1、1 / 63APIC 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 Contents 1.0 FOREWORD 前言2.0 OBJECTIVE 目的3.0 SCOPE 范围4.0 ACCEPTANCE CRITERIA 可接受标准4.1 Introduction 介
2、绍4.2 Methods of Calculating Acceptance Criteria 可接受标准的计算方法4.2.1. Acceptance criteria using health-based data 使用基于健康数据的可接受标准4.2.2 Acceptance criteria based on Therapeutic Daily Dose 基于日治疗剂量的可接受标准4.2.3. Acceptance criteria based on LD50 基于半数致死量的可接受标准4.2.4 General Limit as acceptance criteria 作为可接受标准的通
3、用限度4.2.5 Swab Limits 擦拭限度4.2.6 Rinse Limits 淋洗限度4.2.7 Rationale for the use of different limits in pharmaceutical and chemical production 在药品和化学生产中使用不同限度的合理性5.0 LEVELS OF CLEANING 清洁级别5.1 Introduction 介绍5.2 Cleaning Levels 清洁级别5.3 Cleaning Verification/Validation 清洁验收/验证6.0 CONTROL OF CLEANING PROCE
4、SS 清洁过程的控制7.0 BRACKETING AND WORST CASE RATING 分类法和最差情况分级法7.1 Introduction 介绍2 / 637.2 Bracketing Procedure 分类法程序7.3 Cleaning Procedures 清洁程序7.4 Worst Case Rating 最差情况分级8.0 DETERMINATION OF THE AMOUNT OF RESIDUE 残留量检测8.1 Introduction 介绍8.2 Validation Requirements 验证要求8.3 Sampling Methods 取样方法8.4 Ana
5、lytical Methods 分析方法9.0 CLEANING VALIDATION PROTOCOL 清洁验证方案9.1 Background 背景9.2 Purpose 目的9.3 Scope 范围9.4 Responsibility 职责 9.5 Sampling Procedure 取样程序9.6 Testing procedure 分析方法9.7 Acceptance criteria 可接受标准9.8 Deviations 偏差9.9 Revalidation 再验证10.0 VALIDATION QUESTIONS 验证问题11.0 REFERENCES 参考文献 12.0 G
6、LOSSARY 词汇13.0 COPYRIGHT AND DISCLAIMER 版本及声明 3 / 631.0 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
7、行了更新。The Task Force members are:- 以下是工作组的成员Annick Bonneure, APIC, Belgium Tom Buggy, DSM Sinochem Pharmaceuticals, The Netherlands Paul Clingan, MacFarlan Smith, UK Anke Grootaert, Janssen Pharmaceutica, Belgium Peter Mungenast, Merck KGaA, Germany. Luisa Paulo, Hovione FarmaCiencia SA, Portugal Fil
8、ip Quintiens, Genzyme, Belgium Claude Vandenbossche, Ajinomoto Omnichem, Belgium Jos van der Ven, Aspen Oss B.V., The Netherlands Stefan 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, Belgium Anthony Storey, Pfizer, U.K. Rainer Fendt, BASF, Germany
9、. 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。The integration of Cleaning Validation within an effective Quality System
10、 supported by Quality Risk Management Processes should give assurance that API Manufacturing Operations are performed in such a way that Risks to patients related to cleaning validation are understood, assessed for impact and are mitigated as necessary. 原料药生产企业应将清洁验证与有效的质量体系相结合，由质量风险管理来支持，了解与清洁验证相关的
11、患者风险，评估其影响，并在必要时降低风险。It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage. 重要的是，不能将对制剂生产企业的要求直接用于原料药生产商，
12、而不考虑在此阶段所用生产工艺的差异。For example, higher limits may be acceptable in chemical production compared to pharmaceutical production because the carry-over risk is much lower for technical and chemical manufacturing reasons 例如，与制剂生产相比，化学生产可以接受较高的残留限度，因为技术原因，化学生产所带入后续产品的残留风险会低很多。4 / 63The document reflects th
13、e outcome of discussions between APIC member companies on how cleaning validation requirements could be fulfilled and implemented as part of routine operations. 本文件反映了 APIC 成员公司之间关于如何满足清洁验证的要求及作为日常操作来实施的讨论结果。In addition, APIC is aligning this guidance with the ISPE Risk MaPP Guide11 that follows the
14、 Quality Risk Management Processes as described in the ICH Q9 Guidance on Quality Risk Management. 另外，APIC 将本指南与 “ISPE 基于风险的药品生产指南 ”保持一致，遵守“ICH Q9 质量风险管理”中的“质量风险管理流程”。The criteria of Acceptable Daily Exposure (ADE) is now recommended to be used by companies to decide if Dedicated Facilities are requ
15、ired or not and to define the Maximum Acceptable Carry Over (MACO) of APIs in particular, in Multi-Purpose Equipment. 目前推荐公司使用“可接受日暴露水平”标准来决定是否专用设施需要界定原料药“最大可接受残留 MACO”，特别是针对多用途设备。A new chapter is introduced to define factors that should be considered in Controls of The Cleaning Process to manage th
16、e Risks related to potential chemical or microbiological contamination. 放入了一个新章节，对“清洁工艺的控制”中要考虑的因素进行了定义，以管理与潜在化学和微生物污染有关的风险。The PDA Technical Report No. 29 Points to Consider for Cleaning Validation22 is also recommended as a valuable guidance document from industry. 也推荐企业将“PDA 第 29 号技术报告-清洁验证中应考虑的问
17、题”作为有用的指南文件进行参考。The following topics are discussed in the PDA document: Cleaning process (CIP/COP): design and qualification 以下问题在 PDA 文件中进行了讨论：清洁工艺（CIP/COP）：设计和确认 Types of residues, setting acceptance criteria, sampling and analytical methods 残留类型、设定可接受标准、取样和分析方法 Maintenance of the validated state:
18、 critical parameters measurements, process alarms, change control, trending 可能致癌的产品 Products that are likely to be potent or highly toxic; 可能具有效价或高毒性的产品 Products that are not likely to be carcinogenic, potent or highly toxic. 可能致癌、具有效价或高毒性的产品The corresponding ADEs recommended for these three categor
19、ies are 1, 10, 100 g/day, respectively. 对应此三类所推荐的 ADE 值分别为 1、10 和 100g/天。11 / 63Another possibility to calculate your ADE for intermediates or APIs, with no clinical or toxicological data (e.g. early development), is based upon the exposure duration of your next product. The values of the CHMP guide
20、line on the Limits of Genotoxic Impurities (ref. EMEA/CHMP/SWP/431994/2007) can be used for your ADE. 在没有临床或毒性数据（例如研发早期）时，计算中间体或 API 的 ADE 还有另一个办法，就是基于下一产品的暴露时长。可以将 CHMP 指南 “基因毒性杂质 ”（参见 EMEA/CHMP/SWP/431994/2007）限度值可以用于 ADE 计算。Note - If you decide to employ the concept of levels of cleaning (ref. se
21、ction 5), then different safety factors (ppm limits) may be used for different levels. Especially if the product cleaned out is within the same synthetic chain and covered by the specification of the API, much higher (qualified) levels are acceptable. 注：如果你决定采用清洁水平概念（参见第 5 部分），则对于不同水平可以采用不同的安全系数（ppm
22、 限度）。特别是如果被清洁的产品是在同一条合成链中，且其限度包括在原料药的质量标准中，则残留水平较高（确认过的）时也是可以接受的。4.2.5 Swab Limits 擦拭限度If homogeneous distribution is assumed on all surfaces, a recommended value can be set for the content in a swab. The maximum allowable carry over from one batch to another can be established based on e.g. ADE, NO
23、EL or TDD (see above). If the total direct contact surface is known, the target value for contamination per square meter can be calculated according equation 4.2.5-I. This can be used as basic information for preparation of a method of analysis and detection limit.如果假定所有表面上残留的分布是均匀的，可以给擦拭样品设定一个推荐值。可
24、以根据例如 ADE 值、NOEL 或 TDD（见上）设定一批到另一批的最大允许残留值。如果知道直接接触产品的总面积，则可以根据 4.2.5-I 公式计算单位面积上的污染目标值，该值可以在制订方法验证方案和检测限值时参考。MACOgEquation 4.2.5-I Target value g/dm2 = Total surface dm2MACOg公式 4.2.5-I 目标值 g/dm2 = 总表面积 dm2Also other methods with different swab limits for different surfaces in a piece of equipment a
25、nd/or equipment train can be used. If the equipment can be divided in several parts, different swab limits may be taken for the different parts building up the equipment train. If the result of one part is exceeding the target value, the whole equipment train may still be within the MACO limit. The
26、Carry Over is then calculated according equation 4.2.5-II (see below). 也可以对同一设备和/或设备链不同的表面使用不同的擦拭限度。如果设备被分为几个部分，对可以针对设备链不同部分采用不同的擦拭限度。如果一个部件的结果超出了目标值，整个设备链的残留值仍可能是在 MACO 的限度以内。这时，可以按公式 4.2.5-II（见下）计算残留量。During equipment qualification and cleaning validation hard to clean parts can be determined. Rat
27、her than declaring the hard to clean part as the worst case swab limit for the whole equipment train, it could be separated and dealt with as mentioned above. It should be noted that different types of surfaces (e.g. stainless steel, glass lined, Teflon) may show different recoveries during swabbing
28、. In those cases it may be beneficial to divide the equipment train in several parts, and combine the results in a table or matrix. The total calculated amount should be below the MACO, and the individual swab results should not exceed the maximum expected residues established during cleaning valida
29、tion / equipment qualification. Recovery studies and method validation are necessary when applying swabbing as a method to determine residues. 在设备确认和清洁验证中，可以确定哪个部件是难以清洁的。其实可以采用上述的方法来将难以清洁的部件分开来，而不需要采用最难清洁的部件作为最差擦拭情况的限度用于整个设备链。要注意不同材质表面（例如，不锈钢、搪玻璃、聚四12 / 63氟乙烯）可能有不同的擦拭回收率。在这种情况下，如果把设备链划分为几个部分，将结果在一份表
30、或类别中合并可能会比较好。合计数量应低于 MACO 值，单个擦拭结果不应超过在清洁验证/设备确认中所设立的最大高期望值。在使用擦拭方法测定残留量时，要进行回收率研究和方法验证。Equation 公式 4.2.5-IICO g = (Aidm2 mig/dm2)CO True (measured) total quantity of substance (possible carryover) on the cleaned surface in contact with the product, calculated from results of swab tests.采用擦拭检测结果计算出的
31、与产品直接接触的已清洁表面实际总残留量Ai Area for the tested piece of equipment # i. 所测试的 i 设备的面积mi Quantity in g/dm2, for each swab per area of swabbed surface (normally 1 dm2) 单位擦拭面积的残留数量4.2.5.1. Setting Acceptance Criteria for Swab Limits 对擦拭限度设定可接受标准For each item tested, the following acceptance criteria (AC) appl
32、y. 以下可接受标准适用于各测试项目：AC1. The cleaning result of an individual part should not exceed the maximum expected residue. 单个设备清洁结果应不超过最大可接受残留量。AC2. For the total equipment train the MACO must not be exceeded. 总设备链的 MACO 不得超过。In determining acceptance limits, all possible cases of following products in the r
33、elevant equipment shall be taken into account. It is proposed that a matrix be set up in which the limits for all cases are calculated. Either acceptance criteria for each product in the equipment can be prepared or the worst case of all product combinations may be selected. 在制订可接受限度时，要考虑在相关设备中可能生产的
34、所有后续产品。建议画出矩阵图，在其中对所有情况下的限度进行计算，然后针对在该设备中生产的每个产品分别制订可接受标准，也可以对所产品选择最差情况下的可接受标准。4.2.5.2. Evaluation of results 结果评估When all surfaces have been sampled and the samples have been analyzed, the results are compared to the acceptance criteria. Companies may find it easier to evaluate against the MACO. Ho
35、wever, it is advisable to have a policy for swab limit as well. Especially because analytical methods are validated within a certain range for swab results. Another reason is that some pieces could be very contaminated, and it is not good practice to clean certain pieces very thoroughly in order to
36、let others be dirty. Thus, limits for both MACO and swabs should be set. 在对所有表面取样后，对样品进行分析，将结果与可接受标准进行比较。公司可以发现采用 MACO 来评估会比较容易。但是，还是建议对于擦拭限制订一个原则，主要是因为擦拭样品分析方法的验证是在一定的浓度范围内进行的。另一个原因是有一些部件的污染可能会比较严重，没有理由让一些部件清洁的非常彻底而让另一些部件很脏。因此，应同时设定MACO 限度和擦拭限度。4.2.6. Rinse Limit 淋洗限度The residue amount in equipment
37、 after cleaning can also be determined by taking rinse samples. During equipment qualification it should be established that all direct content parts of the equipment is wetted / reached by the rinsing solvent. After the last cleaning cycle (last rinse), the equipment should be assessed as clean. In
38、 some cases it may be advisable to dry the equipment in order to do 13 / 63a proper assessment. Thereafter, the rinse cycle can be executed, and a sample taken (sampling rinse). The procedure for the rinse cycle and sampling should be well established and described to assure repeatability and compar
39、ability (cycle times, temperatures, volumes, etc.). The choice of the rinse solvent should be established during cleaning validation, taking into account solubility of the contaminations, and reactivity of the rinse solvent towards the contaminants (saponification, hydrolyses, etc). Method validatio
40、n is needed. 设备清洁后的残留量也可以采用淋洗样来检测。在设备确认时，应该识别出设备中所有可以被淋洗溶剂淋到的部件。在最后清洁（最后淋洗）结束后，设备状态应评估为“清洁”方可取样。有时，需要对烘干设备以便进行适当的评估。之后，对设备进行淋洗，取样（淋洗样）。应制订书面程序描述淋洗和取样操作，以保证其可重复性和可比较性（重复次数、温度、体积等）。在清洁验证时应对淋洗用溶剂作出选择，选择时应考虑污染物的溶解度，以及淋洗用溶剂与污染物之间的反应活性（皂化反应、水解反应等）。淋洗方法要进行验证。In a worst case approach, the amount of the resi
41、due in the equipment can be assumed to be equal to the amount determined by analysis of the rinse sample. This can be supported by rinse studies that show a strong decay of a residue in a piece of equipment. 如果采了最差情形方法，可以假定设备中的残留量与对淋洗样品的检测结果相等。这个假设可以通过对一个设备部件上淋洗前后残留物急剧减少来支撑。The MACO is usually calcu
42、lated on each individual product change over scenario according to the procedures outlined above and individual acceptance criteria are established using the following equation: 通常根据上述所列的方法，针对各个产品更换的情况计算 MACO。采用以下公式，可以计算出单个可接受标准：Target value (mg/L) = MACO (mg) / Volume of rinse or boil (L) 目标值 = MAC
43、O/淋洗溶剂体积For quantitation a solvent sample (e.g. 1 L) is taken, the residue in the sample is determined by a suitable analytical method and the residue in the whole equipment is calculated according to the following equation: 对于一定的取样体积（例如 1 升），采用适当的分析方法测定样品中的残留量，根据以下公式计算整个设备中的残留量：M = V*(C-Cb) M Amoun
44、t of residue in the cleaned equipment in mg 已清洁设备中的残留总量V Volume of the last rinse or wash solvent portion in L 最后淋洗或冲洗溶剂的体积C Concentration of impurities in the sample in mg/L 样品中杂质浓度Cb Blank of the cleaning or rinsing solvent in mg/L. If several samples are taken during one run, one and the same bla
45、nk can be used for all samples provided the same solvent lot was used for the whole run.空白淋洗或冲洗溶剂如果在一个轮次中取了几个样品，则可以采用其中一个空白用于该轮中所有样品的计算Requirement: M Target value. 要求：M 目标值The requirement is that M target value. If needed, the sample can be concentrated before analysis. 要求是 M 目标值。那天要时，样品在检测前可以浓缩。The
46、 choice for swab or rinse sampling usually depends on the type of equipment. Areas to be swabbed are determined during equipment and cleaning validation (hard to clean areas), and are preferably readily accessible for operational reasons, e.g. near the manhole. If swabbing of the indicated area is n
47、ot easy, rinse sampling is the alternative. The advantage is that the whole surface of 14 / 63the equipment is sampled for contamination, being provided that during equipment qualification, surface wetting testing was taken into account. Thus equipment used for milling, mixing, filters, etc. are usu
48、ally swabbed, whilst reactor systems are usually sampled by rinsing.选择擦拭样品还是淋洗样品通常取决于设备的类型。擦拭取样点应在设备验证和清洁验证中确定（难以清洁点），最好还要易于操作，例如接受人孔处。如果要取样的地方很难采用擦拭取样，可以采用淋洗取样。淋洗取样的优点是设备的整个表面都能被取样测试污染程度。淋洗取样时，要考虑表面润湿测试，该测试应在设备确认期间完成。鉴于此，用于粉碎、混合、过滤等的设备一般采用擦拭取样，而反应釜系统一般采用淋洗取样。4.2.7 Rationale for the use of different
49、 limits in pharmaceutical and chemical production 在药品和化学生产中使用不同限度的合理性Unlike in pharmaceutical production, where residues on the surface of equipment may be 100 % carried over to the next product, in API production the carry-over risk is much lower for technical and chemical manufacturing reasons. Thus higher limits may be acceptable in chemical production compared to pharmaceutical production. For example chemical processing steps often include dissolution, extraction and filtration steps that are likely to reduce significantly any resi
