1、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
2、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
3、 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
4、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 gre
5、y 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 materia
6、l 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
7、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
8、.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 #Date of Approval批准日期Questions问Answers答defi
9、nition 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
10、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
11、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 testin
12、g 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
13、, and 11.12. Appropriate laboratory controls should be followed ICH Q7, Sections 11.10, 16.10 regardless of who performs the #Date of Approval批准日期Questions问Answers答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
14、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 o
15、r 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
16、 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
17、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】。2.4 June Does ICH Q7 expect that No. ICH Q7 does not prescribe specifically who #Date of Approval批准日期Questions问Answers答2015 sampling be performed by the quality unit?should perform the sampling ICH Q7, Section 2.22. However, the quality unit has responsibility f
18、or 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
19、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。2.5 June 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 campaig
20、n 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 tha
21、n 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#Date of Approval批准日期Questions问Answers答第 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
22、于产品生产周期时长【ICH Q7，第 2.50 部分，ICH Q10，第 2.6 部分】。2.6 June 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
23、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3.1 June 2015What is the intent of the statement inICH Q7, Section 3.12 training should be periodically assessed?In ICH Q7, Section 3.12, the st
24、atement 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
25、”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。3.2 June 2015Does ICH Q7 expect the use of a consultant and can a company delegate tasks and/or responsibility to a ICH Q7 does not expect the use of a consultant. Consultants may perform d
26、elegated tasks and/or provide advice. However, the ultimate responsibility for API quality must not be #Date of Approval批准日期Questions问Answers答consultant? 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
27、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4.1 June 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
28、.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 measure
29、s, 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.
30、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 #Date of Appro
31、val批准日期Questions问Answers答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
32、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】。4.2 June 2015To what extent can quality risk management be used in establishing appropriate containment measures to prevent cross-contamination?The princi
33、ples 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 handl
34、ed 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 #Date of Approval批准日期Questions问Ans
35、wers答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 effective
36、ness 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
37、遏制措施的控制有效性检查非常重要。5. PROCESS EQUIPMENT CLEANING 工艺设备- 清洁5.1 June 2015For dedicated equipment, is visually clean acceptable for verification of cleaning effectiveness, (i.e., no expectation for specific analytical determination)?Visually clean may be acceptable for dedicated equipment based on the abi
38、lity to visually inspect and sufficient supporting data from cleaning studies (e.g., analytical determination to demonstrate cleaning effectiveness) ICH Q7, Section 12.76. Equipment should be cleaned at appropriate intervals (e.g., time or number of #Date of Approval批准日期Questions问Answers答batches) to
39、 prevent build-up and carryover of contaminants (e.g., degradants or objectionable levels of microorganisms) so that they do not adversely alter the quality of the API ICHQ7, Sections 5.23, 12.7.对于专用设施，在清洁有效性确认中使用“目视清洁”是否被接受（也就是说没有特定的分析检测）？基于目视检查的能力，并有充分的清洁研究支持性数据（例如，分析检查来证明清洁有效性）时，对专用设备采用“目视检查”是可以接
40、受的【ICH Q7 第 12.76 部分】。设备应根据适当的时间间隔进行清洁（例如，时间或批次），以防止污染物累积和带入（例如，降解物或达到不可接受的水平的微生物），这样保证其不会对原料药的质量产生不良影响【ICH Q7 第5.23，12.7 部分】。5.2 June 2015Should acceptance criteria for residues be defined for dedicated equipment?Yes. Regardless of whether equipment is dedicated or not, it is expected that acceptan
41、ce criteria for residues be defined and that the equipment be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants. Intervals can be based on number of batches, product change-over, time, etc. ICH Q7, Sections 5.22, 5.23, 5.24, 5.25, 8.50.Cleaning intervals and accepta
42、nce criteria should be established based on an understanding of the process/reactions/degradation, taking into account solubility, potency, toxicity, etc. Establishment of acceptance criteria does not necessarily imply sampling and testing after every cleaning. Visual inspection of equipment for cle
43、anliness is an expectation of ICH Q7, Section 5.21. Where validation data has confirmed effective cleaning, #Date of Approval批准日期Questions问Answers答cleaning procedures should be monitored at appropriate intervalsICH Q7, Section 12.76.专用设备还要定义残留可接受标准么？要。不管设备是否专用，期望定义残留可接受标准，并且要对以适当的时间间隔进行清洁，以防止污染物的累积和
44、残留。清洁的间隔可以是根据生产批次、产品更换情况、时间长度等。【ICH Q7 第 5.22，5.23，5.24，5.25，8.50 部分】。应根据对工艺/反应/降解情况的了解来建立清洁间隔和可接受标准，同时考虑溶解性、效价、毒性等。建立可接受标准并不表示就一定要在每次清洁后取样和检测。对清洁后的设备进行目视检查是【ICH Q7 第 5.21】的期望。如果已经通过验证确认了一个有效的清洁程序，则要对清洁程序以适当的时间间隔进行监测【ICH Q7 第 12.76 部分】。5.3 June 2015Is it expected that equipment cleaning time limits
45、be confirmed in cleaning validation?Yes. Equipment cleaning is addressed in two sections in ICH Q7. While the cleaning validation ICHQ7, Section 12.7 does not specifically address time limits for cleaning, ICH Q7, Section 5.21 indicates that the maximum time between completion of processing and equi
46、pment cleaning (dirty hold time) should be established by the company. This maximum established dirty hold time is the time period for which evidence is available to demonstrate that the equipment can still be reliably cleaned. This maximum established dirty hold time is confirmed during the initial
47、 cleaning validation and can be extended #Date of Approval批准日期Questions问Answers答with appropriate supporting data.While ICH Q7 does not specify the need for time limits between equipment cleaning and use in the next process (clean hold time), ICH Q7, Section 5.21 does state that written procedures sh
48、ould include instructions for the protection of clean equipment from contamination prior to use and inspection of equipment for cleanliness immediately before use, if practicable.是否期望在清洁验证时确认设备清洁时间限制？是的。设备清洁在 ICH Q7 里有 2 个部分讲到了。尽管清洁验证【ICH Q7 第 12.7 部分】中并未特别说明清洁的时间限制，【ICH Q7 第5.21 部分】指出公司应建立工艺结束后到设备清
49、洁之间的最长放置时间（脏设备放置时间）。该最长放置时间是有证据支持的脏设备放置后还能被可靠清洁的时间。脏设备最长放置时间应在初次清洁验证时进行确认，如果有适当的支持性数据还可以延长。尽管 ICH Q7 并没有说明需要确认设备清洁后到下次使用的时间限制（清洁后放置时长），但【ICH Q7 第 5.21 部分】要求在书面程序中包括保护清洁设备在使用前不受污染的指令，以及设备在使用前要检查其清洁。5.4 June 2015Is it expected that campaign manufacturing be addressed in cleaning validation?Yes. The cleaning validation section ICH Q7, Section 12.7 does not specifically address campaign manufacture. However, sections ICH Q7, Sections 5.23, 8.50 set forth the expectations that e
