\`HUMAN DRUG CGMP NOTES´

**(Volume 8, Number 3)**

# September, 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:

-   **1) How can one obtain a copy of the procedures for detecting and
    measuring penicillin contamination in drugs?**

-   **2) Can section 21 CFR 436.104 (Penicillin Activity) continue to
    assist in determining residues of penicillin contamination in
    non-penicillin drugs?**

-   **3) If a chemical company manufactures an active pharmaceutical
    ingredient and sells it to another company, who then formulates the
    finished dosage form, are the manufacturing activities of the
    chemical company covered under CGMP\'s?**

-   **4) For a USP drug, is meeting the specifications in an official
    monograph sufficient to show compliance with CGMPs?**

-   **5) Should reprocessing of a bulk batch of finished product always
    be listed as a CGMP deviation on an FDA‑483?**

-   **6) Are the use of ditto marks and arrows for redundant information
    acceptable practices under CGMP for documentation?**

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.

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.

Since DMPQ decided to publish Human Drug CGMP Notes exclusively in
electronic format, the requests for inclusion on the electronic
subscription list have tapered off. I still receive several requests per
week and continue to answer each of these with an explanatory letter.
Hopefully these requests will cease with this edition

The articles in this edition are a reflection of the many questions we
have received on various CGMP issues, with Penicillin contamination
continuing to be a topic of intense interest. I think you will find
these articles a valuable resource.

Brian Nadel was kind enough to submit an article addressing the issue of
reprocessing of bulk pharmaceuticals prior to his departing the agency.
I wish him well in his new career.

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:**

**1) How can one obtain a copy of the procedures for detecting and
measuring penicillin contamination in drugs?**

References:

21 CFR 211.176, Penicillin Contamination;

FDA By-Lines No.3, Nov. 77, A Review of Procedures for the Detection of
Residual Penicillin in Drugs.

The bioassay referenced in 21 CFR 211.176 can be used whenever there
exists a reasonable possibility that a non-penicillin drug product has
been exposed to cross-contamination with penicillin. The non-penicillin
drug product should be tested for the presence of penicillin and not
marketed if detectable levels are found when tested according to
procedures specified in "Procedures for Detecting and Measuring
Penicillin Contamination in Drugs", which is incorporated by reference.
Copies are available from the Division of Pharmaceutical Analysis,
(HFD-923), Center for Drug Evaluation and Research, Food and Drug
Administration, 8301 Muirkirk Road, Laurel, MD, 20703. To request copies
of the procedure contact:

Valarie A. Flournoy, Tel 301-827-8236, FAX 301-827-8073, E-Mail
FLOURNOY@CDER.FDA.GOV.

For further information contact: Edwin Melendez, 301-594-0098,
[melendeze@cder.fda.gov](../melendeze@cder.fda.gov)

**2) Can section 21 CFR 436.104 (Penicillin Activity) continue to assist
in determining residues of penicillin contamination in non-penicillin
drugs?**

Reference: 21 CFR 211.176, Penicillin Contamination; FDA By-Lines No.3,
Nov.77, A Review of Procedures for the Detection of Residual Penicillin
in Drugs.

No, it can not. Section 436.104 was in part 21 CFR 436. Parts 429
through 460 existed for the purpose of enforcing Section 507 of the FD&C
Act "Certification of Antibiotics". This section of the Act was repealed
by FDAMA (FDA Modernization Act). Therefore, section 436.104 was deleted
from the CFR and does not exist any longer.

Section 436.104 (methodology for penicillin activity) is derived from
the original tests for penicillin contamination in foods and drugs
published in FDA By-Lines No.3 (Nov.1977). The FDA codified method
continues to exist because it still is required in 211.176 -- "...such
drug product shall not be marketed if detectable levels are found when
tested according to procedures specified in 'Procedures for Detecting
and Measuring Penicillin Contamination in Drugs,...". The elimination of
436.104 does not change anything for the following reason: In the
By-lines, the test sensitivity is stated to be 0.01 units/ml as
penicillin G, using S. lutea, equivalent to 0.006 PPM. The 'standard
response line' cited at 436.104 covers a range of concentrations
equivalent to 0.003 to 0.120 PPM, as penicillin G. However, the test
method as cited in 211.176 has always indicated a limit of sensitivity
of 0.006 PPM. We always indicate that the sensitivity should be at 0.006
PPM and not necessarily 0.003 PPM. So nothing has changed because the
By-lines also covers a range of concentrations which can be used as
'standard response lines' similar to 436.104.

For further information contact: Edwin Melendez, 301-594-0098,
[melendeze@cder.fda.gov](../melendeze@cder.fda.gov)

**3) If a chemical company manufactures an active pharmaceutical
ingredient and sells it to another company, who then formulates the
finished dosage form, are the manufacturing activities of the chemical
company covered under CGMPs?**

References:

Federal Food, Drug, and Cosmetic Act, Sec. 501(a)(2)(B)

21 CFR 211

Yes. Section 501(a)(2)(B) of The Food, Drug and Cosmetic Act requires
that all drugs (including active pharmaceutical ingredients), be
manufactured in accordance with CGMPs. Therefore, the manufacturer of an
active pharmaceutical ingredient is required by law to manufacture in
accordance with CGMPs. While the CGMP regulations in 21CFR Parts 210 and
211 apply only to finished products, the statute requires that CGMPs be
followed for all drugs, including active pharmaceutical ingredients. You
may wish to note FDA\'s draft guidance, \"Manufacturing, Processing, or
Holding Active Pharmaceutical Ingredients\" which is available on FDA\'s
web site:

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

Further information is available in the draft ICH guidance "Q7A Good
Manufacturing Practice for Active Pharmaceutical Ingredients"

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

Since these are draft documents, the guidance contained within them may
be subject to change. There might be additional guidance to consider
when they are finalized.

For further information, contact Russ Rutledge, 301-594-0098,
[rutledgec@cder.fda.gov](../rothmanb@cder.fda.gov)

**4) For a USP drug, is meeting the specifications in an official
monograph sufficient to show compliance with CGMPs?**

References:

Federal Food, Drug, and Cosmetic Act, Sec. 501 (a)(2)(B), Sec. 501(b)

21 CFR 211

USP 24, *General Notices*, "Test Results, Statistics, and Standards"
p.10

No. The tolerances in the USP are based upon the consideration that the
drug is manufactured in compliance with good manufacturing practices.
Testing alone is not sufficient to demonstrate CGMP compliance, even
when the results indicate that the drug meets criteria in an official
monograph. Drugs that are not manufactured in compliance with CGMPs, or
do not comply with their official monograph, are considered adulterated
in the FD&C Act.

For further information, contact Barry Rothman, 301-594-0095,
[rothmanb@cder.fda.gov](../rothmanb@cder.fda.gov)

**5) Should reprocessing of a bulk batch of finished product always be
listed as a CGMP deviation on an FDA‑483?**

References:

Subpart F ‑ Production and Process Controls

21 CFR 211.111 Time limitations on

production,

211.113 Control of microbiological

contamination.

211.115 Reprocessing.

Subpart J ‑ Records and Reports

21 CFR 211.192 Production Record

Review

No, reprocessing may be acceptable if it is performed according to CGMP.
It must first be determined whether or not the firm has written and
previously established procedures for reprocessing, according to
211.115. The next question that needs to be answered is did the quality
control unit review and approve this reprocessing, according to
211.115(b).

Consideration should be given to the amount of time that transpired
before the bulk batch was reprocessed. According to 211.111, time limits
for completion of each phase of production shall be established to
assure the quality of the drug product.

Another factor that should be considered is the possibility of
microbiological contamination during the time that the bulk batch is
held for reprocessing. According to 211.113, the firm must follow
written procedures designed to prevent contamination by objectionable
microorganisms. These written procedures must be followed whether or not
the product is sterile.

The stability of reprocessed batches of finished drug products should be
considered. Reprocessing may affect the stability, therefore the firm
should determine if these batches should be placed into their stability
program. Unless the firm has data from prior batches produced under the
same circumstances, the fact that a reprocessed batch was not entered
into the stability program may be included on the FDA‑483.

The fact that a batch of drug product was reprocessed is not per se a
CGMP violation. However, if this reprocessing was not approved by the
QCU, then this should be listed on the FDA‑483, according to 211.115(b).
You should also consider listing on the FDA‑483 that a manufacturing
process is not adequately validated when there is evidence of repeated
reprocessing on multiple batches.

Another item that may be listed on an FDA‑483, if applicable, is the
failure to conduct an investigation when a batch does not meet any of
its specifications, according to 211.192, Production Record Review. Any
time reprocessing occurs, there should be a written record of the
investigation that includes conclusions and follow-up.

Article written by Brian G. Nadel

For further information contact: Edwin Rivera (301) 594‑0098,
[rivera@cder.fda.gov](../rivera@cder.fda.gov)

**6) Are the use of ditto marks and arrows for redundant information
acceptable practices under CGMP for documentation?**

Reference:

21 CFR Part 211, Subpart J, Records and Reports

No. While there is no specific FDA documentation or guidance that
discusses the practice of using ditto marks and arrows in place of
required information, the use of these instead of specific information,
initials, or signatures is not fully informative. Ditto marks and arrows
are not sufficiently descriptive where actual values are needed, and
more importantly, cannot be directly related to the recorder.

For further information, contact Rosa Motta, 301-594-0098,
[mottar@cder.fda.gov](../mottar@cder.fda.gov)

***FAX FEEDBACK***

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

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

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

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I found this issue of HUMAN DRUG CGMP NOTES to be \[check as
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Future editions of HUMAN DRUG CGMP NOTES should address the following
CGMP questions/issues:

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