PDA_TR28 中英 无菌原料药工艺模拟验证(2006年)
PDA TR 80 《制药实验室数据完整性管理体系》中英文对照版
The consequences of failing to uncover data integrity problems through selfdiscovery or internal internal audit programs before they are found by regulatory agency inspectors can impact the outcome of the business. Similarly, the business impact on contract manufacturers, contract laboratories, and suppliers can be very serious if they fail to uncover and disclose data integrity problems before regulators or their customers’ auditors do. One of the responsibilities of regulatory agency investigators is to verify the accuracy, reliability, and integrity of data submitted in written form or other media prior to, during, or after an inspection, or as part of a drug submission for market authorization, annual report, mandatory quality defect report (e.g., Field Alert), or Adverse
原料药无菌工艺模拟验证国际认证要求
原料药⽆菌⼯艺模拟验证国际认证要求原料药⽆菌⼯艺模拟验证国际认证要求⾼海燕1 陈军丽2 丁恩峰3（1. ⽯药集团恩必普药业有限公司，⽯家庄 050031；2. ⽯家庄市第三医院制剂科，⽯家庄 050031；3. 英国施达化学集团公司中国代表处，⽯家庄 050031）在欧美药政法规体系⾥⾯，如果⽆菌制剂采⽤⽆菌原料药（API ）来制备，那么，⽆菌原料药的⽆菌性质对于制剂来说是⾄关重要的。
⽆菌原料药⼀般采⽤两种⽅法来制造：灭菌⼯艺和⽆菌⼯艺。
当原料药采⽤⽆菌⼯艺制造时，因为这种⼯艺⽆菌保证⽔平（SAL ）较低，因此，需要采⽤模拟验证来评估⽆菌⼯艺的保证能⼒。
在⽬前制药⾏业，通常采⽤⽆菌⼯艺模拟验证（也称为培养基灌装）⽅式评估⼯艺⽆菌保证能⼒。
API ；⽆菌⼯艺；模拟验证；培养基灌装；国际认证；美国注射剂协会；⽆菌保证⽔平；微⽣物数据偏差中图分类号： R951⽂献标识码： A⽂章编号： 1008-455X(2011) 02-0024-08International Certification Requirements for Simulating Validation ofAsepsis Process for Raw Material DrugsGao Haiyan, Chen Junli, Ding Enfeng(1. Shijiazhuang Pharma Group EBP Pharmaceutical Co., Ltd Shijiazhuang, 050031;2. Shiajiazhuang No. Hospital Shijiazhuang, 050031;3. China Representative Office, Great Briton Shida Chemical Group Co. Shijiazhuang, 050031)Abstract: In European and American pharmaceutical system, the asepsis level of asepsis raw material drugs is greatly important if asepsis agent is prepared with asepsis raw material drugs. Generally, asepsis raw material drugs are produced with two processes – sterilization process or asepsis process. If raw material drugs are produced with asepsis process, the simulation validation is needed because sterile assurance level in asepsis process is comparatively low. This is the reason that currently simulation validation is often used for asepsis process.Keywords: asepsis process; simulation validation is; media filling, international certification; PDA; sterile assurance level; microbial data deviation关键词摘要收稿⽇期：2010-12-28作者简介：⾼海燕（1976－），⾼级⼯程师，主要从事质量检验、质量保证、质量标准的制定、新药开发、eCTD 编制、计算机系统验证和国际注册等⼯作。
PDATR-29清洁验证中英对照（第一章—简介）
1. Introduction介绍1.1 Background背景In recent years, cleaning has achieved a position of increasing importance in the pharmaceutical industry. The current good manufacturing practices (CGMP) regulations recognize that cleaning is a critical issue to ensure product quality. Virtually every aspect of manufacturing involves cleaning, from the initial stages of bulk production to the final dosage form.近年来清洁作业逐渐在制药界占有重要的地位。
现行的GMP法规也指出清洁作业是保证产品质量的关键性工作。
自大宗原料的生产以迄最终剂型的制造作业，几乎每一个制造工序均含有清洁作业。
The CGMPs in the United States, Europe and other parts of the world have provided the pharmaceutical industry with general guidance for cleaning requirements. For example, in the U.S., section 211.67 of part 21 of the Code of Federal Regulations (CFR) states that "Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements." Section 211.182 of part 21 of the CFR identifies that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established. In addition to CGMPs, various inspectional guideline documents published by the FDA contain expectations regarding cleaning in the pharmaceutical industry. Cleaning is also addressed in the PIC recommendations on cleaning validation and in the SFSTP Commission report "Validation desprocédés de nettoyage."美国、欧洲及全球其他地区均有制药界清洁作业的通则性指南。
PDA_TR28中英无菌原料药工艺模拟验证（2006年）
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。
美国药典_USP28_NF23_附录无菌检查_李文东
除了以下的变更, 其他均按照以下供试品无菌 检查项下的方法进行检测。 薄膜过滤法
格、标准的法典。大多数由国家组织药典委员会编 制, 并由政府颁布, 具有法律的约束力。药典中规定 了常用药物及制剂的质量标准, 并将各种检查的具 体方法收入附录。各国药典在一定程度上可反映该 国家药物生产、医疗和科技的水平。目前, 随着中国 加入 WT O 组织, 药品的原料及各种制剂的进、出口 检验标准及方法均需要参照进、出口国的药典, 同 时, 在进口药品注册及进口药品质量复核时, 相应的 送审资料中均要求药品质量标准的检验方法及其译 文, 并且要求: 各类中文翻译件必须忠实原文, 并符 合中国的专业规范。引用最多的就是药典的附录部 分内容。本文将美国药典( USP 28/ NF 23) 附录中的 无菌检查章节译出, 希望给医药界工作者提供参考。
Sterility Test in USP28-NF23
L i Wen-dong, Wang G uo -lan, Y u L i( Beij ing I nstitu te f or Drug Control, Beij ing 100035)
译者按: 药典( P har macopoeia) 是一个国家记载药品规
硫乙醇酸盐流体培养基置 32. 5±2. 5℃培养。 硫乙醇酸盐培养基替代品
除琼脂和刃天青钠溶液外, 其它组份同硫乙醇 酸盐流体培养基配方, 同上法混合各组份并进行灭 菌, 用前放冷。灭菌后的pH 值为7. 1±0. 2。培养期 间是在厌氧条件下进行培养的。
无菌原料药的工艺模拟
常见的无菌药用化学品
• • • • • • • • • • • Penicillins Cephalosporins Penems Monobactams Other antibiotics Corticosteroids Arginine HCl Sodium Carbonate Sodium Citrate Biological intermediates Other API’s • • • • • • • • • • • 青霉素 头孢菌霉素 青霉烯 单环β-内酰胺类 其它抗生素 皮质类固醇 盐酸精氨酸 碳酸钠 柠檬酸钠 生物中间体 其它原料药
• 材料
– 需大量的培养基 – 在工艺模拟以前，灭 菌工作量很大，这类 灭菌程序均须须证 – 对模拟后大量培养基 检测极为困难 – 用来中和青霉素的β内酰胺酶用量极大
无菌BPC模拟的难点-续
• 残留
– 有必要将模拟分段，因为在许多BPC生产中，同时 会有液体及粉未设备的处理。 – 常规生产工艺采用的温度及pH，它们本身可能抑制 微生物生长 – 许多无菌原料药抑菌性比较强，因此，模拟前须彻 底清洁，去除所有生产的残留物。 – 工艺模拟残留污染会导致产品失败，模拟后应须彻 底清洁，去除工艺模拟的残留物。
• 所开发的工艺必须是完 善的—先决条件！！ • 参与验证的人员必须经 过适当的培训 • 生产环境、设备、分析 方法必须经过验证，为 产品及工艺服务 • 工艺验证方案必须经过 批准并分发相关人员
工艺验证二大组成+三个阶段
• 二大组成：
– 厂房设计、设备及公用系统的确认； – PQ/性能确认（验证）….只有在完成性能确认以后，方可进 入商业性生产阶段。性能确认中生产的产品，如果合格，可 以放行
– Despite these difficulties FDA is largely inflexible with regard to expectations in this area
FDA无菌原料药检查指南-中英文版
GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERSFDA无菌原料药检查指南Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).注：本文件是FDA现场检查官和其他FDA人员的参考资料。
本文件并不束缚FDA，也不赋予任何人任何权利、特权、好处以便获得赦免。
One of the more difficult processes to inspect and one which has presented considerable problems over the years is that of the manufacture of sterile bulk drug substances. Within the past several years, there have been a number of batches of sterile bulk drug substances from different manufacturers which exhibited microbiological contamination. One manufacturer had approximately 100 batches contaminated in a 6 month time period. Another had approximately 25 batches contaminated in a similar period. Other manufacturers have had recalls due to the lack of assurance of sterility. Although the Inspection Guide for Bulk Drug Substances provides some direction for the inspection of the sterile bulk drug substance, it does not provide the detailed direction needed.在过去多年中，现场检查最难的，也是出现问题最多的领域就是无菌原料药的制造。
PDA灌装翻译英中对照1
PDAPROCESS SIMULATION TESTING FORASEPTICALLY FILLED PRODUCTSPDA无菌产品模拟灌装工艺试验PDAASEPTIC PROCESSING MONOGRAPH REVISION TASK FORCEPDA无菌工艺技术专论修订版专题组September 19961996年9月James P. Agalloco. Agalloco＆Associates (Co-chair)James E. Akers,Ph.D.,Akers Kennedy & Associates, Inc.Doris L. Conrad,SmithKline Beecham(Co-choir) ＆Upjohn,IncWilliam R. Frieben,Ph.D.,PharmaciaEdmund M.Fry,PDACarol mpe,Baxter Healthcare CorporationRussell E.Madsen,PDAWilliam R.McCullers, Merck & Company,Inc.Terry E.Munson,Kemper-Masterson,Inc.Ronald F.Tetzlaff,Ph.D.,Kemper-Masterson,Inc.James D. Wilson,Isomedix,Znc.PREFACE前言This document replaces the previous PDA technical documents on the validation of aseptic processing: Technical Monograph No. 2, Validation of Aseptic Filling for Solution Drug Products, 1980; and Technical Report No. 6, Validation of Aseptic drug Powder Filling Processes, 1984. Our intent in this effort was to update these documents and expand the coverage to other dosage forms, as well as embrace the changing nature of aseptic processing technology within the global industry. We have attempted to address the subject as fully as possible, recognizing the notable contributions by other organizations, regulators, compendia and individuals who have worked in this area.这期文件取代了以前关于无菌工艺验证方面的PDA科技文件：1980年第2期科技专论-可溶性药物产品的无菌灌装验证；1984年第6期科技报告-无菌药物粉末分装工艺验证。
中英文-PDA TR54 药品和生物制品生产操作的质量风险管理实施
1.0 Introduction1.0 引言This technical report provides detailed guidance for the application and implementation of quality risk management (QRM) principles throughout the product lifecycle. The report emphasizes QRM application during commercial manufacturing and integrating QRM into the Pharmaceutical Quality System (PQS). Companion documents provide detailed examples of characteristic operations and how QRM principles and tools can be applied for biotechnology and sterile manufacturing of APIs, drug product (liquids and solids) manufacturing, packaging and labeling (e.g., PDA Technical Report No.44).这本技术报告通过产品的生命周期提供了应用和贯彻质量风险管理的详细指导。
报告强调在药品商业生产的过程中使用质量风险管理，并使质量风险管理与制药质量体系融为一体。
类似的文件提供了操作特性的详细例子，以及质量风险管理的原则和工具在生物技术、无菌原料药的生产、药物制剂（液体和固体）的生产，包装和贴标（例如PDA技术报告44）。
QRM is integral to an effective Pharmaceutical Quality System. Per ICH QlO, Pharmaceutical Quality System, QRM is an "enabler" (along with knowledge management) that can provide a proactive (while also supporting a reactive) approach to identifying， scientifically evaluating, and controlling potential risks to product quality and patient safety. QRM facilitates continual improvement of process performance and product quality throughout the product lifecycle (1).质量风险管理对于一个有效的制药质量体系是必须的。
中英文 PDA TR 干热灭菌验证
some may be subject to change in the future. However, the terms used in a validation program must be clearly defined and well understood within the company and clearly defined in internal Standard Operating Procedures (SOPs), standards, and in regulatory filings. For the purposes of this technical report, the following definitions are used. 使用的是当前FDA、ICH以及其他管理当局的名词定义，但技术报告团队添加上更清晰的内容这 种司之间的使用可能是不同的， 而一些术语在未来可能会有变化。但是，验证程序中使用的术语必须清晰定义并且能够在公司 内被清楚理解，在内部标准操作规程（SOP）、标准及管理文件中也应清楚定义。本技术报告 出于这样的目的，使用如下定义。
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1
术方法也可能存在并被应用，如果这些其他方法有合理的科学方法做支持。 This technical report is intended to give information about current industry practices and approaches to validating dry-heat depyrogenation and sterilization processes. In addition, sections will cover various aspects of dry-heat sterilization using biological indicators. 这份技术报告的目的是为目前工业实践以及干热除热原和灭菌工艺验证方法提供信息支持。此 外，报告的一些章节覆盖了干热灭菌使用的生物指示剂的各方面。 This technical report is organized in a chronological fashion, starting with a discussion of the general concepts of depyrogenation and sterilization science which are the foundation upon which to build a robust process. This includes use of biological indicators and endotoxin indicators. Also included are points to consider in equipment design, equipment verification, process development and performance qualification for new systems and the development and validation of processes for existing systems. 该技术报告是以时间顺序排列，以除热原和灭菌科学的通用概念开始，而这是建立稳固工艺的 基础。其中包括了生物指示剂和内毒素指示剂的使用。也包括了新系统的设备设计、设备确证、 工艺开发以及性能确认，还包括现有系统中工艺设计和验证中所需考虑的问题。 In the discussion of process development, particular attention has been given to the load type, loading patterns, and temperature profiles for depyrogenation and sterilization in both ovens and tunnels. The sections are followed by a brief discussion of items for consideration during routine processing and ongoing maintenance of the validated process. 工艺开发的讨论中，对于在烘箱和隧道中进行除热原和灭菌的负载种类、负载模式以及温度曲 线都给予特殊的关注。在已验证工艺的日常操作和持续维护中所需考虑的内容在这一部分也做 了简要讨论。 The background sections on depyrogenation/sterilization science and endotoxin/biological indicators are not comprehensive—but provide information specific to dry-heat processes. Information within the technical report is applicable to both forced hot air dry-heat batch processes (chambers) and to continuous processes (tunnels). Information within this technical report does not apply to dry-heat processes used for the sterilization of oil bases and oil based products, fixed processing streams or to those processes using infrared and microwave heating media. 关于除热原/灭菌科学和内毒素/生物指示剂的背景部分并不全面——但是所提供的信息是针对 干热工艺的。技术报告中的信息既适用于强制热空气干热批生产工艺（腔体），也适用于连续 性工艺（隧道）。本技术报告中的信息不适用于油性基质及油性基质产品，固定工艺流程或者 那些使用红外及微波加热介质的工艺中灭菌所用的干热工艺。 Current FDA, ICH, and other regulatory definitions are used except when more clarity is added by the Technical Report Team. Regulatory guidelines offer other definitions that maybe considered. Variations in the use of some terms may differ from company to company and
PDA TR 80《制药实验室数据完整性管理体系》(中英文对照版)
PDA TR 80《制药实验室数据完整性管理体系》（中英文对照版）PDA TR 80《制药实验室数据完整性管理体系》现已全文翻译完毕，大家可以点击文末“阅读原文”链接下载中英文对照版全文。
由于微信篇幅关系，这里只放出微生物实验室数据完整性的内容：5.0 Data Integrity in the Pharmaceutical Microbiology Laboratory5.0 微生物实验室的数据完整性5.1 General Considerations and Risks一般原则及风险The approaches used to investigate the occurrence of suspected data integrity issues that h recently occurred in a pharmaceutical microbiology laboratory can be challenging and, in some cases, may bevery different than those used to evaluate similar occurrences in an analytical chemistry laboratory, Many microbiological methods are performed manually;subsequently, the recorded results are often based on the visual observations by an individual scientist performing the tests.制药企业微生物实验室对可疑数据完整性问题的调查方法，越来越成为一个挑战，并且在一些情况下，与同样发生可疑数据的化学分析实验室的调查方法完全不同。
很多微生物测试方法都是手动操作，以及所有的测试结果都由微生物测试人员人工检查并记录。
PDA TR29(1998)中英文对照版[1]
![PDA TR29(1998)中英文对照版[1]](https://img.taocdn.com/s3/m/a7cef87f02768e9951e738ca.png)
清洁剂 4.3 Microbiological Contaminants
微生物污染 4.4 Other Contaminants to be Removed
蒲公英论坛首发。Eleven 制作，未经许可请勿在其他网站和论坛发布。
次要设备——主要设备 Materials of Construction 构造材质 2.4 Product Attributes 产品属性 Low Risk——High Risk Drugs 低风险——高风险药物 Highly Characterized——Poorly Characterized 高度特性化——缺乏特性化 Non-Sterile——Sterile 非无菌——无菌 2.5 Formulation Attributes 配方属性 Solids——Liquids 固体——液体 Soluble (Active or Excipient)——Insoluble (Active or Excipient) 可溶活性成分或赋形剂——难溶活性成分或赋形剂 2.6 Operational Issues 操作上的问题 Single Product Facility——Multiple Product Facility 单品种设施——多品种设施 Campaign Production——Batch Production 连续生产——批次生产 Simple Equipment Train——Complex Equipment Train 简单设备组合——复杂设备组合
PDA TR1(中文) 湿热灭菌验证
Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control湿热灭菌工艺验证：周期设 计，制定，验证和持续控制
Technical Report No. 1 (Revised 2007) 技术 报告No. 1（2007年修订） Supplement补充 Vol. 61, No. S-1
(retired) Richard V. Levy, Ph.D., PDA
Steen Loevtrup, Novo Nordisk A/S
Timothy F. Lord, Eli Lilly & Co.
Genevieve Lovitt-Wood, G.I. Lovitt & Associates, Project Manager and Technical Writer
湿热灭菌工艺验证： 周期设计，开发，验证和持续控制
Contributors作者
James P. Agalloco, Agalloco & Associates
James E. Akers, Ph.D., Akers Kennedy & Associates
Wilf Allinson, GlaxoSmithKline
© 2007 by PDA
TABLE OF CONTENTS目录
1.0 INTRODUCTION简介............................................................................................................ 2 1.1 Scope范围..........................................................................................................................2
PDA TR No.22-无菌工艺模拟培训讲义
• Products should perform as described and as expected
18
3
2011-9-5
质量
• 一个特定的产品符合设计或设计要求的程 度 (Duran 1974)
• 产品应安全、有效
• 为确保药品具有预期或所声称的鉴别、浓度、质 量及纯度，应设计、制订好产品及工艺控制的各 种书面规程
17
quality
• The degree to which a specific product conforms to a design or specification (Duran 1974)
US FDA Process Validation Guidance May ‘87
PDA TR 22 Published
Sep ‘96
US FDA Aseptic Pr源自cess Guide Sep ‘04
US FDA CGMP part 211 Revision
Sep ‘08
US FDA Process Validation Guidance Revision Jan ‘11
• 效价 • 效能 • 功效
• 译注 CGMP210.3中有单独的定义(16) Strength means: – (I) The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or – (ii) The potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard).
史上最全的PDA技术报告目录
TR No.68基于风险的药品短缺预防和管理方法
74.
TR No.69制药生产过程中的生物负载和生物膜管理
75.
TR No.70无菌生产设施清洁和消毒程序基础
76.
TR No.71新兴病毒检测方法
77.
TR No.72全球分销的被动热防护系统：资格认证和操作指南
78.
TR No.73生物技术应用的预充式注射器用户需求
TR No.实施使用前灭菌后完整性测试（PUPSIT）的注意事项
104.
TR No.与除菌级过滤器和除菌过滤相关的风险考虑要点
105.
TR No.远程和混合GMP/GDP审计中需要考虑的要点
106.
TR No.PDA考虑要点1无菌工艺2023
107.
TR No.考虑要点9从新冠疫情中吸取的教训
97.
TR NO.91批准后变更管理
98.
TR No.灭菌——药品灭菌技术报告和期刊文章汇编
99.
TR No.ATMP生产中微生物控制的注意事项
100.
TR No.老化设施的考虑要点
101.
TR No.过氧化物氧化敏感性的考虑要点
102.
TR No.在隔离器中对无菌药品进行无菌加工的注意事项
103.
91.
TR No.85弹性封盖和玻璃容器上可见颗粒检测和计数的增强测试方法
92.
TR NO.86药品包装完整性测试的行业挑战和当前技术
93.
TR NO.87药用玻璃瓶处理和加工的当前最佳实践
94.
TR NO.88制药行业微生物数据偏差和（MDD）调查分析
95.
TR NO.89疫苗开发策略
96.
无菌工艺模拟试验指南 英语
无菌工艺模拟试验指南英语Here is an English essay on the topic "Guidelines for Aseptic Processing Simulation Trials" with a word count of over 1,000 words:Aseptic processing is a critical component in the manufacturing of sterile pharmaceutical and biotechnology products. Ensuring the sterility and integrity of the final product is of paramount importance to protect patient safety. One key element of aseptic processing is the implementation of effective aseptic processing simulation trials, also known as media fills. These simulation trials are designed to mimic the actual aseptic manufacturing process and validate the ability of the personnel, facility, and equipment to maintain sterility throughout the process.The primary objective of an aseptic processing simulation trial is to challenge the aseptic process and identify any potential vulnerabilities or areas for improvement. By conducting these trials, manufacturers can assess the reliability and robustness of their aseptic processes, identify training needs for personnel, and ensure that appropriate controls and monitoring systems are in place.When designing and executing an aseptic processing simulation trial,there are several key elements that must be considered. The first step is to carefully plan and design the simulation trial to ensure that it accurately reflects the actual aseptic manufacturing process. This includes identifying the critical process steps, defining the scope and objectives of the trial, and determining the appropriate media and test methods to be used.One important aspect of the trial design is the selection of the growth medium or culture media. The media used should be representative of the actual product being manufactured and should support the growth of a wide range of potential microbial contaminants. The media should also be prepared and handled in a manner that mimics the actual aseptic process, including the use of appropriate sterilization methods and aseptic transfer techniques.The simulation trial should also incorporate all of the critical process steps, including equipment setup, materials preparation, filling, and sealing or closure of the final product containers. The trial should be designed to challenge the aseptic process by introducing potential sources of contamination, such as the introduction of viable microbial organisms or the simulation of equipment malfunctions or operator errors.During the execution of the simulation trial, it is essential to closely monitor and document all activities. This includes tracking themovement of personnel, monitoring environmental conditions, and conducting extensive microbiological testing of the final product containers. Any deviations or issues that arise during the trial should be thoroughly investigated and documented, and appropriate corrective actions should be implemented.One of the key challenges in conducting aseptic processing simulation trials is the need to maintain a high degree of rigor and attention to detail throughout the process. Even minor deviations or lapses in aseptic technique can have significant implications for the sterility of the final product. As such, it is essential that all personnel involved in the trial be thoroughly trained and equipped with the necessary skills and knowledge to execute the trial effectively.In addition to the technical aspects of the simulation trial, there are also regulatory and compliance considerations that must be addressed. Regulatory authorities, such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have established specific guidelines and requirements for the conduct of aseptic processing simulation trials. Manufacturers must ensure that their trials are designed and executed in compliance with these regulations in order to ensure the acceptability of their products and processes.Another important consideration in the design and execution ofaseptic processing simulation trials is the need to ensure the safety of the personnel involved. The introduction of viable microbial organisms and the handling of potentially hazardous materials can pose significant risks to the health and safety of the personnel involved. As such, it is essential that appropriate safety protocols and personal protective equipment (PPE) be in place to mitigate these risks.Overall, the successful execution of an aseptic processing simulation trial requires a comprehensive and well-designed approach that addresses a wide range of technical, regulatory, and safety considerations. By conducting these trials, manufacturers can gain valuable insights into the reliability and robustness of their aseptic processes, identify areas for improvement, and ensure the ongoing safety and quality of their sterile pharmaceutical and biotechnology products.。
PDA TR报告目录
PDA技术报告目录PDA是注射剂协会PDA TR 01 -2007湿热灭菌的验证灭菌程序的设计 2007PDA TR 03 -2013 用于杀菌和除热原干热工艺的验证 2013PDA TR 04 -1983 注射用水的概念设计 1983PDA TR 05 -1984 无菌药品包装：兼容性和稳定性1984PDA TR 07 -1985 热原去除1985PDA TR 08 -1987 注射溶液湿热灭菌的参数放行 1987PDA TR 09 -1988 商业化粒子测量系统的审核1988PDA TR 10 蛋白质和多肽注射制剂：稳定性和稳定剂 1988PDA TR 11 -1988 γ射线灭菌的注射剂 1988PDA TR 12 -1988包装组件的硅化1988PDA TR 13 -2013 环境监控计划基本要素2013PDA TR 14 -2008 蛋白纯化层析系统验证2008PDA TR 15 -2009 生物制药应用中切向流过滤的验证 2009PDA TR 16 -1992 弹性包装材料的辐射灭菌 1992PDA TR 17 Current Practices in theValidation of Aseptic Processing 1993 PDA TR 18 Reporton the Validation of Computer-Related Systems 1995 PDA TR 19 Rapid/Automated ID Methods Survey 1990PDA TR 20 Reporton Survey of Current Industry Gowning Practices 1990 PDA TR 21 -1990 生物负荷量回收率验证1990PDA TR 22 -2011 无菌灌装产品的工艺模拟 2011PDA TR 23 Industry Survey on Current Sterile Filtration Practices 1996 PDA TR 24 Current Practices in the Validation of Aseptic Processing 1996 PDA TR 25 混合均一性分析：验证和中控测试 1997PDA TR 26 -2008 除菌过滤验证2008PDA TR 27 -1998 药品包装的完整性1998PDA TR 28 -2006 无菌原料药工艺模拟验证（EN） 2006PDA TR 29 -2012 清洁验证考虑要点(2013) 2012PDA TR 30 -1999 药物最终灭菌的湿热参数放行 1999PDA TR 31 -1999 计算机化实验室数据收集系统验证 1999PDA TR 32 -2004 计算机系统与服务2004PDA TR 33 -2013 可选择的和快速的微生物检测方法的评价验证与执行 2013 PDA TR 33 -2013 可选择的和快速的微生物检测方法的评价验证与执行 2013 PDA TR 34 -2001 卫生保健产品制造和测试隔离系统的设计与验证 2001 PDA TR 35 -2001 医药行业的微生物作用建议的培训模式 2001PDA TR 36 -2001 无菌工艺验证现行惯例2001PDA TR 38 批准后生产用色谱系统：研发、生产和控制文件 2006PDA TR 39 -2007 温度受控药品的指导原则：在运输环境下保持温度敏感产品的质量 2007PDA TR 40 -2005 气体无菌过滤2005PDA TR 41 病毒过滤 2008PDA TR 42 -2005 蛋白生产验证2005PDA TR 43 药物生产用模型制备和管式玻璃容器的识别和分类 2007PDA TR 44 -2008 无菌过程质量风险管理2008PDA TR 45-2007使用纤维素基础深层过滤器的液体过滤 2008PDA TR 46-2009 最终里程：给最终用户的药物优良销售规范指南 2009PDA TR 47-2010 用于病毒清除研究的病毒加标样制备 2010PDA TR 48 -2010 湿热灭菌系统的设计、调试、运行、确认和维护 2010PDA TR 49 -2010 生物技术清洁验证考虑要点2010PDA TR 50- 2010 支原体检测的替代方法2010PDA TR 51 -2010 气体和气相净化工艺规范、制造、控制和使用的生物指示剂2010 PDA TR 52 药品供应链优良销售规范指南 2011PDA TR 53 -2011 行业指南：支持新药销售的稳定性测试 2011PDA TR 54-1 2012医药生产与生物技术的质量风险管理 2012PDA TR 54-2 2013 附录1：包装和标签质量风险管理案例研究实例2013PDA TR 54-3 2013 附录2：药品药品生产中的案例研究 2013PDA TR 54-4 2014 附录3：生物散装药用物质生产中的质量风险管理案例研究 2014 PDA TR 55 药物和保健行业中2，4，6-三溴苯甲醚和2，4，6-三氯苯甲醚污染和气味的检测和移除 2012PDA TR 56 治疗用蛋白质药用物质研发中与阶段相适当的质量体系和C GMP应用 2012PDA TR 57- 2012 生物技术产品的分析方法验证和转移2012PDA TR 58 温度受控销售风险管理 2012PDA TR 59 -2012 统计方法在生产监控中的应用 2012PDA TR 60 -2013 关于工艺验证生命周期2013PDA TR 61 -2013 在线灭菌2013PDA TR 62 -2013 人工无菌工艺的建议措施 2013PDA TR 63 临床试验临时制备药物的质量要求 2013PDA TR 64 在用温度控制系统：确认指南 2013PDA TR 65 -2014 技术转移2014PDA TR 66 -2014 药物生产中单次使用系统的应用2014PDA TR 67 -2014 非无菌药物、医疗器械和化妆品中致病菌排除2014PDA TR 68 -2015 预防和管理药品短缺基于风险的方法2015PDA TR 69-药品制造中生物负载和生物膜处理 2015PDA TR 70 -2015无菌制造设施的清洁和消毒程序的基本原理2015PDA TR 71病毒检测新方法 2015PDA TR 72 -2015 全球销售控温药品的防热保护系统：确认与操作指南 2015 PDA TR 73 -2015 预灌封注射器用户要求对生物技术的应用2015PDA TR 74 -2016 生物制药再加工 2016用于无菌处理的要点：1部分 2015。
PDA TR28技术报告介绍
模拟粉末的灭菌
在模拟介质选择的过程中，应确认可用适当的灭 菌方法对所选模拟介质进行灭菌。 在工艺模拟验证前，被评估物料应当使用经验证 的方法进行灭菌。 验证研究应包含灭菌过程不会对物料性质产生负 面影响的确认。
空白料抑菌性试验
抑菌性试验通常使用枯草杆菌 和白色念珠菌，还 应包括在无菌工艺区内可以发现的其他微生物。 空白料样品一般接种10-100 CFU的挑战微生物， 在20-25 ℃ 下培养7天，并以无空白料试管做阳 性对照。 液体空白料的促生长试验在接种后采用相同的方 法进行，其接种方法可以采用膜过滤法和直接接 种法。
Disadvantages
（1）无论是否出现微生物，都必须进行无菌检测或微生物计数检测。 （2）空白物料的清洗可能需要使用新的清洗方法。 （3）空白物料必须无抑菌作用 （4）必须验证无菌空白料的无菌性。 （5）可能需要检测大量物料。
无物料模拟
该方法已经用于评价操作程序和人员执行 的离散的操作，如向最终容器分装操作。 在模拟验证完成后，需进行大量的产品接 触面和人员的微生物取样。 根据方案的验收标准要求，表明取样的结 果可以用来确定微生物计数或无菌水平。 无物料模拟具有以下优缺点。
模拟介质样品评估
全部模拟介质评估
该方法是评估在模拟验证中使用的全部数 量的物料。 物料评估可以通过使用合适无菌级别的过 滤器进行过滤或直接接种来实现。 根据验证方案中验收标准的要求，对全部 数量的物料进行微生物计数或无菌检测。 该方法具有以下优缺点。
模拟介质的选择原则 无抑菌 Nhomakorabea用 如介质具有抑菌作用，可能造成假阴性的发生。
模拟介质应具备较好的溶解度
悬浮在培养基中的模拟介质使培养基发生浑浊，影响结果判断
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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 MA TERIALS 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. EV ALUATION OF SIMULATION TEST MA TERIALS 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 MA TERIALS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。