下载文档原格式
FDA清洁验证检查指南（中英文对嬉）清洗过程验证检查指南GUIDE TOINSPECTIONS VALIDATION OF CLEANINGPROCESSES请注意：本指南是检查官和其他FDA人员的参考材料。
本指南不受FDA约束,并没有赋予任何人任何权利、特权、收益或豁免权。
I•介绍L INTRODUCTION自从机构文件，包括原料药化学制剂检查指南和生物制剂检查指南，大体上提到该清洗问题以来，就出现了关于清洗过程验证的大量讨论。
这些机构文件清晰的建立了要验证的清洗过程需要达到的要求。
本指南是为了通过讨论实际操作是可接受的（或不可接受的），来建立检查要求的一致性和统一性。
同时，对清洗验证需要了解的是，像其他过程验证一样，可能有不止一种方法来对过程进行验证。
最后，任何验证过程的测试就是指科学数据是否显示出系统与要求相符和产生的结果是否符合预先定义的参数指标。
本指南只适用于化学残留物的设备清洗。
II•背景对于FDA来说,要求设备在使用前进行清洗并不新奇o1963GMP 法规倍B分133.4）中指出"设备S应该按照清洁和有序的方式进行维K在1978 CGMP法规中也包含了非常相似的有关设备清洗的护***o童节（211.6刀。
当然,清洁设备的主要理由是防止药品被污染或掺假。
在历史上，FDA检查官寻找由于对设备不当的清洗和维护和/或不良的灰尘控制系统而带来的总体不卫生情况。
而且，从历史上来说，FDA对非青霉素药品中的青霉素污染或药品中的活性激素或荷尔蒙交叉污染更加关注。
有很多药品在过去十年中被撤回就是因为实际的或潜在的青霉素的交叉污染。
导致FDA对由于不满足要求的过程导致交叉污染的可能性的进—步关注的案例是，1988年对成品药消胆胺树脂USP的撤回。
用于生产成品的原料药被生产农用杀虫剂中产生的中间体和降解物污染。
本案例中的交叉污染被认为是由于回收溶剂的重新使用。
回收溶剂由于缺乏对溶剂桶的重新使用的控制而被污染。
APIC 201405原料药厂清洁验证指南：4.0可接受标准（上）（中英文）注：本文件是由CEFIC 的APIC内的清洗验证工作组制定。
CEFIC: 欧洲化学工业委员会(cefic,europeanchemicalindustrycouncil)4.0 Acceptance Criteria 可接受标准4.1. Introduction 概述Companies must demonstrate during validation that the cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level. That limit established must be calculated based on sound scientific rational.公司在验证时要证明各设备日常所用的清洁程序能将带入下一产品的潜在残留限制在一个可以接受的水平。
所建立的限度必须进行科学合理的计算。
This section provides practical guidance as to how those acceptance criteria can be calculated. It is important that companies evaluate all cases individually. There may be specific instances where the product mix in the equipment requires further consideration.本部分提供实用的指南，指导如何计算这些可接受标准。
公司对各案进行各案评估是非常重要的。
有时还需要考虑产品从哪步开始混入设备中。
The acceptance criteria preferably should be based on the Acceptable Daily Exposure (ADE) calculations whenever this data is available. The Acceptable Daily Exposure defines a limit at which a patient may be exposed every day for a lifetime with acceptable risks related to adverse health effects. Calculations of Acceptable Daily Exposures of API’s and intermediates are usually done with involvement of industrial hygienists and toxicologists, who review all available toxicology and clinical data to set the limits. The justification of the calculation should be documented.如果可以获得可接受日暴露（ADE）值，最好依据其计算可接受标准。
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。
清洁验证之分析方法-上(中英文版)（PDA TR 49内容节选6）6.0 Analytical Methods分析方法It is essential to a cleaning validation program that the appropriate analytical methods are utilized.一个清洁验证程序使用适当的分析方法是非常必要的。
Analytical methods must be appropriate in that they can adequately detect the residue(s) of concern.分析方法必须适当，能充分检测到相关残留物。
It is also important to understand what can be concluded from the analytical result (e.g., was the productnot removed or was the cleaning agent not removed?).对能从分析结果中推断出什么的理解也是非常重要的（比如：产品没有被去除或清洗剂没有被去除？）。
The results of testing will determine if the cleaning validation cycle is acceptable or if it needs to beredeveloped.检测结果将决定清洁验证周期是否接受或者是否需要重新开发。
Thus, it is important to have confidence in the results.因此，对结果的信任是非常重要的。
This section discusses how to select the appropriate assay methods, detailed information on theapplicability and use of nonspecific assays and microbial test methods,and assay method validation.本部分讨论怎样选择合适的分析方法及其适用性的详细信息，非特定分析和微生物测试方法的使用，和分析方法验证。
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。
一般要求：FDA专家已经为各种设备写了SOP细化清洁过程。
如果一个产品的不同批次有相同的清洁过程，产品变换时用不同的清洁过程。
我们希望这些不同的细节能被写下来。
同样，如果一个过程用于清洗水溶性残留，另一个过程用于清洗非水溶性残留，这些过程应该被写下来，并且要判断这个过程是否实施。
散装的药品决定了特定装备的特定化学生产过程，很难从设备上清洗的残留物和胶状残留。
流体干燥床是另一个常用于特定产品的难以清洗的设备的例子。
任何清洗过程中的残留（溶剂等）要从设备上清洁FDA专家要求有一个清洗过程的书面流程要被验证FDA专家当可接受的验证和重复验证被要求时，希望验证过程确认谁为过程负责，并推进验证研究FDA 专家要求准备在确认样品过程和包括这些方法的敏感性在内的分析方法的每一个生产系统中或单一设备在样品生产过程中的在进一步研究中写下验证参数。
FDA专家要求对应于参数和结果研究文件的验证研究。
FDA专家希望有被经理推进的和标明了是否清洁过程被验证的最后的验证报告。
数据应该支持残留物已经被降到一个“可接受的程度”的结论。
清洁验证的评估第一步聚焦于验证过程的目标，一些企业已经在发展这些目标时失败了。
在看到企业使用清洁过程的特殊样品和实验过程没有真正的评价在评价清洁过程时一些问题要被提出。
例如：一个设备或系统在何时变干净？需要用手清洁吗？是用手还是用溶剂清洗干净？主要的清洗过程一批到一批，一个产品到一个产品很显然吗？这些问题的答案对于检查很重要对于要决定过程的有效性的清洁过程的评估时很重要。
对于分辨提高有效措施何公司资源的结果的步骤这些答案也有帮助。
决定每个设备的清洗过程号。
一个设备或系统有一个清洁过程，然而这将依靠生产的品种，和是否同一产品的批次之间（在一个大的时间段或不同产品的批次间清除干净了。
当清洁过程在同一产品的不同批次间（在大的过程中的不同批量的同一中间体）最严格需要为达到一个标准，设备的“明显清洁”。
这些批次间的清洁不需要验证。
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。
选择产品残留、清洁剂、微生物污染，以及其他任何工艺成分的限度，逻辑上应该基于物料对生产流程和产品的安全性和纯度的影响而定。
清洁生产系统和成分的可接受限度应该“切合实际、可达到、可证实”。
清洁验证的限度一般包含与活性蛋白（或者其他的主要物质成分）相关分析、与清洁剂相关的分析、与生物负载水平相关的分析、与内毒素水平相关的分析，以及设备目检清洁要求。
另外，如果存在任何与活性蛋白或者其他工艺组分相关的特别毒性物质（例如细胞毒性、变应原性、或者生殖危害物），那么生产商的毒理学或生理学团队就需要确定是否有必要改变限度，或者是否需要使用专用的设备。
在接下来的讨论中，限度的考虑应该基于自然残留和生产的各个阶段（例如，原液 vs.配制/分装）。
生产阶段包括主要原液生产（所有的步骤是为了获取活性药物）和配制/分装（将原液加入到成品的制剂以及药品物质的初级包装）。
原液的生产进一步分为上游生产步骤（收获药物前的所有步骤）和下游生产步骤（药物纯化以及后续步骤）。
4.1 key Issues in limits for activesBiotechnology cleaning processes often involvea change of the active molecule itself, which is commonlya protein. Proteinstypically are degraded to some extent by the cleaning processes commonly used inbiotechnology manufacturing. The most important mechanism for degradation is summarized below.In alkaline solutions, such as hot, aqueous solutions containing sodium or potassium hydroxide, proteinsmay hydrolyze to soluble oligomers or free amino acids. Ester groups on actives may be hydrolyzed to analcohol and a fatty acid. A common example of this is saponification of fats and oils to glycerol and fattyacid anions.Sodium hypochlorite is sometimes used inbiotechnology cleaning.Asacleaningagent,itisparticularly effectivein removing denatured protein residues from surfaces. It is a reactive oxidizer which will degrade proteinsin a more random manner to smaller fragments. A general concern with sodium hypochlorite use is its49 © Inc. 25xpossible deleterious effect on stainless steel components. Therefore, it is critical that the rinse cyclefollowing the use of sodium hypochlorite is adequate enough to remove any residual chloride ion beforeadding the subsequent acid wash.Proteins will hydrolyze at a high pH. The parameters of time and temperature have a significant influenceon protein hydrolysis. Therefore, the higher the temperature and pH, the more extensive proteinhydrolysis will occur. Because the protein is typically degraded into smaller fragments and thosefragments tend to be more polar, they are likely to be more water soluble and more readily removed fromequipment surfaces during the washing and rinsing processes. A second effect after protein exposure tohigh pH solutions is a possible irreversible, significant decrease of biological activity due to hydrolysis.4.1 活性物限度的关键问题生物技术的清洁过程经常涉及到活性分子本身的改变，因为这些活性物质通常是蛋白质。
在生物制品制造通常应用的清洁过程中，蛋白质都会在一定程度上发生降解。
下面就总结一下最主要的降解机制。
在碱性溶液中，尤其是高温，溶液中含有氢氧化钠和氢氧化钾，蛋白质就会水解成可溶的寡聚物或者自由氨基酸。
活性物质上的酯旨基团会水解为一个醇和一个脂肪酸，一个最为普遍的例子就是将脂肪和油脂转化为甘油和脂肪酸的皂化反应。
次氯酸钠有时会用于生物技术清洁，作为一种清洁剂，它能非常有效地从表面去除变性蛋白质残留。
它是一种活泼的氧化剂，它能够使蛋白质更随机地降解为更小的片段。
使用次氯酸钠时通常关注其对不锈钢成分的危害作用。
因此，关键的是，使用次氯酸钠后的漂洗循环能将氯离子残留冲洗干净，然后再进行酸清洁。
