HUMAN DRUG CGMP NOTES

**(Volume 8, Number 2)**

# June, 2000

**(A Memo for FDA Personnel on Current Good Manufacturing Practice For
Human Use Pharmaceuticals)**

**Issued By: The Division of Manufacturing**

**and Product Quality, HFD-320**

**Office of Compliance**

**Center for Drug Evaluation and Research**

## Project Manager: C. Russ Rutledge, HFD-325

This level 2 guidance document represents the agency\'s current thinking
on Current Good Manufacturing Practice for human use pharmaceuticals. It
does not create or confer any rights for or on any person and does not
operate to bind FDA or the public. An alternative approach may be used
if such approach satisfies the requirements of the applicable statute,
regulations, or both.

IN THIS EDITION:

Introduction

Russ\'s Ramblings

Policy Questions On:

-   ***What FDA guidance documents pertain to drug repackaging
    operations and how can they be obtained?***

-   ***What is meant by the term "beyond-use date" and does it differ
    from a drug's expiration date?***

-   ***Gas What? Can the Fresh Air document or the February 1989
    Guideline be cited on a FDA-483, in Warning Letters, etc.?***

-   ***Is there a requirement to conduct an annual product review?***

-   ***What is the significance of defects in container-closure
    integrity of an injectable? Can product sterility be affected?***

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-   ***Are firms required to perform an identity test on an approved
    component (either an active or inactive) after it has been moved to
    an off site warehouse and then returned to the manufacturing
    facility for production?***

Subject Contact List

Fax-Feedback (Your input requested)

**RUSS'S RAMBLINGS**

Welcome to another edition of Human Drug CGMP Notes, our periodic
guidance memo for FDA personnel on CGMP for human use pharmaceuticals.

Last edition (March 2000) was my first as the Project Manager. I
appreciate the many warm e-mails you have written welcoming me in this
position.

Your FAX FEEDBACK responses have proven valuable, and we appreciate your
suggestions. This is one way which we identify and attempt to address
items of current interest. Additionally, you may use other means to
communicate with us. Feel free to call, write, or e-mail your comments.
Specific questions on an article would best be answered by the
contributing authors. We also welcome brief articles which other FDAers
may wish to contribute. Subjects should be CGMP related and would be
especially valuable if they address emerging new technologies.

DMPQ decided to publish Human Drug CGMP Notes exclusively in electronic
format posted on the CDER website. This decision was made while the last
edition was being posted. As a result, my editorial and the Fax-Feedback
form contained outdated information on obtaining an e-mail subscription.
Consequently, I received scores of requests for inclusion on the
"mailing list". I answered each of these requests with an explanatory
letter. I apologize for any inconvenience this may have caused you. The
updated Fax-Feedback form is included in this edition.

We have also included an updated list of Division of Manufacturing and
Product Quality subject contacts in this issue. As in many
organizations, we have had our share of turnover this year. Updating
this list is another service we intend to continue.

We receive many inquiries regarding which guidance documents are
available on various subjects, and where to obtain the latest revision.
The first article in this issue addresses this. The last web site
address given (for CDER) contains paths leading to most guidance
documents currently available from CDER. It would be worth your while to
become familiar with this site.

Appended to each edition of the memo is a *FAX FEEDBACK* sheet to make
it easier for us to communicate. In addition to FAX (at 301-594-2202),
you can reach us by interoffice paper mail, using the above address, by
phone at (301) 594-0098, or by electronic mail.

Once again, we're now available exclusively on the Internet at:

[**http://www.fda.gov/cder/dmpq**](http://www.fda.gov/cder/dmpq)

Thanks! *Russ*

**POLICY QUESTIONS:**

***What FDA guidance documents pertain to drug repackaging operations
and how can they be obtained?***

1.  The "Draft Guideline On Repackaging Of Solid Oral Dosage Form Drug
    Products" can be obtained from CDER's Office of Training and
    Communications (OTCOM), phone no. (301) 827-4573. (This guideline is
    not presently available on CDER's web site.)

2.  The following Compliance Policy Guides are available on FDA's Office
    of Regulatory Affairs (ORA) web site:

<http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/Default.htm>

A.  Section 430.100 - Unit Dose Labeling for Solid and Liquid Oral
    Dosage Forms (CPG 7132b.10)

B.  Section 430.200 - Repacking of Drug Products -- Testing/Examinations
    under CGMPs (CPG 7132.13)

C.  Section 446.100 -- Regulatory Action Regarding Approved New Drug and
    Antibiotic Drug Products Subjected to Additional Processing or other
    Manipulations (CPG 7132c.03)

D.  Section 460.100 - Hospital Pharmacies -- Status as Drug Manufacturer
    (CPG 7132.06)

E.  Section 480.200 - Expiration Dating of Unit Dose Repackaged Drugs
    (CPG 7132b.11)

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3.  Compliance with applicable parts of the CGMP regulations in 21
    [CFR]{.underline} Parts 210 and 211, is required for repackagers of
    finished pharmaceuticals. The CGMP regulations are available on
    CDER's web site:

<http://www.fda.gov/cder/dmpq/cgmpregs.htm>

4.  Technical guidance documents that have applicability to drug
    repackaging operations can be found on CDER's web site. These
    include guidance documents pertaining to stability testing and
    container-closure systems. The CDER web site address is:

<http://www.fda.gov/cder/guidance/index.htm>

Contact for further information: Barry Rothman, HFD-325; phone
(301)-594-0098;

e-mail: [rothmanb@cder.fda.gov](../rothmanb@cder.fda.gov)

***What is meant by the term "beyond-use date" and does it differ from a
drug's expiration date?***

References:

USP 24, Supplement No. 1, "General Notices" *Expiration Date and
Beyond-Use Date*, pp. 2589-2590

21 CFR 211.137 and 211.166

FDA Compliance Policy Guide, sections 430.100 and 480.200 (CPG 7132b.10
and 480.200)

The term "beyond-use date" is used by the USP to specify the date placed
by a pharmacy dispenser on the label of a prescription drug, and is
meant to convey to the patient a date beyond-which a drug dispensed
pursuant to a prescription should not be used. Clearly, the use of a
"beyond-use date" applies to pharmacy dispensing practice only, and does
not apply to manufacturers and non-pharmacy type commercial repackagers,
(i.e., repackaging that is not done pursuant to a prescription for an
identified patient). For manufacturers and commercial repackagers of
finished drug products the CGMP regulations require the use of an
expiration date that is based on appropriate stability testing.

Additionally, repackagers may refer to FDA's Compliance Policy Guides
cited above for guidance on deriving an expiration date from the
manufacturer's container for drugs that are repackaged into unit-dose
containers.

Contact for further information: Barry Rothman, HFD-325; (301) 594-0098;

e-mail: [rothman@cder.fda.gov](../rothman@cder.fda.gov)

***Gas What? Can the Fresh Air document or the February 1989 Guideline
be cited on an FDA-483, in Warning Letters, etc.?***

References:

See 21 CFR Parts 210 and 211

U.S.C. Federal Food, Drug, and Cosmetic Act, as amended; 21 U.S.C.
331(k).

This question, which was addressed in the December 6, 1996, edition of
the HUMAN DRUG CGMP NOTES, Volume 4, Issue 4, bears revisiting from time
to time. The answer of course is no.

The Federal Food, Drug, and Cosmetic Act establishes the requirement
that all drugs, including medical gases must be made under \"current
good manufacturing practices \[CGMPs\]." Therefore, CGMP deficiencies on
an FDA-483 must be based on 21 CFR Parts 210 and 211 \[Title 21, Code of
Federal Regulations\], which were promulgated under the authority of the
Food, Drug, and Cosmetic Act.

The \"Fresh Air\" presentation is presented for the sole purpose as FDA
outreach and training. It contains an overview of CGMP information, as
it would apply to the medical gas industry and is not a regulatory
requirement.

We plan on issuing an updated CGMP guidance for medical gases in the
near future.

Contact for further information: Duane S. Sylvia, HFD-325; phone: (301)
594-0095;

e-mail: [sylviad@cder.fda.gov](../sylviad@cder.fda.gov)

***Is there a requirement to conduct an annual product review?***

References:

Subpart J - Records and Reports

21 CFR 211.180 (e), General Requirements

21 CFR 211.192 Production Record Review

Yes, Subpart J - Records and Reports, requires periodic product reviews
under 211.180 (e), General Requirements. These reviews provide valuable
information to the manufacturer for improvement of manufacturing
quality. Also, inspection of the reports of product reviews will save
the investigator time by not having to ask a lot of questions regarding
the number of batches manufactured, released, rejected, etc.

Inspection of a firm's compliance with this requirement should
determine:

-   Does the firm adequately maintain the records required in Part 211?

-   Does the firm have an adequate procedure written for directing the
    review of, at least annually, the maintained CGMP data for
    indications that product specifications or manufacturing or control
    procedures need to be changed?

-   Does the firm perform an adequate review following the procedure?
    Some features of an adequate product review procedure and an
    adequate review are:

-   Does the procedure require a review by product; is the review done
    for each product?

-   Does the procedure require the product review annually or more
    frequently; are the product reviews done annually or more
    frequently?

-   Does the procedure specify the batches and records of batches to be
    reviewed, with adequate provision for selection of a representative
    number of approved and rejected batches/records?

> Representative rejected batches are to be reviewed by the nature of
> the reason for rejection. For example, if 20 batches had been rejected
> in a one-year period and each rejection was due to a different reason,
> all 20 batches should be included in the product review because each
> batch represents a different category of rejection. If 12 of the 20
> batches were rejected for the same reason, a smaller number than 12
> could be included in the product review as representative of the 12 in
> that rejection category.

-   For each product, does the procedure and the product review include
    evaluation of all:

-   Complaints?

-   Recalls?

-   Incidents of returned (non-recall) and salvaged drug products?

-   Investigations of unexplained discrepancies or failures of batches
    or components to meet any specification noted during the production
    or quality control unit review for release of such batches or
    components?

-   Does the procedure require conclusions, and documentation of
    conclusion regarding the need for product changes?

-   Are the conclusions included in the report of the product review,
    and are conclusions of the product review supported adequately by
    the data reviewed and by the findings of the review?

Consider whether the data maintained and reviewed in the product review
indicates deficiencies in the firm's compliance with other requirements
of CGMPs (e.g., adequate complaint files, adequate investigations,
adequate handling of OOS test results, etc).

Deficiencies noted in FDA-483 items should be expressed as inadequate
maintenance of required records, inadequacy of the written procedure for
product reviews, or inadequate product reviews with details as to the
actual inadequacies and how the inadequacies are demonstrated.

Contact for further information: Brian G. Nadel, HFD-325; phone: (301)
594-0098; e-mail: <nadelb@cder.fda.gov>

# 

# What is the significance of defects in container-closure integrity of an injectable? Can product sterility be affected?

References:

211.63 Equipment design, size, and location;

211.110 Written procedures; deviations;

211.186 Master production and control records;

211.192 Production record review

A number of injectable pharmaceuticals have been voluntarily recalled
over the last two years due to critical defects in container-closure
systems. These product integrity problems included glass fractures or
leaks. Product non-sterility was one of the consequences of these
defects.

In the case of most recalls, investigations were not conducted in accord
with 21 CFR 211.192. In some instances, while the cause of the defects
was known, corrective actions were not implemented and impact on past
and future batches was not determined. As a result, new lots were
produced with the same serious quality problem, the defective product
was shipped, and health practitioners began registering complaints with
FDA and the manufacturers.

The critical defects stemmed from various causes. Rough or irregular
handling during specific process steps was a common denominator in each
of the recalls. Some specific examples of causes include:

-   Deficient capping/sealing station design resulted in excessive
    stress to the vial neck.

-   Rough transfer mechanism exerted excessive force on containers while
    being conveyed down the processing line.

-   Lyophilizer operation included rough loading or stoppering step.

-   Container-closure system could not withstand autoclave process.

-   Vial washer was not compatible with the dimensions/durability of a
    new container. The new vial size did not adequately fit with the
    guides in the washer and caused chips in the vial neck.

We have seen several other scenarios in which process deficiencies lead
to loss of vial, ampul, or cartridge integrity. But mechanical problems
have not been the only cause identified. Investigations have also
attributed problems to improper manual handling. Trays dropped by
personnel after final packaging, and rough charging of vials to the
processing line, have resulted in recalls. In the former case, vial
integrity was lost and the product was subsequently found to be
non-sterile. Contaminated water from a washing step performed by the
firm after autoclaving was named as the source of the predominant
water-borne bacterium contaminating the vials.

Just as the container-closure system chosen by a firm needs to be a
robust one to ensure sterility and stability, there must also be
compatibility with the production line on which the product will be
manufactured. As cited above, incompatibility of a new container-closure
with an existing line has resulted in loss of integrity. FDA requires
firms to develop consistent processes employing suitable manufacturing
equipment (see 211.65 and 211.100). This equipment should be qualified
to process product in a manner that assures integrity of the specific
container-closure.

As a final measure, a batch manufacturing operation includes an
inspection stage intended to reject defective units. It is important to
be mindful that final visual/electronic inspection has its limitations.
In particular, the nature (e.g., location, visibility) of a given defect
may make its detection problematic. Some critical defects are difficult
or impossible (e.g., hidden cracks under the crimp, etc.) to detect
during the final inspection stage. This fact underscores the importance
of building quality into a manufacturing operation to prevent serious
defects. For each batch of a parenteral drug product, reconcilatilon
records should document the actual quantities of defective units
detected, categorized by major defect type. These results should be
compared to established specifications, and an investigation triggered
if results are beyond specifications. In addition, upon detection, a
critical defect should be investigated. A lot should not be released for
shipment in the event that it contains units lacking container-closure
integrity.

Contact for further information:

Richard L. Friedman, HFD-325; phone: (301) 594-0098;

e-mail: [friedmanr@cder.fda.gov](../friedmanr@cder.fda.gov)

***Are firms required to perform an identity test on an approved
component (either an active or inactive) after it has been moved to an
off site warehouse and then returned to the manufacturing facility for
production?***

References:

211.42(b) and (c)(1-3).

No, it is not necessary to repeat the identity test if the component lot
was securely packaged for storage at the off site location to reduce the
risk of mix-up and protect lot integrity, otherwise held under CGMP
compliant conditions (including adequate segregation), and properly
labeled. As with other types of contracted manufacturing and testing
facilities, the warehouse becomes an extension of the manufacturing site
and both the manufacturer of the dosage form and the warehouse are
responsible for ensuring compliance with the appropriate CGMP
regulations, e.g., 211.42(b) and (c)(1-3). This applies to active as
well as inactive components. The off site warehouse, however, is not
required to register.

Contact for further information: Brian Hasselbalch, HFD-325; phone:
(301) 827-7283;

e-mail: [hasselbalchb@cder.fda.gov](../hasselbalchb@cder.fda.gov)

# DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320

# SUBJECT CONTACTS

(All numbers in area code 301)

Active Pharmaceutical Edwin Rivera 594-0095

Ingredients Pat Alcock 827-0064

Mike Gavini 594-0095

Application Integrity Policy LuAnn Pallas 594-0098

Implementation/Removal Bruce Hartman 827-0062

Data Integrity Cases

Aseptic Processing Richard Friedman 594-0098

Edwin Melendez 594-0098

Brenda Uratani 594-0095

Biotechnology Products Brian Nadel 594-0098

Brenda Uratani 594-0095

Botanicals Manufacturing Brian Hasselbalch 594-0098

Case Management Fred Blumenschein 594-0098

Cleaning Validation C. Russ Rutledge 594-2455

Pat Alcock 827-0064

Clinical Supplies / IND CGMP Bruce Hartman 827-0062

Computer Validation Karen Moksnes 594-0098

Content Uniformity Monica Caphart 594-2458

C. Russ Rutledge 594-2455

Mike Gavini 594-0095

Electronic Records / Signatures Karen Moksnes 594-0098

Foreign Inspections John Dietrick 594-0095

Impurities Richard Friedman 594-0095

Inspections / Investigations (For Cause) Randall Woods 827-0065

Isolator / Barrier Technology Richard Friedman 594-0098

Edwin Melendez 594-2454

Labeling Controls (CGMP) Barry Rothman 594-0098

Laboratory Issues Monica Caphart 594-2458

C. Russ Rutledge 594-2455

Litigation Guidance and Fred Blumenschein 594-0098

Support Nick Buhay 594-0093

Medical Gases Duane S. Sylvia 594-0095

Paul Haynie 594-0098

NDA / ANDA Pre-Approval Inspections Randall Woods 827-0062

Packaging Barry Rothman 594-0098

Edwin Melendez 594-2454

Penicillin Cross Contamination Edwin Melendez 594-2454

Pharmacies, CGMP LuAnn Pallas 594-0098

Pre-Approval Program Melissa Egas 594-0095

Bruce Hartman 927-0062

Process Validation, General John Dietrick 594-0098

Pyrogen / LAL Test Brenda Uratani 594-0095

Repackaging Barry Rothman 594-0098

Salvaging Barry Rothman 594-0098

Stability / Expiration Dates Barry Rothman 594-0098

Sterility Issues, General Richard Friedman 594-0098

Edwin Melendez 594-2454

Brenda Uratani 594-0095

Topical Drugs Randall Woods 827-0062

Transdermals Brian Hasselbalch 594-0098

Videoconferencing C. Russ Rutledge 594-2455

Water Quality Richard Friedman 594-0098

Edwin Melendez 594-2454

Brenda Uratani 594-0095

***FAX FEEDBACK***

TO: C. Russ Rutledge, HUMAN DRUG CGMP NOTES, HFD-325

FAX: 301-594-2202 (Phone 301-594-0098)

FROM:\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

AT:
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MAIL CODE: \_\_\_\_\_\_\_\_

PHONE: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ FAX:
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I found this issue of HUMAN DRUG CGMP NOTES to be \[check as
appropriate\]:

\_\_not very; \_\_ somewhat; \_\_ very; \_\_ extremely informative and,

\_\_not very; \_\_somewhat; \_\_ very; \_\_ extremely useful to my

inspectional/compliance activities.

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Future editions of HUMAN DRUG CGMP NOTES should address the following
CGMP questions/issues:

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