Product-related impurities biopharmaceutical

Most recombinant biopharmaceuticals are produced in microbial or mammalian cell lines. Thus, although the product is derived from a human gene, all product-unrelated contaminants will be derived from the producer organism. These non-self-proteins are likely to be highly immunogenic in humans, rendering their removal from the product stream especially important. Immunoassays may be conveniently used to detect and quantify non-product-related impurities... 

For biopharmaceuticals, the complexity of analytical test approaches is also reflected in guidelines concerning reference standards and materials (see ICH Q6B [22]). In principle, it is desirable to use the same reference material for both biophar-maceutical assays and physico-chemical testing, but in some cases a separate reference material may be necessary. It may also be necessary to establish distinct reference materials for product-related substances, product-related impurities and process-related impurities. 

NMR is a remarkably flexible technique that can be effectively used to address many analytical issues in the development of biopharmaceutical products. Although it is already more than 50 years old, NMR is still underutilized in the biopharmaceutical industry for solving process-related analytical problems. In this chapter, we have described many simple and useful NMR applications for biopharmaceutical process development and validation. In particular, quantitative NMR analysis is perhaps the most important application. It is suitable for quantitating small organic molecules with a detection limit of 1 to 10 p.g/ml. In general, only simple one-dimensional NMR experiments are required for quantitative analysis. The other important application of NMR in biopharmaceutical development is the structural characterization of molecules that are product related (e.g., carbohydrates and peptide fragments) or process related (e.g., impurities and buffer components). However, structural studies typically require sophisticated multidimensional NMR experiments. 

Biopharmaceuticals are subjected to strict regulations to monitor and quantitate impurities to maintain product safety, quality, integrity, and efficacy.4 The following are definitions that relate to purity ... 

A well-characterized biological (biopharmaceutical) is a chemical entity whose identity purity, impurity, safety, potency, and quality can be determined and controlled [19,93], To be well characterized, the drug substance must be >95% of the main component and/or related isoforms [93], Well-characterized molecules are evaluating using sensitive and discriminating tests that are quantitative and relevant in vivo and in vitro potency assays [93]. The recent explosion in the availability of sophisticated, reliable, analytical instrumentation, combined with extensive, sensitive product analysis methods has resulted in great advancements in defining well-characterized biopharmaceuticals [28]. 

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