A Risk-Based Approach to Evaluate and Control Elemental Impurities in Therapeutic Proteins.

Control of elemental impurities in the drug products evolved from the generic visual testing of heavy metals as their sulfides to specific elements of toxicological concern in the final drug products by instrumental analysis. The International Council for Harmonisation (ICH) Q3D (R1) guideline for elemental impurities describes a risk-based approach to identify, assess, and control the potential elemental impurities in drug products within the established permitted daily exposures (PDE). Challenges to this approach include how to assess the risks associated with contributing sources such as utilities, manufacturing equipment, container-closure systems, and excipients. Defining at what stage of development that such assessment should be performed to identify the risk levels can be equally challenging. In this article, we report an approach to control elemental impurities of toxicological concern, compliant to the Q3D (R1) guideline, and a summary of results obtained on multiple protein therapeutic products. This approach follows the elements of Process Validation, i.e., Design, Qualification, and Continuous Verification. The design includes the selection of excipients and their suppliers that meet the Option 1 requirement of Q3D (R1). It also comprises the selection of manufacturing equipment, container-closure systems, and utilities. The qualification includes the testing of the potential sources of elemental impurities, i.e., excipients, utilities, and leachables/extractables from the manufacturing equipment and container-closure systems. The Continuous Verification comes from the testing of representative batches at the initiation of stability studies of clinical or commercial drug product batches and at the end of shelf-life expiry of the drug product, and when changes are made to the manufacturing equipment, sources of excipients and container closure systems, and any formulation changes. Our experience shows that the risk associated with the impurity levels of the ten elements of toxicological concern in the therapeutic protein drug products, parenterally administered, is well below the control threshold (30% PDE) in the drug product recommended by the ICH Guideline. Although our focus is on the injectable therapeutic proteins, this approach can be applied to the products administered via other routes as well.