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
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.

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。

Manufacturers should plan to implement the new approach to process validation, which covers process design, process qualification and continued process verification throughout the product life cycle.

生产商应计划实施新的工艺验证方法，它包括工艺设计、工艺确认和持续工艺确认，贯穿产品的整个生命周期。

Figure A3.1 shows the phases in the new approach to process validation.

图A3.1展示了新的工艺验证方法的各阶段。

                               
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图A3.1工艺验证各阶段

                               
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4. Process design 工艺设计

Under the life-cycle approach, the focus of validation is shifted from commercial scale batches to development. Product development activities provide key inputs to the process design stage, such as the intended dosage form, the quality attributes and a general manufacturing pathway. Laboratory or pilot-scale models designed to be representative of the commercial process can be used to estimate variability.

在生命周期方法中，验证的焦点从商业化规模批次转移至研发。产品研究发活动提供了关键的工艺设计阶段输出，例如所需的剂型、质量属性和通用生产途径。所设计的代表商业工艺的实验室或中试模型可以用于预测变动性。

Process design should normally cover design of experiments, process development, the manufacture of products for use in clinical trials, pilot-scale batches and technology transfer. Process design should be verified during product development.

工艺设计一般应包括实验设计、工艺研发、临床试验产品生产、中试规模批次和技术转移。在产品研发期间应对工艺设计进行确认。

Process design should cover aspects for the selection of materials, expected production variation, selection of production technology/process and qualification of the unitary processes that form the manufacturing process as a whole, selection of in-process controls, tests, inspection and its suitability for the control strategy.

工艺设计应包括原料的选择、预期生产变动、生产技术/工艺的选择、形成整个生产工艺的单个工艺环节的确认、过程控制、检测、检查的选择，以及其是否适合控制策略。

As part of the process validation life cycle some process validation studies may be conducted on pilot-scale batches (corresponding to at least 10% or 100 000 units, whichever is the greater) of the production scale. Where the batch size is smaller and/or where the process is tailored to the geometry and capacity of specific equipment, it may be necessary to provide production-scale validation data.

作为工艺验证生命周期的一部分，一些工艺验证研究可能需要在中试批次中实施（对应至少10%或100000个制剂单位，取其中大者）。如果批量更小，和/或工艺根据特定设备的几何形状和产能定制，则可能需要提供应放大生产验证数据。

Process qualification and continued process verification should always be linked to process design and be referenced to those specific batches used in studies critical to the development of the product, for example, the batch(es) used for pivotal clinical assessments (biobatch(es)), e.g. bioequivalence testing in the case of multisource products) and toxicological studies. The number of batches included in the process design stage of validation should be appropriate and sufficient to include (but not be limited to) the expected variations in starting materials, and confirm the suitability of the equipment and manufacturing technology. A statistically-based design of experiment approach can be helpful during this stage. Processes and results should be appropriately documented.

工艺确认和持续工艺确认应保持与工艺设计相关联，要参照产品研发中的关键研究所用特定批次，例如，用于关键临床评估（生物批）的批次，例如，多用途产品生物等效性测试和毒理研究。工艺设计阶段验证批次数应适当且充分，应包括（但不仅限于）预期的起始物料变化，确认设备和生产技术的适用性。基于统计学的实验设计方法在此阶段会有所帮助。应适当记录验证过程和结果。

A development report and/or a technology transfer document, formally reviewed and approved by research and development personnel, and formally accepted by manufacturing, engineering and quality personnel, should be prepared. Such a document may include information such as QTPP, desired clinical performance, bills of materials, approved suppliers, finished product specifications and test methods, in-process testing specifications, equipment recommendations, master batch production records, master batch packaging records, stability reports, critical quality attributes, critical process parameters, batch comparisons, data on formulation batches, stability batches, clinical/ biobatches and scale-up batches. These documents should be readily available to the manufacturing site.

应起草研发报告和/或技术转移文件，由研发人员正式审核和批准，由生产、工程和质量部人员正式接受。该文件可以包括一些信息如QTPP、所需要临床表现、物料的帐单、批准的供应商、成品质量标准和检测方法、中控检测质量标准、设备建议、主批记录、主包装记录、稳定性报告、关键质量属性、关键工艺参数、工艺比较、制剂批数据、稳定性试验批、临床/生物批、和放大批。这些文件在生产场所应易于获得。

The goal is to design a suitable process for routine commercial manufacturing that can consistently deliver a product that meets its required quality attributes.

其目的是设计出适当的工艺用于日常商业化生产，可以持续生产出符合所需质量属性的产品。

5. Process qualification 工艺确认

Personnel, premises, utilities, support systems and equipment should be appropriately qualified before manufacturing processes are validated. Materials, environmental controls, measuring systems, apparatus and methods should be considered during validation. The stages of qualification of equipment may include design, installation, operation and performance of equipment (for more details see (WHO Technical Report Series, No. 937, Annex 4 (1)).

在验证生产工艺之前，人员、设施、公用系统、支持性系统和设备应经过适当的确认。在验证过程中要考虑物料、环境控制、测量系统、仪器和方法。设备的确认阶段可以包括设计、安装、运行和性能（更多细节参见WHO第937号技术报告附录4）。

Traditionally, three batches have been considered the normal and acceptable number for process validation; however, the number of batches should be justified and based on a risk assessment that includes, for example, variability of results from the process design stage, variability of materials, product history, where the product is being transferred from and where it will be produced.

传统验证方法中，通常认为三批是可接受的工艺验证批次，但是，验证批次数应基于风险评估来进行论证，其中包括，例如，结果偏离工艺设计阶段、原料变化、产品历史、产品从何地转移而来及要转移到何处去。

Manufacturers should define the stage at which the process is considered to be validated and the basis on which that decision was made. The decision should include a justification for the number of batches used based on the complexity and expected variability of the process and critical quality attributes (CQAs).

生产商应定义在哪个阶段认为工艺是经过了验证的，根据什么做出这样的决定。决定应包括基于工艺复杂性和预期变化以及关键质量属性（CQA）所做出的验证批次数的论证。

Successful completion of process performance qualification stage of the life cycle is required for commercial distribution.

商业化销售要求成功完成生命周期阶段的工艺性能确认。

A risk assessment should be performed for the change from scale-up to commercial batch size. Process qualification should confirm that scale-up in batch size did not adversely affect the characteristics of the product and that a process that operates within the predefined specified parameters consistently produces a product which meets all its CQAs and control strategy requirements.

对商业批量放大时应进行风险评估。工艺确认应确认批量放大不会对产品特性有负面影响，按既定参数操作的工艺可以持续生产中符合所有CQA和控制策略要求的产品。

The process should be verified on commercial-scale batches prior to marketing of the product.

产品上市前应对商业规模批进行工艺确认。

Extensive in-line and/or online and/or at-line controls may be used to monitor process performance and product quality in a timely manner. Results on relevant quality attributes of incoming materials or components, in-process material and finished products should be collected. This should include the verification of attributes, parameters and end-points and assessment of CQA and critical process parameter (CPP) trends. Process analytical technology applications and multivariate statistical process control can be used.

广泛使用远线、近线、在线控制可以及时监测工艺性能和产品质量。应收集进厂物料或组分、在制物料和成品相关质量属性的结果，这些结果可以包括属性、参数和终点的确认、CQA和关键工艺参数（CPP）趋势的评估。可以使用过程分析技术应用工具和多变量统计过程控制。

Manufacturers are encouraged to implement the new validation approach to ensure that processes are of known and acceptable capability. As full implementation of this approach may take time, the traditional approach of prospective validation and concurrent validation (used infrequently and restricted to the scenarios described in section 2) may be acceptable in the interim.

鼓励生产商实施新的验证方法，以保证工艺具有已知的可接受的能力。由于全面实施本方法可能需要一定的时间，传统的前验证和同步验证方法（不经常使用，仅限于第2部分所述的情形）在过渡时间内也可以接受。

A combination of elements of the traditional process validation approach and the new continuous process verification approach may be considered appropriate, subject to appropriate controls being in place, based on scientific justification and risk management principles.

如果具有适当的控制，基于科学论述和风险管理原则，将传统工艺验证方法中的元素与新的持续工艺确认方法相结合是可以接受的，

Validation should be done in accordance with process validation protocols.

验证应根据工艺验证方案进行。

A written protocol is essential for this stage of process validation. The protocol should include or reference at least the following elements:

本阶段工艺验证需要有书面的方案。方案应包括，或参考至少以下内容：

-    the manufacturing conditions including operating parameters, processing limits and component (raw material) inputs;

-    生产条件，包括操作参数、工艺限度和组分（原料）输入

-    the data to be collected and when and how they will be evaluated;

-    要收集的数据，这些数据要在什么时间怎么样评估

-    the type of testing or monitoring to be performed (in-process, release, characterization) and acceptance criteria for each significant processing step;

-    要实施的检测或监测的类型（中控、放行、定性），以及各重要工艺步骤的可接受标准

-     the scientifically justified sampling plan, including sampling points, number of samples and the frequency of sampling for each unit operation and attribute;

-     经过科学论证的取样计划，包括各单元操作和属性的取样点、样品数量和取样频次

-     the number of batches for which additional monitoring is proposed;

-     拟进行额外监测的批次数量

-     status of the validation of analytical methods used in measuring the process, in-process materials and the product;

-     用于工艺、中控物料和产品测量的分析方法的验证状态

-     a description of the statistical models or tools used;

-     所用统计学模型或工具的描述

-     review and approval of the protocol by appropriate departments and the quality unit;

-     由适当的部门和质量部门对方案进行审核和批准

-     a description of the process;

-     工艺描述

-     details of the equipment and/or facilities to be used (including measuring or recording equipment) together with its calibration status;

-     所用设备和/或设备的详细说明（包括测量和记录设备），及其校正状态

-     the variables to be monitored with appropriate justification;

-     要监测的变更及适当的论证

-     the samples to be taken – who, where, when, how, how many and how much (sample size);

-     要取的样品---谁、在什么地方、什么时间、如何取、取多少（样品数量）

-     the product performance characteristics or attributes to be monitored, together with the test methods;

-     要监测的产品性能特性或属性，以及检测方法

-     the acceptable limits;

-     可接受限度

-     personnel responsibilities;

-     人员职责

-     details of methods for recording and evaluating results, including statistical analysis.

-     记录和评估结果的方法细节，包括统计学分析

Data should be collected and reviewed against predetermined acceptance criteria and fully documented in process validation reports. The report should reflect the validation protocol. A dual protocol report can be used; however, such reports must be designed to ensure clarity and sufficient space for recording of results. The outcome should confirm that the acceptance criteria have been met.

应收集数据，并按既定的可接受标准进行审核，并全部记录在工艺验证报告中。报告应反映出验证方案的要求。可以使用方案报告合并的方式，但是，这样的报告的设计必须保证内容的清晰，并留有足够的空间来记录结果。结果应确认符合可接受标准。

Any deviations (including abandoned studies) should be explained and justified.

所有偏差（包括废弃的研究）均应进行解释和论述。

The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next phase for confirmation.

包括操作限度和总体工艺控制策略的计划商业生产和控制记录，应进入下一阶段进行确认。

6. Continued process verification 持续工艺确认

Manufacturers should monitor product quality of commercial batches after completion of process design and process qualification. This will provide evidence that a state of control is maintained throughout the product life cycle.

在工艺设计和工艺确认完成后，生产商应监测商业批次的产品质量，这样可以提供证据证明在产品的生命周期中工艺均维持在受控状态。

The scope and extent of process verification will be influenced by a number of factors including:

工艺确认的范围和深度可能会受到许多因素的影响，包括：

-     prior development and knowledge of the manufacturing of similar products and/or processes;

-     预研究和类似产品和/或工艺生产的知识

-     the extent of process understanding gained from development studies and commercial manufacturing experience;

-     研发过程和商业生产经验中获得的对工艺理解的深度

-     the complexity of the product and/or manufacturing process;

-     产品和/或生产工艺的复杂性

-     the level of process automation and analytical technologies used;

-     所采用工艺自动化和分析技术的水平

-     for legacy products, with reference to the product life-cycle process robustness and manufacturing history since the point of commercialization, as appropriate.

-     对于遗留产品，适当时应参照自商业生产以来产品的生命周期工艺耐用性和生产历史

Manufacturers should describe the appropriateness and feasibility of the verification strategy (in the protocol) including the process parameters and material attributes that will be monitored as well as the validated analytical methods that will be employed.

生产商应描述确认策略的适当性和可行性（在方案中），包括要监测的工艺参数和物料属性，以及要使用的经过验证过的分析方法。

Manufacturers should define:

生产商应界定

-     the type of testing or monitoring to be performed;

-     要实施的检测和监测的类型

-     the acceptance criteria to be applied;

-     将要应用的可接受标准

-     how the data will be evaluated and the actions to be taken.

-     如何收集要进行评估的数据，要采取的措施

Any statistical models or tools used should be described. If continuous processing is employed, the stage at which the commercial process is considered to be validated should be stated based on the complexity of the process, expected variability and manufacturing experience of the company.

应对所有使用的统计学模型或工具进行描述。如果使用的是连续工艺，则应根据工艺的复杂性、预期的波动性和公司的生产经验，说明需要进行验证的商业工艺步骤。

Periods of enhanced sampling and monitoring may help to increase process understanding as part of continuous improvement. Information on process trends, such as the quality of incoming materials or components, in?process and finished product results and non-conformances should be collected and assessed to verify the validity of the original process validation or to identify changes required to the control strategy.

增加取样和监测期间有助于增加对工艺的理解，成为持续改进的一部分。应收集工艺趋势的信息，例如进厂物料或组件的质量、中控和成品结果和不符合性，并进行评估以确认原始工艺验证的有效性，或识别控制策略所需的变更。

The scope of continued process verification should be reviewed periodically and modified if appropriate throughout the product life cycle.

在整个产品的生命周期中，应对持续工艺确认的范围进行定期审核，必要时进行修订。

7. Change management 变更管理

Manufacturers should follow change control procedures when changes are planned to existing systems or processes.

在计划对已有系统或工艺进行变更时，生产商应遵守变更控制程序。

The change control procedure and records should ensure that all aspects are thoroughly documented and approved, including regulatory approval where appropriate (variation).

变更控制程序和记录应保证所有方面均被完整记录和批准，包括适当时的法规批准（变更）。

Sufficient data should be generated to demonstrate that the revised process will result in a product of the desired quality, consistent with approved specifications.

应产生出充分的数据来证明修订后的工艺会使得产品获得所需的质量，符合批准的质量标准。

Validation should be considered when changes to production and/or control procedures are planned. Based on risk assessment, changes that may require revalidation could include (but are not limited to):

当计划对生产和/或控制程序进行变更时，应考虑是否需要进行验证。根据风险评估，可能需要进行再验证的变更可能包括（但不仅限于）：

-    changes in the master formula, methods, starting material manufacturer, starting material manufacturing process, excipient manufacturer, excipient manufacturing process;

-    主配方、方法、起始物料生产商、起始物料生产工艺、辅料生产商、辅料生产工艺变更

-    changes in the equipment or instruments (e.g. addition of automatic detection systems);

-    设备结构变更（例如，增加自动检测系统）

-    changes associated with equipment calibrations and the preventive maintenance carried out, which may impact the process;

-    可能影响工艺的设备校正和预防性维保变更

-    production area and support system changes (e.g. rearrangement of areas or a new water-treatment method);

-    生产区域和支持性系统变更（例如，区域重新规划，或引入新的水处理方法）

-    changes in the manufacturing process (e.g. mixing times, drying temperatures);

-    生产工艺变更（例如，混合时间，干燥温度）

-    transfer of processes to another site;

-    工艺转移至另一场所

-    unexpected changes (e.g. those observed during self-inspection or during routine analysis of process trend data);

-    计划外变更（例如，在自检或常规工艺趋势数据分析中发现的问题引起的变更）

-    changes to standard operating procedures;

-    标准操作规程变更

-    changes to cleaning and hygiene programmes.

-    清洁和卫生程序变更

Depending upon the nature of the change being proposed the change control process should consider whether existing approved specifications will be adequate to control the product subsequent to the implementation of the change.

根据所拟变更的情况不同，变更控制过程应考虑现有已批准的质量标准是否足以控制实施变更后的产品。

References 参考文献

1.         Supplementary guidelines on good manufacturing practices: validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World Health Organization; 2006: Annex 4 (WHO Technical Report Series, No. 937).
GMP增补指南：验证，WHO，2006

2.         WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-fourth report. Geneva: World Health Organization; 2010: Annex 2 (WHO Technical Report Series, No. 957).
WHO原料药GMP，WHO，2010

3.         WHO good manufacturing practices for sterile pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-fifth report. Geneva: World Health Organization; 2011: Annex 6 (WHO Technical Report Series, No. 961).
WHO无菌制剂GMP，WHO，2011

4.         ICH harmonised tripartite guideline, pharmaceutical development Q8(R2), Current Step 4 version, dated August 2009 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf, accessed 15 January 2014).
ICH药物研发Q8(R2)，2014

Further reading 延伸阅读

-     Guideline on process validation. London: Committee for Medicinal Products for Human Use (CHMP), Committee for Medicinal Products for Veterinary Use (CVMP); 2012 (EMA/CHMP/CVMP/QWP/70278/2012-Rev1) (http://www.ema.europa.eu/docs/en ... /04/WC500125399.pdf, accessed 15 January 2015).

-     工艺验证指南，EMA，2012

-     Guidance for industry. Process validation: general principles and practices. Silver Spring (MD): US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM); 2011 (Current Good Manufacturing Practices (CGMP) Revision 1).

-     行业指南：工艺验证：通用原则和规范，美国FDA，2011

-     ICH harmonised tripartite guideline, quality risk management, Q9, Current Step 4 version, dated 9 November 2005.

-     ICH质量风险管理，Q9，2005

-     ICH harmonised tripartite guideline, pharmaceutical quality system, Q10, Current Step 4 version, dated 4 June 2008 (http://www.ich.org/products/guid ... ity-guidelines.html, accessed 15 January 2014).

-     ICH药物质量体系，Q10，2014

-     Quality assurance of pharmaceuticals. WHO guidelines, related guidance and GXP training materials. Geneva: World Health Organization; 2014 (CD-ROM).

-     制剂质量保证，WHO指南，2014

-     WHO good manufacturing practices: main principles for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-eighth report. Geneva: World Health Organization; 2014: Annex 2 (WHO Technical Report Series, No. 986 (http://www.who.int/medicines/areas/quality_safety/quality_assurance/GMPPharmaceuticalProductsMainPrinciplesTRS961Annex3.pdf, accessed 15 January 2015).

-     WHO优良生产规范：制剂产品主要原则，2014

-     WHO guidelines on quality risk management. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-seventh report. Geneva: World Health Organization; 2013: Annex 2 (WHO Technical Report Series, No. 981).

-     WHO质量风险管理指南，2013