1.1 本指南概述了在制药和生物制药的过程分析技术（PAT）范式下基于风险的过程分析方法验证，因此包括评估不当方法验证对产品质量的风险的指南。 1.2 本指南以验证主题的现有标准为基础，重点是将此类标准应用于在线分析的分析方法。特别是，它涉及at在线、在线或在线PAT测量的验证，并涵盖原料药和药品（DP）测量。 1.3 国际协调理事会（ICH）验证参数的定义（如特异性、精密度、重复性等）适用；然而，验证参数的证明方法可能与ICH中描述的不同，本文对此进行了讨论。 1.4 根据美国食品和药物管理局（FDA）工艺验证指南，本文件还简要介绍了在日常使用过程中该方法保持在验证状态的持续保证。 1.5 设备和仪器鉴定不在本指南范围内，但将作为PAT应用分析方法验证的输入参考。 1.6 多元预测模型的验证超出范围，但将作为PAT应用分析方法验证的输入。 1.6.1 PAT方法中使用的任何分析模型的验证对于PAT方法的验证至关重要，但模型验证过程的细节超出了范围。参见术语 模型验证 , 3.1.7 . 1.7 微生物方法超出范围。 1.8 本标准并非旨在解决与其使用相关的所有安全问题（如有）。本标准的用户有责任在使用前制定适当的安全、健康和环境实践，并确定监管限制的适用性。 1.9 本国际标准是根据世界贸易组织技术性贸易壁垒（TBT）委员会发布的《关于制定国际标准、指南和建议的原则的决定》中确立的国际公认标准化原则制定的。 ====意义和用途====== 4.1 本指南支持指南原则 E2500 并将这些原则扩展到PAT应用的分析方法验证。 正在进行的方法验证过程如图所示 图1 ，显示了PAT应用分析方法验证的生命周期。验证的先决条件是确定测量要求和开发满足这些要求的方法。 图1 PAT应用分析方法验证的生命周期 4.2 该方法风险评估还考虑了产品生命周期中进行测量的阶段以及结果数据的使用方式。将这些考虑因素整合到风险评估中有助于确定必要的验证级别，以确保该方法适合目的。 4.3 产品生命周期内可能会发生变化，需要识别测量要求的变化以及方法更新和重新验证。 应制定程序，以评估过程分析方法的持续适用性，并提出适当的建议，以更新产品生命周期内预期用途的过程分析方法。 4.4 在实践中可以找到更多信息示例 D3764 , D6122 , E1655 , E1790 , E2056年 , E2617 和 E2656 ; 和指南 E2891 这涉及方法和模型的验证。其他有用的标准包括ASME BPE2019、ISO 14971、ISO 15839和USP声发射。

1.1 This guide provides an overview to the risk-based validation of process analytical methods under a process analytical technology (PAT) paradigm for pharmaceuticals and biopharmaceuticals and as such includes guidance on assessing risk to product quality from inappropriate method validation. 1.2 This guide builds on existing standards on the topic of validation concentrating on applying such standards to analytical methods for on-line analysis. In particular, it addresses the validation of at-line, on-line, or in-line PAT measurements and covers both drug substance and drug product (DP) measurements. 1.3 The definitions of International Council for Harmonisation (ICH) validation parameters (such as specificity, precision, repeatability, etc.) apply; however, the method of demonstrating the validation parameters may vary from that described in ICH and is discussed. 1.4 As consistent with the U.S. Food and Drug Administration (FDA) process validation guidance, this document also briefly covers ongoing assurance that the method remains in a validated state during routine use. 1.5 Equipment and instrument qualification are out of the scope of this guide but will be referenced as inputs to validation of analytical methods for PAT applications. 1.6 The validation of multivariate prediction models is out of scope but will be referenced as inputs to validation of analytical methods for PAT applications. 1.6.1 The validation of any analytical model used in the PAT method is essential to the validation of the PAT method but, the details of the model validation process is out of scope. See term model validation , 3.1.7 . 1.7 Microbiological methods are out of scope. 1.8 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use. 1.9 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee. ====== Significance And Use ====== 4.1 This guide supports the principles of Guide E2500 and extends these principles to validation of analytical methods for PAT applications. The ongoing process of method validation is graphically represented in Fig. 1 , which shows the life cycle of the validation of analytical methods for PAT applications. Prerequisites for validation are the identification of the measurement requirements and development of a method to meet those requirements. FIG. 1 Life Cycle for the Validation of Analytical Method for PAT Applications 4.2 The method risk assessment also takes into account the stage in the product life cycle at which the measurements are being made and how the resulting data will be used. The integration of these considerations in the risk assessment facilitates the determination of the level of validation necessary to ensure that the method is fit for purpose. 4.3 Changes may occur during the product life cycle necessitating identification of changes to the measurement requirements and method update and revalidation. Procedures should be established to evaluate the continued suitability of the process analytical method and to make appropriate recommendations to update the process analytical method for the intended use during the product life cycle. 4.4 Additional informative examples can be found in Practices D3764 , D6122 , E1655 , E1790 , E2056 , E2617 , and E2656 ; and Guide E2891 that address validation of methods and models. Other useful standards include ASME BPE2019, ISO 14971, ISO 15839, and USP Acoustic Emission <1005>.