1. INTRODUCTION AND SCOPE
Protein-based biotherapeutics are produced by numerous prokaryotic and eukaryotic expression systems such as Escherichia coli (E. coli), yeast (Saccharomyces cerevisiae, Pichia pastoris), human (HEK-293, PER.C6), and CHO cell lines. During the manufacture of such products, HCPs are a significant class of process-related impurities that are coproduced with the desired product. Each HCP has unique physicochemical and biochemical properties. HCPs in biopharmaceuticals are considered a CQA due to their potential impact on product quality, safety, and efficacy. Consequently, residual HCP levels are commonly tested during drug substance release and sometimes as an IPC during the drug substance manufacturing process. Data is often collected for process characterization studies to show clearance capabilities of unit operations and overall process. The analytical challenges for quantifying all of the thousands of potential HCPs are well known. This chapter introduces an emerging methodology that provides new information on the identity as well as the amount of HCP in samples.
The major risks of the presence of HCPs in biological products are their potential to 1) elicit unwanted immune responses in patients and/or 2) exhibit biological activity in patients. In addition, with the common use of liquid formulations, it is increasingly of interest to understand whether HCPs with protease, glycosidase, or lipase activity impact product quality or stability, even at trace levels. Thus, there is an industry-wide challenge to effectively detect and monitor residual HCPs in order to demonstrate product safety and quality through risk assessment or by their removal through processing.
HCP immunoassay, often in the form of a sandwich enzyme-linked immunosorbent assay (ELISA), remains the most common methodology for HCP measurement and control in biopharmaceuticals. Primary applications are in release testing of a drug substance and demonstration of adequate clearance of HCPs through a process. Residual HCP ELISA is a multi-analyte immunoassay that uses polyclonal antibodies raised against a broad HCP population from a host organism. This assay relies on the quality of the critical polyclonal antibody reagents and the HCP antigen used as the assay standard. A more extensive discussion of the use of immunoassay for HCP detection and measurement is described in Residual Host Cell Protein Measurement in Biopharmaceuticals 〈1132〉. As discussed in 〈1132〉, 3. HCP Immunoassay Methods and 〈1132〉, 5. Supporting Technologies for Residual HCP Detection, Identification, and Measurement, this methodology has limitations despite the many advantages of using immunoassay for HCP measurement, such as its high sensitivity, specificity, throughput, automation capability, and quantitative nature. First, polyclonal antibodies used in the immunoassay often have no or limited coverage to particular HCPs that are nonimmunogenic or weakly immunogenic in the animals used to raise antibodies. Secondly, the immunoassay may underestimate or overestimate levels of HCPs when individual HCP levels are very high and the antibody is limiting their detection or when an HCP is highly immunogenic in the immunized species dominating the ELISA signal, respectively. Thirdly, an ELISA assay generates a single value for total HCPs and does not distinguish the contribution of individual HCPs. Lastly, the lack of specific identification prevents a knowledge-based risk assessment of particular HCPs. Therefore, 〈1132〉 and many other recent publications have emphasized the importance of including orthogonal assays to provide additional assurance of product quality.
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