201506 ICH Q7官方问答(中英对照).doc

201506 ICH Q7官方问答Q7 Implementation Working GroupICH Q7 Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical IngredientsQuestions and AnswersCurrent versiondated 10 June 2015In order to facilitate the implementation of the Q7 Guidelines,the ICH Experts have developed a series of Q&As:Q7 Q&AsDocument HistoryICH Q7指南：原料药GMP指南问答2015-6-10CodeHistoryDateQ7 Q&AsApproval by the ICH Steering Committee underStep 410 June 2015ReferencesThese documents are published .ICH E2E Pharmacovigilance Planning November 2004ICH Q1A(R2) Stability testing of new drug substance and products February 2003ICH Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derivedfrom Cell Lines of Human or Animal Origin September 1999ICH Q5B Quality of biotechnological products: Analysis of the construct in cells used for the productionof r-DNA derived protein products November 2005ICH Q5D Quality of Biotechnological Products: Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products July 1997ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products March 1999ICH Q7 Good Manufacturing Practice of APIs November 2000ICH Q8(R2) Pharmaceutical Development August 2009Part I: Pharmaceutical Development November 2006Part II: Annex to Pharmaceutical Development, November 2008ICH Q9 Quality Risk Management and the ICH Q9 Briefing pack November 2005ICH Q10 Pharmaceutical Quality Systems June 2008ICH Q-IWG Training Programme for ICH Q8/Q9/Q10 November 2010ICH Q11 Development and Manufacturing of Active Pharmaceutical Ingredients May 2012Legal Notice:This document is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICHs copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided.The document is provided as is without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document.The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder.Table of ContentsPREFACE . 11. INTRODUCTION - SCOPE . 22. QUALITY MANAGEMENT . 23. PERSONNEL . 34. BUILDINGS AND FACILITIES CONTAINMENT . 45. PROCESS EQUIPMENT CLEANING . 56. DOCUMENTATION AND RECORDS . 67. MATERIALS MANAGEMENT . 78. PRODUCTION AND IN-PROCESS CONTROLS . 89. PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDIATES . 810. STORAGE AND DISTRIBUTION . 811. LABORATORY CONTROLS . 912. VALIDATION . 1113. CHANGE CONTROL . 1114. REJECTION AND REUSE OF MATERIALS . 1215. COMPLAINTS AND RECALLS . 1216. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) . 1317. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS . 1418. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION . 1519. APIS FOR USE IN CLINICAL TRIALS . 1520. GLOSSARY . 1621. ANNEX: Q&AS LINKED TO THE RESPECTIVE SECTIONS OF ICH Q7 . 17PREFACE前言Since the ICH Q7 Guidance was finalised, experience with implementing the guidance worldwide has given rise to requests for clarification of uncertainties due to the interpretation of certain sections. This Question and Answer (Q&A) document is intended to respond to those requests.自从ICH Q7指南定稿，在全球实施中，有不少要求期望对一些内容的不确定性进行澄清。本问答文件就是为了对这些咨询做出回应。The ICH Q7 document should be read in its entirety regardless of the nature of the manufacturing activities being conducted to fully understand the linkages between certain sections and successfully implement appropriate Good Manufacturing practices (GMPs) at all stages of the Active Pharmaceutical Ingredients (API) supply chain, including distribution. A table is provided as an Annex of this document showing the link between each Q&A and the relevant Sections of ICH Q7 and other ICH Quality guidance.ICH Q7文件应作为整体阅读，而不管所实施的生产活动的特性如何，以便全面理解各部之间的联系，成功地在所有API供应链所有环节，包括销售中实施适当的GMP。在本文的附录提供了一份表格，显示出各问答与章节之间的关联，以及ICH Q7与其它ICH质量指南之间的关联。ICH would like to acknowledge the work undertaken by the Pharmaceutical Inspection Co-operation Scheme (PIC/S). PIC/S contributed to this document by selecting and reviewing relevant Q&As that had been collected from training sessions since the implementation of Q7 and transferred the output of these reviews to the ICH Q7 IWG for consideration and consolidation, as appropriate. Additional questions were developed based on responses from an ICH survey. PIC/S further contributed to the development of the document as an ICH Interested Party.IICH希望向PIC/S所做的工作致谢。PIC/S选择和审核了自Q7实施以来在培训课程中收集的相关问答，并将其审核的结果转交给ICH Q7专家工作组供其讨论和成文。还有一些问题是在ICH调查中收到的回复。作为ICH利益相关方，PIC/S对本文的制订做出了贡献。Please note that ICH Q7 should be applied in combination with the principles laid down for development and manufacturing in ICH Q11 (see definition of API starting material; see also ICH Q8(R2) Part II), Quality Risk Management (ICH Q9), and Pharmaceutical Quality Systems (ICH Q10). GMP principles as described in ICH Q7 should be applied regardless which approach is taken in pharmaceutical development and manufacturing.请注意ICH Q7应与在ICH Q11（参见API起始物料定义，参见ICH Q8(R2)第II部分）、质量风险管理（ICH Q9）和药物质量体系（ICH Q10）中对药物研发和生产所给定的原则结合使用。不管在药物研发和生产中使用的是何种方法，都应该应用在ICH Q7里所述的GMP原则。ICH Q7 also describes principles of GMPs to be applied in the manufacture of APIs for use in clinical trials (Section 19) and for APIs manufactured by cellculture/fermentation (Section 18).ICH Q7还描述以适用于临床试验用API（第19部分），以及细胞培养/发酵（第18部分）生产的GMP原则。Q7 Questions and Answers问答#Date of Approval批准日期Questions问Answers答1. INTRODUCTION SCOPE概述-范围1.1June 2015Should GMP according to ICH Q7 be applied for manufacturing Steps before the defined API starting material i.e., Steps not identified in grey in Table 1?ICH Q7 does not apply to Steps prior to the introduction of the API starting material. However, there is an expectation that an appropriate level of controls suitable for the production of the API starting material should be applied ICH Q7, Section 1.3.Normally, the API-starting material is defined in the regulatory filing by the applicant and approved in the regulatory reviewing process. Additional guidance is provided to define and justify API starting material derived from various sources ICH Q11, Section 5; for master cell banks, see ICH Q5B; ICHQ5D.ICH Q7的GMP内容是否适用于界定的原料药起始物料生产步骤，即表1中不是灰色的部分？ICH Q7不适用于原料药起始物料之前的步骤。但是，期望原料药起始物料的生产有适当的控制水平【ICH Q7，第1.3部分】。一般来说，“原料药起始物料”是由申请人在法规申报时定义的，并由法规当局在审核过程中进行批准。关于不同来源的“原料药起始物料”的定义和论证有另外的指南【ICH Q11第5部分】，母细胞库参见【ICH Q5B和ICH Q5D】。1.2June 2015Does ICH Q7 apply to manufacturing Steps for the addition of substance(s)to an API (e.g., to stabilise the API)?When a mixture is classified in the regulatory filing as an API in a region or country in which it is used in a drug product, ICH Q7 should be applied to the manufacturing of these mixtures ICH Q7, Section1.2, 20 see Glossary for definition of API.ICH Q7适用于将其它物质加入原料的生产步骤吗（例如，加入使原料药稳定）？如果一个混合物在法规注册时是作为一种原料药，在注册区域作为药品使用，则ICH Q7适用于这些混合生产步骤【ICH Q7第1.2，20部分-参见原料药定义】。2. QUALITY MANAGEMENT质量管理2.1June 2015What is meant by quality unit(s)independent from production?The intent of the term independent is to prevent any conflict of interest and ensure unbiased decision makingregarding quality-related decisions in the organisation structure. The person in the quality unit who is responsible for final decision-making (e.g., batch release decision) should not have responsibilities for production activities ICH Q7, Section 2.13.“质量部门独立于生产”是什么意思？“独立”一词意在防止利益冲突，保证对与质量相关的决定能在组织结构内以公正的立场作出。质量部分负责最终决定的人员（例如，批放行决定）不应承担生产活动的职责【ICH Q7，第2.13部分】。2.2June 2015Does ICH Q7 expect that the quality unit performs API release testing?While the quality unit has responsibility for the release of the API, which includes oversight of the testing and results, ICH Q7 does not prescribe specifically who performs testing. quality control in the ICH Q7 Glossary ICH Q7, Section 20 refers to the activities, not the organisational structure.For examples of quality responsibility related to testing and release, refer to ICH Q7, Sections 2.13, 2.22, and 11.12. Appropriate laboratory controls should be followed ICH Q7, Sections 11.10, 16.10 regardless of who performs the testing.ICH Q7是否期望质量部门实施原料药放行检测？当质量部门承担原料药放行的职责时，它就包括了监督检测过程和检测结果，ICH Q7并未具体描述谁来执行检测行为。在ICH Q7术语中【ICH Q7第20部分】，“质量部门”指的是一些活动，而不是组织结构。例如，与检测和放行相关的质量职责，参见【ICH Q7，第2.13，2.22和11.12】。不管是谁来执行检测，均应遵守适当的化验室控制【ICH Q7，第11.10，16.10】。2.3June 2015Can other departments outside of the quality unit be held responsible for releasing raw materials and intermediates?Yes. The quality unit is responsible for establishing a system to release or reject raw materials, intermediates, packaging, and labelling materials. This responsibility cannot be delegated ICH Q7, Section 2.22(2). The system established by the quality unit may allow other departments to release raw materials and intermediates (except intermediates that are for use outside the control of the manufacturer ICH Q7, Section 2.22(1) as long as oversight and the overall responsibility of this system remains with the quality unit.质量部门以外的部门是否可以承担放行原料和中间体的职责？可以。质量部门负责建立一个体系来放行或拒收原料、中间体、包材和标签。该职责不可以转授【ICH Q7，第2.22（2）部分】。只要该系统的总体职责和监管还保持由质量部门执行，由质量部门建立的体系可以允许“其它部门”来放行原料和中间体（除了在生产商控制以外的地方使用的中间体外【ICH Q7，第2.22（1）部分】。2.4June 2015Does ICH Q7 expect that sampling be performed by the quality unit?No. ICH Q7 does not prescribe specifically who should perform the sampling ICH Q7, Section 2.22. However, the quality unit has responsibility for reviewing and approving sampling plans ICH Q7, Section 11.12 and procedures. Sampling should be performed by adequately trained personnel ICH Q7, Section 3.10 and be appropriately documented as per ICH Q7, Section 6.52.ICH Q7是否期望由质量部门来取样？不。ICH Q7并未专门说明应该由谁来取样【ICH Q7，第2.22部分】。但是，质量部门具有职责来审核和批准取样计划【ICH Q7，第11.12部分】和程序。取样应该由进行充分培训的人员执行【ICH Q7，第3.10部分】，并应按【ICH Q7第6.52部分】进行适当记录。2.5June 2015What should be the frequency of a product quality review?A product quality review is generally expected annually. Review timeframes can be appropriately adjusted based upon manufacturing and campaign duration with adequate justification. Even if no manufacturing has occurred in the review period, the quality review should be conducted as per section ICH Q7, Section 2.50 and include stability, returns, complaints, and recalls. For example, a product quality review may encompass more or less than 12 months depending upon product campaign duration ICH Q7, Section 2.50; ICH Q10, Section 2.6.产品质量回顾应该按什么频次执行？产品质量回顾一般是期望按年来实施。回顾时间段可以根据生产情况和生产时间周期进行调整，同时进行充分的论证。即使在评估时间段里没有生产，质量回顾还是应该按【ICH Q7第2.50部分】执行，包括稳定性、退货、客户投诉和召回。例如，一个产品质量回顾的时间段可以是多于或少于12个月，这个时间段取决于产品生产周期时长【ICH Q7，第2.50部分，ICH Q10，第2.6部分】。2.6June 2015Should the product quality review of results include trend analysis?Trend analysis is usually an important element in verifying the consistency of the process as part of the product quality review ICH Q7, Sections 2.50, 2.51. Potential tools to use are described in ICH Q9, Annex I.9.结果的产品质量回顾是否要包括趋势分析？在确认工艺的持续时，趋势分析通常是产品质量回顾中很重要的部分【ICH Q7，第2.50，2.51部分】。在【ICH Q9附录I.9】中给出一些可用的工具。3. PERSONNEL人员3.1June 2015What is the intent of the statement inICH Q7, Section 3.12 training should be periodically assessed?In ICH Q7, Section 3.12, the statement training should be periodically assessed refers to a system to evaluate if personnel remain proficient and competent in their job tasks and responsibilities, and whether more frequent, additional, or new training is needed and recurring training is up to date.在【IHC Q7第3.12部分】中，说“培训应定期进行评估”的目的是什么？在【ICH Q7第3.12部分】中，说“培训应定期进行评估”是指应该有一个系统来评估人员是否保持其专业知识并有资格完成其工作任务和职责，是否需要增加培训频次，是否需要增加新的培训，重复培训是否有更新。3.2June 2015Does ICH Q7 expect the use of a consultant and can a company delegate tasks and/or responsibility to a consultant?ICH Q7 does not expect the use of a consultant. Consultants may perform delegated tasks and/or provide advice. However, the ultimate responsibility for API quality must not be delegated ICH Q10,Section 2.7, ICH Q7, Sections 2.2, 3.3.ICH Q7是否期望雇佣顾问，公司是否可以将一些任务和/或职责委任给一个顾问？ICH Q7并未期望公司雇佣顾问。顾问可以履行赋予给他的任务和/或提供建议。但是，原料药质量的无限责任不能委任给顾问【ICH Q10，第2.7部分，ICH Q7第2.2，3.3部分】。4. BUILDINGS AND FACILITIES CONTAINMENT厂房和设施-隔离4.1June 2015When are dedicated production areas expected?ICH Q7 expects dedicated production areas for highly sensitising materials such as penicillins and cephalosporins because of the patient risk (e.g., anaphylactic shock to penicillin-allergic patients) from trace amounts of these compounds in other medicines ICH Q7, Section 4.40.For materials of an infectious nature or high pharmacological activity or toxicity, a risk-based approach should be used to determine appropriate containment measures, which may include validated inactivation, cleaning and/or dedicated production areas ICH Q7, Section 4.41.While ICH Q7 does not define high pharmacological activity or toxicity, these are generally determined by evaluating relevant animal and human data collected during research and development. Important considerations in this evaluation of pharmacological activity or toxicity may include Occupational Exposure Limit (OEL), Permitted Daily Exposure (PDE), Acceptable Daily Exposure (ADE),Threshold for Toxicological Concerns (TTC), No Observed Adverse Effect Level (NOAEL) ICH S Guidelines, ICH E2E, Section 2.1.1, and the consequences of cross-contamination ICH Q9, Section4.3.什么情况下需要使用专用生产区域？ICH Q7期望对于高致敏物料，如青霉素和头孢类物料使用专用生产区域，因为这些物质在其它产品中的痕量残留都可能引起患者风险（如引起青霉素过敏患者的过敏性休克）【ICH Q7，第4.40部分】。但ICH Q7并没有对高药物活性或毒性进行定义，通常是要通过对研发期间收集的相关动物和人类数据进行评估来决定的。在药物活性或毒性评估中需要重点考虑的内容可以包括职业暴露限度（OEL）、允许日暴露量（PDE）、可接受日暴露量（ADE）、毒性关注阈值（TTC）、无可见不良反应水平（NOAEL）、【ICH S指南，ICH E2E第2.1.1部分】，以及交叉污染的后果【ICH Q9第4.3部分】。4.2June 2015To what extent can quality risk management be used in establishing appropriate containment measures to prevent cross-contamination?The principles of quality risk management ICH Q9, Annex II.4 should be applied to the design of buildings, facilities and controls for the purpose of containment, taking into consideration the pharmacological/toxicological/chemical/biological properties of the raw material, intermediate and/or API to be handled or manufactured.Appropriate containment measures and controls ICH Q7, Section 4.42 include but are not limited to the following:?Technical controls (e.g., dedicated production areas, closed/dedicated Heating Ventilation and Air Conditioning (HVAC) system, closed manufacturing systems, use of disposable technologies, design of facility and equipment for containment and ease of cleaning); and?Procedural (organisational) controls (e.g., cleaning, personnel flow, environmental monitoring and training).Monitoring systems are important to check the effectiveness of the containment controls.质量风险管理用于建立适当的遏制措施来防止交叉污染时，可以应用到什么程度？质量风险管理【ICH Q9附录II.4】的原则应在以遏制为目的厂房、设备和控制设计时应用，同时考虑处理或生产的原料、中间体和/或原料药的药理/毒性/化学/生物特性。适当的遏制措施和控制【ICH Q7第4.42部分】包括但不仅限于以下：?技术控制（例如，专用生产区域、封闭/专用空调暖通（HVAC）系统、封闭生产系统、一次性技术的使用、为了遏制和易于清洁目的而做的厂房和设备的设计），以及?程序（组织）控制（例如，清洁、人流、环境监测和培训）监测系统对于遏制措施的控制有效性检查非常重要。5. PROCESS EQUIPMENT CLEANING工艺设