WHO 第992号技术报告 附录3 非无菌工艺验证
Annex 3
Guidelines on good manufacturing practices: validation, Appendix 7: non?sterile process validation Background
The appendices of the Supplementary guidelines on good manufacturing practices:validation currently comprise the following:
Appendix 1. Validation of heating, ventilation and air-conditioning systems Appendix 2. Validation of water systems for pharmaceutical use Appendix 3. Cleaning validation Appendix 4. Analytical method validation Appendix 5. Validation of computerized systems Appendix 6. Qualification of systems and equipment
Appendix 7. Non-sterile process validation – revised text reproduced in this Annex 1. Background and scope 背景和范围 2. Glossary 术语 3. Introduction 概述 4. Process design 工艺设计 5. Process qualification 工艺确认
6. Continued process verification 持续工艺确认 7. Change management 变更管理 References 参考文献
1. Background and scope 背景和范围
Further to the Supplementary guidelines on good manufacturing practices: validation, as published in the World Health Organization (WHO) Technical Report Series, No. 937 (1), additional guidelines to support current approaches to good manufacturing practices (GMP) are published here. These guidelines are intended to further support the concept of process validation linked to quality risk management (QRM) and quality by design principles as described by WHO and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
WHO第937号技术报告中公布了GMP增补指南：验证，此外还公布了一些指南来支持现行的GMP实施方法。这些指南意在为WHO和ICH的质量源于设计原则（QbD）和质量风险管理（QRM）提供更多的工艺验证概念支持。
These guidelines allow for different approaches to process validation. The principles described are mainly applicable to non-sterile finished pharmaceutical dosage forms. Similar approaches may be applicable to active
pharmaceutical ingredients (APIs) and sterile products. (See also recommendations in WHO Technical Report Series, No. 957, Annex 2 (2) and WHO Technical Report Series, No. 961, Annex 6 (3).) A risk-based and life-cycle approach to validation is recommended.
这些指南允许使用不同的方法来实现工艺验证。其所描述的原则主要适用于非无菌制剂。类似方法也可以用于原料药和无菌产品。（参见WHO第957号技术报告附录2，以及WHO第961号技术报告附录6）。推荐采用基于风险的生命周期方法来进行验证。
Thorough knowledge of product and process development studies; previous manufacturing experience; and QRM principles are essential in all approaches to process validation, as the focus is now on the life-cycle approach. 由于现在主要聚焦于生命周期方法，因此在所有工艺验证方法中均需要对产品和工艺研发研究的深入的知识、之前的生产经验以及应用QRM原则。
The life-cycle approach links product and process development, validation of the commercial manufacturing process and maintaining the process in a state of control during routine commercial production.
生命周期方法将产品和工艺研发、商业化生产工艺的验证、在日常商业化生产中将生产工艺维持在受控状态结合了起来。
The use of process analytical technology (PAT), which may include in?line, online and/or at-line controls and monitoring, is recommended to ensure that a process is in a state of control during manufacture.
推荐使用过程分析技术（PAT），包括远线、近线和/或在线控制和监测技术，以保证工艺在生产过程中处于受控状态。 2. Glossary 术语（略）
The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts.
以下给出的定义适用于这些指南中所用的术语。在其它不同语境中可能有不同含义。 at-line.
Measurement where the sample is removed, isolated from, and analysed in close proximity to the process stream. concurrent validation.
Validation carried out during routine production of products intended for sale in exceptional circumstances when data from replicate production runs are unavailable because only a limited number of batches have been produced, batches are produced infrequently or batches are produced by a validated process that has been modified. Individual batches may be evaluated and released before completion of the validation exercise, based on thorough monitoring and testing of the batches. control strategy.
A planned set of controls, derived from current product and process understanding that assures process performance and product quality.
The controls can include parameters and attributes related to API and finished pharmaceutical product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications and the associated methods and frequency of monitoring and control. continued process verification.
Documented scientific evidence that the process remains in a state of control during commercial manufacture.
critical process parameter.
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored and/or controlled to ensure the process produces the desired quality. critical quality attribute.
A physical, chemical, biological or microbiological property or characteristic of materials or products that should be within an appropriate limit, range or distribution to ensure the desired product quality. in-line.
Measurement where the sample is not removed from the process stream: can be invasive or non-invasive. life cycle.
All phases in the life of a product from the initial development through marketing until the product’s discontinuation (ICH Q8 (4)). matrix approach or bracketing.
Bracketing is the assessment of a single parameter or variable by identifying the edge(s) of the range of conditions for the parameter or variable and assessing these during validation to span the possible range of that parameter or variable. For example, bracketing can be applied to process parameters, ultiple pieces of identical equipment and/or different size considerations for the same product. The rationale for using this strategy should be justified, documented and approved.
Matrixing involves the assessment of the effect of more than one parameter or variable by using a
multidimensional matrix to identify the “worstcase” or “extreme” conditions for a combination of parameters or variables.
These conditions are used during validation of the process, rather than validating all possible combinations. Matrixing is typically used when there are significant similarities between products in a product family (e.g. the same product with different strengths in the manufacturing stage or different products with a similar container-closure in the packaging stage). The rationale for using this strategy should be justified, documented and approved. The use of a matrix approach or bracketing design would not be considered appropriate if it is not possible to demonstrate that the extremes are limited to the batches, products, strengths, container sizes or fills. For those excluded from the exercise there should be no risk to process capability. online.
Measurement where the sample is diverted from the manufacturing process, and may be returned to the process stream.
pharmaceutical quality system.
Management system to direct and control a pharmaceutical company with regard to quality. process qualification.
Process qualification combines the actual facility, utilities, equipment (each now qualified) and the trained personnel with the commercial manufacturing process, control procedures and components to produce commercial batches; confirms the process design and demonstrates that the commercial manufacturing process performs as expected.
process validation.
WHO 第992号技术报告 附录3 非无菌工艺验证汇编
