Pfizer Worldwide Research, Development and Medical, Sandwich, United Kingdom;
GlaxoSmithKline, Ware, United Kingdom.
PDA J Pharm Sci Technol. 2024 Aug 23;78(4):399-444. doi: 10.5731/pdajpst.2022.012811.
Quality by design is the foundation of the risk management framework for extractables and leachables (E&Ls) recommended by the Extractables and Leachables Safety Information Exchange (ELSIE). Following these principles during the selection of materials for pharmaceutical product development minimizes the presence of highly toxic substances and decreases the health risk of potential leachables in the drug product. Therefore, in the context of the broad arena of chemicals, it is important to distinguish E&Ls as a subset of chemicals and evaluate this relevant chemical space to derive appropriate analytical and safety thresholds. When considering the health hazards posed by E&Ls, one area presenting a challenge is understanding the sensitization potential and whether it poses a risk to patients. A dataset of E&Ls compiled by ELSIE (n = 466) was analyzed to determine the prevalence and potency of skin sensitizers in this chemical subset and explore a scientifically justified approach to the sensitization assessment of potential leachables in parenteral drug products. Approximately half of the compounds (56%, 259/466) had sensitization data recorded in the ELSIE database and of these, 20% (52/259) are potential skin sensitizers. Only 3% (8/259) of the E&L dataset with sensitization data were considered potent (strong or extreme) sensitizers following in silico analysis and expert review, illustrating that potent sensitizers are not routinely observed as leachables in pharmaceutical products. Our analysis highlights that in silico potency prediction and expert review are key tools during the sensitization assessment process for E&Ls. The results confirm where material selection is anticipated to mitigate the risk of presence of strong and/or extreme sensitizers (e.g., extractable testing via ISO 10993-10), and that implementing thresholds per ICH M7 and/or Masuda-Herrera et al. provides a reasonably conservative approach for establishing the analytical testing and safety thresholds.
基于设计的质量是提取和浸出物（E&Ls）风险管理框架的基础，该框架由提取和浸出物安全信息交换（ELSIE）推荐。在药物产品开发过程中选择材料时遵循这些原则，可以最大限度地减少剧毒物质的存在，并降低药物产品中潜在浸出物的健康风险。因此，在广泛的化学领域中，重要的是将 E&Ls 作为化学物质的一个子集来区分，并评估这个相关的化学空间，以得出适当的分析和安全阈值。在考虑 E&Ls 带来的健康危害时，一个具有挑战性的领域是了解致敏潜力，以及它是否对患者构成风险。对 ELSIE （n=466）汇编的 E&L 数据集进行了分析，以确定这个化学子集的皮肤致敏剂的流行率和效力，并探讨一种科学合理的方法来评估潜在的注射药物中浸出物的致敏性。大约一半的化合物（56%，259/466）在 ELSIE 数据库中记录了致敏数据，其中 20%（52/259）是潜在的皮肤致敏剂。只有 3%（8/259）的具有致敏数据的 E&L 数据集被认为是潜在的强致敏剂（强或极度），这是在计算机分析和专家审查后得出的结果，表明强致敏剂通常不会作为药物产品中的浸出物出现。我们的分析表明，在致敏性评估过程中，计算机预测和专家审查是关键工具。结果证实了在材料选择方面，预期可以降低存在强和/或极度致敏剂的风险（例如，通过 ISO 10993-10 进行的可提取性测试），并且根据 ICH M7 和/或 Masuda-Herrera 等人实施阈值，可以为建立分析测试和安全阈值提供一种合理保守的方法。
