辐照灭菌的过程控制指南(美国医疗器械促进协会)AAMI TIR 29-2002
说明：文章内容仅供预览，部分内容可能不全。下载后的文档，内容与下面显示的完全一致。下载之前请确认下面内容是否您想要的，是否完整无缺。
AAMI TIR29:2002 技术信息报告 辐照灭菌过程控制指南 www.aami.org AAMI 美国医疗器械促进协会（Association for the Advancement of MEDICAL Instrumentation） AAMI 技术信息报告 AAMI TIR29:2002 第1页 总31页 辐照灭菌过程控制指南 Approved 16 July 2002 by 美国医疗器械促进协会 摘要: 关键词: 本技术信息报告增加了ANSI/AAMI/ISO 11137所界定的光子，电子束灭菌的剂量场的建立和规范，过程确认，和常规控制等辐射灭菌。尽管轫致辐射的要求相似，但在这项工作开始的时候缺乏关于轫致辐射装置的设计和运行的经验。所以轫致辐射不包括在此指南之内。 辐射剂量场, 过程确认, 日常加工,剂量确认 第2页 总31页 美国医疗器械促进协会技术信息报告 信息技术报告是美国医疗器械促进协会标准局的刊物，它是为特殊的医疗技术提供。 提交到信息技术报告的材料需要更多专家的意见，发表的信息也得是用的，因为很多行业都急切需要它。 信息技术报告与标准和操作规程建议，读者应该理解这些文件的不同之处。 标准和工业标准由正式的委员会通过收集所有正确的意见和观点，此过程由美国医疗器械促进协会标准局和美国国际标准机构完成。 信息技术报告作为一个标准审核的过程不是一样。但是，信息技术报告由技术委员会和美国医疗器械促进协会标准出版社发布。 另外一个不同的地方，尽管标准和信息技术报告都需要定期审查，一个标准必须经过重申，修改，或撤回，通常每五年或十年需要正式的被认可。对于信息技术报告来说，美国医疗器械促进协会和技术委员会达成一致，规定自出版日期五年后（作为一个周期）进行审查报告是否有用，检查信息是否切题和具有实用性，如果信息没有实用性了，此信息技术报告就被删掉。 信息技术报告肯发展，因为它比标准和操作规程建议能更好响应基础安全和性能问题。或者说因为达成共识是非常困难甚至不可能。信息技术报告与标准不同，它允许在技术问题上由不同的观点。 信息技术报告可以发展，因为它比标准和操作规程有更多的关于基础的安全和性能问题的反馈，或者因为达成一致非常困难甚至不可能。与标准不同，它允许在技术问题上包涵有各种不同观点。 注意： TIR（美国医疗器械促进协会信息技术报告）在任何时候可以被修改和撤回。因为它涉及到以各快速发展的领域或技术，读者应该注意以确保是否有更新更成熟的文件。 AAMI发展所有的标准，操作规程，技术信息报告和其他类型的技术文件时自愿的无偿的，他们的申请是个人的自由和这技术文件使用者的专业判断，有时，他们的这些技术文件可能被政府机构和权威采用，在这种情况下，采用机构负责执行其规则和条例。 被邀请技术信息报告的评论送到美国医疗器械促进协会AAMI, Attn: Standards Department, 1110 N. Glebe Road, Suite 220, Arlington, VA 22201-4795. 由美国医疗器械促进协会出版， Association for the Advancement of Medical Instrumentation 1110 N. Glebe Road, Suite 220 Arlington, VA 22201-4795 © 2002 by the Association for the Advancement of Medical Instrumentation All Rights Reserved Publication, reproduction, photocopying, storage, or transmission, electronically or otherwise, of all or any part of this document without the prior written permission of the Association for the Advancement of Medical Instrumentation is strictly prohibited by law. It is illegal under federal law (17 U.S.C. § 101, et seq.) to make copies of all or any part of this document (whether internally or externally) without the prior written permission of the Association for the Advancement of Medical Instrumentation. Violators risk legal action, including civil and criminal penalties, and damages of $100,000 per offense. For permission regarding the use of all or any part of this document, contact AAMI at 1110 N. Glebe Road, Suite 220, Arlington, VA 22201-4795. Phone: (703) 525-4890; Fax: (703) 525-1067. 第3页 总31页 Printed in the United States of America ISBN 1–57020–177–3 目录 页 协会代表................................................................................................................................v 简介................................................................................................................................................... viii 1 范围........................................................................................................................................................1 2 相关规范 .................................................................................................................................1 3 术语，定义 ...............................................................................................................................1 4 安装确认:辐射剂量场分布.....................................................................................2 4.1 简要 ..........................................................................................................................................2 4.2 珈玛 ..........................................................................................................................................2 4.2.1 均匀剂量场分布（Homogeneous dose maps）..............................................................................................2 4.2.2 附加剂量分布图研究...........................................................................................3 4.2.3 附加测试 Additional tests ................................................................................................................4 4.2.4 审查和分析数据Review and analysis of data............................................................................................4 4.3 电子束Electron beam................................................................................................................................5 4.3.1 均匀剂量场分布（Homogeneous dose maps）...............................................................................................5 4.3.2附加剂量分布图研究Additional dose map studies............................................................................................6 4.3.3附加测试Additional tests ................................................................................................................7 4.3.4审查和分析数据 Review and analysis of data............................................................................................7 5 过程确认Process qualification.................................................................................................................................7 5.1 简要 ..........................................................................................................................................7 5.2 珈玛Gamma ..........................................................................................................................................8 5.2.1 产品转载模式 Product loading pattern ...................................................................................................8 第4页 总31页 5.2.2 产品剂量场Product dose mapping.....................................................................................................8 5.2.3 审查和分析数据 Review and analysis of data............................................................................................9 5.2.4 选择日常监测点位Selection of routine monitoring positions.........................................................................9 5.2.5 文件要求Documentation requirements ..........................................................................................9 5.3 电子束 Electron beam..............................................................................................................................10 5.3.1 产品转载模式Product loading pattern .................................................................................................10 5.3.2 产品计量场 Product dose mapping...................................................................................................10 5.3.3审查和分析数据 Review and analysis of data..........................................................................................11 5.3.4 选择日常监测点位Selection of routine monitoring position.........................................................................11 5.3.5 文件要求 Documentation requirements ........................................................................................11 6 例行监测和控制Routine monitoring and control........................................................................................12 6.1 简述 General ..............................................................................................................................12 6.2 产品验收 Receipt of product..........................................................................................................12 6.3 迦玛辐射计划 Scheduling of gamma irradiators ........................................................................12 6.3.1 辐照装置的特点Irradiator characteristics ........................................................................12 6.3.2 产品的特性 Product specifications....................................................................................................12 6.3.3 单一产品辐照方案 Scheduling of single product runs ....................................................................13 6.3.4 多种产品辐照方案 Scheduling of multiple product runs ...............................................................13 6.4 电子加速器辐射计划 Scheduling of electron beam irradiators ......................................................................................14 6.5 产品的装载Loading of product .......................................................................................................................14 6.6 产品辐照 Processing of product ..................................................................................................................14 6.6.1 介绍 Introduction....................................................................................................................14 6.6.2 迦玛 Gamma..........................................................................................................................14 6.6.3 电子束 Electron beam ...............................................................................................................15 6.7 产品的卸载 Unloading of product....................................................................................................................16 6.8 产品的放行 Release of product.......................................................................................................................16 6.9 产品的运输 Shipment of product.....................................................................................................................16 7 数学模型 Mathematical modeling...........................................................................................................................16 7.1 简要 General ........................................................................................................................................16 7.2 模型的类型 Types of models...........................................................................................................................17 第5页 总31页 7.2.1 介绍 Introduction....................................................................................................................17 7.2.2 点核方法Point Kernel method ......................................................................................................17 7.2.3 蒙特卡罗方法 Monte Carlo method .............................................................................................17 7.3 模型的应用Use of models.......................................................................................................................17 7.3.1 辐照器的设计 Design of irradiators ......................................................................................................17 7.3.2 迦玛辐照器的操作 Operation of gamma irradiators.....................................................................................17 7.3.3 电子加速器辐照的操作Operation of electron beam irradiators .................................................................18 8 过程控制的日常评估Routine evaluation of process quality.........................................................................................18 8.1简述 General ........................................................................................................................................18 8.2 收集和审核数据 Collection and review of data....................................................................................18 9 有效的过程的维持 Maintenance of process effectiveness.....................................................................................19 9.1 简述 General ........................................................................................................................................19 9.2 校准 Calibration....................................................................................................................................19 9.3 辐照装置的安装确认 Irradiator requalification ................................................................................19 9.3.1 介绍 Introduction....................................................................................................................19 9.3.2 程序Requalification documentation requirements ................................................................19 9.4预防性检修和辐照装置性能改变的控制Preventive maintenance and irradiator change control...........................21 9.4.1 预防性检修Preventive maintenance ................................................................................................21 9.4.2 辐照装置性能改变的控制Irradiator change control................................................................................................22 附录 A 日常监测剂量测量的不确定度 Measurement uncertainty in routine monitoring of dose.........................................................................23 B 文献Bibliography............................................................................................................................................28 Tables 1 Gamma irradiator requalification requirements.......................................................................................20 2 Electron 第6页 总31页 beam irradiator requalification requirements ............................................................................21 A.1 产品1剂量分布图数据 Dose map data—Procedure 1 .....................................................................................................24 A.2 产品2剂量分布图数据 Dose map data—Procedure 2 ...................................................................................................25 A.3 最大最小剂量调整因子 Adjustment factors for minimum and maximum dose.....................................................................26 A.4最大剂量的调整因子 Adjustment factors for maximum dose ..........................................................................................27 数据1 方格坐标尺寸的确认 Figures 1 Qualification grid dimensions................................................................................5 2 剂量率的测量和预期剂量 Ratio of measured dose vs. expected dose................................................................................19 Committee representation 介绍 Introduction 这份技术报告致力于γ或电子束辐射的过程控制，是一个辐射灭菌加工中剂量传递给产品重要的部分。加工参数必须建立，然后根据过程控制方法确保得到剂量的可靠性，精确度和重复性的方法，这份技术报告为建立加工参数包括辐射剂量图，加工确认，日常加工和维修确认提供参考。由于放射源的不同，过程控制方法可能不同，所以伽玛和电子束的过程控制也分别在本文中讲述。 对于伽玛灭菌，通常是钴-60，其可靠性和连续性众所周知由放射性核素的衰变率来确定。确保源与货箱处于正确的位置，小范围标记，因为源的衰变，设定的时间需要递增，这样持续加工的产品才能得到同样的剂量。如果只有单一的产品，唯一不同的是剂量测量，这些跟产品位置的变化和剂量测量的不确定因素。 存在几个不同级别伽玛辐射装置，同一批次的辐射装置一次只能加工单一的产品，这个首要条件比较接近地满足，在综合通道的辐射装置以连续辐照为基础辐照不同的产品，源与个别货箱之间的产品的改变能影响剂量的传递，当计划产品加工和过程控制的需考虑货箱之间相互影响定量的条件 There are several different classes of gamma irradiators. In batch irradiators that only process a single product at a time, the preceding conditions are closely achieved. In multi-pass irradiators that irradiate different products on a continuous basis, changes in intervening products between the source and individual containers can affect dose delivery. The effects of intervening products on dosing conditions should be taken into account when scheduling products and process control. 对于电子束灭菌，控制和监测束流传动装置和加工参数就可以确保加工的可靠性和一致性，只要产品的密度，包装和方向没改变，一旦参数建立产品加工时输入指定的参数就能得到指定的剂量。用电子束灭菌时，当辐照不同的产品是相对的比较简单，两个相邻的产品变化极小。 伽玛或电子束灭菌的加工参数必需按安装确认或者加工确认的剂量场测试来数的确定，日常剂量测量数据可以分析用标准统计加工控制技术，结果用来监视和维持加工控制。另外，用数学模型计算可以被用来建立剂量分布和产品密度变化的结果和分布。剂量计算结果能与实验测量的剂量去提供更完整的描述辐照装置的运行的特点，加工控制的合理的管理程序能确保剂量的连续地和精确的传递到产品，提供剂量确认和产品参数的可能性。 第7页 总31页 AAMI Technical Information Report AAMI TIR29:2002 Guide for process control in radiation sterilization 辐射灭菌过程控制导则 1 Scope 范围 本文为伽玛和电子束灭菌（在ANSI/AAMI/ISO 11137定义过的）建立和满足辐照剂量图，加工确认和日常加工要求提供指导，X射线装置也有相似的要求，所以在本报告中没有专门指出。 2 Normative reference 相关标准 The following normative document contains provisions that, through reference in this text, constitute provisions of this TIR. Subsequent amendments （修改）to or revisions （修订）of this publication do not apply. However, parties to agreements based on this TIR are encouraged to investigate the possibility of applying the most recent edition. The Association for the Advancement of Medical Instrumentation maintains a register of currently valid International Standards. ANSI/AAMI/ISO 11137:1994, Sterilization of health care products—Requirements for validation and routine control— Radiation sterilization. 3 Terms and definitions 术语和定义 3.1 base cycle time 基本主控时间: Cycle time selected for processing groups of products. 3.2 center loading 中心装载方式: Method of loading the irradiation container in a manner that centers the product in the irradiation container. 3.3 compensating dummy 模拟产品 : Simulated product used during routine production runs in process loads that contain less product than specified in the loading pattern or simulated product used at the beginning or end of a production run to compensate for absence of product. 3.4 dose zone 产品剂量: Volume within an irradiation container that receives doses with statistically equivalent values. 3.5 effective density 装载密度: Bulk density multiplied by the ratio of product width to container width where width is the dimension perpendicular to the source of radiation. 3.6 homogeneous dose map study 模拟产品剂量场研究: Dose map study performed during irradiator qualification or requalification where only materials of the same density and configuration （外形）are irradiated without changes to cycle time or conveyor speed during execution of each test. 3.7 irradiation container 辐照容器: Carrier, tote, cart, tray, or other container in which product is loaded to traverse the radiation field during processing. In some instances, this may be the actual product package. 3.8 loading pattern 装载方式 : Geometric configuration of the product in the irradiation container. 3.9 mathematical modeling 数学模型 : Use of mathematical methods to determine dose distribution. 3.10 process load : Volume of material with a specified loading pattern irradiated as a single entity. 3.11 product grid 剂量场坐标: Dosimeter placement grid used to determine routine dosimeter monitoring locations. 3.12 product path 辐照路径: Path in which the product transverses the cell during the irradiation process. 第8页 总31页 3.13 qualification dose map grid 坐标确认 : Three-dimensional （空间的）dosimeter placement grid where dosimeter locations are placed in an array to thoroughly examine the potential zones of minimum and maximum dose during irradiator qualification. 3.14 scaling of dose（剂量关系）: Direct relationship between dose and processing parameters such as beam current and conveyor speed for electron beam and source activity and cycle time for gamma. 3.15 statistical equivalent: Doses with magnitudes （量值 振幅）that differ by less than the statistical uncertainty in the measurement process. 1 transit dose: Amount of dose product may receive while the source mechanism is in motion. 2 4 Installation qualification: Irradiator dose mapping 3 General 在进行剂量场测试之前，一个已知精确度和准确度水平的剂量测量系统应该建立入ANSI/AAMI/ISO 11137，当完成设备文件，设备测试和设备校准后，这要与 ANSI/AAMI/ISO 11137一致，做一系列的剂量场分布测试来确定不均匀度，分布和剂量的重复性。 对于伽玛辐照，执行如下： a) 进行同类型的剂量场分布研究， b) 确定剂量场坐标 c) 进行附加剂量分布图研究，研究运行中不同产品过渡区的产品间的影响，传递剂量，不满载情况，及中心转载方式。 d) 测量剂量 e) 复核和分析数据 对于电子束，执行如下： a) b) c) d) 量 e) f) 测量剂量 分析数据 进行同类产品的剂量图分布研究， 确定剂量确认分布图的坐标 通过监测无差异和电子束深度剂量研究电子束的特性 进行附加剂量分布图测试，检查边缘效应，不满载情况，加工中断和通过电子束前的数 第9页 总31页 4.2 伽玛 4.2.1 相似的剂量分布图 在不均匀度，分布，剂量传递重复性和剂量分布图研究等方面描述辐照装置的特性，用足够数量的相似的材料满载进行辐照，相似剂量分布图测试需按每个产品轨道实施并用到日常加工中。 To characterize the irradiator with respect to the magnitude, distribution, and reproducibility of dose delivery, dose map studies using homogeneous material, in sufficient quantities to simulate a full irradiator, are performed. The homogeneous dose mapping studies should be performed for each product path to be used for routine processing. 4.2.1.1 确定坐标 剂量计应该冲分地布在三维空间上来确定最大最小剂量和得到剂量分布情况，剂量计的数量和它们分布是根据空间分辨率得到的，从数学模型或从相似的设计的辐照装置剂量测量数据得到的剂量分布规律可以选来用作坐标，或者从系统设计和处理参数范围来选择坐标。 4.2.1.2 材料的选择 在做剂量场是应该用密度相似的材料，其范围是在曾用到过的产品密度的范围内，通常情况下，代表密度的最小最大，仔细审查后，如果合适，取中间的密度，通常用来做剂量场分布的材料有泡沫聚苯乙烯薄板(approximately 0.01 g/cm –0.03 g/cm)，波纹板(0.13 g/cm – 0.19 g/cm),天花板(0.25 g/cm – 0.27 g/cm),软胶333333合板(0.40 g/cm – 0.60 g/cm)。这对用产品作辐射装置剂量图测试是有利的，被选材料上应能够布置整个辐照容器里剂量分布的剂量计。 4.2.1.3 辐照容器 33用于均匀剂量图研究的辐照容器应该按设计的容积填满，用于均匀剂量辐场测试的照容器需要考虑的重量限制。 在进行均匀研究，足够的照射容器应装满均质材料来模拟一个满载的系统。这通常可以通过填充传递大部分剂量的辐照容器来完成（例如，产品路径直接毗邻源架的）。货柜数量取决于产品的道路。 4.2.1.4 剂量测量 剂量计应置于辐射容器里的由确定剂量图坐标的位置上。该剂量计应将在辐射容器里的均质材料包围（即照射运行中心的部分）。剂量图数据进行重复性测试和数据的统计分析，至少三个货柜的应为布上剂量计用于每个密度的研究。 4.2.1.5 加工条件 均匀剂量图测试运行时没有辐照中断情况，修改主控时间，或者在辐照时的其它中断。所有不寻常的事都需记录和调查，如果任何事件导致无效，整个或部分受影响的试验应重做。 4.2.1.6数据分析 均匀剂量场测试图的结果统计分析应该确定最大、最小剂量的区域以及中间剂量的区域，用这些信息选取最大和最小剂量区域和确定最大和最小剂量率，同样，这也可以为其他的安装确认的剂量场分布图测试的剂量图网格坐标的选取提供参考。（过渡和部分装载剂量分布图） 4.2.2 附加剂量分布图测试 Additional dose map studies 4.2.2.1 过渡剂量分布图 Transition dose maps 如果在同一主控时间照射不同密度的产品，应审查均匀度和剂量分布的影响。这可以按加工顺序处理两个不同的产品密度的产品。要确定产品之间的均匀度和剂量分布的影响，最后一个货柜的第一种产品和第一个货柜的第二种产品的密度应该进行剂量分布图测33试。例如，12个货柜的0.02 g/cm3的产品接着是12个0.15 g/cm3的产品，最后一个货柜的是0.02 g/cm和第一个货柜的是0.15 g/cm 的产品应该进行剂量分布图测试。这种剂量分布图数据应该与相同产品密度剂量分布图数据进行比较。空货柜对均匀度和剂量分布的影响 可以通过空货柜之前或之后的货柜产品的剂量场来确定，当产品引进到一个空货柜或清出货柜，这将提供剂量的信息。剂量分布图网格坐标可以是充分确认剂量分布图网格坐标或剂量分布点。包括因不同产品衰减特性可增加布点。 第10页 总31页 4.2.2.2 部分装载 Partially filled irradiation containers 部分装载比满载可能接受到更高的剂量，对高密度的部分装载模式的最大剂量影响可能更明显，这些货柜的剂量分布图可提供均匀度和剂量分布的信息，最大密度的产品应该用于均匀性剂量分布图测试的研究，同接近的在辐照的部分装载货柜的满载的货柜一样， 剂量计应该布置在部分装载的最高的区域，（Dosimeters should be placed at potential maximum dose zones in the partially filled irradiation containers as well as in full irradiation containers adjacent to the partially filled irradiation containers.）在日常加工条件下，部分装载的货柜应该分布在满载的货柜之间，在循环中，其数量和分布取决于辐照装备的设计。 4.2.2.3 中心装载 Center loading 为满足最大和最小剂量，产品可能需强加一些限制，有必要的可能减少产品的装载的宽度，一般规定装载时把产品装在货柜中心位置，货柜中心装载的剂量均匀度和分布需检查（examined）。 用来做均匀度和剂量分布试验的模拟产品可以用来做这个实验。 中心装载试验的剂量分布图的坐标网格的选择应包括安装确认剂量分布图的剂量计的布置或者由之前剂量场测试图的等同的最大或最小值来确定。三个中心装载的货柜中的一个最小值区域应该布置，从而在一个运行循环里满载的货柜的产品装满货柜设计尺寸的最大限度，其装载密度与之前中心装载的密度相同，运行应该跟满载系统一样。 4.2.2.4 静态加工处理 Off-carrier processing Off-carrier processing（静态加工）可能用不同方法加工，包括特别的传送系统传送产品进出辐照室，或者产品可以人工放置在辐照室固定位置，产品用转盘转动，产品人工控制加工控制台都可以用来提高剂量的无差异性，加工的产品正方形体积的限制应该被定义，一旦定义，剂量测试图应该按4.2.1定义的执行。 应该考虑到卸载处理与装载处理的剂量测量和环境影响，例如，剂量率或温度可能不同，这可能影响到剂量测量系统的实施。 4.2.3 附加测试 Additional tests 4.2.3.1 运输剂量 Transit dose 从源架从安全储存位置升源到辐照位或从辐照位降源到储存位过程，产品继续接受到剂量直到源板完全到达位置。在伽玛辐射正常加工事源的移动使产品接受了额外的剂量应该被考虑。这种剂量的增加跟源架移动时产品的位置有关，通常只考虑到最靠近源板的产品。 附加剂量测试可以用均匀度剂量场测试的产品或空货柜，如果是空货柜，剂量计布置在辐照容器的壁上。 在最高和最低剂量的地方布置剂量计，布在最高近源板的垂直方向的面上。 保证传递剂量在剂量系统的校准范围之内，源升起和降下一定时间，通过测量剂量分布最靠近源的货柜剂量计来获得吸收剂量。 4.2.3.2 剂量范围 Scaling of dose 在实际加工中在一个循环里剂量测试图是不同的，日常加工的主控时间的设置可根据剂量图数据的范围来确定，当产品进出辐照装置提供的吸收剂量和当从一个辐照位置到另一个时的吸收剂量对总剂量是无意义的。 4.2.4 复核和分析数据 Review and analysis of data 辐照装置的剂量分布图的数据用来确定一个货箱里均匀度和剂量的重复性和最大和最小剂量的位置，如果可行，这些数据也可为常规剂量点和最大、最小点关系提供信息。 指定位置剂量的测量或剂量分布图的区域不同，因为测量过程的不确定度。重复测量多个辐照货箱（例如 至少3个）可以被用来计算平均剂量在每个剂量分布图的位置和给出标准偏差和平均值，如果每次剂量分布图的剂量平均值的可变性估计是相似的，剂量分布图可以一起得出标准偏差的单一值，这些数可以用统计计算平均剂量来计算最小值来检测差异。不同的剂量比最低检测值多统计上是相当的，在4.2中的从各种剂量场分布图获得的数据应该复核，结果用来选择剂量分布图的坐标网格和在实际产品装载描述剂量分布。作为从产品网格坐标上选择或省略可能的最小或最大剂量点的理由应该备有证明文件。 4.3 Electron beam 4.3.1 Homogeneous dose maps Dose map studies of an irradiation container filled with homogeneous product should be performed to characterize the irradiator with respect to the magnitude, distribution, and reproducibility of dose delivery. The first aspect of this characterization is mapping the surface of the irradiation container (i.e., the plane of the irradiation container closest to the scan horn). This ensures that the dose at all locations of the irradiation container is consistent. The second aspect of irradiator dose mapping is 第11页 总31页 the measurement of dose as a function of distance from the surface of the irradiation container. This is referred to as depth-dose analysis and, in a homogeneous material, is a function of the angle of the incident beam, the density of the material being processed, and the consistency of the beam energy spectrum. Material interfaces, including the effects of the edge of an irradiation container, can have significant effects on the distribution of dose. Understanding the effect of surfaces and edges during irradiator dose mapping exercises may be valuable in process qualification dose maps. Edge effects are evaluated by analyzing irradiator container dose map data at qualification grid locations near the edge of the container. 4.3.1.1 Determination of the irradiation container qualification grid Three dimensions of the qualification grid should be defined and evaluated during the irradiator dose map. As shown in Figure 1, these dimensions include: a) the direction of conveyor travel (X-direction); b) the direction the beam is being scanned (Y-direction); and c) the direction of beam travel (Z-direction). Figure 1—Qualification grid dimensions 4.3.1.2 Selection of materials Dosimeters for dose uniformity studies should be mounted on a fixture with homogeneous backing material such as a sheet of ethafoam, cardboard, or plastic. 4.3.1.3 Dose mapping in the X- and Y-directions The uniformity in the dose received over the surface area of the product container should be evaluated. A uniform dose should be maintained in the X- and Y-directions (i.e., the direction of conveyor travel and the direction that the beam is being scanned). Surface dose uniformity studies should be carried out using dosimeters in both the X- and Y-directions. The dosimeters may be either continuous dosimeter film strips or discreet dosimeters placed adjacent to each other to form strips. The dosimeter resolution should be sufficient to ensure that there are no gaps in dose delivery to the surface. This confirms that combination of beam spot size, pulse width, pulse repetition rate, and scan frequency is adequate to provide continuous dose coverage. Typically, scan uniformity measurements are performed for the plane of the product container closest to the scan horn. Data should be collected at the extremes of the range of operating conditions to be employed during routine processing, for conveyor speed, beam current, and beam scan. 4.3.1.4 Dose mapping in the Z-direction Doses should be measured on the surfaces of the homogeneous materials at several depths throughout the irradiation container volume. Dosimeters should be placed in a defined grid pattern at each depth, including the corners and centers. A sufficient number of irradiation containers should be mapped to confirm reproducibility of data. All product paths (e.g., single and double pass) to be used during routine production should be examined. 第12页 总31页 The irradiator dose map profile provides confirmation of the consistency of beam penetration throughout the irradiation container. It is impacted by the angle of the incident beam relative to the irradiator container, the density of the homogeneous material being processed, and the consistency of beam energy. Several factors affect the energy of an electron beam, including the accelerating potential of the accelerator, the distance the beam travels through the air prior to reaching the product, and the design and construction of the exit window, as well as the use of scattering foils. NOTE—The depth-dose analysis is only a secondary confirmation of beam energy. The primary measurement and determination of the beam energy is performed during the accelerator-testing portion of the installation qualification. 4.3.2 Additional dose map studies 4.3.2.1 Partial load Partial irradiator container loads are common in routine product processing, and should be addressed during process qualification. Certain types of partial loads may be addressed during irradiator dose mapping, and the resulting dose map data used in the process qualification of homogeneous products. In the direction of conveyor travel, partial containers are typically equivalent to full loads if the irradiator edge effects are taken into account (e.g., no side panels or movable side panels are used to provide a constant edge effect). In the direction of beam scan, uniformity of dose as a function of beam scan should be evaluated and documented. The edge effects in this direction also should be examined. In the direction of beam travel, the depth-dose uniformity should be addressed. Except for extremely homogeneous product, it is difficult to apply the irradiator dose map data to specific process qualifications. 4.3.2.2 Single and double pass More efficient throughputs and lower maximum to minimum dose ratios may be achieved by processing irradiation containers from two sides. This can be accomplished by passing the irradiation container in front of the beam with one side facing the beam, rotating the product such that the other side faces the beam, and then passing the irradiation container in front of the beam a second time. Dose delivered to the product from this double pass process is a superposition of dose received from each pass in front of the beam. The effects of double pass irradiation should be evaluated. This may be accomplished by performing additional dose map studies or, with justification, superimposing single-sided irradiator dose map data. 4.3.3 Additional tests 4.3.3.1 Process interruption The impact of a process interruption event (a system shutdown and restart while processing is in progress) on dose delivery should be characterized and documented. Process interruption characterization data collected during irradiator dose mapping can be used to evaluate the effect of process interruptions during routine production. Examples of process interruptions include conveyor faults, beam faults, safety system faults, and control system faults. The critical factors that will determine the magnitude of dose delivery variation due to process interruption are the dynamics of beam shutdown and restart in relation to conveyor system shutdown and restart. The source of the system shutdown may impact these dynamics. For example, a shutdown caused by a beam fault may have different dynamics than a shutdown from a conveyor fault. There are two categories of process interruptions that should be considered. The first is an interrupt initiated by a system fault (e.g., a safety fault, cooling system fault, or power fault) that triggers the shutdown of both the beam and the conveyor system. The second category of interrupt results from a mechanical fault of the conveyor, which triggers the beam and conveyor system to shut down. In both cases, relationships between the time required for the beam and the conveyor to stop and restart should be characterized and understood. For example, with a system fault, the distance the irradiator container travels after the beam is de-energized and the time required for the irradiator container to begin travel again once the system is re-energized should be determined. The impact of these dynamics on dose delivered to product in an irradiation container in front of the beam during such an incident should be characterized and documented. Dose variation typically is most severe at the irradiator container surface closest to the scan horn. Therefore, this surface should be used for process interruption studies unless other depths from the container surface are justified. Data should be collected at the extremes of the range of operating conditions that can be impacted by processing interruptions (e.g., at the minimum and maximum of process conveyor speeds). 4.3.3.2 Scaling of dose Dose delivered to product may be changed by varying conveyor or beam parameters such as the conveyor speed, beam current, pulse length, pulse repetition rate, or scan width. The parameters that can be varied depend on the type of accelerator and the design features. Doses from irradiator dose mapping studies may be different from doses selected during routine processing of product. In the event that parameters used during the irradiator dose mapping differ from those to be used during routine processing, testing should be performed to determine the relationship between the dose map parameters and those to be used for routine processing. The parameters for routine processing may be determined from direct scaling of the dose map data, provided the beam spot size and beam scan frequency are sufficient to provide continuous dose coverage and scan width is not 第13页 总31页 varied. 4.3.4 Review and analysis of data The irradiator dose map data is used to evaluate the uniformity of dose delivered to the surface of the irradiation container, as well as distribution of dose within the homogeneous product. Dose map data from multiple containers also is used to assess the reproducibility of dose delivery. Statistical analysis of the data as discussed in 4.2.4 may be used to determine dose locations that are statistically equivalent and serve as a guide in selection of dose map grids in process qualification studies. 5 加工确认 Process qualification 5.1 简介 General 加工确认是辐照装置里处理实际产品过程，每个产品的装载模式应该建立和在辐照加工过程中的维持，对于电子束辐照装置，电子束照产品的方向也应该考虑，这考虑伽玛加工不同产品的情况，对于每个装置的路径及装载模式，剂量分布图测试应该找出最低最高的剂量值，对于伽马装置产品的装载应试相同的分布特征（例如 密度 装载方式），这些用于剂量确认的分布图符合加工确认的产品剂量分布图要求。对于医疗产品，确定最大最小剂量的要求详见ANSI/AAMI/ISO 11137. 5.2 伽玛 Gamma 5.2.1 产品装载模式 Product loading pattern 选择一个新产品装载模式前纸盒的重量尺寸应该测量代表性样品来确定，从而计算产品密度。根据这些和效率的因素选择最优的装载模式，例如，这些因素包括货柜重量的限制，装载的难度，剂量差异的要求或者与其他产品一起辐照的兼容性，装载模式容许变化的有部分装载最少装的数量，和用于填满的补偿性产品任何其他要求，都应该文件化。 5.2.2 产品剂量分布图 Product dose mapping 剂量分布图完成是为描述充分数量的辐照容器之间的剂量可变性，特别是期望的最大最小剂量点和日常加工监控点，剂量分布图试验应根据需处理产品种类的密度范围的限制来完成，不考虑剂量大小。每个产品通过辐照装置加工辐照应做剂量场分布图。 5.2.2.1 加工族 Process families 相似剂量的不同产品和吸收剂量特征（例如 密度 装载模式）可以划分成族 来减少剂量分布图测试的要求，族的数量要根据产品的加工特点，首先产品的估计可以从辐照剂量分布图数据中得到，将可能把产品划分为几个族，一般来说，对于用伽玛作为日常加工，族是基于产品的要求，一个族的产品应该由这些有着相同的主控时间而不超过剂量限制的任何产品， 族之间的简化转换时，族应该被选择以至一个族能与下个族一起加工而不超过最大最小剂量值的范围，每个族的典型产品应该做剂量分布图试验。 5.2.2.2 辐照循环的混合密度 Mixed density within the irradiator 不同密度的产品一起辐照，剂量均匀度的影响和对相关产品剂量分布的应该确定，这些是试验在辐照装置确认就已经完成，如果这个试验没做，辐照货柜在两种产品过渡的地方应该进行剂量分布图测试（例如 运行中的第一个或最后一个货柜） 5.2.2.3 同个货柜里的混合密度 Mixed density within the irradiation container 如果不同密度的产品混装进同一个货柜加工，剂量场测试应该按该产品日常加工剂量计位置剂量计来完成 。这应该通过剂量场测试来完成，覆盖一定密度范围内货柜混装，外形（装的方式）对最大最小剂量值由很大影响 5.2.2.4 杂乱的 Heterogeneous 对于大多数医疗产品，方向和在纸盒里位置不用心剂量的均匀度和剂量分布，然而，对象金属植入物和水瓶等高密度的产品，在产品内部位置的剂量分布图是由必要的，如果密度大物品在纸盒中，可能的话有必要在纸盒中布置剂量计进行剂量场试验，剂量计的数量和位置取决于物品的类型和在报纸带内的位置。 5.2.2.5 货柜部分装载 Partially filled irradiation containers 在部分装载的货柜里的最大和最小剂量点可能与满载的不同，这些不同可以填模拟产品满载加工消除，或者增加屏蔽比如金属或硬纸板的，每个方法可能要求增加剂量及来确定最高和最低点。 5.2.2.6 静态加工 Off-carrier processing 剂量分布图是用来确定最大最小剂量点和日常监控点位，产品装入纸盒里进行加工要求使用最小的剂量计。在这个例子中，有相同剂量场分布图的任何产品其加工是一样的。要使产品的纸盒在不同条件下剂量分布图的网格坐标合理，从而为日常静态加工减少使第14页 总31页 用的剂量计提供证明，剂量场分布图的实验应该在所有加工产品的密度范围内，不考虑剂量，静态辐照剂量分布图应该包括对各种尺寸密度轮换或倒置计划，对描述无标准路径的网格坐标和最小剂量监测点，和建立日常加工控制的处理能力 5.2.3 审核和分析数据 Review and analysis of data 加工确认研究的结果是用于建立装载方式和选择日常加工监测点位，辐照器的剂量分布分布图和统计分析的数据可能用来指导把相似装载模式的产品划分为一个剂量分布图的族。剂量分布图的结果用来确定关于日常加工剂量监测相关位置应用的判断因素，分析数据重要一部分是建立测量剂量的不确定度和用这些信息选加工参数来确保（高水平的可信度）所有剂量的测量是可接受的，例子见附件A。 5.2.4 选择日常监测点位 Selection of routine monitoring positions 应该从剂量分布图来确定日常监测点位，其选择方法有以下三种： a) 最大和最小吸收剂量的位置 b) 根据统计地相当于最小和最大剂量确定剂量点位，任何统计的相当的位置可以被选择。 注：—— 剂量分布图常产生两个甚至更多近似的相同的剂量值剂量区域或剂量监测点，例如，剂量分布图数据的统计分析可以用来确定是否不同的剂量值有意义或是结果在测量中统计变异，对统计相当的剂量值选择日常加工最大最小剂量区，包括任何其他点位， c) 相关点可能选择为了原因易用性；剂量计布置可重复性；实际最高和最低剂量点的偏离，相关监测点位是根据与实际最小和最大剂量的关系是已知的，这些关系一般叫做调整因子（AF），最小剂量AF如： AFmin = Dref ÷ Dmin 最大剂量的调整因子 AFmax = Dref ÷ Dmax 注: Dref = 相关剂量 reference dose Dmin = 最小剂量 minimum dose Dmax = 最大剂量 maximum dose 一旦调整因子，测量的相关剂量点和调整因子计算和报告产品最大最小剂量，详见附录A 5.2.5 程序化要求 Documentation requirements 加工确认程序化研究包括： a) 每个相关产品或产品族的剂量分布图数据结果; b) 剂量分布图数据研究； c) 产品路径; d) 装载方式包括纸盒数量其在每个托箱的结构r; e) 产品货柜的重量 密度 尺寸 f) 用于产品中心装载的材料或辐照容器的隔板， 5.3 Electron beam 5.3.1 Product loading pattern A loading pattern should be established for each product type. This loading pattern should include a description of the orientation of the product within the package material and secondary packaging, as well as a description of the product orientation to the sterilization process. A typical way of defining the orientation to the sterilization process is by using the direction of the conveyor travel (the X-direction), the beam scan (the Y-direction), and the direction of the beam travel (the Z-direction). Prior to selection of a loading pattern for a new product, the carton weight and size should be confirmed by measurement of representative samples, and product density should be determined. Several factors affect selection of the loading pattern. These 第15页 总31页 (方程 2) (方程1) factors may include but are not limited to: a) maximum depth of penetration of the electrons in the Z-direction (results of the depth dose studies performed during the installation qualification or empirical relationships may provide guidance relative to this thickness); b) product and packaging materials; c) number of product units per shelf pack; d) number of shelf packs per shipper; e) number of “devices” per packaged unit; f) orientation of materials within the shipper; g) dimensions, mass, and density of shipper, product, packaging, shelf packs, and devices; h) product quantity and orientation of the product units within the shipper; and i) product family groupings. 5.3.2 Product dose mapping Dose mapping should be carried out for representative irradiation containers sufficient in number to determine the variability of dose between representative containers, particularly at the expected maximum and minimum dose zones and routine monitoring position. Dose mapping exercises should be carried out at the limits of the density ranges of product categories to be processed, irrespective of dose. To facilitate measurements and observations, it may be appropriate to cut or section the shipping container, product, or packaging materials, and to use photographs. Permission of the product manufacturer should be obtained prior to initiating any such action. 5.3.2.1 Process families For electron beam irradiation, each product typically is dose mapped. However, to reduce the amount of dose mapping required, product may be grouped into process families. Grouping of products into process families is only appropriate if the product, packaging, and loading pattern are equivalent from a density perspective. The following should be considered: a) orientation of product in both the shipping container and inner containers; b) density and distribution of mass; c) size and shape of package; and d) item count and distribution of product units within the shipping container. Based on the dose map results, products may then be grouped for processing under the same conditions. 5.3.2.2 Dosimeter placement Product units should be reviewed for areas that might result in local dose gradients. This may be due to localized heterogeneities within the product that could result in enhanced or diminished dose due to shielding or scattering effects. This can result in dose gradients within a small volume. More extensive dosimetry measurements should be made in these areas. Examples include material heterogeneity (e.g., metal vs. plastic) or randomized product geometry (e.g., plastic cylinders randomly situated in a carton). Historical data, literature-based references, and user knowledge may all be employed to aid in the determination of dosimeter placements for product dose mapping using dosimeters. The location of dosimeters should be documented. 5.3.3 Review and analysis of data Results of the product dose maps should be used to: a) select routine monitoring location(s) which may be on the surface of the irradiation container or at a reference location; b) determine a statistically based relationship between dose at a reference location and the minimum and maximum doses in the product; and c) define dose specification for the routine monitoring location(s), if used. The data should be analyzed to ensure that minimum and maximum product specifications will be achieved. Due to the sensitivity of dose to location of product units within the irradiation container and high dose gradients that often exist in 第16页 总31页 heterogeneous products irradiated by electron beams, uncertainty in the dose measurement process should be taken into account when setting process parameters. Examples are given in annex A. 5.3.4 Selection of routine monitoring position Routine monitoring positions should be determined from the dose map data. The minimum or maximum dose location may be chosen for monitoring dose during routine processing or, alternatively, a reference location selected for ease and reproducibility of dosimeter placement may be used. The reference location may be on the surface of the package or a position located off the product (e.g., dosimeter holder affixed to an irradiation container or a standalone dosimeter processed next to the irradiation container). The relationship between the actual minimum and maximum doses to the reference position must be known. The AF for minimum dose is given by AFmin = Dref ÷ Dmin (Equation 3) and the adjustment factor for maximum dose is given by AFmax = Dref ÷ Dmax (Equation 4) where Dref = reference dose Dmin = minimum dose Dmax = maximum dose Once established, adjustment factors can then be used to calculate and report the minimum and maximum dose in the product by applying these adjustment factors to a dose measurement at the reference location. Examples are given in annex A. 5.3.5 Documentation requirements Documentation of the process qualification study should include: a) the results of dose map data as it relates to each product or group of products; b) the date the dose map study was performed; c) the product path; d) the loading pattern, including number of cartons and their configuration per irradiation container; e) product container weight, dimensions, and density; f) type of materials used to center load the product or shield the irradiation container; and g) machine settings such as voltage, beam current, and scan width. 6 Routine 监测与控制 monitoring and control 6.1 简要 General 日常加工控制有助于确保产品按ANSI/AAMI/ISO 11137要求加工。日常加工工艺的的加工控制包括辐照器里的产品合适入库 调度 产品的装载 辐照 剂量监测 产品卸载和放行 产品的运输。对于这些项其中的一些，这些要素一般对于伽玛和电子束都需要考虑到，伽玛 和电子束的其他项加工要素是具有独特性的。 6.2 产品的验收 Receipt of product 在产品装入辐照器前，要按照书面程序核实产品的批次，加工说明书，产品的数量 包括样品数和损坏的数量， 6.3 伽玛辐照调度 Scheduling of gamma irradiators 产品运行调度要求了解辐照器的剂量传递的特性和物理特性及描述产品辐照条件，这些信息用于选取主控时间，如果不止一种产品辐照时产品通过辐照器是否允许，产品的分组按顺序处理。另外，这些信息用来确定产品是否需要特别的加工条件满足最小剂量，剂量范围，产品的重量和密度或允许的辐照完成时间 6.3.1 辐照器的特性 Irradiator characteristics 这些信息从安装确认研究 再确认研究 辐照器的物理属性 中得到。 包括： a) 辐照容器的内部尺寸 internal dimensions of the irradiation container; b) 产品通过系统的流畅性 available flows of product through the system; c) 剂量率和剂量体系的各环节 dose rates and partition of dose in various segments of the system; d) 剂量无变异作为产品密度和单位产品的尺寸的函数 dose uniformity as a function of product density and size of product unit; 第17页 总31页 e) 主控时间与产品的传递剂量的关系relationships governing process cycle time and dose delivered to product; and f) 系统限制的重量 weight constraints of the system. 6.3.2 产品的技术规范 Product specifications 从产品加工和加工确认研究及产品的物理性能中建立产品的技术规范或标准操作程序。特殊的加工条件如温度限制包括辐照时 这些信息包括： a) 产品的识别 product identification; b) 特殊处理要求 special handling requirements; c) 装载方式 loading configuration; d) 传递到产品的最大剂量maximum dose to be delivered to the product; e) 传递到产品的最小剂量 minimum dose to be delivered to the product; f) 日常监测剂量计的位置及频率 frequency and location of dosimeters used for routine monitoring; g) 箱子/产品密度和尺寸 case/product density and size; h) 特殊加工条件（温度 支持微生物生长的产品）special processing conditions (e.g., temperature, products that support microbial growth); and i) maximum allowable time from manufacture to sterilization, for products with this specification. 6.3.3 单一产品的运行的调度 Scheduling of single product runs 6.3.3.1 单一产品的运行 Single product runs 在一些批次的辐照器，单一的产品单独运行，另外，产品的技术规范可以要求能处理多种产品的辐照器进行单一产品加工运行。 6.3.3.2 单一产品的调度步骤 Steps in scheduling single product runs 一下是对单一产品运行应用的步骤： a) 产品应该按有效的装载模式装入辐照容器，剂量范围限制和产品密度可以规定装入容器少比多的效率高（中心装载或辐照容器里产品的垫板） b) 产品应该按计划运行来满足完成辐照允许时间。 c) 循环时间应该按要求的最低剂量且不能超过最大剂量被确定， d) 可能影响第一个和最后一个货箱均匀度和剂量分布应该考虑，这可能要对开始和最后的产品补偿。 6.3.4 多种产品运行的调度 Scheduling of multiple product runs 6.3.4.1 产品组的混合运行 Grouping of products for multiple runs 计划辐照不同产品的第一步是把具有相似主控时间的产品划为一组，个别产品的主控时间从辐照器试运行研究和加工确认研究的结果确定，只要产品在这个组剂量在有效的剂量范围内，剂量分布不受混合运行影响，可能没有相同主控时间也能划为一个组一起加工，按辐照器的设计和剂量传递特点决定不同的运行为一组的程度。一个组运行的兼容性用中心装载或垫板是成为可能。 6.3.4.2 混合产品运行调度步骤 Steps in scheduling multiple product runs 混合产品运行调度的步骤: a) 产品应该按有效的装载模式进行装载，产品调度应满足规定加工时间限制。 b) 循环时间应该按要求的最低剂量且不能超过最大剂量被设定。 c) 运行的组可能影响第一个和最后一个货箱均匀度和剂量分布应该考虑 d) 加工中改变主控时间即在连续加工辐照器里从一个基本主控时间到另一个基本主控时间，在这些情况下，产品组可能被空货柜或缓冲产品分开，在从空货柜或缓冲产品开始和结束产品组的货箱的剂量均匀度和分布的影响应该考虑 第18页 总31页 e) 辐照中改变主控时间的缓冲产品的剂量不均匀度和分布可能有影响应该考虑。 6.3.4.3 产品分开运行 Separation of product runs 在连续辐照器里，有几个不同主控时间的产品的运行需要用空货箱，模拟产品或缓冲产品分开运行。货箱的数量根据辐照器的 设计来定。不然，可能一个新的产品来加工之前需要装满整个辐照室，当产品装进辐照室是空的时剂量的影响，特别是最大值应该考虑，有典型的最高合最低剂量限制的缓冲产品也能作为不同组之间的产品，这可能影响加工中改变主控时间的这些缓冲产品的剂量分布应该进行评估。 6.3.4.4 改主控室间 Change in cycle time between product runs 加工中改变主控时间即在连续加工辐照器里从一个基本主控时间到另一个基本主控时间，在这些情况下，产品组可能被空货柜或缓冲产品分开，剂量分布和不均匀度的影响需进行评估。 6.4 电子束辐照的调度Scheduling of electron beam irradiators Electron beam sterilization processing facilities typically only process product from a single process qualification dose map in any given irradiation container at any given time. This is due to the relatively small irradiation volume actually being processed by the beam at any given time. Since only one irradiation container is processed at any given time at typical electron beam sterilization facilities, the product from one irradiation container has little or no impact on adjacent irradiation containers from the perspective of dose delivery. NOTE—If products from different dose map exercises are mixed within an irradiation container, factors similar to those outlined for gamma in 6.3 should be considered. The only potential impact that scheduling may have on an electron beam facility relates to throughput efficiency. This is driven by two factors that depend on the design of the facility. The first factor is the time required to change from one set of beam parameters to another. The second factor relates to routine dosimetry requirements. If either of these factors has a significant effect on process time, it may be desirable from an efficiency perspective to group product with the same beam parameters together. Such grouping also minimizes the number of transitions between different processing parameters, which minimizes the potential for product to be processed incorrectly. 6.5 产品的装载 Loading of product 伽玛或电子束辐照时， 装载产品考虑一下几点： a) 产品应按设计好的装载模式进行装载 b) 产品的数量应该记录（备有证明文件），包括测试样品的数量，但应在加工记录中注明。 c) 不满的货箱应记录在加工记录中。 d) 在装货中发现任何差异应该按建立的规范处理 6.6 产品的加工 Processing of product 6.6.1 简要 Introduction 产品只能在由资质的辐照系统内加工，包括程序化文件，确保建立的程序文件符合加工操作规范，产品的传递剂量应该用校准过的剂量系统监测，这个系统应该用进行校准，使用建立程序文件和可追溯到国家或国际标准，测量剂量的总不确定度应该建立及文件化。 6.6.2 伽玛 Gamma 6.6.2.1 加工参数 Processing parameters 在伽玛辐照加工过程中，这几个参数应该进行监测和文件化，包括：伽玛源的位置，主控时间，主控时间改变的设定，辐照中断，辐照循环的货箱的位置顺序。 6.6.2.2 剂量计的位置 Location of dosimeters 剂量计应该布置在先前根据剂量分布图测试选择的点位，这个位置应该文件化。 6.6.2.3 剂量计的频率 Frequency of dosimeters 第19页 总31页 剂量计建议布置在货箱一开始，中间位置，和运行的结束，相关剂量点应该在运行相等的位置，当加工时至少有一个货箱的剂量计应该布置一个剂量计。 6.6.2.4 部分装载 Partial containers 如果剂量分布图发现最大剂量在测试中超过满载时的最大剂量是， 应该测量部分装载货箱的最大剂量。 6.6.2.5 静态加工 Off-carrier processing 剂量计布置在先期根据剂量分布图选择的点位，点位应该文件化。 6.6.2.6 加工中断 Process interruption 加工中断对均匀度和剂量分布的影响需考虑，如果中断设计到人动使货箱移动，纠正措施和确定加工中断时具体的货箱的位置和恢复都应该记录。 对于能支持微生物生长的产品，加工规程应包括生产完成和辐照灭菌的最大间隔时间，储存条件，运输过程的时间间隔包括辐照。 对于不支持微生物生长的产品，辐射剂量对微生物的作用是累加的，所以，辐射加工中断产生的剂量不必要处理。 6.6.2.7 分析 Analysis ANSI/AAMI/ISO 11137 (7.4.3.3) 提供了在产品加工确认中剂量计分析相对加工操作规程要求进行定义。 6.6.3 Electron beam 6.6.3.1 Processing parameters In meeting the requirement of ANSI/AAMI/ISO 11137 (7.4.1) for control and monitoring of the electron beam process, it is important to differentiate critical beam parameters from secondary parameters. Critical beam parameters may be defined as those that, if they deviate from the specifications, would result in an inappropriate dose being delivered to the product. Secondary parameters may be monitored and controlled, but they do not necessarily impact critical parameters (and, hence, dose delivered to the product) if they deviate from the specification. The ability to monitor, control, and document the state of control of critical beam parameters is an important factor in defining routine processing requirements. If such control is validated as part of the electron beam control system, then the operating procedures become relatively simple. If such control is not a part of the beam control system, then operating procedures should ensure that the beam is operating in a state of control. 6.6.3.2 Process interruption The effect of process interruption on the magnitude and distribution in dose should be taken into account. For products capable of supporting microbial growth, the process specification should include the maximum interval of time that may elapse between completion of manufacture and completion of the sterilization process, and the conditions of storage and transportation to be applied during the time interval, including irradiation. For products not capable of supporting microbial growth, the effect of radiation dose on microorganisms is cumulative; thus, the interruption of the process in the irradiator does not generally necessitate action. 6.6.3.3 Location of dosimeters Dosimeters should be placed in the locations previously selected based upon dose mapping studies. These locations should be documented. 6.6.3.4 Frequency of dosimeters Dosimeters should be placed at the beginning, middle, and end of each processing run that utilizes the same parameters. 6.6.3.5 Analysis ANSI/AAMI/ISO 11137 provides requirements for the analysis of dosimeters relative to process specifications defined during the product qualification studies. 6.7 产品的卸载 Unloading of product 产品卸载时注意： a) 数量的确认 count verification; 第20页 总31页 b) 如果需要堆垛建立操作规程 palletization per established specifications, if required; c) 样品的提取 retrieval of samples; d) 回收剂量计并验证位置正确性，剂量储存环境控制区直到加工。 e) 找出损坏的产品 f) 验证产品的状态和适当储存在设计好的区域。 6.8 产品的放行 Release of product 经辐照加工完成，加工历史记录应该递交给有资格人员复合和认可，加工的历史记录包括： a) 收货记录 receiving records; b) 产品数量验证 product count verification; c) 装货卸货记录 loading and unloading records; d) 加工记录 processing records; e) 传送操作和路径 conveyor operation and/or pathways; f) 源的位置 source position; g) 对电子束，束流特点和传送速度。for electron beam, the beam characteristics and conveyor speed; h) 加工背离和关联调查和纠错行为。processing deviations and associated investigations and corrective action; i) 剂量计数据分析记录 dosimetry analysis data records; and j) 传递剂量的证明书，在ANSI/AAMI/ISO 11137定义 历史记录包含识别最小剂量，设备的质量体系，适当的情况下文字说明， certification of dose delivery. At a minimum, the history records should consist of those identified in, the facility quality system, and written specifications, where applicable. 6.9 产品的运输 Shipment of product 辐照装货之前的运输，需注意： a) 装货卸货的产品数量，最后运输前应比较和差别 b) 产品应该检查损坏和确认需要确认的地方， c) 由合适的人员进行产品的放行 7 数学模型 Mathematical modeling 7.1 简要 General 数学 模型能比较接近的模拟光子的输运和电子穿过辐照器，考虑源与产品间的衰减和散射，伽马辐照的剂量分布的数学模型要求精确地知道源的活度分布，位置及结构和源的位置，源板，产品货柜，辐照辅助结构，临近的散射材料因该精确地知道。任何错误参数的计算剂量率的结构都是错误的，所以剂量分布应该跟剂量分布图来验证。 7.2 模型 类型 Types of models 7.2.1 介绍 Introduction 有很多方法关于辐射输运数学模型，然而，大多数模型使用Point Kernel和Monte Carlo方法，Point Kernel方法为计算伽马辐照剂第21页 总31页 量分布，不能用于电子，对于蒙特卡罗方法两者都使用。 7.2.2 Point Kernel 方法 对于伽马源Point Kernel方法通常包括许多源分布超过一个长方形板或气缸，近似成许多点源，每个计算剂量的点与点源的中间材料从源 辐照器 产品容器的匹配 来确定，中间材料对剂量率的影响估计，如果光子到达剂量点减少与距离的平方正比，衰减系数有材料质量决定，衰减和散射的光子的贡献近似用一个参数叫积累因子表示，积累因子计算不同材料和产品的几何形状的不同能量，然而，公布值之适用简单的几何（如 无穷介质的点源），在实际伽马辐照器中，源的产品不是简单几何，界限的影响和混合材料的限制了积累因子的真实值 7.2.3 蒙特卡罗方法 Monte Carlo method 在蒙特卡罗方法中，每个光子或电子从源穿过产品和辐照材料的输运过程近似的用随机数确定能量沉积和不同相互作用的路径，得到每次作用的概率，理论上，蒙特卡罗方法能精确地模拟实际的光子和电子的输运过程，然而，因为每个光子和电子由唯一的路径，靠每次相互作的概率确定，从大量光子或电子剂量分布只能从大量光子和电子的历史能确认，随机统计波动的不确定度的估计和继续计算直到可接受的统计不确定在计算达到的剂量，然而，即使现代最快的计算机，要求计算要花大量的时间，所以，近似剂量值是经常用到的，这些大概包括偏置计算提供增加较少历史事件。 7.3 模型的应用 Use of models 7.3.1 设计辐照器 Design of irradiators 数学模型广泛的用于辐照器的设计，通过计算原则辐照的几何形状来达到生产力和剂量均匀度。数学模型计算的数据可与确定辐照器的同类产品的辐照，计算提供的信息每千居里活度或电子束每千瓦功率的得到期望剂量值，产品密度剂量的变化，剂量的均匀度比，最高最低点，一些数学模型也能得出产品密度转换的吸收剂量，源移动和关闭电子束时的附加剂量，空的或不同性质的产品的影响，一些模型也能得出在伽马辐照器的不同位置的能谱。 7.3.2 伽玛辐照器的操作 Operation of gamma irradiators 对于伽马辐照，数学模型得出的期望剂量分布信息能用来确定剂量场测试是剂量计的数量和最高最低布点，剂量计应该布在数学模型得出的最低最高的区域，同样其他点也可确定是否跟期望相同，因为数学模型通常假设所有的源，辐照器和产品参数精确地输入，任何这些参数改变的影响只能从剂量计来确定。 剂量分布图测试后确定从数学模型得出结果的可信度，数学模型为测量结果和确定其他密度产品剂量分布和确定密度改变对产品剂量的影响或不同产品导致的剂量变化提供一个有效的工具，数学模型结合剂量出分布图减少剂量场的要求，列举在写面例子中， a) 数学模型计算几种密度不同的同类的产品剂量分布 b) c) d) e) 正常化的计算的结果得到符合剂量分布图数据，确定正常化的因素对产品密度测量因素， 计算中间密度产品的剂量分布和正常化因素应用. 当产品密度不同辐照时， 计算第一个和最后一个货箱产品的剂量分布， 比较不同密度产品连续辐照的计算数据与剂量分布图数据确定数学模型的可信度 当具体的产品一起加工时，数据的结果可以确定是否符合剂量说明书，确定不同密度转换产品的最佳主控时间， 7.3.3 Operation of electron beam irradiators For electron beam irradiators, information on the expected dose distribution provided by mathematical modeling can be used to ensure that a sufficient number of dosimeters are distributed in the expected zones for minimum and maximum doses in the irradiator dose mapping studies. Mathematical modeling also can be used to determine the dose in areas where there may be steep dose gradients (e.g., near edges of product) to ensure that dosimeters provide adequate resolution. Results of mathematical modeling may indicate the need to map areas with strips or sheets of dosimetric film and scan the films to determine doses near product edges. 8 加工质量日常评估 Routine evaluation of process quality 8.1 简要 General 日常数据处理可估计来建立审定维修的信心，例如，数据可以从个别加工记录用预期或指定剂量比较实际的传递剂量评估对连续传第22页 总31页 递指定剂量的加工能力。 加入适当的控制辐照灭菌可掌控和可重复加工的，伽玛辐射指定剂量根据核同位素的衰变，电子加速器的想要的剂量跟速度/电流/能量有关，所以，日常加工输出可以比较计算结果和数学模式得出的结果确定是否能控制， 8.2 复核数据的收集 Collection and review of data 收集组织复核加工数据来评估加工质量，例如，数据包括剂量测量的结果，加工参数，不一致性。分析方法根据数据类型，辐照器的设计和应用和用户的需要，分析的结果用来识别加工运行接近加工说明剂量和加工趋势的可能，允许纠正措施的实施。 一个有用的技术分析是一个控制图表，一个图表的例子如图2. 图 2— 测量剂量率和预期剂量 这个图表说明日常测量剂量与估计（计算）剂量的比值，估计剂量由调整吸收剂量确定，原先有放射同位素衰变和日常产品加工所用的主控时间确定， 控制图标是加工输出图形表示，例如，从开始确认一些加工传递剂量或数据作为日常加工记录提供所需要的数据来建立加工控制图标，实际结果与预期结果比较或说明提供加工控制的客观的评估。 9 维护过程的有效性 Maintenance of process effectiveness 9.1 简要 General 维护确认通过校准和限制程序完成。 9.2 校准 Calibration 关键的加工设备应该按规定时间校准，校准的频率基于仪器设备的稳定性和目的和用途以及仪器厂家的说明书。关键的加工设备有下面： 对于伽马辐照器： a) 剂量系统; b) 重量测量设备 c) 主控实际 For electron beam irradiators: a) dosimetry system; b) weighing and measuring equipment; c) beam energy and current instrumentation; d) scan width and frequency instrumentation; and e) instrumentation for monitoring conveyor speed. 9.3 辐照器重新确认 Irradiator requalification 9.3.1 介绍 Introduction 第23页 总31页 任何设备的设计改变影响剂量分布，可能要求一部分或所有的安装确认重做，记录校准和确认之间的不同时非常重要，重新确认是系统性能测试和促进加工，重新确认包括一个或更多如下：设备的文件化，设备测试，设备校准，辐照剂量场分布图。重新确认的范围要求根据设备改变的属性，表1和2是这些例子需要辐照器的重新确认，实际重新确认可能根据设备的操作人员的不同而改变 9.3.2 文件的重新确认要求 Requalification documentation requirements 下面可用的质量记录应该包括维护的重新确认： a) 辐照器的修改的描述; b) 图纸 说明书的更改; c) 辐照器设计改变的工程的改变记录; d) 源的位置和活度的记录; e) 剂量分布图测量报告 f) 数学模型报告. 表1—伽马辐照器重新确认要求 辐照器剂量分布图 辐照器的改变 加减或重新排布放射源 货箱或辐照容器设计 设备的文件说明 操作测试 设备校准 最小剂量分布图 Homogeneous dose maps Installation qualification— irradiator dose maps Installation qualification— irradiator dose maps Installation qualification— irradiator dose maps a a a a a a a a a a a a a a a a a a a 去掉或迁移辐照室内超过头高的传送机 去掉或迁移关键产品路径内的制动单元 去掉或迁移关键产品路径外的制动单元 源钢绳的替换 源的驱动系统的重新设计 影响源与产品距离的重新设计 a a a a a a Transit dose maps Installation qualification— irradiator dose maps Installation qualification— irradiator dose maps 源板系统的重新设计 a 辐照器主控时间类型的改变 辐照器安全监测设备类型的改变 a a a a a (if applicable) 辐照器池水监测设备的改变 a NOTE 1—Addition of source without reconfiguration of the source geometry may only require that part of the homogeneous dose mapping study be performed to confirm the results of mathematical modeling or modification objectives. Whereas, addition 第24页 总31页 of source with change of source geometry may require that all homogeneous dose maps be repeated in addition to some of the ancillary studies such as center loading or partial load. NOTE 2—Pending results of operational testing (e.g., verification of source position), homogeneous dose mapping may be required following replacement of source cables. Table 2—Electron beam irradiator requalification requirements Equipment Operational documentation testing Equipment Irradiator dose calibration mapping Type of dose mapping Y- and Z-direction dose mapping Y- and Z-direction dose mapping Z-direction dose mapping X-direction dose mapping Y-direction dose mapping X-direction dose monitoring Process interruption testing Irradiator change Accelerator mechanical alignment Steering or focusing magnet systems Bending magnet systems Beam current monitoring system Scanning magnet system Conveyor speed monitoring and/or control circuitry a a a a a a a a a a a a a a a a Conveyor system motors, belts, and gearing a a NOTE 3—(per 4.3.1.1): X-direction: the direction of conveyor travel Y-direction: the direction the beam is being scanned Z-direction: the direction of beam travel NOTE 4—These tables are examples. Actual requirements may vary as a result of differences in the equipment employed. 9.4 定期检修和辐照器改变控制 Preventive maintenance and irradiator change control 9.4.1 定期检修 Preventive maintenance 维修程序需建立包括为以下几个方面的检测做具体准则. 对于伽马辐照器: a) 传送系统 conveyor system (e.g., conveyor drive unit, drive chain, conveyor track, rotators); b) 辐射源系统 radiation source systems (e.g., source hoist, track, sheave, and cables); c) 空压机和压缩系统air compressors and pneumatic systems; d) 转换 升降机transfer lifts and lowerators; e) 通风系统 ventilation systems; f) 水处理系统water treatment system (e.g., chillers, plumbing system, purification system); and g) 辐照容器irradiation containers (e.g., carrier, totes). For electron beam irradiators: a) electron beam accelerator (e.g., scan horn alignment, scan width, beam energy, beam magnet system, power supply); b) conveyor system (e.g., start/stop test, guide rails, conveyor track); c) irradiator support equipment (e.g., electrical wiring); and d) irradiation containers (e.g., carriers, totes). 定期检修应该根据设备厂家要求和设备的特点制作检修计划，定期检修的执行和记录要与文件一致，任何没有计划的维修增加定期检修并文件化。 第25页 总31页 9.4.2 辐照器改变的控制 Irradiator change control 辐照系统设计的改变应该按程序文件记录和测试，这些改变有如下： a) 系统的改变the change made to the system; b) 改变的原因 the reason for the change; c) 改变带来影响的操作程序operating procedures affected by the change; d) 绘制或图表改变导致影响drawings or schematics affected by the change; e)安装 操作 执行确认测试的要求 installation, operational, and performance qualification testing requirements; and f) 复核和批准人 review and approval by appropriate personnel. 附录A 日常监测剂量测量的不确定度 剂量测量处理的不确定度导致在同一个产品运行中的相同的剂量计布点产生的剂量测量可信度的偏差，在剂量值测量的偏差追溯到剂量系统自身和运行时加工条件的偏差。为了测量最小和最大剂量达到高的水平的可信度以至于在可接受的范围内。剂量测量的不确定度应该考虑到日常产品加工参数的设置。由于这些原因，相关点和调整系数的测量用来计算最小和最大，如5.2.3和5.3.3所述，一个不确定度增加的组成部分应该考虑加工参数的设立，从加工确认的多种剂量图统计分析数据可用来估计剂量测量的不确定度。这些信息可用来设定日常产品加工参数，附录下面的部分举例从多剂量分布图估计剂量测量不确定度和怎样用这些信息来设定加工参数。 A.1 关键的统计参数 Key statistical parameters 分析报告包含的几个统计参数，两个关键的参数是重复测量的平均值和标准偏差，剂量值得平均值的测量的散射或分布。标准偏差常表示为偏差的术语，标准偏差的平方。 如果Di,z是由在区域Z的第i剂量计测量的剂量和区域Z有nz独立测量，区域Z期望的平均吸收剂量估计为： If is the dose measured by the dosimeter in zone z and there are independent measurements made of zone z, then the mean absorbed dose expected in each zone z is estimated by: (Davg)z = Σi Di,z/nz 在每个区域，平均剂量测量的偏差估计为： Var(D) = ΣI [Di,z – (Davg)z]/(nz – 1) 2th(方程A.1) (方程A.2) 注意—剂量的重复性测量比较的数被称为自由度，在统计分析数据上是另外一个重要的参数，对于独立剂量测量的数学平均值的单一质量评估自由度等于n-1。一些原因是剂量测量的典型的特点小的自由度，例如，如这样例子，产品剂量分布图用来确定平均剂量，自由度就是3-1或2，对于限制抽样的完全的统计原因，涉及小自由度的分析导致实验标准偏差的重大的不确定度，如果在剂量分布图中每个剂量区域的剂量的偏差的平均假定是相似的，数据的共用时可行的，增加自由度的共用和提高质量的评估。 在方程A.1和A.2中可以看出剂量分布数据是统计分析的适当的条件。在某些情况下，在特别的区域可能不是由于统计的偏差，剂量重复测量有很大的偏差，例如，如果剂量变化程度在给定的剂量分布图内， It is implied in use of Equations A.1 and A.2 that the dose map data is properly conditioned for statistical analysis. In some cases, large variability in replicate measurements of dose in a specific zone may not be due to statistical variations. For example, if large dose gradients exist within a given dose-mapped volume, a slight change in dosimeter location could lead to a significant change in measured dose. In this case, averaging of the data and use of the standard deviation to estimate variability in dose values about the mean may not be appropriate. Other approaches such as selection of the lowest or highest dose value rather than use of a mean value may be preferred, or additional dose map data may need to be generated to better assess statistical variability of the data. The overall uncertainty in the dosimetry system and dose map data taken from irradiator qualification dose map studies provides guidelines for assessing variability in replicate measurements taken from product dose maps. Dose map data containing possible aberrant values also can be tested for outliers using standard methods. A.2 日常剂量测量方法 Methods for routine measurement of dose Three methods are commonly used to monitor dose during a production run. 1 Production dose monitoring procedure 1—This method involves measurement of minimum and maximum dose at several locations in the run. 第26页 总31页 2 Production dose monitoring procedure 2—This method uses reference point dosimetry wherein dose is measured at a reference location and minimum and maximum doses are determined through use of adjustment factors (see 5.2.4 and 5.3.4). 3 Production dose monitoring procedure 3—In this method, minimum dose is measured at several locations in the product run and maximum dose is calculated based on a ratio to the minimum dose. In effect, the minimum dose functions as a reference dose and maximum dose is determined using an adjustment factor. The following sections provide examples of the analysis of product dose map data to (1) determine uncertainty in dose values for each of the three procedures for dose monitoring, and (2) use that information to set process parameters during production processing of product. A.3 剂量监测程序的制作——日常产品加工最大和最小剂量的测量 Production dose monitoring procedure 1—Measurement of minimum and maximum dose inroutine processing of product The following example shows how statistical analysis of product dose map data is used for setting process parameters when minimum and maximum doses are measured at various locations within the production run. The dose map data listed in Table A.1 were taken from three replicate dose maps that were run during the performance qualification studies. Table A.1—Dose map data—Procedure 1 Doses Dose map 1 Dmin Dmax 26.1 kGy 40.0 kGy Dose maps Dose map 2 25.8 kGy 41.0 kGy Dose map 3 25.2 kGy 40.6 kGy For purposes of this example and the subsequent examples given in this annex, specifications for the acceptable minimum and maximum doses were assumed to be 25 kGy and 45 kGy, respectively. A.3.1 计算平均剂量，偏差，标准偏差 Calculation of average dose, variance, and standard deviation Using the minimum and maximum dose values in Table A.1 and Equations A.1 and A.2, determine the average dose, variance, and standard deviation of Dmin and Dmax. Average dose calculation: (Dmin)avg = (26.1 + 25.8 + 25.2)/3 = 25.7 kGy (Dmax)avg = (40.0 + 41.0 + 40.6)/3 = 40.5 kGy Variance calculation: Var(Dmin) = [(26.1 – 25.7) + (25.8 – 25.7) + (25.2 – 25.7)]/(3 – 1) = 0.21 (kGy)2222222 2 Var(Dmax) = [(40.0 – 40.5) + (41.0 – 40.5) + (40.6 – 40.5)]/(3 – 1) = 0.25 (kGy)Standard deviation calculation: S(Dmin) = √Var(Dmin) = 0.46 kGy S(Dmax) = √Var(Dmax) = 0.50 kGy (Square Root of Equation A.2) The quantities Var(D) and S(D) in the preceding calculations are the variances and standard deviations in the respective doses. A.3.2 剂量测量不确定度的评估 Estimate of uncertainty in dose measurements The standard deviation, which is a measure of the dispersion or scatter of dose values about the average dose, can be used to estimate the uncertainty in the measurement of dose. To provide a high level of confidence that the measurement of dose will fall within the interval given by the estimate of uncertainty, the standard deviation is normally multiplied by a coverage factor. This additional measure of uncertainty that provides such a confidence level is termed expanded uncertainty. A coverage factor of 2 corresponds approximately to a confidence level of 95 %, and a coverage factor of 3 corresponds approximately to a confidence level of 99 %. A coverage factor of 2 provides a high level of confidence that measured doses will fall within the acceptable range, and is frequently used to set process parameters. In some cases where a higher level of confidence is desired and process conditions permit it, a coverage factor of 3, which corresponds to a confidence level of 99 %, may be used. 第27页 总31页 The standard deviation usually is expressed in terms of a percentage by dividing its value by the average value of dose. Based on the cited example, the expanded uncertainty in minimum dose at a 95 % confidence level is: 2S(Dmin)/(Dmin)avg x 100 = [2 x 0.46 kGy/25.7 kGy] x 100 = 3.58 % Following the same procedure that was used to calculate the expanded uncertainty in minimum dose, the expanded uncertainty in maximum dose is: 2S(Dmax)/(Dmax)avg x 100 = [2 x 0.50 kGy/40.5 kGy] x 100 = 2.47 % A.3.3 设定加工参数 Setting process parameters A.3.3.1 最小剂量 Minimum dose To have a high level of confidence that no measurement of minimum dose falls below the acceptable value of 25 kGy, processing parameters should be set to deliver a minimum dose of 25.9 kGy, which is 3.58 % greater than 25 kGy. For gamma irradiators, this would involve adjusting the cycle time; in the case of electron beam irradiators, it could involve adjusting conveyor speed or beam current. For example, in the case of gamma irradiators, the cycle time equation developed from results of the operational qualification studies could be used to calculate a cycle time for delivering a minimum dose of 25.9 kGy. Alternatively, the cycle time setting used in the dose map study to deliver an average minimum dose of 25.7 kGy could be increased by the ratio 25.9 kGy/25.7 kGy = 1.008. A similar approach involving adjustment of conveyor speed or beam current could be used for electron beam irradiators to give a high level of confidence that measurements of minimum dose exceed the acceptable value of 25 kGy. A.3.3.2 最大剂量 Maximum dose In addition to setting process parameters to satisfy minimum dose requirements, it also is important to show that no measurement of maximum dose will exceed the acceptable value of 45 kGy to a high level of confidence. Given an expanded uncertainty of 2.47 % in the maximum dose, it can be shown that these conditions are met if measurements of maximum dose on average do not exceed 43.9 kGy. Based on a maximum to minimum dose ratio of 1.58 that is found from analysis of the dose map data in Table A.1, and a minimum dose of 25.9 kGy, maximum dose should not exceed 40.9 kGy, which is significantly less than 43.9 kGy. Therefore, no measurement of dose should exceed the maximum acceptable value of 45 kGy to a high level of confidence. If the maximum to minimum dose ratio had been much greater than 1.58, as may be the case for higher density product, doses could have exceeded 43.9 kGy. In this case, it may be necessary to take appropriate action such as center loading of product to reduce the dose ratio. A.4 剂量监测程序制作 2 —— 在日常产品加工中的相关剂量和使用调整系数来计算最小和最大剂量Production dose monitoring procedure 2—Measurement of reference dose and use ofadjustment factors to calculate minimum and maximum dose in routine processing of product The following example shows how statistical analysis of dose map data is used for setting process parameters when dose is measured at a reference location and adjustment factors are used to calculate doses at the minimum and maximum dose locations. Dose values used in the analysis and adjustment factors are based on the following representative data taken from three replicate dose maps generated during process qualification of the product. Values of minimum and maximum dose are the same as those in Table A.1. Table A.2—Dose map data—Procedure 2 Doses Dose map 1 Dref Dmin Dmax 30.4 kGy 26.1 kGy 40.0 kGy Dose maps Dose map 2 31.2 kGy 25.8 kGy 41.0 kGy Dose map 3 30.6 kGy 25.2 kGy 40.6 kGy A.4.1 调整系数的计算 Calculation of adjustment factors Adjustment factors for the minimum and maximum dose are calculated from equations 1–4 in 5.2.4 and 5.3.4. These expressions are given by: AFmin = (Dref)/(Dmin) and 第28页 总31页 AFmax = (Dref)/(Dmax) The adjustment factors in Table A.3 were derived from these expressions and the data in Table A.2. Table A.3—Adjustment factors for minimum and maximum dose Dose map Dose map 1 Dose map 2 Dose map 3 Mean value AFmin 1.165 1.209 1.214 1.196 ≈ 1.20 AFmax 0.760 0.761 0.754 0.758 ≈ 0.76 A.4.2 调整系数的不确定度Uncertainty attributable to adjustment factors Use of a reference location for routine monitoring of dose introduces an element of uncertainty in the estimate of maximum and minimum dose. This uncertainty should be taken into account when setting process parameters for the run. The variance and standard deviation in the adjustment factors can be determined from the data in Table A.3. Based on the data in Table A.3, the variance and standard deviations in the adjustment factors are: Var(AFmin) = [(1.165 – 1.196) + (1.209 – 1.196) + (1.214 – 1.196)]/(3 – 1) = 7.27 x 10Var(AFmax) = [(0.760 – 0.758) + (0.761 – 0.758) + (0.754 – 0.758)]/(3 – 1) = 1.45 x 10S(AFmin) = √Var(AFmin) = 2.70 x 10-2 222222-4 -5 -3 S(AFmax) = √Var(AFmax) = 3.81 x 10The standard deviations, S(AFmin) and S(AFmax), can be used to correct the adjustment factors. The value of AFmin should be corrected to give the smallest possible value for the minimum dose, and the value of AFmax should be corrected to give the largest possible value for the maximum dose. Using a coverage factor of 2, which is approximately equal to a confidence level of 95 %, the corrected adjustment factors are: (AFmin)corr = 1.20 + 2S(AFmin) = 1.20 + 0.05 = 1.25 and (AFmax)corr = 0.76 – 2S(AFmax) = 0.76 – 0.01 = 0.75 These corrected values for the adjustment factors should be used to calculate minimum and maximum doses for the production run. A.4.3 剂量测量不确定度评估 Estimate of uncertainty in dose measurements Using the minimum and maximum doses of 25 kGy and 45 kGy and corrected values for the adjustment factors, the acceptable minimum and maximum reference doses for the run are: (Dref)min = (AFmin)corr x Dmin = 1.25 x 25 kGy = 31.25 kGy (Dref)max = (AFmax)corr x Dmax = 0.75 x 45 kGy = 33.75 kGy A.4.4 设定价格参数 Setting process parameters To provide a high level of confidence that doses will not fall outside the acceptable minimum and maximum doses of 25 kGy and 45 kGy, process parameters should be set to deliver an average reference dose in the range of 31.3 kGy to 33.8 kGy. Based on the settings used in the dose map run, which resulted in an average reference dose of (Dref)avg = (30.4 + 31.2 + 30.6) = 30.7 kGy, the cycle time or conveyor speed should be adjusted by the factor 31.3 kGy/30.7 kGy ≈ 1.02 for production processing of product. A.5 剂量监测程序的制作 3- 测量最小剂量和使用调整参数计算日常产品加工的最大剂量 Production dose monitoring procedure 3—Measurement of minimum dose and use ofadjustment factor for maximum dose in routine processing of product The following example shows how statistical analysis of product dose map data is used for setting process parameters when minimum dose is measured at several locations within the production run and maximum dose is calculated based on an 第29页 总31页 adjustment factor that uses minimum dose as the reference dose. Dose values used in this analysis are based on the dose map data in Table A.1. Average values of Dmin and Dmax, variances, and standard deviations are given in A.3.1. A.5.1 调整参数的计算 Calculation of adjustment factor In this example, the average minimum dose is used as the reference dose. Therefore, the adjustment factor for maximum dose is given by: AFmax = 25.7 kGy/40.5 kGy = 0.63 where 25.7 kGy is the average minimum dose and 40.5 kGy is the average maximum dose. This value should be corrected for uncertainty in the calculated adjustment factor. The variance in the adjustment factor can be determined from the data in Table A.4. Table A.4—Adjustment factors for maximum dose Dose map Dose map 1 Dose map 2 Dose map 3 Mean value AFmax 0.653 0.629 0.621 0.634 The variance and standard deviation are given by: Var(AFmax) = [(0.653 – 0.634) + (0.629 – 0.634) + (0.621 – 0.634)]/(3 – 1) = 2.78 x 10-4 222 S(AFmax) = √Var(AFmax) = 1.67 x 10The corrected value for the adjustment factor is given by: (AFmax)corr = 0.63 – 2S(AFmax)corr = 0.63 – 0.03 = 0.60 A.5.2 设定加工参数 Setting process parameters As shown in A.3.2, the cycle time or conveyor speed should be adjusted by 3.58 % to deliver a minimum dose of 25.9 kGy, which gives a high level of confidence that measurements of dose will not fall below the acceptable value of 25 kGy. In this example, maximum dose is not measured, rather it is calculated using a corrected adjustment factor of 0.60. Based on a minimum dose of 25.9 kGy and use of 0.60 for the adjustment factor, it is seen that maximum dose is 25.9 kGy/0.60 = 43.2 kGy. This number is less than 43.9 kGy, thus ensuring with a high level of confidence that no value of dose will exceed the maximum acceptable value of 45 kGy. -2 附录 B (informative) 文献检索 Bibliography [1] Sterilization of health care products—Radiation sterilization—Product families, sampling plans for verification dose experiments and sterilization dose audits, and frequency of sterilization dose audits. ANSI/AAMI/ISO TIR15843:2000, AAMI, Arlington, VA, 2001. [2] Cleland MR, O’Neill MT, and Thompson CC. “Sterilization with accelerated electrons.” In: Sterilization Technology—A Practical Guide for Manufacturers and Users of Health Care Products, Chap. 9, Morrissey RF, and Phillips GB, eds., Van Nostrand Reinhold, New York, 1993. [3] Herring CM and Saylor MC. “Sterilization with radioisotopes.” In: Sterilization Technology—A Practical Guide for Manufacturers and Users of Health Care Products, Chap. 8, Morrissey RF, and Phillips GB, eds., Van Nostrand Reinhold, New York, 1993. [4] Miller A. “Approval and control of radiation processes, EB, and gamma.” Radiat Phys Chem 18, 385–394, 1988. 第30页 总31页 [5] Comben M, and Stephens P. “The operational benefits of integrated PC control of gamma irradiation plants.” Radiat Phys Chem 52, 433–437, 1998. [6] Comben M, and Stephens P. “Irradiation plant control upgrades and parametric release.” Radiat Phys Chem 57, 577–580, 2000. [7] Saylor MC, Herring CM, and Shaffer HL. “The practical application of parametric release in radiation processing.” Radiat Phys Chem 57, 701–705, 2000. [8] Sterilization of medical devices—Microbiological methods—Part 1: Estimation of the population of microorganisms on product. AAMI/ISO 11737-1:1995, AAMI, Arlington, VA, 1995. [9] Sterilization of medical devices—Microbiological methods—Part 2: Tests of sterility performed in the validation of a sterilization process. AAMI/ISO 11737-2:1998, AAMI, Arlington, VA, 1998. [10] Sterilization of health care products—Radiation sterilization—Substantiation of 25 kGy as a sterilization dose for small or infrequent production batches. AAMI/ISO TIR 13409:1996, AAMI, Arlington, VA, 1997. [11] Amendment 1 to AAMI TIR 13409, Sterilization of health care products—Radiation sterilization— Substantiation of 25 kGy as a sterilization dose for small or infrequent batches. AAMI/ISO TIR 13409/A1:2000, AAMI, Arlington, VA, 2001. [12] Sterilization of health care products—Radiation sterilization—Selection of a sterilization dose for a single production batch. AAMI/ISO TIR 15844:1998, AAMI, Arlington, VA, 1999. [13] Sterilization of health care products—Radiation sterilization—Substantiation of 25 kGy as a sterilization dose—Method VDmax. AAMI TIR 27: 2001, AAMI, Arlington, VA, 2001. [14] Guide for the expression of uncertainty in measurement. ISO, Case postale 56, CH-1211, Geneva 20, Switzerland, 1993. [15] Practice for use of statistics in the evaluation of spectrophotometric data. ASTM E876, ASTM, West Conshohocken, PA. [16] Standard guide for estimating uncertainties in dosimetry for radiation processing. ISO/ASTM 51707, ASTM, West Conshohocken, PA. [17] Practice for dealing with outlying observations. ASTM E178, ASTM, West Conshohocken, PA. [18] Hald A. Statistical Theory with Engineering Applications. John Wiley, New York, 1952. 第31页 总31页 本文来源：https://www.wddqw.com/doc/82c2e8996adc5022aaea998fcc22bcd126ff4230.html