.@)

3.

6.

What is the purpose of periodic analysis requirement for test or
control article mixtures?

This requirement provides additional assurance that the test system
is being exposed to protocol-speci fied quantities of test article.
Whereas, in most instances proper assurance is obtained through
adequate uniformity-of-mixing studies, adequate SOPs, and trained
personnel, occasionally the mixing equipment can malfunction or other
uncontrollable events can occur which lead to improper dosages.
These events can be recognized through periodic analysis.

For acute studies, does the test article carrier mixture have to be
analyzed (single dose studies)?

Yes, but the analysis need not be done prior to the study provided
the mixture is stable in storage.

For liquid dosing studies where the test article mixture is made by
dilution of the highest dose, which dose should be analyzed?

The lowest dose would be appropriate since it would confirm the
efficacy of the dilution process, however the GLPs do not prohibit
the analysis of any of the other doses.

Do homogeneity studies need to be done on solutions and suspensions
of test articles used in acute nonclinical laboratory studies?

The answers to these questions are yes for suspensions of test
articles and no for true solutions of test articles.

The analysis of test article mixtures that are used in acute studies
is problematic. Usually at the stage of product development, the
analytical method is not fully developed. Also, getting the
analytical department to schedule the analysis is difficult.
Stability is not a problem since fresh solutions are used. In view
of the fact that acute studies are not pivotal in gaining approval of
a research or marketing permit, is it necessary to analyze test
article mixtures?

Yes. Although acute studies may be of lesser importance in assessing
the safety of human drugs, they are important for animal drugs,
biological products and certain food additives. For this reason,
there must be some assurance that the test system was dosed with
protocol specified quantities of test article. The GLPs do not
require that the analysis be done prior to the use of the test
article mixture provided that the mixture is stable on storage.

- 19 -


SUBPART D
EQUIPMENT

Section 58.61 Equipment design.

No questions were asked on the subject.

Section 58.63 Maintenance and calibration of equipment.

1.

Has FDA established guidelines for the frequency of calibration of
equipment (balances) used in nonclinical laboratory studies?

The agency has not established guidelines for the frequency of
calibration of balances used in nonclinical laboratory studies. This
would be a large undertaking in part due to the wide variety of
equipment that is available and to the differing workloads that would
be imposed on the equipment. It is suggested that you work with the
equipment manufacturers and your study directors to arrive at a
suitable calibration schedule. The key point is that the calibration
should be frequent enough to assure data validity. The maintenance

and calibration schedules should be part of the SOPs for each
instrument.

When an equipment manufacturer performs the routine equipment
maintenance, do the equipment manufacturer's maintenance procedures
have to be described in the facilities’ SOPs?

No. The facilities’ SOPs would have to state that maintenance was

being performed by the equipment manufacturer according to their own
procedures.

SUBPART E
TESTING FACILITIES OPERATION

Section 58.81 Standard Operating Procedures.

1.

What amount of detail should be included in the standard operating
procedures (SOPs)?

The GLPs do not specify the amount of detail to be included in the
SOPs. The SOPs are intended to minimize the introduction of
systematic error into a study by ensuring that all personnel will be
familiar with and use the same procedures. The adequacy of the SOPs
is a key responsibility of management. A guideline of adequacy that
could be used is to determine whether the SOPs are understood and can
be followed by trained laboratory personnel.

-13-


Do the GLPs require the entry of raw data into bound notebooks?
No.

Is it acceptable to manually transcribe raw data into notebooks if it
is verified accurate by signature and date?

Technically the GLPs do not preclude such an approach. It is not a
perferred procedure, however, since the chance of transcription
errors would exist. Accordingly, such an approach should be used
only when necessary and in this event the raw data should also be
retained.

SUBPART J
RECORDS AND REPORTS

Section 58.185 Reporting of nonclinical Jaboratory study results.

1.

Do contributing scientist's reports have to be prepared and appended
to final reports or can the contributing scientist's report be
included in the final report prepared by the study director and
signed by each contributing scientist?

The signed reports of contributing scientists should be appended to
the final report.

Does Section 58.115(a) describe the format for submission of a final
report? .

The cited section describes the information that has to be submitted
in a final report but the specific format is left up to the
laboratory.

Do all circumstances that may have affected the quality of the data
have to be described in the final report?

Yes.

Who approves the final report of a nonclinical laboratory study?

The GLPs do not address the issue of approval of the final report.
According to the GLPs, the final report is official when it is signed
and dated by the study director. If persons reviewing the final

report request changes, then such changes must be made by way of a
formal amendment.

-3-


4,

A laboratory conducts animal studies to establish a baseline set of
data for a different test species/strain. No test article is
administered but the toxicology \aboratory facilities and procedures
will be used and the resulting data may eventually be submitted do
the agency. as part of a research or marketing permit. Are the
studies considered to be nonclinical laboratory studies that are
covered by the GLPs?

Generally, a nonclinical laboratory study involves a test article
studied under laboratory conditions for the purpose of determining
its safety. The cited example does not fit the definition so it
would not be covered by the GLPs. Since the data fran the baseline
studies may be used to interpret the results of a nonclinical
laboratory study, it is recommended, but not required, that the study
be conducted in accord with GLPs in order to ensure valid baseline
data.

The definition of “nonclinical laboratory study" excludes field
trials in animals. What is a field trial in animals? ~

A field trial in animals is similar to a human clinical trial. It is
conducted for the purpose of obtaining data on animal drua efficacy
and it is excluded from coverage under the GLPs.

Necrapsies are done by prosectors trained by and working under the
supervision of a pathologist. The necropsy data are recorded by the
prosector on data sheets, and when making the final report, the
pathologist summarizes the data collected by the prosector as well as
by him/herself. What constitutes the raw data in this example?

Both the prosector's data sheets as well as the signed and dated
report of the pathologist would be considered raw data.

Is a computer print-out derived from data transferred to computer
media from laboratory data sheets considered to be raw data?

No.

Are the assay plates used in the 10t1/2 mammalian cell transformation
assay considered to be specimens?

Yes.

If a firm uses parapathologists to screen tissue preparations, are
the parapathologists' data sheets considered to be raw data?

Yes.


SUBPART G
PROTOCOL FOR THE CONDUCT OF A NONCLINICAL LABORATORY STUDY

Section. 58.120 Protocol.

1.

What are the proposed starting and completion dates for a nonclinical
laboratory study?

There is a good deal of confusion on these dates and proper
interpretation impacts on several GLP areas. Accordingly, the
following clarification is offered: At the time of protocol
development, the study director is to propose to management the
approximate time frame of the study. Section 58.120(a)(4),
therefore, requires that the protocol contain the proposed starting
and completion date of the study. These dates are somewhat
discretionary provided that They are identified in the protocol.
Suitable identification can be the date of first dosing of the test
system to the date of last dosing, the date of allocation of the test
system to the experimental units to the date of necropsy of the last
animal on test, the date of receipt of the test system to the date of
final histopathological examination, or any combination of these or
any other logical starting and completion dates. After this, the
protocol is signed by the study director and forwarded for approval
to management. Management approves, if indicated, signs and dates
and at this point the study becomes a regulated study and must be
entered on the Master Schedule Sheet. The study is carried on the
Master Schedule Sheet until the study director submits a signed and
dated final report. Thus, for Master Schedule Sheet purposes, the
starting date of the study is the date of protocol approval by
management and the completion date of the study is the date of
signature of the final report by the study director. Neither of the
foregoing timeframes need be used to define the study terms described
jin section 58.35(b)(3) and section 58.105(d). For these sections,
the traditional terms found in the toxicology literature may be

used.

Must an analytical method be totally contained in the protocol?

No. The protocol must state the type and frequency of tests to be
made. Type can be connoted by reference to literature citations or
the SOPs as applicable.

Does each nonclinical laboratory study require a sponsor-approved
specific protocol?

Yes. However, the laboratory that conducts the study can al so
qualify as the sponsor of the study.

- 20 -


CONFORMING AMENDMENTS

Do acute studies not done in conformity with the GLPs have to be
identified in the conforming amendment statement?

Yes.

How extensive should the conforming amendment statement be for
preliminary exploratory studies that are exempt from GLP coverage?

The statement should be brief and indicate the GLP-exempt status of
the study.

For contracted nonclinical laboratory studies, who is responsible for

preparing the GLP compliance statement required by the conforming
amendments?

The preparation of the conforming amendment statement is the
responsibility of the product sponsor and the statement should be
submitted as part of the application for a research or marketing
permit. The contractor, however, should {identify for the sponsor
those non GLP practices which were used in each nonclinical
laboratory study so that a proper conforming amendment statement can
be prepared.

Who signs the conforming amendment statement?

This can be the same individual in the firm who signs the official
application for a research or marketing permit.

Is a specific conforming amendment statement as required by Part
314(f)(7) to be prepared for each nonclinical laboratory study?

Yes. GLP deviations have to be identified for all nonclinical
laboratory studies. This can be done by preparing a single
comprehensive statement which includes all safety studies in the
respective official filing. The conforming amendment statement in
the official filing should be located in proximity to the animal
safety studies section.

-26 -


oO

Section 58.130 Conduct of a nonclinical laboratory study.

1.

Does raw data collected in nonclinical laboratory studies have to be
cosigned by a second individual.

No.

What are the GLP requirements that are applicable to computerized
data - acquisition systems? .

An acceptable system must satisfy the following criteria:
(1) Only authorized individuals can make data entries,
(2) data entries may not be deleted, but changes may be made in
the form of dated amendments which provide the reason
for data change,

(3) the data base must be made as tamperproof as possible,

(4) the SOPs should describe the procedures used for ensuring
the validity of the data, and

(5) either the magnetic media or hard-copy printouts are
considered to be raw data.

In Japan, employees do not sign raw data records but rather they use
an official seal which is unique to the employee. Is this an
acceptable procedure?

Yes.

Do tissue slides have to carry the complete sample labeling
information stated in the GLPs?

No, accession numbers are permitted providing that these numbers can
be translated into the information required under Section §8.130(c).

Is a positive notation (a statement of what was done in the raw data)
required for routine laboratory operations such as:

(a) identifying animals,

(b) shaving or abrading rabbits,
(c) specific dosing procedures, and
(d) fasting of animals?

Yes.

~ 99 -


12.

13.

14.

15.

Japanese guidelines that are similar, but no less stringent, in the

important particulars with the NIH guidelines would be acceptable to
FDA.

What is the frequency of feed contaminant analysis?

If contaminant analyses are required by the protocol, then the GLPs
require perfodic analysis of the feed to ensure that the contaminant
level is at or below that judged to be acceptable. Statistical
procedures should be used to determine the frequency of analysis
since this is dependent on the specific chemical characteristics of
the interfering contaminant.

It is necessary to use “official” methods of analysis to determine
the levels of interfering contaminants?

No. The methods should be appropriate for the analysis and FDA
reserves the right to examine the raw data supporting the analytical
results. .

Do the GLPs require production facilities to be dedicated to the
manufacture of specific animal feeds used in nonclinical laboratory
studies?

No.

Is a separate room required for animal necropsy?

No. The GLPs require separate areas and/or rooms as necessary to
prevent any activity from having an adverse effect on the study. If

the necropsy is done in an animal room, precautions should be taken
to minimize disturbances that may interfere with the study.

SUBPART F
TEST AND CONTROL ARTICLES

Section 58.105 Test and control article characterization.

1.

Is it necessary to retain samples of feed from nonclinical laboratory
studies in which the feed serves as the control article?

Yes. It is not necessary, however, to retain reserve samples of feed

from studies that involve test article administration by routes other
than feed.

-17-


SUBPART B
ORGANIZATION AND PERSONNEL

Section 58.29 Personnel.

1. For what sequence in the supervisory chain should position
descriptions be available?

Position descriptions should be available for each individual engaged
in or supervising the conduct of the study.

2. Should current summaries of training and experience list attendance
at scientific and technical meetings?

Yes. The agency considers such attendance as a valuable adjunct to
the other kinds of training received by laboratory personnel.

3. If certain specialists (pathologists, statisticians,
ophthalmologists, etc.) are contracted to conduct certain aspects of
a study, need they be identified in the final report?

Yes.

4. Does the QAU have to be composed of technical personnel?
No. Management is, however, responsible for assuring that “personnel
clearly understand the functions they are to perform" (Section
&8.31(f)) and that each individual engaged in the study has the
appropriate combination of education, training and experience
(Section 58.29(a)).

Section 58.31 Testing Facility Management.

1. Can the study director be the chief executive of a nonclinical
Jaboratory?

No. The GLPs require that there be a separation of function between
the study director and the QAU director. In the example, the QAU
director would be reporting to the study director.

Section 58.33 Study director.

1. The GLPs permit the designation of an “acting” or “deputy” study
director to be responsible for a study when the study director is on
Jeave. Should study records identify the designated “deputy” or
“acting” study director?

Yes.

9 -


Must a sponsor reveal toxicology data already collected on a test
article to a contract laboratory?

Ho. If use of the test article involves a potential danger to
laboratory personnel, the contract laboratory snould be aavised so
tnat appropriate precautions can de taken.

Section 58.15 Inspection of a testing facility.

l.

What is the usual procedure for the issuance of a form FD-483?

The FD-483 is the written notice of objectionable

practices or deviations from the regulations that is prepared by the
FOA investigator at the end of the inspection. The items listed on
the form serve as the basis for the exit discussion with laboratory
management at which time management can either agree or disagree with
the items and can offer possible corrective actions to be taken.
Management may also respond to the district office in writing after
it fas had sufficient time to properly study the FO0-483.

Will a laboratory subsequently be notified of GLP deviations not
listed on the FD-483?

This does happen. The FDA investigator prepares an establishment
inspection report (EIR) which summarizes the observations made at the
laboratory and which contains exhibits concerning the studies audited
(Protocols, SOPs, CV's, etc.). The EIR is then reviewed by District
personnel as well as headquarters personnel. This review may reveal
additional GLP deviations that should be and are communicated to
laboratory management.

What kinds of domestic toxicology laboratory inspections does FDA
perform and how frequently are they done?

FDA performs four kinds of inspections related to the GLPs and
nonclinical laboratory studies. These include: A GLP inspection -
an inspection undertaken as a periodic, routine determination of a
laboratory's compliance with the GLPs, it includes examination of an
ongoing study as well as a completed study; A data audit - an
inspection made to verify that the information contained in a final
report submitted to FDA is accurate and reflected by the raw data; A
directed inspection - any of a series of inspections conducted for
various compelling reasons (questionable data in a final report, tips
from informers, etc.); A followup inspection - an inspection made
sometime after a GLP inspection which revealed objectionable
practices and conditions. The purpose of the followup inspection is
to assure that proper corrective actions have been taken. GLP

inspections are scheduled once every two years whereas the other
kinds of inspections are scheduled as needed.

-6-


Section 58.10 Applicability to stucies performed under grants and

1.

contracts.

Certain contracts specify that a series of nonclinical laboratory
studies be-done on a single test article. Oo the GLPs permit the
designation of different study directors for eacn study under the
contract?

Yes.

Do the GLPs require that a sponsor approve the study director for a
contracted study?

No. Testing facility management designates the study director.

A firm functions as a primary contractor for nonclinical laboratory
studies. The actual studies are then subcontracted to nonclinical
jaboratories. Is the firm considered to de a “sponsor?”

The GLPs define “sponsor” as a person who initiates and supports 4
nonclinical laboratory study. Sponsorship in the cited example would
be determined by the specific provisions of the contract.

Who is responsible for test article characterization - the sponsor or
the contractor?

The GLPs do not assign the responsibility in this area. The matter
is a subject of the specific contractual arrangement between the
sponsor and the contractor.

Do contract laboratories have to show the sponsor's name on the
Master Schedule Sheet or can this information be coded?

The information can be coded but the code must be revealed to the FDA
investigator on request.

A sponsor desires to contract for a nonclinical laboratory study to
be conducted in a foreign laboratory. Must the sponsor notify the
foreign laboratory that compliance with the U.S. GLPs is required?

Yes.

Must a contractor include in the final report information on test
article characterization and stability when such information has been
collected by the sponsor?

No. The contractor should identify in its final report which
information will be subsequently supplied by the sponsor.


What expiration date is placed on the label of test articles whose
stability is being assessed concurrently with the conduct of the
study?

In this.situation, the stability of the test article is unknown, but
periodic analysis data exist. The label should contain a statement
such as “see protocol” or “see periodic analysis results" so that
test article users will know that current analytical data should be
examined prior to continued use of the test article.

If analysis of the reserve samples is required by the Study Director
or the QAU, is it permitted?

Yes, but sufficient reserve sample should be retained so that the
sample is not exhausted.

Are physical and chemical tests conducted on test articles required
to be done under the GLPs?

According to section 58.105, such tests conducted to characterize the
specific batch of test article used in the nonclinical laboratory
study are covered.

Section 58.107 Test and control article handling.

1.

With regard to safety studies in large animals (cattle, horses,
etc.), must test article accountability be maintained and can the
animals be used for food purposes?

Test article accountability must be maintained. For guidance on
whether the treated animals can be used for food, you should contact
the appropriate individuals in the Bureau of Veterinary Medicine.

Section 58.113 Mixtures of articles with carriers.

1.

Do the GLPs require tests for homogeneity, concentration, and
stability on mixtures of control articles used as positive controls?

Yes.

Do test or control article concentration assays have to be performed
on each batch of test or control article carrier mixture?

No. The GLPs require only periodic analysis of test or control
article carrier mixtures.

- 18 -


10.

ll.

12.

(a) The GLP regulations;

(b) The Management Briefings Post-Conference Report;

(c) Assorted memoranda and policy issuances;

(d) The GLP Compliance Program;

(e) The protocol of an ongoing study, if available;

(f) The final report of a completed study, if available;
(g) The inspection report of the most recent inspection.

How long does FDA allow a laboratory to effect corrective actions
after an inspection has been made?

If the results of an inspection reveal that significant deviations
from the GLPs exist, the laboratory will be sent a regulatory letter
that lists the major deviations and that requests a response within
10 days. The response should describe those actions that the
laboratory has taken or plans to take to effect correction. The
response should also encompass items that were listed on the FD-483
and those that were discussed during the exit discussion with
Jaboratory management. A specific time table should be given for
accomplishing the planned actions. The reasonableness of the time
table will be determined by FDA compliance staff, based on the needs
of the particular situation.

For less significant deviations, the laboratory will be sent a
Notice of Adverse Findings letter that also lists the deviations but
that requests a response within 30 days. Again, the reasonableness
of the response will be determined by FDA staff.

Does a laboratory's responsibility for corrective action listed on a
FD-483 begin at the conclusion of an inspection or upon receipt of
correspondence from the originating bureau in which corrective
action is requested?

The FD-483 lists observations of violative conditions that have the
capability to adversely affect nonclinical laboratory studies.
Corrective actions should be instituted as soon as possible.

Does FDA preannounce all GLP inspections?

Laboratory management is informed of all routine GLP inspections

prior to the inspection, but special compliance or investigative
inspections need not be preannounced.

-8-


Can the chemistry information required by Section 58.185(a)(4) be
located elsewhere in the application for a research or marketing
permit?

Yes. The final report should, however, reference the location of the
chemistry information.

Does everyone who participated in a study have to be identified in
the final report?

No. The final report need identify only the name of the study
director, the names of other participating scientists, and the names
of all supervisory personnel.

Does the phase of the study which has been inspected need to be
identified in the QAU statement in the final report?

No.

How are protocol deviations which are discovered after the completion
of the study to be handled?

The deviations should be described in the final report and in the
study records.

How does the agency view interim reports of nonclinical laboratory
studies?

Interim reports are to be treated the same as final reports, i.e.

they are to be reviewed by the QAU so that the summarized data
accurately reflects the raw data.

Section 58.190 Storage and retrieval of records and data.

1.

Certain raw data records are not study specific (pest control,
instrument calibration). Must these be filed in the archives in each
study file?

No. These can be filed in a retrievable fashion such as
chronological in the archive.

Where should the QAU records be retafned?

At the completion of a study, QAU records and inspection reports
should be retained in the archives. :


CENTER For DruG EvALuaTION AND RESEARCH

Guidance for Industry

The FDA published Good Guidance Practices in February 1997.
This guidance was developed and issued prior to that date.

Additional copies are available from:
Office of Training and Communications
Division of Communications Management

Drug Information Branch, HFD-210

5600 Fishers Lane
Rockville, MD 20857

(Tel) 301-827-4573
(Internet) http://www fda. gov/cder/guidance/index.htm

U.S. DeparTMENT oF HEALTH AND HuMAN SERVICES, Foop AND DruG ADMINISTRATION



10.

ll.

May the QAU in its periodic reports to management and the study
director recommend actions to solve existing problems?

Yes.

If raw data are transcribed and sent to the sponsor for (a) preparing
the data in computer format or (b) performing a statistical analysis,
what are the responsibilities of the QAU?

For (a) the QAU should assure that the computer formatted data
accurately reflect the raw data. For (b) the statistical analyses
would comprise a report from a participating scientist, therefore it
should be checked by QAU and appended to the final report.

Can the QAU also be responsible for maintaining the laboratory
archives?

Yes.
Can a QAU be constituted asa single person?

Yes, provided that the workload is not excessive and other duties do
not prevent the person from doing an adequate job. It would be
prudent to designate an alternate in case of disability/vacations/
etc.

Who is responsible for defining study phases and designating critica
study phases and can these be covered in the SOP?

The GLPs do not isolate this responsibility. Logically, the task
should be done by the study director and the participating scientists
working in concert with the QAU and laboratory management. It can be
covered by an SOP.

SUBPART C
FACILITIES

Section 58.41 General.

No questions were asked on the subject.

Section 58.43 Animal Care Facilities.

1.

Do the GLPs require clean/dirty separation for the animal care
areas?

No. They do require adequate separation of species and studies.

-ll-


.@)

2.

Is the study director responsible for adherence to the GLPs?

Yes.

Section 58.35 Quality Assurance Unit.

l.

As a QAU person, I have no expertise in the field of pathology. How
do I audit pathology findings?

The QAU is not expected to perform a scientific evaluation of a study
nor to “second-guess” the scientific procedures that are used. QAU
inspections are made to ensure that the GLPs, SOPs and protocols are
being followed and that the data summarized in the final report
accurately reflect the results of the study. A variety of procedures
can be used to do this but certainly the procedures should include an
examination and correlation of the raw data records.

Must the QAU keep copies of all protocols and amendments and SOPs and
amendments? .

The QAU must keep copies of all protocols as currently amended. The
only SOPs that the QAU are required to keep are those concerned with
the operations and procedures of the QAU.

Does the QAU have to monitor compliance with regulations promulgated
by other government agencies?

The GLPs do not require this.

Can an individual who is involved in a nonclinical laboratory study
perform QAU functions for portions of the study that the individual
is not involved with?

No. However, the individual can perfrom QAU functions for a study
that he/she is not involved with.

Does the QAU review amendments to the final report?

Yes.

What studies are required to be listed on the master schedule sheet?
The master schedule sheet should list all nonclinical laboratory

studies conducted on FDA regulated products and intended to support
an application for a research or marketing permit.

- 10 -


Should GLP investigators comment on the scientific merits of a
protocol or the scientific interpretation given in the final report?

No. Their function is strictly a noting of observations and
verification. Scientific judgments are made by the respective
headquarters review units that deal with the test article.

Can a GLP EIR be reviewed by laboratory, management prior to
issuance?

No. The GLP EIR is an internal agency document which reflects the
observations and findings of the FDA investigator. It can not be
released to anyone outside the agency until agency action has been
completed and the released copy is purged of all trade secret
information. Laboratories that disagree with portions of the EIR
should write a letter which contains the areas of disagreement to the
Jocal FDA District Office. The laboratories can ask that their
letters accompany the EIR whenever it is requested under the Freedom
of Information Act.

Can FDA investigators take photographs of objectionable practices and
conditions?

It is the agency position that photographs can be taken as a part of

the inspection and this position has been sustained by a District
Court decision.

The GLP Compliance Program requires the FDA investigator to select an
ongoing study in order to inspect current laboratory operations.
What criteria are used to select the study?

The studies are selected in accord with agency priorities, i.e. the
longest term study on the most significant product.

Does FDA inspect international nonclinical laboratories once every
two years?

No. Overseas laboratories are scheduled for inspection on the basis
of having submitted to FDA the results of significant studies on
important products.

What background materials are used by agency investigators to prepare
for a GLP inspection?

Prior to an inspection, the following materials are usually
reviewed:


Do unforeseen circumstances which occur during a study and which
necessitate minor operational changes have to be reported as protocol
amendments.

Unforeseen ‘circumstances: which have only a one time effect (different
date of sample collection, animal weighings) need to be reported only
in the raw data and the final report. However, such circumstances
which result in a systematic change, e.g. in the SOPs or in the
protocol, should also be made by a protocol amendment. The protocol
amendment need not be made in advance but should be made as rapidly
as possible.

Pathologists at a firm would like to take tissues from animals ina
nonclinical study which would be used to conduct exploratory research
studies. The tissues would not be part of the nonclinical laboratory
study design and the results would not necessarily pertain to the
study objectives. What would the GLPs require in this case?

The protocol should state that tissues are to be taken from the
experimental animals and that the tissues would be used for
exploratory research purposes. If any effects were observed in the
exploratory research studies which would influence the interpretation
of the results of the nonclinical laboratory study, these effects
must be report in the final report.

Does the protocol have to list the SOPs used in a specific study?

The protocol must list the type and frequency of tests, analyses, and
measurements to be made in the study. Where these are covered by
SOPs, they should be listed in the protocol.

Do the GLPs require that absorption studies be done on each test
article?

No. The GLPs require that, if absorption studies are needed to
achieve the scientific objectives of the study plan, the protocol
should describe the methods to be used to determine absorption.
Whether or not absorption studies are required is a scientific issue
to be decided by the study scientists.

Who assesses protocol validity (No. of animals, test article dosage,
test system, etc.)?

This is done by the study scientists using the scientific literature,
published guidelines, advice from regulatory agencies, and prior
experimental work.

-21-


GENERAL

Have any nonclinical laboratories been disqualified since June 20,
1979?

No.

Does FDA reject nonclinical laboratory studies that have not been
conducted in full compliance with the GLPs?

Not necessarily. The GLP Compliance Program provides guidance on the
issue. For FDA to reject a study, it is necessary to find that there
were deviations from the GLPs and that these deviations were of such
a nature as to compromise the quality and integrity of the study
covered by the agency inspection.

Must copies of the SOPs be submitted along with an application for a
research or marketing permit?

No.

What should be done about nonclinical laboratory studies that are
stopped prior to completion?

The agency recognizes that a variety of circumstances (disease
outbreak, power failures, etc.) can Tead to the premature termination
of a nonclinical laboratory study. In these cases, a short final
report should be prepared that describes the reasons for study
termination.

Has the agency established permissible limits for environmental
controls (temperature, humidity and lighting) for the animal
facilities?

No, these are scientific matters that should be described in the.
protocol and/or the SOPs. Of course, accurate records should be
maintained.


Is it possible to obtain an exemption from specific provisions of the
GLPs for special nonclinical laboratory studies?

Yes. The GLPs were written with the aim of being applicable to a
broad variety of studies, test articles and test systems.
Nonetheless, the agency realizes that not all of tne GLP provisions
apply to all studies and, indeed, for some special studies certain of
the GLP provisions may compromise proper science. For this reason,
laboratories may petition the agency for exemption for certain
studies from some of the GLP provisions. The petition should contain
sufficient facts to justify granting the exemption.

Are subcontractor laboratories that furnish a particular service such
as ophthalmology exams, reading of animal ECGs, EEGs, EMGs,
preparation of blocks and slides from tissues, statistical analysis
and hematology covered by the GLPs?

Yes, to the extend that they contribute to a study that is subject to
the GLPs.

Section 58.3 Oefinitions.

lL.

Are animal cage cards considered to be raw data?

Raw data is defined as “any laboratory worksheets, records,
memorandum, notes.....that are the result of original observations
and activities.....and are necessary for the reconstruction and
evaluation of the report of that study." Cage cards are not raw data
if they contain information like animal number, study number, study
dates, and cage number (information that is not the result of °
original observations and that is not necessary for study
reconstruction). However, if an original observation is put on the
cage cards, then all cards must be saved as raw data.

Are photo copies of raw data which are dated and verified by
signature of the copier considered to be “exact” copies of the raw
data?

Yes.

Are records of quarantine, animal receipt, environmental monitoring,
and instrument calibration considered to be raw data?

Yes.


2. Can the study director authorize changes in the SOPs?

No. Approval of the SOPs and changes thereto is a function of
laboratory management.

3. How many copies of the complete laboratory SOPs are needed?

Each work station should have access to the SOPs applicable to the
work performed at the station. A complete set of the SOPs, including
authorized amendments, should be maintained in the archives.

4. Who approves the SOPs of the Quality Assurance Unit?

Laboratory Management.
5. To what extent are computer programs to be documented as SOPs?

The GLPs do not specify the contents of individual SOPs, but the SOP
that deals with computerized data acquisition should include the
purpose of the program, the specifications, the procedures, the end
products, the language, the interactions with other programs,
procedures for assuring authorized data entry and access, procedures
for making and authorizing changes to the program, the source listing
of the program and perhaps even a flow chart. The laboratory's
computer specialists should determine what other characteristics need
to be described in the SOP.

oO Section 58.83 Reagents and solutions.

1. What are the GLP requirements for labeling of reagents purchased
directly from manufacturers?

All reagents used in a nonclinical Jaboratory have to be labeled to
indicate identity, titer or concentration, storage requirements, and
expiration date. Purchased reagents usually carry all these items
except for the expiration date, so the laboratory should label the
reagent containers with an expiration date. The expiration date
selected should be in line with laboratory experience and need not
require specific stability testing.

2. How extensive should the procedures be for confirming the quality of
incoming reagents used in nonclinical laboratory studies?

Laboratory management should make this decision but the SOPs should
document the actual procedures used.

- 14 -


10.

ll.

Does FDA permit the sterilization of animal feed with ethylene
oxide.

No.

For certain test systems (timed-pregnant rodents), it is not possible
to use long quarantine periods. Do the GLPs specify quarantine
periods for each test system?

No. The quarantine period can be established by the veterinarian in
charge of animal care and should be of sufficient length to permit
evaluation of health status.

How are feed and water contaminants to be dealt with?

The protocol should include a positive statement as to the need for
conducting feed analysis for contaminants. If analysis is necessary,
the identities and specifications for the contaminants should be
listed. The need for analysis as well as the specifications should
be determined by the study scientists. Water contaminants can be
handled similarly.

How is the adequacy of bedding materials to be handled?

This can be handled as are the analyses for possible contaminants in
feed and water. The study director and associated scientists should
consider the bedding and its possible impact on the study. The
results of this consideration should appear in the protocol.

What do the GLPs require in regard to assuring the genetic quality of
animals used in a nonclinical laboratory study?

This is a scientific issue that is not specifically addressed by the
GLPs. Suitability of the test system for use in a study is a

protocol matter and any required testing procedure should be arrived
at by the study scientists.

Do the GLPs require specific procedures for the microbiological
monitoring of animals used in nonclinical laboratory studies?

The procedures used should be in accord with acceptable veterinary
medical practice.

The Japanese are preparing animal care guidelines which are similar
but not identical to the U.S. guidelines prepared by NIH. Would
these be acceptable?

Japanese guidelines that are similar, but no less stringent, in the
important particulars with the NIH guidelines would be acceptable to
FDA.

- 16 -


SUBPART A
GENERAL PROVISIONS

Section 58.1 Scope.

L.

analytical metnods used to determine the concentration of test
article in animal tissues and drug dosage forms?

No.

Oo the GLPs apply to the following studies on animal health products:
overdosage studies in the target species, animal safety studies in
the target species, tissue residue accumulation and depletion
studies, and udder irritation studies?

Yes.
Do the GLPs apply to safety studies on cosmetic products?

No. Such studies are not carried out in support of a marketing
permit. However, the GLPs represent good quality control; a goal
that all testing facilities should strive to attain.

Do safety studies done to determine the potential drug abuse
characteristics of a test article have to be done under the GLPs?

Yes they do, but only when the studies are required to be submitted
to the agency as part of an application for a research or marketing
permit.

Do the GLPs apply to the organoleptic evaluation of processed foods?

No.

Do the GLPs apply to all of the analytical support work conducted to
provide supplementary data to a safety study?

The GLPs apply to the chemical procedures used to characterize the
test article, to determine the stability of the test article and its
mixtures, and to determine the homogeneity and concentration of test
article mixtures. Likewise, the GLPs apply to the chemical
procedures used to analyze specimens (e.g. clinical chemistry,
urinalysis). The GLPs do not apply to the work done to develop

chemical methods of analysis or to establish the specifications of a
test article. -


O

7,

3.

At the termination of a nonclinical laboratory study, can a
contractor send all of the raw data, study records, and specimens to
the sponsor of the study?

The regulations do not specifically address this issue. Section
§8.195(g) requires contract ‘laboratories that go out of business to
transfer all raw data and records to the sponsor. Likewise, Section
58.190(b) permits raw data and study records to be stored elsewhere
(other than the contract laboratory Jocation) provided that the
contract laboratory's archives have reference to the other locations
and provided that the final study report identifies the other
locations as directed by Section 58.195(a)(13).

Consequently, it is permissible for the sponsor to retain all raw
data and records from the date of termination of the nonclinical
laboratory study. Common sense dictates, however, that the contract
laboratory keep copies of the material that has been forwarded to the
sponsor.

Can a study director or a pathologist be responsible for storing and
retaining specimens and raw data?

Yes, the GLPs permit multiple archival locations provided that these
locations are identified in the central archives and that they
provide adequate storage conditions and authorized access features.

Section 58.195 Retention of records.

1.

With regard to blood and urine specimens which are analyzed for both
labile and stable constituents, is it necessary to retain the
specimen until the most stable constituent deteriorates?

All specimens should be retained for the term required by the

regulations or for as long as their quality permits meaningful
reevaluation, whichever is shorter.

For a GLP regulated metabolism study, whole tissues are homogenized
and aliquots thereof are used for analysis. Is it necessary to
retain all of the remaining homogenate as a reserve sample?

No, it is only necessary to retain a representative sample large
enough to repeat the original measurements.

If animals used in acute studies are subjected to necropsy, is it
necessary to retain the organs as study specimens.

Yes.

725 -


JUN 1981

GOOD LABORATCRY PRACTICE REGULATIONS

JUESTIONS AND ANSadR5

Since June 20, 1979, the agency nas peen asked many questions on tne Goad
Laboratory Practice regulations (GLPs, 21 CFR 58). In accord with agency
procedures, responses have been prepared and copies of the associated
correspondence have been filed in the Dockets Management 8ranch
(HFA-305). The responses have also been provided to the bioresearch
menitoring program managers and to the district offices in order to
ensure consistency of interpretation and equity of program operation.
Unfortunately, the numerous filed correspondences contain many reseat
questions that are not categorized to relate tc the specific GL? supoart
and section. On occasion, tne answers appear to ce somewnat cryptic.
These disadvantages serve to limit the utility of tne corresconaences 4s
advisories to our headquarters and field offices.

This document, therefore, consolidates all GLP questions answerea by tne
agency during the past 2 years, clarifies the questions and answers as
needed, and relates the questions and answers to the specific vertinent
provisions of the GLPs. It represents a digest of some 30 letters, 160
memoranda of telephone conversations, 34 memoranda of meetings anc 30
miscellaneous correspondences that have been issued by agency personnel.
The document does not duplicate questions and answers that were dealt
with in the August, 1979 Post Conference Report on the Gooa Laporatory
Practice Regulations Management 8riefings.

This document should be reviewed by field investigators prior to making
GLP inspections and by headauarters personnel involved in tne Gi?
program. Questions shculd be directed to:

Or. Paul 0. Lepore

Bioresearcn Monitoring Staff, HFC-30
Food and Orug Administration

5600 Fishers Lane

Rockville, MD 20857

301-443-2390


2. Oo the GLPs require that separate animal rooms be used to house test
systems and conduct different studies?

No. The GLPs require separate areas adequate to assure proper
separation of test systems, isolation of individual projects, animal
quarantine and routine or specialized housing of animals, as
necessary to achieve the study objectives.

3. Do the GLPs require that access to animal rooms be limited only to
authorized individuals?

No. However, undue stresses and potentially adverse influences on the
test system should be minimized.

Section 58.45 Animal Supply Facilities.

No questions were asked on the subject.

Section 58.47 Facilities for Handling Test and Control Articles.

1. Do test and control articles have to be maintained in locked storage
units?

No, but accurate records of test and control article accountability
must be maintained.

Section 58.49 Laboratory operation areas.

No questions were asked on the subject.

Section 58.51 Specimen and data storage facilities.

1. What do the GLPs require with regard to facilities for the archives?
Space should be provided for archives limited to access by authorized
personnel. Storage conditions should minimize deterioration of
documents and specimens.

Section 58.53 Administrative and personnel facilities.

No questions were asked on the subject.

-12-


Do the procedures used for preparing the S9 activator fraction (liver
microsomal fraction fram rats challenged with a toxin) have to be
performed {n accord with the GLPs?

No. The GLPs consider the S9 activator fraction to be a reagent.
Therefore, it must be labeled properly, stored properly, tested prior
to use in accord with adequate SOPs, and it can not be used if its
potency is below established specifications.

Do the GLPs require the use of product accountability procedures for
reagents and chemicals used in a nonclinical laboratory study?

No.

Section 58.90 Animal care.

1.

Can diseased animals received from a supplier be diagnosed, treated,
certified “well” and then entered into a nonclinical laboratory
study? . .

The GLPs provide for this procedure by including provisions directed
towards animal quarantine and isolation. The question of whether
such animals can be entered into a study, however, is a scientific
one that should be answered by the veterinarian-in-charge and the
study director and other scientists involved in the study.

Do the GLPs prohibit the use of primates for multiple nonclinical
laboratory studies?

No. Again, the question is a scientific one and the potential impact
of multiple use on study interpretation should be carefully

assessed.

Is a photocopy of an animal purchase order which has been signed and
dated by the individual receiving the shipment sufficient proof of
animal receipt?

Yes, but actual shipping tickets are also acceptable.

Does FDA have guidelines for animal bedding?

No, but the GLPs prohibit the use of bedding which can interfere with
the objectives of the study.

-~ 15 -