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.
2. 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 operation procedures (SOPs)?
The GLPs do not specify the amount of detail to be inculded 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.
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.
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 laboratory 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.
3. Do the procedures used for preparing the S9 activator fraction (liver microsomal fraction from rats challenged with a toxin) have to be performed in 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.
4. 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 \
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.
2. 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.
3. 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.
4. 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.
5. Does FDA permit the sterilization of animal feed with ethylene oxide. No.
6. For certain test system (timed-pregnant rodents), it is not possible to use long quarantime periods. Do the GLPs specify quarantine periods for each test system?
No. The quarantine period can be extablished by the veterinarian in charge of animal care and should be of sufficient length to permit evaluation of health status.
7. 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 determined by the study scientists. Water contaminants can be handled similarly.
8. 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.
9. 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.
10. 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.
11. The Japanese are preparing animal care guidelines which are similar but no 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.
12. What is the frequency of feed contaminant analysis?
If contaminant analyses are required by the protocol, then the GLPs require periodic 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.
13. Is it necessary to use \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.
14. Do the GLPs require production facilities to be dedicated to the manufacture of specific animal feeds used in nonclinical laboratory studies? No.
15. 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.
2. 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 staetment such as \analysis results\be examined prior to continued use of the test article.
3. 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.
4. 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 articles 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?