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14.09.2017 EMA´s Questions and Answers relating to Flexibilityin Manufacturing Conditions EMA问答：生产条件的灵活性 The European Medicines Agency (EMA) publishedQuestions and Answers (Q&As) on 'Improving the understanding ofNORs, PARs, DSp and normal variability of process parameters' on July 13,2017. The four-page document contains thefollowing five Q&As: EMA于2017年7月13日发布了“改进对NOR、PAR、DSp和工艺参数的正常波动的理解”问答。4页的文件中包括以下5个问答：
NOR (which is not an established ICHterm) describes a region around the target operating conditions thatcontains common operational variability (variability that can’t always becontrolled). NORs alone are not intended to introduce flexibility in theconditions for manufacturing but they can better quantify the actualuncontrollable operational variability of process parameters and thereforeshould be presented in marketing authorizations as what is practicallyachievable. NOR（并不是由ICH制订的术语）描述的是目标操作条件邻近范围，其中包括正常的操作波动（波动并不总能控制）。NOR单独并不会引入至生产条件波动中，但NOR可能会更好地量化实际的工艺参数非受控操作波动，因此需要在上市许可中呈现中实际能达到的水平。
The PAR is defined as a 'characterized range of aprocess parameter for which operation within this range, while keeping otherparameters constant, will result in producing a material meeting relevantquality criteria' (ICH Q8). PARs could be presented in the description of themanufacturing process of the drug substance (DS) and/or the drug product (DP)(in S.2.2 or P.3.3 of the Module 3, respectively) as ranges. Working within theapproved PAR is not considered as a change. Changes to the target value withinthe registered PAR can be managed under the company’s Pharmaceutical QualitySystem (PQS) without regulatory action. Movement out of the PAR is consideredto be a change and will require a post approval change process. PAR定义是“一个经过特征识别的工艺参数范围，操作应在此范围内进行。当保持其它参数恒定时，此参数范围内操作将生成符合相关质量标准的物料”（ICH Q8）。PAR可以放在原料药（DS）和/或制剂（DP）生产工艺描述部分（分别在模块3的S.2.2部分或P.3.3部分）作为工艺范围。在批准的PAR内工作并不是一个变更。在注册的PAR范围内对目标值的变更可以依据公司的药物质量体系（PQS）来管理，不需要注册措施。超出PAR范围则是变更，需要遵守批准后变更流程。 Where interaction effects between different parametersexist and the acceptable range for one process parameter depends on the settingof another parameter, the parameters should be included in a Design Space (seebelow). 如果不同参数之间存在着相互作用，一个工艺参数的可接受范围取决于另一个参数的设置，则参数应放在一个设计空间里（见下）。 Considerations for development (S.2.6/ P.2.3 of Module 3): Several PARs can bepresented and investigated as part of the process understanding anddevelopment. 研发考量（模块3的S.2.6/P.2.3）：几个PAR可以放在工艺理解和研发部分进行呈现和探讨。
The DSp is defined by the 'multidimensionalcombination and interaction of input variables (e.g., material attributes) andprocess parameters that have been demonstrated to provide assurance ofquality'. Working within the approved DSp is not considered as a change.Movement out of the DSp is considered as a change and wouldnormally require a regulatory post approval change process. The DSp isproposed by the applicant and is subject to regulatory assessment and approval(ICH Q8). DSp定义为“输入变更（例如，原料属性）以及被证明能提供质量保证的工艺参数的相互作用和多维组合”。在批准的DSp内工作不是变更，超出DSp则是变更，一般需要遵守批准后的注册变更流程。DSp是由申报人提议，经由注册审评和批准的（ICH Q8）。 A DSp can be restricted by ranges of processparameters only, input material attributes only, or a combination of processparameters and input material attributes. The justification of a DSp should bepresented in the development of the manufacturing process of the DS and/or DP(S.2.6 or P.2.3 of Module 3, respectively). Regarding the required level ofdetails the following should be considered: 一个DSp只可以由工艺参数范围、输入物料属性、或者是工艺参数和输入物料属性的组合来限制。DSp的论证应放在DS和/或DP的生产工艺研发部分（分别为模块3的S.2.6或P.2.3部分）。在所需的详细程度方面应考虑以下内容： · Does the DSp represent parameter ranges that are muchwider than what would normally be accepted as NORs? · DSp呈现的参数范围可否远远宽于常规可接受的NOR？ · Does any area of the DSp represent greater risk toquality than the rest of the DSp? · 是否有DSp的任何区域所呈现的风险是否比DSp的其余区域具有更大的质量风险？ · To what extent do other elements of the controlstrategy contribute to ensuring output material quality? Examples includein-process controls, PAT analytics and downstream processes and controls. · 控制策略的其它要素对确保输出物料质量的影响到何程度？例子包括中控、PAT技术和下游工艺和控制。 If it is claimed that no interaction exists between (process) parameters,this should be adequately justified. Additionally, the development of theDSp should be based on risk management principles (ICH Q9). 如果声明了在（工艺）参数之间不存在相互作用，则应该有充分的论证。此外，DSp的开发应基于风险管理原则（ICH Q9）。
An Extension (i.e. introduction of newmaterial attributes or process parameters, extension of the range of existingmaterial attributes or critical process parameters) of a DSp should besubmitted as a Type II variation (B.I.e.1 or B.II.g.1). DSp放宽（即，引入新物料属性或工艺参数，放宽已有物料属性或关键工艺参数的范围）应作为II类变更（B.I.e.1 或 B.II.g.1）提交。 If the change has already been described in anapproved post-approval change management protocol (PACMP), dependingupon what was agreed, the change can either be submitted as a Type IAin or IBnotification (B.I.e.5 or B.II.g.5). According to the variationsclassification guideline, changes foreseen in PACMP for a biological/immunological medicinalproduct are Type IB. 如果这些变更已经在一份批准的上市后变更管理方案（PACMP）中进行了描述，则根据已达成一致的内容，变更可以按IA或IB通知类提交（B.I.e.5或 B.II.g.5）。根据变更分类指南，在PACMP中可预见生物/免疫药品变更为IB类。 Restrictions to an approved DSp would typically only benecessary if part of the DSp was discovered to not produce satisfactory qualitymaterial. Substantial changes to a process that may have a significant impacton the quality, safety or efficacy of the product should be submitted as a TypeII variation (B.I.a.2.b or B.II.b.3.b). Some changes to specifications orprocess parameters can be relevant to the DSp, even if the DSp does notspecifically cover these parameters. These changes should be sought inaccordance with the variationsclassification guideline, where, depending upon the nature of the changes and type of product,some will be possible as Type IA, whereas others will be possible as Type IBnotifications. The variation categories related to changes to manufacturingsites apply regardless of DSp or not. 'However, the continuedrelevance of any registered DSp should be considered whenever there is amanufacturing site change.' 对已批准DSp的加严则一般只有在发现DSp不能生成令人满意质量的物料时才有必要。可能会对质量、安全或有效性有重大影响的重大工艺变更应作为II类变更提交（B.I.a.2.b或 B.II.b.3.b）。一些质量标准或工艺参数的变更可能与DSp有关，即使DSp并不具体覆盖哪些参数。这些变更应依据变更分类指南执行，这里，根据变更的属性和药品的类型，有些可能会分类为IA类，而另一些可能分类为IB类通知。不论DSp变更与否，与生产场所变更相关的变更适用变更类型。“但是，只要有生产场所变更，均应考虑所有注册的DSp的持续相关性”。
The EMA says, 'the degree of process flexibilityis dependent upon how the manufacturing process and its development ispresented in the marketing authorization dossier. Irrespective of thedevelopment approach, the same requirements apply to the level of details inthe manufacturing process description. Steps in the process should have thenecessary details in terms of appropriate process parameters, along with theirtarget values or ranges.' EMA说，“工艺灵活性的程度取决于生产工艺及其开发在上市许可文件中是如何呈现的。不论研发方法如何，相同的要求适用于生产工艺描述的详细程度。工艺中的步骤应具备足够的适当工艺参数以及其目标值或范围的详细信息。” The establishment of a DSp is optional, but,'when a flexible manufacturing process is requested (i.e. ranges ofprocess parameters that are wider than what would be accepted as a NOR; rangesof input material attributes that can affect the quality of the process output),then the process should be established within the framework of a DSp' (seealso Q/A # 3). According to the EMA, 'the process description isconsidered to be one element of the overall control strategy that ispresented in an application'. A one-sided parameter range (forexample an upper range only) typically represents great flexibility and willhave to be justified by scientific rationale. DSp的制订是可选的，但是，“如果需要有灵活的生产工艺（即，工艺参数范围宽于NOR可接受的范围；可影响工艺输出质量的输入物料属性范围），则应在DSp的框架内制订工艺”（也参见问答3）。依据EMA的要求，“工艺描述是申报资料中呈现的全面控制策略的一个要素”。一个单边参数范围（例如只有上限）一般代表较大灵活性，必须有科学合理的论证。 Read more in EMA´s Questions and Answersdocument: 'Improving theunderstanding of NORs, PARs, DSp and normal variability of process parameters' and in the 'Guideline on Manufacture of the finisheddosage form'. Further information regarding these topics, also relating toanalytical procedures, is expected with the release of the upcoming ICHQ12 Draft on 'Technical andRegulatory Considerations for Pharmaceutical Product Lifecycle Management'. 更多信息参见EMA问答。 |
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