+--------------------------------+-----------------+-------------------+
| **SUBJECT:**                   |                 | **IMPLEMENTATION  |
|                                |                 | DATE**            |
| DRUG MANUFACTURING INSPECTIONS |                 |                   |
|                                |                 | 2/1/2002          |
+--------------------------------+-----------------+-------------------+
|                                |                 | **COMPLETION      |
|                                |                 | DATE**            |
|                                |                 |                   |
|                                |                 | Continuing        |
+--------------------------------+-----------------+-------------------+
| **DATA REPORTING**             |                 |                   |
+--------------------------------+-----------------+-------------------+
| **PRODUCT CODES**              | **PRO           |                   |
|                                | DUCT/ASSIGNMENT |                   |
|                                | CODES**         |                   |
+--------------------------------+-----------------+-------------------+
| All Human Drugs                | Domestic /      |                   |
|                                | Foreign         |                   |
| Industry codes:                | Inspections:    |                   |
|                                |                 |                   |
| 50, 54-56, 59, 60-66           | 56002           |                   |
|                                |                 |                   |
|                                | 56002A Sterile  |                   |
|                                | products        |                   |
|                                | manufacture     |                   |
|                                |                 |                   |
|                                | 56002B          |                   |
|                                | Repackers and   |                   |
|                                | relabelers      |                   |
|                                |                 |                   |
|                                | 56002C          |                   |
|                                | Radioactive     |                   |
|                                | drugs           |                   |
|                                |                 |                   |
|                                | 56002E          |                   |
|                                | Compressed      |                   |
|                                | medical gases   |                   |
|                                |                 |                   |
|                                | 56002F Bulk     |                   |
|                                | pharmaceutical  |                   |
|                                | chemicals       |                   |
+--------------------------------+-----------------+-------------------+

[FIELD REPORTING REQUIREMENTS]{.underline}

Forward a copy of each [Establishment Inspection Report]{.underline}
(EIR) for inspections classified as OAI due to CGMP deficiencies as part
of any regulatory action recommendation submitted to HFD-300. For all
inspections that result in the issuance of a Warning Letter, forward an
electronic copy of each letter to the Division of Manufacturing and
Product Quality, Case Management and Guidance Branch (HFD-325). An
e-mail account has been established to receive copies of Warning
Letters. The account e-mail address is CDERCGMPWL.

This program provides guidance in evaluating compliance with CGMP
requirements. As soon as the District becomes aware of any significant
inspectional, analytical, or other information developed under this
program that may affect the agency\'s new drug approval decisions with
respect to a firm, the District should report the information
immediately according to current FACTS procedures. This includes filing
OAI notifications and removing the notifications.

However, if information is encountered pertaining to inadequate
postapproval reporting (Annual Reports, Supplements, Field Alert
Reports, Adverse Drug Experience Reports, etc.) the information should
be described in accordance with directions provided in those applicable
compliance programs and under separate captions in the EIR. Data system
information about these inspectional activities should be reported using
applicable separate PAC(s). Expansion of coverage under these programs
into a CGMP inspection must be reported under this compliance program.

The Districts are requested to use this revised compliance program for
[all]{.underline} GMP inspections.

[PART I -- BACKGROUND]{.underline}

A primary mission of the Food and Drug Administration is to conduct
comprehensive regulatory coverage of all aspects of production and
distribution of drugs and drug products to assure that such products
meet the 501(a)(2)(B) requirements of the Act. FDA has developed two
basic strategies:

> 1\) evaluating through factory inspections, including the collection
> and analysis of associated samples, the conditions and practices under
> which drugs and drug products are manufactured, packed, tested and
> held, and

2\) monitoring the quality of drugs and drug products through
surveillance activities such as sampling and analyzing products in
distribution.

This compliance program is designed to provide guidance for implementing
the first strategy. Products from production and distribution facilities
covered under this program are consistently of acceptable quality if the
firm is operating in a state of control. The Drug Product Surveillance
Program (CP 7356.008) provides guidance for the latter strategy.

The inspectional guidance in this program is structured to provide for
efficient use of resources devoted to routine surveillance coverage,
recognizing that in-depth coverage of all systems and all processes is
not feasible for all firms on a biennial basis. It also provides for
follow-up compliance coverage as needed.

[PART II - IMPLEMENTATION]{.underline}

[OBJECTIVES]{.underline}

The goal of this program\'s activities is to minimize consumers\'
exposure to adulterated drug products.

Under this program, inspections and investigations, sample collections
and analyses, and regulatory or administrative follow-up are made:

1\) to determine whether inspected firms are operating in compliance
with applicable CGMP requirements, and if not, to provide the evidence
for actions to prevent adulterated products from entering the market and
as appropriate to remove adulterated products from the market, and to
take action against persons responsible as appropriate;

2\) to provide CGMP assessment which may be used in efficient
determination of acceptability of the firm in the pre-approval review of
a facility for new drug applications;

3\) to provide input to firms during inspections to improve their
compliance with regulations; and,

4\) to continue FDA\'s unique expertise in drug manufacturing in
determining the adequacy of CGMP requirements, Agency CGMP regulatory
policy, and guidance documents.

[STRATEGY]{.underline}

A. Biennial Inspection of Manufacturing Sites (includes repackaging,
contract labs, etc.)

Drugs and drug products are manufactured using many physical operations
to bring together components and containers and closures into a product
that is released for distribution. Activities found in drug firms can be
organized into systems that are sets of operations and related
activities. Control of all systems helps to ensure the firm will produce
drugs that are safe, have the identity and strength, and meet the
quality and purity characteristics as intended.

Biennial inspections (every two years) conducted under this program:

1\) reduce the risk that adulterated products are reaching the
marketplace;

2\) increase communication between the industry and the Agency;

3\) provide for timely evaluation of new manufacturing operations in the
firm; and,

4\) provide for regular feedback from the Agency to individual firms on
the continuing status of the firm\'s GMP compliance.

This program applies to all drug manufacturing operations.

Currently there are not enough FDA resources to audit every aspect of
CGMP in every manufacturing facility during every inspection visit.
Profile classes generalize inspection coverage from a small number of
specific products to all the products in that class. This program
establishes a systems approach to further generalize inspection coverage
from a small number of profile classes to an overall evaluation of the
firm. Reporting coverage for every profile class as defined in FACTS, in
each biennial inspection, provides the most broadly resource-efficient
approach. Biennial updating of all profile classes will allow for CGMP
acceptability determinations to be made without delays resulting from
revisiting the firm. This will speed the review process, in response to
compressed time frames for application decisions and in response to
provisions of the Food and Drug Administration Modernization Act of 1997
(FDAMA). This will allow for Pre-approval Inspections/Investigations
Program inspections and Post-approval Audit Inspections Program
inspections to focus on the specific issues related to a given
application or the firm's ability to keep applications current.

The inspection is defined as audit coverage of 2 or more systems, with
mandatory coverage of the Quality System (see system definitions below).
Inspection options include different numbers of systems to be covered
depending on the purpose of the inspection. Inspecting the minimum
number of systems, or more systems as deemed necessary by the District,
will provide the basis for an overall CGMP decision.

B. Inspection of Systems

Inspections of drug manufacturers should be made and reported using the
system definitions and organization in this compliance program. Focusing
on systems, rather than profile classes, will increase efficiency in
conducting inspections because the systems are often applicable to
multiple profile classes. One biennial inspection visit will result in a
determination of acceptability/non-acceptability for all profile
classes. Inspection coverage should be representative of all the profile
classes manufactured by the firm. The efficiency will be realized
because multiple visits to a firm will not be needed to cover all
profile classes; delays in approval decisions will be avoided because
up-to-date profile class information will be available at all times.

Coverage of a system should be sufficiently detailed, with specific
examples selected, so that the system inspection outcome reflects the
state of control in that system for every profile class. If a particular
system is adequate, it should be adequate for all profile classes
manufactured by the firm. For example, the way a firm handles
\"materials\" (i.e., receipt, sampling, testing, acceptance, etc.)
should be the same for all profile classes. The investigator should not
have to inspect the Material System for each profile class. Likewise in
the Production System, there are general requirements like SOP use,
charge-in of components, equipment identification, in-process sampling
and testing which can be evaluated through selection of example products
in various profile classes. Under each system there may be something
unique for a particular profile class: e.g., under the Materials System,
the production of Water for Injection USP for use in manufacturing.
Selecting unique functions within a system will be at the discretion of
the lead investigator. Any given inspection need not cover every system.
See Part III.

Complete inspection of one system may necessitate further follow up of
some items within the activities of another/other system(s) to fully
document the findings. However, this coverage does not constitute nor
require complete coverage of these other systems.

C. A Scheme of Systems for the Manufacture of Drugs/Drug Products

A general scheme of systems for auditing the manufacture of drugs and
drug products consists of the following:

1.  [Quality System.]{.underline} This system assures overall compliance
    with cGMPs and internal procedures and specifications. The system
    includes the quality control unit and all of its review and approval
    duties (e.g., change control, reprocessing, batch release, annual
    record review, validation protocols, and reports, etc.). It includes
    all product defect evaluations and evaluation of returned and
    salvaged drug products. See the CGMP regulation, 21 CFR 211 Subparts
    B, E, F, G, I, J, and K.

2 . [Facilities and Equipment System.]{.underline} This system includes
the measures and activities which provide an appropriate physical
environment and resources used in the production of the drugs or drug
products. It includes:

a\) Buildings and facilities along with maintenance;

b)  Equipment qualifications (installation and operation); equipment
    calibration and preventative maintenance; and cleaning and
    validation of cleaning processes as appropriate. Process performance
    qualification will be evaluated as part of the inspection of the
    overall process validation which is done within the system where the
    process is employed; and,

c)  Utilities that are not intended to be incorporated into the product
    such as HVAC, compressed gases, steam and water systems.

> See the CGMP regulation, 21 CFR 211 Subparts B, C, D, and J.

2.  [Materials System]{.underline}. This system includes measures and
    activities to control finished products, components, including water
    or gases, that are incorporated into the product, containers and
    closures. It includes validation of computerized inventory control
    processes, drug storage, distribution controls, and records. See the
    CGMP regulation, 21 CFR 211 Subparts B, E, H,

and J.

4\. [Production System]{.underline}. This system includes measures and
activities to control the manufacture of drugs and drug products
including batch compounding, dosage form production, in-process sampling
and testing, and process validation. It also includes establishing,
following, and documenting performance of approved manufacturing
procedures. See the CGMP regulation, 21 CFR 211 Subparts B, F, and J.

5\. [Packaging and Labeling System]{.underline}. This system includes
measures and activities that control the packaging and labeling of drugs
and drug products. It includes written procedures, label examination and
usage, label storage and issuance, packaging and labeling operations
controls, and validation of these operations. See the CGMP regulation,
21 CFR 211 Subparts B, G, and J.

6\. [Laboratory Control System]{.underline}. This system includes
measures and activities related to laboratory procedures, testing,
analytical methods development and validation or verification, and the
stability program. See the CGMP regulation, 21 CFR 211 Subparts B, I, J,
and K.

The overall theme in devising this scheme of systems was the subchapter
structure of the CGMP regulation. Every effort was made to group whole
subchapters together in a rational set of six systems which incorporates
the general scheme of pharmaceutical manufacturing operations.

The organization and personnel, including appropriate qualifications and
training, employed in any given system, will be evaluated as part of
that system\'s operation. Production, control, or distribution records
required to be maintained by the CGMP regulation and selected for review
should be included for inspection audit within the context of each of
the above systems. Inspections of contract companies should be within
the system for which the product or service is contracted as well as
their Quality System.

As this program approach is implemented, the experience gained will be
reviewed to make modifications to the system definitions and
organization as needed.

[PROGRAM MANAGEMENT INSTRUCTIONS]{.underline}

A. [Definitions]{.underline}

1\. [Surveillance Inspections]{.underline}

[The Full Inspection Option]{.underline}

The Full Inspection Option is a surveillance or compliance inspection
which is meant to provide a broad and deep evaluation of the firm\'s
CGMP. This will be done when little or no information is known about a
firm\'s CGMP compliance (e.g., for new firms); or for firms where there
is doubt about the CGMP compliance in the firm (e.g., a firm whose
history has documented short-lived compliance and recidivism); or follow
up to previous regulatory actions. Based on findings of objectionable
conditions as listed in Part V in one or more systems (a minimum of two
systems must be completed), a Full Inspection may revert to the
Abbreviated Inspection Option, with District concurrence. See Part III,
Section B.1. During the course of a Full Inspection, verification of
Quality System activities may require limited coverage in other systems.
The Full Inspection Option will normally include an inspection audit of
at least four of the systems, one of which must be the Quality System
(the system which includes the responsibility for the annual product
reviews).

[The Abbreviated Inspection Option]{.underline}

The Abbreviated Inspection Option is a surveillance or compliance
inspection which is meant to provide an efficient update evaluation of a
firm's CGMP. The abbreviated inspection will provide documentation for
continuing a firm in a satisfactory CGMP compliance status. Generally
this will be done when a firm has a record of satisfactory CGMP
compliance, with no significant recall, or product defect or alert
incidents, or with little shift in the manufacturing profiles of the
firm within the previous two years. See Part III, Section B.2. A Full
Inspection may revert to an Abbreviated Inspection based on findings of
objectionable conditions as listed in Part V in one or more systems. The
Abbreviated Inspection Option normally will include an inspection audit
of at least two of the systems, one of which must be the Quality System
(the system which includes the responsibility for the annual product
reviews). The District drug program managers should ensure that the
optional systems are rotated in successive Abbreviated Inspections.
During the course of an abbreviated inspection, verification of quality
system activities may require limited coverage in other systems. Some
firms participate in a limited part of the production of a drug or drug
product, e.g., a contract laboratory. Such firms may employ only two of
the systems defined. In these cases the inspection of the two systems
will comprise inspection of the entire firm and will be considered the
Full Inspection Option.

[Selecting Systems for Coverage]{.underline}

The selection of the system(s) for coverage will be made by the District
Office based on such factors as a given firm's specific operation,
history of previous coverage, history of compliance, or other priorities
determined by the District Office.

2\. [Compliance Inspections]{.underline}

Compliance Inspections are inspections done to evaluate or verify
compliance corrective actions after a regulatory action has been taken.
First, the coverage given in compliance inspections must be related to
the areas found deficient and subjected to corrective actions.

In addition, coverage must be given to systems because a determination
must be made on the overall compliance status of the firm after the
corrective actions are taken. The firm is expected to address all of its
operations in its corrective action plan after a previously violative
inspection, not just the deficiencies noted in the FDA-483. The Full
Inspection Option should be used for a compliance inspection, especially
if the Abbreviated Inspection Option was used during the violative
inspection.

Compliance Inspections include For Cause Inspections. For Cause
Inspections are compliance inspections which are done to investigate a
specific problem that has come to the attention of some level of the
agency. The problems may be indicated in Field Alert Reports (FARs),
industry complaints, recalls, indicators of defective products, etc.
Coverage of these areas may be assigned under other compliance programs,
however, expansion of the coverage to a GMP inspection is to be reported
under this program. For Cause Inspections may be assigned under this
program as the need arises.

3\. [State of Control]{.underline}

A drug firm is considered to be operating in a state of control when it
employs conditions and practices that assure compliance with the intent
of Sections 501(a)(2)(B) of the Act and portions of the CGMP regulations
that pertain to their systems. A firm in a state of control produces
finished drug products for which there is an adequate level of assurance
of quality, strength, identity and purity.

A firm is out of control if any one system is out of control. A system
is out of control if the quality, identity, strength and purity of the
products resulting from that/those system(s) cannot be adequately
assured. Documented CGMP deficiencies provide the evidence for
concluding that a system is not operating in a state of control. See
Part V. Regulatory/Administrative Strategy for a discussion of
compliance actions based on inspection findings demonstrating out of
control systems/firm.

4\. [Drug Process]{.underline}

A drug process is a related series of operations which result in the
preparation of a drug or drug product. Major operations or steps in a
drug process may include mixing, granulation, encapsulation, tableting,
chemical synthesis, fermentation, aseptic filling, sterilization,
packing, labeling, testing, etc.

5\. [Drug Manufacturing Inspection]{.underline}

A drug manufacturing inspection is a factory inspection in which
evaluation of two or more systems, including the Quality System, is done
to determine if manufacturing is occurring in a state of control.

B. [Inspection Planning]{.underline}

The Field will conduct drug manufacturing inspections and maintain
profiles or other monitoring systems which will ensure that each drug
firm receives biennial inspectional coverage, as provided for in the
strategy.

The District Office is responsible for determining the depth of coverage
given to each drug firm. CGMP inspectional coverage shall be sufficient
to assess the state of compliance for each firm.

The frequency and depth of inspection should be determined by the
statutory obligation, the firm\'s compliance history, the technology
employed, and the characteristics of the products. When a system is
inspected, the inspection of that system may be considered applicable to
all products which use it. Investigators should select an adequate
number and type of products to accomplish coverage of the system.
Selection of products should be made so that coverage is representative
of the firm's overall abilities in manufacturing within CGMP
requirements.

Review of NDA/ANDA files may assist in selecting significant drug
processes for coverage in the various systems. Significant drug
processes are those which utilize all the systems in the firm very
broadly and/or which contain steps with unique or difficult manipulation
in the performance of a step. Products posing special manufacturing
features, e.g., low dose products, narrow therapeutic range drugs,
combination drugs, modified release products, etc., and new products
made under an approved drug application, should be considered first in
selecting products for coverage.

The health significance of certain CGMP deviations may be lower when the
drug product involved has no major systemic effect or no dosage
limitations such as in products like calamine lotion or OTC medicated
shampoos. Such products should be given inspection coverage with
appropriate priority.

Inspections for this compliance program may be performed during visits
to a firm when operations are being performed for other compliance
programs or other investigations.

C. [Profiles]{.underline}

The inspection findings will be used as the basis for updating all
profile classes in the profile screen of the FACTS EIR coversheet that
is used to record profile/class determinations. Normally, an inspection
under this systems approach will result in all profile classes being
updated.

[PART III - INSPECTIONAL]{.underline}

[INVESTIGATIONAL OPERATIONS]{.underline}

A. [General]{.underline}

Review and use the CGMPs for Finished Pharmaceuticals (21 CFR 210 and
211) to evaluate manufacturing processes. Use Guides to Inspection
published by the Office of Regional Operations for information on
technical applications in various manufacturing systems.

The investigator should conduct inspections according to the STRATEGY
section in Part II of this compliance program. Recognizing that drug
firms vary greatly in size and scope, and manufacturing systems are more
or less sophisticated, the approach to inspecting each firm should be
carefully planned. For example, it may be more appropriate to review the
Quality System thoroughly before entering production areas in some
firms; in others, the Quality System review should take place
concurrently with inspection of another system or systems selected for
coverage. The complexity and variability necessitate a flexible
inspection approach; one which allows the investigator to choose the
inspection focus and depth appropriate for a specific firm, but also one
which directs the performance and reporting on the inspection within a
framework which will provide for a uniform level of CGMP assessment.
Furthermore, this inspection approach will provide for fast
communication and evaluation of findings.

Inspectional Observations noting CGMP deficiencies should be related to
a requirement. Requirements for manufacture of drug products (dosage
forms) are in the CGMP regulation and are amplified by policy in the
Compliance Policy Guides, case precedents, etc. CGMP requirements apply
to the manufacture of distributed prescription drug products, OTC drug
products, approved products and products not requiring approval, as well
as drug products used in clinical trials. The CGMP regulations are not
direct requirements for manufacture of API's; the regulations should not
be referenced as the basis for a GMP deficiency in the manufacture of
Active Pharmaceutical Ingredients (APIs), but they are guidance for CGMP
in API manufacture.

Guidance documents do not establish requirements. They state examples of
ways to meet requirements.

Guidance documents are not to be referred to as the justification for an
inspectional observation. The justification comes from the CGMPs.
Current Guides to Inspection and Guidance to Industry documents provide
interpretations of requirements, which may assist in the evaluation of
the adequacy of CGMP systems.

Current inspectional observation policy as stated in the IOM says that
the FDA-483, when issued, should be specific and contain only
significant items. For this program, inspection observations should be
organized under separate captions by the systems defined in this
program. List observations in order of importance within each system.
Where repeated or similar observations are made, they should be
consolidated under a unified observation. For those Districts utilizing
Turbo EIR, a limited number of observations can be common to more than
one system (e.g. organization and personnel including appropriate
qualifications and training). In these instances, put the observation in
the first system reported on the FDA-483 and in the text of the EIR,
reference the applicability to other systems where appropriate. This is
being done to accommodate the structure of Turbo EIR which allows
individual citation once per FDA-483. Refrain from using unsubstantiated
conclusions. Do not use the term \"inadequate\" without explaining why
and how. Refer to policy in the IOM, Chapter 5, Section 512 and Field
Management Directive 120 for further guidance on the content of
Inspectional Observations.

Specific specialized inspectional guidance may be provided as
attachments to this program, or in requests for inspection, assignments,
etc.

B. [Inspection Approaches]{.underline}

This program provides two surveillance inspectional options, Abbreviated
Inspection Option and Full Inspection Option. See the definitions of the
inspection options in Part II of this program.

1\. [Selecting the Full Inspection Option]{.underline}. The Full
Inspection Option will include inspection of at least four of the
systems as listed in Part II Strategy, one of which must be the Quality
System.

> a\. Select the Full Inspection Option for an initial FDA inspection of
> a facility. A Full Inspection may revert to the Abbreviated Inspection
> Option, **with District concurrence,** based on finding of
> objectionable conditions as listed in Part V in one or more systems (a
> minimum of two systems must be completed).

b.  Select the Full Inspection Option when the firm has a history of
    fluctuating into and out of compliance. To determine if the firm
    meets this criterion, the District should utilize all information at
    its disposal, such as, inspection results, results of sample
    analyses, complaints, DQRS reports, recalls, etc. and the compliance
    actions resulting from them or from past inspections. A Full
    Inspection may revert to the Abbreviated Inspection Option, **with
    District concurrence,** based on findings of objectionable
    conditions as listed in Part V in one or more systems (a minimum of
    two systems must be completed).

> c\. Evaluate if important changes have occurred by comparing current
> operations against the EIR for the previous Full Inspection. The
> following types of changes are typical of those that warrant the Full
> Inspection Option:
>
> \(1\) New potential for cross-contamination arising through change in
> process or product line.
>
> \(2\) Use of new technology requiring new expertise, significant new
> equipment, or new facilities.
>
> d\. A Full Inspection may also be conducted on a surveillance basis at
> the District\'s discretion.

e\. The Full Inspection Option will satisfy the biennial inspection
requirement.

f\. Follow up to a Warning Letter or other significant regulatory
actions should require a Full Inspection option.

2\. [Selecting the Abbreviated Inspection Option]{.underline}. The
Abbreviated Inspection Option normally will include inspection audit of
at least two systems, one of which must be the Quality System. During
the course of an Abbreviated Inspection, verification of quality system
activities may require limited coverage in other systems.

a.  This option involves an inspection of the manufacturer to maintain
    surveillance over the firm\'s activities and to provide input to the
    firm on maintaining and improving the GMP level of assurance of
    quality of its products.

b.  A Full Inspection may revert to the Abbreviated Inspection option,
    **with District concurrence,** based on findings of objectionable
    conditions as listed in Part V in one or more systems (a minimum of
    two systems must be completed).

c.  An abbreviated inspection is adequate for routine coverage and will
    satisfy the biennial inspectional requirement.

[Comprehensive Inspection Coverage]{.underline}

It is not anticipated that Full Inspections will be conducted every two
years. They may be conducted at less frequent intervals, perhaps at
every third or fourth inspection cycle. Districts should consider
selecting different optional systems for inspection coverage as a cycle
of Abbreviated Inspections is carried out to build comprehensive
information on the firm's total manufacturing activities.

C. [System Inspection Coverage]{.underline}

# QUALITY SYSTEM

Assessment of the Quality System is two phased. The first phase is to
evaluate whether the Quality Control Unit has fulfilled the
responsibility to review and approve all procedures related to
production, quality control, and quality assurance and assure the
procedures are adequate for their intended use. This also includes the
associated recordkeeping systems. The second phase is to assess the data
collected to identify quality problems and may link to other major
systems for inspectional coverage.

For each of the following, the firm should have written and approved
procedures and documentation resulting therefrom. The firm's adherence
to written procedures should be verified through observation whenever
possible. These areas are not limited to finished products, but may also
incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other major
systems that would warrant expansion of coverage. All areas under this
system should be covered; however the depth of coverage may vary
depending upon inspectional findings.

-   Product reviews: at least annually; should include information from
    areas listed below as appropriate; batches reviewed, for each
    product, are representative of all batches manufactured; trends are
    identified; refer to 21 CFR 211.180(e).

-   Complaint reviews (quality and medical): documented; evaluated;
    investigated in a timely manner; includes corrective action where
    appropriate.

-   Discrepancy and failure investigations related to manufacturing and
    testing: documented; evaluated; investigated in a timely manner;
    includes corrective action where appropriate.

-   Change Control: documented; evaluated; approved; need for
    revalidation assessed.

-   Product Improvement Projects: for marketed products

-   Reprocess/Rework: evaluation, review and approval; impact on
    validation and stability.

-   Returns/Salvages: assessment; investigation expanded where
    warranted; disposition.

-   Rejects: investigation expanded where warranted; corrective action
    where appropriate.

-   Stability Failures: investigation expanded where warranted; need for
    field alerts evaluated; disposition.

-   Quarantine products.

-   Validation: status of required validation/revalidation (e.g.,
    computer, manufacturing process, laboratory methods).

-   Training/qualification of employees in quality control unit
    functions.

    FACILITIES AND EQUIPMENT SYSTEM

For each of the following, the firm should have written and approved
procedures and documentation resulting therefrom. The firm's adherence
to written procedures should be verified through observation whenever
possible. These areas may indicate deficiencies not only in this system
but also in other systems that would warrant expansion of coverage. When
this system is selected for coverage in addition to the Quality System,
all areas listed below should be covered; however, the depth of coverage
may vary depending upon inspectional findings.

> 1\. Facilities
>
> \- cleaning and maintenance

-   facility layout and air handling systems for prevention of
    cross-contamination (e.g. penicillin, beta-lactams, steroids,
    hormones, cytotoxics, etc.)

-   specifically designed areas for the manufacturing operations
    performed by the firm to prevent contamination or mix-ups

-   general air handling systems

-   control system for implementing changes in the building

> \- lighting, potable water, washing and toilet facilities, sewage and
> refuse disposal
>
> \- sanitation of the building, use of rodenticides, fungicides,
> insecticides, cleaning and sanitizing agents

2.  Equipment

-   equipment installation and operational qualification where
    appropriate

> \- adequacy of equipment design, size, and location
>
> \- equipment surfaces should not be reactive, additive, or absorptive
>
> \- appropriate use of equipment operations substances, (lubricants,
> coolants, refrigerants, etc.) contacting products/containers/etc.
>
> \- cleaning procedures and cleaning validation
>
> \- controls to prevent contamination, particularly with any pesticides
> or any other toxic materials, or other drug or non-drug chemicals

\- qualification, calibration and maintenance of storage equipment, such
as refrigerators and freezers for ensuring that standards, raw
materials, reagents, etc. are stored at the proper temperatures

\- equipment qualification, calibration and maintenance, including
computer qualification/validation and security

> \- control system for implementing changes in the equipment

-   equipment identification practices (where appropriate)

-   documented investigation into any unexpected discrepancy

    MATERIALS SYSTEM

For each of the following, the firm should have written and approved
procedures and documentation resulting therefrom. The firm's adherence
to written procedures should be verified through observation whenever
possible. These areas are not limited to finished products, but may also
incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems
that would warrant expansion of coverage. When this system is selected
for coverage in addition to the Quality System, all areas listed below
should be covered; however, the depth of coverage may vary depending
upon inspectional findings.

> \- training/qualification of personnel
>
> \- identification of components, containers, closures
>
> \- inventory of components, containers, closures
>
> \- storage conditions
>
> \- storage under quarantine until tested or examined and released

-   representative samples collected, tested or examined using
    appropriate means

> \- at least one specific identity test is conducted on each lot of
> each component
>
> \- a visual identification is conducted on each lot of containers and
> closures

-   testing or validation of supplier\'s test results for components,
    containers and closures

> \- rejection of any component, container, closure not meeting
> acceptance requirements. Investigate fully the firm's procedures for
> verification of the source of components.
>
> \- appropriate retesting/reexamination of components, containers,
> closures
>
> \- first in-first out use of components, containers, closures
>
> \- quarantine of rejected materials
>
> \- water and process gas supply, design, maintenance, validation and
> operation
>
> \- containers and closures should not be additive, reactive, or
> absorptive to the drug product
>
> \- control system for implementing changes in the materials handling
> operations

-   qualification/validation and security of computerized or automated
    processes

-   finished product distribution records by lot

-   documented investigation into any unexpected discrepancy

PRODUCTION SYSTEM

For each of the following, the firm should have written and approved
procedures and documentation resulting therefrom. The firm's adherence
to written procedures should be verified through observation whenever
possible. These areas are not limited to finished products, but may also
incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems
that would warrant expansion of coverage. When this system is selected
for coverage in addition to the Quality System, all areas listed below
should be covered; however, the depth of coverage may vary depending
upon inspectional findings.

> \- training/qualification of personnel
>
> \- control system for implementing changes in processes
>
> \- adequate procedure and practice for charge-in of components

\- formulation/manufacturing at not less than 100%

> \- identification of equipment with contents, and where appropriate
> phase of manufacturing and/or status
>
> \- validation and verification of cleaning/sterilization/
> depyrogenation of containers and closures
>
> \- calculation and documentation of actual yields and percentage of
> theoretical yields
>
> \- contemporaneous and complete batch production documentation
>
> \- established time limits for completion of phases of production
>
> \- implementation and documentation of in-process controls, tests, and
> examinations (e.g., pH, adequacy of mix, weight variation, clarity)

-   justification and consistency of in-process specifications and drug
    product final specifications

> \- prevention of objectionable microorganisms in non-sterile drug
> products
>
> \- adherence to preprocessing procedures (e.g., set-up, line
> clearance, etc.)
>
> \- equipment cleaning and use logs

-   master production and control records

> \- batch production and control records
>
> \- process validation, including validation and security of
> computerized or automated processes

-   change control; the need for revalidation evaluated

-   documented investigation into any unexpected discrepancy

# PACKAGING AND LABELING SYSTEM

For each of the following, the firm should have written and approved
procedures and documentation resulting therefrom. The firm's adherence
to written procedures should be verified through observation whenever
possible. These areas are not limited only to finished products, but may
also incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems
that would warrant expansion of coverage. When this system is selected
for coverage in addition to the Quality System, all areas listed below
should be covered; however, the depth of coverage may vary depending
upon inspectional findings.

> \- training/qualification of personnel
>
> \- acceptance operations for packaging and labeling materials
>
> \- control system for implementing changes in packaging and labeling
> operations
>
> \- adequate storage for labels and labeling, both approved and
> returned after issued
>
> \- control of labels which are similar in size, shape, and color for
> different products
>
> \- finished product cut labels for immediate containers which are
> similar in appearance without some type of 100 percent electronic or
> visual verification system or the use of dedicated lines
>
> \- gang printing of labels is not done, unless they are differentiated
> by size, shape, or color
>
> \- control of filled unlabeled containers that are later labeled under
> multiple private labels
>
> \- adequate packaging records that will include specimens of all
> labels used
>
> \- control of issuance of labeling, examination of issued labels and
> reconciliation of used labels
>
> \- examination of the labeled finished product
>
> \- adequate inspection (proofing) of incoming labeling
>
> \- use of lot numbers, destruction of excess labeling bearing
> lot/control numbers

-   physical/spatial separation between different labeling and packaging
    lines

-   monitoring of printing devices associated with manufacturing lines

> \- line clearance, inspection and documentation
>
> \- adequate expiration dates on the label
>
> \- conformance to tamper-evident (TEP) packaging requirements (see
> 21CFR 211.132 and Compliance Policy Guide, 7132a.17)

-   validation of packaging and labeling operations including validation
    and security of computerized processes

-   documented investigation into any unexpected discrepancy

# LABORATORY CONTROL SYSTEM 

For each of the following, the firm should have written and approved
procedures and documentation resulting therefrom. The firm's adherence
to written procedures should be verified through observation whenever
possible. These areas are not limited only to finished products, but may
also incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems
that would warrant expansion of coverage. When this system is selected
for coverage in addition to the Quality System, all areas listed below
should be covered; however, the depth of coverage may vary depending
upon inspectional findings.

-   training/qualification of personnel

-   adequacy of staffing for laboratory operations

> \- adequacy of equipment and facility for intended use

-   calibration and maintenance programs for analytical instruments and
    equipment

> \- validation and security of computerized or automated processes
>
> \- reference standards; source, purity and assay, and tests to
> establish equivalency to current official reference standards as
> appropriate
>
> \- system suitability checks on chromatographic systems (e.g., GC or
> HPLC)
>
> \- specifications, standards, and representative sampling plans
>
> \- adherence to the written methods of analysis
>
> \- validation/verification of analytical methods
>
> \- control system for implementing changes in laboratory operations

-   required testing is performed on the correct samples

-   documented investigation into any unexpected discrepancy

> \- complete analytical records from all tests and summaries of results
>
> \- quality and retention of raw data (e.g., chromatograms and spectra)
>
> \- correlation of result summaries to raw data; presence of unused
> data

-   adherence to an adequate Out of Specification (OOS) procedure which
    includes timely completion of the investigation

> \- adequate reserve samples; documentation of reserve sample
> examination
>
> \- stability testing program, including demonstration of stability
> indicating capability of the test methods

D. [Sampling]{.underline}

> Samples of defective product constitute persuasive evidence that
> significant CGMP problems exist. Physical samples may be an integral
> part of a CGMP inspection where control deficiencies are observed.
> Physical samples should be correlated with observed control
> deficiencies. Consider consulting your servicing laboratory for
> guidance on quantity and type of samples (in-process or finished) to
> be collected. Documentary samples may be submitted when the
> documentation illustrates the deficiencies better than a physical
> sample. Districts may elect to collect, but not analyze, physical
> samples, or to collect documentary samples to document CGMP
> deficiencies. Physical sample analysis is not necessary to document
> CGMP deficiencies.
>
> When a large number of products have been produced under deficient
> controls, collect physical and/or documentary samples of products
> which have the greatest therapeutic significance, narrow range of
> toxicity, or a low dosage strength. Include samples of products of
> minimal therapeutic significance only when they illustrate highly
> significant CGMP deficiencies.
>
> For sampling guidance, refer to IOM, Chapter 4

E. [Inspection Teams]{.underline}

> An inspection team (See IOM 502.4) composed of experts from within the
> District, other Districts, or Headquarters is encouraged when it
> provides needed expertise and experience. Contact ORO/Division of
> Field Investigations if technical assistance is needed (See also FMD
> 142). Participation of an analyst (chemist or microbiologist) on an
> inspection team is also encouraged, especially where laboratory issues
> are extensive or complex. Contact your Drug Servicing Laboratory or
> ORO/Division of Field Science.

F. [Reporting]{.underline}

> The investigator will utilize Subchapter 590 of the IOM for guidance
> in reporting of inspectional findings. Identify systems covered in the
> Summary of Findings. Identify and explain in the body of the report
> the rationale for inspecting the profile classes covered. Report and
> discuss in full any adverse findings by systems under separate
> captions. Add additional information as needed or desired, for
> example, a description of any significant changes that have occurred
> since previous inspections.
>
> Reports with specific, specialized information required should be
> prepared as instructed within the individual assignment/attachment.

[PART IV - ANALYTICAL]{.underline}

ANALYZING LABORATORIES

1\. Routine chemical analyses - all Servicing Laboratories except WEAC.

2\. Sterility testing:

> [Region]{.underline} [Examining Laboratory]{.underline}
>
> NE NRL
>
> SE SRL
>
> CE NRL
>
> SW, PA SAN-DO

3\. Other microbiological examinations - NRL (for the CE Region), SRL,
SAN, and DEN.

Salmonella Serotyping Lab - ARL

4\. Chemical cross-contamination analyses by mass spectrometry (MS) --
NRL, SRL, DEN, PRL/NW, and PHI. Non-mass spectrometry laboratories
should call one of their own regional MS capable laboratories or
Division of Field Science (HFC-140) to determine the most appropriate
lab for the determinations to be performed.

5\. Chemical cross-contamination analyses by Nuclear Magnetic Resonance
(NMR) spectroscopy - NRL. Non-NMR laboratories should call one of their
own regional labs equipped with NMR or Division of Field Science
(HFC-140) to determine the most appropriate lab for the determinations
to be performed.

6.  Dissolution testing -- NRL, KAN, SRL, SJN, DET, PHI, DEN, PRL/SW and
    PRL-NW. Districts without dissolution testing capability should use
    one of their own regional labs for dissolution testing. Otherwise,
    call DFS.

7\. Antibiotic Analyses:

ORA Examining Laboratory

> Denver District Lab (HFR-SW260)
>
> Tetracyclines

Erythromycins

> Northeast Regional Lab (HFR-NE500)
>
> Penicillins
>
> Cephalosporins

CDER Examining Laboratory

> Office of Testing and Research
>
> Division of Pharmaceutical Analysis
>
> (HFD-473)
>
> All other Antibiotics

7.  Bioassays - Division of Testing and Applied Analytical Research,
    Drug Bioanalysis Branch

(HFN-471).

9\. Particulate Matter in Injectables: NRL, SRL.

10\. Pyrogen/LAL Testing: SRL

[ANALYSIS:]{.underline}

1\. Samples are to be examined for compliance with applicable
specifications as they relate to deficiencies noted during the
inspection. Check analyses will be by the official method, or when no
official method exists, by other validated procedures. See CPG 7152.01.

2\. The presence of cross-contamination must be confirmed by a second
method. Spectroscopic methods, such as MS, NMR, UV-Visible, or infrared
(IR) are preferred. A second confirmatory method should be employed by
different mechanisms than the initial analysis (i.e., ion-pairing vs.
conventional reverse phase HPLC).

3\. Check Analysis for dissolution rate must be performed by a second
dissolution-testing laboratory.

4\. Sterility testing methods should be based on current editions of USP
and the Sterility Analytical Manual. Other microbiological examinations
should be based on appropriate sections of USP and BAM.

[PART V - REGULATORY/ADMINISTRATIVE STRATEGY]{.underline}

Inspection findings that demonstrate that a firm is not operating in a
state of control may be used as evidence for taking appropriate
advisory, administrative and/or judicial actions.

When the management of the firm is unwilling or unable to provide
adequate corrective actions in an appropriate time frame, formal agency
regulatory actions will be recommended, designed to meet the situation
encountered.

When deciding the type of action to recommend, the initial decision
should be based on the seriousness of the problem and the most effective
way to protect consumers. Outstanding instructions in the Regulatory
Procedures Manual (RPM) should be followed.

The endorsement to the inspection report should point out the actions
that have been taken or will be taken and when. All deficiencies noted
in inspections/audits under this program must be addressed by stating
the firm\'s corrective actions, accomplished or projected, for each as
established in the discussion with management at the close of the
inspection.

All corrective action approaches in domestic firms are monitored and
managed by the District Offices. The approaches may range from shut down
of operations, recall of products, conducting testing programs,
development of new procedures, modifications of plants and equipment, to
simple immediate corrections of conditions. CDER/DMPQ/CMGB/HFD-325 will
assist District Offices as requested.

An inspection report that documents that one or more systems is/are out
of control should be classified OAI. District Offices may issue Warning
Letters per RPM, Chapter 4, to warn firms of violations, to solicit
voluntary corrections, and to provide for the initial phase of formal
agency regulatory actions.

Issuance of a Warning Letter or taking other regulatory actions pursuant
to a surveillance inspection (other than a For Cause Inspection) should
result in the classification of all profile classes as unacceptable.
Also, the inspection findings will be used as the basis for updating
profile classes in FACTS.

FDA laboratory tests which demonstrate effects of absent or inadequate
current good manufacturing practice are strong evidence for supporting
regulatory actions. Such evidence development should be considered as an
inspection progresses and deficiencies are found. However, the lack of
violative physical samples is [not]{.underline} a barrier to pursuing
regulatory and/or administrative action provided that CGMP deficiencies
have been well documented. Likewise, physical samples found to be in
compliance are [not]{.underline} a barrier to pursuing action under CGMP
charges.

Evidence to support significant and/or a trend of deficiencies within a
system covered could demonstrate the failure of a system and should
result in consideration of the issuance of a Warning Letter or other
regulatory action by the District. When deciding the type of action to
recommend, the initial decision should be based on the seriousness
and/or the frequency of the problem. Examples include the following:

**[Quality System:]{.underline}**

1)  Pattern of failure to review/approve procedures.

2)  Pattern of failure to document execution of operations as required.

3)  Pattern of failure to review documentation.

4)  Pattern of failure to conduct investigations and resolve
    discrepancies/failures/deviations/complaints.

5)  Pattern of failure to assess other systems to assure compliance with
    GMP and SOPs.

# [Facilities and Equipment]{.underline}

1)  Contamination with filth, objectionable microorganisms, toxic
    chemicals or other drug chemicals, or a reasonable potential for
    contamination, with demonstrated avenues of contamination, such as
    airborne or through unclean equipment

2)  Pattern of failure to validate cleaning procedures for non-dedicated
    equipment. Lack of demonstration of effectiveness of cleaning for
    dedicated equipment.

3)  Pattern of failure to document investigation of discrepancies.

4)  Pattern of failure to establish/follow a control system for
    implementing changes in the equipment.

5)  Pattern of failure to qualify equipment, including computers.

**[Materials System]{.underline}**

1)  Release of materials for use or distribution that do not conform to
    established specifications.

2)  Pattern of failure to conduct one specific identity test for
    components.

3)  Pattern of failure to document investigation of discrepancies.

4)  Pattern of failure to establish/follow a control system for
    implementing changes in the materials handling operations.

5)  Lack of validation of water systems as required depending upon the
    intended use of the water.

6)  Lack of validation of computerized processes.

**[Production System]{.underline}**

1)  Pattern of failure to establish/follow a control system for
    implementing changes in the production system operations.

2)  Pattern of failure to document investigation of discrepancies

3)  Lack of process validation.

4)  Lack of validation of computerized processes.

5)  Pattern of incomplete or missing batch production records.

6)  Pattern of nonconformance to established in-process controls, tests,
    and/or specifications.

**[Packaging and Labeling]{.underline}**

1)  Pattern of failure to establish/follow a control system for
    implementing changes in the packaging and/or labeling operations.

2)  Pattern of failure to document investigation of discrepancies.

3)  Lack of validation of computerized processes.

4)  Lack of control of packaging and labeling operations that may
    introduce a potential for mislabeling.

5)  Lack of packaging validation.

**[Laboratory Control System]{.underline}**

1)  Pattern of failure to establish/follow a control system for
    implementing changes in the laboratory operations.

2)  Pattern of failure to document investigation of discrepancies.

3)  Lack of validation of computerized and/or automated processes.

4)  Pattern of inadequate sampling practices.

5)  Lack of validated analytical methods.

6)  Pattern of failure to follow approved analytical procedures.

7)  Pattern of failure to follow an adequate OOS procedure.

8)  Pattern of failure to retain raw data.

9)  Lack of stability indicating methods.

10) Pattern of failure to follow stability programs.

Follow up to a Warning Letter or other significant regulatory action as
a result of an Abbreviated Inspection should warrant Full Inspection
coverage as defined in this program.

[PART VI - REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS]{.underline}

[REFERENCES]{.underline}

1.  Federal Food, Drug, and Cosmetic Act, as amended

2.  Code of Federal Regulations, Title 21, Parts 210 and 211, as
    revised, including the General Comments (preamble)

3.  Compliance Policy Guides Manual, Chapter 4 Human Drugs

4.  Compressed Medical Gases Guideline

5.  Guideline on General Principles of Process Validation

6.  Guideline on Sterile Drug Products Produced by Aseptic Processing

7.  Guide to Inspection of Computerized Systems in Drug Processes

8.  Regulatory Procedures Manual, Part 8

9.  Inspection Operations Manual (IOM)

10. Guide to Inspections of Dosage Form Drug Manufacturers-CGMPs

11. Guide to Inspections of Lyophilization of Parenterals

12. Guide to Inspections of Pharmaceutical Quality Control Laboratories

13. Guide to Inspections of High Purity Water Systems

14. Guide to Inspections of Validation of Cleaning Processes

15. Guidance to Industry (Draft) Investigation of OOS Test Results

16. 21 CFR Part 11 Electronic Records: Electronic Signatures

17. Compliance Policy Guide7153.17 Enforcement Policy, Part 11
    Electronic Records; Electronic Signatures

18. Electronic Records Guide (4/21/98) (Electronic Signatures, 21 CFR
    Part 11 Answers to Frequently Asked Questions)

[Attachments]{.underline}

Attachments to the Drug Process Inspection program may be issued for
certain industries, dosage forms, and processes with known problems or
unique drug processes. These attachments will contain the guidance
needed to perform these specialized inspections.

Some of the attachments to be issued with this program may include
reporting requirements specifically designed to obtain industry-wide
information on certain practices to permit evaluation of the adequacy of
FDA\'s regulatory efforts.

Attachments and/or reporting requirements will be periodically reviewed
and evaluated and deleted from the program when they are no longer
needed.

[CONTACTS]{.underline}

[ORA]{.underline}

ORO/Division of Field Investigations/Drug Group (HFC-132)

Telephone: (301) 827-5653

ORO/Division of Field Science (HFC-140)

Telephone: (301) 827-7605

[Center for Drug Evaluation and Research]{.underline}

[CGMP Questions]{.underline}

Division of Manufacturing & Product Quality

Chief, Case Management and Guidance Branch (HFD-325)

Telephone: (301) 594-0098

Fax: (301) 594-2202

[Product Quality Problems (NDA/ANDA/Compendial Specifications
deviations)]{.underline}

Division of Manufacturing & Product Quality

Chief, Case Management & Guidance Branch (HFD-325)

Telephone: (301) 594-0098

Fax: (301) 594-2202

[Product Quality Problems (Drug Product Sampling, FAR reporting, ADE
reporting)]{.underline}

Team Leader, Post Market Surveillance Team (HFD-336)

Division of Rx Drug Compliance and Surveillance

Telephone: (301) 594-0101

Fax: (301) 594-1146

[PART VII - CENTER RESPONSIBILITIES]{.underline}

CENTER FOR DRUG EVALUATION AND RESEARCH

The Division of Manufacturing and Product Quality (DMPQ) HFD-320 will
conduct an annual evaluation in order to assess and report on the
effectiveness of this program.

Please send any comments on the operation and efficiency and direct any
questions regarding application of the program to the Chief, Case
Management and Guidance Branch, DMPQ, HFD-325,

301-594-0098, fax 301-594-2202.