Biotechnology-derived

S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals... 

Tab. 14.1 The role ofGMP (good manufacturing practice) in the production and processing of APIs (active pharmaceutical ingredients) from difference sources. It is not yet clear how biotechnology-derived plants fit into this scheme. Modified from the Good Manufacturing Practice Guide for Active Pharmacuetical Ingreedients, ICH (2000).

After the approval of the first product, recombinant insulin, in 1982, progress in the development of new recombinant protein pharmaceuticals was slow ([10], Fig. 17.1). The number of biotechnology-derived drugs and vaccines approved by the US Food and Dmg Administration (FDA) has increased significantly only since 1995. More recently, sales of biologies have skyrocketed, e.g. from 900 million in 1999 to an estimated 3.5 billion in 2001 for monoclonal antibodies [11]. The annual global market for biopharmaceuticals is estimated to have increased from 12 billion US to 30 billion US in 2003 [12]. 500 candidate biopharmaceuticals are undergoing clinical evaluation and over one hundred protein-based therapeutics are in the... 

Seamon, K. 1998. Specifications for biotechnology-derived protein drugs. Current Opinion in Biotechnology 9, 319-325. 

In light of recent experience with biotechnology-derived products, it is reasonable to expect that pharmacogenomics-based drugs will be expensive relative to traditional modes of treatment (Richmond et al., 1999). If the price of these innovations is viewed out of context from the consumption of other health care goods and services, the response may well be to reduce or deny access to these products. In an era of escalating health care cost, "inputs" to the production of health care, such as pharmaceuticals, physician visits, lab-... 

ICH Topic S 6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (CPMP/ICH/302/95). March 1998. 

The International Conferences on Harmonization has published its document S6, Preclincial Safety Evaluation of Biotechnology-Derived Pharmaceuticals. The FDA (the Center for Drug Evaluation and Research, and the Center for Biologies Evaluation and Research jointly) has published the document as a Guidance for Industry (Anon., 1997a, b FDA, 1989, Hayes and Reyffel, 1999). 

Carcinogenicity Studies. These are generally inappropriate for biotechnology-derived pharmaceuticals however, some products may have the potential to support or induce proliferation of transformed cells... possibly leading to neoplasia. When this concern is present, further studies in relevant animal models may be needed. 

Basic Principles for Preclinical Safety Evaluation of Cellular and Gene Therapies. For biotechnology-derived products in general... 

Lumpkin, M. (1996). Guidance for Industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including well-characterized, therapeutic, and biotechnology-derived products, http //www.fda.gov/cder/guidance/phasel.pdf... 

Protein and other biotechnology derived therapeutics have some fundamental differences from traditional small (synthetic organic) molecules. Table 12.2 presents a comparative summary of these differences. 

Some biotechnologically derived pharmaceuticals will cross-react with species that can be evaluated toxicologically, while others cross-react only with nonhuman primates such as the chimpanzee, a protected species. In this case, a well-designed safety, or Phase 0 study at doses higher than the proposed clinical dose may provide valuable safety information. However, a lack of cross-reactivity with any nonhuman species does not necessarily make preclinical safety evaluation impossible, not does it limit toxicity testing to species in which the protein lacks relevant pharmacological activity. Some alternative possibilities are summarized in Table 12.9. 

Clinical trials for biotechnologically derived pharmaceuticals may be more complex than those for conventional pharmaceuticals and so the route and frequency of test... 

Although biotechnologically derived pharmaceuticals often need customized precli-nical development programs, certain issues are common to all. These include species specificity, potential immunogenicity and its impact on the duration of dosing, and the need for special toxicity testing. 

The upshot of these points is that it may not be practical to follow established guidelines for ADME evaluation. Binding proteins, immunoreactive metabolites and antibodies could interfere with the immunoassays used to measure the activity of biotechnologically derived pharmaceuticals. The link between immunoreactivity and... 

AUC and Cmax are commonly measured to identify safety ratios for new chemical entities. Since the analytical methods used for biotechnologically derived pharmaceuticals may lack specificity, a clinical marker of biological activity or efficacy may sometimes be more appropriate than exposure data. 

Biotechnologically-derived products that achieve highly specific receptor targeting (refer to toxicology studies) ... 

The need for DDSs is possibly the greatest in the case of biotechnologically derived products that cannot be orally absorbed, such as peptides, proteins, and oligonucleotides. 

Anon., ICH S6 Preclinical safety evaluation of biotechnology-derived pharmaceuticals, CPMP/ICH/302/95, London, July 16,1997. 

As a result of the pharmacopoeial harmonization process, general chapter 2.2.47. of the Ph.Eur. and general chapter 8 of the JP (Capillary Electrophoresis) and general chapter < 1047) of the USP (Biotechnology-Derived Articles — Tests, Capillary Electrophoresis ) have been harmonized to a major extent. At present some minor differences exist between the text and a few equations in the pharmacopoeia. In these chapters, the following definition of CE is given ... 

The entire chapter <(1047) is harmonized with the Japanese and the European Pharmaceopoeias. In order to have a parallel organization of the harmonized documents, the current chapter <( 1047) will be divided and replaced by six general information chapters, including <(1053) Biotechnology Derived Articles — Capillary Electrophoresis. 

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