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HUMAN DRUG CGMP NOTES
(Volume 3, Number 3)
September, 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:
- Are tablet press RPMs important enough to be a factor in
process validation?
- How long must a contract manufacturer, who performs only part of
the production steps, retain records for those activities?
- Gas What? (Policy Questions on Medical Gases):
1) What are the requirements for the calibration of vacuum
gauges?
2) What are the labeling requirements for cryogenic home
vessels?
- Bulk Beat (Policy Questions on Bulk Drugs):
1) What is the FDA's current policy with respect to validation
of bulk pharmaceutical chemical processes?
2) Do Warning Letters involving bulk drug GMP charges
require center review or concurrence?
- On Stability (Policy Questions on Stability Issues):
1) For injectable drugs in multi-dose containers, is the
number of entries to withdraw a dose a factor in determining
the expiration date?
2) How should the start of the expiration dating period be
calculated for new batches of finished drug products intended for
commercial distribution?
Special Report: CDER Compliance Implementation for New USP Injectables
Labeling Requirements
HUMAN DRUG CGMP NOTES September, 1995
Toward The Electronic Government:
- PDF format added to electronic editions of Human Drug CGMP Notes
Attachments:
DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320, SUBJECT
CONTACTS
FAX FEEDBACK (Your input requested)
***
MOTISE'S NOTEBOOK:
Welcome to another issue of Human Drug CGMP Notes, our periodic memo
on CGMP for human use pharmaceuticals. Your FAX FEEDBACK responses
are still great and we especially appreciate your suggested topics
for coverage. You need not, however, limit the dialog to FAX
FEEDBACK. Feel free to call, write, or send us e-mail. We also
welcome brief articles FDAers may wish to contribute. (For instance,
this edition includes an article on injection labeling changes for
USP drug products and CDER's implementation plan to phase in industry
compliance with the new requirements.) Topics of special value are
those that 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, for the paper version, 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, to update you on CGMP projects in the
works, to provide you with inspectional and compliance points to
consider that will hopefully 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.
Attached 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 an electronic version of this document
via electronic mail, let us know (see the check-off line in FAX
FEEDBACK).
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HUMAN DRUG CGMP NOTES September, 1995
Thanks!
Paul J. Motise
POLICY QUESTIONS:
Are tablet press RPMs important enough to be a factor in process
validation?
References: See 21 CFR 211.110 (Sampling and testing of in-process
materials and drug products), and 211.100 (Written procedures;
deviations).
Yes. Tablet press speed, expressed as revolutions per minute (RPM),
is indeed an important factor that needs to be controlled and
addressed in tableting validation. Granulation flow characteristics
will limit how fast the tableting may proceed; too fast a rate may
not permit enough granulation to fall into the dies, resulting in
sub-potency. Furthermore, tablet hardness is a function of
compression dwell time -- too fast an RPM could mean that the
granulation does not experience sufficient compression, and
conversely too slow an RPM could mean excessive compression.
Contact for Further Info: Charles Ahn, HFD-325, 301-594-0098, e-mail:
ahnc@fdacd.bitnet.
How long must a contract manufacturer, who performs only part of the
production steps, retain records for those activities?
References: See 21 CFR 211.180(a) and (b) (General requirements)
The records retention requirements for the contractor are the same as
those for the prime manufacturer, just as if the activities had been
performed by the prime manufacturer. The retention time is at least
one year after the expiration date of the drug product, or, in the
case of some OTC drug products which are not required to have
expiration dates, three years after the last of the batch has been
distributed.
The retention requirement for the contractor, therefore, means that
the contractor must know what the dosage form expiration date is, or
(for the above OTC products) when the last of the batch has been
distributed. Where the contractor's activities are performed at some
stage prior to formation of the dosage form itself (say a contract
micronizer), some close communication with the dosage form producer
would be needed.
It is important for the contractor's records to be available so that
complete product history is maintained and, more importantly,
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HUMAN DRUG CGMP NOTES September, 1995
investigations of possible problems may be conducted. The records
must be kept at the contract manufacturer's facility, per 211.180(c),
or else the records (or copies of them) may be kept at a different
location if they can be immediately retrieved by computer or other
electronic means.
Contact for Further Info: Paul J. Motise, HFD-323, 301-594-1089, e-
mail: motise@fdacd.bitnet.
Gas What? (Policy Questions on Medical Gases):
1) What are the requirements for the calibration of vacuum gauges?
Reference: 21 CFR 211.68 (Automatic, mechanical, and electronic
equipment).
Vacuum gauges used during the evacuation of high pressure cylinders
require a daily "calibration." This simple calibration consists of an
inspection of the gauge prior to the pulling of a vacuum, and with no
pressure on the line. The needle should return to "zero"; if not, then
an adjustment is required. If the needle cannot be adjusted and returned
to zero, then the gauge should be replaced.
In addition, a firm is required to establish written calibration
procedures describing their process and should document that the
calibration was performed.
2) What are the labeling requirements for cryogenic home
vessels?
Reference: 21 CFR 211.130(a) (Packaging and Labeling Operations)
According to 211.130(a), a firm should establish written procedures
designed to assure that correct labels are used for its drug products.
Until FDA's labeling requirements have been finalized, both high pressure
cylinders and cryogenic home vessels are required to have adequate
labeling. At the current time, we are requiring cryogenic home vessels
to bear labeling similar to that applied to high pressure cylinders, but
for the liquid phase. This includes bearing the statement, "Caution:
Federal law prohibits dispensing without prescription" in accordance with
21 CFR Section 201.100(b)(1).
Please note that this requirement pertains to oxygen used for
therapy, and not emergency use. So, a firm should determine when the
oxygen is intended for emergency use.
Contact for Further Info: Duane Sylvia, HFD-322, 301-594-0095, e-
mail: sylviad@fdacd.bitnet.
Bulk Beat (Policy Questions on Bulk Drugs)
1) What is the FDA's current policy with respect to validation of
bulk pharmaceutical chemical processes?
Reference: Compliance Policy Guides 7132c.08 and 7125.38 (Process
Validation Requirements for Drug Products Subject to Pre-Market
Approval).
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HUMAN DRUG CGMP NOTES September, 1995
FDA expects manufacturers to be actively engaged in a validation
program for all of their BPC products, although we have not insisted that
validations be completed at this time. This agency policy is delineated
in the referenced Compliance Policy Guides. FDA will consider
withholding approval of new drug applications based on the lack of
process validation when (1) a company has not established or is not
following an adequate plan to validate all BPCs; or (2) there is
evidence that the process is not validated as demonstrated by repeated
batch failures due to manufacturing process variability not attributable
to equipment malfunction or operator error.
2) Do Warning Letters involving bulk drug GMP charges require
center review or concurrence?
Reference: Regulatory Procedures Manual, Chapter 8-10-45, Center
Concurrence, (Transmittal Notice 94-2)
Yes. Since June 1, 1994, all Warning Letters with GMP charges
involving bulk drug substances require CDER review and concurrence. This
change was effected with a revision to the above referenced chapter.
For domestic BPC manufacturers, Districts should submit Warning
Letter recommendations to CDER's Office of Compliance, Division of
Manufacturing and Product Quality (HFD-320). Warning Letters
to foreign BPC manufacturers are issued directly by HFD-320. More on
this in future editions.
Contact for Further Info: Edwin Rivera, HFD-322, 301-594-0095,
e-mail: rivera@fdacd.bitnet.
On Stability (Policy Questions on Stability Issues):
1) For injectable drugs in multi-dose containers, is the
number of entries to withdraw a dose a factor in determining the
expiration date?
Reference: 21 CFR 211.166 (Stability testing).
Unless the multi-dose container is labeled to yield a specific number
of doses of a stated volume, there is no limit to the number of
withdrawals that may be made from a multi-dose container before the drug
is depleted or before the drug reaches its expiration date. The primary
concern with multi-dose containers is the potential for contaminating the
product during multiple penetrations through the container stopper.
While the expiration dating assigned to such products would be based on
the stability of the drug product, stability protocols should include
requirements for the testing and evaluation of container-closure
integrity. Container-closure integrity testing may include physical
testing of the closure seal by use of a leak test and by monitoring the
ability of the system to prevent microbial contamination. However, it
does not normally include an evaluation of multiple penetrations through
the container stopper. Furthermore, injectable drug products in
multi-dose containers are generally formulated with an anti-microbial
agent or preservative, as per the approved NDA and USP requirements.
2) How should the start of the expiration dating period be
calculated for new batches of finished drug products intended for
commercial distribution?
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HUMAN DRUG CGMP NOTES September, 1995
Reference: 21 CFR 211.166 (Stability testing), and 211.94 Drug
product containers and closures.
The expiration date assigned to a new batch of finished drug product
should be calculated from the date of release of the finished drug
product, provided that the date of release does not exceed 30 days from
the date of manufacture of the batch. The date of manufacture of the
batch is considered to be the initial date that an active ingredient has
been added to the batch during manufacturing. If greater than 30 days
has elapsed between the date of manufacture and date of release of the
batch, the expiration date should be calculated from within 30 days of
the date of manufacture of the batch, and not the date of release.
Contact for Further Info: Barry Rothman, HFD-325, 301-594-0098, e-
mail: rothmanb@fdacd.bitnet.
Special Report: CDER Compliance Implementation for New USP
Injectables Labeling Requirements
BACKGROUND:
Based on a 1991 review of injectable products' nomenclature, the USP
has revised General Chapter <1> INJECTIONS. Approximately 130
monograph titles will be affected. The greatest number of changes
involve dropping the term "STERILE" from injectable drug titles. The
nomenclature revisions became official in USP 23 on January 1, 1995.
Because the nomenclature revisions affected so many product titles,
CDER believed it was unreasonable to expect manufacturers to comply with
the changes by the official date. Also, concern was expressed that
health care providers should be given time to be apprised of these
changes. The USP agreed with these concerns and announced in the
September-October 1993 Pharmacopeial Forum that there will be an
extension of time for adopting the revised titles. Rather than adopting
all the revised titles at once, title changes will be reproposed for
supplemental revisions.
CDER in turn has prepared an implementation plan based on USP time
frames which addresses both USP and non-USP products. CDER has
decided to apply the USP revised nomenclature uniformly to all
products to lessen confusion that could arise from having similar
products with different titles.
IMPLEMENTATION PLAN:
To assist CDER reviewers and FDA field offices in applying these
nomenclature revisions consistently, the following implementation plan
has been established. [NOTE: CDER reviewers have been advised of this
plan via an April 14, 1995, memorandum entitled "Implementation Plan
for New Injection Nomenclature", from Yana Mille, Chairperson, CDER
Labeling and Nomenclature Committee.]
This plan divides FDA regulated products into two categories:
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HUMAN DRUG CGMP NOTES September, 1995
1. Approved or grandfathered (pre-1938) products subject to USP
monographs; and,
2. Approved or grandfathered (pre-1938) products not subject to
USP monographs.
For products in these two categories, a "flag" or reminder statement
should appear on the labels for a six month period alerting practitioners
to the changes. This should assist practitioners in becoming familiar
with these revised titles. An example of a "flag" would be: "FORMERLY
STERILE (insert drug name) ".
Since the labels and labeling are being revised to comply with
compendial requirements [21 CFR 314.70(d)], revised labels and labeling
may be submitted with an annual report provided the change is described.
However, if the firm prefers to submit revised labels and labeling as a
"Special Supplement - Changes Being Effected" [21 CFR 314.70 (c)], this
type of submission would be accepted since it affords the Agency an
opportunity to approve the new labeling.
Category 1 Products
For USP monograph products, a revised injection title (revised
established name) shall not be used until a USP Supplement, stating the
revised monograph title, has been published. Firms will then have 18
months from the effective date of that Supplement to revise the labels
and labeling to reflect the new title.
Category 2 Products
For those products which are not subject to USP monographs, firms
will have 18 months from the effective date of USP 23 to revise the
affected labels and labeling. In other words, revised labels and
labeling should be in place by July 1, 1996. The changes to be made are
as follows:
1. The term "STERILE" is eliminated from the titles of
injectable products. [NOTE: The term "STERILE" will not be removed from
appropriate monograph titles for WATER that are intended for direct
administration, such as STERILE WATER FOR INJECTION.]
2. For established names of injectable products, the following USP
classification system should be used in determining the product's title:
a. LIQUIDS
(1) Title for liquid preparations that are drug substances or
solutions thereof:
[DRUG] INJECTION
(2) Title for liquid preparations of solids suspended in a
suitable liquid medium:
[DRUG] INJECTABLE SUSPENSION
(3) Title for liquid preparations of drug substances
dissolved or dispersed in suitable emulsion medium:
[DRUG] INJECTABLE EMULSION
b. SOLIDS
(1) Title for dry solids that, upon the addition of suitable
vehicles, yield solutions conforming in all respects to the requirements
for Injections:
[DRUG] FOR INJECTION
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HUMAN DRUG CGMP NOTES September, 1995
(2) Title for dry solids that, upon the addition of suitable
vehicles, yield preparations conforming in all respects to the
requirements for Injectable Suspensions:
[DRUG] FOR INJECTABLE SUSPENSION
Contacts for Further Info: Meade North, HFD-335, 301-594-0104,
e-mail: northm@fdacd.bitnet, and Yana Mille, HFD-611, 301-594-0340,
e-mail: milley@fdacd.bitnet.
Toward The Electronic Government:
PDF format added to electronic editions of Human Drug CGMP Notes
We've added another format to the electronic editions of this
newsmemo, the Adobe (PDF (portable document format). Look for the
letters PDF in the CDER Internet Gopher (address gopher.cder.fda.gov)
and FTP (File Transfer Protocol) server (address cdvs2.cder.fda.gov)
directories that have the name Human Drug CGMP Notes.
PDF files may be viewed or printed using Adobe's widely available
Adobe Acrobat Reader 2.0, which is distributed for different PC
platforms. Adobe distributes the reader free of charge via many on-
line services.
Use of multi-platform electronic file readers and printers along with
their respective common document formats permits people who have
different computer systems to nonetheless view, read, and print
electronic documents in a form that closely matches the layout,
fonts, and styles of the original document; graphics are also
preserved. Thus, if you don't use (for example) WordPerfect as your
word processor, you won't be restricted to using the plain vanilla
ASCII (American Standard Code for Information Interchange) format to
view and print electronic documents. For instance, graphics in this
newsmemo, which don't appear in the ASCII edition, will appear in the
PDF format.
Use of PDF format files is also being explored by other parts of CDER
as a means of exchanging electronic documents.
Division Contact For Further Info: Paul J. Motise, HFD-323, 301-594-
1089, e-mail: motise@fdacd.bitnet.
P. Motise 8/4/95
DOC ID CNOTES95.w60
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HUMAN DRUG CGMP NOTES September, 1995
DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320
SUBJECT CONTACTS
Applications Integrity Policy
LuAnn Pallas 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
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
Data (Application) Integrity
Bruce Hartman 827-0062
LuAnn Pallas 594-0098
Dissolution Monica Caphart 594-0098
Russ Rutledge 594-1089
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
9
HUMAN DRUG CGMP NOTES September, 1995
DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320
SUBJECT CONTACTS (Continued)
Laboratory Issues John Levchuk 594-0095
Monica Caphart 594-0098
Russ Rutledge 594-1089
Lyophilization John Levchuk 594-0095
Manufacturing Changes
Supplements Walter Brown 594-1089
Medical Gases Duane S. Sylvia 594-0095
NDA/ANDA Pre-Approval
Inspections Bruce Hartman 827-0062
Randall Woods "
Penicillin Cross Contamination
Duane S. Sylvia 594-0095
PET Radiopharmaceuticals
(CGMP) John Levchuk 594-0095
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 Tony Lord 594-0095
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 "
Topical Drugs Randall Woods 827-0062
Videoconferencing Russ Rutledge 594-1089
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HUMAN DRUG CGMP NOTES September, 1995
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