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WHO 第992號(hào)技術(shù)報(bào)告附錄3 非無菌工藝驗(yàn)證 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 背景和范圍 2. Glossary 術(shù)語 3. Introduction 概述 4. Process design 工藝設(shè)計(jì) 5. Process qualification 工藝確認(rèn) 6. Continued process verification 持續(xù)工藝確認(rèn) 7. Change management 變更管理 References 參考文獻(xiàn) 1. Background and scope背景和范圍 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號(hào)技術(shù)報(bào)告中公布了GMP增補(bǔ)指南：驗(yàn)證,，此外還公布了一些指南來支持現(xiàn)行的GMP實(shí)施方法。這些指南意在為WHO和ICH的質(zhì)量源于設(shè)計(jì)原則（QbD）和質(zhì)量風(fēng)險(xiǎn)管理（QRM）提供更多的工藝驗(yàn)證概念支持,。 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. 這些指南允許使用不同的方法來實(shí)現(xiàn)工藝驗(yàn)證,。其所描述的原則主要適用于非無菌制劑。類似方法也可以用于原料藥和無菌產(chǎn)品,。（參見WHO第957號(hào)技術(shù)報(bào)告附錄2,，以及WHO第961號(hào)技術(shù)報(bào)告附錄6）。推薦采用基于風(fēng)險(xiǎn)的生命周期方法來進(jìn)行驗(yàn)證,。 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. 由于現(xiàn)在主要聚焦于生命周期方法,，因此在所有工藝驗(yàn)證方法中均需要對(duì)產(chǎn)品和工藝研發(fā)研究的深入的知識(shí)、之前的生產(chǎn)經(jīng)驗(yàn)以及應(yīng)用QRM原則,。 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. 生命周期方法將產(chǎn)品和工藝研發(fā),、商業(yè)化生產(chǎn)工藝的驗(yàn)證,、在日常商業(yè)化生產(chǎn)中將生產(chǎn)工藝維持在受控狀態(tài)結(jié)合了起來。 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. 推薦使用過程分析技術(shù)（PAT）,，包括遠(yuǎn)線,、近線和/或在線控制和監(jiān)測(cè)技術(shù)，以保證工藝在生產(chǎn)過程中處于受控狀態(tài),。 2. Glossary 術(shù)語（略） The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts. 以下給出的定義適用于這些指南中所用的術(shù)語,。在其它不同語境中可能有不同含義。 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. 所有產(chǎn)品均應(yīng)生成工藝驗(yàn)證數(shù)據(jù),，以證明生產(chǎn)工藝的充分性,。所實(shí)施的驗(yàn)證應(yīng)符合GMP要求，驗(yàn)證數(shù)據(jù)應(yīng)保留在生產(chǎn)場(chǎng)所,，檢查中應(yīng)可以獲取,。 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. 工藝驗(yàn)證與產(chǎn)品從工藝設(shè)計(jì)階段到商業(yè)化生產(chǎn)的整個(gè)生命周期中數(shù)據(jù)收集和評(píng)估過程緊密相關(guān)，它提供科學(xué)證據(jù)證明一個(gè)工藝可以持續(xù)地產(chǎn)生一個(gè)具備所需質(zhì)量的產(chǎn)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. 應(yīng)采用風(fēng)險(xiǎn)評(píng)估方法來確定工藝的范圍和深度,，以及可能影響產(chǎn)品質(zhì)量的起始物料波動(dòng)。應(yīng)根據(jù)設(shè)計(jì)階段所實(shí)施的相關(guān)研究和對(duì)工藝的理解,，根據(jù)產(chǎn)品生命周期的不同階段,，對(duì)關(guān)鍵步驟和關(guān)鍵工藝參數(shù)進(jìn)行識(shí)別、論述和記錄,，在工藝驗(yàn)證和確認(rèn)期間,，應(yīng)對(duì)關(guān)鍵工藝參數(shù)進(jìn)行監(jiān)測(cè)。 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. 繪制要驗(yàn)證的工藝中所有操作和控制流程圖將有所幫助,。在對(duì)一個(gè)給定的操作實(shí)施QRM時(shí),，也應(yīng)考慮該操作前后的步驟。 Amendments to the flow diagram may be made where appropriate, and should be recorded as part of the validation documentation. 適當(dāng)時(shí)應(yīng)對(duì)流程圖進(jìn)行修正,，修正內(nèi)容應(yīng)記錄作為驗(yàn)證文件的一部分,。 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. 生產(chǎn)商應(yīng)保證按本指南中所述的工藝驗(yàn)證的原則實(shí)施工藝驗(yàn)證。這包括了在工藝設(shè)計(jì),、放大,、廠房確認(rèn)、公用系統(tǒng)和設(shè)備和工藝性能確認(rèn),、持續(xù)工藝確認(rèn)中的各驗(yàn)證階段,，以保證工藝保持在受控狀態(tài)。 The objectives of process validation include ensuring that: 工藝驗(yàn)證的目的包括保證： - the process design is evaluated to show that the process is reproducible, reliable and robust; - 工藝設(shè)計(jì)經(jīng)過評(píng)估,，顯示出工藝具可重復(fù)性,、可靠性和耐用性 - the commercial manufacturing process is defined, monitored and controlled; - 對(duì)商業(yè)生產(chǎn)工藝進(jìn)行了定義、監(jiān)測(cè)和控制 - assurance is gained on a continuous basis to show that the process remains in a state of control. - 保證工藝持續(xù)保持在受控狀態(tài) 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. 驗(yàn)證應(yīng)包括生產(chǎn)產(chǎn)品的所有劑量,，各生產(chǎn)場(chǎng)所的驗(yàn)證深度應(yīng)根據(jù)風(fēng)險(xiǎn)評(píng)估來確定,。可以使用矩陣法或括號(hào)法（分組法）,，這些方法的使用也應(yīng)該是基于適當(dāng)?shù)娘L(fēng)險(xiǎn)評(píng)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. 可以有不同的工藝驗(yàn)證方法，包括：傳統(tǒng)工藝驗(yàn)證（包括前驗(yàn)證和同步驗(yàn)證）,、工藝設(shè)計(jì)和之后的工藝確認(rèn)和持續(xù)工藝確認(rèn),，或傳統(tǒng)工藝驗(yàn)證方法與這些指南中所述的新方法的結(jié)合。如果對(duì)工藝進(jìn)行了變更,，則需要對(duì)歷史數(shù)據(jù)進(jìn)行評(píng)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. 生產(chǎn)商應(yīng)計(jì)劃實(shí)施新的工藝驗(yàn)證方法，它包括工藝設(shè)計(jì),、工藝確認(rèn)和持續(xù)工藝確認(rèn),，貫穿產(chǎn)品的整個(gè)生命周期。 Figure A3.1 shows the phases in the new approach to process validation. 圖A3.1展示了新的工藝驗(yàn)證方法的各階段,。   圖A3.1工藝驗(yàn)證各階段 4. Process design 工藝設(shè)計(jì) 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,，驗(yàn)證的焦點(diǎn)從商業(yè)化規(guī)模批次轉(zhuǎn)移至研發(fā)。產(chǎn)品研究發(fā)活動(dòng)提供了關(guān)鍵的工藝設(shè)計(jì)階段輸出,，例如所需的劑型,、質(zhì)量屬性和通用生產(chǎn)途徑。所設(shè)計(jì)的代表商業(yè)工藝的實(shí)驗(yàn)室或中試模型可以用于預(yù)測(cè)變動(dòng)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. 工藝設(shè)計(jì)一般應(yīng)包括實(shí)驗(yàn)設(shè)計(jì),、工藝研發(fā)、臨床試驗(yàn)產(chǎn)品生產(chǎn),、中試規(guī)模批次和技術(shù)轉(zhuǎn)移,。在產(chǎn)品研發(fā)期間應(yīng)對(duì)工藝設(shè)計(jì)進(jìn)行確認(rèn)。 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. 工藝設(shè)計(jì)應(yīng)包括原料的選擇,、預(yù)期生產(chǎn)變動(dòng),、生產(chǎn)技術(shù)/工藝的選擇、形成整個(gè)生產(chǎn)工藝的單個(gè)工藝環(huán)節(jié)的確認(rèn),、過程控制,、檢測(cè)、檢查的選擇,，以及其是否適合控制策略,。 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. 作為工藝驗(yàn)證生命周期的一部分，一些工藝驗(yàn)證研究可能需要在中試批次中實(shí)施（對(duì)應(yīng)至少10%或100000個(gè)制劑單位,，取其中大者）,。如果批量更小，和/或工藝根據(jù)特定設(shè)備的幾何形狀和產(chǎn)能定制，則可能需要提供應(yīng)放大生產(chǎn)驗(yàn)證數(shù)據(jù),。 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. 工藝確認(rèn)和持續(xù)工藝確認(rèn)應(yīng)保持與工藝設(shè)計(jì)相關(guān)聯(lián),，要參照產(chǎn)品研發(fā)中的關(guān)鍵研究所用特定批次，例如,，用于關(guān)鍵臨床評(píng)估（生物批）的批次,，例如，多用途產(chǎn)品生物等效性測(cè)試和毒理研究,。工藝設(shè)計(jì)階段驗(yàn)證批次數(shù)應(yīng)適當(dāng)且充分,，應(yīng)包括（但不僅限于）預(yù)期的起始物料變化，確認(rèn)設(shè)備和生產(chǎn)技術(shù)的適用性,?；诮y(tǒng)計(jì)學(xué)的實(shí)驗(yàn)設(shè)計(jì)方法在此階段會(huì)有所幫助。應(yīng)適當(dāng)記錄驗(yàn)證過程和結(jié)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. 應(yīng)起草研發(fā)報(bào)告和/或技術(shù)轉(zhuǎn)移文件,，由研發(fā)人員正式審核和批準(zhǔn)，由生產(chǎn),、工程和質(zhì)量部人員正式接受,。該文件可以包括一些信息如QTPP、所需要臨床表現(xiàn),、物料的帳單,、批準(zhǔn)的供應(yīng)商、成品質(zhì)量標(biāo)準(zhǔn)和檢測(cè)方法,、中控檢測(cè)質(zhì)量標(biāo)準(zhǔn),、設(shè)備建議、主批記錄,、主包裝記錄,、穩(wěn)定性報(bào)告、關(guān)鍵質(zhì)量屬性,、關(guān)鍵工藝參數(shù),、工藝比較、制劑批數(shù)據(jù),、穩(wěn)定性試驗(yàn)批,、臨床/生物批、和放大批,。這些文件在生產(chǎn)場(chǎng)所應(yīng)易于獲得,。 The goal is to design a suitable process for routine commercial manufacturing that can consistently deliver a product that meets its required quality attributes. 其目的是設(shè)計(jì)出適當(dāng)?shù)墓に囉糜谌粘Ｉ虡I(yè)化生產(chǎn)，可以持續(xù)生產(chǎn)出符合所需質(zhì)量屬性的產(chǎn)品,。 5. Process qualification 工藝確認(rèn) 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)). 在驗(yàn)證生產(chǎn)工藝之前,，人員,、設(shè)施、公用系統(tǒng),、支持性系統(tǒng)和設(shè)備應(yīng)經(jīng)過適當(dāng)?shù)拇_認(rèn),。在驗(yàn)證過程中要考慮物料、環(huán)境控制,、測(cè)量系統(tǒng),、儀器和方法,。設(shè)備的確認(rèn)階段可以包括設(shè)計(jì),、安裝、運(yùn)行和性能（更多細(xì)節(jié)參見WHO第937號(hào)技術(shù)報(bào)告附錄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. 傳統(tǒng)驗(yàn)證方法中,，通常認(rèn)為三批是可接受的工藝驗(yàn)證批次，但是,，驗(yàn)證批次數(shù)應(yīng)基于風(fēng)險(xiǎn)評(píng)估來進(jìn)行論證,，其中包括，例如,，結(jié)果偏離工藝設(shè)計(jì)階段,、原料變化、產(chǎn)品歷史,、產(chǎn)品從何地轉(zhuǎn)移而來及要轉(zhuǎn)移到何處去,。 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). 生產(chǎn)商應(yīng)定義在哪個(gè)階段認(rèn)為工藝是經(jīng)過了驗(yàn)證的，根據(jù)什么做出這樣的決定,。決定應(yīng)包括基于工藝復(fù)雜性和預(yù)期變化以及關(guān)鍵質(zhì)量屬性（CQA）所做出的驗(yàn)證批次數(shù)的論證,。 Successful completion of process performance qualification stage of the life cycle is required for commercial distribution. 商業(yè)化銷售要求成功完成生命周期階段的工藝性能確認(rèn)。 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. 對(duì)商業(yè)批量放大時(shí)應(yīng)進(jìn)行風(fēng)險(xiǎn)評(píng)估,。工藝確認(rèn)應(yīng)確認(rèn)批量放大不會(huì)對(duì)產(chǎn)品特性有負(fù)面影響,，按既定參數(shù)操作的工藝可以持續(xù)生產(chǎn)中符合所有CQA和控制策略要求的產(chǎn)品。 The process should be verified on commercial-scale batches prior to marketing of the product. 產(chǎn)品上市前應(yīng)對(duì)商業(yè)規(guī)模批進(jìn)行工藝確認(rèn),。 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. 廣泛使用遠(yuǎn)線,、近線、在線控制可以及時(shí)監(jiān)測(cè)工藝性能和產(chǎn)品質(zhì)量,。應(yīng)收集進(jìn)廠物料或組分,、在制物料和成品相關(guān)質(zhì)量屬性的結(jié)果，這些結(jié)果可以包括屬性,、參數(shù)和終點(diǎn)的確認(rèn),、CQA和關(guān)鍵工藝參數(shù)（CPP）趨勢(shì)的評(píng)估?？梢允褂眠^程分析技術(shù)應(yīng)用工具和多變量統(tǒng)計(jì)過程控制,。 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. 鼓勵(lì)生產(chǎn)商實(shí)施新的驗(yàn)證方法,，以保證工藝具有已知的可接受的能力。由于全面實(shí)施本方法可能需要一定的時(shí)間,，傳統(tǒng)的前驗(yàn)證和同步驗(yàn)證方法（不經(jīng)常使用,，僅限于第2部分所述的情形）在過渡時(shí)間內(nèi)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. 如果具有適當(dāng)?shù)目刂?，基于科學(xué)論述和風(fēng)險(xiǎn)管理原則,，將傳統(tǒng)工藝驗(yàn)證方法中的元素與新的持續(xù)工藝確認(rèn)方法相結(jié)合是可以接受的， Validation should be done in accordance with process validation protocols. 驗(yàn)證應(yīng)根據(jù)工藝驗(yàn)證方案進(jìn)行,。 A written protocol is essential for this stage of process validation. The protocol should include or reference at least the following elements: 本階段工藝驗(yàn)證需要有書面的方案,。方案應(yīng)包括，或參考至少以下內(nèi)容： - the manufacturing conditions including operating parameters, processing limits and component (raw material) inputs; - 生產(chǎn)條件,，包括操作參數(shù),、工藝限度和組分（原料）輸入 - the data to be collected and when and how they will be evaluated; - 要收集的數(shù)據(jù)，這些數(shù)據(jù)要在什么時(shí)間怎么樣評(píng)估 - the type of testing or monitoring to be performed (in-process, release, characterization) and acceptance criteria for each significant processing step; - 要實(shí)施的檢測(cè)或監(jiān)測(cè)的類型（中控,、放行,、定性），以及各重要工藝步驟的可接受標(biāo)準(zhǔn) - the scientifically justified sampling plan, including sampling points, number of samples and the frequency of sampling for each unit operation and attribute; - 經(jīng)過科學(xué)論證的取樣計(jì)劃,，包括各單元操作和屬性的取樣點(diǎn),、樣品數(shù)量和取樣頻次 - the number of batches for which additional monitoring is proposed; - 擬進(jìn)行額外監(jiān)測(cè)的批次數(shù)量 - status of the validation of analytical methods used in measuring the process, in-process materials and the product; - 用于工藝、中控物料和產(chǎn)品測(cè)量的分析方法的驗(yàn)證狀態(tài) - a description of the statistical models or tools used; - 所用統(tǒng)計(jì)學(xué)模型或工具的描述 - review and approval of the protocol by appropriate departments and the quality unit; - 由適當(dāng)?shù)牟块T和質(zhì)量部門對(duì)方案進(jìn)行審核和批準(zhǔn) - a description of the process; - 工藝描述 - details of the equipment and/or facilities to be used (including measuring or recording equipment) together with its calibration status; - 所用設(shè)備和/或設(shè)備的詳細(xì)說明（包括測(cè)量和記錄設(shè)備）,，及其校正狀態(tài) - the variables to be monitored with appropriate justification; - 要監(jiān)測(cè)的變更及適當(dāng)?shù)恼撟C - the samples to be taken – who, where, when, how, how many and how much (sample size); - 要取的樣品---誰,、在什么地方、什么時(shí)間,、如何取,、取多少（樣品數(shù)量） - the product performance characteristics or attributes to be monitored, together with the test methods; - 要監(jiān)測(cè)的產(chǎn)品性能特性或?qū)傩裕约皺z測(cè)方法 - the acceptable limits; - 可接受限度 - personnel responsibilities; - 人員職責(zé) - details of methods for recording and evaluating results, including statistical analysis. - 記錄和評(píng)估結(jié)果的方法細(xì)節(jié),，包括統(tǒng)計(jì)學(xué)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. 應(yīng)收集數(shù)據(jù),，并按既定的可接受標(biāo)準(zhǔn)進(jìn)行審核，并全部記錄在工藝驗(yàn)證報(bào)告中,。報(bào)告應(yīng)反映出驗(yàn)證方案的要求,。可以使用方案報(bào)告合并的方式,，但是,，這樣的報(bào)告的設(shè)計(jì)必須保證內(nèi)容的清晰，并留有足夠的空間來記錄結(jié)果,。結(jié)果應(yīng)確認(rèn)符合可接受標(biāo)準(zhǔn),。 Any deviations (including abandoned studies) should be explained and justified. 所有偏差（包括廢棄的研究）均應(yīng)進(jìn)行解釋和論述。 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. 包括操作限度和總體工藝控制策略的計(jì)劃商業(yè)生產(chǎn)和控制記錄,，應(yīng)進(jìn)入下一階段進(jìn)行確認(rèn),。 6. Continued process verification 持續(xù)工藝確認(rèn) 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. 在工藝設(shè)計(jì)和工藝確認(rèn)完成后,，生產(chǎn)商應(yīng)監(jiān)測(cè)商業(yè)批次的產(chǎn)品質(zhì)量，這樣可以提供證據(jù)證明在產(chǎn)品的生命周期中工藝均維持在受控狀態(tài),。 The scope and extent of process verification will be influenced by a number of factors including: 工藝確認(rèn)的范圍和深度可能會(huì)受到許多因素的影響,，包括： - prior development and knowledge of the manufacturing of similar products and/or processes; - 預(yù)研究和類似產(chǎn)品和/或工藝生產(chǎn)的知識(shí) - the extent of process understanding gained from development studies and commercial manufacturing experience; - 研發(fā)過程和商業(yè)生產(chǎn)經(jīng)驗(yàn)中獲得的對(duì)工藝?yán)斫獾纳疃?br>- the complexity of the product and/or manufacturing process; - 產(chǎn)品和/或生產(chǎn)工藝的復(fù)雜性 - the level of process automation and analytical technologies used; - 所采用工藝自動(dòng)化和分析技術(shù)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. - 對(duì)于遺留產(chǎn)品，適當(dāng)時(shí)應(yīng)參照自商業(yè)生產(chǎn)以來產(chǎn)品的生命周期工藝耐用性和生產(chǎn)歷史 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. 生產(chǎn)商應(yīng)描述確認(rèn)策略的適當(dāng)性和可行性（在方案中）,，包括要監(jiān)測(cè)的工藝參數(shù)和物料屬性,，以及要使用的經(jīng)過驗(yàn)證過的分析方法。 Manufacturers should define: 生產(chǎn)商應(yīng)界定 - the type of testing or monitoring to be performed; - 要實(shí)施的檢測(cè)和監(jiān)測(cè)的類型 - the acceptance criteria to be applied; - 將要應(yīng)用的可接受標(biāo)準(zhǔn) - how the data will be evaluated and the actions to be taken. - 如何收集要進(jìn)行評(píng)估的數(shù)據(jù),，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. 應(yīng)對(duì)所有使用的統(tǒng)計(jì)學(xué)模型或工具進(jìn)行描述,。如果使用的是連續(xù)工藝，則應(yīng)根據(jù)工藝的復(fù)雜性,、預(yù)期的波動(dòng)性和公司的生產(chǎn)經(jīng)驗(yàn),，說明需要進(jìn)行驗(yàn)證的商業(yè)工藝步驟。 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. 增加取樣和監(jiān)測(cè)期間有助于增加對(duì)工藝的理解,，成為持續(xù)改進(jìn)的一部分。應(yīng)收集工藝趨勢(shì)的信息,，例如進(jìn)廠物料或組件的質(zhì)量,、中控和成品結(jié)果和不符合性，并進(jìn)行評(píng)估以確認(rèn)原始工藝驗(yàn)證的有效性,，或識(shí)別控制策略所需的變更,。 The scope of continued process verification should be reviewed periodically and modified if appropriate throughout the product life cycle. 在整個(gè)產(chǎn)品的生命周期中，應(yīng)對(duì)持續(xù)工藝確認(rèn)的范圍進(jìn)行定期審核,，必要時(shí)進(jìn)行修訂,。 7. Change management 變更管理 Manufacturers should follow change control procedures when changes are planned to existing systems or processes. 在計(jì)劃對(duì)已有系統(tǒng)或工藝進(jìn)行變更時(shí)，生產(chǎn)商應(yīng)遵守變更控制程序,。 The change control procedure and records should ensure that all aspects are thoroughly documented and approved, including regulatory approval where appropriate (variation). 變更控制程序和記錄應(yīng)保證所有方面均被完整記錄和批準(zhǔn),，包括適當(dāng)時(shí)的法規(guī)批準(zhǔn)（變更）。 Sufficient data should be generated to demonstrate that the revised process will result in a product of the desired quality, consistent with approved specifications. 應(yīng)產(chǎn)生出充分的數(shù)據(jù)來證明修訂后的工藝會(huì)使得產(chǎn)品獲得所需的質(zhì)量,，符合批準(zhǔn)的質(zhì)量標(biāo)準(zhǔn),。 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): 當(dāng)計(jì)劃對(duì)生產(chǎn)和/或控制程序進(jìn)行變更時(shí)，應(yīng)考慮是否需要進(jìn)行驗(yàn)證,。根據(jù)風(fēng)險(xiǎn)評(píng)估,，可能需要進(jìn)行再驗(yàn)證的變更可能包括（但不僅限于）： - changes in the master formula, methods, starting material manufacturer, starting material manufacturing process, excipient manufacturer, excipient manufacturing process; - 主配方、方法,、起始物料生產(chǎn)商,、起始物料生產(chǎn)工藝、輔料生產(chǎn)商,、輔料生產(chǎn)工藝變更 - changes in the equipment or instruments (e.g. addition of automatic detection systems); - 設(shè)備結(jié)構(gòu)變更（例如,，增加自動(dòng)檢測(cè)系統(tǒng)） - changes associated with equipment calibrations and the preventive maintenance carried out, which may impact the process; - 可能影響工藝的設(shè)備校正和預(yù)防性維保變更 - production area and support system changes (e.g. rearrangement of areas or a new water-treatment method); - 生產(chǎn)區(qū)域和支持性系統(tǒng)變更（例如,，區(qū)域重新規(guī)劃，或引入新的水處理方法） - changes in the manufacturing process (e.g. mixing times, drying temperatures); - 生產(chǎn)工藝變更（例如,，混合時(shí)間,，干燥溫度） - transfer of processes to another site; - 工藝轉(zhuǎn)移至另一場(chǎng)所 - unexpected changes (e.g. those observed during self-inspection or during routine analysis of process trend data); - 計(jì)劃外變更（例如，在自檢或常規(guī)工藝趨勢(shì)數(shù)據(jù)分析中發(fā)現(xiàn)的問題引起的變更） - changes to standard operating procedures; - 標(biāo)準(zhǔn)操作規(guī)程變更 - changes to cleaning and hygiene programmes. - 清潔和衛(wèi)生程序變更 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. 根據(jù)所擬變更的情況不同,，變更控制過程應(yīng)考慮現(xiàn)有已批準(zhǔn)的質(zhì)量標(biāo)準(zhǔn)是否足以控制實(shí)施變更后的產(chǎn)品,。 References 參考文獻(xiàn) 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增補(bǔ)指南：驗(yàn)證，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原料藥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無菌制劑GMP,，WHO,，2011 4. ICH harmonised tripartite guideline, pharmaceutical development Q8(R2), Current Step 4 version, dated August 2009 (http://www./fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf, accessed 15 January 2014). ICH藥物研發(fā)Q8(R2)，2014 |
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