In Tier 2 of this criticality analy

In Tier 2 of this criticality analysis, the individual process parameters within each of the synthetic stepswere evaluated to define their proven acceptable ranges (PARs) and normal operating ranges (NOR),and to assess their potential impact as Critical Process Parameters (CPPs) on the CQAs of the activesubstance. The process parameters studied were chosen based on previous process knowledge gained from process development and manufacturing of batches used in clinical development. Design ofExperiments (DOE) studies were performed to define the PARs and subsequently set the NORs of theprocess within the PARs. The process parameters are variables of the process which can be measured and controlled and must be within a pre-established range, such as temperature, time, solvent ratios,etc. Once the PARs for the process parameters were established, and the effects on the CQAs were known, they were classified as either a CPP or non-CPP. The classification was based on the NORrelative to the PAR (the likelihood and detectability of excursion from the established limits, and the potential impact on either the manufacturing process (i.e., yield, robustness, etc.), or the quality of thefinal active substance.