APIC 发布新指南：变更控制

本文包括APIC发布的变更控制指南英文全文及中文翻译，翻译供参考，请以英文为准。

APIC-Guideline Technical Change Controlrevised Nov 2018

Guideline for the Establishment of aControl Procedure for Technical Equipment, including related Utilities,Computerised Systems and Facilities used in the Manufacture of APIs andIntermediates (revised Nov.2018)

制定用于原料药和中间体制造的技术设备(包括相关公用设施、计算机化系统和设施)控制程序指南(2018年11月修订)

1、Introduction 介绍

The accepted international GoodManufacturing Practice Guide for Active Pharmaceutical Ingredients, ICH Q7,requires under §13.10 that “a formal change control system should beestablished to evaluate all changes that may affect the production and controlof the intermediate or API”. The guidance given in this APIC guideline coversonly the part concerning technical equipment and related, utilities,computerised systems and facilities.

国际公认的药品生产质量管理规范活性药物成分,ICH Q7,要求在§13.10“正式的变更控制系统应该建立对所有可能会影响生产和控制中间或API变更的评估”。在该APIC指南中，其内容只涵盖有关技术设备及有关设施、公用设施、计算机化系统及设施部分。

A formal change control system should beestablished to evaluate all changes that may affect production and control ofthe registered intermediate or API. There should be a written procedure inplace to evaluate the impact of proposed changes on other possibly affectedsystems and to approve them.

应建立正式的变更控制系统，以评估所有可能影响已注册中间体或原料药生产和控制的变更。应该有一个书面程序来评价预期变更对其他可能受影响的系统的影响，并加以批准。

The justification for the level of criticality(e.g. the decision if a technical change has minor or major impact on theproduct) should be documented. For example, in form of a risk assessment and itshould contain the review, and approval by the appropriate organisationalunits, and review and approval by the quality unit(s).

关键分级的合理性(例如，技术变更是否对产品产生较小或较大影响的决策)应形成文档。例如，以风险评估的形式，它应该包含评审，并由适当的组织单位批准，以及质量部门的评审和批准。

As a part of the evaluation process, theneed to obtain approval from or to notify the change to authorities and/orcustomers, must be evaluated. The need to requalify the equipment andeventually to potentially revalidate the process must be assessed and documented.

作为评估过程的一部分，必须评估是否需要获得当局和/或客户的批准或将变更通知他们。必须评估和记录对设备进行再验证并最终可能重新验证工艺的需要。

In case there is an impact on thequalification documentation (e.g. IQ, OQ, PQ), the affected documents should belisted, reviewed and updated and the timelines for their approval defined.

如果对确认文件(如IQ、OQ、PQ)有影响，应列出、审查和更新受影响的文件，并确定批准的时间线。

All the documents should bearchived as necessary in compliance with the company’s policy on documentretention, to demonstrate the history of the changes that took place on theequipment.

 所有文件应根据公司的文件保存政策进行必要的存档，以证明设备发生变更的历史。

2. Authors 作者

略

3. Objectiveof the guideline 该指南的目标

3.1 Purpose 目的

This document isintended to provide guidance for technical change control of equipment andrelated utilities, computerized systems [e.g. Process (PLC) and DistributedControl Systems (DCS)] and facilities for the manufacturing of activepharmaceutical ingredients (APIs) and Intermediates. In the following text,this is referred to as “technical equipment”.

本文件旨在为设备和相关公用设施、计算机化系统的技术变更控制提供指导。用于生产原料药和中间体的过程(PLC)和分布式控制系统(DCS)以及设备。在下文中，这称为“技术设备”。

This guideline isbased on the requirements of the ICH Q7 and industry best practices. Otherrelevant publications (see Appendix) were considered.

该指南基于ICH Q7的要求和行业最佳实践。并考虑了其他有关出版物(见附录)。

This documentprovides an example of commonly applied solutions and practical assistance onhow technical change control can be handled and/ or interpreted. It is notintended to provide an exhaustive list of “how to do” technical change control,which a company should develop subsequently. Adoption of this guidance willprovide companies with the confidence to have accomplished, with the minimalrequirements, a change control system for technical equipment.

本文件提供了一个关于如何处理和/或解释技术变更控制的常用解决方案和实际帮助的示例。它不打算提供一个详尽的“如何做”技术变更控制的列表，公司应该随后开发该列表。采用这一指导方针将使公司有信心以最低的要求完成技术设备的变更控制系统。

3.2 Scope 范围

This guidanceapplies to technical equipment, used in the manufacture of APIs andintermediates for use in human drug (medicinal) products. It does not includeAnalytical Equipment.
本指南适用于人类药物(医药)产品的原料药和中间体所使用的技术设备。它不包括分析设备。

4. Definitions 定义

Change Control 变更控制

A system to propose, review, justify,evaluate, document, implement, approve, and close changes to technicalequipment used in the manufacture of APIs and intermediates to ensure aconstant qualified status of the systems concerned.
对原料药和中间体生产中使用的技术设备的提出、审核、证明、评价、记录、实施、批准和关闭变更的制度，以确保关注的系统的持续合格状态。

Emergency change 紧急变更

An unplanned change of a piece of equipmentas a result of an emergency, which needs to be repaired immediately in order tomaintain personal or environmental safety or preserve the quality of theproduct.

紧急情况下对设备的意外变更，为维护人身或环境安全或产品质量，需要立即修理。

'Like for like'Change “同类”变更

Replacement of a piece of equipment byanother with identical characteristics and function (same material ofconstruction, size, type, etc., but not necessarily from the samemanufacturer). The fact if equipment is like for like needs to be thoroughlyreviewed, justified and recorded with written approval of the Process Owner, QUand if applicable Regulatory Affairs. These changes can be considered minorimpact changes.
将一件设备更换为另一件具有相同特性和功能的设备(相同的结构、尺寸、类型等材料，但不一定来自同一制造商)。如果设备是同类的，则需要在工艺所有者、QU以及适用的监管事务的书面批准下进行彻底的审查、证明和记录。这些变更可以被认为是微小的影响变更。

Major impact changes 主要影响变更

A change expected to have a potential impacton product quality. Changes with an uncertain impact level should be handled asmajor impact changes.

预期对产品质量有潜在影响的变更。具有不确定影响级别的变更应作为主要影响变更处理。

Minor impact changes 次要影响变更

A change not expected to have an impact onproduct quality. Also called Standard change.

预计不会对产品质量产生影响的变更。也叫标准变更。

Process owner 工艺所有者

The person who has the ultimateaccountability for the system which is subject of the proposed change.

对被提议变更的系统负有最终责任的人。

Quality Unit (QU) 质量部门（QU）

An organisational unit independent ofproduction that fulfils both Quality Assurance and Quality Controlresponsibilities.

一个独立于生产的组织单位，同时履行质量保证和质量控制职责。

Standard Changes: 标准变更

See minor changes.参见次要变更

Technical Change 技术变更

A technical change is a planned modification(expansion, replacement, removal, addition) with respect to qualified equipment(defined state of a piece of technical equipment).
技术变更是对经确认的设备(某一技术设备的规定状态)的有计划的调整(扩充、更换、拆除、增加)。

Technical Equipment: 技术设备

Manufacturing equipment, utilities,computerized systems [e.g. Process (PLC) and Distribution and Control Systems(DCS)] and facilities used in the manufacturing of APIs.

制造设备、公用设施、计算机化系统。【如工艺 (PLC)和分配及控制系统(DCS)】和用于API生产的设备。

5. Impact ofChanges on affected Systems 变更对受影响系统的影响

Important repairsand maintenance work, such as replacement of major parts of equipment, mayaffect the performance of the process and the quality of the product.

重要的维修保养工作，如更换设备的主要部件，可能会影响工艺的性能和产品的质量。

Rearrangements inmanufacturing areas (for example rooms with defined environmental conditions)and/or support systems (utilities, e.g.: HVAC systems, systems for water,steam, CIP/SIP-systems) may result in changes in the process and therefore,revalidation/requalification may be necessary.
在制造区域(例如具有确定环境条件的房间)和/或支持系统(公用系统，例如:空调系统、水、蒸汽系统、CIP/ SIP系统)的重新安排可能会导致工艺的变化，因此可能需要再验证/再确认。

6.Responsibilities 职责

6.1 Processowner  工艺负责人

6.1.1 Responsible for technical changes and to follow the validchange control

负责技术变更并遵循有效的变更控制

procedure. 程序

6.1.2 Decides about the impactof the technical change on product quality (major/minor impact). Theparticipation of the QU in this decision should be clearly establishedaccording to the company procedure in this matter.
决定技术变更对产品质量的影响(主要/次要影响)。应根据公司在这一问题上的程序，明确规定QU参与这一决定。

6.1.3 It is recommended that theprocess owner should prepare a list of changes with minor impact on productquality (standard changes).

建议工艺负责人准备一份对产品质量影响较小的变更清单(标准变更)。

6.1.4 Every technical change with major impact should beassessed by the Process Owner.

每个具有重大影响的技术变更都应该由工艺所有者进行评估。

6.2 QualityUnit (QU) 质量部门（QU）

6.2.1 The involvement of the QU is required to decide if thechange has, or potentially will have, impact on the product quality.
需要QU的参与来决定变更是否已经或者可能会对产品质量产生影响。

6.2.2 The QU is responsible for the implementation andmaintenance of the change control system.
QU负责变更控制系统的实施和维护。

6.2.3 The QU must approve theminor or standard changes list. The QU needs to make sure the minor changeslist is up-to-date, and re-approved whenever minor changes are added or removedfrom the list.
QU必须批准次要或标准变更列表。QU需要确保次要变更列表是最新的，并且每当从列表中添加或删除小的变更时，都需要重新批准。

6.2.4 Every technical changewith major impact should be assessed at least by the QU.
每一项具有重大影响的技术变更至少应由QU进行评估。

6.2.5 The QU is responsible for periodical evaluation of thesystem and its effectiveness

质量部门负责定期评估该制度及其成效。

6.3 RegulatoryAffairs (RA) 监管事务（RA）

6.3.1 Every technical change with major impact should beassessed at least by RA. RA is required to assess the potential impact onregulatory filing. RA decides about the measures to be taken to document thechange appropriately. In case an approved change has impact on regulatoryfiling it is the responsibility of the RA department to take appropriateaction.

每一个有重大影响的技术变更都应该至少由RA进行评估。RA被要求评估对监管申报的潜在影响。RA决定为适当地记录更改而采取的措施。如果批准的变更对监管备案产生影响，RA部门有责任采取适当的行动。

6.4 TechnicalDepartment (TD) 技术部门（TD）

6.4.1 The TD is required to evaluate and approve the(technical) impact of a proposed change.

TD须评估及批准拟议变更的(技术)影响。

7. Criteria forcriticality关键性标准

Some typical questionsthat can help further to decide whether technical changes are major or minor,are given below:

以下是一些典型的问题，可以帮助进一步确定技术变更是主要的还是次要的:

If the component to be changed…如果部件会发生变更…

• can directly contact the product or product components,and is not considered a like for like change;
  可直接接触产品或产品部件，且不视为同类变更;

• can directly affect the product quality by normaloperation or control (e.g., impurity profile, crystal form and size, residualsolvent or stability of the API);
  可通过正常操作或控制直接影响产品质量(如杂质概况、晶体形态和尺寸、残留溶剂或原料药的稳定性)。

• indicates and records alarm functions critical to theprocess;
  指示和记录工艺中关键的报警功能。

• is used to record, output or archive data for batchrecords or labels and other GMP documentation or labels;
  是否用于记录、输出或归档批记录或标签以及其他GMP文档或标签的数据。

• is used to demonstrate compliance with the registeredprocess;
  用于证明符合注册流程；

• can influence the quality and performance of supportsystems (e.g., water, steam, HVAC, etc.);
  能够影响支持系统(如水、蒸汽、HVAC等)的质量和性能。

• is used to ensure access control to critical data orfunctions (user identification and authenticity);
  用于确保对关键数据或功能的访问控制(用户标识和真实性)

• is used to perform analytical investigations that arerelevant for batch release;
  用于执行与批放行相关的分析调查

• is used for critical calculations (e.g., analytical datathat are relevant for batch release);
  关键计算(例如，与批放行相关的分析数据)

• is used for batch release;
  用于批放行；

• is used to control batch status or shelf life;
  用于控制批次状态或有效期；

• is used to control the production process (recipe/processdescription);
  用于控制生产过程(配方/工艺描述)

• is used to transfer critical data (interface) to anotherquality relevant system;
  用于将关键数据(接口)传输到另一个质量相关系统；

• is used to give information about the quality of theproduct (e.g. printers for process related data);
  用于提供有关产品质量的信息(例如，用于处理相关数据的打印机)

•  is used to ensure or record critical conditions forwarehouses;
  用于确保或记录仓库的关键条件

• is used to control maintenance or calibration of criticalequipment;
  用于控制关键设备的维护或校准

• is used to create, modify, record, document, review,approve GMP data;
  用于创建、修改、记录、文档、评审、批准GMP数据

then, the changemay have a potential impact on product quality and should therefore be carefullyassessed and reviewed, considering traceability to design base risks, beforeimplementation. These changes are considered major.
然后，变更可能对产品质量产生潜在的影响，因此在实施之前，应该仔细地评估和评审，考虑到设计基本风险的可追溯性。这些变更被认为是重大的。

8. Procedure 程序

8.1 The procedure should always begin with a request for achange. This request should be formalised in some way, for example as a form inpaper or electronic form and be signed by the requestor.
程序应该总是以请求变更开始。这项要求应以某种方式正式化，例如以纸张或电子形式提出，并由提出要求的人签名。

8.2Therequest triggers the question of the potential impact of the change on theproduct quality. It can be necessary to define several levels of impact on the product quality, but it isrecommended there should be at least two categories: major and minor impact.The treatment of these two options should be clearly different and defined aspart of the local process.

该请求触发了变更对产品质量潜在影响的问题。有必要定义对产品质量的几个影响级别，但是建议至少应该有两类影响:主要影响和次要影响。这两种选择的处理应该是明显不同的，并被定义为局部工艺的一部分。

8.3 There should be clear rules for the decision, whether theimpact of the change on the product quality is major or minor: who decides andwhy the decision is taken (See under 6 and 7). All included in the decision(Process Owner, QU, RA, TD) need to sign for approval of the decision. If otheraspects are affected by the change, other department need to be involved aswell. For example, safety aspects, could require EHS department to be involved.Or Computerized System changes could need involvement of Subject MatterExperts.

应当有明确的规则来确定变更对产品质量的影响是主要还是次要:谁决定,为什么决定(见下6和7)。所有这些应在决策中包含(工艺所有者,QU,RA，TD)并需要在批准的决定上签名。如果其他方面受到变更的影响，也需要其他部门的参与。例如，安全方面，可能需要EHS部门的参与。或者计算机化系统的变更可能需要主题专家的参与。

8.4 For the management of changes, an early decision isrequired of who should be involved. The decision should be taken (and recordedon the change request) by the process owner, who normally has the bestknowledge of the impact of changes on the product (or at least can estimate itwith a high degree of certainty). The principle of double checking should beimplemented at this point of the procedure. A signature by the TechnicalDepartment is first required. The QU should be involved as an approver to checkthe decision about product quality impact (unless the proposed change matches apre-approved minor change in the list of minor or standard changes. RA shouldbe involved to assess the potential impact on regulatory filing.

对于变更的管理，需要及早决定谁应该参与其中。决策应该由工艺所有者做出(并记录在变更请求上)，工艺所有者通常对变更对产品的影响有最好的了解(或者至少可以高度确定地估计它)。在程序的这一点上应该实现双重检查的原则。首先需要技术部门的签字。QU应该作为审批人参与检查关于产品质量影响的决策(除非提议的变更与预先批准的微小变更或标准变更列表中的微小变更相匹配)。RA应参与评估对监管申报的潜在影响。

8.5 If the owner has decided that the change will have minorimpact on the quality of the product, and all included in the decision (ProcessOwner, QU, RA, TD) agree with this decision, it can be implemented. The changeshould be adequately documented.
如果所有者已经决定变更对产品质量的影响较小，并且决策中包含的所有人(工艺所有者，QU, RA, TD)都同意该决策，则可以实施。变更应该有充分的文档记录。

8.6 The implementation of changes with minor impact can beachieved in a more rapid and efficient manner using check lists of standardchanges. The list of these changes should have been (pre)approved by the QU.

可以使用标准变更后的检查列表，以更快速和有效的方式来完成影响较小的变更。列表的这些变化应该已经(预先)得到了QU的批准。

8.7 If the decision has been taken that the change can orwill have a major impact on the quality of the product, the QU must be furtherinvolved. An adequate rationale (e.g. a risk assessment) and an appropriateaction plan should accompany such a change request. This builds the basis forthe approval by the QU.

如果决定变更能够或将对产品的质量产生重大影响，那么QU必须进一步参与。一份充分的理由(例如风险评估)和一份适当的行动计划应该伴随这样的变更请求。这为QU的批准奠定了基础。

8.8 After the QU approval, the change can be implemented. Ifother aspects are affected by the change, for example regulatory filing orsafety aspects, additional release activities can be needed. Where suchactivities have been defined, these should be fulfilled before the reuse of theequipment. Release of the equipment itself, can be one of these activities.

在QU批准之后，变更就可以实施了。如果其他方面受到变更的影响，例如法规备案或安全方面，则可能需要额外的放行活动。在已定义此类活动的情况下，应在设备重用之前完成这些活动。设备放行本身，可以是这些活动之一。

8.9 The start of a change control system for technicalequipment should be established immediately after the completion ofqualification. This will ensure that the qualified status is maintained.

技术设备变更控制体系应在确认后立即建立。这将确保维持确认状态。

8.10 There shall be a process in place to manage changes thatmay occur during the qualification.

应有一个适当的程序来管理在确认期间可能发生的变更。

8.11 The change request for emergency changes can beformalised after the replacement. Emergency cases should be defined by eachcompany in an appropriate way.

紧急变更的要求可在更换后正式提出。每个公司都应该以适当的方式定义紧急情况。

9. Appendix 附录

9.1 List ofrelevant Guidelines 相关指南列表

1. ICH, GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICALINGREDIENTS Q7 (CPMP/ICH/4106/00), 2000

2. ICH Q7 Guideline: Good Manufacturing Practice Guide for ActivePharmaceutical Ingredients - Questions and Answers, June 2015

3. Pharmaceutical Inspection Co-Operation Scheme PIC/S PI 006-3,Recommendations on Validation Master Plan, Installation and OperationalQualification, Non-Sterile Process Validation, Cleaning Validation, PIC/SSecretariat, Geneva, September 2007.

4. ISPE Commissioning andQualification Baseline Guide Volume 5.

9.2 List ofAbbreviations 缩略语列表

 API = Active Pharmaceutical Ingrdient  原料药

 CIP = Cleaning in Place 在线清洁

 DCS = Distributed Control System 分布式控制系统

 EHS = Environment Health & Safety  环境、健康、安全

 HVAC = heating, ventilation, air conditioning 空调系统

 PO = Process Owner 工艺拥有者

 PLC = Programmable Logic Controller 可编程序逻辑控制器

 QU = Quality Unit 质量部门

 RA = Regulatory Affairs 法规监管

 SIP = Sterilisation in Place 在线灭菌

 SME = Subject Matter Expert 相关主题专家

 TD = TechnicalDepartment 技术部门

9.3. Enclosure附件

Scheme of the procedure

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