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HUMAN DRUG CGMP NOTES
(Volume 4, Number 1)
March, 1996
(A Memo on Current Good Manufacturing Practice Issues on
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: Paul J. Motise, HFD-325
IN THIS ISSUE:
Motise's Notebook
Policy Questions On:
- Laboratory Issues
1) Does FDA have a CGMP policy on use of recycled
solvents for HPLC columns?
2) Is dissolution testing past the Stage 1 level
significant enough to be cited on FDA-483s?
3) Is routine product pH testing required for
Endotoxin (LAL) Assays?
- On Stability (Policy Questions on
Stability)
1) Is it acceptable for a firm to export expired
drugs for charity?
2) How should the start of the expiration dating
period be calculated for repackaged drugs?
HUMAN DRUG CGMP NOTES March 1996
- Gas What? (Policy Questions on Medical Gases):
1) May a firm use industrial grade nitrogen as a
blanketing agent during the manufacturing of a drug
product?
2) Is it acceptable for the owner of a vessel to
apply a small sticker to denote its ownership, even
though the vessel is filled by a different firm that
is identified in the vessel's labeling?
- What are the respective roles of ORA (field) and
CDER staff in performing reviews of chemistry
data in new drug applications?
Toward The Electronic Government:
1) What is the status of the Electronic Signature
Rule (Proposed Part 11)?
2) Federal Register on the Internet
Division of Manufacturing and Product Quality Subject
Contacts
Attachment:
FAX FEEDBACK (Your input requested)
MOTISE'S NOTEBOOK:
Welcome to the first edition of our fourth year of Human
Drug CGMP Notes, our periodic memo on CGMP for human use
pharmaceuticals. As always we welcome your FAX FEEDBACK
responses and appreciate your suggested topics for
coverage. In addition, feel free to call, write, or send
us e-mail, as several of you have done. We also welcome
brief articles FDAers may wish to contribute. Subjects
should be CGMP related. Your input would be especially
valuable if it addresses emerging new technologies.
Although the document is fully releasable under the
Freedom of Information (FOI) Act, our intended readers
are 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 memo is to enhance field/headquarters communications
on CGMP policy issues and to do so in a timely manner.
This document is a forum to hear and address your CGMP
policy questions, update you on projects in the works,
2
HUMAN DRUG CGMP NOTES March 1996
provide you with inspectional and compliance points to
consider that will hopefully be of value to your day to
day activities, and clarify existing policy and
enforcement documents.
We intend to supplement, not supplant, existing policy
development/issuance mechanisms, and provide a fast means
of distributing interim policy.
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) 594-1089, or by electronic mail.
If you would like to receive the electronic version of
this document via electronic mail, let us know (see the
check-off line in FAX FEEDBACK).
Thanks!
Paul J. Motise
POLICY QUESTIONS:
Laboratory Issues
1) Does FDA have a CGMP policy on use of recycled
solvents for HPLC columns?
References: See 21 CFR 211.67, Equipment Cleaning and
Maintenance, and 211.160(b), General Requirements
The agency has no specific policy on recycled HPLC
solvents above and beyond the CGMP requirements regarding
suitability of laboratory equipment and analytical
methods. Therefore, it would be acceptable to use
recycled solvents which do not interfere with analytical
results or equipment operation.
A potential problem to avoid with using recycled solvents
is the possible retention of drug residues that could
interfere with analytical findings. To minimize the
chances of such interference some firms prudently
restrict reuse of solvents to testing only one drug
product. It's also a good idea to segregate recycled
from virgin solvents.
2) Is dissolution testing past the Stage 1 level
significant enough to be cited on FDA-483s?
Reference: 21 CFR 211.165(a), Testing and release for
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HUMAN DRUG CGMP NOTES March 1996
distribution.
The Center has received several inquiries from industry
regarding the interpretation of dissolution
specifications as outlined in the USP general chapter
on Dissolution <711> [and the chapter on Drug Release
<724>]. The inquiries stemmed from FDA-483 observations
issued by field investigators citing dissolution testing
past the Stage 1 (S1) level as indications of product
failure and/or lack of process control. This has
prompted several pharmaceutical companies to ask the
Agency to set "wider" dissolution specifications which
will allow all batches manufactured to pass at the S1
level. The CDER/OGD Office of Clinical Pharmacology and
Biopharmaceutics works with firms to set dissolution
specifications based on the in vitro results of the
batch(es) used in clinical and/or bioavailability
studies. This is done to ensure the same level of
bioavailability for future batches. If "wider"
dissolution specifications are set, this assurance is
lost.
Similar situations have come to this division's attention
by way of regulatory case review, where, as part of the
GMP violations cited, 483 observations such as "Lack
of failure investigation(s) for lot(s) ... which failed
dissolution testing at the S1 level." or "Lack of process
control for ...product due to dissolution failure at the
S1 level." are made.
Having to test a drug product through the three stages
[S1, S2 and S3] for dissolution does not, by itself,
indicate that there is a problem with the product, nor
does it indicate that there are problems with control of
the manufacturing process. The USP clearly states in the
"Interpretation" section of the chapter on dissolution
<711> [and the chapter on drug release <724>], "Unless
otherwise stated in the individual monograph... Continue
testing through the three stages unless the results
conform at either S1 or S2....".
Depending on the context of the occurrence of dissolution
testing past the S1 level, other 483 observations would
be more appropriate. For example, if a large percentage
of all batches manufactured, within a specific period,
have to be tested past the S1 level, a more appropriate
483 observation would be "Failure to determine why
batches manufactured during this specific period had to
be tested through to S2 or S3." Another example is if a
large percentage of batches manufactured suddenly have to
be tested through S2 or S3, after only rarely having to
be tested past S1; a more appropriate observation would
be "Failure to determine why a majority of recently
manufactured batches now have to be tested through to S2
4
HUMAN DRUG CGMP NOTES March 1996
or S3." Such observations could be made assuming that:
1> Initial dissolution testing for the product
in question only rarely proceeded past S1 and is now
always proceeding to S2 or S3; and,
2> The firm failed to recognize the
possibility of a process or testing problem by this
change in the dissolution profile of its product.
[This issue was also addressed in the March 1995 issue of
Human Drugs CGMP Notes]
Division Contact (for above questions): Monica Caphart,
HFD-325, 301-594-0098, e-mail CAPHARTM@cder.fda.gov
3) Is routine product pH testing required for
Endotoxin (LAL) Assays?
References: See 21 CFR 211.167, Special testing
requirements
No, not unless a firm has committed to such testing in a
new drug application. Measurements of pH on routine
endotoxin samples each time a specimen is tested are not
required for a validated method. The positive product
control on routine testing, which must be included during
each test, will fail if the specimen pH is out of
control.
We do recommend you review the firm's endotoxin
validation and compare this with the finished product
release pH range to make sure the validation lots covered
the upper and lower limits used to release product. If
the validation lots covered only a narrow range this
would be an appropriate issue for a CGMP citation, rather
than the lack of pH testing of each test specimen.
Contact for Further Info: Michael J. Verdi, HFD-322,
301-594-0095, e-mail: verdim@cder.fda.gov
On Stability (Policy Questions on Stability Issues):
1) Is it acceptable for a firm to export expired
drugs for charity?
Reference: 21 CFR 211.137(a) and (d), Expiration Dating
No. While we recognize the dire need for drugs in
distressed parts of the world, once the expiration date
has passed there is no assurance that the drugs have the
safety, identity, strength, quality and purity
characteristics they purport or represent to possess. As
5
HUMAN DRUG CGMP NOTES March 1996
such, expired drugs are adulterated within the meaning of
section 501 (a)(2)(B) of the FD&C Act, and section 301 of
the Act prohibits the introduction or delivery for
introduction into interstate commerce any drug that is
adulterated.
Firms may wish to extend the labeled expiration date,
thus making them suitable for export, provided that any
extension of the expiration dating is supported by
appropriate stability studies. Any extension of the
expiration dating should be of sufficient duration to
ensure that the drugs do not again reach their expiry
before their anticipated use.
2) How should the start of the expiration dating
period be calculated for repackaged drugs?
Reference: 21 CFR 211.137, 211.111, and 211.166; CPG
7132b.10, 7132b.11, 7132.13; CPGM 7356.002b
The CGMP regulations require that drug repackagers use an
expiration date on repackaged drugs that is based on
scientific evaluation and/or testing of the drug in the
container-closure in which the drug is to be marketed.
However, in a limited number of situations a repackager
may extrapolate from the expiration date on the original
manufacturer's container, an expiration date that is
suitable for the repackaged drug, without conducting
additional stability studies. Such situations are
described in the guidance referenced above.
Where an expiration dating period is derived from
stability studies conducted on the repackaged drug, the
repackager should develop controls to ensure that an
appropriate expiration dating period is assigned at the
time of repackaging. For example, it may be appropriate
to assign a two-year expiration date to a drug that is
one-month old at the time of repackaging, whereas it may
not be appropriate to assign a two-year expiry when the
same drug is repackaged after it has been held in the
original manufacturer's container for substantially
longer than one-month, and after the container has been
opened numerous times.
Contact for Further Info: Barry Rothman, HFD-325, 301-
594-0098, e-mail: rothmanb@cder.fda.gov.
Gas What? (Policy Questions on Medical Gases):
1) May a firm use industrial grade nitrogen as a
blanketing agent during the manufacturing of a drug
6
HUMAN DRUG CGMP NOTES March 1996
product?
Reference: 21 CFR 211.110(a) and(c), Sampling and testing
of in-process materials and drug products; 211.165(a),
Testing and release for distribution
Unless the industrial grade product is analyzed for all
possible impurities and contaminants, it would be
unacceptable to use industrial grade products in the
manufacturing of pharmaceutical drugs.
The filling of medical and industrial grade nitrogen
whether it be gaseous or liquid is quite unique. The
problems we have seen are usually not with the product
itself, but rather with the container closure system,
i.e., the high pressure cylinder and hazardous
substances to which they have been exposed.
Industrial cylinders are widely distributed throughout
all types of industry, and are routinely exposed to
hazardous substances, some of which are extremely toxic,
i.e., hydrocarbons, arsenic compounds, chlorine, etc.
Therefore, it would be nearly impossible to determine
what a specific cylinder had been exposed to and to
analyze for that specific contaminant.
On the other hand, medical gas cylinders are prepared
under carefully controlled conditions to ensure that the
drug product meets the requirements of both FDA and the
USP, and are not exposed to contamination from industrial
sources. Each high pressure cylinder undergoes rigorous
pre-qualifying inspections and examinations with one of
the most significant being the vacuum evacuation step,
prior to filling a product.
According to USP23, the General Notices, Tests and
Assays, Foreign Substances and Impurities, it is
impossible to include in each monograph a test for every
impurity, contaminant, or adulterant that might be
present. Tests suitable for detecting such occurrences
should be employed in addition to the tests provided in
the individual monograph.
Refer to the June 1995 HUMAN DRUG CGMP NOTES for
nitrogen produced via pressure swing adsorption and
cryogenic nitrogen.
2) Is it acceptable for the owner of a vessel to apply
a small sticker to denote its ownership, even though the
vessel is filled by a different firm that is identified
in the vessel's labeling?
Reference: 21 CFR 211.130, Packaging and labeling
operations, 201.1, Drugs; name and place of business of
7
HUMAN DRUG CGMP NOTES March 1996
manufacturer, packer, or distributor.
Yes, a firm may place a small sticker, commonly referred
to as a possession/ownership sticker, on a vessel as long
as the sticker does not obstruct required labeling. In
addition, the sticker must not be misleading. For
example, it should be qualified by a statement such as,
"This empty vessel or this vessel when empty is the
property of, or belongs to, `Firm X, address, and
telephone number.'"
Contact for Further Info: Duane Sylvia, HFD-325, 301-
594-0095 e-mail: sylviad@cder.fda.gov.
What are the respective roles of ORA (field) and CDER
staff in performing reviews of chemistry data in new drug
applications?
Reference: Letter of October 14, 1994, issued jointly by
the Director of CDER and the Associate Commissioner for
Regulatory Affairs, to all NDA, ANDA and AADA Applicants
CDER and ORA personnel review the same chemistry data,
but from different perspectives. CDER reviews chemistry
data for scientific/technical adequacy and
appropriateness, and evaluates submitted test methods and
finished product specifications. ORA personnel audit the
same chemistry data to verify authenticity and data
accuracy at the applicant's location.
It is consistent with the referenced letter for field
personnel to place comments on FDA 483's regarding
authenticity and accuracy of data, even when that data
has already been reviewed by CDER. However, be sure to
discuss with CDER reviewers any test methods,
specifications and chemistry data you find questionable.
Such discussions should ideally occur before a 483 is
prepared. ORA staff should contact CDER reviewers when
an applicant:
(1) may have inadvertently omitted chemistry
information from an application; or
(2) has already responded to a deficiency letter on
the same matter and the response is questionable.
It is vital that when field personnel find inadvertently
unsubmitted chemistry information, they promptly alert
CDER reviewers who will evaluate the significance of the
omission.
When ORA and CDER agree about the significance of the
8
HUMAN DRUG CGMP NOTES March 1996
findings, CDER review chemists will decide as to whether
the matter should be noted in a deficiency letter and/or
an ORA prepared 483. Note that field personnel must
never cite deficiency letter items as FDA 483
observations unless specifically directed by a CDER
review chemist.
Contact for Further Info: Randall Woods HFD-324, 301-
827-0062, e-mail: woodsr@cder.fda.gov.
TOWARD THE ELECTRONIC GOVERNMENT:
1) What is the status of the Electronic Signature
Rule (Proposed Part 11)?
Reference: Electronic Records; Electronic Signatures, 21
CFR Part 11, Proposed Rule, Federal Register of August
31, 1994, 59 FR 45160
We have begun preliminary clearance of a final rule
Federal Register notice. We cannot at this point predict
the exact outcome and publication date. However, the
rulemaking remains a high priority in CDER and the
agency.
A total of 49 respondents, representing all FDA regulated
industries as well as other interested parties, submitted
544 discrete comments that addressed almost every part of
the proposed regulations. The 49 included 11 trade
associations that also reflected the same industry
spectrum. However, most respondents represented the
pharmaceutical industry.
2) Federal Register on the Internet
The Federal Register (F/R) is now available on the
Internet s World Wide Web. In addition to 1996 notices,
the U.S. Government Printing Office (GPO) has posted the
1995 and 1994 editions in a searchable database. (Also
included are the Congressional Record, Congressional
Bills, and information in 1400 Federal Depository
Libraries.)
The Internet address for the free service is:
HTTP://WWW.ACCESS.GPO.GOV/SU_DOCS/ .
You can read and download the current daily F/R as ASCII
(American Standard Code for Information Interchange) or
PDF (Adobe s Portable Document Format) files. To view
PDF files you ll need Adobe s Acrobat Reader software, a
widely distributed freebie. Notices in PDF format look
9
HUMAN DRUG CGMP NOTES March 1996
exactly like pages in the paper Federal Register.
Full text database searches are fast and flexible,
allowing for boolean operators (e.g., AND, OR), wildcard
word roots, hunts of multiple databases back to 1994, and
results of up to 200 hits (records that contain your
search term.)
Search results reports are comprehensive. They show the
selected database(s), the number of hits, a time stamp
(year, month, day, hour, minute and second), and a
warning that the report is a temporary file that self-
destructs (at GPO) after about one hour. A brief
description of each hit states the F/R cite (e.g.,
FR31AU94), title, file size, and hyperlinks for TEXT (to
download the full text in ASCII), SUMMARY (to download
the ASCII file of only the notice s Summary section), and
PDF (to download full notices back to 1995 in a PDF
file.)
Be aware of a few limitations. The 1994 database lacks
page numbers. Page numbers (ranges), volume and issue
numbers are given for 1995 onward. The TEXT link search
results files display your search terms in bold
characters, but SUMMARY and PDF formats don t (Acrobat
Reader can highlight a search term offline, however).
Graphics in 1994 notices are in TIFF format and must be
downloaded separately. Graphics in newer notices are
embedded in PDF files.
You should find this service a valuable tool that helps
you stay current, and obtain F/R notices in convenient
formats for your own files and for answering industry and
public requests.
Division Contact For Further Info: Paul J. Motise, HFD-
325, 301-594-1089, e-mail: motise@cder.fda.gov.
P. Motise 3/1/96
DOC ID CNOTESW6.396
10
HUMAN DRUG CGMP NOTES March 1996
DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320
SUBJECT CONTACTS
Applications Integrity Policy LuAnn Pallas 594-0098
Bruce Hartman 827-0062
Aseptic Processing John W. Levchuk 594-0095
Biotechnology Walter Brown 594-1089
Bulk Drugs Edwin Rivera 594-0095
Rick Friedman "
Case Management Joseph Famulare 594-0098
CGMP Guidelines Paul Motise 594-1089
Civil Litigation Guidance Nick Buhay 594-0098
Clinical Supplies/IND CGMP Paul Motise 594-1089
Bruce Hartman 827-0062
Computer Validation Paul Motise 594-1089
Charles Ahn 594-0098
Content Uniformity Monica Caphart 594-0098
Russ Rutledge 594-1089
Criminal Litigation Support Nick Buhay 594-0098
Electronic Records/Signatures Paul Motise 594-1089
Facility Reviews Russ Rutledge 594-1089
Foreign Inspections John Dietrick 594-0095
Inspections/ Investigations Randall Woods 827-0065
(For Cause) John Singer 827-0071
Labeling Controls (CGMP) Paul Motise 594-1089
Laboratory Issues John Levchuk 594-0095
Monica Caphart 594-0098
Russ Rutledge 594-1089
11
HUMAN DRUG CGMP NOTES March 1996
DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320
SUBJECT CONTACTS (Continued)
Lyophilization John Levchuk 594-0095
Manufacturing Changes Walter Brown 594-1089
Supplements
Medical Gases Duane S. Sylvia 594-0095
NDA/ANDA Pre-Approval Bruce Hartman 827-0062
Inspections Randall Woods "
Mark Lynch "
Penicillin Cross Contamination Duane S. Sylvia 594-0095
PET Radiopharmaceuticals John Levchuk 594-0095
Pharmacies, CGMP John Levchuk 594-0095
LuAnn Pallas 594-0098
Pre-Approval Program Dave Doleski 827-0072
Melissa Egas 594-0095
Process Validation, General John Dietrick 594-0098
Paul Motise 594-1089
(Sterile Dosage Forms) John Levchuk 594-0095
Recycling Plastic Containers Paul Motise 594-1089
Repackaging Barry Rothman 594-0098
Salvaging Paul Motise 594-1089
Stability/Expiration Dates Barry Rothman 594-0098
Sterile Facility Construction John W. Levchuk 594-0095
(Clean Rooms) Michael Verdi 594-0095
Sterilization Validation John W. Levchuk 594-0095
12
HUMAN DRUG CGMP NOTES March 1996
DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320
SUBJECT CONTACTS (Continued)
Topical Drugs Randall Woods 827-0062
Transdermals Brian Hasselbalch 594-0098
Videoconferencing Russ Rutledge 594-1089
Water Quality Michael Verdi 594-0095
Rick Friedman "
13
HUMAN DRUG CGMP NOTES March 1996
FAX FEEDBACK
TO: Paul Motise, HUMAN DRUG CGMP NOTES, HFD-325
FAX: 301-594-2202 (Phone 301-594-1089)
FROM:
______________________________________________________
AT: ______________________ MAIL CODE: ___________
PHONE: ________________________ FAX: __________________
E-MAIL ADDRESS: _______________________________
To receive the electronic version of HUMAN DRUG CGMP
NOTES via E-mail, check here _____.
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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
inspection/compliance activities.
Here's my question for: ________________________________
on the subject of:
_________________________________________________________
_________________________________________________________
_________________________________________________________
Future editions of HUMAN DRUG CGMP NOTES should address
the following CGMP questions/issues:
_________________________________________________________
_________________________________________________________
_________________________________________________________
14
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August 2, 1996
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