PDA TR29 清洁验证(中英文)

清洁验证可接受限度（中英文版）（PDA TR 49内容节选3）4.0 Acceptance Limits Cleaningvalidation is performed to demonstrate the effectiveness and consistency of a cleaningprocedure. The rationale for selecting limits for product residues, cleaning agents and microbialcontamination, as well as any other process components, should be logically based on the materials thatimpact the manufacturing process and the safety and purity of the product. The acceptable limits forcleaning manufacturing systems and component s should be “practical, achievable and verifiable.” (8)Limits for cleaning validation generally contain some measure related to the active protein (or othermajor component of interest), some measure related to the cleaning agent, some measure related tobioburden levels, some measure related to endotoxin levels, and a requirement that the equipment bevisually clean. In addition, if there are any specific toxicity concerns related to the active protein or otherprocess components (for example, cytotoxicity, al lergenicity, or reproductive hazards), the manufacturer’stoxicology or pharmacology groups may determine if a modification of limits is required, or whether theuse of dedicated equipment is needed.In the discussion that follows, issues for limits are considered based on the nature of the residue and onthe stage of manufacturing (e.g., bulk active vs. formulation/fill). Manufacturing stages include bulk activemanufacturing (all steps resulting in the bulk active drug substance) and formulation/ fill (formulation ofthe bulk active into a finished drug product and primary packaging of that drug product). Bulkmanufacturing is further divided into upstream process steps (all process steps through harvesting) anddownstream process steps (purification and following steps).4.0 可接受限度清洁验证的目的是为了证明清洁程序的高效性与一致性。

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）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。

APIC原料药厂清洁验证指南（201405 中英文）ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC)GUIDANCE ON ASPECTS OF CLEANING VALIDATIONIN ACTIVE PHARMACEUTICAL INGREDIENT PLANTSAPIC 原料药工厂中清洁验证指南May 2014Table of Contents1.0 FOREWORD 前言The original version of this guidance document has now been updated by the APIC Cleaning Validation Task Force on behalf of the Active Pharmaceutical Ingredient Committee (APIC) of CEFIC.本指南文件的原版本现已由APIC清洁验证工作组代表CEFIC的APIC委员会进行了更新。

The Task Force members are:- 以下是工作组的成员Annick Bonneure, APIC, BelgiumTom Buggy, DSM Sinochem Pharmaceuticals, The NetherlandsPaul Clingan, MacFarlan Smith, UKAnke Grootaert, Janssen Pharmaceutica, BelgiumPeter Mungenast, Merck KGaA, Germany.Luisa Paulo, Hovione FarmaCiencia SA, PortugalFilip Quintiens, Genzyme, BelgiumClaude Vandenbossche, Ajinomoto Omnichem, BelgiumJos van der Ven, Aspen Oss B.V., The NetherlandsStefan Wienken, BASF, Germany.With support and review from:- 以下为提供支持和进行审核的人员Pieter van der Hoeven, APIC, BelgiumAnthony Storey, Pfizer, U.K.Rainer Fendt, BASF, Germany.The subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has continued to receive a large amount of attention from regulators, companies and customers alike.原料药生产工厂的清洁验证一直是法规人员、公司和客户等关注的问题。

清洁验证可接受限度-下（中英文版）（PDATR49内容节选4）清洁验证可接受限度-下（中英文版）（PDA TR 49内容节选4）4.2 limits for Cleaning agentsLimitsLimits for cleaning agents will also depend on the stage of manufacturing (formulation/fill vs. bulk activemanufacture). Typical cleaning processes for biotechnology involve either a caustic wash followed by aphosphoric acid step, or an alkaline detergent followed by an acidic detergent. Each of these situationswill be handled separately.4.2 清洁剂的限度清洁剂的限度也取决于生产的各个阶段（制剂/分装与原液生产）。

典型的生物制药清洁程序包括强碱清洗以及下一步的磷酸物的清洗，或者是碱性清洁剂以及随后的酸性清洁剂。

这些过程都是分开处理的。

4.2.1 limits for Commodity ChemicalsIf only commodity chemicals such as sodium hydroxide and phosphoric acid are used for cleaning, it iscommon practice to set limits for these indirectly as a conductivity value. Preferably, an acceptable levelof sodium hydroxide or phosphoric acid is established based on toxicity carryover calculations or based onthe effects on process parameters. The conductivity limit is then set at a level equivalent to thatconcentration at a specified temperature. It is typically the case that the conductivity limit established in this way is well above the conductivity limit for WFI at the same temperature. Therefore, limits are basedon either WFI specifications or on a slightly higher value (such as 5 μS/cm). The rationale for this is that itis more stringent than the “scientific” calculation allows.Furthermore, in many cases, phosphate ionsand/or sodium ions may be part of anysubsequently manufactured product. Therefore, carryover of smallamounts is not significant. It should also be noted that calculations based on toxicity of the commoditychemicals are extreme, since sodium hydroxide is not carried over into a final product as sodiumhydroxide, and phosphoric acid is not carried over into final product as phosphoric acid. If such chemicalswere carried over intact at high concentrations, process checks (such as a significant change in pH) wouldalso cause a non-conformance. Thus, the purpose is not to confirm compliance with WFI specifications,but rather to confirm low amounts of a cleaning agent. The rationale for allowing a conductivity limitslightly higher than the WFI limit is that the WFI limit applies to water in the recirculating WFI loop. Assoon as the water is taken out of that loop and passed through clean equipment (particularly throughspray devices where it can pick up carbon dioxide from the air), there is no expectation that it willnecessarily meet the WFI conductivity limit.4.2.1 市售化学试剂的限度如果只有市售化学试剂如氢氧化钠和磷酸用于清洁，那么通常的做法是用电导率的值为其设定间接的限度。

清洁验证之取样方法（PDA TR 49内容节选5 中英文版）5.0 Sampling Methods 取样方法It is essential to a cleaning validation program that the appropriate sampling techniques are utilized.Sampling must be conducted with techniques appropriate for the equipment surfaces and for the natureof the study, including the analytical methods used. This section discusses types of sampling methods,sampling recovery validation studies, and the training and qualification of samplers.在清洁消毒验证中采用适当的取样技术是必要的。

取样过程中涉及的技术方法应与设备表面和研究本质相适应，包括使用的分析方法。

这一部分讨论了取样方法的类型，验证取样回收研究以及取样人员的培训及资质。

5.1 Sampling Method Selection取样方法选择Selection of a sampling method depends on the nature of the equipment and the nature of the residue being measured. Sampling methods discussed here are direct surface sampling, swabbing, rinse watersampling and placebo sampling. It should be noted that while regulatory documents refer to swabbing as“direct” sampling and to rinse water sampling as “indirect” sampling, it is preferable and more descriptiveto refer to those sampling methods as “swab sampling” and “rinse sampling,” and reserve the term“direct sampling” for techniques such as the use of visual inspection.取样方法的选择取决于设备性质以及检测残留物的性质。

引言清洁验证对于降低来自生产设备的药品污染的可能性有着重要作用。

它证明了合适的清洁工艺可以持续充分除去生产设备上/系统中产品残留、工艺残留和环境污染，所以该设备/系统可以安全地生产后续产品（相同或不同产品）。

在本技术报告中，其他处方类型。

如果仅针对用于各种生产情况。

读者应自行决定这些原则和规范是否适用他/她的具体情况。

本报告建立在1998年PDA技术报告第29清洁验证(1)的基础上。

该报告还利用2010年PDA技术报告第49号“生物技术清洁验证的要点”的原则盒要点(2)。

本修订版技术报告第29号作者非常感谢这两个较早版本的工作组成员，使我们的工作变得更容易。

本修订版技术报告提出了更新的信息，即结合了生命周期的验证方法和国际协调会议（ICH）的指导原则Q8 (R2) -药物开发、Q9-质量风险管理和Q10-制药质量体系 (3,4,5)。

此外，这份报告也有助于读者建立或评估自己的设备、设施的清洁验证计划。

该工作组是由欧盟和北美的制药专家、清洁化学品供应商和咨询公司组成。

该报告经过了一个全球性的技术同行评审，确保概念、术语、规范科学、合理，可在全球范围使用。

1.1目的/范围本技术报告涵盖了药品生产商清洁验证的各个方面，包括药物活性成分和药物制剂生产商。

也可以用于生物制药，但读者应该查阅PDA 技术报告第49 号“生物技术清洁验证要点”(2)，获得生物技术制造方面更多的细节和特性。

我们采用了生命周期的清洁验证方法，包括清洗工艺的设计/开发、工艺确认（包括方案实施）和持续验证维护。

尽管采用了基于风险的方法，本报告没有详细论述基于风险的生产。

PDA已经成立了撰写该主题技术报告的工作组。

我们怎么强调风险分析在清洁工艺的选择和验证过程中的重要性也不为过。

这包括传统的基于对产品质量和对患者的影响的风险分析。

也包括商业风险的考虑，例如采取措施将产品污染损失降至最低（即使有检测系统防止受污染的产品被放行）。

本技术报告中的这些规范和相关指南是基于技术考虑并可以用于所有监管环境。

清洁验证之分析方法-下(中英文版)（PDA TR 49内容节选7）6.5 Analytical Method Validation6.5 分析方法验证This section focuses on analytical method validation for “chemical” residues.这部分关注化学残留的分析方法验证Typically, endotoxin methods are compendia methods and do not require formal validation but require a confirmation for their application of use or suitability.内毒素方法是药典方法，不需要正式的验证，但需要使用或者适用性确认。

Microbiological methods that are approved microbiology laboratory methods do not require additional method validation.被微生物学实验室方法批准的微生物方法不需要额外的方法验证。

6.5.1 General Principles6.5.1 基本原则Since one key part of cleaning validation is setting residue limits and then measuring (using an analytical method) the actual residues left on surfaces after cleaning, it is critical that the analytical method be appropriately validated.因为清洁验证主要的一部分是设定残留限度，然后测量(使用分析方法)清洁后表面的实际残留。

生物制品清洁验证考虑要点（中英文版）(PDA TR49 节选1) 1.0 Introduction 介绍Cleaning validation plays an important role in reducing the possibility of product contamination from biopharmaceutical m a n u f a c t ur i n g equipment. It demonstrates that the cleaning process adequately and consistently removes product residues, process residues and environmental contaminants f r o m the cleaned eq u i p m e n t / s y s t e m , so that this eq u i p m e n t / s y s t e m can be safely used for t h e m a n u f a c t ur e of defined subsequent products (which may be the same or a different product). As used in this Technical Report, “product” may be a drug product, bulk active, intermediate, o r another type of f o rmu l a t i on .If “drug product” is intended, that terminology will be utilized. While cleaning validation for biotechnology m a n u f a c t ur i n g has many of the same elements as for o t h e r pharmaceutical manufacturing, there are enough differences such that a separate Technical Report focusing on biotechnology cleaning validation is appropriate.清洁验证在生物制药生产设备降低产品污染方面扮演了一个重要的角色。

Validation of Cleaning Processes (7/93) 清洁工艺验证GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES清洁工艺验证检查指南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：此指南是FDA 检查官和其工作人员的参考资料。

此文件不约束FDA，也不赋予任何人任何权利，特权，利益或豁免权。

I. Introduction 介绍Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.自从FDA的各文件，包括化学原料药检查指南和生物技术检查指南简单地提出了清洁验证这个话题之后，关于清洁工艺的验证已经引发了相当多的讨论。

这些官方的文件，都清楚地确定了对于清洁工艺需要被验证的期望。

清洁验证之取样方法（PDATR49内容节选5中英文版）清洁验证之取样方法（PDA TR 49内容节选5 中英文版）5.0 Sampling Methods 取样方法It is essential to a cleaning validation program that the appropriate sampling techniques are utilized.Sampling must be conducted with techniques appropriate for the equipment surfaces and for the natureof the study, including the analytical methods used. This section discusses types of sampling methods,sampling recovery validation studies, and the training and qualification of samplers.在清洁消毒验证中采用适当的取样技术是必要的。

取样过程中涉及的技术方法应与设备表面和研究本质相适应，包括使用的分析方法。

这一部分讨论了取样方法的类型，验证取样回收研究以及取样人员的培训及资质。

5.1 Sampling Method Selection取样方法选择Selection of a sampling method depends on the nature of the equipment and the nature of the residue being measured. Sampling methods discussed here are direct surface sampling, swabbing, rinse watersampling and placebo sampling. It should be noted that while regulatory documents refer to swabbing as“direct” sampling and to rinse water sampling as “indirect” sampling, it is preferable and more descriptiveto refer to those sampling methods as “swab sampling” and “rinse sampling,” and reserve the t erm“direct sampling” for techniques such as the use of visual inspection.取样方法的选择取决于设备性质以及检测残留物的性质。

清洁验证状态维护（PDA TR 49内容节选中英文版）8.0 maintenance of Validated state8.0 验证状态维护A key part of the validation life cycle for any system is maintenance of the validated state. This section deals with activities after the cleaning process has been designed and developed and after the formal validation protocols have been successfully executed. This is critical for cleaning validation, because a lapse in the validated state has the potential to adversely impact the quality, safety and purity of subsequent batches of the same or different products. The main tools for ensuring the continued maintenance of the validated state are change control, risk-based periodic monitoring and data trending review. Additionally, training and retraining are important areas of control for manual cleaning processes, as they are the primary mechanisms for controlling the cleaning cycle. In each of these three areas, knowledge of the design space (see Section 3.8) should be applied.验证状态维护是任何系统的验证生命周期的一个关键组成部分。