Vaccine production safety tests

As a general rule, products that are used only once or a few times have to undergo fewer safety tests than products which will administered regularly or over a longer time. Less - if any - side reactions are tolerated for products intended to be used in healthy individuals (e.g. vaccines) than for products which are used in diseased individuals. In any case the benefits must clearly outreach any potential side-effects. 

Vaccine excipients (adjuvants and other substances used in the formulation) are treated in the same way as chemical substances. If new substances are introduced, a full safety assessment is required. It may be necessary to assess their toxic potential separately from the vaccine, since the vaccine formulation may interfere with a proper testing. In addition the normal pharmacological and safety tests for vaccines must be performed with the final, formulated product. 

The development of veterinary products for cattle, pigs, sheep, poultry and other food producing animals also includes residue testing of all new pharmaceutical products, including adjuvants or other excipients in vaccines. Residue safety studies address the potential risk to humans due to the consumption of food from treated animals. Accordingly, the test substances in these toxicity studies are applied orally. Residue depletion studies (pharmacokinetic studies) in the target species must be carried out to define the occurence, concentration and elimination of the substance and its metabolites in edible tissues, milk and eggs. 

Because many vaccines are derived from basic materials of intense pathogencity — the lethal dose of tetanus toxin for a mouse is estimated to be 3 x 10-5pg— safety testing is of paramount importance. Effective testing provides a guarantee of the safety of each batch of every product and most vaccines in the final container must pass one or more safety tests as prescribed in a pharmacopoeial monograph. This generality does not absolve a manufacturer from the need to perform in-process tests as required, but it is relaxed for those preparations that have a final formulation that makes safety tests on the final product either impractical or meaningless. 

Figure 10.2-1 Maximizing the benefit-to-risk in vaccine development. No vaccine can be administered to humans without solid data showing safety. Product development and safety testing for these products relies very heavily on animal studies which are relied upon to predict both efficacy and safety. Toxicity assessments for vaccines are challenging because, in general, vaccines trigger complex immune reactions.There must be a balance between desired immunogenicity and unwanted adverse side effects.

The health status of animals from which starting materials are derived and of those used for quality control and safety testing should be monitored and recorded. Staff employed in animal quarters must be provided with special clothing, changing facilities and showers. Where monkeys are used for the production or quality control of biological products, special consideration is required, as laid down in the revised Requirements for Biological Substances No. 7 (Requirements for Polio-myelitis Vaccine (Oral))(5). 

Several DNA vaccines have been tested in clinical trials. As such, DNA vaccines have progressed part of the way through the development process. However, these clinical trials were done at an early stage and were more or less extended studies of research candidates. Such early stage clinical trials differ greatly from those required for licensable products, as usually only an abbreviated preclinical development has been performed in order to make clinical trial products available at the earliest possible time. Many more detailed quality analyses and very long, complex, and expensive safety studies will have to be performed to arrive at a marketable DNA vaccine that is sufficiently safe and efficacious to justify its widespread application in healthy individuals. 

The single-component bacterial vaccines are listed in Table 15.1. For each vaccine, notes are provided of the basic material fkm which the vaccine is made, the salient production processes and tests for potency and for safety. The multicomponent vaccines that are made by blending together two or more of the single component vaccines are required to meet the potency and safety requirements for each of the single components that they contain. The best known of the combined bacterial vaccines is the adsorbed diphtheria, tetanus and pertussis vaccine (DTPerWac/Ads) that is used to immunize infants, and the adsorbed diphtheria and tetanus vaccine (DTWac/Ads) that is used to reinforce the immunity of school entrants. 

Clinical trials, also known as clinical studies, test potential treatments in human volunteers to see whether they should be approved for wider use in the general population. A treatment could be a drug, medical device, or biologic, such as a vaccine, blood product, or gene therapy. Potential treatments, however, must be studied in laboratory animals first to determine potential toxicity before they can be tried in people. Treatments having acceptable safety profiles and showing the most promise are then moved into clinical trials. 

Unlike the analogous attenuated malaria sporozoite vaccine (Hoffman et a/., 2002), the schistosome counterpart has not been tested in humans but our recent demonstration of protection in a small-scale chimpanzee trial (Eberl et a/., 2001) attests to its potential as a basis for the development of a recombinant vaccine. However, attempts to replicate the success of the attenuated schistosome vaccine by administration of recombinant antigens have had only limited success. It is notable that, faced with similar problems in replacing the attenuated malaria vaccine with recombinant antigens, it is now proposed to develop a cryopreserved product that meets regulatory, potency and safety requirements, for use in humans (Luke and Hoffman, 2003). 

An example of the role(s) that primate research has played is in the development of the poliomyelitis vaccines. Although many studies on poliomyelitis in humans were conducted in the late nineteenth century, the cause of the disease remained unknown until scientists succeeded in transmitting the virus to monkeys in 1908. There followed many years of research with primates until scientists were able, in the early 1950s, to grow the virus in human cell cultures and development of a vaccine became possible. At that point in time, in order to ensure the safety and effectiveness of the vaccines, tests were conducted with monkeys. Furthermore, in order to produce the vaccines in pure form in great quantities, it was necessary to use kidney tissue taken from monkeys. Today, an alternative to the use of monkey kidneys has been developed for the production of the vaccine. 

No adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine. Therefore preclinical and toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/ vaccine combination [60], Evaluation in preclinical studies is important for identifying the optimum composition and formulation process and also for allowing development of tests for quality control [61]. Data from these studies also helps plan protocols for subsequent clinical trials from which safety and efficacy in humans can be evaluated. 

Therefore quality control (QC) testing of vaccines normally includes the following assays, which must be passed prior to material being released for use in preclinical toxicology studies sterility, endotoxin, general safety, identity, mass, potency, purity, and stability [62], These assays should be performed on the final product using the clinical formulation. 

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