Advancing toxicology in RiskMAPP: setting ADEs based on the subsequent drug substance.

Cleaning validation programs are developed to demonstrate acceptable carryover of drug substances/products when multiple drug substances are manufactured in shared process equipment. The International Society of Pharmaceutical Engineers (ISPE) developed a guidance document in 2010 describing the Risk-Based Manufacture of Pharmaceutical Products (referred to as RiskMAPP) (ISPE, 2010). This guidance document developed the concept of an acceptable daily exposure (ADE), which is the toxicologically acceptable daily dose for the first drug substance used in processing drug equipment (DS(A)) without prior knowledge of the subsequent drug substance (DS(B)). This paper discusses an extension of the ADE methodology called the product-specific ADE (PSADE) which is derived when DS(B) is known. Four case studies demonstrate examples in which the PSADE can be scientifically supported in lieu of the ADE and highlight some limitations in its application. The PSADE approach can be used to justify higher acceptance limits for cleaning validation when the ADE based acceptance limits are below the process capability limit of the cleaning process or limit of quantitation of the analytical method.