PDA - TR28 中英 无菌原料药工艺模拟验证（2006年）

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 PDA's and PhRMA's 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。

Table of Conents 目录

1. INTRODUCTION 简介 1.1 Purpose 目的

1.2 Sterile Bulk Pharmaceutical Chemicals. 无菌原料药 1.3 Scope 范围

1.4 Sterile BPC Production Technology 无菌BPC生产技术 1.4.1 Closed Systems 封闭系统 1.4.2 Open Systems 开放系统 1.5 Considerations 需考虑事项

2. PROCESS SIMULATION CONCEPTS AND PRINCIPLES工艺模拟的概念和原则 2.1 Number and Frequency of Tests 测试的数量的频率 2.2 Worst Case 最差条件

3 PROCESS SIMULATION TEST METHODS 工艺模拟测试的方法 3.1 Total Process Simulation 总工艺模拟

3.2 Unit 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 4.1 Growth Medium Simulations 生长介质模拟 4.2 Placebo Material Simulation 安慰剂原料模拟 4.3 Simulation Without Material 无原料模拟 4.4 Production Material Simulation 生产原料模拟

5. EVALUATION OF SIMULATION TEST MATERIALS 模拟测试原料的评估 5.1 Evaluation of Entire Test Material 全体测试原料的评估 5.2 Evaluation 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 SIMULATION TESTS 工艺模拟测试的评估 8.1 Interventions 干扰

8.2 Duration of Simulation 时间模拟

8.3 Production Batch Size/Process Simulation Test Size 产品的批产量/工艺模拟的批量 8.4 Incubation Conditions 培养条件 8.5 Operating Procedures 作业流程 8.6 Staffing Considerations 人员的思考 8.7 Campaigns 活动

8.8 Equipment Qualification 设备限制

9. INTERPRETATION OF RESULTS AND ACCEPTANCE CRITERIA 结果的解释和可接受水平 9.1 Background 背景

9.2 Approaches for Acceptance Criteria 可接受水平的判定方法 9.2.1 Quantitative 定量 9.2.2 Qualitative 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,SELECTION AND STERILIZATION OF TEST 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 following definitions 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 \(see below). While it is recognized that a \system is generally preferred, there are process and equipment limitations such that \train for a sterile BPC may include both \must include all portions of the system whether \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 \the surrounding environment. A \

“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 \“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 sterilization processes 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, identifi-cation 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 11—Periodic 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

? The production material must be evaluated for lack of inhibitory effects on microorganisms, or a neutralizing agent must be added.

必须评价生产物料对微生物没有抑制作用，或必须添加中和剂。 ? The production materials may be extremely costly. 生产物料可能很昂贵。

? Testing of large quantities of material may be required. 需要测试大量的物料。

5. EVALUATION OF SIMULATION TEST MATERIALS 模拟测试物料的评价

Regardless of the material chosen for use in the simulation trial, it is important to evaluate that material to determine whether microorganisms were present as well as its microbial growth support characteristics.

不管模拟试验使用中所选择的物料是什么，评价物料以决定是否有微生物存在以及它的微生物生长支持特性是重要的。

5.1. Evaluation of Entire Test Material 全部测试物料的评价

The entire quantity of material (product, placebo or growth medium) utilized in the simulation is evaluated. This can be accomplished by filtration (after reconstitution for solid materials) through an appropriate sterilizing grade filter or by direct incubation of filled containers. The filter is tested to quantify the microbial bioburden of the material. Care must be taken to test (and reconstitute if necessary) using methods, controls, procedures, equipment and facilities which will not introduce contamination into the material being tested. The entire quantity of material can be subjected to microbial count or sterility testing depending upon the acceptance criteria requirements of the protocol. 评 价模拟试验中所使用的所有数量的物料（产品。安慰剂，或生长培养基）。可通过适当的无菌级过滤器（固体物料的重新组合）进行过滤，或直接接种在所分装的容 器中。测试过滤器以量化物料的微生物负荷。特别注意使用的测试方法（必要时重新组合）、控制、程序、设备和设施，测试时不得将污染引入物料中。所有数量的 物料应接受微生物计数或无菌测试，决定于方案需要的可接受标准。 Advantages 优点

? Evaluates all of the material processed in the equipment. 评价设备中加工的所有物料。 Disadvantages 缺点

? Testing of large quantities of material is required which can prove quite cumbersome. 需要测试大量的物料，消耗很大。

? Validation of sampling and testing methods, including the sterilization of all apparatus. 取样和测试方法的验证，包括所有装置的灭菌。

? Limited information is available for use in detecting the source of contamination in the event of failure. 在失败事件出现时，检测污染的来源能利用的信息很有限。

? Isolation and identification of microorganisms from the filter may be difficult with certain materials. 某些物料中从过滤器分离和鉴定微生物可能很困难。

? The test (and reconstitution) procedures may introduce contamination into the sample. 测试（重新组合）程序可能引入污染到样品中。

? Poorly suited to powder materials where the handling required to prepare the material for test in this fashion has substantial potential for the introduction of contamination.

该方法中，很少有合适的需操作的粉末物料可用来准备物料以满足测试要求，极有可能引入污染。 ? Direct incubation mandates a pass/fail acceptance criteria. 直接接种授权合格/失败的可接受标准

5.2. Evaluation of Test Material Samples 测试物料样品的评价

Samples may be taken to assess the potential for contamination at intervals during the process simulation. These samples may be of benefit in identifying when and where contamination was introduced into the process train. The use of a sampling method for either the qualitative or quantitative confirmation of process asepsis is inappropriate.

在工艺模拟期间应定期取样以评价潜在的污染。这些样品对确定何时和何处对工艺链引入了污染很有益。无论是定性或定量确定工艺缺陷，使用取样的方法是不合适的。

6. DOCUMENTATION 文件

Documentation is one of the most important elements of a process simulation test program. Regulatory bodies will rely heavily on the documentation to judge the adequacy of the simulation.

文件是工艺模拟试验方案的最重要因素之一。法规管理机构非常依靠文件来判断模拟的适当性。

The first step is to define the process to be simulated. The process generally is defined as all steps from the sterilization of the sterile BPC, solvents, reactants, containers and to the point the final sterile BPC is sealed in its shipping container. The process definition should include a description of all points that require aseptic intervention. Once the process has been clearly defined, the simulation protocol(s) or procedures can be written. These documents should include but not be limited to the following information:

第一步是定义模拟的工艺。工艺一般定义所有的步骤，从无菌原料药的灭菌，溶剂，反应物，包装容器直到无菌原料药密封进最终的发货容器中。工艺定义应包括无菌干涉所需要的所有点的描述。一旦工艺清楚定义后，可编写模拟方案或程序。这些文件应包括但不仅限于下列信息： Identification of the process to be simulated 确定所模拟的工艺。

? Identification of the process train and equipment to be used 使用的工艺链和设备的确定。

? Type of container/closure to be used 使用的包装容器/密封的类型

? Number of personnel participating 参与的人员数量

? Test material to be used 使用的测试物料

? Environmental monitoring to be performed 进行的环境监控

? A copy of the batch record to be used 使用的批记录的副本

? Acceptance criteria to be utilized 使用的可接受标准

? Description of the documentation required for the final report 最终报告所需要的文件的描述

? Rationale for the \ 选择的“最差状况”参数的理由

The above list should not be considered all-inclusive. Other factors may have to be considered due to the nature of the process to be simulated.

上述列表不能认为以全部列出。按照所模拟的工艺的特性应考虑其他因素。

Execution of the protocol is generally performed through the use of a batch record. The batch record gives detailed instructions on how to perform the process simulation test(s). It should be written in the same format as a normal batch record and contain the normal data and sign-off elements. Information which normally would be attached to a batch record also should be attached to the simulation batch record, i.e., sterilization records for equipment, containers, and utensils, etc. The next step is to document the following:

方案的执行一般通过使用批记录执行。批记录给出了进行工艺模拟试验的详细指导说明。应按照于正常批记录的相同格式填写，包括正常数据和签名元素。正常需要添加于批记录的信息也应添加在模拟批记录后，即设备、容器和工具等灭菌记录。下一步是用文件记录下列： ? Number of organisms detected, if any 检测到的生物体的数量，如有

? Results of environmental testing performed. 进行的环境测试的结果

The final report is a summation of the data from the batch record, bioburden testing of simulation material and environmental monitoring samples. Based upon this information, a conclusion is formulated regarding the acceptability of the manufacturing process and facility.

最终的报告是批记录、模拟物料的生物负荷测试和环境监控取样的数据总结。以此信息为基础，形成关于生产工艺和设施的可接受性的结论。

7. ENVIRONMENTAL MONITORING 环境监控

Details concerning elements of an effective environmental monitoring program, including sample site selection, sample frequency, alert and action levels, methodology and interpretation of data, can be found in the literature (12).

关于有效的环境监测方案元素的细节，包括取样位置选择，取样频率，警戒和行动限，方法和数据的解释，可在参考文献(12)中找到。

8. ELEMENTS OF PROCESS SIMULATION TESTS 工艺模拟测试的要素

This section contains important general information to consider when conducting process simulation tests. These issues play an important role in effectively simulating the production process.

该部分包括了进行工艺模拟试验时需要考虑的重要常规信息。这些主题对有效模拟产品工艺扮演了重要角色。 8.1. Interventions 干扰

Process simulation tests must include the normal activities that occur during an aseptic process (i.e., equipment adjustments, container-closure re-supply, sampling, etc.) in order to substantiate the acceptability of those practices in routine operation. Non-routine (corrective) interventions may be incorporated into the process simulation. It is possible that non-planned interventions may occur during the simulation and that it will be necessary to correct for fluid leakage, equipment malfunction, etc. To the extent that these types of problems occur on their own, and are rectified during a successful process simulation test, they can be defended as acceptable during normal operations (1, 13).

工艺模拟试验必须包括无菌工艺时会出现的正常活动（即设备调整、包装容器-密 封再供应，取样等），为了证实这些行为在正常操作中的可接受性。非日常（纠正）干扰可结合进工艺模拟中。在模拟时可能会出现非计划的干扰，可能有必要进行 流体泄漏、设备故障等的纠正。对于这些类型的问题本身出现的程度，在工艺模拟试验中进行成功矫正以后，在正常操作时能够辩护为是可接受的。 8.2. Duration of Simulation 模拟持续时间

Process simulation tests should be of sufficient duration to evaluate the normal manipulations necessary for the process. Activities such as initial set-up activities, changing equipment and manual maintenance operations should be included in the process simulation tests. Process simulation tests also should be of sufficient duration to include a representative number of routine and atypical interventions which might occur during an actual production operation. Where they are part of normal operations, gown changes, breaks and shift changes should be simulated. The time duration of the process simulation has greatest relevance in operations such as milling and subdivision where repetitive tasks are performed and personnel borne contamination may be of greater relevance.

工艺模拟试验应持续足够的时间以评价工艺需要的正常操作。最初的设置活动、替换设备和人工维护操作等活动应包括在工艺模拟试验中。工艺模拟试验也应持续足够 的时间以包括在实际生产操作时可能出现的有代表性数量的日常和典型的干扰。作为正常操作的部分，更衣、休息和班次轮换也应模拟。工艺模拟的持续时间跟操作 有重要关系，例如粉碎和再次分装时进行重复性的操作，人员可能成为了重要的污染源。 8.3. Production Batch Size/Process Simulation Test Size 产品批量/工艺模拟试验规模

A process simulation test should utilize sufficient material to expose most, if not all contact surfaces to the material. It is essential that the aseptic manipulations in the simulation closely resemble those utilized in production; however the actual number need not be identical.

工艺模拟试验应利用足够的物料来展露最大的，如果不是所有的物料接触表面。模拟时的无菌操作应尽可能类似于生产时使用的方法是关键的；但是不需要等同于实际数量。

8.4. Incubation Conditions 培养条件

It is widely accepted that process simulation tests should be incubated for a minimum of 14 days. The temperature at which the medium is incubated, however, varies from firm to firm. The temperature chosen should be based upon its ability to recover microorganisms normally found environmentally or in the product bioburden. This same panel of microorganisms should be used in growth testing the medium-filled containers. A single incubation temperature in the range of 20-35°C may be used. Data should be available to show the suitability of the selected incubation temperature to support the growth of environmental and pre-sterilization bioburden isolates. The selected temperature should be controlled and monitored continuously throughout the incubation period.

普遍接受工艺模拟试验应培养至少14天。但是介质培养的温度各个公司不同。所选择的温度应基于对环境中正常发现的微生物或产品中的生物负荷的恢复能力， 应使用培养基灌装容器促生长试验中使用的微生物的同一平板。也可使用单一的20-35°C的培养温度范围。应存在数据显示所选择的培养温度的合适性以支持环境和预灭菌生物负荷分离菌株的生长。在整个培养期间应对所选择的温度进行持续控制和监测 8.5. Operating Procedures 操作程序

The instructions provided to the operators whether in the batch record proper or in supportive procedures must be sufficiently detailed to insure the reproducibility of the process. Process simulation instructions should follow the production procedures closely and must be similarly detailed. Close correspondence between the production and process simulation methodology confirms the acceptability of the procedures utilized.

在适当的批生产记录或支持性程序中提供的对操作人员的指示应足够详细，以确保工艺的重现性。工艺模拟说明应尽可能按照生产程序，同时应详细。生产和工艺模拟方法之间的近似关联性证明了所利用的程序的可接受性。 When the production batch size is small, there may be greater prevalence of manual operations in the preparation of sterile products. The process simulation of a manual process of this sort is carried out in accordance with the methods and practices outlined in this document, with one addition. Each operator who performs this type of manual process should be individually evaluated to establish the acceptability of their aseptic technique.

当产品批量很小时，无菌产品制备的手工操作非常流行。该类手工工艺的工艺模拟按照该文件中列出的方法和规范进行，另外增加一点。从事该类手工工艺的每个操作人员应逐个评价以设立他们无菌技术的可接受性。 8.6. Staffing Considerations 人员考虑

Each person who works in an aseptic production suite should participate in a successful process simulation test on a periodic basis.

在无菌生产组工作的每个人员应以一定的周期基础参加一次成功的工艺模拟。 8.7. Campaigns 生产周期

Multiple lots of sterile BPCs may be produced following a single sterilization without intervening cleaning of the equipment requiring a breech in the integrity of the system. The process simulation program should confirm the acceptability of this production mode for open systems. The simulation should be planned to effectively balance the goals of simulating, as closely as possible, the actual manufacturing process, and minimizing those conditions that would inhibit the recovery of microorganisms. As stated previously the duration of campaign length for closed systems is established through preventive maintenance and monitoring of physical data from the system.

在 单次灭菌后进行无菌原料药多批产品的生产，期间不进行清洗干扰，需要系统很好的完整性。工艺模拟方案应证明开放系统该生产模式的可接受性。计划的模拟应有 效平衡模拟试验的目标，尽可能接近实际生产工艺，并尽可能减少抑制微生物恢复生长的条件。按照先前的描述，密闭系统生产周期的持续时间长度通过该系统的预 防性维护和物理数据的监控来设立。 8.8. Equipment Qualification 设备确认

Process equipment and utility systems used in the preparation of sterile bulk systems should be subjected to documented qualification to confirm their acceptability for their intended use. This should include installation considerations including drawings, materials of construction, calibration, preventive maintenance program, etc.

无菌原料制备系统的工艺设备和公用系统应接受形成文件的确认，以证明它们满足预定目的的可接受性。应包括安装考虑，包括图纸、制造材料、校正、预防性维护方案等。

Of equal importance is the operational phase of the qualification in which operating procedures are verified, along with leak rates and pressure differentials. A part of this confirmation is measurement of process and equipment variables

during the simulated execution of the process. This confirmation can be used to establish a baseline of acceptable performance for the equipment which can be used to support the continued integrity of the process train over the length of a production campaign.

同样重要的是运行阶段的确认，此时操作程序被确认，以及泄漏率和压差。该确认的一部分是工艺模拟执行期间的工艺和设备变量的测量。也使用该确认设立设备可接受性能的基线，能用于支持整个生产周期期间工艺链的持续完整性。

9. INTERPRETATION OF RESULTS AND ACCEPTANCE CRITERIA 结果解释和可接受标准 9.1. Background 背景

The adoption of limits and acceptance criteria for process simulation tests is one of the more contentious subjects within the industry in recent years. Whatever the number of organisms allowed in a process simulation, the ultimate goal for the number of organisms in any process simulation test (at either the bulk or filling stage) should be zero (4).

近年来行业内工艺模拟试验采用的限度和可接受标准是一个更有争议的主题。不论工艺模拟测试中允许多少微生物量，任何工艺模拟试验中微生物数量的最终目标应为零（在原料和分装阶段）。

The acceptance criteria utilized for the simulation can be either qualitative (pass/fail) or quantitative (CFU/ simulation). The criterion choice depends upon the simulation methods utilized.

模拟使用的可接受标准可为定性（合格/失败）或定量（菌落数每次模拟）。标准的选择依赖于使用的模拟方法。 The selection of acceptance criteria for aseptic processing validation is the central issue to be resolved in the conduct of process simulation tests. This section offers guidance which can be used to establish appropriate limits and acceptance criteria for aseptic process simulation tests.

无菌工艺验证中可接受标准的选择是进行工艺模拟测试涉及的中心主题。该部分提供了指南，可用于为无菌工艺模拟试验设立适当的限度和可接受标准。

9.2. Approaches for Acceptance Criteria 可接受标准方法 9.2.1. Quantitative 定量

The dominant methodology for the validation of aseptic processes utilized for drug product compounding and filling utilizes a media process simulation approach. In conjunction with the execution of this evaluation, a firm typically selects an acceptance criterion (8). An adaptation of the final product container approach, that relies on a quantitative assessment of contamination levels, for sterile bulks is possible.

药物产品混合和分装使用的无菌工艺的验证的有效方法是利用培养基工艺模拟方法。与该评价的执行结合，一个公司选择一个特定的可接受标准。适应最终产品包装方法，无菌原料药可能可以依靠污染物水平的定量评估。 A microbiological growth medium is designed specifically to support or stimulate the growth of microorganisms. As it is a more rigorous challenge than processed products, which often provide neutral and sometimes hostile microbial growth environments, some low number other than zero is chosen as an acceptance criterion. Nevertheless, a contaminated process simulation should be a rare occurrence. Any contamination in a process simulation must be investigated.

特定设计的微生物生长培养基来支持或刺激微生物的生长。由于它是比所加工的产品更严格的挑战，经常是提供中性和有时候是不利的微生物生长环境，选择除了零之外的低数量作为可接受标准。但是，工艺模拟很少会出现受污染的情况。工艺模拟中的任何污染必须调查。

There are, however, significant technical problems in achieving this goal. Microbiological growth media and simulated products do not match real products perfectly in terms of their processing characteristics and microbiological growth support properties. Direct application of the process simulation acceptance criteria for aseptic filling to sterile bulk pharmaceutical chemicals is inappropriate for a number of reasons including:

因此，为达到此目的存在重大的技术问题。微生物生长培养基和模拟的产品在加工特性和微生物生长支持特性上与实际产品不能完美匹配。无菌原料药的无菌灌装直接应用工艺模拟可接受标准是不合适的，包括下列一些理由： ? introduction of extra processing equipment; 引入了额外的加工设备； ? added aseptic manipulations; 增加了无菌操作

? relatively few large containers are required; 几乎不需要相对大量的容器； ? inspectional difficulties in large containers; 大容量容器中的检查困难

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