ABSTRACT
Within the pharmaceutical industry, the term biotechnology, in its broadest definition, refers to the use of live organisms to produce biomedicines. The general regulatory scheme for biotechnological products is the same as for products made by traditional methods, with additional specific requirements based on their biological origin. The aim of this chapter is to consider the criteria for the production and quality control of products obtained through biotechnological techniques. In Chapter 14 (Regulatory aspects), complementary information is supplied about controls required by governmental organizations for product registration and quality guarantees, during a product’s lifetime in the market. These controls are part of a set of regulations and guidelines known as Good Manufacturing Practice (GMP). The main difference between traditional and biotechnological pharma-
ceutical products lies in the fact that the latter are produced from live organisms that are often genetically modified. This category includes not only proteins or polypeptides derived from recombinant DNA (rDNA) but also monoclonal antibodies (mAbs). In the production stages, all the pharmaceutical products, even those of biotechnological origin, share the same basic requirements for process validation, environmental control, aseptic production, and quality control systems. However, the biotechnological systems usually present a greater degree of complexity. The rDNA-derived products may contain potentially harmful contami-
nants that are normally not present in their equivalents prepared by chemical methods, and which the purification process must be capable of eliminating, such as the endotoxins expressed in bacterial cells, cellular DNA, and viruses of animal origin. Contamination with nucleic acid from transformed mammalian cells is of particular concern due to the possible presence of potentially oncogenic DNA. The selected production procedure affects the nature and level of
potential contaminants. The possible variability of the system during production may result in modifications that favor the expression of alternative genes in the host-vector system or produce lower product efficiency, or quantitative and qualitative differences in the present impurities. An example of such variability is a change in the profile of proteases
and this should be evaluated, as this may affect the quality of the recombinant protein produced (Kratje et al., 1994). The production of continuous cultures is subjected to similar considerations. Therefore, it is important to rely on procedures that assure the uniformity of the conditions of production and consequently the uniformity of the final product. The development of biological materials as therapeutic agents must
involve guarantees about their safety, efficacy, and quality. Safety and efficacy are established through well controlled toxicity studies and clinical trials. Biological tests are important as a direct measure of biological activity and as safety indicators that may detect potential deviations related to efficacy and safety. Quality should be confirmed using a variety of analytical techniques, which can evaluate purity, biological potency, stability, and consistency of production. With the aim of establishing lot-to-lot consistency, the characterization
of a target protein should be performed during its development, to establish the required analytical criteria for production. This characterization may be continued during its manufacture. The evaluation of a product is based on its adequate characterization before and during process development. This involves exhaustive research on the structure, physicochemical properties, and biological activity, as well as its potential contaminants (Jeffcoate et al., 1993). For a full overall evaluation, it is necessary to use a combination of these procedures, as none of these can provide enough information on their own. Biotechnological production processes may include the following
stages.
