PDA_TR28 中英 无菌原料药工艺模拟验证(2006年).doc

无菌原料药（BPCs）的工艺模拟PDA第28份技术报告（2006年）This document provides guidance relative to the validation of aseptic processing activities associated with the production of sterile bulk pharmaceutical chemicals. It draws upon the concepts and principles developed in PDAs and PhRMAs prior publications on aseptic processing technology (1, 2, 3). This effort expands upon those documents to provide assistance for individuals and firms producing sterile bulk pharmaceutical chemicals. Our goal in this revision was to update the document to reflect 6 years of industry experience with it, as well as an acknowledgement of acceptance criteria limitations that were present in the first edition (4). We have also endeavored to address some of the issues raised by FDA in their review of the earlier edition.本文档提供了无菌原料药生产加工有关的验证指导。它借鉴了FDA和PhRMA以前出版的无菌加工技术（1，2，3）的概念和原则。这使得该文件可以为个人和企业的无菌原料药生产提供帮助。我们在这次修订的目的是更新文件，以归纳6年来的行业经验，以及验收标准的规定，这将在第1版（4）中称述。我们还大量列举一些美国FDA在其早期版本的回顾中提到的一些问题。The preparation of sterile materials in the quantity and scale used in the manufacture of bulk pharmaceutical chemicals generally requires equipment and procedures quite different from those used in the manufacture of finished pharmaceuticals. The uniqueness of the production methods for sterile bulks precludes the direct extrapolation of the process simulation approaches employed for aseptically produced sterile formulations.原料药生产中，无菌原料在数量和规模上的准备，一般都需要相当的设备和过程，这与成品药的制造有所不同。无菌原料生产方法的独特，排除了用于无菌制剂的无菌生产上的工艺模拟直接推断方法。This technical report was disseminated in draft for public review and comment prior to publication. Many of the submitted comments have been included in the final document. We believe this approach accomplished the widest possible review of the document and ensures its suitability as a valuable guide to industry in the area of process simulation testing for sterile bulk pharmaceutical chemicals.This document should be considered as a guide; it is not intended to establish any mandatory or implied standard.这份技术报告以草案形式提前发布供公众审查和评论。大多数提交的意见将被列入最后版本中。我们相信，这种方法实现了对文件最广泛的审查，并确保作为一个针对无菌原料药的工艺模拟试验领域的宝贵的指导性文件的合格性。这份文件应被视为指南，而不是任何强制规定或标准。TableofConents目录1.INTRODUCTION简介1.1Purpose目的1.2Sterile Bulk Pharmaceutical Chemicals.无菌原料药1.3Scope范围1.4Sterile BPC Production Technology无菌BPC生产技术1.4.1Closed Systems封闭系统1.4.2Open Systems开放系统1.5 Considerations需考虑事项2.PROCESSSIMULATION CONCEPTS ANDPRINCIPLES工艺模拟的概念和原则2.1Number and Frequency of Tests测试的数量的频率2.2Worst Case最差条件3 PROCESS SIMULATION TEST METHODS工艺模拟测试的方法3.1Total Process Simulation总工艺模拟3.2Unit Operation(s) Simulations单元操作模拟4.TEST MATERIALS USED IN PROCESS SIMULATION过程模拟中用到的测试原料4.1Growth Medium Simulations生长介质模拟4.2Placebo Material Simulation安慰剂原料模拟4.3Simulation Without Material无原料模拟4.4Production Material Simulation生产原料模拟5.EVALUATION OF SIMULATION TEST MATERIALS模拟测试原料的评估5.1Evaluation of Entire Test Material全体测试原料的评估5.2Evaluation of Test Material Samples测试原料单体的评估6.DOCUMENTATION文件7.ENVIRONMENTAL MONITORING环境监测8.ELEMENTS OF PROCESS SIMULATIONTESTS工艺模拟测试的评估8.1Interventions干扰8.2Duration of Simulation时间模拟8.3Production Batch Size/ProcessSimulation TestSize产品的批产量/工艺模拟的批量8.4Incubation Conditions培养条件8.5Operating Procedures作业流程8.6Staffing Considerations人员的思考8.7Campaigns活动8.8Equipment Qualification设备限制9.INTERPRETATION OF RESULTS AND ACCEPTANCE CRITERIA 结果的解释和可接受水平9.1Background背景9.2Approaches for Acceptance Criteria可接受水平的判定方法9.2.1Quantitative定量9.2.2Qualitative品质10.FAILURE INVESTIGATION AND CORRECTIVE ACTION 失败评估和纠正措施11.PERIODIC REASSESSMENT定期再评估APPENDIX1,SELECTIONANDSTERILIZATIONOFTEST MATERIALS附件1，测试原料的选择和灭菌APPENDIX 2, DEFINITIONS附件2，定义APPENDIX 3, REFERENCES附件3，参考文献1. INTRODUCTION简介1.1. Purpose目的The preparation of sterile bulk pharmaceutical chemicals requires the combination of classical chemical/ biological production methods with the well-defined concepts for the preparation of sterile materials. The integration of these fields entails process equipment and operating procedures which are often substantially different from ordinary practice in either discipline. This document outlines process simulation practices for sterile bulk pharmaceutical chemicals (sterile BPCs), utilizing concepts drawn from both bulk pharmaceutical chemical operations and sterile product manufacturing and adapted to fit the unique nature of these materials. It presents options for determining the adequacy of aseptic operations performed during large scale manufacturing while allowing for realistic acceptance criteria for such operations.无菌原料药的制备需要典型的生化生产方法与无菌原料制备概念的明确理解相结合。这些领域的合并意味着工艺设备和作业流程实质上往往与通常做法不同。本文件概述了无菌原料药（无菌BPCs）的工艺模拟实践，系统采用批量原料药作业和无菌产品制造的概念来适应这些材料的独特性质。报告在允许这些作业的实际验收标准的同时，陈述了在大规模生产中无菌作业的充分性的鉴定观点。The aseptic procedures utilized in the production of sterile BPCs can be evaluated using a process simulation methodology. However, in certain instances the use of a microbiological growth medium in a bulk manufacturing plant can pose significant problems. It is often necessary to consider other simulation options which pose less potential risk to the manufacturing area. It is useful to utilize a narrower definition of a process simulation in these cases. The followingdefinitions make a clear distinction between possible methods:无菌BPCS生产过程中使用的无菌流程可以用工艺模拟方法论来评估。然而，在某些情况下，在批量制造工厂中微生物培养基的使用可能造成重大问题。常常有必要考虑能减少对制造领域构成潜在风险的其他模拟方案。利用这些案件中工艺模拟的狭义定义是非常有意义的。下面的定义为各可行方法作出明确区分：1.Process Simulation(without microbiological growth media)工艺模拟（无微生物培养基）Method of evaluating an aseptic process employing methods which closely approximate those used for sterile materials using an appropriate placebo material.与使用适当安慰剂原料的无菌原料评估方法相类似的无菌工艺的评价方法，2.Process Simulation(with microbiological growth media)工艺模拟（有微生物培养基）Method of evaluating an aseptic process using a microbial growth medium employing methods which closely approximate those used for sterile materials (5).与无菌原料评估方法相类似的使用微生物的生长方法的无菌工艺评价方法。The process simulation test also provides a way to evaluate changes made to an aseptic processing operation which might affect the sterility of the final product. It can be useful in identifying potential weaknesses in an aseptic processing operation which might contribute to the microbiological contamination of the product.这个过程模拟试验也提供了一种方法来评估可能影响最终产品失败的无菌工艺的变化。它可以有助于鉴定在无菌工艺中的潜在弱点，这些弱点可能导致产品的微生物污染。1.2.Sterile Bulk Pharmaceutical Chemicals无菌原料药For the purposes of this document, a sterile bulk pharmaceutical chemical is defined as a sterile material derived from chemical, fermentation or semi-synthetic sources which is final packaged or stored in bulk form. The bulk material may be an active pharmaceutical ingredient (API) or an excipient. Sterile BPCs are typically solids, but may be solutions or suspensions.本文件的目的是定义无菌原料药是由那些最后以批量的形式被包装或存储的化学药品，发酵物或半派生的无菌材料而派生。其中大部分材料可能是一个活性成份（API）或赋形剂。无菌BPCs系统通常是固体，但也可能是溶液或悬浮物。1.3.Scope范围This document addresses the validation of aseptic processing during sterile bulk manufacturing activities (referred to as primary manufacturing in many parts of the world). It describes methods and procedures for the conduct of process simulation tests, including crystallization, separation, purification, drying, milling, blending and bulk packaging of sterile bulk pharmaceutical chemicals which are aseptically produced. Aseptic operations required in the preparation of sterile formulations are not a part of this document and have been addressed by PDA elsewhere (4).这份文件涉及到无菌原料生产活动（在世界的许多地方也叫作二次生产）的无菌工艺的验证。它描述了管理工艺模拟实验的方法和程序，包括结晶，分离，纯化，干燥，加工，混合与无菌生产的无菌原料药品的无菌包装。有无菌操作要求的无菌原料和生物技术过程不包括在这份文件中，而在PDA（4）中被陈述。1.4.Sterile BPC Production Technology无菌BPC生产技术The preparation of sterile bulk materials entails the completion of a series of unit operations under aseptic conditions. The equipment utilized for these aseptic unit operations is sterilized using a validated procedure prior to the introduction of the sterile BPC. Depending upon the process, the equipment may be classified as either a closed or an open system (see below). While it is recognized that a closed system is generally preferred, there are process and equipment limitations such that open systems are the only means available for the execution of certain unit operations. The process train for a sterile BPC may include both open and closed portions. The test methods used forthe process simulation must include all portions of the system whether open or closed and transitions between them (see Section 3).大量无菌原料的制备需要在无菌条件完成一系列的单元作业。这些无菌单元操作所使用的设备预先采用无菌BPC技术进行了灭菌。该设备可以分类为“封闭”或“开放”系统（见下文）。人们认识到，虽然一个“封闭”系统被普遍采用，但由于工艺及设备的限制，“开放”系统对于某些单元操作来说是唯一可以利用的系统。无菌BPC的工艺培养可能既包括“开放”又包括“封闭”部分。在工艺模拟过程中使用的测试方法必须包括系统的所有部分，不论是“开放”或“封闭”，或者是它们之间的过度系统的所有部分（见第3节）。1.4.1. Closed Systems封闭系统A closed system is one that is designed to prevent the ingress of microorganisms by means of physical separation from the surrounding environment. A closed system:“封闭”系统是旨在通过物理分离方法来防止周围环境中的微生物的侵入。“封闭”系统：Is constructed, installed and qualified in a manner which demonstrates integrity is maintained throughout the full range of operating conditions, and over a time period inclusive of the longest expected usage (i.e., manufacturing campaign). The qualification is done according to a formal protocol, following generally accepted engineering principles, and is documented.建造，安装的方式保持完整合格的整个运作情况，并且在一段时间内最长的包容性的预期使用（即生产活动）。遵循普遍接受的工程原则、根据正式协议，条约被制定并记录在案。Is sterilized-in-place or sterilized while closed prior to use using a validated procedure就地消毒或在使用验证程序前封闭消毒Can be utilized for its intended purpose without breach to the integrity of the system可以利用其设计而不违反该系统的完整性Can be adapted for fluid transfers in and/or out while maintaining asepsis保持无菌的状况下适应液体的流进和/或流出。Is connectable to other closed systems while maintaining integrity of all closed systems (e.g., Rapid Transfer Port, steamed connection, etc.)在保持所有封闭系统的完整性的同时可与其他封闭系统连接（例如，快速传输接口，蒸汽连接等）Is safeguarded from any loss of integrity by scheduled preventive maintenance.是否有防护措施以避免定期预防性维修产生的完整性损失。Utilizes sterilizing filters for sterilization of process streams which are integrity tested and traceable to each product lot.利用除菌过滤器进行工艺线的灭菌，过滤器进行完整性测试并可追溯到每一个产品批次。By virtue of their design, closed systems provide a substantially increased measure of protection to the materials processed within. Where a sterile BPC can be processed in its entirety within closed systems, the risk of contamination is negligible.由于他们的设计的优越性，封闭系统提供了内部材料加工保护措施。无菌BPC可以在整个封闭的系统内处理，污染的危险是微不足道的。1.4.2. Open Systems开放系统An open system lacks one or more of the features of a closed system.“开放”系统缺乏一个或多个“封闭”系统的功能。1.5. Considerations要考虑的事项A holistic approach must be used to adequately validate and control aseptic processes. A process simulation test is only a point-in-time representation of the capabilities of an aseptic processing system, including environment, equipment, procedures and personnel.验证和控制无菌加工过程必须充分使用一个全面解决办法。一个工艺模拟试验只是一个无菌处理系统能力的反映，包括环境，设备，程序和人员。It does not ensure that sterile bulk materials produced at other times will have the same level of microbiological quality.它并不能保证在其他时间生产的无菌散装物料将有相同的微生物质量水平。However, through control and validation of related processes, such as environmental monitoring, qualification of personnel and validation of cleaning and sterilization cycles, it is possible to maintain the level of asepsis demonstrated during the process simulation test.但是，通过控制和相关的进程的验证，如环境监测，人员评估和清洗验证以及消毒周期验证，它有可能在这个工艺模拟测试中保持无菌水平。Therefore, it is important to validate the related sanitization and sterilizationprocesses independently, such as sterilization/depyrogenation of the product, sterilization of the process equipment including product contact surfaces, sterilization of containers (intermediate and final packaged bulk), and support systems such as air, water, or nitrogen (6, 7, 8).因此，重要的是要独立验证相关的消毒和灭菌过程，例如灭菌/产品的除热原，工艺设备的灭菌，包括产品接触表面，容器的灭菌（中间产品和最终包装），支持系统，如空气，水，或氮（6，7，8）。Confidence in the sterility of a specific production lot is gathered through a number of process controls and procedures including: documented and validated sterilization/sanitization procedures, in-process controls regulating the production process, environmental monitoring, comprehensive batch records, extensive qualification of process equipment, and training of operating personnel.对一个具体生产批次的无菌的确信是通过过程控制和程序的序列号来收集，包括：被记载和验证过的杀菌/消毒程序，对生产过程监察的实时过程控制，环境监测，全面记录，工艺设备的全方位条件，和培训操作人员。2. PROCESS SIMULATION CONCEPTS AND PRINCIPLES工艺模拟的概念和原理2.1. Number and Frequency of Tests实验的次数和频率For a new facility or production process, process simulations can be performed as part of the overall validation. Initial process simulation tests, if performed, are conducted after equipment qualification, sterilization process validation, and personnel training have been performed, and environmental monitoring has demonstrated that the new facility is under the desired state of control (9, 10, 11). If a process simulation test fails in the absence of this supportive work, identification of a possible root cause will usually be more difficult. Three consecutive successful process simulation tests are performed when evaluating a new facility or process. Prior to release of the new facility, or new process for production use, acceptable results from these process simulation tests should be achieved to demonstrate the reproducibility of the process.对应一个新的设施或生产工艺，工艺模拟应该作为所有验证的一部分。最初的工艺验证应该在设备确认、灭菌工艺验证、人员培训已经完成并且环境监测证明新的设施已经在预期的状态中受控之后进行(9, 10, 11)。如果没有作这些支持性的工作，工艺模拟实验失败的话，将很难确定可能的原因。当确认一个新的设施或工艺时，验证一个工艺应该进行三次连续成功的模拟工艺实验。在为生产使用正式批准一个新的设施、新的工艺之前，应该完成这样连续的可接受的结果，以证明工艺的可重复性。In existing facilities, a process simulation test program should be considered for each aseptic process. Additional process simulation tests may be considered to evaluate changes to procedures, practices or equipment configuration (See Section 11Periodic Reassessment).在现有设施，过程模拟测试程序应被考虑到每个无菌过程。追加工艺模拟试验可被用来评估程序、实践或设备配置的变更（见第11期再评估表）。Process simulations for closed systems can be performed after sterilization to confirm the acceptable sterilization of the systems as well as the appropriateness of the procedures employed within. The duration of campaigns for closed system may be established through physical monitoring of such aspects as pressure differentials, leak rates, filter integrity tests, etc. and is further supported by a preventive maintenance program. End of campaign process simulations are thus not required for the closed portions of a process system. The duration of campaigns for open systems may be confirmed through appropriate process simulations conducted at the end of a real or simulated campaign.封闭系统的过程模拟可以在灭菌后实施，以确认该系统的灭菌合格性以及内部程序的适当性。在封闭系统的工作持续时间可能将通过如压力差，泄漏率，过滤器完整性测试等物理等方面的监测来被确定，并进一步被预防性维修计划所支持。工作过程模拟的完成不需要一个工艺系统的封闭部分。开放系统的工作持续时间可能通过真实或模拟的工作结束时进行的适当的工艺模拟来被确认。2.2. Worst Case最差条件One of the more prevalent techniques used in the validation of pharmaceutical processes is the employment of worst case scenarios.在制药工艺验证中最常采用的技术之一是采用“最差条件”。The use of worst case situations is intended to provide a greater challenge to the process, system or equipment being validated than that experienced under routine processing conditions.采用“最差条件”是有意对工艺、系统、设备在更高的挑战条件下进行验证。If, under the circumstances of the worst case challenge, acceptable results are achieved, then there is greater confidence in the reliability of the system under more normal situations.如果在“最差条件”的挑战下，仍能够达到预期的可接受标准，那么在正常条件下，对系统的可靠性将有更高的信心。Process simulation tests readily lend themselves to worst case challenges. Some of the types of challenges which may be employed where possible are:工艺模拟实验很容易进行“最差条件”的挑战。下面提供了一些类型的挑战：using materials, equipment, utensils and other items which have remained in the aseptic processing area for extended periods after sterilization。使用的原料、设备、器具等在灭菌后于无菌工艺区保留时间超出期限。using the maximum number of personnel necessary to process the batch。使用人员数超过灌装工艺所需。increasing the time period between the completion of equipment sterilization and the start of the process simulation。设备消毒的完成与开始模拟之间时间间隔过长using a growth promoting medium or placebo material in the process simulation test rather than an inhibitory material。在工艺模拟实验中使用促生长培养基或安慰剂，而不是使用有抑制性的处方。performing a process simulation test after completion of the last lot in a production campaign。在最后的生产完成后进行工艺模拟实验。The conduct of a process simulation for a sterile bulk typically includes activities and manipulations that are specific for its execution.对于无菌原料的工艺模拟的进行通常包括大量特定的活动和操作。These added steps introduce a higher potential for contamination than is inherent in the routine process and pose an increased risk for process simulation failure.相比固有的常规工艺，这些额外的步骤导致了更高的潜在污染，增加了过程模拟失败的风险。In the development of protocols or procedures used for the definition of process simulation tests, the use of worst case challenges such as those described above is an essential element of a well-founded program.在建议用于定义工艺模拟试验的方案或过程时，一个有良好根据的程序会使用上面提到的“最差条件”的挑战。The worst case challenges selected may vary based upon the specific type of process simulation utilized (see Sections 3 and 4).对“最坏条件”的挑战的选择可能会根据运用的工艺模拟的类型特点有所不同（见第3和4章）。Risk assessment approaches such as hazard analysis and critical control point (HACCP), failure effects mode analysis (FEMA) or fault tree analysis (FTA) may be used to determine appropriate challenges.正式的风险评估方法，例如HACCP、FEMA或FTA可以用于确定合适的挑战。3. PROCESS SIMULATION TEST METHODS工艺模拟试验方法The application of these general procedures to any specific aseptic procedure may require modification of the methods described herein. These adaptations should be accomplished in a manner which will not improve the result