HUMAN DRUG CGMP NOTES

**(Volume 7, Number 2)**

# June, 1999

**(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:**

Policy Questions On:

-   ***Are there CGMP regulations or guidances specific to Botanicals?
    What other references are available?***

-   ***How often must manufacturers examine finished product reserve
    samples? Can FDA investigators visually examine a manufacturer's
    reserve samples?***

-   ***Is there a requirement specifying the level of light intensity
    when performing visual inspection of parenteral drug products for
    the presence of particulates?***

-   ***When should a firm perform a sterility re-test? How should a
    microbiology laboratory handle deviations during sterility
    testing?***

    Gas What! (Policy questions on medical gases)

-   ***1) NEW Compliance Aid On The Medical Gas Home Page
    \[http://www.fda.gov/cder/dmpq/gases.htm\] under Medical Gas
    Regulatory Actions***

-   ***2) Must firms validate use of non-USP testing methods for USP
    medical gases?"***

    On Stability:

-   ***Are manufacturers of excipient (inactive) components required to
    label the drugs with expiration or retest dates?***

    CGMP Sorites

    Toward The Electronic Government:

-   ***1) Under part 11, when a firm uses a contracted T1 line to a
    remote facility, is the system considered closed? Contrast this with
    communicating over the public Internet as being an open system.***

-   ***2) CPG on Y2K published***

CGMP Crossword Puzzle #2 (answer at http:/www.fda.gov/cder/dmpq)

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
great and we appreciate your suggestions and questions. In addition 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 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 memo is to enhance field/headquarters communications on
CGMP issues in a timely manner. This document 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 publication 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.

Thanks!

*Paul J. Motise*

POLICY QUESTIONS:

***Are there CGMP regulations or guidances specific to Botanicals? What
other references are available?***

Reference: FDA Guidance "Guideline For Submitting Supporting
Documentation in Drug Applications For The Manufacture of Drug
Substances", 2/87; FDA draft guidance, "Guidance For Industry, Botanical
Drug Products," 8/98

There are no regulations specific to Botanicals, per se, but there are
some applicable guidance documents. Botanicals are generally either
starting materials for the production of active pharmaceutical
ingredients or drug substances for use as ingredients in dosage forms.
In either case there are no applicable CGMP regulations for preparation
of Botanicals as components. Note that the CGMP regulations (21 CFR
Parts 210 and 211) do, however, apply to production of dosage forms that
incorporate botanical drug substances.

The agency has addressed factors that affect quality attributes of
Botanicals in the Guideline for Submitting Supporting Documentation In
Drug Applications. The document notes the following points:

> The description of the collection and preparation should include the
> botanical species and part of the plant. That is, what part of the
> plant contains the desired chemical. Is it the leaves, the roots, the
> fruits and berries, or the whole plant? Other factors which influence
> the quality or composition of the final product should be described.
> These should include: geographical location where the plant is grown,
> storage and transportation issues, drying conditions, and grinding
> conditions. Also, seasonal variations in active constituents may be an
> important factor in determining the best time for harvest.
>
> The description of the collection and preparation procedure should
> include the test method(s) for identity and assay for the drug
> substance in the original and crude material. Attention should be
> devoted to identification of impurities and minor components.

Be aware that an August 1998 draft guidance called "Guidance For
Industry, Botanical Drug Products" was published for comment. However,
this document addresses use of Botanicals in drug products for clinical
investigation.

As a point of information, USP monographs for active ingredients used in
drug products generally focus on single synthetic compounds. By
contrast, Botanicals generally consist of complex mixtures of active
ingredients that work in synergy. Traditionally, before Botanicals are
used in drug manufacturing it is important that the active ingredients
that provide the pharmacological properties be identified.

The USP has several monographs for Botanicals. These include Belladonna
Leaf, Opium, Senna, and Witch Hazel. Where such articles are not dosage
forms the CGMP regulations would not apply. Nonetheless, the general
CGMP provisions of Section 501(a)(2)(B) of the Act apply to the
manufacture of dosage form components regardless of whether or not those
substances are Botanicals. Keep in mind, though, that FDA has not
published regulations or guidance documents that address CGMPs for
dosage form components that are Botanicals.

Contact for further info: Brian G. Nadel, HFD-325, 301-594-0098; e-mail:
nadelb@cder.fda.gov

***How often must manufacturers examine finished product reserve
samples? Can FDA investigators visually examine a manufacturer's reserve
samples?***

Reference: 21 CFR 211.170(b), Reserve Samples; 211.192, Production
record review; 211.160, General requirements \[Subpart I, Laboratory
Controls\]

The CGMP regulations, at section 211.170, require that at least annually
manufacturers visually examine reserve samples from representative lots
of each drug product manufactured, unless such examination would affect
the integrity of the samples. This section also requires firms to use
acceptable statistical procedures in selecting the samples. (Note that
the regulation exempts medical gases, radioactive drug products, and
radioactive drug kits from the reserve sample retention requirement;
therefore, the examination provision would, of course, not apply to
those products.)

Per section 211.160, firms must have written procedures for those
reserve sample examinations.

Although section 211.170 specifies at least annual visual examination,
firms may themselves determine that for certain products, and under some
circumstances, a more frequent interval may be warranted. The regulation
gives manufacturers considerable leeway in this regard. For example, as
part of complaint or failure investigations performed in accordance with
section 211.192 (that requires a thorough investigation of any
unexplained discrepancy or failure of a batch to meet specifications), a
firm may, in addition to conducting an immediate examination of the
reserves, conclude that reserve samples for one or more products, or
particular lots of one or more products, merit more frequent visual
examination for a given period of time.

During inspections, investigators should not on a surveillance basis
routinely examine a manufacturer's reserve samples. However, on a for
cause basis, such as when investigating product contamination or
mix-ups, it may be appropriate for investigators to open and examine a
manufacturer's reserve samples. In those situations, if the manufacturer
produces evidence that such examination would affect the integrity of
its remaining reserve samples, an attempt should be made to examine
samples of the suspect products taken from other sources, such as
commercial inventories.

Contact for further information: Barry Rothman, HFD-325, 301-594-0098,
e-mail: rothmanb@cder.fda.gov

***Is there a requirement specifying the level of light intensity when
performing visual inspection of parenteral drug products for the
presence of particulates?***

Reference: 21 CFR 211.160 (b), Laboratory Controls, General Requirements

No. However, 21 CFR 211.160 (b) requires that laboratory controls
include the establishment of scientifically sound and appropriate test
procedures designed to assure that drug products conform to appropriate
standards of identity, strength, quality and purity. Accordingly, a test
method for the visual detection of particulates would be expected to
account for the intensity of the light as well as backgrounds that may
be needed for the adequate visual detection of particulates in the
finished drug product. We would assess, on a case by case basis, the
adequacy of a firm's determination of what levels of light would be
sufficient.

Contact for further information: Tracy Roberts, HFD-325, 301-594-0098,
e-mail: robertst@cder.fda.gov

***When should a firm perform a sterility re-test? How should a
microbiology laboratory handle deviations during sterility testing?***

Reference: 1987 Guideline on Sterile Drug Product Produced by Aseptic
Processing; USP 23, Section \<71\>, Sterility Tests; 21 CFR 211.22,
Responsibilities of quality control unit; 211.192, Production record
review; 211.160 General Requirements \[Subpart I, Laboratory Controls\]

The USP Sterility Test is limited in its ability to detect whether a
batch contains contaminated units. Finding any unit that exhibits growth
is a serious matter, and the subsequent investigation is generally quite
involved and covers both the laboratory and production areas. The drug
product lot fails the USP test requirement if any microbial growth is
found and the test is not invalidated. The USP (Supplement 8) states
that a firm should not perform a sterility re-test without evidence that
the sterility test positive can be attributed to contamination
introduced by the laboratory. Further, the 1987 Aseptic Guideline
explains that a batch should not be released without clear documented
evidence that the contamination occurred during testing.

It is difficult to justify invalidation of an initial sterility positive
result. For example, the presence of any specific microorganism in both
the test sample and the sterility testing environment would not alone
rule out the aseptic manufacturing operation as the origin of the
contamination. A comprehensive evaluation of manufacturing and testing
operations, as well as multiple trending reports (e.g., long term trends
at specific environmental monitoring locations) which can be revealing,
would be consistent with section 211.192 of the CGMP regulations.
Because of the low sensitivity of sterility testing, a finding of no
growth during retesting should be afforded minimal weight relative to
other parts of the investigation.

In summary, a high threshold of justification is needed for a decision
to invalidate a sterility test positive result and perform re-testing.
When investigations into the origin of the product\'s contamination are
inconclusive, the decision to release or reject the batch should err on
the side of patient safety.

Per section 211.160 of the CGMP regulations, when deviations occur
during sterility testing, they should be documented concurrent with the
test, investigated, and remedied. As explained in the 1987 guideline,
such deviations should be trended, with corrective measures taken in a
timely manner. If any of these deviations may have compromised the
integrity of the sterility test, it would be consistent with CGMP not to
proceed with the test. For example, if asepsis is compromised during
sample manipulation, then samples should not be incubated. Finally, it
is important to note that an unreliable laboratory is an objectionable
condition that underscores the need to err on the side of safety when
investigating a sterility positive rather than risk overlooking a
genuine production problem.

Contacts for further information: Richard L. Friedman, HFD-322,
301-594-0095; e-mail: friedmanr@cder.fda.gov; Tracy Roberts, HFD-325,
301-594-0098, e-mail: robertst@cder.fda.gov

**Gas What! (Policy questions on medical gases)**

***1) NEW Compliance Aid On The Medical Gas Home Page***

***\[http://www.fda.gov/cder/dmpq/gases.htm\] under Medical Gas
Regulatory Actions***

The Division of Manufacturing and Product Quality and the Division of
Compliance Management Operations has compiled, and posted to the
Internet at the above address, a listing of all medical gas warning
letters issued for Fiscal Years 1993 to the present.

This list was developed to assist the field in determining if a facility
or multiple site corporation received prior notice and whether more
severe regulatory enforcement may be warranted (i.e., seizure,
injunction, etc.) on a corporate wide basis.

It would be inappropriate to issue consecutive warning letters (i.e.,
back to back) to the same location or to multiple sites of the same
corporation. Such issuances would be contrary to the Regulatory
Procedures Manual (RPM), Chapter 4, Warning Letters, under Follow-up
Enforcement Action (page 82, August 1997 Revision). Note that the RPM
states that post warning letter regulatory actions should include
seizure, injunction, etc., but not another warning letter.

Firms having multiple sites that have received warning letters may also
use this information to signal that they may need to make corporate wide
CGMP corrections.

***2) Must firms validate use of non-USP testing methods for USP medical
gases?***

Reference: 21 CFR 211.160, General requirements \[Subpart I, Laboratory
Controls\]; 211.165(e), Testing and release for distribution; 211.194,
Laboratory records

Yes. The CGMP regulations, at sections 211.165(e) and 211.194(a)(2),
require a firm or individual utilizing a non-U.S.P. testing methodology
to perform a validation study establishing and documenting the accuracy,
sensitivity, specificity, and reproducibility of the test method
employed.

This would include paramagnetic analyzers, handheld analyzers, pressure
differential methods, etc.; all would be required to undergo validation.
In addition, any firm using one of these non-U.S.P. testing methods must
have complete documentation, per 211.194, for the entire validation
study, not just the data.

Contact for further information: Duane Sylvia, HFD-325, 301-594-0095,
e-mail: sylviad@cder.fda.gov

**On Stability**

Are manufacturers of excipient (inactive) components required to label
the drugs with expiration or retest dates?

Reference: Guide To Inspection of Bulk Pharmaceutical Chemicals, 9/91;
Inspection Technical Guide #41, Expiration Dating and Stability Testing
for Human Drug Products, 10/18/85; FD&C Act, Section 501(a)(2)(B)

Expiration or retest dates are not a CGMP requirement for all
excipients, and generally their absence from excipients is not
objectionable.

Assigning an expiration date or a retest date to bulk pharmaceutical
chemicals is not required by the CGMP regulations because the
regulations are applicable to the manufacturing of finished
pharmaceuticals (i.e., dosage forms.)

In the broader context of section 501(a)(2)(B) of the FD&C Act, the
excipient manufacturer would have to implement controls to ensure that
the drug has the identity and strength, and meets the quality and purity
characteristics that it purports or is represented to possess. The
chemical stability of the excipient would be relevant in this context.

In determining the need for an expiration or retest date it would be
important for the manufacturer to begin with some baseline information
about the relative stability of the drug. That information may be found
in scientific literature. For example, although most excipients are
known to be chemically inert, others, such as certain preservatives and
antioxidants, can be expected to have a limited shelf-life.

Where stability information about the drug is absent, or indicates that
one may expect a relatively limited shelf life, it would be feasible and
valuable for the firm to perform stability studies. It would be
consistent with CGMP for those studies to support a labeled expiration
or retest date.

Contact for further information: Barry Rothman, HFD-325, 301-594-0098,
e-mail: rothmanb@cder.fda.gov

**CGMP Sorites**

Reference: 21 CFR 211.186, Master production and control records

Sorites are, in fact, extended syllogisms (i.e., series of syllogisms.)
The most basic syllogism is a categorical syllogism. This is a valid
logical argument relating three categories (i.e., sets or classes) in
three propositions. These three categories are two premises and a
conclusion.

In the following simple syllogism, the concept of set inclusion will be
demonstrated. An example of set inclusion is when all members of one
set/class are included in another set, whose members are then included
in a third set. By virtue of the form of this argument, it follows
necessarily that any member of the first set is a member of (or included
in) the third set. This is known as a valid argument.

Notice as you solve this syllogism, how you need to identify the subject
and predicate of each proposition, in essence identifying the sets.
Furthermore, take note that each subject and predicate are each a set.

Now try the following CGMP syllogism.

\- Proposition -- As required by 21 CFR 211.186, all batch to batch
uniformity (bbu) shall be assured by the preparation of master
production (pmp) and control records (i.e., the preparation, dating and
signing by one person and the independent checking, dating and signing
by a second person.)

\- Proposition -- As required by 21 CFR 211.186, the preparation of
master production and control records shall be described (i.e., assured)
in a written procedure (wp) and followed.

The conclusion appears after the last article in this edition of the
notes.

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

**Toward the Electronic Government**

***1) Under part 11, when a firm uses a contracted T1 line to a remote
facility, is the system considered closed? Contrast this with
communicating over the public Internet as being an open system.***

Reference: 21 CFR 11.3(b)(4) and (9), Definitions; paragraphs 41 and 44
of the 3/20/97 final rule Federal Register Notice, Electronic Records,
Electronic Signatures (62 FR 13430 at 13440 and 14331)

In classifying a system as open or closed, a firm needs to determine if
it controls access to the system that holds records for which it is
responsible. Lacking such control, its records could be vulnerable to
unauthorized disclosure or modification; trade secret and confidential
information may be at risk. Therefore, firms may wish to put into place
added record protections such as encryption. Part 11 does not mandate
those added controls in all cases, but rather permits firms to make that
decision for themselves based on the circumstances. How well a firm
safeguards its records may reflect the degree to which it regards the
information as trade secret.

Let's assume that the firm is responsible for the content of the records
in question and that the remote facility holds the firm's records.
First, we need to consider if the communications line to the facility
uses store and forward technology, meaning the records are stored on one
or more servers before arriving at the remote facility. If the firm
controls who can access those intermediate holding systems as well as
the remote facility itself, the records would be in a closed system from
the firm's perspective. On the other hand, if the firm does not control
access to either those intermediate holding systems or the final remote
facility, the system would be open. Faced with an open system, the firm
would need to evaluate the circumstances (such as the contents of the
records themselves) and decide if added controls were warranted.

On the Internet, store and forward technology is customary, and the firm
would not control access to servers that held its records (i.e., the
system would be open.)

***2) CPG on Y2K published***

Reference: Compliance Policy Guide (CPG), Sub Chapter 160 -- Regulatory,
Section 160-800 Year 2000 (Y2K) Computer Compliance; 21 CFR Part 7,
Enforcement Policy

On April 26, 1999 the subject CPG was issued. It represents current
agency thinking on FDA regulated products that may not perform properly
before or during the transition to the year 2000. The CPG notes that
most FDA regulated products are vulnerable to Y2K computer problems. (In
the drug CGMP arena, examples include inaccurate computations of
expiration dates, erroneous scheduling of equipment maintenance, and
certain process control problems.)

The CPG makes the follow key regulatory points.

> 1\. Because lack of Y2K compliance is not in and of itself a violation
> of FDA regulation, it would be inappropriate to list such a condition
> as an FDA 483 observation. However, it is proper to list observations
> regarding specific processes or product deficiencies related to Y2K.
>
> 2\. When an FDA regulated product held for sale or in commercial
> distribution is relabeled, returned, reprocessed, repaired, or
> replaced to resolve a product problem caused by Y2K before that
> problem is manifest, the action will be considered a market withdrawal
> (21 CFR 7.3(j)), not a recall. Conversely, the action will be
> considered a recall (21 CFR Part 7, Subpart C) if the regulated
> product manifests the problem before the correction or removal is
> completed. For example, the action would be a recall where a drug
> product labeled with the wrong expiration date is recovered from the
> market.
>
> 3\. The agency may exercise enforcement discretion and consider
> unusual or extenuating circumstances bearing on each enforcement
> decision.
>
> 4\. Factors to consider in pursuing regulatory actions include:
>
> \(a\) Public health risks;
>
> \(b\) impact on product quality;
>
> \(c\) availability of critical use products and their substitutes to
> meet public health needs;
>
> \(d\) the adequacy of the firm's Y2K mitigation plans and efforts;
> and,
>
> \(e\) where violative products enter the market, identification of
> those firms that hold responsibility for taking Y2K preventive
> measures before the products were released for distribution.
>
> 5\. Districts should, as appropriate, consult with respective center
> program monitors before recommending regulatory actions, and should
> get monitor concurrence for warning letters regarding Y2K.
>
> 6\. Regulatory citations should reference the underlying regulations
> and statutes involved in the product or process deficiency.

Contact for further information: Paul J. Motise, HFD-325, 301-594-0098,
e-mail: motise@cder.fda.gov

Conclusion to CGMP sorities:

All batch to batch uniformity shall be assured by written procedures
that are followed.

Notice the form - all BBU is PMP; all PMP is WP; therefore all BBU is
WP.

P. Motise 06/01/99

DOC ID CNOTES69.doc

**CGMP Puzzle #2**

![](media/image1.png){width="3.685416666666667in"
height="3.685416666666667in"}

**Across**

1 Cookie man

5 Photosynthesis organ

9 Kind of pepper

14 Controlled area cover up

15 Sailor\'s patron saint

16 Practice

17 Quechua

18 Arabian gulf

19 Ponder

20 Soviet dictator

22 HFR-MW3594\'s turf

24 Kind of recall, briefly

25 They surround gelatin

28 Body fluids

29 Core garment

33 Partners to p/ws

36 Russian parliament

39 It\'s drainless at core

40 210/211 apply to them

44 Macabre

45 First name in scat

46 D.C. in March

47 It could be hidden

49 Hence

52 Beneath the surface

58 Hood\'s home

61 Type of culture

62 Snuggle

63 High

65 Scratch

67 Ms. Ferber

68 Two time Nobelist (chemistry and physics)

69 With 12 down, cleanroom garb characteristic

70 Kind of ticket

71 Revise

72 Sampling ports

73 War god

**Down**

1 Anabaptist sect

2 Horse blanket, in Madrid

3 Movie prize

4 Viking poets

5 Mona\'s man?

6 Shade tree

7 Gather

8 Hot dip

9 Suffocate

10 Chance

11 Egyptian flyer

12 Navel collection?

13 483 follower

21 Cool

23 Cleric robe

26 It\'s sometimes pregnant

27 Alone

30 Pulled apart

31 Field refs.

32 Formerly, formerly

33 It could be bright or big

34 Fermentation sediment

35 Positive

37 Bad in Paris

38 Part of 58 down

41 Deseeds cotton

42 Took away

43 Otological woes

48 He\'s on 64 down

50 Antelope

51 Swelling

53 Split

54 Extreme

55 More unusual

56 Arm bones

57 They could be official

58 It\'s generally not on 29 across

59 Astringent ingredient

60 Caliber

64 Two make ten

66 Mushroom

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