Biopharmaceutical drug characterization

Analytical methods are important not only in the development and manufacture of commercial biopharmaceutical drugs, they also play a vital role in the whole drug development life cycle. Drug discovery and preclinical research require development and application of analytical methodologies to support identification, quantitation, and characterization of lead molecules. It is difficult to perform a comparative potency assay on lead molecules if one does not know how much of each is going into the assay or how pure the molecule is. Analytical methods are typically developed, qualified, and validated in step with the clinical... 

The physicochemical and other properties of any newly identified drug must be extensively characterized prior to its entry into clinical trials. As the vast bulk of biopharmaceuticals are proteins, a summary overview of the approach taken to initial characterization of these biomolecules is presented. A prerequisite to such characterization is initial purification of the protein. Purification to homogeneity usually requires a combination of three or more high-resolution chromatographic steps (Chapter 6). The purification protocol is designed carefully, as it usually forms the basis of subsequent pilot- and process-scale purification systems. The purified product is then subjected to a battery of tests that aim to characterize it fully. Moreover, once these characteristics have been defined, they form the basis of many of the QC identity tests routinely performed on the product during its subsequent commercial manufacture. As these identity tests are discussed in detail in Chapter 7, only an abbreviated overview is presented here, in the form of Figure 4.5. 

For an extended-release dosage form, at least three test time points are chosen to characterize the in vitro drug-release profile for the routine batch-to-batch quality control for approved products. Additional sampling times may be required for formulation development studies, biopharmaceutical evaluations, and drug approval purposes. An early time... 

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In the development of new biopharmaceutical molecules, there is a constant need for analytical methods that provide critical information in areas that range from early characterization to routine analysis of approved products. Past experience indicates there are few projects in drug development that can be addressed by standard analytical procedures. Even well-established techniques often have to be modified to better suit the analysis of new samples. For this reason, a broad range of techniques is already an integral part of laboratories in the biopharmaceutical industry. 

There has been significant advancement in the applications of NMR to the development of small-molecule pharmaceutical products. For example, advances in NMR automation (e.g., flow-injection analysis) and directly coupled methods (e.g., LC-MS-NMR analysis) have made analysis and characterization of small-molecule drugs much easier.23 25 These improvements have helped chemists to develop and characterize small-molecule combinatorial libraries and to screen for active compounds.4 6 It is likely some of these techniques can also be used in biopharmaceutical product development. 

There are four different drug products under Part II chemical active substance(s), radiopharmaceutical products, biological medicinal products, and vegetable medicinal products. For example, the GMP production report for biological medicinal products includes description of the genes used, strain of cell line, cell bank system, fermentation and harvesting, purification, characterization, analytical method development, process validation, impurities, and batch analysis (GMP production of biopharmaceuticals is described in Chapter 10). A DMF (Exhibit 8.8) is submitted. 

To date, most approved protein-based drugs are for therapeutic or replacement therapies. They are recombinant versions of natural proteins such as insulin and erythropoietin. Their characteristics and functions are relatively well defined and known. The next phase of biopharmaceuticals, such as antibodies and vaccines, is more complex and requires more tests and characterizations. Controls for the reliability, contamination, and fidelity of expression systems will be high on the agenda in the coming decade. 

In biopharmaceutics, effective methods are strongly needed, not only to characterize the interactions of drugs and vehicles with biological structures in order to optimize pharmaceutical vehicle systems, but also to study the interactions between biological molecules and to investigate immunoreactions. 

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