(完整版)欧盟GMP附录

附录1 无菌产品生产文件日期：2020-02-20目录•文件结构图• 1 范围• 2 原则• 3 药品质量体系（PQS）• 4 厂房• 5 设备• 6 公共设施•7 人员•8 生产和具体技术•9 活性微粒及非活性微粒的环境监测和工艺监测•10 质量控制（QC）•11.术语1 范围无菌产品的生产涵盖多种无菌产品类型（原料药，无菌辅料，内包装材料和成品制剂），包装规格（单剂量到多剂量），工艺（从高度自动化系统到手动工艺）和技术（如生物技术，传统小分子生产和密闭系统）。

本附录提供了运用质量风险管理（QRM）原则的所有无菌产品生产应施用的一般性指导，以确保最终产品中无微生物、微粒和热原污染。

QRM缩写适用于本文件全文，不会在具体段落中加以说明。

在列出具体限度或频率时，这些限度或频率应视为最低要求。

这些陈述是由于监管历史经验，即曾出现这些问题并影响了患者的安全。

本附录的目的是为无菌产品的生产提供指导。

然而，一些原则和指导，例如污染控制策略、厂房设计、洁净室分类、确认、监测和人员更衣，可用于支持其它非无菌、但有必要控制和减少微生物、微粒和热原污染的产品（例如某些液体、乳膏、软膏和低生物负荷的生物中间体）的生产。

如果生产商选择将本指南应用于非无菌产品，生产商应清楚地记录已施用了哪些原则，并应证明符合这些原则。

2 原则2.1 无菌产品的生产应符合特殊要求，以尽量降低微生物、微粒和热原污染的风险。

应考虑以下关键领域：i.应按照药品生产质量管理规范（GMP）指南的相关章节优化、确认和验证设施、设备和工艺设计。

应考虑使用适当的技术（例如，限制进入隔离系统（RABS），隔离器，自动系统，快速微生物检测和监测系统），以增强对产品的保护，防止潜在的外来微粒和微生物污染源（例如人员、物料和周围环境），并帮助快速检测环境和产品中的潜在污染物。

ii.人员应具备合适的资质和经验，培训和态度，尤其是生产、包装和发运过程中无菌产品保护所涉及的原则。

欧盟GMP(EUGMP)中文版欧洲药品生产和质量管理规范附录1,无菌药品生产盟欧盟 GMP cfu/4 小时 cfu/碟5 指手套cfu/手套A <1 <1 <1 <1B 10 5 5 5C 100 50 25 －D 200 100 50 －注：（a）表中各数值均为平均值。

（b）单个沉降碟的暴露时间可以少于 4 小时。

6.应当对微粒和微生物监控制定适当的警戒和纠偏标准。

操作规程中应详细说明结果超标时应采取的纠偏措施。

隔离技术 7.采用能最大限度降地低生产区人员影响的隔离技术，可大大降低无菌生产中环境对产品微生物污染的风险。

隔离操作台和传递装置的设计可以有多种形式。

隔离操作台及其所处环境的设计，应能保证相应区域空气的质量达到设定标准。

隔离操作台所采用的材料在某种程度上易被穿剌或易产生渗漏。

传输装置可设计成单门的、双门的，甚至可以是同灭菌设备相连的全密封系统。

将物品放入隔离操作台或从中取出属污染风险最为严重的操作过程。

尽管人们认为这类隔离操作器的工作区内不一定要有层流，但是，隔离系统通常是用于进行高污染风险操作的场所。

隔离操作台所处环境的级别取决于它们的设计及其应用。

无菌操作的隔离操作台所处环境的级别应予控制，至少为 D 级。

8.隔离操作台只有经过适当的验证之后方可投入使用。

验证时应当考虑到隔离技术的所有关键性因素，例如，隔离系统内部和外部（所处环境）的空气质量、隔离操作台的消毒、传递操作以及隔离系统的完好性。

9.隔离操作器和隔离用袖管/手套系统应进行常规监测，这包括经常进行必要的检漏试验。

吹气/灌装/密封技术 10.吹气/灌装/密封系统是一套专用机械设备，连续操作，从一个热塑性颗粒吹制成容器至灌装和密封，整个过程由一台全自动机器完成。

用于无菌生产的吹气/灌装/密封设备本身装有 A 级空气风淋装置，在操作人员按A/B 级区要求着装的条件下，该设备可以安装在洁净度至少为C 级的环境中。

eugmp附录1解读
附录1是欧洲药品管理局（European Medicines Agency，简称EMA）制定的监管要求之一，是一份关于良好药品管理规范（Good Manufacturing Practice，简称GMP）的补充材料。

附录1主要是对药品生产过程中的各个环节进行详细说明，并提供了与药品生产相关的技术指南和要求。

附录1的编制目的是为了确保药品的质量、安全性和有效性。

它适用于所有类别的药品，包括化学药品、生物制品、放射性药品等。

附录1中明确了药品生产过程中的各个关键环节，如设备、材料、人员、记录等方面的要求。

附录1中对设备要求了很高的标准，例如要求设备必须符合国家和国际规定的技术要求，并且要有适当的验证和维护程序。

对于生产过程中使用的材料，附录1要求必须符合相关法规，并且需要有严格的供应商评估程序。

附录1还对人员的培训和资质要求进行了规定。

生产厂商必须确保员工具有足够的知识和技能，且接受了适当的培训。

此外，附录1还强调了记录的重要性，包括对生产过程和质量审核的记录要求。

附录1是一份重要的药品生产指南，通过对各个环节的详细规定，旨在确保药品的质量和安全性。

作为一份国际标准，它对药品生产企业来说具有指导意义和法律约束力。

药品生产企业应认真遵守附录1的要求，并确保生产过程符合相关技术要求和法规，以保证药品的质量和可靠性。

欧盟GMP附录11标题：计算机系统原则在生产系统中引入计算机系统，包括贮存、发运和质量控制中，并不意味着可以不需要遵循《CMP基本要求》中相关的原则。

凡用计算机系统代替人工操作时，都不得造成降低产品质量或影响质量保证的后果。

应当考虑到减少生产人员的参与，有可能会带来原系统特点受到损害的风险。

人员1．关键人员与计算机系统人员之间紧密合作是至关重要的。

管理人员在其分管的职责中使用计算机时，应接受使用和管理计算机系统的适当培训。

这包括确保有适当的专业人员，对计算机系统的设计、验证、安装和运行等方面进行培训和指导。

验证2．应根据多种因素来决定计算机系统验证的必要范围，这些因素包括：计算机用在哪个系统，属前验证还是回顾性验证，在系统中采用是否创新元件等。

应当将验证看作计算机系统“整个生命周期”的组成环节。

这个生命周期包括计划、设定标准、编程、测试、试运行、文档管理、运行、监控和修改更新等阶段。

系统3．应注意设备安装在适当的位置，以防止外来因素干扰系统的工作。

4．应有一详细阐述系统的文件（必要时，要有图纸），并须及时更新。

此文件应详细描述系统的工作原理、目的、安全措施和适用范围、计算机运行方式的主要特征，以及如何与其他系统和程序楣接。

5．软件是计算机系统的重要组成部分。

软件的使用者应采取适当的措施，保证所编制的软件符合质量保证系统的要求。

6．必要时，系统应当有数据正确输入和处理的内置复核功能。

7．在计算机化系统使用之前，应当对系统全面进行测试，并确认系统可以获得预期的结果。

当计算机系统替代某一人工系统时，作为测试和验证的内容，二个系统（人工和计算机）应平行运行一段时间。

8．数据的输入或修改只能由受权的人员进行。

杜绝未经许可的人员输入数据的手段有：使片j钥匙、密码卡、个人密码和权限对计算机终端的访问。

应当就输入和修改数据制订一个授权、取消、授权变更，以及改变个人密码的规程。

同时，应当考虑系统能记录未经授权的人员试图访问系统的行为。

欧洲共同体：European Communities (EC)。

欧洲联盟：European Union (EU)，简称欧盟。

人用药品注册技术标准国际协调会：ICH欧盟GMP附录1无菌药品的生产注：冻干瓶轧盖的条款自2010年3月1日开始实施。

原则为降低微生物、微粒和热原污染的风险，无菌药品的生产应有各种特殊要求。

这在很大程度上取决于生产人员的技能、所接受的培训及其工作态度。

质量保证极为重要，无菌药品的生产必须严格按照精心制订并经验证的方法和规程进行。

产品的无菌或其它质量特性绝不能仅依赖于任何形式的最终操作或成品检验。

注：本指南没有对微粒、浮游菌和表面微生物等测试方法详细进行阐述，可参阅欧洲标准或国际标准（CEN/ISO）及药典资料。

总则1.无菌药品的生产必须在洁净区内进行，人员和（或）设备以及物料必须通过缓冲进入洁净区。

洁净区应当保持适当的洁净度，洁净区的送风须经具有一定过滤效率过滤器的过滤。

2.原料配制、产品加工和灌装等不同操作必须在洁净去内彼此分开的单独区域内进行。

生产工艺可分为两类：一类是最终灭菌工艺；第二类是部分或全部工序为无菌操作的工艺。

3.应按所需环境的特点确定无菌产品的洁净级别。

每一步生产操作都应达到适当的动态洁净度，以尽可能降低产品（或原料）被微粒或微生物污染。

洁净区的设计必须符合相应的“静态”标准，以达到“动态”的洁净要求。

“静态”是指安装已经完成并已运行，但没有操作人员在场的状态。

“动态”是指生产设施按预定的工艺模式运行并有规定数量的操作人员进行现场操作的状态。

应确定每一洁净室或每组洁净间的“动态”及“静态”标准。

无菌药品生产所需的洁净区一般可分为4个级别：A级：高风险操作区，如：灌装区，放置胶塞桶、敞口安瓿瓶、敞口西林瓶的区域及无菌装配/连接操作的区域。

通常用单向流操作台/罩来维护该区的环境状态。

单向流系统在其工作区域必须均匀送风，风速为0.36-0.54m/s（指导值）。

附录1 无菌产品生产文件日期：2020-02-20目录•文件结构图• 1 范围• 2 原则• 3 药品质量体系（PQS）• 4 厂房• 5 设备• 6 公共设施•7 人员•8 生产和具体技术•9 活性微粒及非活性微粒的环境监测和工艺监测•10 质量控制（QC）•11.术语1 范围无菌产品的生产涵盖多种无菌产品类型（原料药，无菌辅料，内包装材料和成品制剂），包装规格（单剂量到多剂量），工艺（从高度自动化系统到手动工艺）和技术（如生物技术，传统小分子生产和密闭系统）。

本附录提供了运用质量风险管理（QRM）原则的所有无菌产品生产应施用的一般性指导，以确保最终产品中无微生物、微粒和热原污染。

QRM缩写适用于本文件全文，不会在具体段落中加以说明。

在列出具体限度或频率时，这些限度或频率应视为最低要求。

这些陈述是由于监管历史经验，即曾出现这些问题并影响了患者的安全。

本附录的目的是为无菌产品的生产提供指导。

然而，一些原则和指导，例如污染控制策略、厂房设计、洁净室分类、确认、监测和人员更衣，可用于支持其它非无菌、但有必要控制和减少微生物、微粒和热原污染的产品（例如某些液体、乳膏、软膏和低生物负荷的生物中间体）的生产。

如果生产商选择将本指南应用于非无菌产品，生产商应清楚地记录已施用了哪些原则，并应证明符合这些原则。

2 原则2.1 无菌产品的生产应符合特殊要求，以尽量降低微生物、微粒和热原污染的风险。

应考虑以下关键领域：i.应按照药品生产质量管理规范（GMP）指南的相关章节优化、确认和验证设施、设备和工艺设计。

应考虑使用适当的技术（例如，限制进入隔离系统（RABS），隔离器，自动系统，快速微生物检测和监测系统），以增强对产品的保护，防止潜在的外来微粒和微生物污染源（例如人员、物料和周围环境），并帮助快速检测环境和产品中的潜在污染物。

ii.人员应具备合适的资质和经验，培训和态度，尤其是生产、包装和发运过程中无菌产品保护所涉及的原则。

欧盟GMP附录1无菌药品布鲁塞尔,2008年2月14日欧盟药事法规第4卷欧盟人用与兽用药品生产质量管理规范指南1 附录无菌药品生产文件历史日期前一版本从2003年5月30日开始实斲 2003年9 月修订调整洁冷室分类表,包括模拟介质指南,生物负荷检测以及冶2005年11月至2007年12月干瓶的轧盖1开始实斲以及终止日期 2009年3月1日1 1 说明:冶干瓶的压盖将于2010年3月1日开始实斲。

附录1无菌药品的生产原则无菌药品生产以特殊要求为条件,以使得微生物,微粒和热源污染的风险最小。

其很大秳度上要叏决于所涉及到人员技术水平,培训不态度。

质量保证特别重要,这个类型的生产,必须严格遵守小心建立的幵经过验证的生产斱法和工作秳序。

不能单独依靠无菌不其它质量斱面测试来叏代最终过秳或成品测试。

1 / 22注:本指南没有觃定测定空气,表面等微生物不微粒洁冷度的详细斱法。

请参阅例如EN/ISO标冸的其它文件。

总则1. 无菌产品生产应当在洁冷区域内进行,进入这些区域内的人员,和/或,设备不物料,应当通过气闸室。

洁冷区必须保持一定的洁冷级别标冸,空气必须通过适当效率过滤器供给。

2. 各种部件冸备,产品冸备不灌装,应当隔离的洁冷区进行。

生产操作分为两类,第一类是产品最终灭菌型,第二类是部分过秳或全过秳的无菌操作型。

3. 无菌产品生产洁冷区,按照所需要的环境特性进行分级。

每一步生产操作,在操作状态,对环境有相应的洁冷级别的要求,以使对所处理的物料或产品造成粉尘或微生物的污染最小。

为达到"动态"的条件,这些区域在设计上要达到"静态"安装状态的空气洁冷度。

"静态"设备已经安装幵运行中,生产设备就位但是没有操作人员在场。

"动态"是指在设备正常运转状态下和有觃定的工作人员在场的情冴下。

应当对每个清洁室或每套清洁室都分别确立"静态"和"动态"。

验证与确认公布详细指南的法律依据:指令2001/83/EC第47款关于人药共同体代码，和2001/82/EC第51款关于兽药共同体代码的要求。

本文件为指令2003/94/EC中制订的人药GMP以及指令91/412/EEC兽药GMP 原则和指南提供诠释。

文件状态：修订变更理由:自从附录15在2001年公布以来,生产和法规环境已发生了重大变化，有必要对此附录进行更新以反映环境的变化。

本次对附录15的修订考虑了欧洲药事法卷4第一部分其它部分的变化，与第二部分、附录11、ICH Q8 Q9 Q10以及Q11、QWP的工艺验证指南的关系，以及生产技术的变化。

最后实施时间:2015年10月1日原则本附录描述了确认和验证的原则，该原则适用于药品生产用设施、设备、公用系统和工艺，也可用作活性物质的可选补充指南，但并不对欧盟药事法第4卷第二部分引入附加要求。

GMP要求生产商通过在产品和工艺的整个生命周期中进行确认和验证,对其操作关键方面进行控制。

所有可能影响产品质量的设施、设备、公用系统和工艺计划变更均应进行正式记录,并评估其对验证状态和控制策略的影响。

用于药品生产的计算机化系统也应根据附录11的要求进行验证。

同时还应考虑ICH Q8 Q9 Q10和Q11是的相关概念和指南要求。

通则质量风险管理的方法应贯穿药品的整个生命周期。

作为质量风险管理系统的一部分，决定确认和验证的范围和程度时应基于对设施、设备、公用系统和工艺的论证和书面风险评估.回顾性验证不再被认为是可以接受的方法。

如果经过论证,并且获得数据的整个过程有足够控制保证，也可以使用从生产商自身程序以外获得的用于支持确认和/或验证研究的数据.1。

确认和验证的组织和计划1。

1.所有确认和验证活动应进行计划，并考虑设施、设备、公用系统、工艺和产品的生命周期;1.2.确认和验证活动应由经过适当培训的人员实施，并遵守已批准的程序；、1。

3.确认/验证实施人员应根据药品质量体系中指定的要求进行报告，尽管并不一定是报告给质量管理或质量保证部门。

EUROPEAN COMMISSIONENTERPRISE AND INDUSTRY DIRECTORATE-GENERALConsumer goodsPharmaceuticalsBrussels, 25 November 2008 (rev.)EudraLexThe Rules Governing Medicinal Products in the European UnionVolume 4EU Guidelines toGood Manufacturing PracticeMedicinal Products for Human and Veterinary UseAnnex 1Manufacture of Sterile Medicinal Products(corrected version)Document HistoryPrevious version dated 30 May 2003, in operation since September 2003Revision to align classification table of clean rooms, to include guidance on media simultations, bioburden monitoring and capping of vials November 2005 to December 2007Date for coming into operation and superseding 01 March 20091 Please note correction on the implementation of provisions for capping of vials!1Note: Provisions on capping of vials should be implemented by 01 March 2010.Commission Européenne, B-1049 Bruxelles / Europese Commissie, B-1049 Brussel – Belgium. Telephone: (32-2) 299 11 11ANNEX 1MANUFACTURE OF STERILE MEDICINAL PRODUCTSPrincipleThe manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.Note:This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards.General1. The manufacture of sterile products should be carried out in clean areas entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.2. The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages.3. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled.In order to meet “in operation” conditions these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy state. The “at-rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present. The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms.For the manufacture of sterile medicinal products 4 grades can be distinguished.Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated.A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes.Grade B: For aseptic preparation and filling, this is the background environment for the gradeA zone.Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.Clean room and clean air device classification4. Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne particle concentration for each grade is given in the following table.Maximum permitted number of particles per m 3 equal to or greater than the tabulated sizeAt rest In operation Grade0.5 µm 5.0µm 0.5 µm 5.0µm A3 520 20 3 520 20 B3 520 29 352 000 2 900 C352 000 2 900 3 520 000 29 000 D3 520 000 29 000 Not defined Not defined 5. For classification purposes in Grade A zones, a minimum sample volume of 1m 3 should be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥5.0 µm. For Grade B (at rest) the airborne particle classification is ISO 5 for both considered particle sizes. . For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.6. Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles ≥5.0µm in remote sampling systems with long lengths of tubing. Isokinetic sample heads shall be used in unidirectional airflow systems.7. “In operation” classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation is required for this. EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications.Clean room and clean air device monitoring8. Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.9. For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in theprocess that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk. Monitoring during simulated operations should also be performed. The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of ≥5.0 µm particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. 10. It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. The importance of the particle monitoring system should be determined by the effectiveness of the segregation between the adjacent Grade A and B zones. The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.11. Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points connected by manifold to a single particle counter; or a combination of the two. The system selected must be appropriate for the particle size considered. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing. The selection of the monitoring system should take account of any risk presented by the materials used in the manufacturing operation, for example those involving live organisms or radiopharmaceuticals.12. The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.13. In Grade A and B zones, the monitoring of the ≥5.0 µm particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure. The occasional indication of ≥5.0 µm particle counts may be false counts due to electronic noise, stray light, coincidence, etc. However consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated. Such events may indicate early failure of the HVAC system, filling equipment failure or may also be diagnostic of poor practices during machine set-up and routine operation.14. The particle limits given in the table for the “at rest” state should be achieved after a short “clean up” period of 15-20 minutes (guidance value) in an unmanned state after completion of operations.15. The monitoring of Grade C and D areas in operation should be performed in accordance with the principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operations carried out, but the recommended “clean up period” should be attained.16. Other characteristics such as temperature and relative humidity depend on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness standard.17. Examples of operations to be carried out in the various grades are given in the table below (see also paragraphs 28 to 35):Grade Examples of operations for terminally sterilised products. (see paragraphs 28-30)A Filling of products, when unusually at riskC Preparation of solutions, when unusually at risk. Filling of productsD Preparation of solutions and components for subsequent fillingGrade Examples of operations for aseptic preparations. (see paragraphs. 31-35)A Aseptic preparation and filling.C Preparationofsolutions to be filtered.D Handling of components after washing.18. Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation.19. Recommended limits for microbiological monitoring of clean areas during operation:Recommended limits for microbial contamination (a)Grade air samplecfu/m3settle plates(diameter 90 mm)cfu/4 hours (b)contact plates(diameter 55 mm)cfu/plateglove print5 fingerscfu/gloveA < 1 < 1 < 1 < 1B 10 5 5 5C 100 50 25 -D 200 100 50 -Notes(a) These are average values.(b) Individual settle plates may be exposed for less than 4 hours.20. Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action.Isolator technology21. The utilisation of isolator technology to minimize human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms.22. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devices.23. The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing it should be at least grade D.24. Isolators should be introduced only after appropriate validation. Validation should take into account all critical factors of isolator technology, for example the quality of the air inside and outside (background) the isolator, sanitisation of the isolator, the transfer process and isolator integrity.25. Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system.Blow/fill/seal technology26. Blow/fill/seal units are purpose built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and non viable limits at rest and the viable limit only when in operation. Blow/fill/seal equipment used for the production of products which are terminally sterilised should be installed in at least a grade D environment.27. Because of this special technology particular attention should be paid to, at least the following:•equipment design and qualification•validation and reproducibility of cleaning-in-place and sterilisation-in-place•background clean room environment in which the equipment is located•operator training and clothing•interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling.Terminally sterilised products28. Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination, suitable for filtration and sterilisation. Where the product is at a high or unusual risk of microbial contamination, (for example, because the product actively supports microbial growth or must be held for a long period before sterilisation or is necessarily processed not mainly in closed vessels), then preparation should be carried out in a grade C environment.29. Filling of products for terminal sterilisation should be carried out in at least a grade C environment.30. Where the product is at unusual risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing, the filling should be done in a grade A zone with at least a grade C background. Preparation and filling of ointments, creams,suspensions and emulsions should generally be carried out in a grade C environment before terminal sterilisation.Aseptic preparation31. Components after washing should be handled in at least a grade D environment. Handling of sterile starting materials and components, unless subjected to sterilisation or filtration through a micro-organism-retaining filter later in the process, should be done in a grade A environment with grade B background.32. Preparation of solutions which are to be sterile filtered during the process should be done in a grade C environment; if not filtered, the preparation of materials and products should be done in a grade A environment with a grade B background.33. Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B background.34. Prior to the completion of stoppering, transfer of partially closed containers, as used in freeze drying should be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment.35. Preparation and filling of sterile ointments, creams, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered.Personnel36. Only the minimum number of personnel required should be present in clean areas; this is particularly important during aseptic processing. Inspections and controls should be conducted outside the clean areas as far as possible.37. All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in disciplines relevant to the correct manufacture of sterile products. This training should include reference to hygiene and to the basic elements of microbiology. When outside staff who have not received such training (e.g. building or maintenance contractors) need to be brought in, particular care should be taken over their instruction and supervision.38. Staff who have been engaged in the processing of animal tissue materials or of cultures of micro-organisms other than those used in the current manufacturing process should not enter sterile-product areas unless rigorous and clearly defined entry procedures have been followed.39. High standards of personal hygiene and cleanliness are essential. Personnel involved in the manufacture of sterile preparations should be instructed to report any condition which may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable. Actions to be taken about personnel who could be introducing undue microbiological hazard should be decided by a designated competent person.40. Wristwatches, make-up and jewellery should not be worn in clean areas.41. Changing and washing should follow a written procedure designed to minimize contamination of clean area clothing or carry-through of contaminants to the clean areas.42. The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. 43. The description of clothing required for each grade is given below:•Grade D: Hair and, where relevant, beard should be covered. A general protective suit and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area.•Grade C: Hair and where relevant beard and moustache should be covered. A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes should be worn. They should shed virtually no fibres or particulate matter.•Grade A/B: Headgear should totally enclose hair and, where relevant, beard and moustache; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets. Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or disinfected footwear should be worn. Trouser-legs should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body.44. Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. For every worker in a grade A/B area, clean sterile (sterilised or adequately sanitised) protective garments should be provided at each work session. Gloves should be regularly disinfected during operations. Masks and gloves should be changed at least for every working session.45. Clean area clothing should be cleaned and handled in such a way that it does not gather additional contaminants which can later be shed. These operations should follow written procedures. Separate laundry facilities for such clothing are desirable. Inappropriate treatment of clothing will damage fibres and may increase the risk of shedding of particles. Premises46. In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to minimize the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents, and disinfectants where used.47. To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid those uncleanable recesses; sliding doors may be undesirable for this reason.48. False ceilings should be sealed to prevent contamination from the space above them.49. Pipes and ducts and other utilities should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean.50. Sinks and drains should be prohibited in grade A/B areas used for aseptic manufacture. In other areas air breaks should be fitted between the machine or sink and the drains. Floordrains in lower grade clean rooms should be fitted with traps or water seals to prevent back-flow.51. Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimize microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should, in the at-rest state, be the same grade as the area into which it leads. The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. In general hand washing facilities should be provided only in the first stage of the changing rooms.52. Both airlock doors should not be opened simultaneously. An interlocking system or a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time.53. A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different grades should have a pressure differential of 10 - 15 pascals (guidance values). Particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which a product and cleaned components which contact the product are exposed. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations.54. It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should be taken to ensure that air flows do not distribute particles from a particle-generating person, operation or machine to a zone of higher product risk.55. A warning system should be provided to indicate failure in the air supply. Indicators of pressure differences should be fitted between areas where these differences are important. These pressure differences should be recorded regularly or otherwise documented. Equipment56. A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel).57. As far as practicable equipment, fittings and services should be designed and installed so that operations, maintenance and repairs can be carried out outside the clean area. If sterilisation is required, it should be carried out, wherever possible, after complete reassembly.58. When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected and/or sterilised where appropriate, before processing recommences if the required standards of cleanliness and/or asepsis have not been maintained during the work.59. Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality. They should not be operated beyond their designed capacity. Water for injections should be produced,stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70°C.60. All equipment such as sterilisers, air handling and filtration systems, air vent and gas filters, water treatment, generation, storage and distribution systems should be subject to validation and planned maintenance; their return to use should be approved.Sanitation61. The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a written programme. Where disinfectants are used, more than one type should be employed. Monitoring should be undertaken regularly in order to detect the development of resistant strains.62. Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.63. Fumigation of clean areas may be useful for reducing microbiological contamination in inaccessible places.Processing64. Precautions to minimize contamination should be taken during all processing stages including the stages before sterilisation.65. Preparations of microbiological origin should not be made or filled in areas used for the processing of other medicinal products; however, vaccines of dead organisms or of bacterial extracts may be filled, after inactivation, in the same premises as other sterile medicinal products.66. Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill).Selection of the nutrient medium should be made based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilisation of the nutrient medium.67. The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. It should also take into account various interventions known to occur during normal production as well as worst-case situations.68. Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system, equipment, process and number of shifts. Normally process simulation tests should be repeated twice a year per shift and process.69. The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth and the following should apply:。

Conte nts 欧盟概况欧盟药品审评及检查欧盟GMP基本要求1 附录1无菌药品的生产经济领域 公共卫生 社会方针和政策科研消费者和环保 合作程序（共同 决定程序）条约〜法令、法规〜指导方针、指南d 951-7-25欧洲煤钢共同体d 958-1-1欧洲经济共同体 欧洲原子能共同体1967-7-1 欧洲共同体d 993-11-1欧共体更名欧盟截止2004年1月25成员国，4.56亿丿欧盟概况・EU欧洲联盟•EuropeanCouncil欧洲理事会•Council of•Commission ofEU欧盟委员会•European Parliament 欧洲议会•Court of justice欧洲法院•支柱产业之一•占全球40%Ministers欧盟理事会•欧盟委员会企业理事会下属药品部•EMEA•EDQM药品安全性评价药品有效性评价EMEA使命(Eu「opean Agency for the Evaluation of Medicinal Prod欧盟药品审评及检查用药品委员兽药委员会用药品委员草药委员会4个专家委员会•由EMEA 颁布实施 的一些技术性指南(Guidelines)和 对一些法规条款所 做出H ? E ； I 0欧盟药品审评及检查欧盟药事法规三层次品注册监督管理程GMP 指南技术性指南 我术注释•由欧盟委员会依? 有关法冬和法规H 颁布实施的药品哲 册监督管理程序牙 GMP 指南•由欧盟议会和 理事会颁布实才 少部分由欧盟M 会颁布实施•Directives •Regulations的技术注释(Notes)是国家药品监督管理部" 门认可，负责确保每批11 药品己经按国家相关法律法规生产、检验和放行的人员。

-------- X 法规保证2001/83/EC 第48、49> 5152条。

既强化了企业对药品质量的个人责任，也有助于保证产品相关信息的可追溯性。

产品放行责任人- —---- QPQualified Person合成、提取或发酵获得的有机 聾无机原料药（活性成分）或组分一 在药品生产或制备过程中，使用有传染 _性克雅氏症病原体风险的任何产品-任何草药相关的制剂tothe monoqraphs of the Euj^Dean Pharmacopoeia)评及检查H ? E ：I欧盟药品审 EDMF 欧洲药品主档案文件对专论控制原料药化学纯度和微生物质量适用性的评估 T 根据新的通则，对降低TSE 风险进行评估 一或对以上二方面同时评估欧盟常用网址一览表洲药晶管理局 http://www.emea.eu.int药品检查合作组织PIC/S •・.•・・1 欧洲药品质量理事会Tjlfp:〃www.pheur.og))品注册标准技术要求国际协调会ICH /丿Q 美国FDA /•••“•6美国注射剂协会 /O国际制药工程协会/•世界卫生组织WHO http://www.who.int/基木要求1人用药品及兽药制剂生产质量管理规范•附录1无菌药品的生产•附录2人用生物制品的生产•附录3放射性药品生产•附录4兽用非免疫药品的生产•附录5免疫类兽药制品的生产•附录6医用气体生产•附录7草药制剂的生产•附录8原辅包装材料的取样，附录9液剂霜剂和油膏的生产Q 付录io定量吸入式气雾剂的生•附录11计算机系统•附录12药品生产中电离辐射的应用•附录13临床试验用药的生产附录14人血液或血浆制品的生产•附录15确认和验证•附录16药品放行责任人签发证书和放行批产品•附录17参数放行［附录19对照样品和留样驸录20质量风险管理基木要求2原料药生产质量管理规范EU-GMP目录欧盟GMP附录Mil厂欧盟GMP附录•:•人用药品及兽药生产质量管理规范（基本要求1） 2005年10月3日彳勺第一章质量管理Quality Managemento 第二章人员Personnel ；第三章厂房与设备Premises and Equipment第四章文件和记录Documentation11 第五章生产Production __________________________________彳号第六章质量控制Quality Control __________________________（爭第七章委托生产和委托检验Contract Manufacture and Analysis彳爭第丿l章投诉和药品召回Complaintsand Product Recall暫勒療则：药品生产企业必须确保所生产的产品适用于预定的用途, 符合药品注册批准的要求，并不使患者承担安全、质量和疗效的风险。

布鲁塞尔，2008年2月14日欧盟药事法规第4卷欧盟人用与兽用药品生产质量管理规范指南附录1无菌药品生产文件历史日期前一版本从2003年5月30日开始实施2003年9 月修订调整洁净室分类表，包括模拟介质指南，生物负荷检测以及冻2005年11月至2007年12月干瓶的轧盖开始实施以及终止日期2009年3月1日111 说明：冻干瓶的压盖将于2010年3月1日开始实施。

附录1无菌药品的生产原则无菌药品生产以特殊要求为条件，以使得微生物,微粒和热源污染的风险最小。

其很大程度上要取决于所涉及到人员技术水平，培训与态度。

质量保证特别重要,这个类型的生产，必须严格遵守小心建立的并经过验证的生产方法和工作程序。

不能单独依靠无菌与其它质量方面测试来取代最终过程或成品测试。

注:本指南没有规定测定空气，表面等微生物与微粒洁净度的详细方法。

请参阅例如EN/ISO标准的其它文件。

总则1. 无菌产品生产应当在洁净区域内进行，进入这些区域内的人员，和/或，设备与物料，应当通过气闸室。

洁净区必须保持一定的洁净级别标准，空气必须通过适当效率过滤器供给。

2. 各种部件准备，产品准备与灌装，应当隔离的洁净区进行。

生产操作分为两类，第一类是产品最终灭菌型，第二类是部分过程或全过程的无菌操作型。

3. 无菌产品生产洁净区，按照所需要的环境特性进行分级。

每一步生产操作，在操作状态，对环境有相应的洁净级别的要求，以使对所处理的物料或产品造成粉尘或微生物的污染最小。

为达到"动态"的条件，这些区域在设计上要达到"静态"安装状态的空气洁净度。

"静态"设备已经安装并运行中，生产设备就位但是没有操作人员在场。

"动态"是指在设备正常运转状态下和有规定的工作人员在场的情况下。

应当对每个清洁室或每套清洁室都分别确立"静态"和"动态"。

无菌产品生产有4个环境级别:A级: 高风险操作区，如，灌装区，加盖区，安瓿与瓶开口区,进行无菌连接。

欧盟GMP(EUGMP)欧洲药品生产和质量管理规范附录15验证和确认EU GMP ANNEX 15 Qualification and validation (July 2001) ACUANNEX 15 附件15Qualification and Validation确认和验证Table of Contents 目录1. Qualification and Validation 确认和验证2. Planning for Validation 验证计划3. Documentation 文件4. Qualification 确认5. Processs Validation. 工艺验证6. Cleaning Validation 清洁验证7. Change Control 变更控制8. Revalidation 再验证9. Glossary 术语表Principle 原理This Annex describes the principles of qualification and validation which are applicable to the manufacture of medicinal products. It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation.本附件描述了确认和验证的原理，适用于医药产品的生产者。

欧盟GMP附录.对除菌过滤的14条要求本文对欧盟GMP附录《无菌药品生产》中除菌过滤相关的条款进行了总结，其中液体除菌过滤方面有14条要求，如下：1、如果产品不能在其最终容器中进行灭菌，则溶液或液体应通过除菌级过滤器（最大孔径0.22 μm,经过适当验证能得到无菌滤液）过滤进行灭菌，然后无菌灌装到预先灭菌的容器中。

所选择的过滤器应确保与产品相容并符合上市许可。

延伸：选择除菌过滤的前提条件是一一产品不能进行最终灭菌。

选择的除菌滤器，其相容性需要经过确认。

2、可在整个生产过程的多个环节使用预过滤器和/或除菌级过滤器，以确保在最终除菌过滤器前液体中的微生物限度低且受控。

由于除菌过滤工艺和其他灭菌工艺相比有潜在的额外风险，应通过除菌滤器进行额外过滤，且应尽可能靠近灌装点，过滤工艺应被视为污染控制策略（CCS）的一部分。

延伸：最终除菌过滤前需要取样测试待过滤液体的微生物限度，应低于IOCFU/IOOmL最终除菌过滤应尽可能靠近分装点，同时在污染控制策略中应描述产品最终除菌过滤的位置及选择依据。

当由于特殊原因不能在分装前设置除菌过滤时（比如：添加佐剂的疫苗或除菌过滤大幅降低活性蛋白时..），应有对应的分析及研究以支持相应的工艺。

3、过滤系统组件的选择及其在过滤系统内的互连和布置，包括预过滤器，应基于产品的关键质量属性，并经过论证和记录。

过滤系统应尽量减少纤维和颗粒的产生，不会导致或产生不可接受的杂质，不能有改变产品质量和功效的特性。

同样，过滤器特性应与液体相容，且不受待过滤产品的不利影响。

应评估产品成分的吸附和过滤器成分的提取/浸出。

延伸：过滤系统应根据在工艺中接触溶液的特点进行评估，以选择可提取物测试、吸附性、浸出物测试、兼容性的测试范围，通常接触产品活性成分的滤器应进行浸出物测试及吸附性测试，如果仅接触其他溶液，应考虑进行可提取物测试。

同时，还要考虑滤器是否会引入其他杂质。

4、过滤系统的设计要点：允许在经过验证的工艺参数范围内操作。

欧盟GMP附录1 无菌药品的生产欧盟GMP附录2 人用生物制品的生产欧盟GMP附录3 放射性药品生产'欧盟GMP附录4 兽用非免疫药品的生产欧盟GMP附录5 免疫类兽药制品的生产欧盟GMP附录6 医用气体生产欧盟GMP附录7 草药制剂的生产欧盟GMP附录8 原辅包装材料的取样欧盟GMP附录9 液剂、霜剂和油膏的生产欧盟GMP附录10 定量吸人式气雾剂的生产欧盟GMP附录11 计算机系统欧盟GMP附录12 药品生产中电离辐射的应用欧盟GMP附录13 临床试验用药的生产欧盟GMP附录14 人血液或血浆制品的生产欧盟GMP附录15 确认和验证欧盟GMP附录16 药品放行责任人签发证书和放行批产品欧盟GMP附录17 参数放行欧盟GMP附录19 对照样品和留样欧盟GMP附录20 质量风险管理欧盟GMP术语读修订版欧盟GMP附录15：确认与验证的体会1，草案版和正式版在文件结构上都是以2001版的结构为基础而来。

草案版在内容上进行了扩充，在标题上进行了小幅改动。

（具体），同时引入了大量新的理念，体现了其修订的目的是要与当前的新形式接轨。

在结构上，正式版相对于草案版除将再确认提前到第三章外，未做其他调整，但更注意遣词造句。

在遣词方面：对Validation，Qualification，Verification 这三个词的使用环境进行了进一步的明确，确认仅针对设施、设备系统的各阶段，确证仅针对运输，阅读时应充分注意。

造句方面：语言相对草案版更加注重通顺性和逻辑严密性，调整了部分语句结构，删除部分重复提到的内容。

2，加强了同其他相关新法规、指南和理念的联系和保持一致性，如ICH、EMA其他相关指南。

3，在原则中提到"critical aspects"这个词，但在后文中未做任何描述，术语中也未对其进行解释。

在ASTM E2500-13第6.4 Critical Aspects of Manufacturing Systems章节是这么定义和描述它的"生产系统的关键方面通常是功能，特征，性能，和持续保持产品质量和病人安全所必须的生产工艺和系统的性能或特征。

欧盟GMP附录16药品放行责任人签发证书和放行批产品1.范围本GMP附录系欧共体（EC）或欧洲经济区（EEA）药品放行责任人（.）为药品生产企业的产品或出口产品签发药品证书和在放行产品的指南。

相关立法规定见欧共体法令2001/83/EC第51款或法令2001/82/EC第55款条。

本附录还包括如此一些特殊情形，即当一个产品不同的生产步骤或不同的测试不在同一处完成，或由不同的企业承担，和一批中间产品或一批待包装产品分为数批成品的情形。

另外，附录还包括欧盟与第三国无互认协议条件下，从第三国入口到EC/EEA药品的放行。

本指南也适用于临床实验用药品，相关法规的具体规定及其不同，参见GMP指南附录13。

本指南既没有对法规许诺的所有可能的方式都作详细的论述，也没有对官方查验机构依照法令2001/83/EC第11款和109及110放行某些血液和免疫产品进行讨论。

产品注册资料规定了批产品放行的大体要求。

本附录的内容不超越产品注册资料的要求。

2.原那么只有经药品放行责任人出具药品合格证明后，每批药品方可在欧共体及欧洲经济区（EC/EEA）销售或出口。

以这种方式放行药品的目的如下：（1）确保批产品投放市场前，产品已按注册要求、欧盟的GMP及指导方针或按互认协议第三国等效的GMP要求生产、查验和复核；（2）如需要对一批有缺点的产品进行调查，或召回一批产品时，保证能方便地查明放行该批产品的药品放行责任人及相关记录。

3.引言批产品的生产，包括质量操纵能够在不同的地址，由不同的企业完成，但每步操作都要按产品注册资料的要求、GMP及成员国的法律进行。

药品放行责任人在出具药品合格证书，放行产品前应考虑这些因素。

但是，从制药企业实际情形看，药品放行责任人通常不可能一个人深切到生产的每步操作，因此，他出具产品合格证明在必然程度上依托于其他人的建议和各类决定。

他应从个人把握的信息，或从他认可的质量体系中其他药品放行责任人对证量系统的确认，在保证这种信任有良好基础的条件下出具合格证明。