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HUMAN DRUG CGMP NOTES
(Volume 3, Number 2)
June, 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:
- Is the sale of expired OTC drugs by a retailer a violation of the
Food, Drug and Cosmetic Act?
- Does FDA "prefer" polyvinylidene difluoride over stainless
steel for construction of recirculating loops in water for injection
(WFI) systems?
- What should manufacturers do if they have one of the "flawed"
Pentium(r) chips in their computerized systems?
- Cleaning Validation:
1) What is the level of detergent residue that would be
acceptable to FDA? What is the basis for arriving at this level, if
any?
2) If the ability of a procedure to clean a piece of equipment
made of a particular material, such as 316 stainless steel, is shown to
be acceptable and validated, can that "material" specific cleaning
procedure be used without "extensive" validation for other pieces of
equipment and compounds?
- Bulk Beat (Policy Questions on Bulk Drugs):
1) What is the current regulatory status of bulk pharmaceutical
chemicals in the United States?
2) What is the FDA doing to address the lack of GMP regulations
for BPC's?
- Gas What? (Policy Questions on Medical Gases):
1) What is pressure swing adsorption (PSA) and what are the
requirements for the nitrogen produced by PSA, if the product is used
HUMAN DRUG CGMP NOTES June, 1995
during the manufacture of a drug product, such as tablets, capsules,
etc.?
2) What's the current policy regarding the filling of a
vacationing patient's vessel, either high pressure cylinder or cryogenic
home vessel?
Final Rule on Cut Labeling Controls: Effective Date Partially Extended
Toward The Electronic Government:
- What is the status of the proposed rule on electronic signatures
and electronic records?
- CDER launches Internet gopher server.
Attachment:
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. Your FAX FEEDBACK responses are
still excellent 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, as several of you have
done. 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.
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 paper copies) 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, present 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
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HUMAN DRUG CGMP NOTES June, 1995
electronic mail .
If you would like to receive an electronic version of this document via
electronic mail, see the checkoff line in FAX FEEDBACK, or else send e-
mail to MOTISE, or DOCNOTES@FDACD.BITNET.
Thanks!
Paul J. Motise
POLICY QUESTIONS:
Is the sale of expired OTC drugs by a retailer a violation of the Food,
Drug and Cosmetic Act?
We have received calls from both FDAers and state agencies inquiring as
to what violation can be charged against a retailer found to be selling
expired OTC drugs. We have been told of instances where retailers were
found to be selling expired OTC drugs at a discounted price. Some
retailers apparently feel that as long as they openly disclose to
customers that the drugs being offered for sale are expired, they can be
sold legally. Some state and local agencies have indicated they lack
authority under their laws to pursue legal action against purveyors of
expired OTC drugs, and therefore seek support for a legal action under
the FD&C Act.
We regard expired drug products to be adulterated within the meaning of
Section 501(a)(2)(B) of the Food, Drug and Cosmetic Act, which states
that drugs must be manufactured, processed, packed, and held in
conformance with current good manufacturing practice. The holding of
drug products past their expiration dates supports the 501(a)(2)(B)
charge. It should be noted that it would not be appropriate to cite a
retailer for deviations from the CGMP regulations in 21 CFR Parts 210
and 211, because the CGMP regulations apply to drug product
manufacturers. Additionally, openly disclosing that the drugs are
expired is not any basis for an exemption from the Act. From a public
health standpoint, there is no assurance that drug products held past
their expiration dates are safe and effective, even if they are OTC
drugs.
Contact for Further Info: Barry Rothman, HFD-325, 301-594-0098, e-mail:
rothmanb@fdacd.bitnet.
Does FDA "prefer" polyvinylidene difluoride over stainless steel for
construction of recirculating loops in water for injection (WFI)
systems?
Reference: 21 CFR Sec. 211.65, Equipment construction, and Sec. 211.67,
Equipment cleaning and maintenance.
There is no official agency preference for one material over another.
Whatever material a firm selects for its water for injection system must
be suitable for the intended use. This holds true for virtually any
production equipment.
In the case of a WFI system, factors to consider in evaluating the
suitability of the piping would include interior smoothness, the ability
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HUMAN DRUG CGMP NOTES June, 1995
to withstand high temperatures and pressures, and the ability to hold up
to sterilizing and sanitizing agents.
As a general matter, equipment surfaces that contact components, in-
process materials, or drug products must not be reactive, additive, or
absorptive so as to alter the drug product's safety, identity, strength,
quality, or purity beyond its official or established requirements.
Contact for Further Info: John Levchuck,
HFD-322, 301-594-0095, e-mail: levchukj@fdacd.bitnet.
What should manufacturers do if they have one of the "flawed" Pentium(r)
chips in their computerized systems?
References: See 21 CFR Sec. 211.68, Automatic, mechanical, and
electronic equipment.
As covered by numerous press reports, certain early versions of
Pentium(r) processors, manufactured by Intel Corp. of Santa Clara, CA
since May of 1993, contain a defect that will cause incorrect results
if certain mathematical calculations are performed with computers
containing the Pentium(r) processor. The error happens when floating
point divide instructions use certain pairs of numbers. Intel has
undertaken a program to replace, without charge, defective Pentium(r)
processors with new Pentium(r) processors that do not contain the
defect.
During your inspections, you may encounter computer systems which
contain the Pentium(r) processor and which are being used to monitor or
control manufacturing or laboratory functions, within the context of
CGMP.
We expect firms to ensure that computer systems are suitable for their
intended use and that, as part of production or lab processes such
systems monitor or control, they have been covered by validation of
those processes. The Pentium(r) processors may be in personal computers
or in other automated systems. We expect firms to know what systems may
contain the processors in question (if they don't know, then equipment
vendors should be able to advise them).
Firms should replace defective processors as soon as possible, or, where
such replacement is impractical, firms should determine if floating
point divide instructions are used in the manufacturing or analytical
application. No immediate remedial action need be taken if floating
point divide instructions can't, under any circumstances, be performed
in that application.
If floating point divide instructions can be performed in a CGMP
application, firms should evaluate the application to determine if
potential errors will be detrimental to the process control or
analytical functions; firms should be mindful of possible errors caused
by compounding.
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HUMAN DRUG CGMP NOTES June, 1995
No immediate remedial action is necessary where firms determine that
potential errors are not detrimental . On the other hand, if firms find
that potential errors are detrimental and replacement of the defective
Pentium(r) processor is impractical, software designed to prevent the
errors should be installed. If appropriate remedial action cannot be
taken, manufacturers should stop using the equipment containing
defective Pentium(r) processors.
Where firms install a replacement processor or remedial software,
equipment should be qualified using appropriate validation methods. Of
course, we expect firms to thoroughly document their evaluations,
remedial actions and re-validation efforts.
Contact for Further Info: Paul J. Motise, HFD-323, 301-594-1089, e-mail:
motise@fdacd.bitnet.
Policy Questions on Cleaning Validation:
Reference: 21 CFR Sec. 211.67, Equipment cleaning and maintenance; and,
Guide to Inspections of Validation of Cleaning Processes, July 1993
(reformatted May 1994).
1) What is the level of detergent residue that would be acceptable
to FDA? What is the basis for arriving at this level, if any?
FDA has repeatedly stated that it is the firm's responsibility to
establish acceptance limits and be prepared to provide the basis for
those limits to FDA. Thus, there is no fixed standard for levels of
detergent residue. Any residues must not adversely alter drug product
safety, efficacy, quality, or stability.
2) If the ability of a procedure to clean a piece of equipment made
of a particular material, such as 316 stainless steel, is shown to be
acceptable and validated, can that "material" specific cleaning
procedure be used without "extensive" validation for other pieces of
equipment and compounds?
No. The design of the equipment is a major component of its
cleanability. Therefore, firms should have data that relate to a given
piece of equipment.
Contact for Further Info: Anthony Lord, HFD-322, 301-594-0095, e-mail:
lord@fdacd.bitnet.
Bulk Beat (Policy Questions on Bulk Drugs):
Reference: Guide to Inspection of Bulk Pharmaceutical Chemicals,
September, 1991.
1) What is the current regulatory status of bulk pharmaceutical
chemicals in the United States?
At present, the United States does not have a good manufacturing
practice regulation for bulk pharmaceutical chemicals. The CGMP
regulations promulgated under the Food, Drug, and Cosmetic Act
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HUMAN DRUG CGMP NOTES June, 1995
and codified in Title 21 of the Code of Federal Regulations, Parts 210
and 211, apply only to finished pharmaceuticals. Although the drug CGMP
regulations have been used as a general guide where applicable to BPC
processing, they were not intended to be applied to the production of
BPCs. The preamble to the September 1978 revision of the CGMP
regulations states:
"These CGMP regulations apply to finished dosage form drugs (under
Sections 210.3(b)(4) and 211.1) and are not binding requirements for
chemical manufacturing. The Commissioner maintains that these
regulations can serve as useful guidelines in the manufacture of
chemicals."
Nonetheless, the definition of "drug" in the Food, Drug, and Cosmetic
Act encompasses bulk pharmaceutical chemicals and Section 501(a)(2)(B)
of the Act also requires that all drugs be manufactured, processed,
packed, and held in accordance with CGMPs. No distinction is made
between BPCs and finished pharmaceuticals in the Act, and failure of
either to comply with CGMP constitutes a violation of the Act.
2) What is the FDA doing to address the lack of GMP regulations for
BPC's?
FDA recently formed a task group to develop a good manufacturing
practice regulation specific to bulk pharmaceutical chemicals and to
define acceptable approaches or "points-to-consider" when validating
BPC processes. This task group consists of representatives from the
Office of Regional Operations, the Office of General Counsel, CDER,
CBER, and CVM. We will provide additional details on this effort
in future editions of Human Drug CGMP Notes.
Contact for Further Info: Edwin Rivera, HFD-322, 301-594-0095, e-mail:
rivera@fdacd.bitnet.
Gas What? (Policy Questions on Medical Gases):
1) What is pressure swing adsorption (PSA) and what are the
requirements for the nitrogen produced by PSA, if the product is used
during the manufacture of a drug product, such as tablets, capsules,
etc.?
Reference: 21 CFR Sec. 211.110(a & c), Sampling and testing of
in-process materials and drug products.
We have received numerous inquiries regarding the use of PSA in the
manufacture of pharmaceutical drug products, where the nitrogen will be
used as a blanketing agent, etc.
The principle of PSA is where a stream of air is compressed, filtered,
and then passed through a molecular sieve which selectively adsorbs
oxygen, leaving the remaining process gas stream nitrogen rich. Some
units are capable of producing flow rates up to 100,000+ scfh and purity
levels as high as 99.9995% with purification.
If a firm is using PSA, then it should establish control procedures to
monitor the output and to validate the performance of those
manufacturing processes that may cause variability in the
characteristics of in-process material and the drug product. This would
also pertain to nitrogen received in large cryogenic vessels, i.e., tube
trailers, storage tanks, etc.
2) What's the current policy regarding the filling of a vacationing
patient's vessel, either high pressure cylinder or cryogenic home
vessel?
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HUMAN DRUG CGMP NOTES June, 1995
Reference: 21 CFR Sec. 211.84, Testing and approval or rejection of
containers and
closures; 21 CFR Sec. 211.94(c), Drug product containers and closures;
21 CFR Sec. 211.165(a), Testing and release for distribution.
This type of scenario, which is similar to the filling of a cryogenic
vessel at a patient's home, is considered an emergency need for the drug
product. If a patient is on vacation and/or traveling away from his/her
residence, and encounters a need for oxygen, then a firm would be
allowed to fill the patient's vessel without performing all the required
testing or all the required prefill inspections, provided 1) the firm
receives a prescription, 2) the patient remains at the firm, i.e.,
cannot leave the premises, 3) the employee who receives the vessel
performs the filling and returns it promptly to the patient, 4) the
incoming drug product has been tested and meets all specifications, and
5) the minimum visual inspections are performed, i.e., valve and
external examination, labeling, coloring, correct valve, etc. Finally,
the firm should obtain the patient's final destination including an
address and a telephone number, in case of a recall.
Contact for Further Info: Duane Sylvia, HFD-322, 301-594-0095, e-mail:
sylviad@fdacd.bitnet.
Final Rule on Cut Labeling Controls: Effective Date Partially Extended
Reference: 60 FR 20897, No. 82, April 28, 1995
In the above FR notice, FDA announced that the date for compliance with
Sec. 211.122(g) for items of labeling other than immediate container
labels is being extended to August 2, 1996. The date of compliance for
all other provisions of the final rule, as published in the Federal
Register of August 2, 1994 (at 59 FR 39255), remains the same.
The agency is taking this action in order to adequately assess comments
received on the scope of that rule.
Be aware that Sec. 211.125 makes a waiver of labeling reconciliation
conditional on a 100 percent examination for correct labeling performed
in accordance with Sec. 211.122(g)(2), meaning the labeling
reconciliation must still be performed until Sec. 211.122(g) is in
effect for labeling other than immediate container labels.
Division Contact for Further Info: Paul J. Motise, HFD-323,
301-594-1089, e-mail:
motise@fdacd.bitnet.
Toward The Electronic Government:
What is the status of the proposed rule on electronic signatures and
electronic records?
Reference: Federal Register, 59 FR 45160, No. 168, August 31, 1994.
The comment period for proposed Part 11 has closed and the agency has
begun its deliberations toward a final rule. A total of 49 respondents
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HUMAN DRUG CGMP NOTES June, 1995
submitted about 544 discrete comments. The agency-wide effort garnered
comments from virtually all FDA regulated industries, although the
pharmaceutical industry provided most of the comments.
The rulemaking project has been put on a fast track, as part of the
administration's reinventing government project.
While it is impossible to predict a final outcome, our best guess at
this point is that a final rule would not be published prior to the last
quarter of this calendar year.
CDER Launches Internet Gopher Server.
CDER recently inaugurated an Internet gopher (file retrieval facility)
server to help distribute electronic documents (including this
newsmemo). Internet savvy readers can point their gopher clients to
gopher.cder.fda.gov to see a simple menu structure of available files,
their formats and sizes. A typical menu entry for a file looks like
this (filename, date and time, size and file type):
hdcgmpw5.395 [13-Feb 12:52, 547KB] (PC Bin)
Downloading files from gopher is much easier than from FTP servers.
Typically, client applications call for you to position your cursor on
the line corresponding to the target file and then type the letter "s"
for save; programs generally let you rename the file for your local
system, and then the transfer begins.
CDER's strategic information technology plans call for the establishment
of a CDER World Wide Web server/home page, but that's still sometime
off.
All in all, the center is committed to distributing documents
electronically and using information technology to enhance communication
with field units, industry and the public.
Contact for Further Info: Paul J. Motise, HFD-323, 301-594-1089, e-mail:
motise@fdacd.bitnet.
P. Motise 5/9/95
DOC ID CNOTESW6.695 8
HUMAN DRUG CGMP NOTES June, 1995
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July 31, 1996
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