【技术交流】20140813 EU GMP 第5章：生产

【技术交流】20140813 EU GMP 第5章：生产2014-09-10 Julia 翻译 蒲公英杂志

Chapter 5: Production

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.

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

生效日期：2015年3月1日

Principle

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：

       Technical Measures 技术措施

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

Organisational Measures 组织措施

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

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