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.
2. 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.
3. 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-specified 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.
4. 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.
5. 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.
6. 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.
7. 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.
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 clarificaion 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 necropsy of the last animal of 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 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 foregooing timeframes need be used to
define the study terms described in section 58.35 (b)(3) and section 58.105(d). For these sections, the traditional terms found in the toxicology literature may be used.
2. 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.
3. Does each nonclinical laboratory study require a sponsor-approved specific protocol?
Yes. However, the laboratory that conducts the study can also qualify as the sponsor of the study.
4. 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 weghings) 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.
5. Pathologists at a firm would like to take tissues from animals in a 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 reported in the final report.
6. 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.
7. 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.
8. 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.
Section 58.130 Conduct of a nonclinical laboratory study.
1. Does raw data collected in nonclinical laboratory studies have to be cosigned be a second individual.
No.
2. 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.
3. 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.
4. 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 58.130 ?
5. Is a positive notation (a statement of what was done in the raw data) required for routine laboratory operations such as:
(a) identifying animal,
(b) shaving or abrading rabbits,
(c ) specific dosing procedures, and
(d) fasting of animals? Yes.
6. Do the GLPs require the entry of raw data into bound notebooks? No.
7. 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.
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RECORDS AND REPORTS
Section 58.185 Reporting of nonclinical laboratory 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.
2. 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.