[Federal Register Volume 61, Number 87 (Friday, May 3, 1996)]
[Proposed Rules]
[Pages 20104-20115]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-11094]




[[Page 20103]]


_______________________________________________________________________

Part VIII





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Parts 210 and 211



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

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

[[Page 20104]]



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: ``[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

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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

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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