Safety assessment of protein A and derivation of a parenteral health-based exposure limit

Protein A (PA) is a bacterial cell wall component of Staphylococcus aureus whose function is to bind to Immunoglobulin G (IgG). Given its ability to bind IgG as well as its stability and resistance to harsh acidic and basic cleaning conditions, it is commonly used in the affinity chromotography purification of biotherapeutics. This use can result in levels of PA being present in a drug product and subsequent patient exposure. Interestingly, PA was previously evaluated in clinical trials as well as supporting nonclinical studies, resulting in a database that enables the derivation of a health-based exposure limit (HBEL). Given the widespread use of PA in the pharmaceutical industry, the IQ DruSafe Impurities Safety Working Group (WG) evaluated the available information with the purpose of establishing a harmonized parenteral HBEL for PA. Based on this thorough, collaborative evaluation of nonclinical and clinical data available for PA, a parenteral HBEL of 1.2 μg/kg/dose (60 μg/dose for a 50 kg individual) is expected to be health protective for patients when it is present as an impurity in a biotherapeutic. • PA is used in the purification of biotherapeutics and can be an impurity in a DP. • PA has been evaluated in nonclinical studies and clinical trials. • The parenteral HBEL for PA based on available nonclinical data is 3 μg/kg. • The parenteral HBEL for PA based on available clinical data is 1.2 μg/kg. • A conservative parenteral HBEL for PA is 1.2 μg/kg/dose.