 |
HUMAN DRUG CGMP NOTES
(Volume 3, Number 1)
March, 1995
(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-323
Addressee Database Manager: Russ Rutledge, HFD-323
IN THIS ISSUE:
Motise's Notebook
Policy Questions On:
- What kinds of USP dissolution test failures are significant enough
to be noted on Forms FD-483 ?
- Is pressure sensitive labeling on a roll considered to be cut
labeling?
- Would FDA disapprove a pharmaceutical plant because it was located
next to a landfill site?
- Is it acceptable for two employees to verify correctness of hand
applied labeling inserts by inspecting the insert bar codes or bleed lines (for correct
alignment)?
- Gas What? (Policy Questions on Medical Gases):
1) What is the significance of the air liquefaction statement? Is
further testing required if this statement is not available?
2) Has the odor test been eliminated from the prefill inspections,
due to concerns over pathogenic contamination or other dangerous compounds?
Published In Final:
- CGMP revisions; retrospective review, final rule, 1/20/95, effective
2/21/95.
Toward The Electronic Government:
- Human Drug CGMP Notes; 1995 Cumulative issues to be posted to
Internet FTP server.
Focus On: Media Fill Contamination Rate
HUMAN DRUG CGMP NOTES March, 1995
Attachments:
Division of Manufacturing and Product Quality, HFD-320 Subject Contacts
FAX FEEDBACK
(Your input requested)
MOTISE'S NOTEBOOK:
Welcome to another edition of Human Drug CGMP Notes, our periodic memo
on CGMP for human use pharmaceuticals. This begins our third year.
Your FAX FEEDBACK responses are still excellent and we especially
appreciate your suggested topics for coverage. We've revised FAX
FEEDBACK to enable us to better respond to your particular questions on
a given topic. You need not, however, limit the dialog to FAX FEEDBACK.
Feel free to call, write or send us e-mail, as several of you have done.
Also welcome are brief articles FDAers may wish to contribute. Subjects
should be CGMP related and would be especially valuable if they address
emerging new technologies.
As a reminder, although the document is fully releasable under the
Freedom of Information (FOI) Act, our intended readership is FDA field
and headquarters personnel. Therefore, for now, we cannot extend our
distribution list to people outside the agency. The primary purpose of
this communication 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, to update you on
CGMP projects in the works, to provide you with inspectional and
compliance points to consider that we hope will be of value to your day
to day activities, and to clarify existing policy and enforcement
documents.
We intend to supplement, not supplant existing policy
development/issuance mechanisms, and to 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 the Policy and Guidance Branch, HFD-323, by interoffice paper
mail, using the above address, by phone at (301) 594-1089, or by
electronic mail (under the agency e-mail system, address your message
to the last name of the contact, such as Rutledge, or Motise.)
FDA staffers may receive an electronic version of this document via
electronic mail, by letting us know (see the check off line in FAX
FEEDBACK).
Thanks!
Paul J. Motise
2
HUMAN DRUG CGMP NOTES March, 1995
POLICY QUESTIONS:
What kinds of USP dissolution test failures are significant enough to be
noted on Forms FD-483 ?
References: See 21 CFR 211.165(a), Testing and release for distribution.
Routine failure of manufactured batches of a product to pass USP
Dissolution tests at Stage 1 is not significant enough to be noted on Forms
FD-483; neither is occasional failure of individual dosage units at Stage
2. A batch does not fail the USP Dissolution Test until it fails at Stage
3. However, frequent failures at Stage 2 are significant when other
batches of the same product have Stage 3 failures, and therefore should be
noted on Forms FD-483..
CDER requires submission of test data for twelve dosage units in every new
drug application, or supplement thereto, that requires dissolution test
information. CDER and the USP define the dissolution test at Stage 2
(twelve units tested). We anticipate that manufacturers should have to
test at Stage 2 routinely, and that there will be occasional failures of
individual dosage units at Stage 2. That is why the USP Acceptance Table
in Chapter <771> provides for a third level of testing (24 units). CDER
and the USP consider Stage 1 (six units tested) to be a bonus situation in
which, because all of the dosage units tested dissolved so well, we permit
manufacturers to do less than the expected amount of testing on the batch.
CDER has been working with the USP for some time to upgrade many USP
Dissolution tests that have low tolerances, long test times, and/or high
apparatus speeds. Several upgraded tests that have been published in
Pharmacopeial Forum have drawn criticism from a number of pharmaceutical
manufacturers because the upgraded test would be likely to require
companies to do Stage 2 testing--which would precipitate Form FD-483
observations that would not be warranted.
Contacts for Further Info: Monica Caphart, HFD-325, 301-594-0098, and
Bob Rippere, HFD-335, 301-594-0104.
Is pressure sensitive labeling on a roll considered to be cut labeling?
References: See 21 CFR 211.122(g), Materials examination and usage
criteria.
No, not unless peeled off the roll prior to being brought to the
labeling line. Some misinformation appears to have been circulated in
the pharmaceutical industry that FDA considers pressure sensitive
labeling to be cut labeling -- this is not correct. Pressure sensitive
labeling on a roll is roll labeling which does not require 100%
verification, unless a firm wants to eliminate reconciliation, in which
case 100% verification must be performed. However, if any type of
labeling is received on rolls but is removed from the rolls by peeling
them off or cutting off individual pieces prior to being brought to the
labeling line, then we consider the pieces to be cut labeling.
Is it acceptable for two employees to verify correctness of hand applied
labeling inserts by
inspecting the insert bar codes or bleed lines (for correct alignment)?
3
HUMAN DRUG CGMP NOTES March, 1995
Yes, as long as the firm can document adequate (representative) sampling
and inspection (proofing) of the incoming lot of inserts to ensure that
the correct inserts had been received. Bar codes on the inserts could
also be scanned using hand or pen type scanners as long as the equipment
is able to create an electronic record of the number of pieces scanned
and this information is archived so that it can be checked against the
packaging records during inspections.
Contact for Further Info on above labeling issues: Anthony Lord, HFD-
322, 301-594-0095.
Would FDA disapprove a pharmaceutical plant because it was located next to
a landfill site?
Reference: 21 CFR Part 211, Subpart C, Buildings and Facilities,
generally.
Not necessarily. More important than a facility's proximity to sources
of contamination is the adequacy of measures the firm takes to prevent
such contamination from adversely affecting drug product quality. It
would be far from prudent to locate a pharmaceutical establishment
alongside a land reclamation facility (which conjures up visions of such
potential sources of contamination as rodents, insects, birds, and
ground water toxic leachates). The task of protecting the drug product
and production environment from such contamination would be challenging,
but not insurmountable. Field investigators who encounter such a
situation should, of course, pay close attention to how the firm
isolates production operations from potential contaminants. However, in
the absence of demonstrated routes of contamination, we would not
disapprove of the facility based solely on its proximity to the
landfill.
Division Contact for Further Info: Paul J. Motise, HFD-323, 301-594-
1089.
Gas What? (Policy Questions on Medical Gases):
1) What is the significance of the air liquefaction statement? Is further
testing required if this
statement is not available?
Reference: 21 CFR 211.165(f), Testing and release for distribution.
The United States Pharmacopeia XXIII Oxygen monograph states that if the
air liquefaction statement is present then a firm is exempt from performing
the carbon dioxide and carbon monoxide impurities testing.
Let's look at it another way; there are four (4) required tests listed
under the oxygen monograph. They are the identification test, the carbon
dioxide impurity test, the carbon monoxide impurity test
4
HUMAN DRUG CGMP NOTES March, 1995
and the assay. As long as the air liquefaction statement is available
either by a letter from the supplier or by a certificate of analysis, then
the identification and the assay are the only tests required.
2) Has the odor test been eliminated from the prefill inspections, due to
concerns over pathogenic contamination or other dangerous compounds?
Reference: 21 CFR 211.84(d)(3), Testing and approval or rejection of
components, drug product containers, and closures; 211.94(b&c), Drug
product containers and closures; and, 211.113(a), Controls of
microbiological contamination.
No. The Compressed Medical Gases guideline, page 5 and 6, states that
since the containers and closures for medical gases are reused over and
over again, they require special considerations, i.e., inspections, prior
to filling. Therefore, an odor test of each cylinder to detect foreign
odors is required. Of course, the odor test should not be performed on
anesthetic gases such as nitrous oxide, or on carbon dioxide.
At the present time, we are unaware of any problems and have received no
reports of medical gases becoming contaminated with pathogens. However, if
this is a problem or a major concern, then a medical gas manufacturer would
be required in accordance with 21 CFR 211.113, Control of Microbiological
Contamination, to establish written procedures designed to prevent
objectionable microorganisms in the drug product.
Division Contact for Further Info: Duane Sylvia, HFD-322, 301-594-0095.
Published In Final:
CGMP revisions; retrospective review, final rule, 1/20/95, effective
2/21/95.
Reference: 60 FR 4087, No. 13, 1/20/95.
The changes to the CGMP regulations include: clarifying the degree of
discretion provided to manufacturers to determine whether separate or
defined areas of production and storage are necessary, clarifying the
standard used to determine the degree of scrutiny necessary to check the
accuracy of the input to and output from computer systems, exempting
investigational new drug products from bearing an expiration date,
permitting the use of a representative sampling plan for examination of
reserve samples, and clarifying the manufacturer's responsibilities
regarding batch records during the periodic evaluation of drug product
quality standards. The revisions come as a follow up to the
2/12/91 (56 FR 5671) proposed rule, as part of the agency's ongoing
retrospective review, and are expected to provide regulatory relief while
maintaining product quality.
Division Contact for further info: Paul J. Motise, HFD-323, 301-594-
1089. Contact for docket and FR info: Howard P. Muller, Jr., HFD-362,
301-594-1046.
5
HUMAN DRUG CGMP NOTES March, 1995
Toward The Electronic Government:
Human Drug CGMP Notes; 1995 Cumulative issues to be posted to Internet FTP
server.
Beginning with this volume, we will post cumulative issues of Human Drug
CGMP Notes to CDER's Internet FTP (File Transfer Protocol) Server
(address: CDVS2.CDER.FDA.GOV). Each edition will be posted in
WordPerfect 5.1 and ASCII (American Standard Code For Information
Interchange) formats. The file names will appear in the format
"HDCGMPxx.myy" where "xx" will appear as "w5" for WordPerfect 5.1, or
"as" for ASCII text, and "myy" will represent the date, where "m" will
be "1" through "9" for months January through September, "o", "n" and
"d" represent October, November and December, and "yy" will be the last
two digits of the year, respectively. Thus, this edition in WordPerfect
format, for example, will be posted as "HDCGMPW5.395".
Division Contact For Further Info: Paul J. Motise, HFD-323, 301-594-
1089.
Focus On: Media Fill Contamination Rate
References: 21 CFR 211.113(b), Control of microbiological contamination;
and Guideline on Sterile Drug Products Produced by Aseptic Processing; PDA
Journal of Pharmaceutical Science & Technology, Sept./Oct. 1994, Vol 48,
No. 5, letter to the editor by Kunio Kawamura, Ph.D., Takeda Chemical
Industries
The performance of media fill runs is a standard industry practice for the
purpose of:
- simulating aseptic assembly operations of sterile product without
actual product fill;
- prompting the need for evaluation of the assembly operation when
positive contaminated units result during a media fill run;
- identifying environmental and human caused operational deficiencies
and any other causes for discrepancies and their correction;
- validating the aseptic assembly process.
Recent industry and FDA discussions have focused on the question of media
fill contamination rates and the adequacy of statistical methods for
determining acceptable sterility assurance levels (SALs). This is based on
the percentage of filled media units that are found to be contaminated.
FDA's Guideline On Sterile Drug Products Produced By Aseptic Processing
references a media fill contamination rate of .1% in two separate
instances. Currently, contamination rates >.1% are expected to prompt
industry to:
- investigate thoroughly records of the processes, equipment,
environment and personnel associated with the failed media fill;
6
HUMAN DRUG CGMP NOTES March, 1995
- identify the causes and correct the problems; and,
- revalidate with three additional media fill runs.
However, the result of a media fill contamination rate <.1% (even as low as
the incidence of one contaminated unit out of any number of units) in a
media fill should be regarded by an aseptic operator as sufficient reason
to:
- investigate (e.g. speciate and identify the possible origins of the
organisms in the contaminated unit(s), considering potential developing
trends over many media fills, etc.)
- evaluate results to determine the need for an expanded investigation
to identify contamination causes and make corrections if possible.
Although the Guideline On Sterile Drug Products Produced By Aseptic
Processing states that FDA recognizes the scientific and technical limits
of validation, it should be noted that there are also limits in the degree
of confidence with which one can state that observed contaminated units in
any media fill represent the true contamination rate. Although the degree
of confidence in perceiving the true contamination rate increases as the
total number of units in a media fill increases, it must also be recognized
that there can never be absolute certainty that an observed incidence of
even one contaminated unit is the actual number of such units in any given
media fill. Some media fills, statistically, will not accurately represent
the true contamination rate. The guideline associates a 95% confidence
probability with a media fill run totaling 3000 units. Therefore, the
chances are that in 20 media fill runs, one of the runs will not accurately
represent the true contamination rate.
In summary, true values of the contamination rate of any media fill can
only be known to a degree of probability. It is thus never definitely
known whether the result (i.e. contamination rate) of any particular media
fill is actually a true value or not. To err on the side of patient safety
would be for each contaminated unit to be investigated and corrective
action taken if necessary.
Division Info. Contact: Randall Woods, HFD-324, 301-827-0062
P. Motise 3/1/95
DOC ID CNOTESas.395
7
HUMAN DRUG CGMP NOTES March, 1995
DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320
SUBJECT CONTACTS
Applications Integrity Policy John Dietrick 594-0098
Aseptic Processing John W. Levchuk 594-0095
Edwin Rivera "
Tony Lord "
Biotechnology Walter Brown 594-1089
Bulk Drugs Edwin Rivera 594-0095
CGMP Guidelines Paul Motise 594-1089
Civil Litigation Guidance:
Non-Sterile John Dietrick 594-0098
Sterile Tony Lord 594-0095
Clinical Supplies/IND CGMP Paul Motise 594-1089
Bruce Hartman 827-0062
Computer Validation Paul Motise 594-1089
Content Uniformity Tony Lord 594-0095
Charles Ahn 594-0098
Criminal Litigation Support Nick Buhay 594-0098
Data (Application) Integrity Bruce Hartman 827-0062
LuAnn Summy 594-0098
Dissolution Monica Caphart 594-0098
Electronic Records/Signatures Paul Motise 594-1089
CGMP for Pharmacies John Levchuk 594-0095
Inspection (For Cause)
Assignment Preparation Randall Woods 827-0062
Labeling Controls (CGMP) Tony Lord 594-0098
Laboratory Issues John Levchuk 594-0095
Monica Caphart 594-0098
Lyophilization John Levchuk 594-0095
i
HUMAN DRUG CGMP NOTES March, 1995
DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320
SUBJECT CONTACTS (Continued)
Medical Gases Duane S. Sylvia 594-0095
NDA/ANDA Pre-Approval
Inspections Bruce Hartman 827-0062
Randall Woods "
Brenda Holmes "
Penicillin Cross
Contamination Duane S. Sylvia 594-0095
PET Radiopharmaceuticals
(CGMP) John Levchuk 594-0095
Walter Brown 594-1089
Process Validation (Non-Sterile
Dosage Forms) John Dietrick 594-0098
Process Validation (General) Paul Motise 594-1089
Recycling Plastic Containers Paul Motise 594-1089
Repackaging William Crabbs 594-1089
Salvaging Paul Motise 594-1089
Stability/Expiration Dates Barry Rothman 594-0098
Sterile Facility Construction
(Clean Rooms) Tony Lord 594-0095
Sterilization Validation John W. Levchuk 594-0095
Edwin Rivera "
Supplements for Sterilization William Crabbs 594-1089
Validation
Topical Drugs Randall Woods 827-0062
Videoconferencing Russ Rutledge 594-1089
ii
HUMAN DRUG CGMP NOTES March, 1995
FAX FEEDBACK
TO: Paul Motise, HUMAN DRUG CGMP NOTES, HFD-323
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 _____.
This FAX consists of this page plus ______ page(s).
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.
Here's my question for _________________, on the subject of
______________:
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
Future editions of HUMAN DRUG CGMP NOTES should address the following
CGMP questions/issues:
________________________________________________________________
________________________________________________________________
________________________________________________________________
 Back to CGMP Notes
Date created: July 31, 1996; last update: July 6, 2005 |
|
