c)(3) are met. 

(Comment 30) One comment 

proposed broadening § 211.101(c) to 

clarify that the weighing, measuring, 

and subdividing operations could be 

either performed by automated 

equipment or checked by automated 

equipment after being performed 

manually. 

(Response) We decline to make this 

suggested change for the reasons 

provided in response to comments 19 

and 25. Revised § 211.101(c) only 

permits human checking of weighing, 

measuring, and subdividing operations 

performed by automated equipment; we 

did not propose to allow automated 

checking of these operations. We 

continue to believe that human 

verification of these processing steps is 

necessary. 

(Comment 31) One comment stated 

that with respect to medical gases, there 

is no measurement of components to be 

dispensed for manufacturing that needs 

to be double-checked to ensure that the 

right quantity of the right component 

was added, because transfers of pure 

gases are within product-specific 

systems. However, the comment stated, 

with respect to gas mixtures, it is 

appropriate to have a verification of 

hook-ups as different components are 

added unless there is subsequent purity 

testing for each component. 

(Response) We decline to exempt 

single gas filling operations from certain 

requirements of § 211.101(c) as 

recommended because such a change 

would exceed the scope of our proposed 

change to § 211.101(c), which only 

addressed human checking of weighing, 

measuring, and subdividing operations 

performed by automated equipment. We 

might consider in a future rulemaking 

whether it is appropriate to exempt 

medical gases from certain requirements 

of § 211.101(c). 

4. Verification of Components Added to 

the Batch (§ 211.101(d)) 

Proposed § 211.101(d) would have 

required that each component be either 

added to the batch by one person and 

verified by a second person or, if the 

components are added by automated 

equipment under § 211.68, only verified 

by one person. 

(Comment 32) One comment stated 

that eliminating a double check for 

adding materials to a batch is 

problematic because an error in those 

operations would be difficult to detect 

and might not be discovered before the 

product is distributed, which could 

result in patient injury and product 

recall. The comment recommended 

deleting or modifying the ability to use 

a sole verifier for operations involving 

addition of materials. 

(Response) The comment appears to 

suggest that we proposed to eliminate 

the requirements concerning 

verification that appropriate 

components were added to a batch. The 

revisions we are adopting do not 

eliminate the requirement to verify 

performance in § 211.101(d); they 

simply codify our longstanding policy 

that components may be added either by 

a person or by suitable automated 

equipment. The addition of components 

still must be checked by a person. 

(Comment 33) One comment stated 

that under the proposed change to 

§ 211.101(d), if a validated system 

performs a function, it is acceptable for 

one person to verify that action, but if 

an automated system prompts an 

operator to perform a function, a second 

person would be required to confirm the 

proper execution of the action. The 

comment recommended changing 

§ 211.101(d) to state that each 

component must be added to the batch 

by one person and verified by a second 

person, ‘‘unless the components are 

added by automated equipment under 

§ 211.68, in which case verification can 

be performed by one person.’’

(Response) We decline to accept the 

suggested change because we do not 

believe that it constitutes a substantive 

difference from the language of 

proposed § 211.101(d). It is irrelevant 

whether use of a particular automated 

system for component charge-in 

requires an operator to perform a related 

function; in either case, verification of 

the charge-in operation(s) must be 

performed by a person. 

(Comment 34) One comment 

recommended changing § 211.101(d) to 

specify that the weighing, measuring, or 

subdividing operations might be 

performed by automated equipment or 

checked by automated equipment after 


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being performed manually. The 

comment also stated that in many 

instances, the verification by a person of 

actions performed by automated 

equipment can only be done on the 

basis of outputs from the equipment. As 

an example, the comment stated, when 

the introduction of components in a 

liquid production line is fully 

automated, there is no possibility for the 

operator to check that the correct 

amount of materials was incorporated 

into the batch other than by relying on 

information given by the same 

automated equipment. The comment 

stated that in that case, the verification 

would consist of confirming that the 

component’s incorporation process was 

completed without errors or alarms. 

(Response) We decline to make this 

suggested change for the reasons stated 

in response to comments 19 and 25. 

Revised § 211.101(d) only permits 

human checking of component 

additions performed by automated 

equipment; we did not propose to allow 

automated checking of component 

additions performed by humans. In the 

example given in the comment, human 

verification that components were 

properly added to the liquid production 

line by the automated equipment would 

be needed to ensure that the equipment 

performed properly. We continue to 

believe that human verification of this 

processing step is necessary. 

5. Calculation of Yield (§ 211.103) 

We proposed, in § 211.103, to require 

that calculations of actual yields and 

percentages of theoretical yields be 

performed by one person and 

independently verified by a second 

person or, if the yield is calculated by 

automated equipment under § 211.68, 

be independently verified by one 

person. 

(Comment 35) One comment stated 

that it is not necessary to have a person 

recalculate a yield manually after a 

validated system does it automatically. 

The comment asked that § 211.103 be 

revised to limit the human interaction to 

data entry and data verification, but not 

recalculation of yields if yields are 

calculated by a validated, automated 

system. A similar comment stated that 

§ 211.103 should be changed to state 

that if the yield is calculated by 

automated equipment, a person must 

verify the data entries, rather than 

regenerate the calculations. 

(Response) We do not believe that the 

recommended changes are needed or 

appropriate. Revised § 211.103 does not 

require that all yield calculations be 

repeated manually. Manual 

recalculation might be a suitable 

approach to verifying yield calculations, 

but § 211.103 also permits the use of 

other approaches, including verification 

that automated equipment functioned 

properly while performing yield 

calculations. 

(Comment 36) One comment 

reiterated the views expressed in its 

comments on the CGMP for medical 

gases draft guidance. Thus, the 

comment requested that the 

requirements for yield calculation in 

§ 211.103 not be applied to medical 

gases because of the atmospheric-gasseparation and cylinder-filling processes 

associated with medical gases. In further 

support of its position, the comment 

referred to an FDA publication (Human 

Drug CGMP Notes, vol. 5, no. 2, June 

1997) in which the agency stated that it 

would propose to revise the CGMP 

regulations to exempt medical gases 

from the requirements for yield 

reconciliation. 

(Response) We decline to exempt 

medical gases from the requirements for 

yield calculation in § 211.103 as 

recommended because this would 

exceed the scope of our proposed 

change to § 211.103, which addressed 

only human checking of yield 

calculations performed by automated 

equipment. We might consider in a 

future CGMP rulemaking whether it is 

appropriate to exempt medical gases 

from certain requirements of § 211.103. 

In addition, we might consider 

providing specific recommendations to 

medical gas manufacturers to help them 

comply with the requirements for 

calculating yields in the course of 

finalizing the draft guidance on CGMP 

for medical gases. 

6. Equipment Cleaning and Use Log 

(§ 211.182) 

We proposed, in § 211.182, to require 

the persons performing and doublechecking equipment cleaning and 

maintenance (or, if the cleaning and 

maintenance is performed using 

automated equipment under § 211.68, 

only the person verifying the cleaning 

and maintenance done by the automated 

equipment) to date and sign or initial 

the log indicating that the work was 

performed. 

(Comment 37) One comment stated 

that eliminating a double check for 

cleaning equipment is problematic 

because an error in those operations 

would be difficult to detect and might 

not be discovered before the product is 

distributed, which could result in 

patient injury and product recall. The 

comment recommended deleting or 

modifying the ability to use a sole 

verifier for operations involving 

equipment cleaning. 

(Response) The comment appears to 

suggest that we proposed to eliminate 

the requirements concerning 

verification that equipment was 

appropriately cleaned and maintained. 

The revisions we are adopting do not 

eliminate the requirement to verify 

performance in § 211.182; they simply 

codify our longstanding policy that 

equipment may be cleaned and 

maintained either by a person or by 

suitable automated equipment. Cleaning 

and maintenance of equipment must 

still be checked by a person. 

(Comment 38) One comment stated 

that operations addressed by §§ 211.182 

and 211.188(b)(11) are often performed 

using semi-automated equipment that 

requires an operator to select the correct 

menu. The comment stated that major 

pieces of equipment such as ‘‘Clean in 

Place’’ (CIP) skids and vial washers 

often require the operator to select the 

appropriate process menu before the 

execution of the actual automated cycle 

by the equipment’s controller. The 

comment asked whether, when operator 

input is necessary to select but not 

perform an operation, the signature of 

the operator selecting the menu is 

required in cases when there is a second 

signature that verifies the performance 

of the cycle. One comment requested 

that we verify in § 211.182 or the 

preamble of the final rule that a single 

verification remains sufficient when 

automated but portable cleaning skids 

are used. 

(Response) We do not believe that 

initiation of the automated cleaning 

cycle by a human operator constitutes 

performance of the cleaning process for 

purposes of revised § 211.182. The 

revised regulation requires that after an 

automated cleaning process (such as 

CIP) is completed, the human operator 

must date and sign or initial the log 

verifying that the equipment performed 

the automated cleaning process 

properly. The regulation does not 

require the operator to date and sign or 

initial the log simply for the initiation 

of the automated cleaning cycle. This 

approach applies to both portable 

equipment skids and fixed equipment. 

(Comment 39) One comment stated 

that in many instances, the human 

verification of an action performed by 

automated equipment can only be done 

on the basis of outputs from the 

equipment. As an example, the 

comment stated, when equipment is 

cleaned through CIP, the verification 

should consist of confirming that the 

system reports the cleaning as 

successfully completed without alarms. 

(Response) What constitutes adequate 

verification that equipment has been 

properly cleaned or maintained using 


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automated equipment in accordance 

with revised § 211.182 depends on the 

particular circumstances. The outputs 

from the automated equipment will 

normally be key factors, but not 

necessarily the only ones. The 

manufacturer should determine the 

reliability of the outputs and 

periodically check them. For example, it 

might be appropriate to verify that an 

alarm is working properly and is 

successfully monitoring the equipment’s 

critical functions. There might be other 

ways of verifying the adequate 

performance of cleaning and 

maintenance by automated equipment, 

such as by monitoring the usage of 

cleaning supplies in a cleaning cycle or 

conducting an independent check of the 

rinse. 

(Comment 40) One comment stated 

that for most medical gas systems, 

routine or periodic cleaning is not 

performed because the industry is 

characterized by product-specific closed 

systems that undergo an appropriate 

cleaning process before initial use. The 

comment stated that because of the high 

number of batches produced on a 

weekly/monthly basis in the medical 

gas industry, it is more appropriate to 

keep cleaning and maintenance records 

separate from batch records. The 

comment maintained that although 

requiring documentation of equipment 

cleaning, maintenance, and use in 

individual equipment logs may be 

appropriate for traditional 

pharmaceuticals (where key processing 

equipment may be used for multiple 

products and lot numbers), applying 

this requirement to medical gases would 

make retrieval and management of 

cleaning and maintenance records much 

more difficult. The comment added that 

use logs are not appropriate for medical 

gases because batch record 

documentation provides a consecutive 

listing of products manufactured on 

each system. 

(Response) We decline to exempt 

medical gases from certain requirements 

of § 211.182 as recommended because 

this would exceed the scope of our 

proposed change to § 211.182, which 

addressed human verification of 

cleaning steps performed by automated 

equipment. We might consider in a 

future CGMP rulemaking whether it is 

appropriate to exempt medical gases 

from certain requirements of § 211.182. 

7. Batch Production and Control 

Records (§ 211.188(b)(11)) 

Section 211.188 concerns batch 

production and control records. 

Proposed 211.188(b)(11) specified that 

when a significant step in the operation 

is performed by automated equipment 

under § 211.68, the record would need 

to identify the person checking the 

significant step performed by the 

automated equipment. 

(Comment 41) One comment stated 

that § 211.188(b)(11) should be changed 

to state that a significant manufacturing 

step could be either performed or 

checked by automated equipment. The 

comment stated that this approach is 

permitted by CPG 425.500. 

(Response) We decline to make this 

suggested change. As stated in our 

response to comment 28, CPG 425.500 

does not, as the comment implies, state 

that human oversight is unnecessary 

when an automated system is involved 

in the performance, supervision, or 

checking of production steps. To revise 

§ 211.188(b)(11) as recommended by the 

comment might be interpreted as 

permitting manufacturers to rely solely 

on automated equipment to verify the 

human performance of certain 

production steps. As stated in our 

response to comments 19 and 25, we 

believe that human verification of 

processing steps is still necessary. 

F. Miscellaneous Minor Changes Based 

on 1996 Proposal 

We proposed to make miscellaneous 

minor changes to CGMP regulations to 

clarify certain manufacturing, quality 

control, and documentation 

requirements and to align the 

regulations with industry practice. 

1. Storage of Untested Components, 

Drug Product Containers, and Closures 

(§ 211.82(b)) 

The version of § 211.82(b) amended 

by this final rule stated: ‘‘Components, 

drug product containers, and closures 

shall be stored under quarantine until 

they have been tested or examined, as 

appropriate, and released.’’ We 

proposed to replace the phrase ‘‘as 

appropriate’’ with the phrase 

‘‘whichever is appropriate’’ to eliminate 

any ambiguity in § 211.82(b) and to 

emphasize that it is accepted industry 

practice to conduct some testing or 

examination before components, drug 

product containers, or closures are 

released from quarantine. 

(Comment 42) One comment 

requested that medical gas containerclosure assemblies returned from 

customers and reused be exempted from 

§ 211.82(b). The comment stated that 

assembled cylinder/valve medical gas 

combinations are reused and handled 

differently than they would be at the 

time of initial receipt. The comment 

stated that returned assemblies are 

individually inspected for all critical 

quality issues immediately before 

filling; those assemblies that do not 

meet the inspection criteria are moved 

to a quarantine area. The comment 

stated that this practice satisfies the 

intention that components, containers, 

and closures be inspected to ensure that 

unacceptable assemblies are not used in 

the manufacturing process. 

(Response) Under revised § 211.82(b), 

manufacturers of medical gases would 

retain the ability to sequester and 

inspect returned valve/cylinder 

assemblies before refilling in accordance 

with the industry practice described by 

the comment. The practice described by 

the comment is to have the assembled 

valve/cylinders placed in a segregated 

area (apparently not identified using the 

word ‘‘quarantine’’), examined for 

conformance to quality standards, and, 

if the criteria are met, immediately 

made available for refilling. This 

practice would meet the requirement for 

a quarantine status if goods in such 

areas or under such a status are not 

acceptable for use as-is unless and until 

they are qualified to be suitable for use. 

Therefore, we do not believe that the 

practice as described violates revised 

§ 211.82(b), and there is no need to 

exempt medical gas manufacturers from 

this requirement. 

2. Cleaning of Component Container 

Samples (§ 211.84(c)(1)) 

The version of § 211.84(c)(1) amended 

by this final rule stated: ‘‘The containers 

of components selected [for sampling] 

shall be cleaned where necessary, by 

appropriate means.’’ We proposed to 

replace the phrase ‘‘where necessary, by 

appropriate means’’ with the phrase 

‘‘when necessary in a manner to prevent 

introduction of contaminants into the 

component.’’ This change was intended 

to clarify that the act of cleaning is done 

for a particular purpose—to prevent the 

introduction of contaminants—and 

must be done unless cleaning is not 

necessary to prevent contamination. 

(Comment 43) One comment 

expressed concern that the proposed 

change might be interpreted to require 

validation of this prevention of 

contamination during sampling. The 

comment requested that we confirm that 

our intent is to place the contamination 

concern into the controls and 

procedures for sampling and into the 

training of staff who perform these 

activities, rather than to require 

validation of the absence of 

contamination. 

(Response) Revised § 211.84(c)(1) 

does not require manufacturers to 

conduct validation studies to prove that 

the method of sampling prevents 

contamination. When properly designed 

and followed, the cleaning procedures, 

training, and facility and equipment 


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controls, along with supervisory and 

quality unit oversight, should ensure 

compliance with § 211.84(c)(1). 

3. Editorial Changes (§§ 211.84(d)(3) and 

211.160(b)(1)) 

We proposed minor editorial changes 

to two regulations, §§ 211.84(d)(3) and 

211.160(b)(1). The version of 

§ 211.84(d)(3) amended by this final rule 

stated: ‘‘Containers and closures shall be 

tested for conformance with all 

appropriate written procedures.’’ We 

proposed to replace the word 

‘‘conformance’’ with ‘‘conformity’’ and 

the word ‘‘procedures’’ with 

‘‘specifications.’’ The first sentence of 

the version of § 211.160(b)(1) amended 

by this final rule stated: ‘‘Determination 

of conformance to appropriate written 

specifications for the acceptance of each 

lot within each shipment of 

components, drug product containers, 

closures, and labeling used in the 

manufacture, processing, packing, or 

holding of drug products.’’ We proposed 

to replace the word ‘‘conformance’’ with 

‘‘conformity’’ and the word 

‘‘appropriate’’ with ‘‘applicable.’’ We 

stated in the preamble to the direct final 

rule that these revisions would provide 

clarity without changing the meaning or 

intent of these regulations. We received 

no comments on these proposed 

changes, and we have revised these 

provisions as proposed. 

IV. Analysis of Impacts 

FDA has examined the impacts of this 

final rule under Executive Order 12866 

and the Regulatory Flexibility Act (5 

U.S.C. 601–612), and the Unfunded 

Mandates Reform Act of 1995 (Public 

Law 104–4). Executive Order 12866 

directs agencies to assess all costs and 

benefits of available regulatory 

alternatives and, when regulation is 

necessary, to select regulatory 

approaches that maximize net benefits 

(including potential economic, 

environmental, public health and safety, 

and other advantages; distributive 

impacts; and equity). The agency 

believes that this final rule is not a 

significant regulatory action as defined 

by the Executive order, because the rule 

either clarifies the agency’s 

longstanding interpretation of, or 

increases latitude for manufacturers in 

complying with, existing CGMP 

requirements. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because this final rule does not 

impose any new regulatory obligations, 

the agency believes that the rule will not 

have a significant economic impact on 

a substantial number of small entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $127 

million, using the most current (2006) 

Implicit Price Deflator for the Gross 

Domestic Product. This rule does not 

result in any 1-year expenditure that 

would meet or exceed this amount. 

The purpose of this final rule is to 

update the codified language to reflect 

current practice and to harmonize 

requirements in the CGMP regulations 

with requirements in other regulations 

and with international CGMP standards. 

It does not impose any additional 

requirements; therefore, industry will 

not incur incremental compliance costs 

for these proposed changes. 

V. Environmental Impact 

FDA concludes that issuing these 

clarifying amendments to the CGMP 

regulations will not have a significant 

impact on the human environment. 

Therefore, an environmental impact 

statement is not required. 

VI. Federalism 

FDA has analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. We have 

determined that the rule does not 

contain policies that have substantial 

direct effects on the States, on the 

relationship between the National 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. Accordingly, we 

have concluded that the rule does not 

contain policies that have federalism 

implications as defined in the Executive 

order and, consequently, a federalism 

summary impact statement is not 

required. 

VII. Paperwork Reduction Act of 1995 

This final rule contains collections of 

information that are subject to review by 

the Office of Management and Budget 

(OMB) under the Paperwork Reduction 

Act of 1995 (44 U.S.C. 3501–3520) (the 

PRA). The collections of information 

(recordkeeping requirements) in part 

211 have already been approved by 

OMB under control number 0910–0139. 

The final rule amends certain sections 

of part 211 as well as § 210.3 (§ 210.3 

does not contain information collection 

requirements). As concluded in section 

IV of this document, ‘‘Analysis of 

Impacts,’’ the purpose of the final rule 

is to update the regulations to reflect 

current practice and to harmonize 

requirements in the CGMP regulations 

with requirements in other regulations 

and with international CGMP standards. 

The final rule does not impose any 

additional requirements. Thus, because 

the final rule does not substantively 

revise the information collection 

requirements in part 211 or add new 

information collection requirements, 

there is no need to conduct an analysis 

under the PRA. 

List of Subjects 

21 CFR Part 210 

Drugs, Packaging and containers. 

21 CFR Part 211 

Drugs, Labeling, Laboratories, 

Packaging and containers, Prescription 

drugs, Reporting and recordkeeping 

requirements, Warehouses. 

■ Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, 21 CFR parts 210 

and 211 are amended as follows: 

PART 210—CURRENT GOOD 

MANUFACTURING PRACTICE IN 

MANUFACTURING, PROCESSING, 

PACKING, OR HOLDING OF DRUGS; 

GENERAL 

■ 1. The authority citation for 21 CFR 

part 210 continues to read as follows: 

Authority: 21 U.S.C. 321, 351, 352, 355, 

360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264. 

■ 2. Section 210.3 is amended by 

revising paragraph (b)(6) to read as 

follows: 

§ 210.3 Definitions. 

(b) * * * 

(6) Nonfiber releasing filter means any 

filter, which after appropriate 

pretreatment such as washing or 

flushing, will not release fibers into the 

component or drug product that is being 

filtered. 

* * * * * 

PART 211—CURRENT GOOD 

MANUFACTURING PRACTICE FOR 

FINISHED PHARMACEUTICALS 

■ 3. The authority citation for 21 CFR 

part 211 continues to read as follows: 

Authority: 21 U.S.C. 321, 351, 352, 355, 

360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264. 

■ 4. Section 211.67 is amended by 

revising paragraph (a) to read as follows: 


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51932 Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 / Rules and Regulations 

§ 211.67 Equipment cleaning and 

maintenance. 

(a) Equipment and utensils shall be 

cleaned, maintained, and, as 

appropriate for the nature of the drug, 

sanitized and/or sterilized at 

appropriate intervals to prevent 

malfunctions or contamination that 

would alter the safety, identity, strength, 

quality, or purity of the drug product 

beyond the official or other established 

requirements. 

* * * * * 

■ 5. Section 211.68 is amended by 

adding paragraph (c) to read as follows: 

§ 211.68 Automatic, mechanical, and 

electronic equipment. 

* * * * * 

(c) Such automated equipment used 

for performance of operations addressed 

by §§ 211.101(c) or (d), 211.103, 

211.182, or 211.188(b)(11) can satisfy 

the requirements included in those 

sections relating to the performance of 

an operation by one person and 

checking by another person if such 

equipment is used in conformity with 

this section, and one person checks that 

the equipment properly performed the 

operation. 

■ 6. Section 211.72 is revised to read as 

follows: 

§ 211.72 Filters. 

Filters for liquid filtration used in the 

manufacture, processing, or packing of 

injectable drug products intended for 

human use shall not release fibers into 

such products. Fiber-releasing filters 

may be used when it is not possible to 

manufacture such products without the 

use of these filters. If use of a fiberreleasing filter is necessary, an 

additional nonfiber-releasing filter 

having a maximum nominal pore size 

rating of 0.2 micron (0.45 micron if the 

manufacturing conditions so dictate) 

shall subsequently be used to reduce the 

content of particles in the injectable 

drug product. The use of an asbestoscontaining filter is prohibited. 

■ 7. Section 211.82 is amended by 

revising paragraph (b) to read as follows: 

§ 211.82 Receipt and storage of untested 

components, drug product containers, and 

closures. 

* * * * * 

(b) Components, drug product 

containers, and closures shall be stored 

under quarantine until they have been 

tested or examined, whichever is 

appropriate, and released. Storage 

within the area shall conform to the 

requirements of § 211.80. 

■ 8. Section 211.84 is amended by 

revising paragraphs (c)(1), (d)(3), and 

(d)(6) to read as follows: 

§ 211.84 Testing and approval or rejection 

of components, drug product containers, 

and closures. 

* * * * * 

(c) * * * 

(1) The containers of components 

selected shall be cleaned when 

necessary in a manner to prevent 

introduction of contaminants into the 

component. 

* * * * * 

(d) * * * 

(3) Containers and closures shall be 

tested for conformity with all 

appropriate written specifications. In 

lieu of such testing by the manufacturer, 

a certificate of testing may be accepted 

from the supplier, provided that at least 

a visual identification is conducted on 

such containers/closures by the 

manufacturer and provided that the 

manufacturer establishes the reliability 

of the supplier’s test results through 

appropriate validation of the supplier’s 

test results at appropriate intervals. 

* * * * * 

(6) Each lot of a component, drug 

product container, or closure with 

potential for microbiological 

contamination that is objectionable in 

view of its intended use shall be 

subjected to microbiological tests before 

use. 

* * * * * 

■ 9. Section 211.94 is amended by 

revising paragraph (c) as follows: 

§ 211.94 Drug product containers and 

closures. 

* * * * * 

(c) Drug product containers and 

closures shall be clean and, where 

indicated by the nature of the drug, 

sterilized and processed to remove 

pyrogenic properties to assure that they 

are suitable for their intended use. Such 

depyrogenation processes shall be 

validated. 

* * * * * 

■ 10. Section 211.101 is amended by 

revising paragraphs (c) and (d) to read 

as follows: 

§ 211.101 Charge-in of components. 

* * * * * 

(c) Weighing, measuring, or 

subdividing operations for components 

shall be adequately supervised. Each 

container of component dispensed to 

manufacturing shall be examined by a 

second person to assure that: 

(1) The component was released by 

the quality control unit; 

(2) The weight or measure is correct 

as stated in the batch production 

records; 

(3) The containers are properly 

identified. If the weighing, measuring, 

or subdividing operations are performed 

by automated equipment under 

§ 211.68, only one person is needed to 

assure paragraphs (c)(1), (c)(2), and 

(c)(3) of this section. 

(d) Each component shall either be 

added to the batch by one person and 

verified by a second person or, if the 

components are added by automated 

equipment under § 211.68, only verified 

by one person. 

■ 11. Section 211.103 is revised to read 

as follows: 

§ 211.103 Calculation of yield. 

Actual yields and percentages of 

theoretical yield shall be determined at 

the conclusion of each appropriate 

phase of manufacturing, processing, 

packaging, or holding of the drug 

product. Such calculations shall either 

be performed by one person and 

independently verified by a second 

person, or, if the yield is calculated by 

automated equipment under § 211.68, 

be independently verified by one 

person. 

■ 12. Section 211.110 is amended by 

revising paragraph (a) introductory text 

and by adding paragraph (a)(6) to read 

as follows: 

§ 211.110 Sampling and testing of inprocess materials and drug products. 

(a) To assure batch uniformity and 

integrity of drug products, written 

procedures shall be established and 

followed that describe the in-process 

controls, and tests, or examinations to 

be conducted on appropriate samples of 

in-process materials of each batch. Such 

control procedures shall be established 

to monitor the output and to validate 

the performance of those manufacturing 

processes that may be responsible for 

causing variability in the characteristics 

of in-process material and the drug 

product. Such control procedures shall 

include, but are not limited to, the 

following, where appropriate: 

* * * * * 

(6) Bioburden testing. 

* * * * * 

■ 13. Section 211.113 is amended by 

revising paragraph (b) to read as follows: 

§ 211.113 Control of microbiological 

contamination. 

* * * * * 

(b) Appropriate written procedures, 

designed to prevent microbiological 

contamination of drug products 

purporting to be sterile, shall be 

established and followed. Such 

procedures shall include validation of 

all aseptic and sterilization processes. 

■ 14. Section 211.160 is amended by 

revising paragraph (b)(1) to read as 

follows: 


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Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 / Rules and Regulations 51933 

1 68 FR 4422–4429 (January 29, 2003). 

2 71 FR 1971–1976 (January 12, 2006). 

§ 211.160 General requirements. 

* * * * * 

(b) * * * 

(1) Determination of conformity to 

applicable written specifications for the 

acceptance of each lot within each 

shipment of components, drug product 

containers, closures, and labeling used 

in the manufacture, processing, packing, 

or holding of drug products. The 

specifications shall include a 

description of the sampling and testing 

procedures used. Samples shall be 

representative and adequately 

identified. Such procedures shall also 

require appropriate retesting of any 

component, drug product container, or 

closure that is subject to deterioration. 

* * * * * 

■ 15. Section 211.182 is revised to read 

as follows: 

§ 211.182 Equipment cleaning and use log. 

A written record of major equipment 

cleaning, maintenance (except routine 

maintenance such as lubrication and 

adjustments), and use shall be included 

in individual equipment logs that show 

the date, time, product, and lot number 

of each batch processed. If equipment is 

dedicated to manufacture of one 

product, then individual equipment logs 

are not required, provided that lots or 

batches of such product follow in 

numerical order and are manufactured 

in numerical sequence. In cases where 

dedicated equipment is employed, the 

records of cleaning, maintenance, and 

use shall be part of the batch record. 

The persons performing and doublechecking the cleaning and maintenance 

(or, if the cleaning and maintenance is 

performed using automated equipment 

under § 211.68, just the person verifying 

the cleaning and maintenance done by 

the automated equipment) shall date 

and sign or initial the log indicating that 

the work was performed. Entries in the 

log shall be in chronological order. 

■ 16. Section 211.188 is amended by 

revising paragraph (b)(11) to read as 

follows: 

§ 211.188 Batch production and control 

records. 

* * * * * 

(b) * * * 

(11) Identification of the persons 

performing and directly supervising or 

checking each significant step in the 

operation, or if a significant step in the 

operation is performed by automated 

equipment under § 211.68, the 

identification of the person checking the 

significant step performed by the 

automated equipment. 

* * * * * 

Dated: August 22, 2008. 

Jeffrey Shuren, 

Associate Commissioner for Policy and 

Planning. 

[FR Doc. E8–20709 Filed 9–5–08; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF THE TREASURY 

Office of Foreign Assets Control 

31 CFR Part 501 

Economic Sanctions Enforcement 

Guidelines 

AGENCY: Office of Foreign Assets 

Control, Treasury. 

ACTION: Interim final rule with request 

for comments. 

SUMMARY: The Office of Foreign Assets 

Control (OFAC) of the U.S. Department 

of the Treasury is issuing this interim 

final rule, ‘‘Economic Sanctions 

Enforcement Guidelines,’’ as 

enforcement guidance for persons 

subject to the requirements of U.S. 

sanctions statutes, Executive orders and 

regulations. This interim final rule 

supersedes the Economic Sanctions 

Enforcement Guidelines set forth in 

OFAC’s proposed rule of January 29, 

2003 1 (with the exception of the 

proposed Appendix to the Cuban Assets 

Control Regulations, 31 CFR Part 515, 

set forth therein) and the Economic 

Sanctions Enforcement Procedures for 

Banking Institutions set forth in OFAC’s 

interim final rule of January 12, 2006.2

These Enforcement Guidelines are 

published as an appendix to the 

Reporting, Procedures and Penalties 

Regulations, 31 CFR Part 501. 

DATES: The interim final rule is effective 

September 8, 2008. Written comments 

may be submitted on or before 

November 7, 2008. 

ADDRESSES: You may submit comments 

by any of the following methods: 

Federal eRulemaking Portal: http:// 

www.regulations.gov. 

Follow the instructions for submitting 

comments. 

Fax: Attn: Request for Comments 

(Enforcement Guidelines) (202) 622–

1657. 

Mail: Attn: Request for Comments 

(Enforcement Guidelines), Office of 

Foreign Assets Control, Department of 

the Treasury, 1500 Pennsylvania 

Avenue, NW., Washington, DC 20220. 

Instructions: All submissions received 

must include the agency name and the 

Federal Register Doc. number that 

appears at the end of this document. 

Comments received will be made 

available to the public via 

regulations.gov or upon request, without 

change and including any personal 

information provided. 

FOR FURTHER INFORMATION CONTACT: 

Elton Ellison, Assistant Director, Civil 

Penalties, (202) 622–6140 (not a toll-free 

call). 

SUPPLEMENTARY INFORMATION: 

Electronic Availability 

This document and additional 

information concerning OFAC are 

available from OFAC’s Web site 

(http://www.treas.gov/ofac) or via 

facsimile through a 24-hour fax-ondemand service, tel.: (202) 622–0077. 

Procedural Requirements 

Because this interim final rule 

imposes no obligations on any person, 

but only explains OFAC’s enforcement 

policy and procedures based on existing 

substantive rules, prior notice and 

public comment are not required 

pursuant to 5 U.S.C. 553(b)(A). Because 

no notice of proposed rulemaking is 

required, the provisions of the 

Regulatory Flexibility Act (5 U.S.C. 

chapter 6) do not apply. This interim 

final rule is not a significant regulatory 

action for purposes of Executive Order 

12866. 

Although a prior notice of proposed 

rulemaking is not required, as discussed 

in more detail below, OFAC is soliciting 

comments on this interim final rule in 

order to consider how it might make 

improvements to these Guidelines. 

Comments must be submitted in 

writing. The addresses and deadline for 

submitting comments appear near the 

beginning of this notice. OFAC will not 

accept comments accompanied by a 

request that all or part of the submission 

be treated confidentially because of its 

business proprietary nature or for any 

other reason. All comments received by 

the deadline will be a matter of public 

record and will be made available to the 

public via regulations.gov. 

The collections of information related 

to the Reporting, Procedures and 

Penalties Regulations have been 

previously approved by the Office of 

Management and Budget (OMB) under 

control number 1505–0164. A small 

adjustment to that collection has been 

submitted to OMB in order to take into 

account the voluntary self-disclosure 

process set forth in these Guidelines. An 

agency may not conduct or sponsor, and 

a person is not required to respond to, 

a collection of information unless it 

displays a valid control number 

assigned by OMB. This collection of 


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