Essentials of the Production of Safe and Efficacious State-of-the-Art Polyclonal IgG Concentrates

Severe noninfectious adverse events (AEs) and transmission of pathogens by plasma-derived protein concentrates from the very beginning of their clinical use were threats for recipients (see Chap. 10.1007/978-3-319-68038-5_11 for additional information). “Standard IgG” preparations were the first available for clinical use. They were produced by the cold-ethanol fractionation methods and did not make an exception. Noninfectious severe AEs occurred while infectious AEs were rarely reported. Indeed, prior to the introduction of mass screening for infection markers of plasma donations, inadvertent transmission of HIV to recipients of factor VIII and factor IX concentrates did occur, while IgG concentrates obtained from the same plasma pool did rarely transmit HIV (Morgenthaler 2001). Rare transmissions were restricted to products not exposed to low pH. The very few incidences of HIV and some incidences of HCV transmission by IgG concentrates in the early 1990s together with many cases of coagulation factor concentrates transmitted viral disease clearly demonstrated the need to establish standardized measures to render plasma products pathogen safe. In the second half of the 1990s, authorities shifted regulatory emphasis from a scientific review of the processes to a focus on compliance to current good manufacturing practice (cGMP). The focus on cGMP compliance was applied to all aspects of plasma fractionation and the clinical use of plasma products. Court injunctions and warning letters were the consequences of this paradigm shift by authorities. This in turn resulted in a paradigm shift how the modern plasma industry operates (Steinhardt 1998).