how to do-Q7A 问答中文版

原料药委员会

原料药GMP：

“如何实施”文件

ICH-Q7a指南解释

原文：2010年六修订版

翻译：徐禾丰

英-汉对照版

2010年二月，第六版ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE

原料药委员会

GMPs for APIs:

原料药GMP：

“How to do” Document

“如何实施”文件

Interpretation of the ICH Q7a Guide

ICH-Q7a指南解释

Version 6

版本6

“How to do”-Document

“如何实施”-文件

1. INTRODUCTION绪论

1.1 Objective 目的

Historical Background

历史背景

When the initiative was taken by PIC/S at the Canberra meeting in September 1996 to draft a globally harmonised Good Manufacturing Practices

(GMP) guide for the Production of Active Pharmaceutical Ingredients (API’s), the recommendation wa s made that this should essentially be a “what

to do”, rather than a “how to do” document.

在1996年九月堪培拉会议上，药品生产检查互认公约合作组织(PIC/S)发起起草一份全球协调的原料药(APIs)生产GMP指南，该推荐在

本质应当是一个“做什么”，而不是一个“怎样做”的文件。

After that initiative the International Conference on Harmonisation (ICH), which consists of the three major pharmaceutical regions of the world-USA,

Japan and Europe-took the topic on board. The ICH established an Expert Working Group (EWG) which membership was due to the importance of the

topic extended beyond the three regions to WHO, PIC/S members, India, China and OTC and Generic industry representatives. The EWG, of which

CEFIC APIC was a member of, has compiled the 'GMPs for APIs' Guide within 2 ? years time. The document was finalized by November 2000 and

is now at the stage to be implemented within the three regions.

在发起后，由世界三个主要药品区域-美国、日本和欧盟-组成的人用药注册技术要求国际协调会议(ICH)采纳了这一提议。ICH专门为

此成立了一个专家工作组(EWG)，因为该提议的重大意义，其成员组成超出了上述三个地区，扩展到世界卫生组织(WHO)、药品生产检查

互认公约合作组织成员国、印度、中国以及非处方(OTC)和仿制药行业代表。欧洲化工协会原料药委员会(CEFIC-APIC)也是其成员。专家

工作组在两年半的时间内完成了原料药GMP指南。该文件最终于2000年十一月定稿，现在处于三个区域贯彻实施阶段。

Purpose of the Document

文件目的

This document was written by experts from the European Industry (CEFIC APIC). It is essentially an interpretation of “how to” implement the ICH

Q7a Guide based on practical experience. Other relevant publications (e.g. ISPE Baseline Guides, other ICH Guidelines) were taken into account and

references included.

本文件由欧洲业界(CEFIC-APIC)专家进行撰写，实际上是基于实践经验解释“如何”执行ICH-Q7a指南。文件还参阅了其它相关出版物

(例如，ISPE的Baseline指南，以及其它ICH指南等)。

This document does not intend to provide an exhaustive list of “how to” comply with the above mentioned requirements and recommendations. It does

however provide examples of commonly applied solutions and practical assistance on how requirements and recommendations can be met and /or

interpreted.

文件并不打算就“怎样做”满足上述要求与建议提供一份详尽清单。但它确实提供了通常解决例子，以及如何符合，和/或解释要求与推

荐方面的实际帮助。

Industry should avoid needless paperwork and administrative burden. As indicated in the Q7a document the focus should be-for the benefit of the

patient-on identifying the critical controls and procedures that assure the quality of the API. Therefore, sound scientific judgement should prevail when

setting up a quality system incorporating GMP.

业界应尽量避免那些不必要的文书工作和行政管理负担。正如在Q7a文件中所指出的那样，关注焦点应当放在-为了患者的利益-辨识关

键控制和关键程序，以确保原料药的质量。因此，在建立整合GMP的质量体系时，良好而科学的判断不可或缺。

Finally, APIC/CEFIC cannot guarantee that adhering to the principles laid down in this document will consistently result in trouble free inspections.

Adoption of the guidance given will however provide both industry and regulators with a much greater confidence in the quality of global bulk active

pharmaceutical ingredients manufacture.

最后，APIC-CEFIC不能确保如果坚持执行本文件所开列的各项原则，检查就一定会毫无异议地通过。但是采用该指南会使无论是业内

人士还是药政人员对全球原料药制造质量树立更强信心。

The word ?should?is extensively used in the final version of the ICH Q7a Guide. It indicates

requirements and recommendations that are expected to

apply unless shown to be inapplicable or replaced by an alternative that can be shown to provide at least an equivalent level of quality assurance. Hence,

?should?does not mean that because it is only a ?should?, and not a ?must?, then this requirement does not have to be met.

“应当(should)”一词在最后版本ICH-Q7a指南中广泛使用。它表明希望采纳的要求和建议，除非这些要求与建议不具备适用性，或可以

由其它要求和建议所替代，并至少能够达到同等程度的质量保证水平。因此，“应当”不意味着因为它仅仅是“应当(should)”，而不是“必需

(must)”，就可以不去遵守。

This document is meant to be a “living document” to describe current practice and to help with the implementation of the GMP Guide for APIs.

Suggestions and/or questions from industry or regulators to CEFIC APIC (2110175ebe23482fb4da4cc8) are welcomed. These will be discussed regularly by the

industry experts and clarifications and improvements incorporated into the document.

本文件是“活的文件”，可用来对现行规范进行描述，并为贯彻执行原料药GMP 指南提供帮助。欢迎业内或药政人士向

CEFIC-APIC(2110175ebe23482fb4da4cc8)多提意见和建议，所有这些建议将有业内专家进行定期讨论，以使文件得到提高与改善，条理层次更加清

晰明朗。

“How to do”-Document

“如何实施”-文件

Regulatory Requirements

药政要求

Companies should be aware that the regulatory filing requirements might differ from the application of GMP as defined by Q7a. There may be cases

where more information may be required by regulatory authorities, but inspections for compliance with the Q7a Guide should only cover the GMP

relevant steps.

企业应当清楚药政注册方面规要求可能与Q7a所规定GMP应用有所不同，药政当局有时可能要求提供更多的信息，但在检查其是否符

合Q7a指南相关规定时，检查只应涵盖与GMP相关的步骤。

1.2 Regulatory Applicability 药事法规的适用性

-

1.3 Scope 范围

API Starting Materials

原料药起始物料

Companies are responsible for proposing the API Starting Material(s). This is one of the most significant changes proposed in the ICH Q7a document.

The technical and quality groups should work closely with regulatory groups to ensure no disagreement occurs on the proposed starting materials.

Ideally the registration of New API’s will start from the same Starting Materials defined from a GMP perspective. However, based on current

regulatory requirements it is likely that the regulatory authorities will require further information on API Starting Materials where only one or two

synthetic steps exist between the API starting Material and the API or where the API Starting Material is an API itself.

企业有责任建议原料药起始物料，这是ICH-Q7a文件所建议的最显著的变更之一。技术和质量部门应当同药政部门密切合作，以确保

在所建议的始物料方面达成一致。理想的是，新原料药注册应从符合GMP定义的起始物料开始。但根据现行药政要求，只有当原料药起始

物料与原料药之间仅仅一个或两个合成步骤，或者原料药起始物料就是原料药本身时，药政部门才有可能要求进一步提供原料药起始物料

的相关信息。

The companies should review the synthetic process of each API and based on technical and quality assessments define what are the significant

structural fragments beyond which the GMP standards defined in ICH Q7a should apply. In general, the source of the API Starting Materials is not the

major factor.

企业应当对每一种原料药的合成工艺进行审核，并在技术和质量评价的基础上确定哪些显著的结构碎片需要采用ICH-Q7a中所定义的

GMP标准。通常，原料药起始物料来源并不属于主要因素。

The regulatory authorities may also require further details for late stage API Starting Materials, though recent examples are known that in specific cases

FDA has accepted final intermediates as API Stating Materials (e.g. the widely commercially available substance 6-APA for the manufacture of

semi-synthetic penicillin's)

尽管近年来一些例子表明美国食品药品管理局(FDA)在特定情况下同意将最终中间体(例如，半合成青霉素生产所需，可广泛商业采购

的6-APA)作为原料药起始物料，但药政部门可能仍然会要求进一步提供原料药起始物料后期的详细资料。

Guidance on How To Define API Starting Materials

如何定义原料药起始物料指南

Follow the guidance given in ICH Q7A and involve technical, quality and regulatory departments in agreeing the definition of the API Starting

Materials. Where possible use the same definition of API starting material in regulatory filings and in defining the steps for which the GMP

requirements of ICH Q7a apply.

下列指南在ICH-Q7a中给出，且所涉及的技术、质量和药政部门均应同意所定义的原料药起始物料。在药政文件和确定哪些步骤应

采用ICH-Q7a的GMP要求时，应尽可能采用相同的原料药起始物料定义。

Further guidance on How To Define the API Starting Materials and regulatory strategy is given in the article:

有关如何进一步定义原料药起始物料的指南及相应法规及策略将在下列文章中给出：

“The Active Pharmaceutical Ingredients Sta rting Material (APISM) and other materials in API manufacture: Scientifically-based

principles for the Common Technical Dossier” Helga Moller and Chris Oldenhof, Drug Information Journal, V olume 33, Number 3,

1999, pages 755-761.

See also Eudralex V ol. 2b, page 162 (“Validation of the process should be carried out…for steps of the manufacturing process which

are critical for the product”)

也可以参考Eudralex V ol. 2b, page 162 (“Validation of the process should be carried out…for steps of the manufacturing process

which are critical for the product”)。

The API Starting Material Decision Tree, developed by CEFIC/APIC and FIP, is the central feature of this guidance (see table at the end of the

chapter).

由CEFIC-APIC和国际制药联合会(FIP)所设计的原料药起始物料判断树，是本指南的主要特点(参见本章末尾的图表)。

“How to do”-Document

“如何实施”-文件

Where the proposed API Starting Material is close to the API itself e nsure that details on the synthetic process and analytical controls used to

manufacture the API Starting Material are available in case these would still be (justifiably) requested by the regulators. Where the API

Starting Material is a commercial molecule the requirement to provide these details (if needed for confidentiality reasons: directly to the

authorities only) may be included in the commercial contract.

如果所提议的原料药起始物料和原料药本身很接近的话，就要确保可以提供原料药起始物料制造过程中所使用的合成工艺和分析

控制，以备药政人员(合理)要求所需。若原料药起始物料属于一种商业可供的化学分子物质，提供相应详细信息(如果出于保密目

的，可直接向官方机构提交)的要求应在商业合同中列明。

Similarly, Change Control requirements should be defined in the commercial contract for supply of API Starting Materials. Any significant

changes to the synthetic route, analytical controls or specifications by the manufacturer of the API Starting Materials in general needs

notification to and acceptance by the API manufacturer.

同样，在原料药起始物料供应合同中也应明确有关变更控制的要求。通常情况下，原料药起始物料生产企业合成路线，分析控制

或相应规格等方面发生任何重大变更时，需通知原料药制造企业，并取得他们的批准。

While API Starting Materials do not require to be manufactured to the GMP requirements defined in ICH Q7a, manufacturers of intermediates

and / or API’s should have a system for evaluating the suppliers of critical materials (Reference Q7a Section 7.11). Appropriate qualification

of API Starting Material suppliers is required.

然而原料药起始物料并不需要按照ICH-Q7a所规定的GMP要求进行制造，中间体和/或原料药制造企业应建立起相应体系以对关键

物料供应企业进行评价(参考Q7a指南7.11节)。原料药起始物料供应企业应具备适

当的资质。

Companies should consider redefining the API Starting Material for wellestablished products. This offers the opportunity to reduce the overall

GMP requirements for early manufacturing steps and to shift the focus to be on the control of the critical synthetic steps starting from the

redefined API Starting Materials. Any proposed re-definitions to API Starting Materials should of course be agreed with the regulatory

authorities. The FDA have already indicated their willingness to reduce the filing requirements for certain well established “Qualified

Products”, including those relating to the final API synthesis steps.

对于成熟品种，企业应当考虑重新定义原料药起始物料。这将有助于减轻早期制造过程GMP压力，并将工作重点转移到对关键合

成步骤经过重新定义的原料药起始物料控制上。任何有关原料药起始物料的重新定义都应当经过药政部门的批准。对于一些优良

的“确认的产品”，FDA 已经表明愿意降低对此类产品的文件要求。

“How to do”-Document

“如何实施”-文件

Table: Decision Tree for help to define the API Starting Material

表格：有助于确定原料药起始物质的判断图

Start process description with description of

micro-organism and media components plus their

specifications. No specific starting material to

Is the API synthetic or semi-synthetic? 是YES Is the API produced by direct fermentation? 是E be defined, unless one component is structually

是否是合成或半合成原料药? 原料药是否直接发酵得到? Y S closely related to the API

从微生物及培养基成分和规格标准开始描述工艺。不需要

定义特别的起始物质,除非某个成分在结构上与原料药密

切相关

是

Y

E

S

Is there sufficient evidence that the last

intermediate is

analytically fully controlled in terms of

否

identity, assay and impurities? (cf. ICH guideline 是YES The last intermediate is the starting material

on impurities in drug substances) 最后中间体是起始原料N

是否有足够的证据来证明最后的中间体在鉴别,含量以及O

杂质项目上进行全面的分析控制?(参照ICH原料药杂质指

南)

否

N

O

Same question for the next to the last The next to the last intermediate is the starting

intermediate 是YES material Is the API extracted from natural sources?

对最后中间体的前一个中间体问同样问题最后中间体的前一个中间体是起始原料原料药是否从自然资源中提取?

是

Y

E

S

否

N

O

Describe the purification process and/or define

API SM based on a scientific rationale which may

include risk assessment

Same question for the intermediate preceeding the The intermediate preceeding the next to the last 否描述精制工艺和/或基于科学原理定义原料药起始物料(可

N

O

next to the last intermediate 是E

Y S intermediate is the starting material

能有风险)

对中间体的前一个中间体问同样问题加工中间体的前一个中间体是起始原料

否

S

N

E

O

Y

是

This substance is the starting material (may be

Continue until the answer is yes more than one in convergent synthesis schemes) Is the API manufactured from mined ore?

是YES 该物质是起始原料原料药是否由矿物生产?

继续,直至回答是在合成中可能有一个以上

“How to do”-Document

“如何实施”-文件

2. Quality management质量管理

2.1 Principles 原则

Among GMP other aspects, such as quality systems, environmental controls, and safety, are necessary to be taken into account in order to be in

compliance with regulations. Business efficiency and continuous improvement are needed to be competitive. Therefore GMP compliance should be

incorporated into an overall Quality Management Systems (QMS) as it is recommended in the EU GMP philosophy.

为了与相关法规相符，GMP的一些其它方面，例如质量体系、环境控制和安全等因素也应列入考虑范畴。而且也需要企业的效率和企

业的持续改进具备一定竞争性。正如欧盟GMP体系所建议的那样，与GMP的符合性要整合到全面的质量管理体系(QMS)中。

The importance of an effective QMS on customer relations, continuous improvement, regulatory compliance and inspection readiness should be

pointed out, which directly ensures benefit to the patient.

有效的质量管理体系对于客户关系、持续改进、法规的符合性和备查状态等均具有重要意义，而且将直接关系到患者利益。

To implement a QMS integrating GMP issues, please refer to the Guide “Quality Management System for A ctive Pharmaceutical Ingredients Manufacturers”, APIC, September 2005.

为贯彻整合GMP到质量管理体系，请参考APIC于2005年9月颁布的“Quality Management System forActive Pharmaceutical Ingredients

Manufacturers”指南。

2.10 Company management should empower Quality responsibility to the appropriate organisational functions to apply the Quality policy and

procedures. Assignment of clear Roles & Responsibilities for duties and decisions is the basic rule and can be achieved by e.g. process

descriptions including principles of RASCI (Responsible, Accountable, Consulted, Supportive and Informed) and decision trees.

企业管理者应当将质量职责赋予适当的组织机构，以落实相应质量方针和规程。

明确的职责与决策角色与职责分配是基本的法则

并能通过例如，过程描述包括RASCI(责任、义务、协商、支持与了解情况)以及决策树来实现。

Delegated responsibilities should be trained, documented and periodically re-trained.

对所委托的职责应当进行培训，记录应当哪个定期保留。

2.11 A clearly defined QMS (as defined e.g. in the APIC Guide (see above), ICH Q10 and ISO 9001: 2000 or later) integrating API GMP

requirements, should be documented, implemented and described e.g. in the Quality Policy.

应当记录、实施并描述一个明确规定的质量管理体系(例如，在APIC指南(前面所提到的)、ICH-Q10与ISO-9001:2000或其后的文本

中所描述的)整合原料药GMP要求，例如质量方针。

2.12 -

2.13 For the release of APIs there is no need for a “Qualified Person” (pharmacist) as defined by the European GMP Guideline (EudraLex, The

Rules Governing Medicinal Products in the European Union, V olume 4: EU Guidelines to Good Manufacturing Practice, Medicinal Products

for Human and Veterinary Use) unless required by a specific law of the EU member state.

除非欧盟成员国特殊的法律要求以外，对于原料药的放行，并不需要按照欧洲药品GMP指南(EudraLex, The Rules Governing

Medicinal Products in the European Union, Volume 4: EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and

Veterinary Use)所规定的那样由“质量授权人(药剂师)”执行。

The responsibilities for quality duties (e.g. process and control review, validation, change control, equipment qualification, batch

documentation review, batch release, regulatory compliance, auditing, process deviation, OOS treatments and complaint investigation) should

be clearly assigned to one or more person(s) or function(s). The QU should be involved in many, if not all, of these issues.

质量职责(如生产工艺和控制审核、验证、变更控制、设备确认，批记录审核、批放行、法规符合性、审计、工艺偏差，超标数据

处理和投诉调查等)应当明确地分派给一个或多个人员或职能部门。而质量部门(QU)，如果不能介入全部，则应介入大部分上述问

题。

If the QA and QC department are separated units the roles and responsibilities of each unit must be clearly described and approved by the

management.

如果QA与QC部门是单独的单位，必须明确描述每个单位的角色与职责，并得到管理层的批准。

2.14 Release of raw materials and intermediates meeting the specifications (for internal use only) by Production is acceptable, provided QU has

approved specifications and test methods. Production personnel should be adequately trained for these duties, the training recorded and all

equipment used qualified and calibrated at regular intervals. The QU, as part of their responsibility for batch release, has the right to review

all test results and data.

如果质量部门已经批准了相应规格标准和检验方法，那么对于符合标准要求(仅限于企业内部使用)的原材料和中间体来说，由生产

部门放行是可以接受的。生产人员应当接受有关责任的充分培训，并应定期对培训进行记录，且对所使用的全部设备进行确认和

定期校准。因为质量部门的部分职责是产品放行，所以他们有权审核所有检验结果和数据。

APIs and intermediates (for use outside of the control of the company) have to be released by a designated person of the QU. Deputy(s) for

such designated person should be nominated.

“How to do”-Document

“如何实施”-文件

原料药与中间体(在企业控制范围外使用时)必须由指定的质量部门人员放行。实施上述职责的指定人员应当经过任命。

2.15 All activities should be directly recorded at the time they are performed in legible documents like note-books, electronic records, etc., which

are retrievable and traceable.

所有活动在执行时就应当直接记录于清晰易读的文件中，如笔记本或电子记录等，这些记录应当是可找回和可追溯的。

Recording in non-traceable documents like a blank sheet of paper (re-writing afterwards into traceable documents) is not acceptable.

采用不可追溯的文件形式进行记录是不被接受的，例如空白纸张(随后应在可追溯文件中重抄一遍)。

Electronic documents and recording requires appropriate validation of the systems used (see chapter 5.4 and 6.10).

要求对电子文件和记录所使用的系统进行适当验证(参考5.4节和6.10节)。

2.16 Documented explanations should be in place for every deviation. When deviations are considered critical, the QU should make sure that a

formal investigation occurs, the findings should be recorded and, if defined, corrective actions should be implemented. See chapter 8.15 for

a more detailed explanation.

每一个偏差都应当具有恰当的书面解释。如果认为是重大偏差，质量部门应当保证进行正式调查，并记录结果，若得到确定，则

需执行相应的纠正措施。参考8.15节中更详尽的解释。

2.17 The release of an API or intermediate does not automatically require that all corrective measures or actions identified in deviation

investigations have to be completed in advance (e.g. corrective actions related to ongoing training, maintenance, process investigations).

原料药或中间体的放行并不机械地要求在放行前必须完成偏差调查所确定的所有纠正措施或行为(例如，与正在进行的培训、维护、

工艺调查相关的纠正行为)。

2.18 As an example a regular report system should be made available to senior management by the QU informing of acute occurrences (quality

related complaints, critical deviations, recalls, etc.). Senior management should review and agree any recommendations and ensure that

appropriate resources are made available.

作为一个例子，质量部门应当定期向高层管理者提交实际的情况(与质量相关的投诉、关键的偏差、召回等)的资料。高层管理者应

当对所有建议进行审核及批准并确保具备相应资源。

Quality (or: key) performance indicators could be installed to evaluate continuous quality improvement of the department.

应当建立质量(或:关键)的性能指标，来评价部门持续的质量改进。

2.2 Responsibilities of the Quality Unit(s)质量部门职责

2.20 QU duties may be delegated to other departments/functions provided there are systems in place to ensure that the QU has adequate control /

supervision. Different levels of control depending on the nature of the activity are required by ICH: “make sure” (for example: put systems in

place, verify by audi ting, assigns responsibilities), “be involved” (means personal involvement of the QU responsible) or “establishing” (QU

issues a system or procedure on its assigned duties).

如果存在一个系统能够保证质量部门对其职责进行充分的控制/监督，则可以将质量部门的职责委派给其它部门/职能单位。根据活

动的性质采取不同的控制水平，如ICH所规定的：“确保”(例如：有一个系统、核实审计、责任分派)，“介入”(指质量部门职责中的

个人介入)，或“建立”(质量部门在其指定的职责内签发的系统或程序)。

2.21 -

2.22 Although in this section it is stated “…should not be delegated” it is likely that company’s will face problems during inspections if they come

up with alternatives; this “should” has to be interpreted as “must”.

尽管在本节中提到“…不应该进行委派”，是乎如果公司用另外的方法，则在检查过程中将会面临一些问题；这时“应该”将不得不

解释成“必须”。

Only the batch production records of critical (Reference to critical see Glossary) steps (a step could be the entire unit operation, e.g.

conversion of the final intermediate to the API or a single parameter such as temperature control at an earlier step) including laboratory

records have to be reviewed by the QU, whilst the review of all other steps may be delegated (6.71). (subpoint 3).

只有关键(参考术语中关键)步骤(该步骤可以是一个完整的单元操作，例如：由最终中间体向原料药的转变，或一个单个的参数，

如，在早期步骤中的温度控制)的批生产记录和实验记录必须由质量部门进行审核，其余步骤的审核可以委派给其它部门(6.71节)(第

3小点)。

There should be a system in place defining what changes are likely to “impact intermediate or API quality” (subpoint 9). Neverthel ess any

change has to be evaluated and communicated.

应该建立一个系统以确定什么样变更“会对中间体或原料药的质量造成影响”(第9小点)。不过，所有的变更都应该进行评价和沟通。

Stability data for intermediates are only required if they are intended to be sold (for reference see chapter 11.60), but there isn't the need to

apply a full stability program as described in ICH Q1a and Q1b documents. In many instances, a retest of the material prior to use or shipment

is sufficient to demonstrate that the product is still meeting its specifications. (However it is recommended to derive some data during the

development phase or during validation to support storage periods of intermediates during campaign production or storage of left–over

“How to do”-Document

“如何实施”-文件

between two campaigns.) For details see also chapter 8.2.1. (sub-point 14)

只有当中间体要被用于出售时，才需要提供有关中间体的稳定性数据(参考11.60节)，但是并不需要使用ICH-Q1a和Q1b文件中所要

求一整套完整的稳定性程序。很多例子中，原材料在使用或运输前的复检，足够证明产品是符合质量标准的。( 当然，建议在研发

阶段或验证过程中得到一些数据，来支持中间体在生产活动中的储存条件，或在两次战役性活动之间的余料的储存)。详细内容参

见8.21节(第14小点)。

For filed specifications of Raw Materials and Intermediates, documented periodical review by the quality unit for delegated release to

production should occur (ref. 2.5).

对于已经形成规格标准的原料与中间体，在于委托生产部门放行情况下质量部门定期审核记录(参考2.5)。

2.3 Responsibility for Production Activities 生产活动职责

2.30 An additional advice for the assignment of quality related duties to Production and other functions / departments can be found in “EudraLex,

The Rules Governing Medicinal Products in the European Union, V olume 4: EU Guidelines to Good Manufac-turing Practice, Medicinal

Products for Human and Veterinary Use.”

有关与质量相关的职责在生产和其它职能部门之间分配的附加建议可以在“EudraLex, The Rules Governing Me-dicinal Products in the

European Union, V olume 4: EU Guidelines to Good Manufac-turing Practice, Medicinal Products for Human and Veterinary Use.”中查中查

到。

2.4 Internal Audits (Self-Inspections) 内部审计( 自检)

See draft of CEFIC “Auditing” Guideline for how to manage an effective internal audit/self inspection programme.

可以参考有关如何管理一个有效的内部审核/ 自检程序的CEFIC审计指南草案。

Internal Audits (Self Inspections) are a valuable management tool to evaluate if the company is in compliance with the principles of GMP and

additional requirements of the company which are integrated in the QMS. The evaluation should be made by trained auditors, experienced in

auditing skills and recruited from various departments of the company, if possible.

内部审计( 自检)是一个有效的管理工具，可以用来评价企业是否符合GMP原则，以及与质量管理体系整合的企业附加要求。这个

评价应该由经过培训的，在审计方面有一定经验的审计员者进行，如果可能，最好是来自企业的不同部门。

Quality Inspection Teams (QIT) of normally 2 persons are recommended, however (depending on the focus of the audit) recruiting of

additional experts (e.g. engineers, micro-biologists etc.) could increase audit efficiency.. QU should always be represented in a team, but not

always taking the lead for not being accused to be the "policeman”. The QU should be responsible for co-ordinating activities such as follows:

建议质量检查组(QIT)一般由两个人组成，当然(根据审计焦点的不同)，其它方面专家(例如，工程师、微生物学家等)的加入将会使

审核更加有效。质量部门应该总是参与质量检查组，但不一定总是作为受人指责的“警察”。质量部门应该负责协调如下活动：

pre-audit meetings for the QIT (brain storming)

质量检查组的审计前会议(头脑风暴)

identifyin g major areas of concern and preparation of questions (questionnaire)

辨识涉及的主要方面并准备问题(调查表)

collecting historic information such as deviations, changes, complaints, previous internal audit reports

收集历史信息，例如，偏差、变更、投诉、以前的内部审计报告

issuing the agenda and distribution to the auditee in due time

建立日程，并在适合的时候向被检查者公布

co-ordinating the activities of the QIT

协调质量检查组的活动

starting the (inte rnal) audit and summarising the findings in a close out meeting

开始进行( 内部)审计，并在结束会议上总结调查结果

issuing the audit report, on the basis of the close out meeting

在结束会议后的基础上签发审计报告

propose correctiv e measures or improvements to management

向管理层建议的纠正和改进措施

schedule (propose) a re-audit in case of major findings

“How to do”-Document

“如何实施”-文件

对于一些重要的调查结果制定再审核日程(建议)

follow-up.

贯彻执行。

Other members of the QIT could be involved in asking and taking extensive notes. The whole auditing process should be clearly defined and

the following standard documents should be considered to be available in a generic

layout form:

质量检查组的其他成员将实施询问，并做好大量的笔头工作。整个审计过程应该被清楚地确定下来，应该以普通格式提供下述标

准文件：

Definition of auditing process, system or product

定义审计过程、系统或产品

Covering Letter

说明函

Report Form

报告表格

Audit Team Evaluation Form

质量检查组评价表格

Follow-up Report

执行报告

Training Programme

培训程序

The frequency of the self-inspections should be based on risk (a formal risk assessment may not be necessary) as well as the compliance status

of the area to be audited. It may vary from half a year to three years, and the rationale behind the frequency should be documented.

内部检查的频次应当基于风险(可能不需要正式的风险评价)以及所审计方面的符合性状况。可以从半年一次调整到三年一次，并且

应当记录频次后面的基本原理。

The compliance status of the area to be audited and may vary from half a year to three years. All participants in the QIT should have the

commitment from the management to use the specified time for preparing, performing and reporting the internal audit. Also un-announced

audits or spot checks should be considered besides the “normal” audit programme.

根据将审计方面的符合性状况，频次可以可以从半年一次调整到三年一次。在质量检查小组内的各方应当有来自管理层的承诺使

用特定的时间来制作、实施雨季报告内部审核结果。同样，在“常规”的审计日程外,也应当考虑不事先宣布的审计或对点的核查。

If possible internal audits should not take more than to 3 - 4 hours. Remember to include at a minimum twice the time for preparing and

writing the audit reports.

如果可能，内部审计时间应不超过3-4个小时。但至少要花费两倍的时间用于审计报告的准备和编写。

It is important to define deadlines for issuing (recommendation: 2 weeks) and finalizing (recommendation: 4 weeks) the report and for the first

follow-up meeting.

确定报告的发布(推荐：2星期)和完成(推荐：4星期)以及首次执行会议的最终期限是很重要的。

The internal Audit Report as well as the Follow-up Report should be kept confidential and should not be shown to external personnel,

especially inspectors from authorities.

内部审计报告和执行报告都应该保密，不要给外部人员看，特别是对来自官方的检查员。

All (Internal) Audit Reports should be made available for the management, and the findings discussed. Management is responsible to initiate

necessary corrective actions and investments.

管理者应该可以取得所有的( 内部)审计报告，并对调查结果进行讨论。管理者应该对必要的纠正行为和资金投入负责。

If the API manufacturer at the same time the MA holder for the final drug product, there is an expectation that the finished product QP has

access to all internal audit reports.

如果原料药制造企业同时是药品上市许可持有人，制剂产品的产品放行人希望能够使用所有的内部审计报告。

2.41 -

“How to do”-Document

“如何实施”-文件

2.5 Product Quality Review 产品质量审核

2.50 The major objective of the Product Quality Review is to evaluate the compliance status of the manufacture (process, packaging, labelling and

tests) and to identify areas of improvement based on the evaluation of key data.

产品质量审核的主要目标是评价制造(工艺、包装、标签和检验)的符合情况，并在对关键数据评价基础上辨识需要改进的地方。

Product quality reviews should not be solely performed by QU personnel. It is important that other departments, like Production, Engineering,

Maintenance, Purchase, etc. are also involved. QU is held responsible for the release and approval of the final report.

产品质量审核并不是只能由质量部门人员来完成。其它部门，如生产部、工程部、维护部、采购部等也应该被包括在内。质量部

门对最终报告的发放和批准负责。

To ensure that key data is reviewed it is essential for each production process to identify the critical in process controls and critical API (or

relevant intermediate) test results. These would normally be the critical API test results which may be used to indicate the consistency of the

process or to assess potential deviations in the quality of the API itself. In addition the critical reaction parameters should be evaluated. Ideally

the critical parameters are identified in the development report prepared prior to process validation but may also be based on experience for

well established processes.

为了确保关键数据经过评审，对每一个生产工艺识工艺控制的关键点以及关键的原料药(或相关中间体)检验结果结果是必要的。这

些通常是关键原料药检验结果，其可以被用来指示生产工艺的连续性，并可以对原料药本身质量中的潜在偏差进行评价。另外，

应当评价关键的反应参数。理想的情况是，在工艺验证之前的研发报告中确定关键参数，但是也可以根据已经建立的生产工艺中

的经验来确定关键的参数。

In nearly all cases specification limits for the critical test results are in place. Therefore the first evaluation would consider the failure

frequency to meet such limits. In addition any trends in data should be evaluated across

本文来源：https://www.bwwdw.com/article/3bse.html