WHO 第992号技术报告 附录3 非无菌工艺验证

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:validationcurrently 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.

The collection and evaluation of data, from the process design stage through to commercial production, which establishes scientific evidence that a process is capable of continuously delivering the finished pharmaceutical product meeting its predetermined specifications and quality attributes. quality target product profile (QTPP).

A prospectively documented summary of the quality characteristics of a finished pharmaceutical product (FPP) that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the FPP. The QTPP forms the basis of design for the development of the product and typically would include: - intended use in clinical setting, route of administration, dosage form, delivery systems; - dosage strength(s); - container-closure system;

- therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g.

dissolution, aerodynamic performance) appropriate to the FPP dosage form being developed;

- FPP quality criteria (e.g. sterility, purity, stability and drug release) appropriate for the intended marketed

product.

real-time release testing.

The ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls. state of control.

A condition in which the set of controls consistently provides assurance of continued process performance and product quality. 3. Introduction 概述

Process validation data should be generated for all products to demonstrate the adequacy of the manufacturing process. The validation should be carried out in accordance with GMP and data should be held at the manufacturing location whenever possible and should be available for inspection.

所有产品均应生成工艺验证数据，以证明生产工艺的充分性。所实施的验证应符合GMP要求，验证数据应保留在生产场所，检查中应可以获取。

Process validation is associated with the collection and evaluation of data throughout the life cycle of a product – from the process design stage through to commercial production – and provides scientific evidence that a process is capable of consistently delivering a quality product.

工艺验证与产品从工艺设计阶段到商业化生产的整个生命周期中数据收集和评估过程紧密相关，它提供科学证据证明一个工艺可以持续地产生一个具备所需质量的产品。

A risk assessment approach should be followed to determine the scope and extent to which process(es) and starting material variability may affect product quality. The critical steps and critical process parameters should be identified, justified and documented and based on relevant studies carried out during the design stage and on process knowledge, according to the stages of the product life cycle. During process validation and qualification, the critical process parameters should be monitored.

应采用风险评估方法来确定工艺的范围和深度，以及可能影响产品质量的起始物料波动。应根据设计阶段所实施的相关研究和对工艺的理解，根据产品生命周期的不同阶段，对关键步骤和关键工艺参数进行识别、论述和记录，在工艺验证和确认期间，应对关键工艺参数进行监测。

It may be helpful to use a flow diagram depicting all the operations and controls in the process to be validated. When applying QRM to a given operation, the steps preceding and following that operation should also be considered.

绘制要验证的工艺中所有操作和控制流程图将有所帮助。在对一个给定的操作实施QRM时，也应考虑该操作前后的步骤。

Amendments to the flow diagram may be made where appropriate, and should be recorded as part of the validation documentation.

适当时应对流程图进行修正，修正内容应记录作为验证文件的一部分。

Manufacturers should ensure that the principles of process validation described in these guidelines are implemented. These cover the phases of validation during process design, scale-up, qualification of premises, utilities and equipment and process performance qualification, and continuous process verification to ensure that the process remains in a state of control.

生产商应保证按本指南中所述的工艺验证的原则实施工艺验证。这包括了在工艺设计、放大、厂房确认、公用系统和设备和工艺性能确认、持续工艺确认中的各验证阶段，以保证工艺保持在受控状态。 The objectives of process validation include ensuring that: 工艺验证的目的包括保证：

- the process design is evaluated to show that the process is reproducible, reliable and robust; - 工艺设计经过评估，显示出工艺具可重复性、可靠性和耐用性 - the commercial manufacturing process is defined, monitored and controlled; - 对商业生产工艺进行了定义、监测和控制

- assurance is gained on a continuous basis to show that the process remains in a state of control. - 保证工艺持续保持在受控状态

The validation should cover all manufactured strengths of a product and the extent of validation at each manufacturing site should be based on risk assessment. A matrix approach or bracketing may be acceptable and should also be based on appropriate risk assessment.

验证应包括生产产品的所有剂量，各生产场所的验证深度应根据风险评估来确定。可以使用矩阵法或括号法（分组法），这些方法的使用也应该是基于适当的风险评估。

There are various approaches to process validation which include: traditional process validation (consisting of prospective and concurrent validation); process design followed by process qualification and continued process verification; or a combination of traditional process validation and the new approach described in these guidelines. Historical data should be evaluated in cases where there have been changes to the process.

可以有不同的工艺验证方法，包括：传统工艺验证（包括前验证和同步验证）、工艺设计和之后的工艺确认和持续工艺确认，或传统工艺验证方法与这些指南中所述的新方法的结合。如果对工艺进行了变更，则需要对历史数据进行评估。

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