欧盟GMP指南 第5章生产(中英文20150123)

EU GMP 第1部分第5章生产

——增加基因毒性的评估生效时限

2015-02-25 11:50:00

（粉色字为2015年1月23日新增内容，红字斜体为2014年8月13日修订内容）

EUROPEAN COMMISSION

HEALTH AND CONSUMERS DIRECTORATE-GENERAL

Public Health and Risk Assessment

Medicinal products – quality, safety and efficacy

Ref. Ares(2015)283689 - 23/01/2015

Brussels, 13 August 2014

Ares(2014)2674301

EudraLex

The Rules Governing Medicinal Products in the European Union

Volume 4

EU Guidelines for

Good Manufacturing Practice for

Medicinal Products for Human and Veterinary Use

Part 1

人兽药EU GMP指南

第1部分

第5章：生产

Legal basis for publishing the detailed guidelines: Article 47 of Directive 2001/83/EC on the Community code relating to medicinal products for human use and Article 51 of Directive 2001/82/EC on the Community code relating to veterinary medicinal products. This document provides guidance for the interpretation of the principles and guidelines of good manufacturing practice (GMP) for medicinal products as laid down in Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use.

Status of the document: Revision [a]

Reasons for changes: Changes have been made to sections 17 to 20 to improve the guidance on prevention of cross-contamination and to refer to toxicological assessment guidance. Changes were also introduced in sections 26 to 28 on the qualification of suppliers in order to reflect the legal obligation of manufacturing authorisation holders to ensure that active substances are produced in accordance with GMP. The changes include supply chain traceability. Section (33) is inserted to clarify and harmonise expectations of manufacturers regarding the testing of starting materials while section (68) introduces guidance on notification of restrictions in supply.

变更理由：对17-20条进行变更，以改进指南中防止交叉污染的部分，及引用毒理学评估指南。还增加了26-28条关于供应商确认部分，以反映上市许可持有人所承担的保证活性物质根据GMP要求生产的责任。变更包括供应链可追溯性。加入第33条，以澄清并保持关于原辅料生产商期望一致性，增加68条中引入了供应受限通知的内容。

Deadline for coming into operation: 1 March 2015. However, the toxicological evaluation mentioned in section 20 has to be carried out:

生效日期：2015年3月1日。 但是，在第6部分提到的基本毒性的评估实施日期如下：

from 1 June 2015 onwards for any medicinal product newly introduced into shared

manufacturing facilities;

共用生产设施中新引入的所有药品自2015年6月1日起，

before 1 December 2015 for medicinal products already produced in a shared manufacturing

facility producing only medicinal products for human use or both producing medicinal products for human use and veterinary medicinal products on 31 May 2015;

仅生产人用药品或人药兽药均生产的共用生产设施中，在2015年5月31日前已引入的药

品自2015年12月1日起实施

before 1 June 2016 for veterinary medicinal products already produced in a shared

manufacturing facility producing only veterinary medicinal products on 31 May 2015.

仅生产兽药产品的共用生产设施中，在2015年5月31日前已引入的兽药产品自2016年6

月1日起实施

Principle原则

Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practice in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorisations.

生产操作必须按规定的程序进行，必须符合GMP的原则，以确保产品达到所要求的质量，并满足相关生产许可和上市许可的要求。

General 通则

5.1 Production should be performed and supervised by competent people.

应由有能力的人员进行生产操作和生产监督。

5.2 All handling of materials and products, such as receipt and quarantine, sampling, storage, labelling,

dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded.

物料和产品的处理，如接收和待检、取样、贮存、发料、生产、包装和销售等应按照书面规程或指令进行，并作必要的记录。

5.3 All incoming materials should be checked to ensure that the consignment corresponds to the order.

Containers should be cleaned where necessary and labelled with the prescribed data.

应对所有的进货进行检查，以确保到货的物料与订单相符，必要时对包装进行清洁，并贴签标明规定的内容。

5.4 Damage to containers and any other problem which might adversely affect the quality of a material

should be investigated, recorded and reported to the Quality Control Department.

对包装破损及其它任何可能影响物料质量的问题应进行调查和记录，并报告质量控制部门。

5.5 Incoming materials and finished products should be physically or administratively quarantined

immediately after receipt or processing, until they have been released for use or distribution.

接收的物料和生产出的成品应立即进行物理或行政隔离，直至其被放行使用或销售。

5.6 Intermediate and bulk products purchased as such should be handled on receipt as though they were

starting materials.

对于外购的中间体和待包装产品，在接收时视同原辅料接收。

5.7 All materials and products should be stored under the appropriate conditions established by the

manufacturer and in an orderly fashion to permit batch segregation and stock rotation.

所有物料和产品都应按生产厂家确定的合适的条件贮存，并有序存放，以使批次间有区分及方便库存周转。

5.8 Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that

there are no discrepancies outside acceptable limits.

应检查收率和数量平衡，确保差异未超出可接受的限度。

5.9 Operations on different products should not be carried out simultaneously or consecutively in the same

room unless there is no risk of mix-up or cross-contamination.

不同产品的生产操作不得在同一房间内同时或连续进行，除非该操作不会产生混淆或交叉污染风险。

5.10 At every stage of processing, products and materials should be protected from microbial and other

contamination.

在生产的所有阶段，均应保护产品和物料不受微生物和其它污染。

5.11 When working with dry materials and products, special precautions should be taken to prevent the

generation and dissemination of dust. This applies particularly to the handling of highly active or sensitising materials.

加工干燥物料和产品时，应采取特殊预防措施以防止产尘和扬尘，尤其是在处理高活性或高致敏性物料时。

5.12 At all times during processing, all materials, bulk containers, major items of equipment and where

appropriate rooms used should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and batch number. Where applicable, this indication should also mention the stage of production.

在整个生产过程中，对所有物料、包装容器、主要设备和使用房间均应标识，或以其它方式指明正在生产的产品或物料、规格和批号，必要时标明生产步骤。

5.13 Labels applied to containers, equipment or premises should be clear, unambiguous and in the

company’s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (for example, quarantined, accepted, rejected, clean).

用于包装容器、设备或房间的标签应清晰、准确，并采用公司统一的格式。除在标签上使用文字外，使用颜色标明其状态（如，待验、合格、不合格、清洁等）很有益处。

5.14 Checks should be carried out to ensure that pipelines and other pieces of equipment used for the

transportation of products from one area to another are connected in a correct manner.

应对将产品从一个区域传送到另一个区域所使用的管线和设备接口进行检查，确保其正确连接。

5.15 Any deviation from instructions or procedures should be avoided as far as possible. If a deviation

occurs, it should be approved in writing by a competent person, with the involvement of the Quality Control Department when appropriate.

应尽量避免任何与规程或程序不符的偏差，如果有偏差发生，应得到指定人员的书面批准，必要时需质量控制部门参与。

5.16 Access to production premises should be restricted to authorised personnel.

生产区应仅限于经过批准的人员进入。

Prevention of cross-contamination in production 生产中防止交叉污染

5.17 Normally, the production of non-medicinal products should be avoided in areas and with equipment

destined for the production of medicinal products but, where justified, could be allowed where the measures to prevent cross-contamination with medicinal products described below and in Chapter 3 can be applied. The production and/or storage of technical poisons, such as pesticides (except where these are used for manufacture of medicinal products) and herbicides, should not be allowed in areas used for the manufacture and / or storage of medicinal products.

一般应避免在生产区域使用药品生产设备生产非药用产品。但如果经过适当的论证，采取了如下及和3章所述防止该非药用产品与药品交叉污染的措施，则这种行为是允许的。有毒物质，例如杀虫剂（除了用于药品生产的以外）和除草剂，的生产和/或存贮不应在药品生产和/或存贮区域进行。

5.18 Contamination of a starting material or of a product by another material or product should be prevented.

This risk of accidental cross-contamination resulting from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances, other starting materials, and products in process, from residues on equipment, and from operators’ clothing should be assessed. The significance of this risk varies with the nature of the contaminant and that of the product being contaminated. Products in which cross-contamination is likely to be most significant are those administered by injection and those given over a long time. However, contamination of all products poses a risk to patient safety dependent on the nature and extent of contamination.

应防止原辅料或产品被另一物料或产品所污染。由于未受控制而释放的粉尘、气体、蒸汽、空气中微粒、基因类物料或来自活性物质、其它原辅料、在制品设备残留及操作者着装中的有机物产所生的意外交叉污染的风险应进行评估。该类风险的重要性因污染物的属性及被污染产品的属性不同而不同。一旦受到交叉污染后果比较严重的是那些注射给药和长期给药的产品。但是，对任何产品的污染都会对患者安全产生风险，其风险程序取决于污染的属性和程度。

5.19 Cross-contamination should be prevented by attention to design of the premises and equipment as

described in Chapter 3. This should be supported by attention to process design and implementation of any relevant technical or organizational measures, including effective and reproducible cleaning processes to control risk of cross-contamination.

如第3章所述，防止交叉污染应从厂房和设备的设计开始，并要注意工艺设计和所有相关技术或生产组织措施的实施，包括可重复的有效清洁程序，用以控制交叉污染风险。

5.20 A Quality Risk Management process, which includes a potency and toxicological evaluation, should be

used to assess and control the cross-contamination risks presented by the products manufactured. Factors including; facility/equipment design and use, personnel and material flow, microbiological controls, physico-chemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from the evaluation of the products should also be taken into account. The outcome of the Quality Risk Management process should be the basis for determining the necessity for and extent to which premises and equipment should be dedicated to a particular product or product family. This may include dedicating specific product contact parts or dedication of the entire manufacturing facility. It may be acceptable to confine manufacturing activities to a segregated, self contained production area within a multiproduct facility, where justified. 一个质量风险管理过程，包括对效价和毒性的评估，要应用于评估和控制产品生产中会出现的交叉污染风险。还要考虑以下这些因素，包括：厂房/设备设计和使用、人员和物流、微生物控制、

活性物质的理化特性、工艺特性、清洁程序和相对于根据产品评估所建立的相关限度的分析能力。应根据质量风险管理过程的结果来决定某个厂房是否必须或到哪个程度地专用于某个特定的产品，或系列产品。这可能包括专用特定的产品接触部分，或整个生产厂房专用。如果经过论证，可以接受在一个多功能厂房里有一个隔离封闭的区域用于特定的生产活动。

5.21 The outcome of the Quality Risk Management process should be the basis for determining the extent of

technical and organisational measures required to control risks for cross-contamination. These could include, but are not limited to, the following:

应根据质量风险管理过程的结果来决定用于控制交叉污染风险所需的技术和组织方面的措施。这些措施可以包括，但不仅限于以下：

i. Dedicated manufacturing facility (premises and equipment); 专用生产设施（厂房和设备） ii. Self-contained production areas having separate processing equipment and separate

heating, ventilation and air-conditioning (HVAC) systems. It may also be desirable to isolate

certain utilities from those used in other areas; 自我封闭生产区域，具有独立的加工设备

和独立的暖通空调（HVAC）系统。如果将公用系统与其它区域中分开则更好。

iii. Design of manufacturing process, premises and equipment to minimize opportunities for

cross-contamination during processing, maintenance and cleaning; 生产工艺、厂房和设备

的设计将生产、维护和清洁过程中交叉污染的机会降至最小

iv. Use of “closed systems” for processing and material/product transfer between equipment;

使用“封闭系统”进行设备间物料/产品转移

v. Use of physical barrier systems, including isolators, as containment measures; 使用物理隔

离系统，包括分离器，作为封闭措施

vi. Controlled removal of dust close to source of the contaminant e.g. through localised

extraction; 控制接近污染源的灰尘的清除，例如进行就地提取

vii. Dedication of equipment, dedication of product contact parts or dedication of selected parts

which are harder to clean (e.g. filters), dedication of maintenance tools; 设备专用、产品接

触部件专用或难以清洁部件专用（例如过滤器）、维护工具专用

viii. Use of single use disposable technologies; 使用一次性技术

ix. Use of equipment designed for ease of cleaning; 使用设计易于清洁的设备

x. Appropriate use of air-locks and pressure cascade to confine potential airborne

contaminant within a specified area; 适当使用气锁和压差，以将可能的空气尘埃污染物

限制在一个特定的区域

xi. Minimising the risk of contamination caused by recirculation or re-entry of untreated or

insufficiently treated air; 将空气循环或重新送入未经处理或未经充分处理的空气所带来

的污染风险降至最低

xii. Use of automatic clean in place systems of validated effectiveness; 使用有效性经过验证的

自动化在线污染系统

xiii. For common general wash areas, separation of equipment washing, drying and storage

areas. 对于一般清洁区域，将清洁、干燥和存贮区域分开

i. Dedicating the whole manufacturing facility or a self contained production area on a

campaign basis (dedicated by separation in time) followed by a cleaning process of validated

effectiveness; 专用整个生产设施或采用自我封闭的生产区域，在经过一个生产周期（单

独专用时间）后采用有效性经过验证的清洁程序进行清洁

ii. Keeping specific protective clothing inside areas where products with high risk of

cross-contamination are processed; 在交叉污染风险较高的产品生产区域内保持特殊的

防止着装

iii. Cleaning verification after each product campaign should be considered as a detectability

tool to support effectiveness of the Quality Risk Management approach for products deemed

to present higher risk; 在每个产品生产周期结束后进行清洁确认，作为一个检测工具，

用以支持较高风险产品质量风险管理方法的有效性

iv. Depending on the contamination risk, verification of cleaning of non product contact

surfaces and monitoring of air within the manufacturing area and/or adjoining areas in

order to demonstrate effectiveness of control measures against airborne contamination or

contamination by mechanical transfer; 根据污染风险，对非产品接触面进行清洁确认，

监控生产区域内和/或连接区域内的空气质量，以证明防止空气尘埃污染和机械转移污

染的控制措施的有效性

v. Specific measures for waste handling, contaminated rinsing water and soiled gowning; 对

水处理、被污染的淋洗水和脏的服装采用特殊措施

vi. Recording of spills, accidental events or deviations from procedures; 记录洒出物、意外事

件和偏差

vii. Design of cleaning processes for premises and equipment such that the cleaning processes

in themselves do not present a cross-contamination risk; 对设施和设备的清洁程序进行设

计以使得清洁程序本身不会带入交叉污染风险

viii. Design of detailed records for cleaning processes to assure completion of cleaning in

accordance with approved procedures and use of cleaning status labels on equipment and

manufacturing areas; 对清洁详细记录进行设计，使根据批准程序进行清洁的完整性得

到保证，使用清洁状态标识

ix. Use of common general wash areas on a campaign basis; 按生产周期使用常规清洁区域

x. Supervision of working behaviour to ensure training effectiveness and compliance with the

relevant procedural controls. 对操作行为进行监督，以保证培训的有效性，保证操作符

合相关程序要求的控制

5.22 Measures to prevent cross-contamination and their effectiveness should be checked periodically

according to set procedures.

应根据设定的程序定期对防止交叉污染的措施及其有效性进行检查。

Validation 验证

5.23 Validation studies should reinforce Good Manufacturing Practice and be conducted in accordance with

defined procedures. Results and conclusions should be recorded.

验证是对GMP的加强，应按制订的程序进行验证，验证结果和结论应有记录。

5.24 When any new manufacturing formula or method of preparation is adopted, steps should be taken to

demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality.

当采用任何一种新的生产处方或制备方法时，应验证其在常规生产中的适宜程度。应证明所确定的工艺、原辅料和设备可得到始终符合质量标准的产品。

5.25 Significant amendments to the manufacturing process, including any change in equipment or materials,

which may affect product quality and/or the reproducibility of the process, should be validated.

对生产工艺的任何重大修订（包括可能影响产品质量和/或工艺中现行的设备或物料的任何变更）均应进行验证。

5.26 Processes and procedures should undergo periodic critical re-validation to ensure that they remain

capable of achieving the intended results.

应对工艺和程序定期进行关键的再验证，以确保其达到预期的结果。

Starting materials 原辅料

5.27 The selection, qualification, approval and maintenance of suppliers of starting materials, together with

their purchase and acceptance, should be documented as part of the pharmaceutical quality system.

The level of supervision should be proportionate to the risks posed by the individual materials, taking account of their source, manufacturing process, supply chain complexity and the final use to which the material is put in the medicinal product. The supporting evidence for each supplier / material approval should be maintained. Staff involved in these activities should have a current knowledge of the suppliers, the supply chain and the associated risks involved. Where possible, starting materials should be purchased directly from the manufacturer of the starting material.

原辅料供应商的选择、确认、批准和维护以及其采购、接收均应作为药品质量体系的一部分进行记录。监管水平应与各物料的风险水平相适宜，应考虑原料的来源、生产工艺、供应链复杂程度及最终用途。批准各供应商/物料的支持性证据应保留并维护。参与相关活动的人员应具备对供应商、供应链和相关潜在风险的相应知识。应尽可能直接从原辅料生产商处采购原辅料。

5.28 The quality requirements established by the manufacturer for the starting materials should be discussed

and agreed with the suppliers. Appropriate aspects of the production, and control, including handling, labelling, packaging and distribution requirements, complaints, recalls and rejection procedures should be documented in a quality agreement or specification.

制剂生产商建立的原辅料质量要求应经过讨论，并与供应商达成一致。应通过质量协议或质量标准记录关于生产、控制各方面内容，包括处理、标识、包装和分销要求、客诉处理、召回和退货程序。

5.29 For the approval and maintenance of suppliers of active substances and excipients, the following is

required:

对于活性物质和辅料生产商的批准和维护要求如下：

Supply chain traceability should be established and the associated risks, from active substance starting materials to the finished medicinal product, should be formally assessed and periodically verified. Appropriate measures should be put in place to reduce risks to the quality of the active substance. 应建立供应链的可追溯性，从活性物质起始物料或制剂成品相关联的风险应定期进行正式验证。应制订适当的措施降低对活性物质质量的风险。

The supply chain and traceability records for each active substance (including active substance starting materials) should be available and be retained by the EEA based manufacturer or importer of the medicinal product.

每种活性物质（包括活性物质起始物料）的供应链和追溯记录应在留存在EEA区域内的生产商或药品进口商手中并可以获得。

Audits should be carried out at the manufacturers and distributors of active substances to confirm that they comply with the relevant good manufacturing practice and good distribution practice requirements. The holder of the manufacturing authorization shall verify such compliance either by himself or through an entity acting on his behalf under a contract. For veterinary medicinal products, audits should be conducted based on risk.

对活性物质生产商和分销商要进行审计，确认其符合相关的GMP和GDP要求。生产许可持有人应亲自或签订中同委托一个实体对该符合性进行确认。对于兽药产品，可以基于风险决定是否进行审计。

Audits should be of an appropriate duration and scope to ensure that a full and clear assessment of GMP is made; consideration should be given to potential cross- contamination from other materials on site. The report should fully reflect what was done and seen on the audit with any deficiencies clearly identified. Any required corrective and preventive actions should be implemented.

审计应有适当的时间长度 覆盖范围，以保证进行全面和清楚的GMP评估，要考虑在同一场所的其它物料产生的交叉污染。报告应全面反映在审计期间做了什么和看了什么，并清楚界定所有缺陷。应实施必要的CAPA。

Further audits should be undertaken at intervals defined by the quality risk management process to ensure the maintenance of standards and continued use of the approved supply chain.

应根据质量风险管理程序界定下次进行审计的时间间隔，以保证标准的维护及持续使用批准的供应链。

Excipients and excipient suppliers should be controlled appropriately based on the results of a formalised quality risk assessment in accordance with the European Commission Guidelines on the formalised risk assessment for ascertaining the appropriate Good Manufacturing Practice for excipients of medicinal products for human use .

对于辅料和辅料供应商，应根据EC指南（人药用辅料GMP适用性确定的正大风险评估指南）进行正式的质量风险评估，再根据评估结果进行适当的控制。

5.30 For each delivery of starting material the containers should be checked for integrity of package,

including tamper evident seal where relevant, and for correspondence between the delivery note, the purchase order, the supplier s labels and approved manufacturer and supplier information maintained by the medicinal product manufacturer. The receiving checks on each delivery should be documented. 每次收到原辅料时，应检查各包装的完整性，包括封口（如有），检查送货单、采购单，供应商的标签和批准的生产商及制剂生产商保存的供应商信息是否相符。每次接收时所做的检查均应记录。

5.31 If one material delivery is made up of different batches, each batch must be considered as separate for

sampling, testing and release.

如果一次到货的同一种物料由不同批次构成时，应对每一批次分别取样、检验和放行。

5.32 Starting materials in the storage area should be appropriately labelled (see section 13). Labels should

bear at least the following information:

存贮区域的原辅料应进行适当标识（参见第13部分）。标签至少应包括以下信息：

– The designated name of the product and the internal code reference where applicable; 产品名称

和内部编码

– a batch number given at receipt; 接收批号

– Where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected); 适

用时，内容物的状态 （例如，待检、检测中、放行、拒收）

– Where appropriate, an expiry date or a date beyond which retesting is necessary.适用时，有效期

或复验期

When fully computerised storage systems are used, all the above information need not necessarily be in a legible form on the label.

如果使用的是全计算机存贮管理系统，则上述信息不一定采用明确方式标识在标签上。

5.33 There should be appropriate procedures or measures to assure the identity of the contents of each

container of starting material. Bulk containers from which samples have been drawn should be identified (see Chapter 6, item 13).

应制订适当的程序或措施以确保对每一个包装的内容物进行鉴别。已取样的包装上应有取样标识（见第6章第13条）。

5.34 Only starting materials which have been released by the Quality Control Department and which are

within their retest period should be used.

只有经质量控制部门放行，并在复验期内的物料才可被使用。

5.35 Manufacturers of finished products are responsible for any testing of starting materials [3] as

described in the marketing authorisation dossier. They can utilise partial or full test results from the approved starting material manufacturer but must, as a minimum, perform identification testing [4] of each batch themselves according to annex 8.

制剂生产商对原辅料按上市许可申报文件中的描述所进行的全部检测项目承担责任。生产商部分或全部使用经过批准的原辅料生产商的检验结果，但必须至少根据附录8对每个批次进行鉴别检测。

5.36 The rationale for the outsourcing of this testing should be justified and documented and the following

requirements should be fulfilled:

将上述检测外包应进行合理论证并记录，且应满足以下要求：

i. Special attention should be paid to the distribution controls (transport, wholesaling, storage and

delivery) in order to maintain the quality characteristics of the starting materials and to ensure that test results remain applicable to the delivered material;

对于销售记录应特别注意（运输、批发、存贮和发运），以维持原辅料的质量特性，并保证所收到的物料质量仍与原始检测结果相符合。

ii. The medicinal product manufacturer should perform audits, either itself or via third parties, at

appropriate intervals based on risk at the site(s) carrying out the testing (including sampling) of the starting materials in order to assure compliance with Good Manufacturing Practice and with the specifications and testing methods described in the marketing authorisation dossier;

制剂生产商应亲自或委托第三方进行审计，审计时间间隔应基于对测试原辅料（包括取样）的场所的风险来确定，以保证其符合GMP，并按上市许可申报文件中描述的质量标准和检测方法进行检验。

iii. The certificate of analysis provided by the starting material manufacturer/supplier should be

signed by a designated person with appropriate qualifications and experience. The signature assures that each batch has been checked for compliance with the agreed product specification unless this assurance is provided separately;

原辅料生产商/供应商提供的分析报告应由指定的具备适当资质和经验的人员签字。签字表示保证每批均经过检查且符合共同同意的产品质量标准，否则应单独提供上述保证。

iv. The medicinal product manufacturer should have appropriate experience in dealing with the

starting material manufacturer (including experience via a supplier) including assessment of batches previously received and the history of compliance before reducing in-house testing. Any significant change in the manufacturing or testing processes should be considered;

制剂生产商应具备适当的与原辅料生产商打交道的经验（包括通过中间商采购的经验），包括对之前收到的批次的评估，在减少内控测试前对其历史符合性的评估。要考虑所有生产或检测程序的重大变更。

v. The medicinal product manufacturer should also perform (or via a separately approved contract

laboratory) a full analysis at appropriate intervals based on risk and compare the results with the material manufacturer or supplier s certificate of analysis in order to check the reliability of the latter. Should this testing identify any discrepancy then an investigation should be performed and appropriate measures taken. The acceptance of certificates of analysis from the material manufacturer or supplier should be discontinued until these measures are completed.

制剂生产商还应（或通过一个单独批准的合同化验室）根据风险在一定时间间隔进行完整检测，并与原料生产商或中间商检验报告书上的结果进行比较，以检查后者的可靠性。如果该检测发现有不符合处，则应进行调查并采取适当的措施。在这些措施完成前，不应继续接受来自原料生产商或中间商的分析报告书。

5.37 Starting materials should only be dispensed by designated persons, following a written procedure, to

ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.

原辅料应由指定人员根据书面程序进行分料，保证正确的物料被准确地称量或测量至清洁并适当标签的容器内。

5.38 Each dispensed material and its weight or volume should be independently checked and the check

recorded.

各分装好的物料要逐一复核其重量或体积，并进行记录。

5.39 Materials dispensed for each batch should be kept together and conspicuously labelled as such.

为同一个生产批号所分装的物料应摆放在一起，并醒目标识。

Processing operations: intermediate and bulk products 生产操作：中间体和待包装产品

5.40 Before any processing operation is started, steps should be taken to ensure that the work area and

equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation.

在任一生产操作开始前，应确认工作区域和设备的清洁，且本次生产操作不相关的原辅料、产品、产品余料或文件均已清出现场。

5.41 Intermediate and bulk products should be kept under appropriate conditions.

中间体和待包装产品应保存在适宜条件下。

5.42 Critical processes should be validated (see "Validation" in this Chapter).

关键工艺应经过验证（见本章验证部分）。

5.43 Any necessary in-process controls and environmental controls should be carried out and recorded.

所有要求的中控和环境控制均应实施并记录。

5.44 Any significant deviation from the expected yield should be recorded and investigated.

所有与预期收率重大偏差均应记录并调查。

Packaging materials 包装材料

5.45 The selection, qualification, approval and maintenance of suppliers of primary and printed packaging

materials shall be accorded attention similar to that given to starting materials.

内包材和印字包材供应商的选择、确认、批准和维护应参照对原辅料的要求进行。

5.46 Particular attention should be paid to printed materials. They should be stored in adequately secure

conditions such as to exclude unauthorised access. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by authorised personnel following an approved and documented procedure.

应特别注意印字包材。印字包材应存贮在适当安全的条件下，以避免未 许可的人员接近。裁切过的标签和其它印字包材应按类别置于密闭的包装容器内存贮和传送，以避免混淆。包材只能由有权限的人员按照批准的书面程序发放使用。

5.47 Each delivery or batch of printed or primary packaging material should be given a specific reference

number or identification mark.

每次交货或每批内包材和印字包材应给定批号或识别标记。

5.48 Outdated or obsolete primary packaging material or printed packaging material should be destroyed

and this disposal recorded.

过期或作废的内包材或印字包材应销毁并记录。

Packaging operations 包装操作

5.49 When setting up a programme for the packaging operations, particular attention should be given to

minimising the risk of cross-contamination, mix-ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation.

制订包装计划时，应特别注意使用产生交叉污染、混淆或差错的风险降至最小。不同的产品不得在相信的包装线上进行包装，除非对其进行物理隔离。

5.50 Before packaging operations are begun, steps should be taken to ensure that the work area, packaging

lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance should be performed according to an appropriate check-list.

在包装操作开始前，应采取措施确保工作区域、包装线、印刷设备和其它设备的清洁，无上次使用本次不需要的产品、物料或文件。应根据适当的检查清单进行清场。

5.51 The name and batch number of the product being handled should be displayed at each packaging

station or line.

在每一包装工作台或包装生产一上应标明正在生产的产品的名称和批号。

5.52 All products and packaging materials to be used should be checked on delivery to the packaging

department for quantity, identity and conformity with the Packaging Instructions.

所有将要使用的产品和包材在送到包装车间时，应对其品种、数量以及是否与包装指令相符合进行检查。

5.53 Containers for filling should be clean before filling. Attention should be given to avoid and remove any

contaminants such as glass fragments and metal particles.

灌装用的容器在灌装前应是洁净的。应注意避免和清除玻璃碎片和金属颗粒等污染物。

5.54 Normally, filling and sealing should be followed as quickly as possible by labelling. If it is not the case,

appropriate procedures should be applied to ensure that no mix-ups or mislabelling can occur.

通常灌封后应尽可能快地进行贴签。否则，应制订适当的程序以保证不会出现混淆或者误贴标签。

5.55 The correct performance of any printing operation (for example code numbers, expiry dates) to be done

separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand which should be re-checked at regular intervals.

应对所有印字操作（如代码、有效期）的正确性单独进行检查，可在包装过程中进行检查并记录。要注意手工印制操作，该操作应进行定期复核。

5.56 Special care should be taken when using cut-labels and when over-printing is carried out off-line.

Roll-feed labels are normally preferable to cut-labels, in helping to avoid mix-ups.

当使用裁切标签和不在线套打操作时应特别注意。通常，卷式标签要优于裁切标签，因为卷式标签有助于避免混淆。

5.57 Checks should be made to ensure that any electronic code readers, label counters or similar devices are

operating correctly.

应对所有电子读码器、标签计数器和类似的装置进行检查，以保证其操作正确。

5.58 Printed and embossed information on packaging materials should be distinct and resistant to fading or

erasing.

包材上的打印或压印信息应清晰，不易褪色或擦除。

5.59 On-line control of the product during packaging should include at least checking the following:

包装过程中对产品的在线控制至少应包括以下：

i. General appearance of the packages; 包装外观

ii. Whether the packages are complete; 包装是否完整

iii. Whether the correct products and packaging materials are used; 产品和包材是否正确

iv. Whether any over-printing is correct; 套打是否正确

v. Correct functioning of line monitors. 在线监控是否工作正常

Samples taken away from the packaging line should not be returned.

从生产线上取走的样品，不得再放回包装线。

5.60 Products which have been involved in an unusual event should only be reintroduced into the process

after special inspection, investigation and approval by authorised personnel. Detailed record should be kept of this operation.

涉及到异常事件的产品只有在经过特别检查、调查和受权人的批准后才能重新纳入生产过程。该类操作应详细记录。

5.61 Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product

and printed packaging materials and the number of units produced should be investigated and satisfactorily accounted for before release.

在待包装产品和印字包材的数量以及成品数量的衡算过程中发现任何重大或异常的不平衡时，均应进行调查，做出合理说明后方可放行。

5.62 Upon completion of a packaging operation, any unused batch-coded packaging materials should be

destroyed and the destruction recorded. A documented procedure should be followed if uncoded printed materials are returned to stock.

包装操作全部完成后，应将印有批号但没有用完的包装材料销毁，销毁应有记录。如果将未印批号的包材退库，则应按书面程序规定执行。

Finished products 成品

5.63 Finished products should be held in quarantine until their final release under conditions established by

the manufacturer.

成品在最终放行前，应按企业制订的贮存条件存放于待检区。

5.64 The evaluation of finished products and documentation which is necessary before release of product for

sale are described in Chapter 6 (Quality Control).

成品放行销售前应根据第6章（质量控制）的要求对成品及相关文件记录进行评价。

5.65 After release, finished products should be stored as usable stock under conditions established by the

manufacturer.

成品放行后，应在企业制订的贮存条件下贮存。

Rejected, recovered and returned materials 不合格、回收和退货物料

5.66 Rejected materials and products should be clearly marked as such and stored separately in restricted

areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by authorised personnel.

不合格物料和产品应有醒目标识，并单独存放于限制区。不合格物料应退回供应商，适当时，产品应返工或销毁。无论采取何种处理方式，均应由经授权的人员批准和记录。

5.67 The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the

final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. Record should be kept of the reprocessing.

对于不合格产品的返工应为例外情况。只有当成品质量不会受到影响，最终成品符合质量标准，对相关风险进行评估后根据既定的批准程序进行时才被允许。返工记录应保留。

5.68 The recovery of all or part of earlier batches which conform to the required quality by incorporation

into a batch of the same product at a defined stage of manufacture should be authorised beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded.

将符合既定质量标准的同一产品较早批次中的一部分或整批回收加入指定的某生产工序时，应事先得到批准。该回收应在评估相关风险包括所有可能对货架期的影响后，根据既定程序进行。回收操作应有记录。

5.69 The need for additional testing of any finished product which has been reprocessed, or into which a

recovered product has been incorporated, should be considered by the Quality Control Department. 质量控制部门应考虑是否需要对返工批和加入回收产品的批次增加附加测试。

5.70 Products returned from the market and which have left the control of the manufacturer should be

destroyed unless without doubt their quality is satisfactory; they may be considered for re-sale, re-labelling or recovery in a subsequent batch only after they have been critically assessed by the Quality Control Department in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for re-issue or re-use, although basic chemical reprocessing to recover active ingredient may be possible. Any action taken should be appropriately recorded.

对于退货且曾在生产厂家控制以外的产品，应予以销毁，除非确信其质量符合要求：只有在质量控制部门根据书面程序评估后方考虑退货产品的重新销售、重新贴签或加入后续批次的产品中进行回收利用。评估时应考虑产品的性质、特殊贮存条件、产品状况和历史，以及成品发货至今的时间等因素。若对产品质量有任何疑问，即使通过基本的化学方法返工后可回收有效成人，也不适用于再发货或再使用。所采取的任何措施均应有相应的记录。

Product shortage due to manufacturing constraints 由于生产受限使得产品短缺

5.71 The manufacturer should report to the marketing authorisation holder (MAH) any constraints in

manufacturing operations which may result in abnormal restriction in the supply. This should be done in a timely manner to facilitate reporting of the restriction in supply by the MAH, to the relevant competent authorities, in accordance with its legal obligations1[5].

生产商应向上市许可持有人报告所有可能使用生产操作受限，从而导致供应异常的问题。报告应及时，以便上市许可持有人向相关的药监当局履行其法定的报告义务。

2[a] In January 2015 the deadline for coming into operation was adapted with regard to the toxicological evaluation to align with the coming effect of the EMA guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. Furthermore, correction of the reference in footnote 2 took place. 在2015年1月，增加了了关于基因毒性的评估生效期限，以与EMA指南“在共用设施中生产不同药品时风险识别所用的基于健康暴露限度的设定”保持一致。另外对脚注2中引用进行纠正。

3[2] Specific requirements apply to the importation of active substances to be used in the manufacture of medicinal products for human use in article 46b of Directive 2001/83/EC.

4[3] A similar approach should apply to packaging materials as stated in section 5.45. 类似的方法也应用于5.45的包材管理。

5[4] Identity testing of starting materials should be performed according to the methods and the specifications of the relevant marketing authorisation dossier. 要根据相关上市许可文件中的质量标准和检验方法对起始物料进行鉴别测试。

6[5] Articles 23a and 81 of Directive 2001/83/EC

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