EMA实时放行指南解读zhulikou431作品

25 February 2010 EMA/CHMP/QWP/811210/2009 Rev 1 Committee for Medicinal Products for Human Use (CHMP) Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) 实时放行测试指南（以前指南名字是参数放行） Draft 草案 This guideline replaces the Note for Guidance on Parametric Release CPMP/QWP/3015/99 Comments should be provided using this template. The completed comments form should be sent to QWP@ema.europa.eu Keywords：Parametric release, batch release, sterilisation, Process Analytical Technology, Quality by Design, real time release testing 【翻译者注释】本作品是根据EMA指南草案翻译而成，后将汇集各相关机构专家 审核意见，推出精华解读对照本，敬请期待。 有任何宝贵意见，请联系zhulikou431@126.com Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) Table of contents目录 Executive summary行政概述 1. Introduction (background)介绍（背景） 2. Scope范围 3. Legal basis法规基础 4. Real Time Release Testing实时放行测试 4.1. Real Time Release Testing and Specifications 实时放行测试和标准 4.2. Application of RTR testing 实时放行测试应用 4.2.1. Application of RTR testing to biological/biotechnological products 实时放行测试在生物产品/生物技术产品上的应用 4.2.2. RTR testing examples 实时放行测试案例 5. Documentation for RTR testing实时放行测试文件要求 5.1. General requirements一般要求 5.2. Documentation文件 6. Parametric Release and Sterilisation参数放行和灭菌 6.1. Sterilisation by heat热力灭菌 6.2. Sterilisation by radiation辐射灭菌 Definitions定义 References 参考文献 Executive summary行政概述 Medicinal products must comply with the approved specifications before they are released into the market. Compliance with release specifications can be demonstrated by performing a complete set of tests on the finished product, according to the approved specifications. Under certain conditions, an alternative strategy to routine testing is possible. So far this concept has been only applied to sterility testing of terminally sterilised products (parametric release). Recent guidelines adopted in the ICH context (ICH Q8, Q9 and Q10) have made possible to apply a similar release strategy to tests other then sterility, this approach has been called Real Time Release testing. 在放行销售进入市场之前，药品必须符合批准的标准。要符合放行标准，对于药 品而言，可以执行一套完整的检测项目来证明符合批准的标准。在某些情况下， 也可能采用例行的替代测试的策略。到目前为止，这个概念仅仅应用于最终灭菌 工艺生产的药品的无菌测试（参数放行）。近来ICH采用的指南（ICHQ8/Q9/Q10） 使得对于除了无菌项目以外其他项目采用类似放行策略也是可能的，这个方法已 经被称为实时放行测试。 This guideline addresses the requirements for application of RTR testing to different kinds of products e.g. chemical and biological products and its scope is to facilitate the introduction of RTR testing. The guideline replaces the previous guideline on parametric release and does not introduce new requirements, so the parametric release part on the previous guideline is retained unchanged. 这个指南涉及将RTR测试应用于不同种类药品的要求，例如化学药品和生物产 品，这个指南也涉及协助引入RTR测试的品种范围。这个指南替代了以前的参数 放行指南并没有引入新的要求，因此以前指南中关于参数放行部分并没有变化。 Introduction (background)介绍（背景） Medicinal product must comply with the requirements stated in the authorised specifications for release and shelf life. Real Time Release (RTR) is a system of release that gives assurance that the product is of intended quality, based on the information collected during the manufacturing process, through product knowledge and on enhanced process understanding and control. RTR recognises that under specific circumstances a comprehensive set of in-process controls (Real Time Release testing (RTR testing)) may provide greater assurance of product quality than end-product testing.). The RTR principle is already authorised for use as an optional alternative to routine sterility testing of products terminally sterilised in their final container i.e. parametric release1,2. Enhanced product knowledge and process understanding, the use of quality risk management principles and the application of an adequate pharmaceutical quality system, as defined within ICH Q8,Q9 and Q10 provide the platform for establishing RTR testing mechanisms for other applications, for new products as well as established marketed products, 药品必须符合批准的用于放行和有效期内需要符合的标准要求。RTR测试一套放 行系统，基于在制造过程中搜集的信息，通过产品知识和加强的工艺理解和控制， 确保产品达到预期的质量。RTR测试确认，在特定情况下，一套完善的过程控制 （RTR测试）可能比最终产品检测方法提供更大的关于产品质量的保证。RTR原 则已被授权使用作为最终灭菌产品的例行无菌检测的替代方法，即参数放行。强 化的产品知识，工艺理解，质量风险管理原则的使用和足够的制药质量体系的应 用，正如ICH Q8/Q9/Q10所规定的，为其他应用提供了建立RTR测试机制的平台， 这个平台适用于新的产品，正如适用于已经上市产品一样。 This guideline elaborates on the application of RTR testing to a number of areas of pharmaceutical development and manufacture, in addition to sterilisation. It will thereby replace the “Note for Guidance on Parametric Release. 这个指南主要描述将RTR测试应用于很多药品研发和制造的领域，另外包括灭菌 工艺。因此这个指南代替以前的《参数放行指南注释》。 Scope 范围 This document is intended to outline the requirements for applications that propose RTR testing for active substances, intermediates and finished products. The guideline highlights the different requirements that have to be fulfilled in the application and the role of related inspections (pre authorization and routine GMP inspections). 这个指南目的是概括将推荐的RTT测试应用于活性物质、中间产品和制剂的要 求。这个指南强调了在应用中和相关检查（批准前检查和例行的GMP检查）中 的作用的不同要求。 Legal basis法规基础 This guideline has to be read in conjunction with the introduction and general principles (4) and part I of the Annex I to Directive 2001/83 as amended. 这个指南必须和Directive 2001/83指令的介绍部分、一般原则（4）部分、附录1 的第一部分，以及随后的修正案等文件一起来使用。 Real Time Release Testing实时放行测试 Real Time Release Testing and Specifications实时放行测试和标准 Before a medicinal product is released for sale, the Qualified Person responsible for its release should take into account, among other aspects, the conformity of the product to its specifications7. In the case of approved RTR testing, this conformity would not routinely be supported by results of end product testing. Nevertheless product specifications have to be established and each batch of a product should comply with them if tested. Product specifications are also necessary for stability studies, in order to establish a product shelf-life as well as for OMCL controls. The application for RTR testing should contain adequate data of a running in period with both end product testing data and RTR testing data. 在一个药品被放行销售之前，负责放行的QP应该考虑确认产品符合标准，也包 括其他方面。就批准RTR测试而言，确认不应该由最终产品测试的结果来进行例 行的支持。否则，必须建立产品标准，如果测试的话，每批产品都应该符合这些 标准。对于稳定性研究，也有必要建立产品标准，目的是建立产品有效期，就像 OMCL控制一样。RTR测试应用应该包含足够的数据，来自运行一段时间，同时 保存最终产品测试数据和RTR测试数据。 When RTR testing has been approved this should be routinely used for batch release. In case the test results of an approved RTR testing fail or are trending toward failure it may not be substituted by end-product testing. Any failure should be investigated and trending should be followed up appropriately. 当 RTR 测试已经被批准，这个策略应该用于例行的批放行。假如一个批准的 RTR 测试结果是失败的，或者有朝向失败的趋势，不能被最终产品测试的方法来代替。 应该调查任何失败情况，并且失败趋势应该被恰当的跟踪调查。 Batch release decisions will need to be made based on the results of these investigations, and must comply with the content of the marketing authorization and current GMP requirements. 批放行的决定需要基于这些调查结果来做出，必须符合上市批准要求和目前 GMP要求。 The control strategy provided in the application should include a proposal for use of alternative testing or monitoring approaches in case of equipment failure. In this situation, the alternative approach could involve use of end-product testing or other options, while maintaining an acceptable level of quality. Testing or monitoring equipment breakdown needs to be managed in the context of a deviation under the Quality Management System and can be covered by GMP. 申请中包括的控制策略应包括一个采用替代测试的建议，或者当设备失误时需要 采用的监控方法。在这种状态下，替代测试方法可能包括使用最终产品测试或者 其他选择，而维护一个可以接受水平的质量。根据质量管理系统和GMP要求， 设备失败的测试或者监控需要在偏差处理文件中被管理。 For products coming from third countries into the EU it is a requirement in Directive 2001/83/EC “that each production batch has undergone in a Member State a full qualitative analysis, a quantitative analysis of at least the active substances and all the other tests or checks necessary to ensure the quality of medicinal products in accordance with the requirements of the marketing authorization” (9). This normally means a complete reanalysis of the product according to the approved specifications. When a company has got approval for RTR testing for one or more tests in the specifications, these tests would not be considered a “necessary test or check to ensure the quality of the medicinal product in accordance with the requirements of the marketing authorization”. Therefore a relief from this testing will be accepted. 对于从其他第三方国家进口到EU的产品，需要符合Directive 2001/83/EC，“每 个生产批次需要被某成员国检验机构进行全面定量分析、定性分析，最少测试 API和所有其他测试，或者进行必要检验来确保药品质量符合上市要求”。这通 常意味着根据批准的标准对药品进行完整的分析。当一个公司获得涉及质量标准 1项或者多项测试的RTR测试批准时，这些测试将不被认为是确保药品质量符合 上市标准的必要的测试。因而，减少测试是可以被接受的。 Application of RTR testing实时放行测试的应用 Process monitoring may be applied to various manufacturing processes, such as tabletting, on the basis of appropriate testing at various stages in the process. Some parameters are usually checked routinely at defined intervals regardless of the design of the manufacturing process of a tablet. Uniformity of mass, crushing strength and disintegration are such examples. The results of a comprehensive set of in-process tests and controls in these cases may constitute sufficient grounds for replacing the corresponding end product testing and may also offer greater assurance of the finished tablet meeting certain criteria in the specification, without the tests being repeated on a sample of the finished product, as the number of tested units will in general be substantially larger. 工艺监控可以被用于各种不同的制造工艺，例如压片工艺，在工艺不同阶段进行 恰当的控制。通常，例行地在一定时间间隔检查某些参数，不管片剂制造工艺的 设计 领导形象设计圆作业设计ao工艺污水处理厂设计附属工程施工组织设计清扫机器人结构设计 。重量均匀度、冲模规格、脆碎度是这样的例子。在这些例子中，一套全面 的中控测试和措施的结果，可以构成替代相应最终产品检查的坚实基础，也可以 为最终产品提供更大的保证来满足标准中的某些项目，而不需要重复测试最终产 品的样品，因为测试单元的数量通常将足够多。 RTR testing will in general comprise other technologies such as process analytical chemistry test methods, e.g. vibrational spectroscopy techniques like near infrared spectroscopy (NIR) and Raman spectroscopy, usually applied in combination with multivariate analysis. Spectral data monitored on-line controlling content of active substance, polymorphism, water content, blending homogeneity, particle/powder properties or film thickness could thereby replace end-product testing like e.g. uniformity of content, tablet strength and drug dissolution. 通常，RTR测试将和其他技术组合使用，例如工艺分析化学测试方法，例如振动 光谱技术，像NIR技术、raman光谱技术，通常以组合形式应用于多变量分析。 对原料药采用在线光谱数据监控含量，晶型、水分、混合均匀性、粒度/粉末性 质，或者膜浓度，因而可以代替最终产品测试，例如含量均匀度，片剂含量和药 品溶出度。 When RTR testing is applied, the attribute that is indirectly controlled (e.g. sterility, uniformity of content) together with a reference to the associated test procedure, should still be included in the specifications. The relation between end-product testing and material attributes and process monitoring, including acceptance criteria, should be fully explained and justified, including the use of any prediction models. 当采用RTR测试时，间接控制的属性项目（例如无菌、含量均匀度）属于和相关 测试规程在一起作为参考的，仍然应该被包括在标准中。最终产品测试、物料属 性和工艺监控的关系，包括接受标准，应该被全面解释和论证，包括使用任何预 防性的模式。 Application of RTR testing to biological/biotechnological products 实时放行测试在生物产品/生物技术产品上的应用 RTR testing may be applied to biological/biotechnological products. For instance, the level of process related impurities such as residual host cell DNA or host cell proteins (HCP), which are typically tested on a routine basis on the active substance, may be evaluated using a routine testing approach and/or a validation approach. RTR测试可能会用于生物产品/生物技术产品。例如，工艺相关杂质的水平，例 如宿主细胞DNA残留或者宿主细胞蛋白（HCP）等，对这些杂质典型控制策略 就是基于活性物质来进行例行测试的，可能采用例行测试方法和/或者验证方法 来评估。 A routine testing approach would be based on the monitoring, using suitable analytical tools, of the level of those impurities at appropriate step(s) of the process, in order to ensure acceptable levels in the final product. 一个例行测试方法将基于监控、合适的分析手段、在工艺恰当的步骤杂质的水平， 目的是确保最终产品可以接受的水平。 A validation approach would be based on evidence of successful validation of the manufacturing process establishing that at given steps of the purification scheme, those impurities are removed in a consistent and reproducible manner to an acceptable level. This may be supported by demonstration the process clearance capability, based on reduction factors. In such situations, the review of the documentation on process monitoring may be carried out during manufacturing without direct measurements of the quality attributes. Therefore a relief from this testing may be accepted. 一个验证方法将作为纯化框架下地设定步骤的制造工艺建立被成功验证的证据， 那些杂质将采取持续的、可以重复的方式来去除以达到可以接受的水平。这可能 以工艺清除能力的展示为支持，基于减少因素。在这样的情况下，关于工艺监控 文件的审核可以在制造过程中完成，而无须直接测定其质量属性。因而，减少这 类测试是可以接受的。 A combination of routine testing and validation approaches is also possible. Such approach could be used, for instance, where the application data alone are not sufficient to completely remove routine testing (e.g. reduction factor not sufficient). In this situation, routine testing at an earlier step, before a purification step which has been demonstrated to appropriate clearance capability with regards to the given impurities, in order to ensure acceptable levels in the final product level, if tested. 将例行测试和验证方法组合起来也是可能的。例如，可以使用这样的方法，单独 的申请数据不足够支持完全去除例行测试（例如减少因素不足够）。在这种情况 下，在较早的阶段的例行测试，处于纯化步骤之前，已经展示出对于特定杂质具 有恰当的清除能力。如果有必要测试，是为了确保最终产品中杂质处于可以接受 的水平。 TR testing examples实时放行测试案例 For illustrative purposes some examples are given, which are not intended in any way to limit the scope of the application of RTR testing. 为了展示的目的，提供了一些例子，这些例子的目的不是限制RTR使用的范围。 A combination of in-process tablet weight, blend content uniformity measurement e.g. by NIR, drug substance purity and particle size could serve as a control strategy for drug content of a high dose tablet if the relationships has been demonstrated. Core tablet weight, blend uniformity, drug substance purity and particle size in this example are the RTR tests. The production batches are released by the Qualified Person based on the outcome of the RTR tests, any other required tests and GMP compliance. 如果相互关系已经被证实，组合策略，就是中控片重检测、混合含量均匀度检测 例如采用NIR，活性物质纯度和粒度，可以作为控制高剂量片剂的药品含量的组 合策略。片心重量检测、混合均匀度、活性物质纯度和粒度在这个例子中是RTR 测试。由QP放行的生产批次基于RTR测试的结果、任何其他要求的测试和GMP 符合性。 Properties relating to the properties of a tablet granule such as porosity, particle size, surface area etc. could be shown to have a relationship with dissolution behaviour and serve as RTR testing surrogates for dissolution testing. These dependencies would have to be confirmed on a product-by-product basis. 和片剂颗粒属性相关的属性，例如多孔性、粒度、 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 面积等，可以被证明和溶出 行为具有关系，进而采用RTR测试来代替溶出度测试。这些独立性必须基于就事 论事的基础来确认。 Documentation for RTR testing实时放行测试的文件要求 General requirements一般要求 For some substances and dosage forms, the different stages of manufacturing process will be discrete, thus allowing sampling at critical parts of distinct stages of the process. For other substances and dosage forms, the manufacturing process may be more or less continuous, necessitating a more integrated process monitoring. It is therefore not possible to specify in a guideline, specific details of how RTR testing can be applied. This must be assessed in each individual case verifying that the requirements of appropriate Notes for Guidance are met. 对于一些活性物质和制剂，制造工艺不同阶段是分离的，因此允许在工艺不同阶 段关键部分进行取样。对于其他活性物质和制剂，制造工艺可能或多或少的连续 的，有必要采取更整合的工艺监控措施。因而不可能在指南中具体规定，关于如 何采用RTR测试的具体细节。必须针对单独例子进行评估，确认符合恰当指南的 要求。 The authorization of the RTR testing programme will be granted for specified sites on the basis of an assessment of how well the manufacturing process concerned is founded. Monitoring of critical parameters must be capable of demonstrating that pre-determined validated conditions have been achieved throughout the batch. In addition, assessors will evaluate the choice and limits of the critical parameters in relation to their effect on the technical characteristics, stability and bioavailability of the product and its packaging. Methods of controlling critical parameters will also be assessed. 基于制造工艺被多大程度的建立的评估，RTR测试项目授权将针对特定地址来批 准。关键参数监控必须能够展示预先确认验证情况在整个批次中已经被达到。另 外，评估者将评估关键参数的选择和限度，这些参数和药品以及包装材料的技术 特征、稳定性、生物利用度有关。控制关键参数的方法也将被评估。 The introduction of RTR testing must be based on sufficient experience with the process and evaluation of the GMP compliance at the actual site. RTR测试的引入，必须基于在实际地址的和工艺相关的足够经验和对GMP符合 性的评估。 Documentation文件 The application upon which an authorization may be granted should demonstrate: 一个申请授权被批准，应该展示 that the risk assessment identifies the critical quality attributes, 风险评估确定关键质量属性 that the manufacturing process is validated adequately, 制造工艺是足够验证的 that it is reliably controlled, 具有可靠的控制 relation between end-product testing and process monitoring, including justification of acceptance criteria 最终产品检测和工艺监控之间的关系，包括接受标准的论证。 that in process requirements chosen for approval/rejection are decided on the basis of the acceptance criteria defined in the validation records, 用于决定是否批准/拒收的中控要求基于验证记录中确定的接受标准。 that clear, specified procedures are in place describing the reporting and actions to be taken on approval/rejection 具有清楚地、具体的规程来描述关于涉及批准/拒收的需要采取的 报告 软件系统测试报告下载sgs报告如何下载关于路面塌陷情况报告535n,sgs报告怎么下载竣工报告下载 和行动。 that the applied technologies gives an adequate quality 采用的技术要提供足够的质量保证。 Parametric Release and Sterilisation参数放行和灭菌 Parametric release is referred to in the European Pharmacopoeia monograph ”Methods of preparation of sterile products”9. This states ”When a fully validated terminal sterilisation method by steam, dry heat or ionising radiation is used, parametric release, that is the release of a batch of sterilised items based on process data rather than on the basis of submitting a sample of the items to sterility testing, may be carried out, subject to the approval of the competent authority.” 参数放行和EP各论《无菌药品制备方法》相关。各论说明“当采用被充分验证 的湿热灭菌、干热灭菌或者辐射灭菌工艺时，参数放行，就是一批产品放行基于 工艺数据而不是基于样品无菌检测，可以实施，只要被相关当局批准。” The statistical limitations of the sterility test in predicting sterility assurance are well known and based on a) the small number of samples required for testing in relation to the batch size and b) the limited ability of the culture media to enable growth of all potential microorganisms. Thus the sterility test will only detect major deviations in the process resulting in the contamination of a large number of units. By accurately monitoring relevant sterilisation parameters e.g. temperature, pressure and time, data derived from in-process monitoring of a validated terminal sterilisation process can provide more accurate information since the probability of product bioburden surviving the process in any single unit can be calculated to be less than one in a million. Approval for parametric release eliminates the requirement for a finished product sterility test as a condition for batch release. The release of each batch is dependent on the successful demonstration that pre-determined, validated sterilising conditions have been achieved throughout the load. 预测无菌保证程度的无菌检查统计限度已经被熟知，并基于 ---要求进行无菌检测样品小的数量和批量关系 ---培养基促进潜在所有微生物生长的有限的能力 因而无菌检测将主要侦测工艺中导致大批量污染的主要缺陷。通过精确监控相关 灭菌工艺参数，例如温度、压力和时间、来自验证的最终灭菌工艺中控监控的数 据，可以提供更精确的信息，因为任何单位产品中生物负荷量存活的可以计算得 出少于百万分之一的概率。参数放行的批准豁免了最终产品无菌检测作为批次放 行条件的要求。每个批次放行依赖于成功展示预先确定的，验证的灭菌条件已经 被达到，贯穿整个负载。 The sterilisation process in an application for parametric release of sterility must be in accordance with the requirements of the European Pharmacopoeia. Consequently, parametric release can only be applied to products sterilised in their final containers by moist heat, dry heat or radiation9. The choice of a sterilisation process must be well founded considering both the knowledge of the stability of the product under relevant conditions and the data gained in development studies where critical process parameters are identified. 无菌产品参数放行中应用的灭菌工艺必须符合EP要求。对应的，参数放行只可 以应用于最终灭菌产品，可以是湿热灭菌、干热灭菌和辐射灭菌。灭菌工艺选择 必须建立在某种条件下产品的稳定性和研发中获得的数据的充分考虑基础上，在 研发中，关键工艺参数已经被确认。 As regards inspections conducted based on an application for parametric release the inspector checks that standard operating procedures for the various stages in the manufacturing process that are of significance for sterility are in place. In particular,