Vaccine Pre-clinical Toxicology Testing

Brief Overview of Vaccine Manufacture

Safety-related elements of current Good Manufacturing Practices (cGMP) should be implemented before Phase 1, i.e., adequate documentation (traceability), sterility assurance, safety assessments, and control over the manufacturing process. However, Quality Control and Quality Assurance are expected to be refined as product development proceeds. Consequently, GMP develops with process development and thus, resulting product development. Full compliance with GMP is hardly ever met at the pre-clinical phase of product development. As stated in 21 CFR 312.23(a)(7) "Although in each phase of the investigation sufficient information is required to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information necessary to make that assurance will vary with the phase of the investigation, proposed duration, dosage form and amount of information otherwise available."

The following will provide a general description of vaccine manufacture to support pre-clinical toxicology studies. Details of the vaccine manufacturing process, aspects of quality control, or other product characterization issues, such as adventitious agent testing and other in vivo and in vitro assays conducted to assess product safety, are not covered here. Nevertheless, it is understood that product characterization data and lot release data demonstrating the safety, purity, and potency of the vaccine candidate are critical components to support vaccine safety. Pre-clinical safety assessments may also include immunogenicity studies (which may be a measure of potency); pyrogenicity studies (as part of the evaluation of vaccine purity); as well as challenge/protection studies (if appropriate animal models exist). For guidance in this area, reference is made to applicable guidance for industry documents (http://www.fda.gov/cber/reading.htm).

As illustrated below in flowchart 2, a number of requirements have to be met before the manufactured vaccine product(s) can be used in pre-clinical safety testing. Performing pre-clinical safety testing on material that is not sufficiently well characterized may result in invalid studies. It is preferable to perform the pre-clinical studies on the same lot of vaccine that you intend to use in the initial clinical trial(s), although it is acceptable to perform the studies on pilot lots made by the exact same manufacturing process provided product characterization data are available demonstrating comparability of the pilot and clinical lots.

Clinical doses are frequently based on a dose(s) shown to be immunogenic in "proof of concept" or immunogenicity studies conducted in animal models. After the manufacture of the final bulk material under GMP, vaccines are generally filled for pre-clinical safety studies based on the dose(s) described in the protocols. At a minimum, the highest dose to be used in the proposed clinical trial should be studied in the animal model. Although aliquots of bulk vaccine material can be diluted or formulated into doses within a day or two before animal immunization, these doses must be verified to be what they were supposed to be either at the pre-clinical safety testing site or by the vaccine manufacturer or designee. This testing should include a potency determination (even if a final validated potency test is not developed yet). In cases when it is necessary for the pre-clinical safety testing facility to formulate the doses to be given in the pre-clinical study(ies), dose verification (e.g., potency verification), dose stability under the conditions of use, and uniformity testing must be performed to verify the delivered immunization dose(s).

A portion of the bulk may be reserved for performing stability studies and for filling clinical trial material. Formulating and filling of final containers for the clinical trials usually is not performed until after results from the pre-clinical testing indicates no significant toxicity was observed at or above the proposed clinical dose. Clinical doses proposed in the final clinical protocol should be based on the outcomes of pre-clinical safety (highest safe dose) and immunogenicity (optimal immunogenicity) studies. Hopefully, the optimal immunogenic dose determined will be well below the highest safe dose [comparable to the concept of a maximum tolerated dose (MTD) determined for toxic drugs. An MTD may or may not be determined in the pre-clinical toxicology study because often vaccines do not cause significant toxicity at the doses tested in the toxicology study and an MTD cannot be determined. Because of this, generally one does not refer to an MTD for a vaccine. However, because it is a concept commonly understood by drug toxicologists, it is explained herein].