Current Good Manufacturing Practice; Proposed Amendment of Certain Requirements for Finished Pharmaceuticals

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: ``[email protected]''.

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

[[Page 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 Sec. 211.220 to the

CGMP regulations specifying the nature and extent of validation that

are necessary to

[[Page 20106]]

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 Sec. 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 Sec. 211.165(e) to

Sec. 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-by-

substance 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 cross-contamination 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 cross-contamination, 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 cross-contamination. 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 cross-contamination; 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

[[Page 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-of-specification 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

Sec. 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 Sec. 210.3(b) defines various terms that are used in the

CGMP regulations in parts 210 to 226.

This proposed rule would amend Sec. 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

Sec. 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 Sec. 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

Sec. 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 Sec. 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 Sec. 210.3(b)(27), ``process suitability'' would

mean the established capacity of the manufacturing process to produce

effective and reproducible results consistently.-

Proposed Sec. 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

Sec. 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, in-process materials, labeling, and drug products conform to

appropriate standards of identity, strength, quality, and purity.

Proposed Sec. 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 Sec. 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 Sec. 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, Sec. 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

[[Page 20108]]

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 Sec. 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 Sec. 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

Sec. 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

Sec. 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 Sec. 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 Sec. 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

(Sec. 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 Sec. 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 Sec. 211.110 establishes several requirements for the

sampling and testing of in-process materials and drug products. For

example, Sec. 211.110(a) requires written procedures for in-process

controls and tests or examinations to be conducted on appropriate

samples of in-process materials of each batch, whereas Sec. 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

[[Page 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 Sec. 211.110(d) to help

ensure adequate testing. (The current paragraph (d) would be

redesignated as paragraph (e).) Proposed Sec. 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 Sec. 211.110(f) that

validation of manufacturing processes be conducted in accordance with

process validation requirements in proposed Sec. 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, Sec. 211.111 currently

requires, when appropriate, time limits for the completion of each

phase of production.

This proposed rule would revise Sec. 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 Sec. 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 Sec. 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, Sec. 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 Sec. 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

Sec. 211.165(e) and redesignate paragraph (f) as paragraph (e).

M. Section 211.166--Stability Testing

Currently, Sec. 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 Sec. 211.166(c) and (d) as Sec. 211.166(d) and (e),

and add new Sec. 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

Sec. 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-of-

specification 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-of-

specification result.

[[Page 20110]]

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-of-specification 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-of-specification result. If the out-of-specification 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 Sec. 211.192 to read

``Production, control, and laboratory record review and investigation

of discrepancies,'' and would amend Sec. 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-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; 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 Sec. 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:

Sec. 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 Sec. 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 Sec. 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 Sec. 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

[[Page 20111]]

documented and the manufacturer would be required to retain such

documentation.

Proposed Sec. 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 Sec. 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 Sec. 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

Sec. 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. Cross-contamination 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 Sec. 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 Secs. 211.42(d) and 211.176 regarding separate facilities for

manufacturing penicillin and penicillin contamination and to

incorporate their requirements in Sec. 211.240.

Proposed Sec. 211.240(a) would require the implementation of

written procedures designed to prevent objectionable chemical and

physical contamination, including cross-contamination. 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 Sec. 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 cross-contamination, proposed Sec. 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-of-specification 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.

[[Page 20112]]

----------------------------------------------------------------------------------------------------------------

Estimated Reporting Burden \1\

-----------------------------------------------------------------------------------------------------------------

Number of Responses per Total Annual Hours Per

CFR Section Respondents Respondent Responses 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

----------------------------------------------------------------------------------------------------------------

\1\ Because 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 one-time 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 cost-effective option evaluated. Several of the rejected

alternatives considered (such as revisions to Sec. 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

[[Page 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:

Sec. 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 Sec. 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:

Sec. 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.

* * * * *

Sec. 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:

Sec. 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:

Sec. 211.82 Receipt and storage of untested components, drug product

containers, and closures.

* * * * *

(b) Components, drug product containers, and closures shall be

stored under quarantine until they have been tested or examined 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:

Sec. 211.84 Testing and approval or rejection of components, drug

product containers, and closures.

* * * * *

(c) * * *

(1) The containers of components selected shall be cleaned 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:

Sec. 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:

Sec. 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.

[[Page 20114]]

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:

Sec. 211.110 Sampling and testing of in-process 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 Sec. 211.220.

12. Section 211.111 is amended by revising the first sentence to

read as follows:

Sec. 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 Sec. 211.220. * * *

13. Section 211.113 is amended by revising the last sentence in

paragraph (b) to read as follows:

Sec. 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:

Sec. 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. * * *-

* * * * *

Sec. 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:

Sec. 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.

* * * * *

Sec. 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:

Sec. 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 Sec. 211.137, 3 years after distribution

of the batch.

* * * * *

19. Section 211.192 is revised to read as follows:

Sec. 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 Secs. 211.220 and 211.222, is

added to read as follows:

[[Page 20115]]

Subpart L--Validation

Sec.

211.220 Process validation.

211.222 Methods validation.

Subpart L--Validation

Sec. 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.

Sec. 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

Sec. 211.194(a)(2).

21. New subpart M, consisting of Sec. 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

cross-contamination.

(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 cross-contamination, 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