Defining Your Product Profile and Maintaining Control Over It , Part 1 Session One of the WCBP CMC Strategy Forum , 19 – 20 July 2004

JUNE 2005 A well-characterized biopharmaceutical product is defined during its development by identification and quantification, when at all possible, of both process-related and product-related impurities. The expanding repertoire and sensitivity of the latest analytical methodologies enable detection and measurement of process impurities and product variants at increasingly lower levels and in greater detail. Although a complete and well-defined product profile is understood to be the goal for a marketable biopharmaceutical, the extent of product characterization expected at earlier stages in development of a product is unclear. Expectations for permissible levels of residual processing components or product variants throughout the product development life cycle are also unestablished. Several factors contribute to the difficulty in standardizing those requirements. Safety is a relative attribute depending on the dose, route and schedule of administration, and patient population — in addition to individual response patterns. Process capability to reduce unwanted components — and potential consequences of varying levels of impurities on product quality characteristics such as stability — highly depend on the structure(s) and nature of the active moieties. Such idiosyncratic variables have led to a “case-by-case” model for regulatory assessment of impurities to be specified and acceptable limits for control. The absence of clear guidance contributes to uncertainty in the fitness of product development plans, potential misalignment of priorities, delay in regulatory review of filings as these questions are evaluated anew with each dossier, and inconsistent standards from product to product and sponsor to sponsor. Burgeoning clinical and market experience with biopharmaceuticals, especially with categories such as monoclonal antibodies (MAbs) and Eschericia coli–derived recombinant proteins, now affords sufficient data to suggest the possibility of setting upper limits for general acceptability of the most common impurities: host-cell proteins (HCPs), residual Protein A, and aggregate forms of the active molecule. Expanded use of in-process feedstream analysis and improved process capabilities to validate reduction of certain impurities below detectable levels well upstream from bulk drug pools may obviate the need for routine specification of such impurities at the bulk drug stage. Establishment of appropriate standards for acceptable levels of processand product-related impurities, along with strategies for removal and requirements for specification would facilitate efficient and cost-effective development, production, and availability of safe and beneficial new products.

[1]  M. Powell,et al.  Compendium of excipients for parenteral formulations. , 1998, PDA journal of pharmaceutical science and technology.

[2]  David C. Anderson,et al.  Harrison’s Principles of Internal Medicine, 16th Edition , 2005, Neurology.

[3]  S Nema,et al.  Excipients and their use in injectable products. , 1997, PDA journal of pharmaceutical science and technology.