20104 Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 210 and 211

[Docket No. 95N–0362]

RIN 0910–AA45

Current Good Manufacturing Practice;

Proposed Amendment of Certain

Requirements for Finished

Pharmaceuticals

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend certain requirements of the

current good manufacturing practice

(CGMP) regulations for finished

pharmaceuticals. These amendments

would clarify certain manufacturing,

quality control, and documentation

requirements and would ensure that the

regulations more accurately encompass

CGMP. In addition, the agency is

updating the requirements for process

and methods validation to incorporate

guidance previously issued to industry

and to reflect current practice. These

proposed amendments are intended to

enhance the integrity of the drug

manufacturing process and the safety of

drug products.

DATES: Submit written comments on the

proposed rule by August 1, 1996.

Submit written comments on the

information collection requirements by

June 3, 1996. FDA proposes that any

final rule that may issue based upon this

proposal become effective 90 days after

its date of publication in the Federal

Register.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857. Submit

written comments on the information

collection requirements to the Office of

Information and Regulatory Affairs,

OMB, New Executive Office Bldg., 725

17th St. NW., rm. 10235, Washington,

DC 20503.

FOR FURTHER INFORMATION CONTACT:

Thomas C. Kuchenberg, Center for

Drug Evaluation and Research

(HFD–7), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–594–

1046; or

John M. Dietrick, Center for Drug

Evaluation and Research (HFD–

325), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–594–

0098; or

William G. Marnane, Center for

Veterinary Medicine (HFV–143),

Food and Drug Administration,

7500 Standish Pl., Rockville, MD

20855, 301–594–0678; or

Nancy Roscioli, Center for Biologics

Evaluation and Research (HFM–

205), Food and Drug

Administration, 1401 Rockville

Pike, Rockville, MD 20852–1448,

301–827–3031.

To obtain a copy of this document,

contact the Division of Congressional

and Public Affairs (HFM–44), Center for

Biologics Evaluation and Research,

Food and Drug Administration, 1401

Rockville Pike, Rockville, MD 20852–

1448. Send one self-addressed adhesive

label to assist that office in processing

your requests.

The document may also be obtained

by mail or FAX by calling the Center for

Biologics Evaluation and Research

Voice Information System at 1–800–

835–4709.

Persons with access to the INTERNET

may obtain the document in several

ways.

Users of ‘‘Web Browser’’ software,

may obtain this document via the World

Wide Web by using the following

Uniform Resource Locators (URL’s):

http://www.fda.gov/cber/cberftp.html or

ftp://ftp.fda.gov/CBER/

The document may also be obtained

via File Transfer Protocol (FTP).

Requesters should connect to the FDA

FTP Server,

FTP.FDA.GOV(192.73.61.21). The

Center for Biologics Evaluation and

Research (CBER) documents are

maintained in a subdirectory called

‘‘CBER’’ on the server. Logins with the

user name of anonymous are permitted,

and the user’s e-mail address should be

sent as the password.

The ‘‘READ.ME’’ file in that

subdirectory describes the available

documents which may be available as

an ASCII text file (*.TXT), or a

WordPerfect 5.1 or 6.x document

(*.w51,wp6), or both.

Finally, the document can be obtained

by ‘‘bounce-back e-mail’’. A message

should be sent to:

‘‘CGMP@a1.cber.fda.gov’’.

SUPPLEMENTARY INFORMATION:

I. History of the CGMP Regulations

On October 10, 1962, Congress

enacted the Drug Amendments of 1962

(Pub. L. 87–781). The amendments

include section 501(a)(2)(B) of the

Federal Food, Drug, and Cosmetic Act

(the act) (21 U.S.C. 351(a)(2)(B)), which

deems a drug to be adulterated if:

* * * the methods used in, or the facilities

or controls used for, its manufacture,

processing, packing, or holding do not

conform to or are not operated or

administered in conformity with current

good manufacturing practice to assure that

such drug meets the requirements of this Act

as to safety and has the identity and strength,

and meets the quality and purity

characteristics, which it purports or is

represented to possess.

In the Federal Register of June 20,

1963 (28 FR 6385), FDA published the

first CGMP regulations (now codified as

21 CFR parts 210 through 226).

FDA has amended these regulations

several times since 1963 to ensure that

they reflect the level of control

necessary and that they incorporate

current technology to the extent that it

influences compliance with CGMP.

Major revisions of the CGMP regulations

were issued in the Federal Registers of

January 15, 1971 (36 FR 601), September

29, 1978 (43 FR 45014), and January 20,

1995 (60 FR 4087). The latter revision

came about as the result of a

comprehensive assessment of the CGMP

regulations, pursuant to the Regulatory

Flexibility Act (Pub. L. 96–354). During

the assessment, the agency solicited

comments from the public with respect

to any regulations that might be

perceived as being unnecessarily costly,

burdensome, or lacking public benefit.

The revisions that became final in

January 1995 were based on the

comments that FDA received as well as

the agency’s experience in applying

those regulations.

II. Background of the Regulations

Since the development of the CGMP

regulations, FDA has balanced the need

for precise, easily understood standards,

which ease both compliance and

enforcement burdens, with the need to

encourage innovation and the

development of improved

manufacturing technologies. The agency

continues to balance such issues as part

of the regulatory process, and to choose

the means of regulation most suited to

any particular aspect of the

manufacturing process. The agency

strives to provide manufacturers with

the discretion on how to achieve the

level of control necessary under CGMP,

recognizing that in a few instances,

more direction from the agency is

necessary because of the potential for

harm, the narrow range of acceptable

means to accomplish a particular CGMP

objective, or to provide a uniform

standard to the entire industry. The

CGMP regulations are based on

fundamental concepts of quality

assurance: (1) Quality, safety, and

effectiveness must be designed and built
Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules 20105

into a product; (2) quality cannot be

inspected or tested into a finished

product; and (3) each step of the

manufacturing process must be

controlled to maximize the likelihood

that the finished product will be

acceptable (Ref. 1).

To accomplish these objectives, the

agency must periodically reassess and

revise the CGMP regulations to

accommodate advances in technology

that further safeguard the drug

manufacturing process. As technology

and scientific knowledge evolve, so

does understanding of the critical

material, equipment, and process

variables that must be defined and

controlled to ensure end product

homogeneity and conformity with

appropriate specifications. The CGMP

regulations would not achieve their

statutorily mandated purposes if they

were not periodically reassessed to

identify and eliminate obsolete

provisions or to modify provisions that

no longer reflect the level of quality

control that current technology dictates

and that the majority of manufacturers

have adopted.

Despite the agency’s historic

preference for a general regulatory

approach in the CGMP regulations,

experience has shown that additional

specificity is warranted in certain areas.

In addition, FDA regulatory activities,

and particularly its enforcement

activities, have demonstrated a need for

greater uniformity in certain procedures

to protect the integrity of the drug

product. When experience has

demonstrated that the acceptable

choices with respect to any given

regulation are limited, FDA believes that

the regulations will better serve the

public by reflecting the actual processes

and procedures that are acceptable to

FDA. In those relatively few instances

where such specificity has been

introduced into the regulations, FDA

believes industry will benefit by being

able to focus its resources on activities

and processes that are known to be

appropriate, rather than on those that

may eventually be found to be deficient.

FDA has determined that revisions to

the CGMP regulations are necessary at

this time for a number of reasons. Rapid

changes in technology have created

situations not anticipated when the

CGMP regulations were originally

written or last revised. The agency’s

enforcement and litigation experience

has revealed persistent lack of

understanding among a limited number

of manufacturers with respect to certain

of the CGMP regulations. Some

pharmaceutical firms have not subjected

their procedures to sufficient scrutiny,

while others have failed to update such

procedures to accommodate changes or

advances in the manufacturing process.

In some cases, manufacturers may be

relying on methods and procedures that

were acceptable at some time in the

past, but that are not acceptable in light

of current standards.

In addition, FDA investigators have

encountered serious validation

deficiencies at a number of firms. FDA

is particularly concerned with

validation procedures designed to

ensure the quality of the manufacturing

process. Enforcement and compliance

actions have also revealed a need for

greater clarity and specificity in some

portions of the regulations.

These proposed revisions would,

therefore, amend certain requirements,

define or redefine certain terms, and

clarify industry obligations with respect

to several portions of the regulations. In

addition, the agency is proposing to

revise certain laboratory control and

cross-contamination requirements and

to clarify proper testing procedures.

FDA believes that the procedures that

would be required by this proposal

reflect practices already used by many

manufacturers and represent the

prevailing industry standard. The

agency emphasizes, however, that for a

given practice to be considered a current

good manufacturing practice (or

promulgated as such in the regulations),

it is not a prerequisite that the practice

actually be in use by a majority, or a

specific percentage of, the industry.

FDA has endeavored to ensure that

the drug manufacturing process will

consistently produce products that are

safe and have the quality and purity

which they purport to have, while

recognizing the interests of firms in

retaining some discretion in achieving

the level of control necessary to comply

with CGMP. FDA believes that the

proposed rule successfully addresses

this balance; however, FDA invites

comments addressing specific

proposals.

Other organizations have developed

standards to define quality in the

manufacturing process. One such

organization is the International

Organization of Standardization (ISO).

The purpose of the ISO 9000 Standards

is to provide generic guidance on

quality in manufacturing processes to

both industry and vendors supplying

industry. Five standards (9000–9004)

have been developed by the ISO Council

and are intended to be accepted

worldwide. These standards are

applicable to any industry and are not

specific to the pharmaceutical industry.

Compliance with the standards is

voluntary. The principles and practices

elucidated in the ISO standards are not

in conflict with those provided by the

CGMP regulations. Indeed, the

voluntary ISO standards share common

principles with FDA’s CGMP

requirements.

III. Highlights of the Proposed Rule

The proposed rule would amend or

revise a number of CGMP provisions as

follows:

A. Process Validation

The proposed rule would define

‘‘process validation.’’ Process validation

is a quality assurance function that

helps to ensure drug product quality by

providing documented evidence that the

manufacturing process consistently does

what it purports to do. Although process

validation is widely practiced by

industry, FDA continues to find firms

that have never validated manufacturing

processes for some finished products.

Manufacturing process validation is a

continuous undertaking through which

the process performance is constantly

monitored and evaluated. The

complexities of modern manufacturing

processes may make it necessary to

adapt or alter existing parameters while

unexpected variables may affect the

manufacturing process and the finished

product. For example, a slight change in

the physical characteristics of an

ingredient, or in the order of adding

ingredients, may alter the bioavailability

of a drug product. In such a case, a

sample of the finished product could

meet compendial dissolution criteria

but present a substantially different

dissolution pattern than that produced

before changes were made. Because of

such effects, revalidation may be

necessary after any change in process or

product characteristics or control

procedures.

Although FDA has found numerous

instances in which some firms have

failed to revalidate their processes for

many years, the agency recognizes that

most of industry establishes and follows

process validation standards. Moreover,

most in industry recognize the need for

revalidation (Ref. 2):

To preserve the validated status of a

process, measures must be taken that will

allow any significant process changes to be

recognized and addressed promptly. Such

change control measures can apply to

equipment, standard operating procedures,

manufacturing instructions, environmental

conditions, or any other aspect of the process

system that has an effect on its state of

control, and therefore on the state of

validation.

Accordingly, the agency is proposing

to add new § 211.220 to the CGMP

regulations specifying the nature and

extent of validation that are necessary to
20106 Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules

ensure that the resulting products have

the identity, strength, quality, and

purity characteristics that they purport

to possess. The proposed regulation also

clarifies this requirement by using the

term ‘‘validation’’ for those elements of

the manufacturing process under the

control of the manufacturer, while the

term ‘‘verification’’ is used for those

items produced by a person other than

the manufacturer or otherwise not under

the control of the manufacturer.

FDA believes that the proposed rule

reflects current industry standards and

processes that are implemented by

many in the industry. The proposed rule

is necessary to: (1) Clarify the

requirement to those firms that have not

implemented or properly conducted

validation; (2) ensure that all

manufacturers are applying, and are

evaluated against, the same standard;

and (3) clarify any remaining confusion

about the importance of validation in

CGMP. FDA invites comments on

whether this proposal adequately

achieves these goals in a manner

consistent with current industry

practice.

B. Methods Validation

This proposed rule would also define

in § 210.3 ‘‘methods validation,’’ which

is the documented, successful

evaluation of an analytical method that

provides a high level of assurance that

such method will consistently yield

results that are accurate within

previously established specifications.

The agency is proposing to move the

requirement for methods validation

from § 211.165(e) to § 211.222 for

emphasis and to change the word

‘‘established’’ to ‘‘validated’’ for

clarification. Current regulations require

regulated firms to validate all analytical

methods that vary from compendial

methods. The suitability of a chosen

method may be measured by such

analytical variables as precision,

accuracy, limit of detection, limit of

quantitation, selectivity, range, linearity,

and ruggedness. Methods validation is

intended to provide a high level of

confidence that the method selected is

scientifically sound and that it serves its

intended analytical purpose.

Methods validation is central to

ensuring the reliability of all evidence

that supports a product’s identity,

strength, quality, and purity. For test

results to be useful, significant, and

reliable, the methods used to analyze

the data in such test results must also

be validated. In other words, a firm

must establish that the analytical

methods it uses to assess or evaluate a

manufacturing process accurately

measure variables affecting process

control.

FDA recognizes that the scientific

soundness of most of the methods used

by firms is well established.

Compendial methods, for example,

reflect years of experience and

evaluation and, in most cases, do not

need to be revalidated. In some

instances, however, no generally

recognized analytical method exists or

problems may develop with existing

methods. Product modification may also

lead to innovative analytical methods.

FDA inspections have revealed that

some firms use methods that have

become outdated, or claim to use

analytical methods that bear little

relationship to those actually being

used. In such cases, new or revised

analytical methods must be established

as scientifically sound and

reproducible. FDA invites comments on

this proposal with respect to alternative

means, if any, of assuring the reliability

of analytical methods.

C. Contamination

Drug products can become

contaminated in a variety of ways. For

example, ineffective cleaning

procedures may leave residues of the

product or cleaning agents in the

equipment, production workers may fail

to take proper precautions while

transporting a substance from one area

to another thereby introducing a

contaminant to the second production

area, or particles may become airborne

and travel to production areas

throughout the facility. Drug products

may become contaminated by a number

of substances such as dust, dirt, debris,

toxic substances, infectious agents, or

residue of other drugs or drug

components. Most contamination can be

controlled to an acceptable level

through measures such as proper

planning and implementation of

cleaning processes, employee training,

gowning, and air filtration. Under

CGMP, a manufacturer will set

contamination limits on a substance-bysubstance basis, according to both the

potency of the substance and the overall

level of sensitivity to that substance.

However, controlling or reducing the

likelihood of contamination is

inadequate when substances are present

that may pose a serious risk to humans

or animals because their presence in

even trace amounts may render toxic an

otherwise safe product. This is of

particular concern because a toxic

reaction resulting from crosscontamination may not be apparent to a

health professional treating a patient

suffering from such a reaction, or may

be impossible to trace to product

contamination. Penicillin, for example,

is a substance that poses an

unacceptable risk of contamination

because of the severe reaction some

humans have to it even at very low

levels of exposure. Penicillin has long

been subject to specific CGMP

regulations designed to reduce the

danger of cross-contamination. Because

other substances, such as cytotoxic

agents or other antibiotics, pose at least

as great a risk of toxicity due to crosscontamination, FDA is proposing to

expand the contamination control

requirements to encompass other

sources of contamination.

FDA has determined that substances

posing a serious threat of

contamination, i.e., substances to which

humans or animals show a particular

sensitivity even at extremely low levels,

should be controlled through dedicated

production processes. For example,

dedicated facilities, air-handling

equipment, and process equipment may

be necessary. The agency has refrained

from establishing a list of drugs or drug

products that present such an

unacceptable risk, because such a list

would quickly become obsolete.

Moreover, the agency believes that most

manufacturers are knowledgeable about

risks that are associated with products

that they produce, as well as with the

effective means to prevent crosscontamination. FDA stresses that

prevention of cross-contamination of

potentially toxic substances is the goal

of this proposed rule. Because, in even

small amounts, those drugs may be toxic

to humans or animals, FDA expects

manufacturers to identify any drugs that

they produce that present the risk of

cross-contamination and to implement

measures necessary to eliminate that

risk. FDA recognizes that, depending on

the drug product, a variety of measures

may be acceptable to eliminate crosscontamination; there may, however, be

situations in which nothing short of

dedicated facilities or equipment will be

sufficient. FDA invites comments on

this proposal especially with respect to

any alternative means of addressing and

preventing cross-contamination.

D. Testing

FDA has concluded through its

inspection and enforcement activities

that many manufacturers are not

conducting adequate testing procedures

and are not adequately evaluating test

discrepancies or investigating failures.

Such an investigation is crucial to

ensure that the manufacturing process is

adequately controlled.

FDA recognizes the need to clarify the

CGMP requirements in this area so that

all manufacturers are applying the same
Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules 20107

minimum standards and so that all

manufacturers are thoroughly assessing

test results and discrepancies to ensure

that all drug products are safe and of the

quality and purity which they purport

to be. This proposed rule would amend

procedures for the testing of

components, calculation of yield, and

blend testing. It would also provide

procedures for dealing with out-ofspecification results. FDA invites

comments on alternate means of

achieving adequate followup of testing

discrepancies or failures.

E. Quality Control

To further ensure that validation

procedures are current, this proposed

rule would make the quality control

unit responsible for reviewing changes

in product, process, equipment, or

personnel, and for determining if and

when revalidation is required. The

agency believes that placing

responsibility for oversight of validation

procedures in quality control units

emphasizes the importance of proper

validation to quality control. This

proposed rule stresses the importance of

validation by ensuring that a

manufacturer will have a certain

employee or employees who are

responsible for and accountable for

ensuring that the firm adequately

evaluates its manufacturing process,

validates the processes and testing that

must be validated, and thoroughly

assesses any discrepancies. FDA

believes that this proposed regulation

will enhance compliance with CGMP

through a means acceptable to most

manufacturers while providing FDA the

ability to ensure accountability and

compliance.

IV. Description of the Proposed Rule

In general, the proposed rule would

add new definitions to § 210.3 to clarify

existing terms in the CGMP regulations

and to reflect proposed changes to the

CGMP regulations for finished

pharmaceuticals. This proposal would

also revise the CGMP regulations for

finished pharmaceuticals in part 211 to

incorporate validation, test, and

documentation procedures necessary to

protect the integrity of the drug

manufacturing process. Specific

provisions are described in more detail

below.

A. Section 210.3—Definitions

Current § 210.3(b) defines various

terms that are used in the CGMP

regulations in parts 210 to 226.

This proposed rule would amend

§ 210.3(b) to include new definitions to

clarify existing terminology and to

define new terms introduced in other

provisions of this proposal. Under

proposed § 210.3(b)(23), ‘‘validation

protocol’’ would mean a written plan

describing the process to be validated,

including production equipment and

how validation will be conducted. Such

a plan would address objective test

parameters, product and process

characteristics, predetermined

specifications, and factors which will

determine acceptable results.

Proposed § 210.3(b)(24) would define

‘‘process validation’’ as establishing,

through documented evidence, a high

degree of assurance that a specific

process will consistently produce a

product that meets its predetermined

specifications and quality

characteristics.

This proposal would define ‘‘methods

validation’’ in § 210.3(b)(25) as

establishing, through documented

evidence, a high degree of assurance

that an analytical method will

consistently yield results that accurately

reflect the quality characteristics of the

product tested.

Proposed § 210.3(b)(26) would define

‘‘equipment suitability’’ as the

established capacity of process

equipment and ancillary systems to

operate consistently within established

limits and tolerances.

Under proposed § 210.3(b)(27),

‘‘process suitability’’ would mean the

established capacity of the

manufacturing process to produce

effective and reproducible results

consistently.

Proposed § 210.3(b)(28) would define

‘‘out-of-specification’’ as an

examination, measurement, or test

result that does not comply with

preestablished criteria. This definition

would be consistent with § 211.160(b),

which requires laboratory controls for

finished pharmaceuticals to include the

establishment of scientifically sound

and applicable specifications, standards,

sampling plans, and test procedures

designed to ensure that components,

drug product containers, closures, inprocess materials, labeling, and drug

products conform to appropriate

standards of identity, strength, quality,

and purity.

Proposed § 210.3(b)(29) would define

‘‘reprocessing’’ as a system of reworking

batches that do not conform to

standards or specifications, including

‘‘the steps taken to ensure that the

reprocessed batches will conform to all

established standards, specifications,

and characteristics.’’ Under the

proposal, ‘‘reprocessing’’ would include

a step or steps in the manufacturing

process that are out of the normal

processing sequence or that are not

specifically provided for in the process.

Under proposed § 210.3(b)(30),

‘‘manufacturing process’’ would mean

all manufacturing and storage steps in

the creation of the finished product

from the weighing of components

through the storing, packaging, and

labeling of the finished product,

including, but not limited to, the

following: Mixing, granulating, milling,

molding, formulating, lyophilizing,

tableting, encapsulating, coating,

sterilizing, and filling.

B. Section 211.22—Responsibilities of

Quality Control Unit

Current § 211.22 describes a quality

control unit’s responsibilities. These

responsibilities include ‘‘the

responsibility and authority to approve

or reject all components, drug product

containers, closures, in-process

materials, packaging material, labeling,

and drug products’’ as well as the

authority to review production records

to determine whether errors have

occurred. If errors have occurred,

§ 211.22 also gives quality control units

the authority to determine whether a

firm has fully investigated the error.

The agency understands that some

manufacturers would prefer that the

term ‘‘quality control’’ be replaced with

‘‘quality assurance,’’ that the functions

of quality control and quality assurance

be somehow differentiated, or that a

number of other terms be incorporated

into the regulation to reflect the

distribution of quality oversight

responsibilities in various

manufacturing settings.

FDA does not believe that such

changes in terminology would be useful.

The difference between ‘‘quality

assurance’’ and ‘‘quality control’’ is

recognized to be operational. The

quality control unit is usually

responsible for performing the testing to

assure that proper specifications and

limits are adhered to, while the quality

assurance unit is responsible for

auditing methods, results, systems, and

processes, and for performing trend

analyses. The functions described in the

proposed rule as the responsibility of

the quality control unit are designed to

be implemented by all manufacturers,

regardless of size or organizational

structure. However, such procedures

can easily be accommodated under

organizational structures which utilize

quality assurance and quality control

departments. The agency stated in the

preamble to the 1978 CGMP regulation

and reiterates here, that the term quality

control ‘‘unit’’ is used in the regulations

‘‘because it is a term broadly applicable

to any group within a manufacturing

establishment charged with the

responsibility of quality control. The
20108 Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules

Commissioner is not concerned about

the name given by a firm to its own unit

that is responsible for quality control

functions’’ (43 FR 45014 at 45032).

Proposed 211.22(a) would require that

firms be accountable with respect to

validation provisions and would give

quality control units the additional

responsibility of reviewing and

approving validation protocols to assess

their adequacy. Quality control units

would also be responsible for reviewing

product, process, equipment, or other

changes to determine if and when

revalidation is warranted. This change

is intended to make the quality control

unit responsible for keeping validation

current and is a logical extension of the

quality control unit’s role in ensuring

product quality. The agency believes

that, by making clear such

accountability, compliance with the

validation provisions will be more

consistent and reliable.

C. Section 211.68—Automatic,

Mechanical, and Electronic Equipment

Current § 211.68(b) requires

appropriate controls over computer or

related systems to ensure that only

authorized personnel make changes in

master production and control records

or other records. The current regulation

also requires that ‘‘A backup file of data

entered into the computer or related

system shall be maintained except

where certain data, such as calculations

performed in connection with

laboratory analysis, are eliminated by

computerization or other automated

processes.’’ If computerization or other

automated process has eliminated such

calculations, ‘‘a written record of the

program shall be maintained along with

appropriate validation data.’’

Proposed § 211.68(b) would replace

the phrase ‘‘appropriate validation data’’

with ‘‘data establishing proper

performance.’’ This change is intended

to emphasize that the manufacturer

must actually establish proper

performance.

D. Section 211.82—Receipt and Storage

of Untested Components, Drug Product

Containers, and Closures

Section 211.82 governs the receipt

and storage of untested components,

drug product containers, and closures.

Section 211.82(b) currently states, in

part, that, ‘‘Components, drug product

containers, and closures shall be stored

under quarantine until they have been

tested or examined, as appropriate, and

released.’’ This provision is designed to

prevent the premature release of

untested components, containers, and

closures that might be unsuitable for use

in the manufacturing process.

The proposal would remove the

words, ‘‘as appropriate,’’ to eliminate

any ambiguity in the existing regulation.

Although testing or examination may

vary with the particular component,

drug product container, or closure, the

revision would also emphasize that it is,

in fact, accepted industry practice to

conduct some testing or examination

before the components, drug product

containers, or closures are released from

quarantine.

E. Section 211.84—Testing and

Approval or Rejection of Components,

Drug Product Containers, and Closures

Section 211.84 pertains to the testing

and approval or rejection of

components, drug product containers,

and closures. Under current

§ 211.84(c)(1), containers of components

‘‘shall be cleaned where necessary, by

appropriate means.’’

This proposed rule would replace the

phrases ‘‘where necessary’’ and ‘‘by

appropriate means’’ with ‘‘in a manner

to prevent introduction of contaminants

into the raw material.’’ This change will

clarify that the act of cleaning

component containers is done for a

particular purpose, to prevent the

introduction of contaminants, and that

purpose must, in all cases, be achieved.

FDA proposes to correct a

typographical error in the text of

§ 211.84(c)(5) which requires that

sample containers be identified so that,

among other things, the date on which

the sample was taken can be

determined. The current regulation

erroneously states ‘‘the data on which

the sample was taken.’’ FDA proposes to

correct this by changing ‘‘data’’ to

‘‘date.’’ Additionally, proposed

§ 211.84(d)(3) would make two editorial

changes by replacing the word

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

‘‘procedure’’ with ‘‘specifications.’’

F. Section 211.101—Charge-In of

Components

Current § 211.101 requires written

production and control procedures to

assure that drug products have the

identity, strength, quality, and purity

they purport or are represented to

possess. Section 211.101(c) requires that

weighing, measuring, or subdividing

operations be adequately supervised

and that each container of component

dispensed to manufacturing be

examined by a second person to ensure

that: (1) The component was released by

the quality control unit; (2) the weight

or measure, as stated in batch

production records, is correct; and (3)

the containers are properly identified.

The proposed rule would add a fourth

requirement (§ 211.101(c)(4)) that drug

ingredients conform to the quality

specifications for the intended drug

product. Active and inactive ingredients

come in varying grades and may not be

interchangeable. This proposal would

require examination of the component

by competent and responsible

individuals to ensure that the correct

material is used. This provision would

provide additional assurance that the

raw materials used are appropriate for

the intended batch, but is not intended

to require testing in addition to that

required under subpart E of part 211.

G. Section 211.103—Calculation of

Yield

Section 211.100 currently requires

maintenance of written procedures for

production and process controls to

ensure that drug products have the

identity, strength, quality, and purity

they purport or are represented to

possess. Section 211.103 currently

requires that actual yields and

percentages of theoretical yield be

determined at the conclusion of

appropriate phases of manufacturing,

processing, packaging, or holding of the

drug product. These calculations are

performed by one person and

independently verified by a second

person. Section 211.192 currently

requires any unexplained discrepancy

(including a percentage of theoretical

yield exceeding the maximum or

minimum percentages established in

master production and control records)

to be thoroughly investigated.

This proposed rule would amend

§ 211.103 to make clear that there must

be a written production and control

procedure that will require an

investigation of any significant

unexplained discrepancies between

actual yields and percentages of

theoretical yield of the drug product.

This provision would help ensure that

the source of any potential problem is

quickly and accurately identified and

addressed.

H. Section 211.110—Sampling and

Testing of In-Process Materials and Drug

Products

Current § 211.110 establishes several

requirements for the sampling and

testing of in-process materials and drug

products. For example, § 211.110(a)

requires written procedures for inprocess controls and tests or

examinations to be conducted on

appropriate samples of in-process

materials of each batch, whereas

§ 211.110(b) states that valid in-process

specifications shall be consistent with

drug product final specifications and

shall be derived from previous

acceptable process average and process
Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules 20109

variability estimates where possible and

determined by the application of

suitable statistical procedures. The

regulation is designed to protect the

integrity of the manufacturing process

and thus the safety and efficacy of the

drug product.

Sampling and testing techniques,

however, are valid only insofar as they

provide a realistic representation of the

material being sampled or tested. Blend

testing is important because it increases

the likelihood of quickly detecting

uniformity problems that may produce

inferior batches. A large sample can

mask differences that may be significant

in individual dosage units. Therefore,

sample size must approximate dosage

size to provide an accurate

representation of blend uniformity. This

proposal would create new § 211.110(d)

to help ensure adequate testing. (The

current paragraph (d) would be

redesignated as paragraph (e).) Proposed

§ 211.110(d) would also require that

sampling be demonstrated through

validation to be representative of all

portions of the blend.

This proposal would also require in

new § 211.110(f) that validation of

manufacturing processes be conducted

in accordance with process validation

requirements in proposed § 211.220.

Validation of these processes is

intended, among other things, to ensure

that the sample is representative of all

portions of the blend. For example,

firms sampling from drums containing

the finished blend must demonstrate

that their sampling technique produces

samples representative of the entire

batch.

I. Section 211.111—Time Limitations on

Production

To assure the quality of the drug

product, § 211.111 currently requires,

when appropriate, time limits for the

completion of each phase of production.

This proposed rule would revise

§ 211.111 to require for time-sensitive

procedures that manufacturers establish

and validate maximum time for

completion of such procedures as part

of the validation required under

§ 211.220. FDA expects that the

validation of time-sensitive procedures

will be part of process validation.

J. Section 211.113—Control of

Microbiological Contamination

Section 211.113(b) requires the

establishment of, and adherence to,

written procedures designed to prevent

microbiological contamination of drug

products purporting to be sterile. The

provision also requires that such

procedures include ‘‘validation of any

sterilization process.’’

This proposed rule would amend

§ 211.113(b) to refer to validation of

‘‘any sterilization or aseptic process.’’

This change is intended to reflect the

fact that whether pharmaceutical firms

use aseptic processing techniques or

whether they use terminal sterilization,

either technique must be validated.

K. Section 211.160—General

Requirements

Currently, § 211.160(b) requires that

laboratory controls include the

establishment of scientifically sound

and appropriate specifications,

standards, sampling plans, and test

procedures designed to ensure that

components, drug product containers,

closures, in-process materials, labeling,

and drug products conform to

appropriate standards of identity,

strength, quality, and purity.

This proposal would specify a

requirement for the establishment of

scientifically sound resampling,

retesting, and data interpretation

procedures.

Currently under § 211.160(b)(1),

laboratory controls shall include a

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.

This proposal would make editorial

changes, replacing ‘‘conformance’’ with

‘‘conformity’’ and ‘‘appropriate’’ with

‘‘applicable.’’

L. Section 211.165—Testing and Release

for Distribution

Section 211.165(e) requires that the

accuracy, sensitivity, specificity, and

reproducibility of test methods used by

a firm be established and documented.

Because other revisions in this proposal

would clarify and set forth this

requirement, the proposal would

remove § 211.165(e) and redesignate

paragraph (f) as paragraph (e).

M. Section 211.166—Stability Testing

Currently, § 211.166 requires a written

stability testing program and provides

the elements of such a program. The

current provision requires that an

adequate number of batches be tested to

determine an appropriate expiration

date. This proposal would redesignate

current § 211.166(c) and (d) as

§ 211.166(d) and (e), and add new

§ 211.166(c) to require placing at least

one additional batch into the stability

testing program each year.

For some time, requirements for new

drug and abbreviated new drug

applications and biological products

applications have included as a

condition for approval a commitment to

place the initial three production

batches and at least one additional batch

annually into the stability testing

program. It is necessary to place the

three initial batches in the stability

testing program to account for batch

variability and to confirm the previously

established expiration date.

There are, however, variations in the

production process during the lifetime

of a drug product such as changes in

personnel, raw materials and suppliers,

manufacturing environment, and

equipment. Because a dosage form is

typically a complex unit, such changes

may have an impact on drug product

stability. Because of this, the agency

believes it is imperative that ongoing

production be periodically monitored to

ensure the stability of the product. The

agency believes, further, that the

necessity for continued stability testing

is recognized by the industry and is now

standard industry practice. The agency

invites comments on this proposed

provision.

N. Section 211.180—General

Requirements

Section 211.180(a) requires the

retention of production, control, or

distribution records specifically

associated with a batch of a drug

product, for at least 1 year after the

expiration date of the batch. FDA

believes that validation records,

including the validation protocol,

production and control records, data,

and the study report, should not be

discarded after the validation batches

expire. They should be retained for as

long as the validated process is used

and as long as any batches made by the

validated process may be available to

consumers. The proposal would

therefore amend this section to add a

requirement that the validation records

required by proposed new § 211.220

also be retained for at least 1 year after

the expiration date of all batches

associated with that validated process.

O. Section 211.192—Production Record

Review

FDA’s experience has revealed a

variety of written and unwritten

practices and procedures under which

firms have disregarded out-ofspecification laboratory results, after

minimal retesting, resampling,

inappropriate averaging of results, or

inappropriate outlier testing. Some

firms then proceeded to release a

product without a thorough

investigation or an adequate

justification for disregarding an out-ofspecification result.
20110 Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules

Out-of-specification results can be

caused by laboratory error, nonprocess

or operator error, or by process-related

error. The agency recognizes that

laboratory errors occur and that a

thorough investigation, supported by

evidence and documentation, may, for

instance, indicate an out-ofspecification result caused by laboratory

personnel errors or equipment failures.

However, unless and until an

investigation indicates that this is the

case and the investigation is completed

and documented, FDA believes that the

out-of-specification result should not be

discarded or disregarded. Moreover,

FDA emphasizes that, although retesting

may be an appropriate part of an

investigation, an investigation

consisting solely of repeated retesting is

clearly inadequate. If quality is not built

into a drug product, retesting cannot

make it conform to specifications.

FDA recognizes the distinction

between the limited investigation that

may be necessary to identify a

laboratory error and the more extensive

investigation and testing necessary

when out-of-specification results may be

attributed to another cause. The agency

also recognizes that the industry may

impose additional criteria beyond those

required to ensure identity, strength,

quality, and purity under CGMP

regulations or as required by a drug

application. The agency encourages

such internal controls. Under such

circumstances, a manufacturer could

have test results that violate internal

standards although they would not be

out-of-specification, as defined in these

regulations.

FDA believes, however, that CGMP

requires written procedures to be in

place to determine the cause of any

apparent failure, discrepancy, or out-ofspecification result. If the out-ofspecification result cannot be clearly

attributed to laboratory error, then the

quality control unit should ensure that

a thorough investigation is conducted

and supported by a written record.

Certain elements and procedures are

crucial to a systematic and orderly

investigation. Consequently, this

proposed rule would revise the section

heading of § 211.192 to read

‘‘Production, control, and laboratory

record review and investigation of

discrepancies,’’ and would amend

§ 211.192(b) to require written

procedures including the following: (1)

Procedures for attempting to identify the

cause of the failure or discrepancy; (2)

criteria for determining whether out-ofspecification results were caused by

sampling or laboratory error; (3)

scientifically sound procedures and

criteria for the exclusion of any test data

found to be invalid due to laboratory or

sampling error; (4) scientifically sound

procedures and criteria for additional

sampling and testing, if necessary,

during the investigation; (5) procedures

and criteria for extending the

investigation to other batches or other

products; (6) procedures for review and

evaluation of the investigation,

including all test results, by the quality

control unit, to ensure a thorough

investigation; and (7) criteria for final

approval or rejection of the batch

involved, and for taking action on other

batches and products if indicated by the

investigation.

The number of retests performed

before a firm concludes that an

unexplained out-of-specification

laboratory result is invalid, or that a

product is unacceptable, is a matter of

scientific judgment. FDA does not

intend to issue regulations on specific

retesting procedures. Rather, the

proposed rule would require each firm

to have written investigation and

retesting procedures, applying

scientifically sound criteria, that limit

the amount of retesting permitted and

indicate the point at which testing ends

and the product is evaluated.

Proposed § 211.192(c) would require

written records of the investigation to be

made and shall include: (1) The reason

for the investigation; (2) a description of

the investigation made, including all

laboratory tests; (3) the results of the

investigation including all laboratory

test results involved in the

investigation; (4) scientifically sound

and appropriate justification for

excluding any out-of-specification

laboratory result found to be invalid; (5)

if laboratory results are found to be

invalid, the subsequent laboratory

results supporting the final

determination of the tested item’s

conformity to appropriate specifications

for acceptance; (6) the conclusions and

subsequent actions concerning all

batches and products that may have

been associated with the failure or

discrepancy; (7) the signature(s) and

date(s) of the person(s) responsible for

approving the record of the

investigation; and (8) the signature(s)

and date(s) of the person(s) responsible

for the final decision on disposition of

the batch, and on other batches and

products involved. The agency

specifically invites comments on these

proposed requirements.

P. Section 211.220—Process Validation,

and Section 211.222—Methods

Validation

FDA proposes to add new subpart L

to part 211 entitled ‘‘Validation.’’ The

new subpart would consist of two

regulations: § 211.220 for ‘‘process

validation’’ (establishing through

documented evidence a high degree of

assurance that a specific process will

consistently produce a product that

meets predetermined specifications and

quality characteristics), and § 211.222

for ‘‘methods validation’’ (establishing

through documented evidence a high

degree of assurance that an analytical

method will consistently yield results

that accurately reflect the quality

characteristics of the material tested).

These proposed regulations are

intended to clarify the requirements for

validation and to provide the basic

elements of an acceptable validation

procedure. FDA believes, in general,

that scientific knowledge and industry

experience have defined the basic

elements of a sound validation system.

Validation has proven to be an effective

technique for protecting the integrity of

the drug manufacturing process.

Although the particular requirements

of process validation will vary

according to such factors as the nature

of the drug product (e.g., sterile versus

nonsterile) and the complexity of the

process, the requirements of the

proposed subpart are generally

applicable to all drug products and

provide a foundation for building a

comprehensive approach to process

validation.

Proposed § 211.220(a) would require

validation of all drug manufacturing

processes including, but not limited to,

computerized systems involved in the

manufacturing process. Under the

proposal, the manufacturing process

would include all manufacturing steps

in the creation of the finished product,

including, but not limited to, cleaning,

weighing, measuring, mixing, blending,

compressing, filling, packaging, and

labeling. Time-sensitive steps in the

manufacturing process would be

validated. Such validation ensures that

the impact of any interruption in the

manufacturing process on drug product

safety and efficacy is fully understood

by the manufacturer.

Proposed § 211.220(b) would establish

requirements for a validation protocol.

The validation protocol is the blueprint

of the validation process for a particular

drug product. The protocol would

specify a sufficient number of replicate

process runs to demonstrate

reproducibility and provide an accurate

measure of variability among successive

runs. Validation documentation would

include evidence of the suitability of

materials and the proper performance

and reliability of the equipment and

systems used to manufacture a drug

product. The execution of the protocol

and the test results would be
Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules 20111

documented and the manufacturer

would be required to retain such

documentation.

Proposed § 211.220 would require

that equipment and processes be

designed and selected to be consistently

capable of achieving product

specifications. Determining equipment

suitability would include testing to

verify whether the equipment is capable

of performing adequately within the

operating limits of the process. A

determination of process suitability

would include rigorous testing and

documentation to demonstrate that the

process is both effective and

reproducible. A manufacturer should

test those parts of the process that may

affect product quality or may cause

variability.

Proposed § 211.220(d) would require

a quality assurance system to implement

revalidation procedures whenever there

are changes, including reprocessing,

that could affect product effectiveness

or product characteristics, or whenever

changes are observed in product

characteristics.

Proposed § 211.222, ‘‘methods

validation,’’ would require the

manufacturer to establish and document

the accuracy, sensitivity, specificity,

reproducibility, and any other attribute

necessary to validate test methods. The

validation would be required to meet

the existing requirements for laboratory

records provided at § 211.194(a)(2).

These requirements include a

‘‘statement of each method used in the

testing of the sample,’’ indicating the

location of the data that establish that

the methods used in testing the sample

meet proper standards of accuracy and

reliability as applied to the tested

product. The proposed provision is

designed to ensure that testing methods

used are relevant to product quality and

the integrity of the manufacturing

process. FDA invites comments on this

proposal, especially on alternative

means, if any, of assuring the reliability

of manufacturing processes and

analytical methods.

Q. Section 211.240—Control of

Chemical and Physical Contaminants

FDA’s experience indicates that the

potential dangers of contamination are

more extensive and varied than once

believed; for example, high potency

drugs, such as penicillin,

cephalosporins, and cytotoxic

anticancer agents, may pose health risks

even at low levels of exposure. Crosscontamination may result in the

adulteration of other drugs, and even

minimal amounts could have serious

adverse effects on persons who are

allergic to the contaminant. Moreover,

because the identity or even the

presence of the contaminant may be

unknown, health care professionals

providing care to a patient suffering

from such an adverse effect may be

unable to provide appropriate medical

intervention.

FDA is thus proposing to add new

subpart M, which would be directed to

the control of chemical and physical

contaminants. The new subpart,

consisting of proposed § 211.240, would

require firms to anticipate and prevent

specific contamination problems,

including, but not limited to, those

presented by penicillin. As a result,

FDA is also proposing to remove

§§ 211.42(d) and 211.176 regarding

separate facilities for manufacturing

penicillin and penicillin contamination

and to incorporate their requirements in

§ 211.240.

Proposed § 211.240(a) would require

the implementation of written

procedures designed to prevent

objectionable chemical and physical

contamination, including crosscontamination. Section 211.240(b)

would require dedicated production,

which may include facilities, air

handling, or process equipment, in

those circumstances in which

contaminants pose a special danger to

human or animal health. Such

contaminants include, but are not

limited to, penicillin, cephalosporins,

cytotoxic anti-cancer agents, and

infectious agents (e.g., spore-bearing

organisms and live viruses). Dedicated

production would also be required

under proposed § 211.240(b) if there are

no reasonable methods for the cleaning

and removal of a drug substance or

compound residues from buildings,

facilities, and equipment.

If there is a reasonable possibility that

a drug has been exposed to crosscontamination, proposed § 211.240(c)

would require that the product be tested

for the potential contaminant. It would

also require the establishment of limits

for potential contaminants, and prohibit

the release of a product for distribution

if these limits are exceeded.

The proposed contamination

provisions are designed to accommodate

technological changes. For example,

under the proposed rule, a manufacturer

might develop a drug product of high

therapeutic potential that also poses a

high risk of contamination. If this

hypothetical drug product

contamination posed a special danger to

human health, dedicated facilities

would be required. If, however,

experience demonstrated that the drug

product did not pose such a risk, or if

changes in manufacturing technology

greatly reduced the risk, dedicated

facilities might no longer be required.

V. Environmental Impact

The agency has determined under 21

CFR 25.24(a)(8) that this action is of a

type that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

VI. Paperwork Reduction Act of 1995

This proposed rule contains

information collections which are

subject to review by the Office of

Management and Budget (OMB) under

the Paperwork Reduction Act of 1995

(Pub. L. 104–13). The title, description,

and respondent description of the

information collection are shown below

with an estimate of the annual reporting

and recordkeeping burden. Included in

the estimate is the time for reviewing

instructions, searching existing data

sources, gathering and maintaining the

data needed, and completing and

reviewing the collection of information.

Title: Current Good Manufacturing

Practice; Proposed Amendment of

Certain Requirements for Finished

Pharmaceuticals.

Description: FDA is proposing to

amend its CGMP regulations to establish

procedures and specifications for

testing, sampling, and other quality

control activities; to establish criteria for

initiating and performing out-ofspecification investigations; and to

control chemical and physical

contaminants. These amendments

would clarify certain manufacturing,

quality control, and documentation

requirements and ensure that the

regulations more accurately encompass

CGMP. In addition, the agency is

updating the requirements for process

and methods validation to incorporate

guidance previously issued to industry

and to reflect current practice. These

proposed changes are intended to

enhance the integrity of the drug

manufacturing process and the safety of

drug products. The total recordkeeping

requirements are estimated at 89,884

hours, as a one-time reporting burden.

Description of Respondents:

Businesses or other for profit and small

businesses or organizations.
20112 Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules

Estimated Reporting Burden 1

CFR Section Number of Respondents

Responses per RespondentTotal Annual ResponsesHours Per Response Total Hours

211.160(b) and (b)(1) 1,077 1 1 8.2 8,871

211.192(a) 4,184 1 1 6.7 28,060

211.192(b) 4,184 1 1 9.6 40,156

211.240 2,205 1 1 6.3 12,797

Total 89,884

1Because some of the numbers underlying these estimates have been rounded, figures in this table are approximate. There are no maintenance and operation costs nor start up and capital costs. The chart represents a one time burden.

As required by section 3507(d) of the

Paperwork Reduction Act of 1995, FDA

has submitted a copy of this proposed

rule to OMB for its review of these

previously approved information

collection requirements. The agency

solicits comments on the information

collection requirements in order to: (1)

Evaluate whether the proposed

collection of information is necessary

for the proper performance of the

functions of the agency, including

whether the information will have

practical utility; (2) evaluate the

accuracy of the agency’s estimate of the

burden of the proposed collection of

information, including the validity of

the methodology and assumptions used;

(3) enhance the quality, utility, and

clarity of the information to be

collected; and (4) minimize the burden

of the collection of information on those

who are to respond, including through

the use of appropriate automated,

electronic, mechanical, or other

technological collection techniques or

other forms of information technology,

e.g., permitting electronic submission of

responses. Organizations and

individuals desiring to submit

comments on the information collection

requirements should direct them to the

Office of Information and Regulatory

Affairs, OMB, New Executive Office

Bldg., rm. 10235, 725 17th St. NW.,

Washington, DC 20503, Attention: Desk

Officer for FDA.

VII. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(Pub. L. 96–354). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity). The agency

believes that this proposed rule is

consistent with the regulatory

philosophy and principles identified in

the Executive Order. The detailed data

for the cost analysis were developed by

Eastern Research Group, Inc., under

contract to FDA, and their full report is

on file at the Dockets Management

Branch (address above).

The proposed changes to the CGMP

regulations will affect manufacturers of

finished human and veterinary

pharmaceuticals, including medical

gases, and repackers and relabelers of

drug products. The majority of the

proposed changes clarify existing

manufacturing, quality control, and

documentation requirements and

represent current industry practice for

the majority of firms. As such, they will

have little or no economic impact on the

majority of the industry. Some firms are

not, however, operating in conformance

with CGMP and the estimates represent

the agency’s best assessment of the

incremental increase in costs that these

firms would incur in implementing full

compliance with the proposed changes.

The total cost is estimated to be a onetime expenditure of $2,900,000 ($0.7

million annualized over 5 years at a 7

percent discount rate). These costs

would be generated by proposed

changes that would require some

manufacturers to revise existing, or

develop new, standard operating

procedures.

The Regulatory Flexibility Act

requires agencies to analyze regulatory

options that would minimize any

significant impact on small entities.

Because this regulation will not impose

significant new costs on a large number

of drug manufacturing operations, the

agency certifies that the proposed rule

will not have a significant economic

impact on a substantial number of small

entities. The agency estimates that, to

comply with the proposal,

establishments will incur additional

annualized costs ranging from

approximately $60 to $450 for

establishments with fewer than 100

employees and from approximately

$175 to $600 for establishments with

250 or more employees. For individual

establishments, the impact of the

proposal will depend on numerous

factors, such as the type of

establishment, the level of current

conformance with the proposed

changes, and the number and nature of

products produced. Provisions of this

proposal represent the most costeffective option evaluated. Several of

the rejected alternatives considered

(such as revisions to § 211.84(d)(2) and

(d)(3)) would have increased total costs

by $14 to $27 million.

As a result of its analysis, FDA has

determined that the proposed revision

to the CGMP regulations for human and

veterinary pharmaceuticals is not a

significant regulatory action as defined

by Executive Order 12866, and that the

proposal will not have a significant

economic impact on a substantial

number of small entities. Therefore,

under the Regulatory Flexibility Act, no

further analysis is required.

VIII. Effective Date

FDA proposes that any final rule that

may issue based on this proposal

become effective 90 days after the date

of its publication in the Federal

Register.

IX. Request For Comments

Interested persons may, on or before

August 1, 1996, submit to the Dockets

Management Branch (address above)

written comments regarding this

proposal. Two copies of any comments

are to be submitted except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. Received

comments may be seen in the office

above between 9 a. m. and 4 p.m.,

Monday through Friday.

X. References

The following references, which have

been consulted in the drafting of this

proposed rule, are readily and publicly

available in a variety of locations. They

have also been placed on display in the

Dockets Management Branch (address
Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules 20113

above) and may be seen by interested

persons between 9 a.m. and 4 p.m.,

Monday through Friday.

1. Juran, Quality Control Handbook, 4th

ed., McGraw-Hill, 1988.

2. Pharmaceutical Manufacturers

Association’s (now known as Pharmaceutical

Research and Manufacturers of America)

Validation Advisory Committee, ‘‘Process

validation concepts for drug products,’’

Pharmaceutical Technology, September

1985, p. 82.

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, it is proposed that

21 CFR parts 210 and 211 be amended

as follows.

PART 210—CURRENT GOOD

MANUFACTURING PRACTICE IN

MANUFACTURING, PROCESSING,

PACKING, OR HOLDING OF DRUGS;

GENERAL

1. The authority citation for 21 CFR

part 210 continues to read as follows:

Authority: Secs. 201, 501, 502, 505, 506,

507, 512, 701, 704 of the Federal Food, Drug,

and Cosmetic Act (21 U.S.C. 321, 351, 352,

355, 356, 357, 360b, 371, 374).

2. Section 210.3 is amended by

adding new paragraphs (b)(23) through

(b)(30) to read as follows:

§ 210.3 Definitions.

* * * * *

(b) * * *

(23) Validation protocol means a

written plan describing the process to be

validated, including production

equipment, and how validation will be

conducted, including objective test

parameters, product and/or process

characteristics, predetermined

specifications, and factors which will

determine acceptable results.

(24) Process validation means

establishing, through documented

evidence, a high degree of assurance

that a specific process will consistently

produce a product that meets its

predetermined specifications and

quality characteristics.

(25) Methods validation means

establishing, through documented

evidence, a high degree of assurance

that an analytical method will

consistently yield results that accurately

reflect the quality characteristics of the

product tested.

(26) Equipment suitability is the

established capacity of process

equipment and ancillary systems to

operate consistently within established

limits and tolerances.

(27) Process suitability is the

established capacity of the

manufacturing process to produce

effective and reproducible results

consistently.

(28) Out-of-specification means an

examination, measurement, or test

result that does not comply with

preestablished criteria, as required by

§ 211.160(b) of this chapter.

(29) Reprocessing is a system of

reworking batches that do not conform

to standards or specifications. It

includes the steps taken to ensure that

the reprocessed batches will conform to

all established standards, specifications,

and characteristics. It includes a step or

steps in the manufacturing process that

are out of the normal processing

sequence or that are not specifically

provided for in the process.

(30) Manufacturing process means

manufacturing and storage steps in the

creation of the finished product from

the weighing of components through the

storing, packaging, and labeling of the

finished product. Such steps include,

but are not limited to, the following:

Mixing, granulating, milling, molding,

formulating, lyophilizing, tableting,

encapsulating, coating, sterilizing, and

filling.

PART 211—CURRENT GOOD

MANUFACTURING PRACTICE FOR

FINISHED PHARMACEUTICALS

3. The authority citation for 21 CFR

part 211 continues to read as follows:

Authority: Secs. 201, 501, 502, 505, 506,

507, 512, 701, 704 of the Federal Food, Drug,

and Cosmetic Act (21 U.S.C. 321, 351, 352,

355, 356, 357, 360b, 371, 374).

4. Section 211.22 is amended by

adding a sentence at the end of

paragraph (a) to read as follows:

§ 211.22 Responsibilities of quality control

unit.

(a) * * * The quality control unit shall

be responsible for the review and

approval of validation protocols and for

the review of changes in product,

process, equipment, or other changes to

determine if and when revalidation is

warranted.

* * * * *

§ 211.42 [Amended]

5. Section 211.42 Design and

construction features is amended by

removing paragraph (d).

6. Section 211.68 is amended by

revising the fifth sentence in paragraph

(b) to read as follows:

§ 211.68 Automatic, mechanical, and

electronic equipment.

* * * * *

(b) * * * In such instances, a written

record of the program shall be

maintained along with data establishing

proper performance. * * *

7. Section 211.82 is amended by

revising the first sentence in 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 and released. * * *

8. Section 211.84 is amended by

revising paragraph (c)(1), by removing

in paragraph (c)(5) the word ‘‘data’’ and

adding in its place the word ‘‘date’’, and

by removing in the first sentence of

paragraph (d)(3) the word

‘‘conformance’’ and adding in its place

the word ‘‘conformity’’ and removing

the word ‘‘procedures’’ and adding in its

place the word ‘‘specifications’’ 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 in a manner to

prevent introduction of contaminants

into the raw material.

* * * * *

9. Section 211.101 is amended by

revising paragraph (c)(3) and by adding

new paragraph (c)(4) to read as follows:

§ 211.101 Charge-in of components.

* * * * *

(c) * * *

(3) The containers are properly

identified; and

(4) The components conform to the

quality specifications for the intended

drug product.

* * * * *

10. Section 211.103 is amended by

adding a new sentence to the end of the

paragraph to read as follows:

§ 211.103 Calculation of yield.

* * * There shall also be a written

production and control procedure for

investigating any discrepancies in yield

outside the maximum or minimum

percentages established in master

production and control records.
20114 Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules

11. Section 211.110 is amended by

redesignating paragraph (d) as

paragraph (e) and by adding new

paragraphs (d) and (f) to read as follows:

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

* * * * *

(d) When blend uniformity testing is

needed to determine blend

homogeneity, the sample size in both

validation and ordinary production

batches should approximate the dosage

size. Sampling shall be demonstrated

through validation to be representative

of all portions of the blend.

* * * * *

(f) Validation of manufacturing

processes required by this section shall

be conducted in accordance with

§ 211.220.

12. Section 211.111 is amended by

revising the first sentence to read as

follows:

§ 211.111 Time limitations on production.

When appropriate, the manufacturer

shall establish and validate maximum

time limits for each phase of production

as part of validation procedures

required under § 211.220. * * *

13. Section 211.113 is amended by

revising the last sentence in paragraph

(b) to read as follows:

§ 211.113 Control of microbiological

contamination.

* * * * *

(b)* * * Such procedures shall

include validation of any sterilization or

aseptic process.

14. Section 211.160 is amended by

revising the first sentence in the

introductory text of paragraph (b) and

the first sentence in paragraph (b)(1) to

read as follows:

§ 211.160 General requirements.

* * * * *

(b) Laboratory control shall include

the establishment of scientifically sound

and applicable written specifications,

standards, sampling plans, and test

procedures including resampling,

retesting, and data interpretation

procedures designed to ensure that

components, drug product containers,

closures, in-process materials, labeling,

and drug products conform to

appropriate standards of identity,

strength, quality, and purity. * * *

(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. * * *

* * * * *

§ 211.165 [Amended]

15. Section 211.165 Testing and

release for distribution is amended by

removing paragraph (e) and

redesignating paragraph (f) as paragraph

(e).

16. Section 211.166 is amended by

redesignating paragraphs (c) and (d) as

paragraphs (d) and (e), respectively, and

by adding new paragraph (c) to read as

follows:

§ 211.166 Stability testing.

* * * * *

(c) After the expiration date has been

determined, there shall be an ongoing

testing program for each drug product to

ensure product stability. At least one

batch of each drug product shall be

added to the stability program annually.

* * * * *

§ 211.176 [Removed]

17. Section 211.176 Penicillin

contamination is removed.

18. Section 211.180 is amended by

revising paragraph (a) to read as follows:

§ 211.180 General requirements.

(a) Any production, control,

validation, or distribution record that is

required to be maintained in

compliance with this part and is

specifically associated with a batch of a

drug product shall be retained for at

least 1 year after the expiration date of

the last batch produced with that

validated process or, in the case of

certain OTC drug products lacking

expiration dating because they meet the

criteria for exemption under § 211.137,

3 years after distribution of the batch.

* * * * *

19. Section 211.192 is revised to read

as follows:

§ 211.192 Production, control, and

laboratory record review and investigation

of discrepancies.

(a) Written procedures shall be

established and followed requiring the

review and approval by the quality

control unit of all drug product

production, control, and laboratory

records, including packaging and

labeling, to determine compliance with

all established and approved written

procedures and specifications before a

batch is released or distributed.

(b) Written procedures shall be

established and followed requiring the

thorough investigation of any

unexplained discrepancy (including a

percentage of theoretical yield

exceeding the maximum or minimum

percentages established in master

production and control records) or the

failure of a batch or any of its

components or in-process materials to

meet any of its specifications (including

any out-of-specification test result),

whether or not the batch has already

been distributed. The investigation shall

extend to other batches of the same drug

product and other drug products that

may have been associated with the

specific failure or discrepancy. Such

procedures shall include:

(1) Procedures for attempting to

identify the cause of the failure or

discrepancy.

(2) Criteria for determining whether

out-of-specification results were caused

by sampling or laboratory error.

(3) Scientifically sound procedures

and criteria for the exclusion of any test

data found to be invalid due to

laboratory or sampling error.

(4) Scientifically sound procedures

and criteria for additional sampling and

testing, if necessary, during the

investigation.

(5) Procedures and criteria for

extending the investigation to other

batches or other products.

(6) Procedures for review and

evaluation of the investigation,

including all test results, by the quality

control unit, to ensure a thorough

investigation.

(7) Criteria for final approval or

rejection of the batch involved, and for

taking action on other batches and

products if indicated by the

investigation.

(c) A written record of the

investigation shall be made and shall

include:

(1) The reason for the investigation.

(2) A description of the investigation

made, including all laboratory tests.

(3) The results of the investigation,

including all laboratory test results

involved in the investigation.

(4) Scientifically sound and

appropriate justification for excluding

any out-of-specification laboratory

result found to be invalid.

(5) If laboratory results are found to be

invalid, the subsequent laboratory

results supporting the final

determination of the tested item’s

conformity to all appropriate

specifications for acceptance.

(6) The conclusions and subsequent

actions concerning all batches and

products that may have been associated

with the failure or discrepancy.

(7) The signature(s) and date(s) of the

person(s) responsible for approving the

record of the investigation.

(8) The signature(s) and date(s) of the

person(s) responsible for the final

decision on disposition of the batch,

and on other batches and products

involved.

20. New subpart L, consisting of

§§ 211.220 and 211.222, is added to read

as follows:
Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed Rules 20115

Subpart L—Validation

Sec.

211.220 Process validation.

211.222 Methods validation.

Subpart L—Validation

§ 211.220 Process validation.

(a) The manufacturer shall validate all

drug product manufacturing processes

including, but not limited to,

computerized systems that monitor and/

or control the manufacturing process.

The manufacturing process includes all

manufacturing steps in the creation of

the finished product including, but not

limited to, the following procedures:

Cleaning, weighing, measuring, mixing,

blending, compressing, filling,

packaging, and labeling.

(b) Validation protocols that identify

the product and product specifications

and specify the procedures and

acceptance criteria for the tests to be

conducted and the data to be collected

during process validation shall be

developed and approved. The protocol

shall specify a sufficient number of

replicate process runs to demonstrate

reproducibility of the process and

provide an accurate measure of

variability among successive runs.

Validation documentation shall include

evidence of the suitability of materials

and the performance and reliability of

equipment and systems. The

manufacturer shall document execution

of the protocol and test results.

(c) The manufacturer shall design or

select equipment and processes to

ensure that product specifications are

consistently achieved. The

manufacturer’s determination of

equipment suitability shall include

testing to verify that the equipment is

capable of operating satisfactorily

within the operating limits required by

the process. Process suitability shall

include documented rigorous testing to

demonstrate the effectiveness and

reproducibility of the process. Parts of

the process that may cause variability or

otherwise affect product quality shall be

tested.

(d) There shall be a quality assurance

system in place which requires

revalidation whenever there are changes

in packaging, component

characteristics, formulation, equipment,

or processes, including reprocessing,

that could affect product effectiveness

or product characteristics, and

whenever changes are observed in

product characteristics.

§ 211.222 Methods validation.

The accuracy, sensitivity, specificity,

and reproducibility of test methods used

by a manufacturer shall be validated

and documented. Such validation and

documentation shall be accomplished in

accordance with § 211.194(a)(2).

21. New subpart M, consisting of

§ 211.240, is added to read as follows:

Subpart M—Contamination

Sec.

211.240 Control of chemical and physical

contaminants.

Subpart M—Contamination

211.240 Control of chemical and physical

contaminants.

(a) The manufacturer shall implement

written procedures designed to prevent

objectionable chemical and physical

contamination, including crosscontamination.

(b) Dedicated production, which may

include facilities, air handling

equipment, and/or process equipment,

shall be employed where contaminants,

such as penicillin, pose a special danger

to human or animal health or if there are

no reasonable methods for the cleaning

and removal of drug substances and/or

component residues from buildings,

facilities, and equipment.

(c) If a reasonable possibility exists

that a drug has been exposed to crosscontamination, the manufacturer shall

test the product for the presence of the

potential contaminant. The

manufacturer shall establish appropriate

limits for such potential contaminants.

Products that exceed the established

limits shall not be released for

distribution.

Dated: March 29, 1996.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 96–11094 Filed 5–2–96; 8:45 am]

BILLING CODE 4160–01–F