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 reflect6years 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.本文提供了无菌原料药生产加工有关的验证指导。
它借鉴了PDA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。
我们还尽量列举一些FDA对其早期版本的审查中提出的一些问题。
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，一般都需要与成品药的制造完全不同的设备和程序。
无菌原料生产方法的独特性，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1.1Purpose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1.5Considerations需考虑事项2.PROCESS SIMULATION CONCEPTS AND PRINCIPLES工艺模拟的概念和原理2.1Number and Frequency of Tests测试的数量的频率2.2Worst Case最差条件3PROCESS SIMULATION TEST METHODS工艺模拟的测试方法3.1Total Process Simulation总工艺模拟3.2Unit Operation(s)Simulations单元操作模拟3.TEST MATERIALS USED IN PROCESS SIMULATION工艺模拟中用到的测试原料4.1Growth Medium Simulations培养基模拟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测试原料样品的评估6.DOCUMENTATION文件7.ENVIRONMENTAL MONITORING环境监测8.ELEMENTS OF PROCESS SIMULATION TESTS工艺模拟测试的要素8.1Interventions干扰8.2Duration of Simulation模拟的持续时间8.3Production Batch Size/Process Simulation Test Size生产批量/工艺模拟测试的批量8.4Incubation Conditions培养条件8.5Operating Procedures操作程序8.6Staffing Considerations全体人员的考虑8.7Campaigns活动8.8Equipment Qualification设备资质9.INTERPRETATION OF RESULTS AND ACCEPTANCE CRITERIA结果的解释和可接受标准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失败调查和纠正措施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APPENDIX2,DEFINITIONS附件2，定义APPENDIX3,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的明确的概念相结合。