HUMAN DRUG CGMP NOTES

**(Volume 8, Number 1)**

# March, 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:

-   **For a non-sterile compendial drug product, which includes an
    antimicrobial preservative in the original formulation, is it
    acceptable to release and market lots of this drug product that have
    initial release test results exhibiting out-of-specification total
    aerobic plate counts, when these lots test within specification two
    weeks later?**

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-   **Does the OGD Draft Guidance document on Blend Uniformity Analysis
    (BUA) represent CGMP requirements?**

Penicillin Issues:

1.  **What do the CGMPs mean by separate facilities? Must the buildings
    be totally separated, or are the CGMPs satisfied when the floors are
    physically separated with separate air filtration units installed?**

2.  **Is it acceptable to manufacture penicillin and non-penicillin
    products in the same facility on a campaign basis, with adequate
    cleaning validation procedures in place?**

3.  **Is it acceptable to manufacture penicillin products in the same
    facility as Cephalosporin?**

*Fax-Feedback* (Your input requested)

INTRODUCTION:

Dear Readers- I just wanted to make some comments as we change project
managers for the Human Drug CGMP Notes. Paul Motise has departed the
Division and we want to wish him well in his new endeavors. We also want
to continue this valuable publication with Russ Rutledge taking on this
important task. This publication is written for all of FDA. We welcome
and encourage articles from folks in headquarters and the field alike
who have a stake in CGMP issues and can contribute articles on CGMP
issues.

Joe Famulare

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.
As many of you are aware, our first and only project manager (Mr. Paul
Motise) has departed the Division of Manufacturing and Product Quality
for another exciting career opportunity. This left the division with a
deep void and a choice- should we continue to publish CGMP Notes or
accept the easier solution of letting it quietly go away? The feedback
received over the past 7 years has been overwhelmingly positive, from
the field and the regulated industry, so we concluded that this
newsletter is serving a valuable function and should live on. I
volunteered to step into this position, so here is my first attempt to
continue what I consider a tough act to follow. Paul- I wish you well in
your new 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.
These may be addressed to any individual in DMPQ, especially the
contributing authors. We also welcome brief articles FDAers may wish to
contribute. Subjects should be CGMP related and would be especially
valuable if they address emerging new technologies.

Although the document is fully releasable under the Freedom of
Information Act, our intended readership is FDA field and headquarters
personnel. Therefore, we cannot extend our distribution list for the
paper edition to people outside the agency. The primary purpose of this
document is to enhance field/headquarters communications on CGMP issues
in a timely manner. This is a forum to hear and address your CGMP
questions, update you on CGMP projects, and help you apply real life
situations to existing policy and enforcement documents. This memo does
not supplant existing policy development/issuance mechanisms.

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.

If you would like to receive an electronic version of this document via
electronic mail, see the check-off line in *FAX FEEDBACK*. We're also on
the Internet at
[**http://www.fda.gov/cder/dmpq**](http://www.fda.gov/cder/dmpq).

Thanks! *Russ*

POLICY QUESTIONS:

**For a non-sterile compendial drug product, which includes an
antimicrobial preservative in the original formulation, is it acceptable
to release and market lots of this drug product that have initial
release test results exhibiting out-of-specification total aerobic plate
counts, when these lots test within specification two weeks later?**

References:

> 21 CFR 211.113(a)
>
> 21 CFR 211.165(f)
>
> USP 24 General Chapter \<51\>

No! 21 CFR 211.113(a) provides for appropriate written procedures to be
followed during manufacturing to assure that objectionable
microorganisms are not introduced into drug products not required to be
sterile. This regulation mandates the establishment and adherence to
written procedures to prevent the inclusion of objectionable organisms
in drug products during manufacture.

Additionally, the second paragraph of USP 24 General Chapter \<51\>
reads in part:

> "...Antimicrobial preservatives should not be used as a substitute for
> good manufacturing practices or solely to reduce the viable microbial
> population of a nonsterile product or control the presterilization
> bioburden of multidose formulations during manufacturing\... "

This compendial section advises against the use of antimicrobial
preservatives as a sole means of reducing viable microbial populations
in nonsterile products. We interpret this to mean that drug
manufacturers should not rely upon antimicrobial preservatives to reduce
initial out-of-specification plate counts to within specification levels
and then market the product. This is particularly true when the initial
out-of-specification results may have been due to organisms that were
contributed to the product during the manufacturing process.

For example, in a recent case, a drug manufacturer had initial release
test results for several lots of a non-sterile drug product that were
each out-of-specification for total aerobic count. Testing a short time
later on samples from the same lots gave results that were in
specification. We did not regard it acceptable for the manufacturer to
release and market these products, even though a reduction of microbial
counts to levels near zero had been demonstrated to be attributable to
the effectiveness of the preservative.

21 CFR 211.165(f) mandates that drug products failing to meet
established standards or specifications shall be rejected. A company's
reliance on an antimicrobial preservative to reduce out-of-specification
levels of microbes to within specification levels does not disqualify
the initial release test. We would still expect the manufacturer to
reject the drug product based on the initial out-of-specification
results found upon release testing.

It is also not acceptable for a company to allow an inappropriate amount
of time to pass before testing the product to permit the preservative to
reduce levels of microbes possibly added during manufacture. This is
particularly true when testing data demonstrates that initial release
testing conducted a short time after manufacture shows the drug product
to be frequently out-of-specification for total aerobic plate count.

Finally, manufacturing procedures should be reviewed to determine
procedures or equipment that might be contributing organisms to the
process and product. In the case discussed above, standing water that
had been allowed to remain in equipment after cleaning, was identified
as a CGMP deficiency likely to have contributed to microbial growth in
the product. Removal of the standing water has resulted in no detectable
total aerobic counts to date. Adherence to CGMPs should prevent
manufacturing conditions that contribute microbes to the finished
product.

Contact for further information: Randall Woods, HFD-324; phone
(301)-827-0062; e-mail: <woodsr@cder.fda.gov>

**Does the OGD Draft Guidance document on Blend Uniformity Analysis
(BUA) represent CGMP requirements?**

References:

> Draft Guidance for Industry ANDAs: Blend Uniformity Analysis August
> 1999
>
> 21 CFR 211.110 Sampling and testing of in-process materials and drug
> products

No, this Office of Generic Drugs (OGD) guidance document presents
recommendations for application filing based on 21 CFR 314, not on CGMP
regulations. Also, this is a draft document subject to review and
comment, and has not yet been implemented. OGD current policies are
based on earlier policy documents rather than on this draft guidance.
Additionally, the guidance document presents recommendations only, not
requirements. Alternative approaches may also be used to submit data
with an application.

The CGMP regulations, 21 CFR 211.110, do not require Blend Uniformity
Analysis (BUA). It requires some type of test or examination on each
batch, but that test or examination does not have to be BUA as described
in the guidance document. Failure to perform BUA type testing on routine
production batches should not be cited as a CGMP deficiency. BUA type
testing is recommended for low dose powder blend products *(e.g., less
than 50% or 50 mg)* but other approaches may also be used to satisfy
this CGMP requirement.

The draft guidance also permits the submission of a supplement to delete
BUA testing. This is also an application filing issue and does not
exempt a manufacturer from the CGMP requirement for some type of test or
examination on each batch. If BUA type testing is discontinued, an
alternate approach to comply with 21 CFR 211.110 should be implemented.

Contact for further information: John Dietrick, HFD-322; (301) 594-0095;
e-mail: [dietrickj@cder.fda.gov](mailto:melendeze@cder.fda.gov)

PENICILLIN ISSUES:

1.  **What do the CGMPs mean by separate facilities? Must the buildings
    be totally separated, or are the CGMPs satisfied when the floors are
    physically separated with separate air filtration units installed?**

References:

> 21 CFR 211.42(d) Design, and construction features
>
> 21 CFR 211.46(d) Ventilation, air filtration, air heating and cooling
>
> 21 CFR 211.176 Penicillin contamination
>
> Federal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the
> CGMPs at comment 142

CGMP regulations \[21 CFR 211.42(d) and 211.46(d)\] require separation
of penicillins from non-penicillins during processing. The discussion of
the comments in the preamble to the regulations note that "...isolation
of penicillin production operations...can be achieved by sealing
off...the two operations." "...does not necessarily mean...separate
buildings." Thus, there can be a "building within a building"- i.e. two
buildings are not required. However, there must be total separation of
operations, meaning every aspect of the operations must be separate.
Adequate separation should include physical barriers and separate air
handling systems. Personnel and equipment from the penicillin facility
should not enter the non-penicillin facility. These should operate with
well established written procedures and controls. The separation should
be audited, procedures validated, and where necessary monitored.

Even with separation, if any possibility of contamination exists, the
non-penicillin products must be tested (21 CFR 211.176). An example of
possible contamination could be inadequate controls over movement of
equipment or personnel. Section 211.176 requires non-penicillin products
to be tested for traces of penicillin where the possibility of exposure
exists, and not marketed if detectable levels of penicillin are found.

While this section prohibits marketing of products found to be
contaminated with penicillin, it does not sanction marketing of
non-penicillin products based only on test results that show no
detectable levels of such contamination. Other CGMP requirements must
still be met. For a discussion on this issue, please review the article
"Is it acceptable under section 211.176 to release products to market as
long as the products are tested and no penicillin is found?" published
in "Human Drug CGMP Notes" (Volume 6, Issue 2, June 1998).

Cross contamination issues have been a concern for a number of years,
and continue to be problematic. In one penicillin cross-contamination
case reviewed it was demonstrated how a non-penicillin facility was
contaminated by a separate penicillin facility located in the same
manufacturing campus. This occurred due to lack of controls regarding
movements of personnel, equipment and materials. In another case, CDER
concurred with a district recommendation to withhold approval on a
sensitizing beta-lactam manufacturing facility that was adjacent to
another drug processing building, due to the lack of containment
controls which ensured against cross contamination of the other drugs.

2.  **Is it acceptable to manufacture penicillin and non-penicillin
    products in the same facility on a campaign (i.e., the conversion of
    production facilities to a different product line on a routine
    basis) basis, with adequate cleaning validation procedures in
    place?**

References:

> 21 CFR 211.42(d) Design, and construction features
>
> 21 CFR 211.46(d) Ventilation, air filtration, air heating and cooling
>
> 21 CFR 211.176 Penicillin contamination
>
> Federal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the
> CGMPs at comment 148

No, it is not acceptable. The discussion of the comments in the preamble
to the regulations state that "...it is important to make clear in these
regulations that completely separate air-handling facilities for
penicillin and non-penicillin production are required.". And "...because
it is possible for air-handling systems between penicillin and
non-penicillin production areas to be interconnected, \...the
Commissioner finds it necessary to state that any such interconnection
would be unacceptable."

Campaign production of penicillin and any non-penicillin product in the
same facility and with the same equipment violates the CGMP regulations
\[211.42(d) and .46(d)\]. A concern is that the cleaning validation
process does not include the air handling system throughout the
facility. This is important because campaign production has the
potential for recontamination of the air handling systems and
facilities, and can lead to cross contamination of non-penicillin
products with penicillin. The concept of decontamination is broader than
a typical cleaning procedure validation, in that sampling is extended to
include the environment, as well as surfaces of the facility and
equipment that are to be decontaminated.

A facility contaminated with penicillin could not begin non-penicillin
production until extensive decontamination and clean-up of the facility
is accomplished in accordance with the established procedures, and
representative environmental samples demonstrate that the facility
conforms with its decontamination protocol/specifications.

Current technology makes decontamination of air handling systems
difficult. This is because the decontamination/cleaning procedures would
necessitate sampling and residual testing of other parts of the air
handling system, to include the ductwork. This would be difficult
because the air handling system throughout its length has uneven areas
and crevices that create the possibility of penicillin residue build-up,
with slough-off at undetermined periods during the non-penicillin
production period. Thus penicillin contamination would not be uniformly
distributed in the air handling system, and "representative" samples
(retain, surface and/or air) may not be an accurate portrayal of the
level of contamination.

21 CFR 211.176 indicates that where the possibility of exposure exists,
non-penicillin products must be tested for traces of penicillin and not
marketed if detectable levels are found. This means that representative
samples from all batches of non-penicillin products produced in each
campaign must be tested with an acceptable method and found
non-detectable for the penicillin product produced prior to the start-up
of the non-penicillin campaign.

One case we reviewed demonstrated a positive environmental surface
sample from the fan blade of an exhaust hood in the repack room for
beta-lactam residue, even though the most recent beta-lactam repackaging
operation had been performed more than six months prior to sampling.

3.  **Is it acceptable to manufacture penicillin products in the same
    facility as cephalosporin?**

References:

> 21 CFR 211.28 Personnel responsibilities
>
> 21 CFR 211.42(b),(c)&(d) Design, and construction features
>
> 21 CFR 211.46(c)&(d) Ventilation, air filtration, air heating and
> cooling

21 CFR 211.67 Equipment cleaning and maintenance

> 21 CFR 211.80(b) Control of components and drug product containers and
> closures
>
> 21 CFR 211.176 Penicillin contamination

Beta-lactams are products with a chemical substructure that contains the
beta-lactam ring. They have the potential to sensitize and cause
allergic response in humans. Hypersensitivity, due to intolerance of
beta lactam ingredients, can trigger reactions which range from a rash
to life-threatening anaphylaxis**.** There is evidence that
cross-sensitivity exists between penicillins and cephalosporins. Thus,
patients who are intolerant of penicillin may also be intolerant of
cephalosporins, and further, cephalosporins may induce anaphylaxis in
patients with a history of penicillin anaphylaxis.

The immune system is exquisitely sensitive and can distinguish between
very subtle changes in chemical composition. Patients may be tolerant of
a given drug but intolerant of another drug with closely related
chemical structures. There is evidence that patients tolerant of
penicillin may be intolerant of cephalosporins. CDER recognizes the
considerable potential for cross-sensitivity and the possible
life-threatening consequences of unintended exposure. Therefore,
although not a specific requirement of sections 211.42 (d), 211.46(d)
and 211.176, it is recommended that manufacturing operations for
cephalosporins, penems and cephems, be separated from non-beta-lactam
products and other beta-lactam drug products. For example cephalosporin
type products would be separated from penicillin type products or
non-beta-lactam products.

Production of cephalosporin type products can be approached from two
different regulatory/compliance perspectives:

1\) If cephalosporins are considered to be non-penicillin drugs, they
could not be manufactured in a facility lacking adequate separation from
penicillin products. 2) For cephalosporin production with other
non-beta-lactam drug products, similar health concerns exist for
patients sensitive to cephalosporins who should not be exposed to it in
a non-beta-lactam product.

For fundamental CGMP reasons and because of the difficulties in
demonstrating and validating appropriate sampling and testing
methodology for measuring cross-contamination, penicillin production
should be performed in facilities separated from non-beta-lactam drug
products and other beta-lactam drug products unless adequate separation
is demonstrated. We don't know of a satisfactory shared facility as of
today.

Furthermore, if necessary, other sections of the CGMP regulations
\[i.e., 211.28; 211.42(b) & (c); 211.46(c); 211.67; and 211.80(b)\]
could be applied to control contamination between beta-lactam and
non-beta-lactam drug products. In summary the Agency considers the
separation of production facilities for sensitizing beta-lactam based
products to be current good manufacturing practice.

Contact for further information: Edwin Melendez, HFD-322; (301)
594-0095; e-mail: <melendeze@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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