A Safety Risk-Based Extractables and/or Leachables Qualification Strategy for Packaged Drug Products.

During storage and distribution of a packaged drug product, chemical substances present in or on the packaging may leach into the drug product, potentially adversely affecting the drug product's key quality attributes, including safety. Thus, the packaging is profiled for extractables as potential leachables and/or the drug product is profiled for leachables over shelf life via the process of chemical characterization. In so doing, the packaging and the packaged drug product are qualified as being suited for their intended use. It is reasonable to propose that the extent of chemical characterization required to qualify the packaging and the packaged drug product depends on the risk that leached substances could adversely affect drug product quality; the higher the risk, the more extensive and rigorous the required qualification. Although regulatory guidance supports and advocates such a risk-based approach to chemical characterization, the existing guidance is founded on an overly simplified approach to risk assessment, leading to incongruous risk classifications for certain classes of drug products. Furthermore, the existing guidance no longer links risk to current requirements concerning the extent of chemical characterization necessary to secure regulatory approval of drug product applications. To address these circumstances, this manuscript proposes and justifies a risk classification process (risk evaluation matrix) for drug products and packaging and a risk-based approach to chemical characterization requirements, linking risk to the degree and rigor of the chemical characterization process and establishing chemical characterization requirements for individual risk classes.