THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 4

… several different analytical methods are needed to characterize the many different structural and functional features of any monoclonal antibody product. Additionally, a variety of analytical methods are essential in the development and control of monoclonal antibody manufacturing processes including methods that can be performed on process intermediates that are in different buffers and contain more contaminants than the final product. Analytical methods used in the analysis and characterization of monoclonal antibody process intermediates and final purified products include methods to determine the protein identity, purity, safety, and potency as well as to investigate the multiple forms of the monoclonal antibody that may be present. Some methods used in analyzing monoclonal antibodies, such as the determination of protein concentration by a dye-binding assay or by absorbance of UV light at 280 nm are commonly used and easily applied without modification to most monoclonal antibody products.

… In the US, the requirement for analytical testing and characterization of a new monoclonal antibody product is outlined in 21CFR312.23 as it is for all investigational products in the US. For approved products, the requirements for in-process and final release testing are further defined in 21CFR210 and 21CFR211. Recently, FDA acknowledged that during the development of a new drug, full compliance with the regulations in 21CFR210 and 21CFR211 is not required until later in the development process and, in July, 2008, issued an amendment specifying that 21CFR211 no longer applies to Phase 1 investigational drugs. The Phase 1 guidance document places emphasis on the early validation of analytical methods used to assure the safety of the product, including sterility and absence of endotoxins. While acknowledging that many of the methods used to analyze a new drug may not be validated during early product development, FDA requires manufacturers or Sponsors of new products to control any aspect of manufacturing that is reasonable, including exercising control over raw materials used in the manufacturing process. For monoclonal antibody products under development in the EU as well as the US, the requirements for the development and validation of analytical methods required for testing and characterization of a new monoclonal antibody product are outlined in a series of ICH guidance documents listed in Table 4.1.

Table 4.1.  ICH Guidance Documents Covering the Testing and Characterization of Monoclonal Antibody Products

Since no single set of analytical methods can provide complete and robust characterization of a monoclonal antibody product, many of the attributes of the product must be measured using a combination of analytical methods... Like all pharmaceutical products, each batch of monoclonal antibody product must be tested for identity, purity, safety, and potency. Identity may be demonstrated using a single assay or a combination of two or more analytical methods, as long as the methods are sufficient to confirm that the product is the intended product. The purity of a monoclonal antibody is demonstrated through a variety of assays that measure the purity and/or the level of specific impurities that may be present. Safety is assessed by measurement of the microbiological purity of the product, the level of bacterial endotoxin present, and the amount of particulates present in the final drug product, and these essential assays are required by all regulatory agencies. Potency is often measured using multiple assays, including methods that demonstrate binding to the target or cell-based methods that assess biological impact in a reporter cell based system.

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