The Selection and Control of Starting Materials Should be Governed by Science and Risk-Based Approaches

Patient safety and efficacy fundamentally rely on demonstrated assurance of pharmaceutical product quality and consistency. Material and product specifications confirm that critical product quality attributes (CQAs) are controlled. However, a definition of a robust functional relationship between product CQAs and material attributes and/ or process parameters is the most effective means of reducing risk and increasing confidence in quality throughout the lifecycle of the product. In fact, the safety of a product is frequently attributed to its purity, as characterized by its impurity/degradation profile. Some impurities can originate from starting materials used in the manufacture of the active drug substance (API). In recent years, the quality and reliability of the supply chain, particularly the control of starting materials, have increasingly become the focus of industry and regulator concerns. While ICH Q11 provides scientifically justifiable guidance and guiding principles for the selection of starting materials, significant differences in the interpretation of that guidance has not engendered the expected level of global harmonization. ICH Q11 was finalized and adopted in 2012 and provided a long anticipated opportunity to harmonize the selection and justification of starting materials for the manufacture of drug substances. The success or failure of any starting material proposal in a regulatory submission has global implications with respect to current Good Manufacturing Practices (cGMPs), process validation requirements and inspection-related activities (ICHQ7). In addition, the rejection of a proposed starting material can and has resulted in compliance disconnects for qualification of commercial launch supplies. The ICH Q11 guideline recommends a threshold of criteria within themanufacturing process supply chainwhere the risk of upstream change is sufficiently low to pose negligible risk to drug substance quality. In fact, a science and risk based approach can effectively establish this threshold in the manufacturing process for a specific drug substance to adequately characterize the fate and demonstrate purge of upstream impurities. Nevertheless, a perception that a specific number of steps and/ or isolation/purification operations will always be needed to insulate API quality from unknown impurity risks remains and results in a palpable concern of inconsistent application of ICH Q11 principles. The appropriate scientific threshold in a manufacturing process is reflected by a control strategy that effectively manages the supply chain for starting materials by accommodating changes in the source and preparation of starting materials and ensuring the requisite quality of the drug substance has been demonstrated within a company Pharmaceutical Quality System. That control strategy, by definition, is established based on relative risk associated with the detection and control of impurities. ICH Q11 states: