Biotechnology products classes

In 1996, about 10 years after the introduction of the first recombinant DNA product for human use, the FDA modified and streamlined the approval process for biotechnology products considered to be well characterized. These modifications, in essence, established the direction of how biologic macromolecules are researched and developed today in biotechnology-based and traditional pharmaceutical companies [2]. Well-characterized biotechnology products include (1) synthetic peptides consisting of fewer than 20 amino acids, (2) monoclonal antibodies and derivatives, and (3) recombinant DNA-derived products. Anticipating future developments, the FDA is also prepared to consider DNA plasmid products as well-characterized when the first medicinal in this class is submitted for approval. CBER now approves well-characterized biopharmaceuticals under the BLA process [3]. 

A review of capillary electrophoresis applications in pharmaceutical analysis was published in 1993, and the goal of this chapter is to provide an update on the various disciplines within the technique and includes selected applications. Recent developments in the areas of capillary technology, instrumentation, and detection will be reviewed here. Useful strategies for method development involving several classes of pharmaceuticals and biotechnology products will be addressed. The formats within capillary electrophoresis have evolved to such an extent that this chapter is not comprehensive in scope. Therefore, the reader will be directed to other reviews on the various aspects of capillary electrophoresis. Of particular interest to many separation scientists may be a special issue of an Applied Biosystems Newsletter, which addresses the future role of CE, method development in CE, and selected applications in the area of drug analysis and protein separations [7]. 

Over the past two decades many biotechnology-derived products have been approved in the United States. A selected list of these products is provided in Table 6.2. The products include recombinant endogenous-replacement proteins, cytokines, monoclonal antibodies, and fusion molecules. Other chapters in this book give more detailed product-class-specific descriptions of the preclinical development programs for many of these molecules. 

In 1997 the ICHS6 guidance on preclinical safety evaluation of biotechnology-derived products [2] introduced the concept of the case-by-case approach. This means that each new test article (product) or product class must have a science-based testing program custom prepared for that product... 

Poly(jS-hydroxyalkanoates) (PHAs) are a class of poly(esters) which are synthesised by many bacteria as energy reserve and carbon source when exposed to an excess of carbon under unbalanced growth conditions [82]. The produced PHAs can account for up to 80% of the bacterium s dry weight. This has led to the biotechnological production of PHAs. Depending on the substrates provided to the bacteria, different monomers can be produced which results in different PHA (co)polymers [83]. 

A total of almost 250 ISPR projects in microbial whole cell biotechnology are listed in Table 2. Over one third of these projects have dealt with the production of organic solvents such as ethanol, butanol, acetone or propanol (90 projects). Ethanol (70% of all the solvents) has been by far the most important microbial product for which different ISPR techniques have been applied. The second most important class of products involved in ISPR projects have been organic acids such as lactic, acetic, butyric, or propionic acid (54 projects). Most of effort in this product class has focused on lactic acid (55% of all organic acids). Important ISPR activities have also been reported for the microbial production of various aromas and fine chemicals (30 projects in each product category). A considerable amount of ISPR approaches have been shown in steroid conversions (17 projects) and the production of secondary metaboHtes and various enzymes (13 projects in each product category). 

Complex carbohydrates (in particular, glycoproteins) play an important role in various biological processes and in biotechnological production of glycoproteinaceous pharmaceuticals. To elucidate the relationship between bioactivity and structures of complex carbohydrates, it is necessary to determine the sites of attachment of the oligosaccharide chains to the polypeptide backbone and to characterize the oligosaccharide class (N- or 0-linked, high mannose, hybrid, etc.). 

Companies were asked to provide information on general strategies for designing safety evaluation programmes for products of biotechnology and, in addition, to provide information on the type of studies conducted for specific product classes with which they had experience, up to a maximum of two per respondent. The type of information requested reflected the concerns of the industry which were identified in a previous CMR International... 

The overall aim of the survey was to provide background information on studies which either warrant consideration or may be deemed unnecessary in the non-clinical safety evaluation of particular product classes. It was not the aim of the survey to be prescriptive with regard to the studies that should be conducted to evaluate pharmaceutical products of biotechnology. 

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