APIC 原料药厂清洁验证指南-中英文2014.05

APIC 201405原料药厂清洁验证指南（中英文）

GUIDANCE ON ASPECTS OF CLEANING VALIDATION IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS

原料药工厂中清洁验证指南

May 2014

Table of Contents 1.0 FOREWORD 2.0 OBJECTIVE 3.0 SCOPE

4.0 ACCEPTANCE CRITERIA 4.1 Introduction

前言 目的 范围 可接受标准 介绍

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 使用基于健康数据的可接受

标准 data

基于日治疗剂量的可接受标4.2.2 Acceptance criteria based on 准 Therapeutic Daily Dose

4.2.3. Acceptance criteria based on LD50 4.2.4 General Limit as acceptance criteria 4.2.5 Swab Limits 4.2.6 Rinse Limits

基于半数致死量的可接受标准

作为可接受标准的通用限度 擦拭限度 淋洗限度

4.2.7 Rationale for the use of different limits 在药品和化学生产中使用不in pharmaceutical and chemical production 同限度的合理性 5.0 LEVELS OF CLEANING 5.1 Introduction 5.2 Cleaning Levels

5.3 Cleaning Verification/Validation 6.0 CONTROL OF CLEANING PROCESS

清洁级别 介绍 清洁级别 清洁验收/验证 清洁过程的控制

分类法和最差情况分级法 7.0 BRACKETING AND WORST CASE RATING 7.1 Introduction 7.2 Bracketing Procedure 7.3 Cleaning Procedures 7.4 Worst Case Rating

介绍 分类法程序 清洁程序 最差情况分级

8.0 DETERMINATION OF THE AMOUNT OF 残留量检测 RESIDUE

8.1 Introduction

8.2 Validation Requirements 8.3 Sampling Methods 8.4 Analytical Methods

9.0 CLEANING VALIDATION PROTOCOL 9.1 Background 9.2 Purpose 9.3 Scope 9.4 Responsibility 9.5 Sampling Procedure 9.6 Testing procedure 9.7 Acceptance criteria 9.8 Deviations 9.9 Revalidation

10.0 VALIDATION QUESTIONS 11.0 REFERENCES 12.0 GLOSSARY

13.0 COPYRIGHT AND DISCLAIMER

介绍 验证要求 取样方法 分析方法 清洁验证方案 背景 目的 范围 职责 取样程序 分析方法 可接受标准 偏差 再验证 验证问题 参考文献 词汇 版本及声明

1.0 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, 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 Filip 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.

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 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，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。

The document reflects the 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 Guide 1[1] that follows the 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 required or not and to define the Maximum Acceptable Carry Over (MACO) of API’s 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 the 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 Validation 2[2] is also recommended as a valuable guidance document from industry.

                                                             1[1] ISPE Baseline? Pharmaceutical Engineering Guide, Volume 7 – Risk-Based Manufacture of Pharmaceutical Products, International Society for Pharmaceutical Engineering (ISPE), First Edition, September 2010, www.ispe.org.

2[2] Parenteral Drug Association (PDA) Guidance for Industry. Technical Report No. 29 (Revised 2012)

也推荐企业将“PDA第29号技术报告----清洁验证中应考虑的问题”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: critical parameters measurements, process

alarms, change control, trending & monitoring, training and periodic review — 维护验证状态：关键参数测量、工艺警示、变更控制、趋势&监控、培

训和周期性评审 — Documentation — 文件记录 2.0 Objective 目的

This document has been prepared to assist companies in the formulation of cleaning validation programmes and should not be considered as a technical standard but a starting point for internal discussions. The document includes examples on how member companies have dealt with specific areas and issues that arise when performing cleaning validation.

本文件的目的是帮助公司制订清洁验证程序，不能作为是一个技术标准，只应该作为内部讨论的出发点。本文包括了成员公司如何处理其特殊领域的例子，以及在实施清洁验证时提出的问题点。 3.0 Scope 范围

Six specific areas are addressed in this Guidance document: 本指南文件包括6个方面  Acceptance Criteria  可接受标准  Levels of Cleaning  清洁水平

 Control of the cleaning process

                                                                                                                                                                               Points to Consider for Cleaning Validation, Destin A. LeBlanc, Gretchen Allison, Jennifer L. Carlson, Koshy George, Igor Gorsky, Irwin S. Hirsh, Jamie Osborne, Greg Randall, Pierre-Michel Riss, George Verghese, Jenn Walsh, Vivienne Yankah

 清洁工艺的控制

 Bracketing and Worst Case Rating  分类法和最差情况分级

 Determination of the amount of residue  残留量的检测

 Cleaning Validation Protocol  清洁验证方案

Finally, the most frequently asked questions are answered to give further guidance on specific points related to cleaning validation.

最后是一些常见问题及回答，对一些与清洁验证有关的特殊情况给予指导。 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。可接受日暴露限度定义的是患者终身每天暴露于该浓度，但对健康的不良影响仍处于可接受风险水平。原料药和中间体的ADE一般由企业的卫生学家和毒理学家来制订，他们会审核各种可以获得的毒性和临床数据来设定限度。计算的合理性要进行记录。

In many cases Occupational Exposure Limits (OEL) will be defined for API’s, Intermediates and Industrial Chemicals by Industrial Hygienists and toxicologists and the OEL data is then used to define containment measures such that operators are adequately protected while working with the chemicals.

在很多情况下，会由行业卫生学家和毒理学家对原料药、中间体和工业级化学品的职业暴露限度（OEL）值进行界定，这时应使用OEL数据来制订限制措施，例如，操作人员在操作化学物质时需要受到充分保护。

The OEL data can also be used to calculate the ADE for cleaning of equipment. OEL数据也可以用于计算设备清洁的ADE值。

In certain cases where availability of pharmacological or toxicological data is limited, for example for chemicals, raw materials, intermediates or API’s in early phase clinical trials, cleaning limits based on fraction of clinical doses, LD50 or general cleaning limits may be calculated. In these cases, carcinogenic, genotoxic and potency effect of these structures should be evaluated by toxicologists.

在特定情况下，如果药性或毒性数据有限，例如，化学物质、原料、中间体或处于早期临床试验的原料药，其清洁限度可以基于临床剂量、半数致死量或一般清洁限度来计算。在这种情形下，需要有毒理学家对其结构的致癌性、基因毒性和效价影响进行评估。

The acceptance criteria for equipment cleaning should be based on visually clean in dry conditions and an analytical limit.

设备清洁的可接受标准应依据干燥状态下目视清洁及分析限度。

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. Therefore all the following examples for calculating the limits can be adapted to the suitable situation by using different factors. A competent chemist with detailed knowledge about the equipment and the chemical processes and the properties of the chemicals involved such as solubility should justify this factor by evaluating the specific situation. 在制剂生产中，设备表面残留会100%被带入下一产品，而在原料药生产中，由于技术和化学生产原因，带入风险要低很多。因此，以下限度计算举例可以采用不同安全因子后用于适当的情形。应有一名具备设备和化学工艺知识，知晓所涉及化学品特性，如溶解度的化学家对特定情形下应使用的安全系统进行评估。 4.2. Methods of Calculating Acceptance Criteria 计算可接受标准的方法 4.2.1 Acceptance criteria using health-based data 采用健康基础数据的可接受标准

The Maximum Allowable Carryover (MACO) should be based upon the Acceptable Daily Exposure (ADE) when this data is available. The principle of MACO

calculation is that you calculate your acceptable carry-over of your previous product, based upon the ADE, into your next product.

在可以获得可接受日暴露水平（ADE）值时，最大允许残留（MACO）应基于ADE计算。MACO计算的原则是基于ADE值，计算你允许从你的上一个产品带入下一个产品中的残留量。 Procedure 程序

Calculate the ADE (Acceptable Daily Exposure) according to the following equation and use the result for the calculation of the MACO.

根据以下公式计算ADE值，将结果用于MACO值的计算：

MACO =

NOAEL × BW UFc × MF × PK

From the ADE number, a MACO can be calculated according to: 根据以下公式从ADE值计算MACO值：

MACO =ADE previous × MBSnext TDDnext MACO =

ADE上一产品 × MBS下一产品

TDD下一产品

允许最大残留：从上一产品MACO Maximum Allowable Carryover: acceptable transferred amount from the 带入下一产品的最大可接受previous product into your next product 量 (mg) ADE

Acceptable Daily Exposure (mg/day)

可接受日暴露水平

NOAEL No Observed Adverse Effect Level 未观察到副反应的水平

(mg/kg/day) BW UFc

Is the weight of an average adult (e.g. 70 平均成人体重 kg)

Composite Uncertainty Factor: 组分不确定因子：反映单个combination of factors which reflects the 变量之间、不同品种差异、inter- individual variability, interspecies 亚急性折算为急性外推、differences, sub-chronic-to-chronic LOEL折算为NOEL外推、extrapolation, LOEL-to-NOEL 数据完整性等补偿因素的综extrapolation, database completeness. 合系数 Modifying Factor: a factor to address 修正因子：用于表达未被其uncertainties not covered by the other MF

factors

PK

Pharmacokinetic Adjustments

它因子覆盖的不确定因素 药动学调整

TDDnext Standard Therapeutic Daily Dose for the 下一产品的标准治疗日服用

next product (mg/day) 剂量 MBSnext Minimum batch size for the next 下一产品的最小批量product(s) (where MACO can end up) （MACO全部带入其中） (mg) The draft EMA/CHMP/CVMP/SWP/19430/2012 makes reference to the Permitted Daily Exposure (PDE). The PDE uses the no observed effect level (NOEL) instead of the no observed adverse effect level (NOAEL) used in the ADE calculation. The PDE may also be used as alternative to the ADE to calculate the MACO.

EMA/CHMP/CVMP/SWP/19430/2012草案中引用了允许日暴露（PDE）值。PDE采用了无可见影响水平（NOEL）代替无可见不良反应水平（NOAEL）用于ADE的计算。PDE值也可以用于代替ADE值来计算MACO值。

Instead of calculating each potential product change situation, the worst case scenario can be chosen. Then a case with most active API (lowest ADE) is chosen to end up in the following API with the smallest ratio of batch size divided with TDD (MBS/TDD ratio).

可以选择最差情况方案来替代对每个可能的产品更换情况下的残留计算。这时，可以选择活性最强的原料药（ADE最低）作为上一产品，选择批量TDD比值（MBS/TDD比值）最小的原料药作为后续产品。

If OEL data is available, the ADE can be derived from the OEL. 如果可以获得OEL值，则可以从OEL值计算ADE值。

4.2.2. Acceptance criteria based on Therapeutic Daily Dose 基于日治疗剂量的可接受标准

When limited toxicity data is available and the Therapeutic Daily Dose (TDD) is known, this calculation may be used. It is used for final product changeover API Process —A to API Process —B.

如果可以获得有限毒性数据和日治疗剂量（TDD）值，可以采用本计算方式。它可以用在原料药生产工艺A更换到原料药生产工艺B。 Procedure 程序

Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation.

根据以下公式建立允许最大残留（MACO）值：

MACO =TDD previous × MBSnext

MACO =

MACO

SF × TDDnext

TDD上一产品 × MBS下一产品SF × TDD下一产品

Maximum Allowance Carryover: 允许最大残留：从上一产品中可以

acceptable transferred amount from the 接受转入下一产品的数量(mg) previous product into your next product (mg)

TDDprevious Standard Therapeutic Daily Dose of the 所讨论的产品的日标准治疗剂量

investigated product (in the same dosage （以下一产品TDD计的同样剂量）from as TDDnext) (mg/day) (mg/day) TDDnext MBSnext

Standard Therapeutic Daily Dose for the 下一产品的日标准治疗剂量next product (mg/day) (mg/day) Minimum batch size for the next 下一产品的最小批量（MACO会携product(s) (where MACO can end up 入的产品）(mg) (mg)

Safety factor (normally 1000 is used in 安全系数（一般基于TDD值采用calculations based on TDD). 1000来计算）

SF

4.2.3. Acceptance criteria based on LD50 基于半致死量的可接受标准

In cases where no other data is available (e.g. ADE, OEL, TDD,…) and only LD50

data is available (e.g. chemicals, intermediates, detergents, …), the MACO can be based upon LD50 data.

如果没办法获得其它数据（例如，ADE、OEL、TDD等值），只能获得半数致死量数据（例如化学物质、中间体、清洁剂……），MACO可以基于半数致死量数据来计算。 Procedure 程序

Calculate the so called NOEL number (No Observable Effect Level) according to the following equation and use the result for the establishment of MACO (See [3] oe page 53 - for reference).

根据以下公式，计算NOEL值（无可见影响水平），用于建立MACO值（参见第53页的【3】部分，供参考）

NOEL =

LD50× BW 2000

From the NOEL number a MACO can be calculated according to:

从NOEL值，用以下公式计算MACO值：

MACO =NOELprevious× MBSnext SFnext × TDD next MACO =

MACO

NOEL上一产品 × MBS下一产品 SF下一产品 × TDD 下一产品

Maximum Allowance Carryover: 允许最大残留：从上一

acceptable transferred amount from the 产品中可以接受转入下previous product into your next product 一产品的数量(mg) (mg)

无可见影响水平(mg/day)

50%的动物致死量，单位mg/kg。动物种类（大鼠、小鼠等）和摄入途径（注射、口服等）也很重要(mg/kg)

NOELprevious No Observed Effect Level (mg/day) LD50

Lethal Dose 50 in mg/kg animal. The identification of the animal (mouse, rat etc.) and the way of entry (IV, oral etc.) is important (mg/kg)

BW 2000 TDDnext MBSnext

Is the weight of an average adult (e.g. 成年人平均体重（例如70 kg) (kg) 70kg）(kg) 2000 is an empirical constant

经验常数

Standard Therapeutic Daily Dose for 下一产品的日标准治疗the next product (mg/day) 剂量(mg/day) Minimum batch size for the next 下一产品的最小批量product (s) (where MACO can end up) （MACO会携入的产

品）(mg) Safety factor

安全系数

SFnext

The safety factor (SF) varies depending on the route of administration (see below). Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms.

安全系数（SF）根据摄入途径不同而不同（见下）。一般系数200用于口服剂型原料药生产。 Safety factors: 安全系数 Topicals 10 – 100 局部给药 Oral products 100 – 1000 口服给药

Parenterals 1000 – 10 000 注射给药

4.2.4 General Limit as acceptance criteria 可接受标准的一般限度

If MACO calculations result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a general limit may be suitable. Companies may choose to have such an upper limit as a policy. The general limit is often set as an upper limit for the maximum concentration (MAXCONC) of a contaminating substance in a subsequent batch.

如果MACO计算结果太高，不能接受，或者与带入数字不相关，或中间体毒性数据未知，则适用通用限度方法。公司可以选择例如一个最高限度作为原则。通用限度一般设定为一种污染物质在后续批次中最大浓度上限（MAXCONC）。 Procedure 程序

Establish MACOppm, based on a general limit, using the following equations. 利用以下公式，基于一个通用限度建立MACO限度，ppm为单位。 MACOppm = MAXCONC x MBS

允许最大残留：所讨论的MACOppm Maximum Allowable Carryover: acceptable transferred amount from the 产品（上一产品）被带入investigated product (“previous”). 下一产品的可接受值，一Calculated from general ppm limit. 般表达为ppm限度 MAXCONC General limit for maximum allowed 允许上一产品在下一产concentration (kg/kg or ppm) of 品中的最大浓度通用限“previous” substance in the next batch. 度（kg/kg或ppm） MBS

Minimum batch size for the next 下一产品的最小批量 product(s) (where MACO can end up)

E.g. for a general limit of 100 ppm: MACO = 0.01% of the minimum batch size (MBS), and for a general limit of 10 ppm: MACO = 0.001% of the minimum batch size (MBS).

例如，对于通用限度为100ppm：MACO = 最小批量（MBS）的0.01%，对于通用限度为10ppm：MACO = 最小批量（MBS）的0.001%。

Remarks: The ICH impurity document (Q 3) indicates that up to 0.1% of an individual unknown or 0.5% total unknowns may be present in the product being tested.

注：ICH杂质文件（Q3）指出，在被测试的产品中，单个未知杂质可以达0.1%，总未知杂质可以达到0.5%。

A general upper limit for the maximum concentration of a contaminating substance in a subsequent batch (MAXCONC) is often set to 5-500 ppm (100 ppm in APIs is very frequent) of the previous product into the next product depending on the nature of

products produced from the individual company (e.g. toxicity, pharmacological activity …).

根据各公司所生产产品的属性不同（例如，毒性、药物活性等），从上一产品带入下一产品中的污染物质最大浓度通用上限通常设定为5-500ppm（原料药中100ppm是很常见的）。

The Threshold of Toxicological Concern (TTC) concept could be applied to intermediates or API’s with no clinical (e.g. early development) or toxicological data. This concept includes three categories of products with limited or no data:

毒性关注阈值（TTC）概念可以应用于没有临床（例如早期研发阶段）或毒性数据的中间体或原料药。这个概念将数据有限或没有数据的产品分为3个类别  Products that are likely to be carcinogenic;  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 ADE’s recommended for these three categories are 1, 10, 100 μg/day, respectively.

对应此三类所推荐的ADE值分别为1、10和100μg/天。

Another possibility to calculate your ADE for intermediates or API’s, 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 guideline 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. section 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, NOEL 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。 Equation 4.2.5-I

Target value [μg/dm2] =

公式 4.2.5-I

目标值 [μg/dm2] =

MACO[μg] Total surface [dm2] MACO[μg] 总表面积 [dm2]

Also other methods with different swab limits for different surfaces in a piece of equipment and/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 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. Rather 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. 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 validation / 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-II

CO [μg] = Σ(Ai[dm2] × mi[μg/dm2])

CO

True (measured) total quantity of substance 采用擦拭检测结果计算出(possible carryover) on the cleaned surface in 的与产品直接接触的已清contact with the product, calculated from 洁表面实际总残留量 results of swab tests.

Area for the tested piece of equipment # i.

所测试的 i 设备的面积

Ai mi

Quantity in μg/dm2, for each swab per area of 单位擦拭面积的残留数量 swabbed surface (normally 1 dm2)

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) apply. 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 relevant 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. However, 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 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 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 some cases it may be advisable to dry the equipment in order to do a 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 comparability (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 validation 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 residue 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 calculated 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 = MACO/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 V C Cb

Amount of residue in the cleaned equipment 已清洁设备中的残留总量 in mg

Volume of the last rinse or wash solvent 最后淋洗或冲洗溶剂的体积portion in L

Concentration of impurities in the sample in 样品中杂质浓度 mg/L

Blank of the cleaning or rinsing solvent in mg/L. If several samples are taken during one run, one and the same blank 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 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 not easy, rinse sampling is the alternative. The advantage is that the whole surface of the 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 usually 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 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 residue left from previous production and cleaning operations. A factor of 5-10 could be applied to the MACO calculated using the Acceptable Daily Exposure Limit or the secondary criteria defined in the previous sections.

在药品生产中，设备表面残留可能会100%被带入下一产品。与之不同的是，在原料药生产中，由于技术和化学生产原因，残留带入风险要低很多。因此，与药品生产相比，在化学生产中采用较高的残留限度是可以接受的。例如，化学工艺步骤经常包括溶出、提取和过滤，这些步骤可能会显著降低上一产品和清洁操作所残留的东西。如果采用ADEL值计算MACO，则可以使用5-10的安全系数，或者采用上述部分中界定的中等标准。

In all cases, the limits should be justified by a competent chemist with detailed knowledge about the equipment and the chemical processes, following Quality Risk Management Principles and the limits should be approved by Operations and Quality Assurance Managers.

在所有情况下，所有的限度均应由具备资质的化学家进行论证。他应该具备关于设备和化学工艺的知识，遵守质量风险管理原则。所制订的限度应由操作和质量保证经理批准。

The following description shows an example where the carry-over risk for a residue in chemical production equipment is much lower than in pharmaceutical production equipment.

以下例子说明了在化学生产设备中，其残留的带入风险比药品生产设备要低很多。 Assuming that the common criteria (ADE, 1/1000th dose, LD50 NOEL/ADI with SF 100-1000, 10 ppm) represent the state of the art for pharmaceutical production and are considered sufficiently safe, then the calculation of limits in API manufacture must reflect the different processes in pharmaceutical production and in the chemical production of active pharmaceutical ingredients to allow comparable risk analyses to be undertaken.

假定常用标准（ADE，1000分之一剂量，LD50 NOEL/ADI安全系数100-1000，10ppm）代表药品生产理想状态，被认为是足够安全的，这时原料药生产中的限

度计算必须反映化学原料药生产与药品生产工艺的不同，使得可以进行风险分析比较。

Pharmaceutical production, Chemical production physical process 药品生产、化学生产的物理处理

In pharmaceutical production a residue remaining on the surface of equipment after cleaning is, in the next production cycle, distributed in a mixture of active substance and excipients if it does not remain on the surface. In the worst case it will be 100 % transferred to the first batch of next product.

在药品生产中，清洁后残留保存在设备表面，在下一个生产循环中，如果这些残留不再停留在设备表面，则会分布在原料药和辅料的混合物中。最差情况是这些残留100%地被带入下一产品的第一个批次。

Chemical production/processing 化学生产/工艺

In chemical production a 100 % carry-over of residue from the equipment surface to the next product to be manufactured is very unlikely based on the way the process is run and on technical considerations. The residue remaining on the equipment surface can, during the next production cycle, be carried over into the reaction mixture consisting of solvent and raw materials. In most cases, however, any residue in solution will be eliminated from the process together with the solvent, and insoluble residue by physical separation processes (e.g. filtration), so likely carry over into the end-product will be low.

在化学生产中，考虑到工艺运行的方式，以及技术问题，残留物被100%地从设备表面带入下一产品中的情形不太可能发生。残留在设备里的东西，在下一生产循环中，会被带入溶剂和原料所组成的混合反应液中。在大多数情况下，所有溶液中的残留都会与溶剂一起被从工艺中去除，不溶性残留会被物理分离工艺（例如过滤）减少，因此，可能被带到最终产品中的残留会很低。

The final step in a multi-step chemical synthesis is selective purification of the API (e.g. by crystallization), during which contaminants are removed from the process and/or insoluble residues are removed by physical separation). From the original reaction mixture of educt, agent and solvent there remains only a fraction of the original mass as API at the end of the chemical process.

在多步化学合成的最后一步，一般是原料药选择性精制（例如，通过结晶方式）。在精制过程中，污染物被从工艺中去除，不溶性残留被物理分离所去除。在经过这些化学工艺后，原来那些由离析物、试剂和溶剂所组成的混合反应液只剩下一些原来物质的片断，在最后成为原料药。 【译者：第一句有一个半括号，原文如此】

It is also to be noted that, during subsequent pharmaceutical production, the API is further diluted through the excipients that are added.

还要注意的一点是，在后续的药品生产过程中，原料药通过加入辅料被进一步稀释了。

Conclusion: 结论

Assuming that there is no intention to impose more stringent yardsticks during API production than in pharmaceutical production but that they should be approximately the same, the logical conclusion is that the limits in chemical production should be set higher than in pharmaceutical production. Based on this rationale, a factor of 5 - 10 compared to the established pharmaceutical production limits is both plausible and, in terms of pharmaceutical risk, acceptable.

假定我们并无意将比药品生产更严格的标尺强加给原料药生产，而只是要将它们保持大致相同，则从逻辑上得到的结论就是在化学生产中的限度应该设定得比药品生产中的限度要高。基于此理论，相比于已建立的药品生产限度，对原料药生产采用5-10的安全系数既貌似合理，从药品风险角度来说，也是可以接受的。 Chemical production “physical processes” (drying, mixing, filling,) 化学生产的“物理处理”（干燥、混合、充填……）

Apparatus and equipment that is used for physical end-treatments such as drying, mixing or milling may either be operated together with the previous synthesis equipment or generally be used separately. During separate physical end-treatments of APIs, there is no decrease of contaminants compared to the aforementioned chemical process. Consequently, we recommend in this case that the calculation methods applied should be those normally used in pharmaceutical production, (ADE, 1/1000th dose, LD50 NOEL/ADE with SF 100-1000, 10 ppm). The Limits for carry over into the final API should be the same as those calculated in the previous sections. 用于最终物理处理，如干燥、混合或磨粉，的设备仪器，可以与之前的合成设备一起使用，通常是单独使用。在原料药单独的物理最终处理过程中，与之前提到的化学过程相比，其污染物不会减少。因此，我们推荐在这种情况下，应采用制剂产品中常用的计算方法（ADE、千分之一剂量、半数致死量、NOEL/ADE和安全系统 100-1000、10ppm）。带入最终原料药的残留量限度应与之前各部分所计算的相同。

ANNEX 1: Examples of MACO calculations.

附录1：MACO计算的例子 Example 1: ADE calculation 例1：ADE计算

Product A has a NOAEL70kg of 100 mg/day human oral dose. Uncertainty factors applied to calculate the ADE are an UFS of 3 (extrapolation from an acute dose to subchronic/chronic dosing) and UFH of 8.13 (the inter-individual variability based upon a PK (kinetic component) of 2.54 and PD of 3.2 (dynamic component)). The MF is 10 (extrapolation from a ‘generally healthy’ population to a more susceptible sick patient population). Product B is an oral product (PK = 1).

A产品NOAEL70kg人类口服剂量为100mg/天， 用于计算ADE的不确定因子UFS为3（从急性剂量到亚慢性/慢性给药外推得到），UFH为8.13（根据PK（动力学组成）为2.54和PD为3.2（动力学组成）所得的内在个体变化）。MF为10（从“一般健康”人群外推至易感人群）。 产品B为口服产品（PK = 1）.

ADE =

100（mg/day） 3×8.13×10×1

= 410（μg/day）

Result: ADE oral is 410 μg/day 结果：口服ADE值为410μg/天

If product B is a parenteral product and the PK is 62.5 (based upon an oral bio-availability study in human after parenteral).

如果产品B是一个注射产品，PK值为62.5（基于人体注射后的口服生物利用度研究）

ADE =

Result:

100（mg/day） 3×8.13×10×62.5

= 6.6（μg/day）

ADEparenteral is 6.6 μg/day

结果：注射ADE值为6.6μg/天 Example 2: ADE calculation 例2：ADE计算

A teratogenic product A has a LOAEL of 1 mg/kg.day human oral dose (BW is 70 kg). Uncertainty factors applied to calculate the ADE are an UFL of 3 (extrapolation from LOAEL to NOAEL), an UFH of 10 (the inter-individual variability) and a MF of 10 (severity of effect: teratogenicity). Product B is an oral product (PK = 1).

ADE =

1（mg/kg day）× 70kg

3×10×10×1

= 231（μg/day）

Result: ADEoral is 231μg/day. 结果：口服ADE值为231μg/天。

Example 3: Acceptance criteria based on Acceptable Daily Exposure 例3：根据可接受日暴露值计算可接受标准

Product A will be cleaned out. The product has an ADE of 2 mg and the batch size is 200 kg. The next product B has a standard daily dose of 250 mg and the batch size is 50 kg. Calculate the MACO for A in B.

产品A要被清洁，其ADE值为2mg，批量为200kg。 下一产品B标准日剂量为250mg，批量为50kg。 计算A在B中的允许最大残留量。

MACO =

0.002（mg）× 50 000 000 (mg)

250 (mg)

= 400(mg)

Result: MACO is 0.4g (400mg).

结果：允许最大残留值为0.4g（400mg）。

Example 4: Acceptance criteria based on Therapeutic Daily Dose 例4：根据日治疗剂量计算可接受标准

Product A will be cleaned out. The product has a standard daily dose of 10 mg and the

batch size is 200 kg. The next product B has a standard daily dose of 250 mg and the batch size is 50 kg. Both A and B are administrated orally and SF is set to 1000. Calculate the MACO for A in B.

产品A要被清洁，其标准日剂量为10mg，批量为200kg。 下一产品B标准日剂量为250mg，批量为50kg。 A和B都是口服摄入，安全系数SF设定为1000。 计算A在B中的最大允许残留量MACO。

MACO =

10（mg）× 50 000 000 (mg)

1000 × 250 (mg)

= 2000(mg)

Result: MACO is 2g (2000mg).

结果：允许最大残留值为2g（2000mg）。 5.0 Levels of Cleaning 清洁级别 5.1 Introduction 介绍

The manufacturing process of an Active Pharmaceutical Ingredient (API) typically

consists of various chemical reaction and purification steps followed by physical

changes. In general, early steps undergo further processing and purification and so potential carryover of the previous product would be removed.

原料药的生产工艺一般由不同化学品经过反应和纯化步骤，再经过一些物理变化组成。一般来说，较早的步骤会经进进一步处理和纯化，因此上一产品潜在的残留会被清除掉。

The level of cleaning required in order to ensure that the API is free from unacceptable levels of contamination by previous substances varies depending on the step being cleaned and the next substance being manufactured in the same piece of equipment (train).

为保证下一原料药被上一产品污染水平可接受，所需进行的清洁程度取决于清洁所针对的工艺步骤，以及在同一设备（链）中生产的下一产品。

API`s and related intermediates are often produced in multi-purpose equipment with frequent product changes which results in a high amount of cleaning. To minimize the cleaning effort the concept of using different levels of cleaning as a function of the level of risk related with the possible carryover may be applied without affecting the safety of the API.

原料药和相关的中间体一般会在多用途设备中生产，频繁的更换产品会导致大量的清洁操作。为了将清洁工作量降至最小，在不影响原料药的安全性的前提下，可以考虑使用不同的清洁级别来应对与可能的残留相关的不同风险水平。 5.2 Cleaning levels 清洁级别

It is recommended that at least three levels of cleaning in the production of a commercial product may be implemented. This approach is outlined in the table below, however it should be mentioned that additional levels might be necessary depending on the nature of the process and requirements of individual companies but should always be based on risk assessment where the characteristics of the previous and subsequent products such as solubility, recovery studies, nature of residues, process step, etc. should be considered.

在商业化产品生产中，推荐使用至少3个清洁水平。以下表格中列出了该方法，但值得一提的是，根据各公司的工艺特性和要求，可能需要增加更多水平。不管怎样，要始终基于风险评估，考虑上一次品和下一产品的特性，如溶解度、回收率研究、残留特性、工艺步骤等来做决定。

Cleaning verification Cleaning

Level Thoroughness of cleaning Visual Analytical

validation

inspectionverification Carryover of the previous product is critical. Cleaning required until 2 Yes Yes Mandatory

predetermined stringent carry over limits are met. High risk.

Carryover of the previous product is 1 less critical. Cleaning should reduce Yes Yes Recommended

the potential carry over to a less 0 水平

stringent limit as required for level 2. Medium risk.

Only gross cleaning if carryover of the previous product is not critical. Low Yes risk.

No No

清洁彻底程度

清洁验收

目视检测试验清洁验证 查 收

是

必须

2

1 0

上一产品的残留很关键。要求清洁直至符是 合严格预定的残留限度。高风险。

上一产品的残留不太关键。清洁应将潜在残留降低到比水平2要求更低的限度。中是 等风险。

如果上一产品的残留并不关键，则只需要

就

粗清。低风险。

是 否

推荐 不要

A general approach how these levels could be established for typical product changeover situations in a multi-purpose API-plant is outlined in the figure below. 下图列出了在一个多用途原料药工厂，针对典型的产品更换情况如何建立3个水平的通用方法。

Figure 1: Typical Product Changeover Scenarios 图1：典型的更换产品情况

The levels established as shown in figure 1 are based on the approach that in general the thoroughness of cleaning will increase and the acceptable carryover of the previous product will decrease from early steps in the route of synthesis to the final API due to the fact that early steps undergo further processing and/or purification and so the potential carry over will be reduced by further processing. Physical operations, which mean e.g. powder handling such as drying, sieving or milling obviously do not reduce the potential carry over. During the risk assessment it should be taken in consideration that the residues may contribute to a degradation of the next product’s quality or safety and ultimately have a detrimental effect on the final consumer. 建立图1中所示的清洁级别的依据是在一般情况下，随着合成步骤越来越接近原料药成品，清洁的彻底程度会增加，上一产品在下一产品中允许残留量会减少，由于较前面的步骤会经历进一步工艺过程和/或精制，因此潜在的残留物会被后续的工艺过程降低。物理操作，例如粉料处理如干燥、过筛或粉碎，很显然不会降低潜在残留量。在风险评估过程中，要考虑残留物可能会引起下一产品质量或安全性变差，最终对产品消费者产生不利的影响。

Fig 1 shows examples of several possibilities of equipment usage patterns 图1显示了几种可能的设备使用模式。

1) The following product is the next step in the synthetic chain 下一产品是合成链中的下一步骤

A typical manufacturing process applied to production of Active Pharmaceutical Ingredients consists of various chemical reaction and purification steps followed by physical changes, as can be generally illustrated by the sequence of the production line of a product A or B. In this case level 0 may be applied because the previous product is the starting material of the following manufacturing step and the analytical methods applied for the following product are usually suitable to detect the previous product which is covered and limited by the impurity profile.

典型的原料药生产工艺由不同化学反应和精制步骤组成，之后再进行物理变更，因此一般可以由产品A或B的生产顺序来表示。这种情况下，可以作为0级，因为上一产品是后续生产步骤的起始物料，后续产品所使用的分析方法一般适用于检测上一产品，上一产品实际上包括在杂质谱中，并设定了限度。 2) Between different steps of the same synthetic chain 同一合成链不同步骤之间 In general there is a higher potential for contamination of the API if the following product in a sequence is close to the final API - step. So progression of levels from early steps to later steps in the synthetic chain is expected as outlined in figure 1. In the example of product changeover “A – 2” to “Final API A” level 2 may be chosen if “A – 2” is not specified in the specification of “API A” or “A – 2” is a toxic compound. If it is specified or is purged during the process or harmless, level 1 may be acceptable.

一般来说，如果序列中的后续产品接近于原料药成品步骤，则对原料药产生的潜在污染水平会比较高。因此，从合成路线中较早步骤到较后步骤，其预期水平如

图1所示。在例中，生产完“A-2”后，再生产“原料药成品A”，如果“A-2”在“原料药成品A”质量标准中并未作为杂质列明，或者“A-2”为毒性物质，则可以选择水平为2级。如果“A-2”作为杂质列明，或在工艺中被清除，或该物质对人体无害，则选择水平为1级是可以接受的。

3) Between batches of different product lines 不同产品线所生产批次之间

The level of cleaning required depends on the stage of manufacture. If the following product is an early stage in the API chain, in general lower levels are required than if it is an intermediate or final stage.

所要求的清洁水平取决于生产的步骤。如果后续产品在原料药工艺路线中为较早的步骤，一般来说相对于中间或最终步骤来说其要求水平更低。

The progression of levels is outlined in figure 1, however an individual risk assessment for each potential product changeover scenario has to be performed to decide which level is applicable. This risk assessment should address the following topics:

分级的层次在图1列出，但对每种可能的产品更换情况应进行单独的风险评估，以决定适用哪个水平。风险评估应说明以下情况：  Easiness of cleaning  清洁难易程度

 Toxicological / pharmacological activity of the previous product, its side

products or degradants  上一产品的毒性/药物活性，其副产物和降解产物  Maximum daily dose of the following product  下一产品的最大日剂量  Microbiological growth  微生物滋长

 Batch size of the following product  下一产品的批量

 Solubility, experience, difficult to remove previous product  溶解度、经验、上一产品清除难度  Chemical interactions  化学相互反应

 Campaign lengths should be evaluated and determined as part of the risk

assessment.  要评估和确定生产周期的长度，作为风险评估的一部分

Consideration should be given to any heels present and whether they need to be removed on a regular basis.

要考虑所有可能的情况，以及法规是否要求对其清除。

Instead of the investigation of each individual cleaning situation, similar situations could be grouped and classified using bracketing concepts (ref. section 7).

可以对相似的情形划分为同一组，采用分类法的概念进行分类，代替对各清洁情形所进行的研究（参见第7部分）。

5.3 Cleaning Verification/validation 清洁确认/验证

The cleanliness status and validation of cleaning procedures is verified against pre-defined acceptance criteria.

清洁状态和清洁程序的验证要根据预定的可接受标准进行验收。 5.3.1 Cleaning verification 清洁确认 The cleaning verification can be made by: 清洁确认可以按以下方式进行：  visual inspection or  目视检查或

 visual inspection and analytical verification (e.g., swabbing and/or rinsing).  目视检查以及分析确认（例如，擦拭和/或淋洗） Visual inspection: 目视检查

After cleaning procedures performed equipment should be dried to allow the visual inspection. No residue should then be visible. Visual inspection should be performed using the best known capabilities.

在对设备进行清洁后，应干燥以便目视检查，这时应目视无残留。应使用已知最好的能力进行目视检查。

During visual inspection the following situations should be considered: 在目视检查中，要考虑以下情况：

 Discoloured surfaces, worn or torn parts;  部件表面褪色、磨损或破损

 Solid residues (for final product equipment used downstream of last filtration,

the residues should be evaluated also by passing the final washing through a rough filter media (e.g. a lint-free cloth));  固体残留（对于最终过滤后所用的设备，残留要通过粗滤介质（例如，

无纺布）进行最终冲洗进行评估）

Visual inspection is usually applied in Level 0 where no cleaning validation is required.

目视检查一般适用于0级，这时不需要进行清洁验证。 Analytical verification 分析确认

Analytical verification should be performed with scientifically sound methods. 要采用科学合理的方法进行检测验收。

The analytical methods should be validated before use in cleaning validation (see 5.3.2), unless they are compendial methods (see chapter 8.2).

除药典方法外（参见8.2），分析方法在用于清洁验证前，应进行验证（参见5.3.2）。 5.3.2 Cleaning validation 清洁验证

The cleaning validation involves a series of stages over the lifecycle of the product and cleaning process: cleaning process design, cleaning process qualification and continued cleaning process verification. Details on the work to be performed and acceptance criteria should be defined in a protocol. The cleaning procedure can be prepared per equipment or set of equipment and should include detail enough to reduce operator’s variability (see chapter 7.3).

清洁验证涉及产品和清洁工艺的一系列阶段：清洁工艺设计、清洁工艺确认和持续清洁工艺确认。在方案中应确定要实施的工作细节和可接受标准。清洁程序可以针对各设备单独制订，也可以针对一套设备制订。清洁程序的内容应详细，以减少操作人员的不确定性（参见7.3）。

The strategy should be defined and taken in consideration in the validation activities. 要制订验证活动的策略，并在实施时加以考虑。

The validation consists in successive applications of the cleaning procedure complying with the acceptance criteria defined, in a minimum of 3 successful applications. The success of the applications should be consecutive unless the cause of failure is clearly identified as not related to the process or procedure.

验证包括连续至少3次成功实施清洁程序，并符合制订的可接受标准。除非清楚地识别出失败的原因与清洁工艺或清洁程序不相关，否则验证实施批次必须是连续的。

Depending on the individual product changeover situation it may take some time to finalize the cleaning validation with the third application (see chapter 8 bracketing and worst case rating). In these cases cleaning verification using validated analytical methods has to be performed in the meantime.

根据各产品交替情况，可能需要一些时间来采用第三种工具来决定清洁验证（参见第8章分类法和最差情形分级法）。在这些情况下，同时需要采用经过验证的分析方法进行清洁确认。

At this stage analytical methods should be validated and suitable to quantify at the acceptance criterion level. The limit of detection must be lower than or equal to the acceptance criterion level. Blanks must be evaluated to ensure that there is no significant interference with the recovery of the analyte. In dedicated facilities, validation of cleaning procedures is not normally required but a risk assessment should be performed to make sure that there is no potential for degradation and or microbial contamination that may adversely impact the quality of the product. 在此阶段，分析方法需要进行验证，且在可接受标准水平应该可以定量。检测限必须低于或等同于可接受标准水平。必须对空白进行评估，以保证对分析物的回收率没有严重的干扰。在专用设施中，清洁程序的验证一般是不需要的，但应进行风险评估，以保证没有会对产品质量有负面影响的降解的可能性，或微生物污染。

For both dedicated and multi-product facilities, the frequency with which the cleaning procedure should be performed should be validated to assess risks related to potential degradation and microbiological contamination.

对于专用和多功能设施，均要验证需验证的清洁程序的频率，评估与潜在降解和微生物污染有关的风险。

The validation of the Dirty Hold Time (DHT) should be an outcome of the cleaning validation. Whenever the DHT is exceeded, analytical verification should be performed and the extension of the DHT should be handled through change control procedure.

清洁验证还在确认在脏的情况下可放置的时长（DHT）。一旦放置时间超过了DHT，则需要进行分析确认。延长DHT应通过变更控制程序来处理。 5.3.2.1. Cleaning process design 清洁工艺设计

Cleaning process design intends to design, develop and understand the cleaning process residues and to establish the strategy for the cleaning process control. 清洁工艺设计目的是设计、研发和了解清洁工艺的残留，建立清洁工艺的控制策略。

The main activities in this stage are evaluation of the chemical and physical properties of the residue; determination of the most difficult to clean residue; evaluation of residue solubility and stability.

在此阶段的主要活动是评估残留物中的化学和物理特性，评估最难清洁的残留物，评估残留物的溶解度和稳定性。

5.3.2.2. Cleaning process qualification 清洁工艺确认

In this stage it should be demonstrated that the cleaning procedure works as expected. The following activities are included among others: qualification of specific equipment used in the cleaning such as Clean In Place (CIP) systems, cleaning

operational parameters (e.g. temperature, flow rates, pressure, etc.); identification of the most difficult cleaning locations; training of operators.

在此阶段，要证明清洁工艺能起到预期的作用。下列活动包括在其它活动中：在清洁中使用的特定设备的确认，例如在线清洁系统（CIP）、清洁操作参数（例如温度、流速、压力等）、最难清洁点的识别以及对操作人员的培训。 5.3.2.3 Continued cleaning process verification 持续清洁工艺确认

In this stage it should be demonstrated that the cleaning process remains in control throughout the product lifecycle.

在本阶段，要证明清洁工艺在整个产品生命周期受控。

The following should be considered in this stage: Post validation monitoring; Change control; Periodic management review.

在此阶段要考虑以下内容：验证后监控、变更控制、定期管理评估。 Post validation monitoring 验证后监控

After cleaning validation, the analytical verification may be omitted or replaced by simpler analytical methods (e.g. conductivity; pH; etc.) that have proven to be suitable for the intended use. However, visual inspection should be maintained in the dried equipment and no visible residues should be observed.

在清洁验证之后，可以不需要进行分析确认，或采用更简单的分析方法替代验证所用的方法（例如，电导率、pH值等），只要是被证明适用于既定用途即可。但是，对干燥后的设备仍要保留目视检查，且不应有目视可见残留。

The confirmation of the validation status should be performed periodically according to the periodicity defined in the validation report. 验证状态可以根据验证报告中界定的周期进行确认。 Change control 变更控制

Any change to the cleaning procedure, analytical methods, manufacturing process, equipment, etc. during the execution of the cleaning validation protocol or after the validation is concluded should be handling through the change control procedure in place in the organization. The impact on the cleaning validation process should be evaluated.

在清洁验证方案实施期间或在验证完成后，对清洁程序、分析方法、生产工艺、设备等进行变更应根据内部的变更控制程序进行处理。要评估变更对清洁验证工艺产生的影响。

Periodic management review 周期性管理评审

Deviations, non-conformances, changes in the cleaning procedure and/or product manufacturing process, trends should be periodically reviewed with the aim to

continuously improve the cleaning process, reduce variability and to assess the validation status of the procedure.

应对偏差、不符合情况、清洁程序变更和/或产品生产工艺趋势进行周期评审，目的是持续提高清洁工艺，减少波动，评估清洁程序的验证状态。 6. CONTROL OF CLEANING PROCESS 清洁工艺的控制

In order to validate a cleaning process, the cleaning process needs to be repeatable and sufficiently robust for the to-be-cleaned load. It should be clear which steps are considered part of the production process/ unit operation and which are part of the cleaning process, for example if the pre-rinse or wash-out which may be routinely applied to bring the equipment in a good starting position is part of the overall cleaning process or not. Another example is the cleaning of chromatography columns, which are typically cleaned with buffers prior to the chromatography skid cleaning. 为了对清洁工艺进行验证，清洁程序应是可重复的，针对将要清洁的负载，具有足够的清洁能力。要清楚说明，哪个操作是生产工艺/单元操作的一部分，哪个是清洁工艺的一部分。例如，对设备进行前期冲洗或淋洗，以使其成为一个洗前的起始状态，是否是整个清洁工艺的一部分。

To assure repeatability and robustness of the cleaning, adequate cleaning instructions are required.

为保证清洁的可重复性和耐用性，要制订充分的清洁指令。

For manual cleaning, this is typically accomplished by sufficiently detailed cleaning instructions, including an unambiguous description of the attributes to be used and how to handle these, together with adequate training.

对于手动清洁，一般是根据详细的清洁指令来完成的，其中包括对清洁方法的清楚描述，如何操作，并需要进行充分的培训。 The detailed description should consider: 1. the system boundaries

2. cleaning agents/solvents to be used 3. volumes and or concentrations 4. reflux or rinse times, and temperatures

5. the sequence of cleaning steps or pre-defined repeats 6. in process analyses

7. description of pumps used (if needed) 8. sample instructions (if needed) 详细描述应考虑 1、 系统界限

2、 使用的清洁剂/清洁溶剂 3、 体积和/或浓度 4、 冲洗或淋洗时间、温度 5、 清洁步骤或预定重复顺序 6、 过程中检测

7、 所用泵的描述（必要时） 8、 取样指令（必要时）

For automated cleanings this should be ensured by the equipment design together with the cleaning software, cleaning recipe and built-in control mechanisms. 要保证自动化清洁设备设计中包括了清洁软件、清洁配方和内置控制结构。 For automated systems, it is expected that a cleaning instruction covers: 对于自动化设备，要求清洁指令覆盖以下内容：

1) The applied cleaning phases, for example once-through versus re-circulating versus soak versus reflux-mode rinse/wash phases

所采用的清洁工序，例如一过性、再循环、浸泡、回流方式淋洗/冲洗工序 2) The sequences of the cleaning phases 清洁工序的顺序

3) Time of each of the cleaning phases 各清洁工序的时间

4) Action applied during the cleaning process. Note that the mechanical action/impact is often flow/pressure related (e.g. if spray balls are being used).

在清洁过程中所执行的操作。注意机械性操作/冲击通常会与流动/压力相关（例如，如果采用喷淋球）

5) Used cleaning agents and/or cleaning solvents 所用的清洁剂和/或清洁溶剂

6) The concentrations and/or quality of the used cleaning agents and/or cleaning solvents

所用的清洁剂和/或清洁溶剂的浓度和/或质量

7) Temperatures applied during the various cleaning phases 不同清洁工序的温度

Because of the uncertainties on cleaning parameters, like a.o. flow, time, temperature, detergent concentration and starting conditions (inclusive Dirty Hold Time and

soiling), and the geometric aspects of the cleaned system, the cleaning process is susceptible to variability/ spread. The mean effectiveness of the cleaning process together with its spread should be adequately removed from the edge of failure of the cleaning process, which can be established by performing the MACO calculations as discussed in the previous chapters. At minimum, the level of cleaning should support a cleaning result (including the spread) below the obtained MACO level. Schematically, this can be depicted as:

由于清洁参数的不确定性，例如流动情况、时长、温度、清洁剂浓度和起始条件（包括清洁前放置时长DHT和污染程度），以及被清洁系统的几何结构，清洁工艺具有很大的不确定度。这些清洁过程的不确定因素加上平均效果应该从清洁工艺的失效边缘中扣除，失效边缘是通过前章节中MACO的计算来确定的。至少，清洁级别应该可以获得在MACO水平以下的清洁结果（包括其延展区）。下图对此做出了示意：

The level of cleaning should be commensurate to the level of risk that the cleaning process poses in relation to the related production processes. Notice that the cleaning risk can be further reduced either by:

清洁水平应与相关生产工艺所具的清洁工艺风险水平相适应。应注意可以通过以下方式进一步降低清洁风险：

1) improving the cleaning cycle to improve cleaning effectiveness and shift the mean cleaning result further away from the MACO level, which typically requires cleaning development studies;

改善清洁轮次，以提高清洁效果和转换平均清洁结果，使其远低于MACO水平，这一般需要进行清洁研究；

2) reducing process variability, which is typically established by increasing the level of control on the cleaning process parameters. An improved level of control on cleaning parameters such as flow, temperature and time, may not only result in more robust cleaning processes with smaller process variability, but may also create cleaning optimization opportunities (e.g. reduced chemical and water consumption). 降低工艺变数，这一般通过增加对清洁工艺参数的控制来实现。对于清洁参数，例如流动情况、温度和时长，的控制水平的提升，不仅可以通过减少工艺波动来增加清洁工艺的耐受性，而且可以创造优化清洁的机会（例如，降低化学物和水的消耗）。

For automated systems, the level of control can often be enhanced by applying in-line measurements together with enhanced controlling capabilities. Improved monitoring capabilities often results into enhanced cleaning process knowledge and may be used in a Process Analytical Technology (PAT) framework.

对于自动化系统，通过实施在线测量和加强控制能力，可以增强控制水平。提升监控能力通过可以增加对清洁工艺的了解，可以用于工艺分析技术（PAT）框架。 7.0 Bracketing and Worst Case Rating 分组法（括号法）和最差情况分级 7.1 Introduction 介绍

The cleaning processes of multiple product use equipment in API facilities are subject to requirements for cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used.

原料药工厂中的多产品设备清洁要求进行清洁验证。清洁工作量会比较大。为了减少验证的工作量，可以采用最差情形方法进行验证。 By means of a bracketing procedure the substances are grouped. 采用分组法时，物质按类进行分组。

A worst case rating procedure is used to select the worst case in each group. 然后在每组中采用最差情形分级法选择各组中最差的情况。

Validation of the worst case situation takes place. However, it is of utmost importance that a documented scientific rational for the chosen worst cases exists.

对最差情形进行验证。至关重要的是，选择最差情形的科学合理性要进行记录。 This chapter gives an overview of the suggested work to be carried out, the acceptance criteria and the methodology for evaluation of the data. It should be emphasized that this is only an example to give guidance. The equipment, the substances produced and the procedures in place may vary; and this results in other solutions than those given in this example.

本章介绍了所需要进行的工作、可接受标准和数据评估方法。需要强调的是，这只是一个指导性的例子，而实际情况下，设备、生产的物质和清洁程序可能有所不同，则可能需要采用与例中不同的解决方案。

The worst case rating priority will then support a conclusion that the cleaning procedures are effective for all drug substances and other chemicals within the bracket, including those not individually tested.

最差情形分级优先性是用来支持清洁方法对组内所有原料药和化学物均有效的结论的，包括那些并没有进行单独检测的物质。 7.2 Bracketing Procedure 分组法

The objective of a bracketing project, is for the company to demonstrate that it has a scientific rationale for its worst case rating of the substances in the cleaning validation program. The first thing to do is to make groups and sub groups - which we will term “bracketing”, from which worst cases will later be selected based on the results from the rating. The bracketing procedure should be included in a company policy, or an SOP or an equivalent document on cleaning validation. A multipurpose facility, Clean Company, is presented as an example we will follow.

分组法的目的是让公司可以证明清洁验证方案中，对原料药进行最差情形分级具有科学合理性。首先要做的是进行分组和分小组----我们称为“分组法（括号法）”，在一个组中，再根据分级结果选择一个最差情形。分组流程应包括在公司方针中，或在SOP或相当清洁验证文件中。以下的例子中我们假定有一个多功能工厂、一个清洁公司。

a) Equipment Train The Clean Company is a multipurpose site for synthesis and isolation of organic substances (see figure 1). It is divided into six equipment trains separated from each other and intended for different use (earlier API steps, final API purification, drying etc.). In Train A 9 substances can be produced, in Train B 9 substances can be produced, in Train C 8 substances can be produced, in Train D 8 substances can be produced, in Train E 10 substances can be produced, and in Train F 11 substances can be produced. With no bracketing and worst case rating, cleaning validation studies would be required for each of the 55 substances.

设备链：清洁公司是一个多功能场所，生产有机物质合成和分离步骤（参见图1）。其设备被分为6条生产设备链，相互独立，用于不同用途（较早的原料药步骤、

最终原料药精制、干燥等）。在A链中，可以生产9种物质，在B链中，可以生产9种物质，在C链中可以生产8种物质，在D链中，可以生产8种物质，在E链中可以生产10种物质，在F链中可以生产11种物质。如果不采用分组法和最差情形法的话，则需要对55种物质分别进行清洁验证。

The first grouping criteria are that the substances in a group are produced in identical equipment trains and cleaned out following the same cleaning procedure/SOP. The ideal with regard to cleaning validation (as will be discussed in 7.3) each train could be considered as a group. Then 6 worst cases would ideally be identified. In reality, the number of worst cases identified will often be something between these two extremes (more than 6, but less than 55).

进行分组的第一个标准是组内的物质是在同一条设备链中生产，并采用同一个清洁程序/SOP进行清洁。理想状态是每条链可以作为一个组来进行清洁验证（如7.3中讨论的一样）。这样，理想状态下需要识别出6种最差情形。现实中，最差情形的识别可能会是两个极端情况（多于6个，但少于55个）。 Clean Company 清洁公司

Figure 1 Clean Company’s ideal example (1 train considered as 1 group) gives 6 worst cases.

In this example the main classes in this bracketing are based on the different Trains. The following equipment classes are maintained:

图1：清洁公司的理想案例（设备链1被作为第一组）给出了6个最差情形。 在此例中，组内主要级别是基于不同生产链的。以下设备分级不变： ? Train A ? Train B

? Train C ? Train D ? Train E ? Train F

b) Substances 物质

If the company has two or more trains used for the same purpose (such as earlier API steps, final API purification, drying etc.) a choice of which products to be produced in each of the trains used for the same purpose is done. The combination of substances (starting materials, intermediates or APIs) in a train can be chosen based on one or more of the following strategies, or combinations of them:

如果公司有2个或更多设备链用于同一个生产目的（例如，更早的原料药生产步骤、最终原料药精制、干燥等），已选好了在每个设备链中生产哪个产品。在一个设备链生产哪些物质（起始物料、中间体或原料药）可以采用以下策略或联合策略来做选择：

 Produce in the same train substances with the same cleaning procedure;  在同一设备链里生产可以采用相同的清洁程序的物质

 Produce in the same train substances with very low therapeutic doses and/or

low batch sizes (and the opposite);  在同一设备链中生产治疗剂量很低和/或批量很小（以及相反情况）的物

质  Produce in the same train substances with very low ADE values (and the

opposite).  在同一设备链中生产ADE值非常低（以及相反情况）的物质

Also a choice of maximum flexibility can be used, but this could result in low limits for residues (for example if the substance to be cleaned out has a very low therapeutic dose, and the following substance has a small batch size and/or a very high daily dose) and thus longer cleaning times. Advantages and disadvantages with several cleaning procedures, compared to one cleaning procedure, will be discussed in section 7.3. More explanations on effects of different strategies will be evident from section 7.4. 也可以选用具有最大灵活性的方式，但这样可能会使得残留限度非常低（），导致清洁时间会很长。在7.3中讨论了选用几个不同的清洁程序相比于选用同一个清洁程序的优缺点。在7.4中对不同策略的效果给出了进一步解释。 7.3 Cleaning Procedures 清洁程序

For one train, in which several substances are being produced, several cleaning procedures often exist. In order to be able to defend the bracketing into groups, the

second criterion is that the same cleaning procedure (method) shall be used for the substances within a group.

对于一条设备链，如果在其中生产几种物质，通常会有几种清洁程序。为了将所涉及的产品进行分组，第二个标准就是对同一组里的产品使用相同的清洁程序（方法）。

Cleaning procedures (before change of products) can for example be considered to be the same if:

例如在以下情况下，可以认为清洁程序是相同的：

1. Same or equivalent issued cleaning batch records/cleaning SOPs; 相同或等同签署的清洁批记录/清洁SOP

2. Same solvent, solubility or similar properties. 相同溶剂、溶解度或相似特性 Advantages and disadvantages with several cleaning procedures, compared to one cleaning procedure, are presented in the following table.

下表列出了采用几个清洁程序与采用同一个清洁程序的优缺点。

The same cleaning procedure for all substances (chosen to clean out the most difficult substance)

所有物质（选取最难清洁的物质做验证）采用同一清洁程序

+ Minimum number of cleaning - Not optimal cleaning procedure validation studies (perhaps only one) for each substance →longer clean out

times on average as well as higher consumption of solvents

- Normally a low limit for residues valid for all substances

+ 减少清洁验证的次数（可能只需验证- 对所有物质都不是最优的清洁方一次） 法→平均清洁次数会比较多，同时溶

剂消耗量大

- 一般对所有物质采用同一个较低的残留限度

Optimised cleaning procedures for each substance优化每个物质的清洁程序 + Minimum clean out time on average

- Maximum number of cleaning validation studies (as many as there are cleaning procedures) - 增加清洁验证的最大次数

+ 降低平均清洁时间

In the example the Clean Company has evaluated the cleaning procedures. The cleaning procedures have been examined and categorised into different classes.

Substances in the same class are cleaned in the same way, using the same solvents and usually exhibit some chemical similarity with each other (e. g. salts, chemical structure etc.). In this example, totally, four cleaning procedure classes are included: 在案例中，清洁公司评估了清洁程序，通过检查将其分为不同类别。同一类别中的物质采用相同方法清洁，采用相同的溶剂，通常其所含的化学物质相互类似（例如，盐、化学结构等）。在本例中，共包括四类清洁程序： — Class I water soluble substances. — 一类：水溶性物质

— Class II methanol soluble substances. — 二类：甲醇可溶性物质

— Class III acetone soluble substances. — 三类：丙酮可溶性物质

— Class IV separate class for special substances with defined solubility — 四类：根据溶解度制订的特殊物质特定级别

7.4 Investigations and Worst Case Rating (WCR)/Risk assessment 调查和最差情况（WCR）风险评估

A worst case rating study/Risk assessment, will prioritise existing drug substances, in a cleaning validation program, based on information on applicable criteria chosen by the company. Clean company chose the following criteria which are relevant to the molecule preparation in their facility (companies should evaluate individual situations):

进行最差情形分类研究/风险评估时，根据公司选择的可采用标准，对清洁验证程序中已有原料药进行优先顺序排列。清洁公司选择了以下标准，该标准与在该工厂中生产的产品分子相关（公司应对自己的情况进行单独评估） a) Hardest to clean: experience from production; 最难清洁：生产所得的经验 b) Solubility in used solvent; 在所用溶剂中的溶解度

c) Lowest Acceptable Daily Exposure( If ADE data are not available, other pharmacological (dose) , OEL or toxicity data ( LD50 ) may be used (see chapter 4); 可接受最低日暴露量（如果不能获得ADE数据，可以使用（参见第4章）其它药学（剂量）数据、OEL或毒性数据（LD50）

d) Lowest therapeutic dose (or toxicity data LD50 ); 最低治疗剂量（或毒性数据LD50）

In order to present documented evidence supporting the scientific rating for each criterion, investigations (a formalized Risk assessment) should be carried out and formal reports should be written. For each criterion groups of rating with corresponding descriptive terms should be presented. When available, the descriptive

terms can be chosen from the scientific literature on the subject (i. e. for solubility and toxicity). For other cases the rating is based on scientific investigations carried out by the company and collecting experience regarding details on the cleaning processes (i.e. \"experience from production”).

为了形成书面证据来支持各标准分级的科学性，应进行研究（正式的风险评估）并形成书面的正式报告。每个标准中，要列出分级组所对应的描述性术语。如果可能，应从科学文献中选取相应的术语描述（例如溶解性和毒性）。其它情况下，分类也可以根据公司的科学研究和在清洁工艺方面积累的经验（即“生产经验”）。 Clean Company chose to execute the WCR according to a formal protocol, in which the rating system was identified and the rating documented. In a Risk assessment report the results including the WCR were summarised, as well as conclusions. 清洁公司选择根据一份正式的方案进行最差情形分级（WCR），对清洁情况进行分级并记录分级结果。在风险评估报告中，对结果，包括WCR，和结论进行综述。

a) Hardest to Clean out - Experience from Production 难以清洁---生产中得出的经验

One criterion which can be used is, experience from production with regard to how difficult a substance is to clean out. The study is recommended to be in the form of interviews with operators and supervisors. A standardised sheet with questions could be used in which the answers are noted. Hard-to-clean substances are identified and the difficulty of cleaning could be rated according to the three categories suggested below. The opinions of the personnel are subjective, and therefore should be supported by a scientific rationale.

分级可以使用的一个标准是生产中获得的关于该物质被清洁难度的经验。建议通过与操作人员和主管沟通进行该项研究。可以采用了一份标准化问卷，让操作人员和主管在问卷中标出答案，从问卷统计中找出最难清洁物质，然后根据以下三级进行分级。人们的观念可能会有主观性，因此，还需要有科学合理性来支持本方法。

Category: 1 = Easy 2 = Medium 3 = Difficult 分级：1=易清洁 2=中等 3=难清洁 b) Solubility 溶解度

A solubility-rating should be carried out based on the solubilities of the substances in the solvents used for cleaning. Suggested rating numbers, with explanations, are presented in the table below. The descriptive terms are given in [1] - page 53 - USP 24 under —Reference Tables (Description and Solubility, 2254)“.

溶解度分级应根据物质在清洁用溶剂中的溶解度来分级。下表中给出了推荐的分级数及相关解释。描述性术语在USP24第53页“参考表格”（描述和溶解度，2254）中可以找到。

Group 1 2 3

Included descriptive terms Very soluble Freely soluble Soluble

Sparingly soluble Slightly soluble

Very slightly soluble Practically insoluble Insoluble

所包括的描述性术语

Approximate quantities of solvent by volume for 1 part of solute by weight Less than 1 part from 1 to 10 parts From 10 to 30 parts From 30 to 100 parts From 100 to 1000 parts From 1000 to 10000 parts More than 10000 parts

分组 1

一份溶质所需的溶剂份数，以重量计 小于1份 1-10份 10-30份 30-100份 100-1000份 1000-10000份 大于10000份

极易溶解 易溶

2 可溶

略溶

3 微溶

极微溶解 几乎不溶 不溶

译者：上述溶解度中文术语系参照《中国药典》2010第二部凡例十五。 c) ADE concept ADE概念

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 (see chapter 4).

可接受日暴露剂量界定的是在对健康不产生副作用的前提下，患者在终生时长内每天可以暴露于该物质的浓度限度（参见第4章）。

An example of rating numbers, with explanations, is presented in the table below. 下表中给出了一个分级数的例子及解释：

Group 分组 1 2 3 4 5

If ADE data are not available, other pharmacological (dose), OEL or toxicity data ( LD50 ) may be used (see chapter 4).

ADE >500μg 100-500μg 10-99μg 1-9μg <1μg

如果不能获得ADE数据，也可以使用（参见第4章）其它药学（剂量）、OEL或毒性数据（LD50）。 d) Therapeutic Doses 治疗剂量

An investigation of therapeutic doses is typically base on oral and/or parenteral data. In the cases where the therapeutic doses are not available, corresponding values based on the toxicity could be used (recalculated according to company procedure). An example of rating numbers, with explanations, are presented in the table below. 治疗剂量的研究一般是根据口服和/或注射数据的。如果无法获得治疗剂量，可以使用对应的毒性数据（根据公司程序进行再次计算）。下表给出了一个分级数的例子及其解释：

Group

Include dose intervals

(smallest therapeutic dose)

包括给药间隔（最小治疗剂量） >1000mg 100-1000mg 10-99mg 1-9mg <1mg

分组 1 2 3 4 5

7.5. Worst Case Rating 最差情况分级

The substances are scientifically matrixed by equipment class (train/equipment) and cleaning class (procedure). Each existing combination of the classes is considered as a group. When this bracketing has been carried out, the - “Worst Case Rating (WCR)”- can start. For at least one worst case in each group, cleaning validation studies shall be carried out. The rating procedure for Clean Company presented as an example could be used.

所有物质按设备类别（设备链）和清洁类别（清洁程序）进行科学的矩阵列表。每个类别的组合被作为一个组。在进行分组时，可以开始最差情形分级（WCR）。在一个组中，至少要验证一个最差情形的清洁验证。以下为清洁公司的分级程序举例，实践中可以使用。 a) Rating Procedure 分级程序

During a worst case rating, the results of the investigations are summarised for each substance in each equipment class. If the evaluation of the cleaning procedures indicates that some of the substances have unique cleaning procedures, then each of those substances will be considered as a group (with one group member which is the worst case).

在最差情形分级过程中，对每个设备类别中每个物质的研究结果进行总结。如果清洁程序的评估结果显示有些物质需要独特的清洁程序，则这些物质作为一组（每个组员均是最差情形）。

If all the substances in a cleaning class (train/equipment) will be tested, then individual limits may be used for each substance. In case of groups, where only some \"worst cases\" are tested, the strategy described below shall be followed. The following methodology shall normally be applied when a priority based on a worst case shall be used.

如果在一个清洁类别（设备链/单个设备）中的所有物质均需要进行检测，则每个物质适用不同的限度。如果组中只有一些“最差情形”需要检测，则应按以下策略进行检测。如果采用了按优先顺序排列选择最差情形，则一般适用以下方法。 Choice of common, general residual limit 通用残留限度选择

Evaluate if the lowest calculated limit is reasonable to apply on all substances. If that is the case, this limit shall be valid as a common general limit for the specific equipment. If the lowest limit is found to be too low as common limit for all substances, then the second lowest limit is evaluated and so on.

评估最低计算限度用于所有用物质是否合理。如果合理，则该限度可以作为特定设备的通用限度。如果发现最低限度太低，不能作为所有物质的通用限度，则需要对第二低限度进行评估，以此类推。

Criteria for the validation of the cleaning processes: 清洁工艺验证标准

1. For the substances with common, general limit, it is required that the substance with the lowest solubility (in the cleaning solvent/solution) shall be tested for each cleaning method. If more than one substance fulfils this criterion, then the substance shall be chosen which, based on experience is most difficult to clean.

对于具有通用限度的物质，针对每个清洁方法要检测具有最低溶解度的物质（在清洁溶剂/溶液中）。如果不止一个物质满足该标准，则应根据最难清洁经验选择一个物质用于通用标准检测。

2. Any substance which does not fall within this 'bracket' must be validated individually.

所有不能落在“括号”中的物质必须单独验证 b) Evaluation of Rating 分级评估

The worst case rating can be executed according to an issued protocol in which the methods and procedures for the rating will be identified. The applicable investigations presented in section 7.4 a-d would then be used (and could be enclosed to the protocol or a report, to support the rationales for the rating). A matrix system, for each equipment class (such as a dryer), can be set up as evident from the following table where Train A of Clean Company has been chosen. In this case a formal rating matrix has been filled in for Train A. Altogether two cleaning classes were identified for the

substances produced in Train A. All the categories are introduced as columns in a matrix.

可以根据签发的方案对最差情形进行分级。在方案中，要说明分级的方法和流程。可以使用7.4 a-d中所述的可用调查方法（可以附于方案或报告中，支持分级的合理性）。对于每个设备类别（例如干燥器），可以建立一个矩阵系列。作为案例，清洁公司在下表中选择了设备链A，制订了一个正式的分级矩阵，为设备链A中生产的物质建立了两个清洁类别。所有类别在矩阵表中引入作为一列。 Cleaning

a):

Method d):

Hardest to b): Substance Class c):

Solubility Ther.dose

clean*最难ADE 物质

清洁方法分溶解度 治疗剂量

清洁

级

E substance III 2.3 1 4 3 F substance III 2.2 1 2 4 C substance III 2.1 1 3 2 L substance III 1.9 1 3 3 O substance III 2.8 2 2 3 M substance III 2.5 2 2 3 P substance I 2.2 1 2 3 R substance I 2.6 2 3 3 T substance I 1.8 1 2 3

* Each figure is the main value for different questions answered by operator and supervisors.

*各数值是由操作工和主管回答不同问题的主要值。

For the products in this train two cleaning methods (Class I and III) are used. 在该设备链中生产的产品使用了两种清洁方法（I类和III类）。 Therefore two groups have to be validated. 因此，需要分为两组来进行验证。

The worst case product (for the validation study) for class III is O substance (Solubility 2 and Hardest to clean* 2.8).

III类中最差情形产品（用于验证研究）为O物质（溶解度2和最难清洁 2.8） The worst case product (for the validation study) for class I is R substance (Solubility 2 and Hardest to clean* 2.6).

I类中最差情形产品（用于验证研究）为R物质（溶解度2和最难清洁2.6） In both cases the limit should be calculated with the most active substance (ADE 4). 在两种情形下，均需要计算活性最高物质的限度（ADE4）。

If ADE data are not available, the limit should be calculated with the most active substance (Therapeutic dose 4).

如果无法获得ADE值，则根据活性最强的物质计算（治疗剂量4）。

If the limit calculated with ADE 4 or Therapeutic dose 4 is achievable for all products, this limit can be chosen for both groups.

如果采用ADE4或治疗剂量4可以计算所有产品的限度，则可将该限度用两组产品。

If the limit calculated with ADE 4 or Therapeutic dose 4 is too low and not achievable for all products, E substance and F substance should be considered as separate groups or produced in dedicated equipment.

如果采用ADE4或治疗剂量4所计算出的限度太低，有的产品不能达到，则应考虑将E物质和F物质单列为一组，或在专用设备中生产。

The limit for the remaining group should be calculated with the most active substance (ADE 3 or Therapeutic dose 3).

剩下的组的限度应根据活性最强的物质（ADE 3 或治疗剂量3）来计算限度。 In case a substance of top priority is not produced regularly, the substance with the second highest priority will be tested in order to show that the cleaning procedure is sufficient for all the other substances in that class. The substance of top priority will then be tested at the first possible occasion.

如果一种物质其优先级为最上，但不常生产，可以同时测试该物质和第二高优先级别的物质，以检查清洁是否对该类中其它所有物质均已足够。这样，最高优先级的物质会在第一次生产时进行测试。

The WCR/Risk assessment could typically result in a report including a priority, based on the rating, for the substances in the cleaning validation program. It is recommended that the applicable background investigations shall be completed, approved and enclosed to the cleaning protocol or the report.

WCR和风险评估一般会形成一份报告，其中包括对清洁验证程序所涉及的物质界定优先级别、进行分类情况。建议将完整的应用背景调查及其批准情况附入清洁验证方案或报告中。 c) Re-rating 重新分级

Change control should be applied to the WCR. If the conditions for the rating are changed, then a re-rating procedure should be carried out. The following listing gives examples where a formal re-rating procedure may be required:

对WCR也要实施变更控制。如果分级条件进行了变更，则要进行重新分级。以下列出了需要重新分级的例子：  Changed cleaning method

 变更清洁方法  Changed process  变更工艺

 Changed / additional new product  变更/增加新产品  Changed / new equipment  变更/增加新设备

After re-rating, it is recommended to issue an official controlled document including a worst case listing or table, with the same type of result presented for the involved substances/ equipment/methods, as for the original rating.

在重新分级后，建议签发一份正式的控制文件，其中包括一份最差情况清单或表格，与原始分级所用的型式相同，在其中列出所涉及的物质/设备/方法结果。 8.0 Determination of the Amount of Residue 残留量的检测 8.1 Introduction 介绍

This section provides a practical guidance for the determination of the amount of residue in cleaned equipment based on the requirements from regulatory authorities 3[1] and current guidelines on analytical validation.4[2] Specific requirements for the validation of analytical and sampling methods for cleaning validation purposes are provided in this section, in addition to examples of sampling methods and the appropriate use of analytical methods.

本部分根据药监当局的要求和现行分析方法验证指南，提供了检测已清洁设备中残留物数量的实用指南。在本部分中给出了清洁验证中所用分析方法和取样方法的验证要求，以及取样方法和适当使用分析方法的例子。

The carryover acceptance limit (Mper) is a calculated figure that represents the specification limit for the equipment cleanliness (see Section 4.0, Acceptance Limits), however, the determination of the actual amount of residue (M) remaining in the equipment following cleaning must be achieved using appropriate methods i.e. for both the sampling method and the quantitation of the contaminant in the sample. 允许残留限度（Mper）是一个计算出的数值，代表设备清洁程度的质量标准限度（参见4.0部分，可接受限度），但是，对清洁后设备中残留物（M）实际数量的检测必须使用适当的方法来获得，即，针对取样方法和样品中污染物的定量。 Since the decision on the acceptable cleanliness of the equipment bears a potential risk to product quality, the method(s) used for the determination of M must be

                                                             3[1] FDA Guide to Inspections Validation of Cleaning Processes, http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074922.htm

4[2] ICH Q2 (R1), Validation of Analytical Procedures: Text and Methodology, November 2005

validated1 and the specificity, sensitivity and recovery of the method(s) should be determined as a minimum.

由于对设备可接受清洁度的决定会对产品质量有潜在风险，因此用于M检测的方法必须进行验证，必须至少验证方法的专属性、灵敏度和回收率。 8.2 Validation Requirements 验证要求 8.2.1 General 通则

The requirements for analytical method validation are defined in ICH Q2(R1), Validation of Analytical Procedures: Text and Methodology, November 2005. There are four types of analytical methods with principally different validation requirements; these are identification tests, tests for impurities (both quantitative and limit tests) and assay tests. The validation requirements for each method type are shown Table 1. 分析方法验证的要求在ICH Q2(R1)“分析方法验证：检验和方法学，2005年11月”中已给出。其中列出了四种不同类型的分析方法，各适用不同的验证要求，它们分别是：鉴别测试、杂质检验（定量和限度测试）和含量测试。每种类型方法的验证要求在表1中列出。

The list should be considered typical for the aforementioned analytical procedures, however, exceptions should be dealt with on a case-by-case basis. It should be noted that robustness is not listed in the table and should be considered at an appropriate stage in the development of the analytical procedure.

在上述的分析方法中必须考虑该清单，但是，要根据各案处理例外情况。要注意耐用性在表中并未列出，但在方法的研发过程中适当阶段需要进行考虑。 In practice, it is usually possible to design the experimental work such that the appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance; specificity, linearity, range, accuracy and precision.

在实际应用中，通常可以设计一个试验性工作，使得在方法设计时可以同步考虑方法的验证特性，例如，专属性、线性、范围、准确度和精密度。

The validation of an analytical method should occur in compliance with pre-established acceptance criteria that should be documented in a written general policy or Validation Plan. However, there should be one validation report per validated method that summarises the specific results.

分析方法验证必须符合预定的可接受限度。可接受限度应记录在书面的通用方针或验证中。但是，对每个验证过的方法必须有一个验证报告，总结验证结果。 TABLE 1 Requirement List for Analytical Validation Characteristic Accuracy

Type of Analytical Procedure Testing for Impurities

Identification

Quantitative Limit — + —

Assay +

Precision Repeatability + — + Intermediate

— +1 — + Precision

Specificity2 + + + + Detection Limit — —3 + + Quantitation

— + — — Limit

Linearity — + — + Range — + — + — Signifies that this characteristic is not normally evaluated. + Signifies that this characteristic is normally evaluated.

1 In cases where reproducibility has been performed,

Key intermediate precision is not needed.

2 Lack of specificity of one analytical procedure could be

compensated by other supporting analytical procedure(s). 3 May be needed in some cases.

表1 方法验证需求清单

分析方法类型

特性 准确度 精密度 重复性 中间精密度 专属性2 检测限 定量限 线性 范围

杂质检测

含量

定量测试 限度测试

— + — + + — + — +1 — + + + + + — —3 + + — + — — — + — + — + — + — 表示该特性一般不需要评估。 + 表示该特性一般要进行评估。

1 如果做了重复性测试，则不需要做中间精密度。

2 如果一个方法缺乏专属性，则可以用另一个支持性分析

方法进行补偿。 3 有时需要。 鉴别

说明

The requirements for ‘Testing for Impurities’ are typically employed for the validation of analytical methods specific to cleaning validation. 在清洁验证专用分析方法验证中，一般应用“杂质检测”的要求。

The requirements for ‘Quantitative Testing for Impurities’ can apply, for example, in cases where a method should be suitable for several possible acceptance limits and

therefore quantitation of the residue over a certain range may be necessary e.g. the measured amount of residue M must be compared with acceptance limits between 5 and 750 g/equipment. This is possible when the method will be used for several changeovers.

有时可以应用“杂质定量检测”要求，例如，如果一个方法适用于几个可能的可接受限度，因此可能需要对一定水平范围内的残留物进行定量检测，例如，残留物M的测得量必须与可接受标准5-750g/设备相比较。如果方法要用于几个产品更换情况下的检测，则可以使用上述方法。

The requirements for ‘Limit Testing for Impurities’ can apply, for example, in cases where the method should be suitable for one specific acceptance limit e.g. the measured M must be compared with Mper ≤ 105 g/equipment.

有时可以应用“杂质限度检测”要求，例如，如果方法需要符合一个特定的可接受限度，例如，对M的测量必须与Mper ≤ 105 g/设备进行比较。

8.2.2 Analytical Method Validation for Cleaning Validation 清洁验证所用分析方法验证

In the following sections, aspects of analytical method validation specific to cleaning validation are emphasised. For further details refer to ICH Q2 (R1).

在以下部分强调了清洁验证专用的分析方法要点。更详细的要求参见ICH Q2(R1)。

Specificity is a basic requirement for all analytical methods (see Table 1), however, in the case of cleaning validation it may occur, that not all potential impurities are clearly specified. It is important to note that in such a situation a specific method may not always detect all impurities. Studies should be performed to characterise the unknown impurities, develop and validate suitable analytical methods. However, this can be an unacceptably time consuming task. In this case a method that detects all potential impurities together can be suitable, even when it is not specific for each of the impurities. For example, in a situation where only non-volatile impurities occur, a dry residue determination method that is specific for the sum of non-volatile impurities could be used, provided that the validation requirements according to Table 1 are satisfied. In order to consider the equipment acceptable for use it must be assumed that the dry residue consists of the worst case impurity (most toxic, most active etc.). In some cases a combination of several methods can achieve the necessary specificity.

专属性是所有分析方法（见表1）都适用的基本要求，但是，在清洁验证中，可能并不是所有潜在杂质都能被明确，在这种情况下要重点注意即使是专属的方法，也并不一定能检测出所有杂质。可以研究未知杂质的特性，建立适当的检验方法并验证，但这样做所耗费的时间可能是无法接受的。这时，可能会适当的办法是采用一个能检出所有潜在杂质的方法，即使该方法对有些杂质不具有专属性。例如，如果只有不挥发性杂质产生，只要验证结果符合表1的要求，可以使用非专属性方法蒸发残渣来检测所有不挥发性杂质的总和。考虑到要使设备清洁程度可

以接受，必须假定蒸发残渣结果中会包括最差情形的杂质（毒性最强、活性最强等）。有时，可以联合使用几个方法来达到必需的专属性要求。

After the completion of a cleaning validation study an unspecific method (e.g. dry residue) may be used for the routine verification of equipment cleaned by the validated cleaning procedure provided that it is shown that the unspecific method is suitable for the intended purpose. If possible, the sensitivity of impurity detection for cleaning validation should be determined for both the sampling and analytical methods together (see Section 7.2.4).

在清洁验证完成后，可以使用非专属性方法（例如，蒸发残渣）对按验证过的清洁程序清洁后的设备进行日常检测，只要该方法适合其既定用途。可能的情况下，清洁验证所用检验方法对杂质检测的灵敏度应与取样方法和分析方法一起测试（参见7.2.4部分）。

8.2.3 Detection and Quantitation Limits 定量限和检测限

Measured values below limit of quantification (LOQ) should be reported as the LOQ value (worst case approach). For example if the LOQ is 10 mg/l, the measured blank is 7 mg/l and the measured residue amount is 3 mg/l, the reported value for the sample should be equal to the LOQ i.e. 10 mg/l.

低于定量限（LOQ）应报告为定量限值（最差情况法）。例如，如果LOQ为10mg/L，测得空白结果为7mg/L，测得残留值为3mg/L，则该样品的残留值应报告为LOQ，即10mg/L。

Usually it can be assumed that, for quantitative impurity determination, the LOQ should approximately be 0.5 of the specification i.e. for cleaning validation 0.5 of the acceptance limit or lower. LOQ should never be higher than the acceptance limit. In the following sections three methods of LOQ/LOD determination are outlined: 一般可以假定，在杂质定量检测时，LOQ应为质量标准的约0.5倍，即对于清洁验证来说，可接受限度的0.5或更低。LOD不得高于可接受限度。在以下部分，列出了三种确定LOQ/LOD的方法： ? Based on Visual Evaluation 目视评估

Visual evaluation may be used for non-instrumental methods but may also be used with instrumental methods. Frequently this approach is used for TLC.

目视评估可以用于非仪器方法，但也可用于仪器分析方法。这种方法经常用于TLC。

? Based on Signal-to-Noise Approach 信噪比方法

This approach can only be applied to analytical procedures which exhibit baseline noise (e.g. GC, HPLC). A signal-to-noise ratio (S/N) between 3 or 2:1 is generally considered acceptable for estimating the detection limit (LOD) and a typical ratio for acceptable quantitation limit is 10:1 (LOQ). The value for S/N can be calculated according to Equation 1 and Figure 1:

本方法只能用于产生基线噪声的分析方法（例如，GC、HPLC）。信噪比（S/N）为2-3：1时，一般可以作为估计的检测限（LOD），10：1可以作为定量限（LOQ）。信噪比值可以根据公式1和图1计算：

Where: H is the height of the peak from the mean baseline.

hn is the maximum deviation of the baseline within the range of 5 to 20 fold width of peak at half height.

其中：H为基线平均值的峰高

hn是基线在5-20部半峰高时峰宽范围内最大偏差

? Based on the Standard Deviation of the Response and the Slope 根据响应和斜率的标准偏差

The detection limit may be expressed by Equation 2 and the quantitation limit by Equation 3.

检查限可以采用公式2表示，定量限可以用公式3表示。

8.2.4 Determination of Recovery 回收率测定

If possible, the recovery of impurity detection for cleaning validation should be determined for the sampling and analytical methods together at least for recovery and

sensitivity (Limit of Quantitation - LOQ, or Limit of Detection - LOD). This can be achieved, for example, by spiking a surface equivalent to the equipment surface (e.g. material, polish grade) with different known amounts of the impurity. The impurity can then be recovered and analysed using the same sampling and analytical methods that will be used for the cleaning validation study. The overall results from this procedure are then compared to criteria for detection or quantitation limits as defined in ICH Q2 (R1). Validation of the limits may be achieved by the analysis of samples known to be near at the limits.

可能的话，可以针对取样方法和检验方法同时进行清洁验证中杂质检测的回收率和灵敏度（定量限-LOQ，或检测限-LOD）。例如，可以采用与设备表面材质相同的表面材料（例如，材质、粗糙度），在上面加不同已知数量的杂质，然后采用与清洁验证研究相同的方法取样并分析。再将使用该方法所得的总体结果与ICH Q2(R1)中定义的检测限或定量限标准进行比较。可对接近限度的已知样品进行分析来验证分析方法的检测限和定量限。

The measured results are then compared to the actual amount applied to the surface. The recovery is typically determined during the accuracy determination and should be reported as a percentage of the known applied amount of the impurity.

将检测结果与实际数量进行比较，用于表面残留计算。回收率一般是在准确性测试中确定，应报告为已知杂质数量的百分比。

As an example, quantitative impurity determination recoveries of ≥ 90 % are usually regarded acceptable. For cleaning validation, recoveries of ≥ 90 % do not need to be taken into account for the calculation of the true value for M. Recoveries of < 90 % must be included in the calculation for M (see Equation 4) and recoveries of < 50 % should be omitted.

例如在杂质定量测试中，回收率≥ 90 %时一般认为是可以接受的。在清洁验证中，如果回收率≥ 90 %，在M残留量真值计算中可以不需要考虑回收率；如果回收率< 90 %，则需要在M计算时加以考虑（参见公式4），如果回收率<50%，则该方法不适用。

Where: M: True value for the amount of residue remaining in the equipment after cleaning;

Mres: The measured amount of residue (sampling and then analytical measurement); R Recovery in % divided by 100 (e.g. for 75%, 75/100 = 0.75). 公式4：

其中M：清洁后设备上残留物的数量真值 Mres：测得残留量（取样后分析测量）

R：回收率除以100（例如，对于75%即为75/100=0.75）

8.2.5 Validation Requirements for Quantitative Testing of Impurities 杂质定量测试的验证要求

The requirements for the validation of quantitative testing of impurities according to ICH Q2 (R1) are shown in Table 2, including proposed acceptance criteria (as an example only). Alternative acceptance criteria may be established based on sound scientific rationale.

根据ICH Q2(R1)，杂质定量检测方法的验证要求在表2中列出，包括制订的可接受标准（只是举例）。可以根据科学合理的原则制订适当的可接受标准。 It is important to note, that the summarised requirements should be used for the validation of quantitative testing for impurities during cleaning validation studies. Validation of quantitative testing for impurities is usually applied when the analytical method will be used for several specifications of the residue amount in the equipment. 重点要注意的是，在清洁验证研究中，定量检测方法验证应满足所有要求。如果分析方法将用于设备中残留量有不同的几个质量标准，则一般采用杂质定量方法验证要求。

The lowest foreseen acceptance limit is referred to as Mper Min and the highest limit as Mper Max in Table 2. For only one specific acceptance limit normally limit testing for impurities and the corresponding validation of the analytical method is sufficient. If the validation of quantitative testing for impurities will be used for one specific acceptance limit, then Mper Min = Mper Max = Mper.

最低预期可接受限度，在表2中称为MperMin，和最高限度，称为MperMax。对于只有一个特定的可接受限度，一般可以使用杂质限度测试方法，对方法只要做相应的验证即可。如果要将杂质定量方法的验证用于单一可接受限度，则Mper Min = Mper Max = Mper。

For the experimental work described in Table 2, the samples can be spiked with appropriate levels of the impurities (when standards are available) or compared with another well-characterised procedure (when standards are not available) to obtain the true value of the analyte concentration.

表2中试验里，可以采用杂质（如果可以获得标准品的话）加入样品中至适当的浓度水平，或与另一个经过确认的检验方法进行对比（如果不能得到标准品的话），以得到被分析物的真实浓度值。 TABLE 2 Validation Requirements Experiments

Possible Acceptance Criteria

Accuracy:

Perform a minimum of 9 determinations over a minimum of 3 concentration levels covering the specific range (e.g. 3 concentrations/3 replicates each of the total analytical procedure). Determine analyte with respect to the total amount of residue in

the sample (e.g. weight/weight). Report: □ Accuracy as percent recovery or 90.00-110.00% □ Difference between the mean and the accepted true ≤10.00% (P=95%) value.

□ Confidence intervals. Precision:

Investigate using homogenous, authentic samples or (if not possible) artificially prepared sample. Perform a minimum of 9 determinations covering the specified range for the procedure (e.g. 3 concentrations/3 replicates each) or a minimum of 6 determinations at 100% of the test concentration. Repeatability (intra-assay precision):Establish precision under the same operating conditions over a short interval of time. Report:

□ Standard deviation (interdependent with S) See S □ Overall relative standard deviation over the whole ≤10.00% range of the method

□ Relative standard deviation within one concentration ≤20.00% level

□ Confidence interval

Intermediate Precision (may include robustness, ruggedness):

establish precision on different days, for different analysts, on different equipment and after variation of method parameters (= robustness, e.g. stability of solutions, variations of pH, of mobile phase composition, of flow rate, of temperature, of columns etc.). It is not necessary to study these effects individually. Experimental design (matrix) may be applied. Report:

□ Standard deviation (interdependent with relative See S standard deviation)

□ Relative standard deviation 3×S from repeatability or 10% whichever is greater

□ Confidence interval Specificity:

Demonstrate the discrimination of analyte in the presence of the other impurities:

□ Test samples containing the analyte and other Specify acceptable impurities. Obtain positive and correct results for the deviation analyte.

□ Test samples without the analyte. Negative results

□ For chromatographic procedures use representative Specify acceptable chromatograms to document specificity. Label resolution of peaks individual components appropriately. Linearity:

Measure a minimum of 5 concentrations across the range of the procedure (dilute standard stock solution or prepared synthetic mixtures). Plot the signals as function of concentration. Evaluate the plot: □ Visually Linear □ Statistically (e.g. regression line by the method of least squares)

Correlation coefficient ≥0.99000 y-intercept Confidence band (P = 95%)

Slope of the regression line Residual sum of squares Range:

Confirm that the analytical procedure provides an acceptable degree of linearity, accuracy and precision within or at the extremes of the specified range. Minimum specified ranges:

□ From the reporting level to 120% of MperMax. The From LOQ or 80% of reporting level for cleaning validation reasonably will MperMin to 120% of be the LOQ. However, the reporting level must be MperMax. below MperMin and should be below or at 80% of MperMin.

表2 验证要求 测试项目 可能的可接受标准 准确度

在指定的浓度范围内对3个浓度进行至少9次检测（例如，3个浓度各按完整的分析方法检测3次）。测试残留物在样品中的总量（例如重量/重量）。 报告：

90.00-110.00% □ 精密度，表达为回收率百分比或

≤10.00% (P=95%) □ 平均值与所接受的真值之间的差异.

□ 置信区间

精密度:

使用均匀的具有标准值的样品或（如果没有标准样品的话）人为制备的样品，在指定范围内采用指定方法（例如，3个浓度各3次重复检测）检测至少9次，或在检测浓度100%水平测试至少6次。 重复性（含量精密度）

建立相同操作条件下较短时间内的精密度 报告：:

□ 标准偏差（与S相互依存） 参见 S

≤10.00% □ 整个方法浓度范围内的总体相对标准偏差

≤20.00% □ 一个浓度水平的相对标准偏差

□ 置信区间

中间精密度（可以包括耐用性）

在不同天、不同化验员采用不同设备对方法参数进行变动（=耐用性，例如，溶液稳定性、pH值变化、流动相比例、流速、温度、柱子等）检测方法精密度。不需要单独研究各因素的影响，可以使用试验设计（矩阵）。 报告：

□ 标准偏差（依赖于相对标准偏差） 参见S □ 相对标准偏差 重复性中的S值乘3或

10%，取大者 □ 置信区间

专属性

证明被分析物与其它杂质的分离度

□ 检验含有被测试物和杂质的样品，得到被分析物指定可接受偏差

contains 0

的符合的正确结果。

□ 检测不含被分析物的样品。 测试结果不含被分析物 □ 对于色谱方法，采用代表性图谱记录专属性。对指定各峰间的可接受分离各化合物进行恰当标识。 度 线性

检验方法范围内最少5个浓度检测（稀释标准贮备液或制备的合成混合物）。画出浓度-信号点，评估： □ 目视 线性

□ 统计数据（例如，最小平方法回归线）

≥0.99000 相关系数

Y轴截距 置信区间 (P 95%)

contains 0 回归线斜率

残差平方和

范围：

确认检验方法的线性可以接受，精密度和准确度在指定的范围内或在范围极值。最小指定范围：

□ 报告限至最大样品浓度的120%。合理的清洁验从定量限或最小浓度的证的报告水平应在定量限，但是报告水平必须低80%到最大浓度的120%。于最小样品浓度，低于或等于最小样品浓度的80%。

8.3 Sampling Methods 取样方法

In order to demonstrate that the plant equipment is verified clean and meets the pre-defined acceptance criteria, sampling and analysis should be carried out using the methods described in the following sections. Justification should be provided for the selection of the appropriate verification technique on a case by case basis. A combination of the two methods is generally the most desirable. For all methods the sampling points should be fixed in a manner such that the true contamination of the equipment will be reflected.

为了证明工厂设备是清洁的，且符合预定的可接受标准，应采用以下部分所述的方法进行取样和分析。应各案论述对选择技术的恰当性。一般最好采用同时采用两种取样方法。对所取样方法，取样点应以一定方式固定，以反映设备中的真实污染情况。

8.3.1 Swab sampling (Direct Surface Sampling) 擦拭取样（表面直接取样） Swab sampling of the direct surface is designed to test small sections of the equipment surface for the presence of residues. Samples should be taken from all main equipment items and since swab sampling does not cover the entire equipment surface area, justification should be provided for the choice of the area for swabbing. 对设备表面进行直接擦拭取样设计用于检测设备上小面积上残留物。样品应从所有主要设备上取样，由于擦拭取样并不覆盖整个设备表面，因此要对于取样部位的选择做出论述。

Typically a small area of the cleaned equipment is swabbed with a material according to a pre-defined method i.e. swab material, solvent and technique. The swab sample can then be extracted and examined using a suitable analytical method.

一般来说，对已清洁设备的一个较小面积采用预定的方法，例如擦拭材料、溶剂和方法，进行擦拭取样。对擦拭样品进行提取，采用适当的分析方法进行检测。 The quantified residue obtained from the sample is then extrapolated to the whole equipment (see Equation 6).

将样品测试所得的残留量值外推至整个设备（参见公式6）。 It is important: 以下内容应重视

l That the validation of the swab sampling is performed on the same surface

(material, polish grade, area in dm2) and with the same materials as the routine sampling of the equipment. l 擦拭取样方法验证应采用相同表面（材质、光洁度、面积以dm2为单位），

以及设备常规取样时相同的取样棒 l That the choice of swabbing material considers extractable materials that could

interfere with the expected residue. l 选择擦拭材料时，要考虑可萃出物料可能对预期的残留物产生影响 l To ensure that the sampling points represent the worst case areas of the

equipment. l 要保证取样点代表设备的最差面积

The disadvantage of this sampling method for often complex API equipment is that difficult to reach areas (e.g. sealings, condensers, transfer pipework) may not be accessible by swabbing. Nevertheless these areas may be the critical areas for the determination of the amount of residue in the equipment.

该取样方法的缺点是有些原料药设备比较复杂，有些部分难以取到擦拭样品（例如，密封处、冷凝器、转移用管道），而这些面积可能对于设备残留量的测定比较关键。

M

Amount of residue in the cleaned equipment 已清洁设备中残留量mg in mg.

WF Recovery rate for the whole chain 整个设备链的擦拭/分析方

swab/analytical method (e.g. 0.8 for 80%). 法回收率（例如0.8代表

80%） Ftot

The entire inner surface of the equipment in 设备整个内表面积，平方分

dm2

Mi Ci CBi

米

Amount of residue (e.g. previous product) in 样品中的残留量（例如，上the sample i in mg. 一产品）mg Gross amount of residue in the sample i in 样品 i 中残留总量mg mg.

Blank of the sample i in mg. To establish the blank, a swab (or several swabs) can be treated in the similar way as a sampling swab except swabbing of the contaminated surface. Usually one and the same blank can be used for all N sampling swabs. Area swabbed by the swab i in dm2. Number of swab samples.

空白样品 i 重量mg 为建立空白，可以将一个（或几个）取样用空白棉签采用与样品同等方法处理。一般一个相同的空白可以用于所有N个取样棉签。 擦拭取样的面积，平方分米样品数量

Fi N i

Sample identifier (current number from 1 to 样品识别号（现在编号为1

N). 至N）

The first production batch of the following product may be sampled and analysed for

impurities (for preceding product) since chromatographic analytical methods will typically be used (e.g. HPLC, GC, TLC).

由于现在普遍使用色谱分析方法（例如HPLC、GC、TLC），可以对下一产品的第一个生产批号取样，分析其中（上一产品）杂质。 8.3.2 Rinse or Wash Solvent Sampling 淋洗或冲洗取样

In cases where swabbing is not possible, for example restricted access, swabbing may be substituted by the analysis of final rinse solutions. Rinse samples can be used to determine the carryover of residues over a large surface area and cover all main process items including transfer pipework. In cases where swab sampling is not practical, it is acceptable to analyse only rinse samples, however this should be justified as part of the validation study.

如果没办法进行擦拭取样，例如不能入口受限，可以对最终淋洗液进行检测来替代擦拭样品。淋洗样品可以用于确定一个很大表面积上的残留量，并覆盖所有主要工艺设备，包括物料管道。如果擦拭取样不实际，可以接受只对淋洗样品进行检测，但应作为验证研究的一部分进行论述。

This section outlines the quantitation of the amount of residue remaining in the equipment after cleaning based on the amount of residue in the last rinse of the routinely used cleaning procedure.

本章列出了根据清洁程序中最后一次淋洗液中残留量，计算清洁后设备中残留量的定量方法。

The residue amount in the equipment can be assumed to be equal to the amount of residue in the last wash or rinse solvent portion. The assumption is based on the worst case consideration that a further rinse (or any reaction) would not remove more than the same amount of residue present in the analysed rinse sample.

可以假定设备中残留量等于最后冲洗或淋洗溶剂中的总量。该假设是基于最差情形考虑，即进一步淋洗（或任何反应）将无法得到比分析用淋洗样品结果更高的残留物。

The advantage of the rinse sampling method is the whole equipment will be reached by the solvent, including difficult to reach locations that cannot be disassembled. Therefore, if appropriately designed, this method will give the best indication of the amount of residue remaining in the equipment.

淋洗取样方法的优点是整个设备都会被溶剂洗到，包括最难触及且不能拆卸的部位。因此，如果对淋洗方法进行了适当的设计，该方法能最好地显示设备中残留量。

For quantitation, a solvent sample (e.g. 1 litre) is removed and the residue in the sample is determined by a suitable analytical method, which can then be extrapolated to the whole equipment according to Equation 5.

在定量检测时，取一个溶剂的样品（例如1L），对样品中的残留采用适当的分析方法进行检测，然后根据公式5外推至整个设备。 Equation 5: M = V × (C – CB) Where 其中

M Amount of residue in the cleaned equipment 清洁后的设备中的残留量mg

in mg. V Volume of the last rinse or wash solvent 最后淋洗或冲洗溶剂体积，L

portion in litres. C

Concentration of impurities in the sample in 样品中杂质浓度，mg/l mg/l.

清洁或淋洗溶剂空白水平，mg/l 如果在一个轮次中取了几个样品，并且在整个轮次中使用的溶剂是同一个批号，则可以在所有样品计算中使用同一个空白。

CB Blank of the cleaning or rinsing solvent in

mg/l. If several samples are taken during one run, one and the same blank can be used for all samples provided the same solvent lot was used for the whole run.

8.3.3 Stamps 邮戳法

In this exceptionally used sampling method, “coins” (or stamps) are placed on appropriate sampling points in the equipment during the manufacture of the previous product and during cleaning. After cleaning, the contamination on the

coins can be analysed and the overall contamination can be calculated by extrapolation to the whole equipment. For quantitation, the coins may be firstly swabbed followed by further analysis of the samples.

这是一种在例外情况下使用的取样方法。取一个“圆片”（或邮票），置于设备中适当的取样点上，进行上一产品的生产及清洁。在清洁后，对硬币上的污染物进行检测，采用外推法计算整个设备的全部污染。如果是要进行定量分析，则对圆片进行擦拭取样，然后对样品进行进一步分析。 8.4 Analytical Methods 分析方法

A sample isolated by either of the sampling methods discussed in Section 8.3 should be analysed by a suitable analytical method (e.g. HPLC, GC, GC-MS, TLC, dry residue, TOC, UV, titration, conductivity or pH). The suitability of the method can be documented by appropriate validation as detailed in Section 8.2.

按第8.3部分所讨论的取样方法之一所获得的样品应采用适当的分析方法（例如，HPLC、GC、GC-MS、TLC、蒸发残渣、TOC、UV、滴定、电导率或pH值）进行检测。方法的适用性可以依据8.2部分指导进行适当的验证并记录。 A combination of analytical methods can be used if appropriate. For example evaporation of the solvent sample and analysis of the dry residue by another method (e.g. HPLC) can enhance the sensitivity of the final analytical method by a factor 106. Alternatively, the use of several methods (e.g. titration, HPLC) can provide the required specificity.

适当时，可以合并使用几个分析方法。例如，将溶剂样品蒸发，采用另一个方法（例如HPLC）分析残渣。这样可以增加最后分析方法的灵敏度到100万倍；而采用几个方法（例如，滴定、HPLC）可以达到所需的专属性。

9.0 Cleaning Validation Protocol 清洁验证方案

PREPARED BY (DEPT.): DATE: 起草人（部门）： 日期： REVIEWED BY (DEPT.): DATE: 审核人（部门）： 日期： APPROVED BY (DEPT.): DATE: 批准人（部门）： 日期： APPROVED BY (DEPT.): DATE: 批准人（部门）： 日期： APPROVED BY (DEPT.): DATE: 批准人（部门）： 日期：

TITLE方案标题:

PROTOCOL NO: 方案编号：

PROTOCOL ISSUE DATE: 方案签发日期：

CLEANING SOP REFERENCE AND ISSUE NO: 清洁SOP索引号和发放号：

TABLE OF CONTENTS 目录 9.1 Background 9.2 Purpose 9.3 Scope 9.4 Responsibility 9.5 Sampling procedure 9.6 Testing procedure 9.7 Acceptance criteria 9.8 Deviations 9.9 Revalidation 9.1 Background 背景

Equipment X is routinely cleaned after product Y (or group of products*) according to procedure XXX......

设备X在产品Y（或产品组）生产结束后，根据程序XXX进行常规清洁…… *If group of products describe rational for choosing this grouping strategy. *如果产品组说明了选择该分组策略的理由。 Describe: Equipment

Cleaning method Cleaning agents.

描述：设备、清洁方法、清洁剂 9.2 Purpose 目的

背景 目的 范围 职责 取样程序 检测方法 可接受标准 偏差 再验证

The purpose of this study is to demonstrate that remaining product residues previous in a piece of equipment are always within the established acceptance criteria if the equipment is cleaned by a defined cleaning method.

本研究的目的是证明如果根据制订的清洁程序进行清洁，上一产品在一个设备中的残留物总能保持在所制订的可接受标准以内。 9.3 Scope 范围

A visual test and a chemical evaluation of the equipment will be performed after a clean to demonstrate that product residue(s) (active ingredient, intermediates and / or excipients) and cleaning agent residues (exclude solvents used in process) have been removed to levels within the acceptance criteria.

在清洁完成后，对设备进行目视检查和化学评估，证明产品残留物（活性成分、中间体和/或辅料）和清洁剂残留（除工艺所用的溶剂外）已被清除至可接受标准以内。

The equipment cleanliness will be proven by testing and evaluation of samples in accordance with this protocol from Z* consecutive cleans. (*Z: Generally three consecutive cleans are acceptable, however, companies should determine the number adequate for their operation.)

根据本方案，实施Z次连续清洁，通过对样品的检测和评估证明设备的清洁度（*Z：一般三次连续清洁是可以接受的，但是，公司应针对自己的操作决定清洁验证的轮次）。

At least a visual revision of the working areas will performed to minimize the risk of cross contamination that results from e.g. contamination on the surface of the process room.

对工作区域至少要进行目视检查，以将，如工艺房间表面污染带来的，交叉污染风险降至最小。

In order for the cleaning procedure to be deemed valid all data generated during the study should be within the acceptance criteria detailed in section 9.7 of this protocol. 为证明本清洁程序有效，所有在研究过程中产生的数据均应符合本方案9.7部分描述的可接受标准。

A report will be written assessing the data generated and thus determining the validity of the cleaning process.

应起草一份报告，评估所产生的数据，决定清洁工艺的有效性。

The equipment should not be used to process another product until clearance indicating that the equipment is adequately clean has been received from the validation department in accordance with process transfer SOP AAA (or detail whatever system is in-place to ensure that equipment is not used).

根据工艺转移SOP AAA（或在此详述已有系统的要求，以保证设备不会被误用）从验证部门接收到设备经过充分清洁的证明后，方可将该设备用于另一产品的生产。

9.4 Responsibility 职责

The responsibility for completion of this study lies as follows (for example): 完成本研究的责任列明如下（举例）：

Scheduling: Manufacturing, QA, QC and Engineering. Cleaning of equipment: Manufacturing Removal of samples: QA Testing of samples: QC

Review of data and approval of study: Validation / Manufacturing / QC 计划：生产部、QA、QC和工程部 设备清洁：生产部 取样：QA 样品测试：QC

研究数据审核和批准：验证部、生产部、QC 9.5 Sampling Procedure 取样程序

Remove swab and rinse samples from the equipment as detailed in section 8.3 of this guidance document.

按本指南文件8.3部分描述从设备中取擦拭样和淋洗样。 SWAB SAMPLES: 擦拭样

See attached equipment sampling diagram (It is important to show clearly where the sampling locations are). Definition of sampling locations should be based on a Risk Assessment.

参见所附设备取样示意图（要清楚显示取样位置）。应根据风险评估来确定取样位置。

Swab samples should be removed according to swabbing procedure SOP BBB (or if there is no SOP in place describe in the text the validated sampling technique for the QA sampler).

擦拭样应根据SOP BBB擦拭程序进行取样（或如果没有SOP，则在验证取样技术中进行描述，以指导QA取样人员）。 The swab sampling locations are as follows: 擦拭取样位置如下：

Product residue samples: list of sample locations and no of swabs to be removed. 产品残留样：取样位置清单，应取擦拭样的数量

Cleaning agent samples: list of sample locations and no of swabs to be removed. 清洁剂样品：取样位置清单，应取擦拭样的数量

Samples should be removed from the locations on the equipment deemed to be ‘worst case’ i.e. most difficult to clean locations and therefore where product is most likely to reside if cleaning has not been adequate. It is important that these locations have been determined scientifically and can be rationalised if necessary.

样品应取自设备中“最差情况”的位置，即最难清洁位置，如果设备清洁不充分的话，产品最可能残留在这些地方。重要的是必要时，已经科学合理地对这些位置进行了确认。

RINSE SAMPLES: 淋洗样

Rinse samples should be removed according to procedure SOP CCC (or if there is no SOP in place describe the sampling technique for the QA sampler).

淋洗样要根据程序SOP CCC（或如果没有该SOP，则在此为QA取样人员描述取样技巧）取样。

The volume of liquid used to rinse the equipment should be detailed. (volume must be shown to be sufficient to cover all product contact surfaces of the equipment). The volumes of the rinse samples should also be stipulated in the protocol.

用于淋洗设备的液体体积要详细描述（体积必须足以覆盖所有与设备表面接触的产品）。淋洗样品的体积也应该在方案中说明。 MICROBIOLOGICAL TESTING 微生物检测

See attached equipment sampling diagram (It is important to show clearly where the sampling locations are)

参见所附的设备取样示意图（要清洁显示从哪些位置取样）。

Microbiological test samples should be removed according to procedure SOP DDD (or if there is no SOP in place describe the sampling technique for the QA sampler). 微生物检测样品应根据程序SOP DDD（或如果没有该SOP，则在此为QA取样人员描述取样技巧）取样。

The microbiological testing locations are as follows: 微生物检测位置如下：

List of sample locations and no of microbiological tests samples to be removed 样品位置清洁，要取的微生物检测样品数量

All sampling details (swab, rinse and microbiological) should be referenced in Table Samples should then be sent to the QC department for analysis. Any relevant sample transfer conditions should be noted.

所有的样品详细情况（擦拭、淋洗和微生物）应在样品表中进行索引，然后送QA部门进行检测。要注意所有有关样品的送样条件。 9.6 Testing procedure 检验方法

Rinse samples should be tested for: 淋洗样应检测

— Product residues in accordance with analytical protocol — 根据检验方案检测产品残留

— Cleaning agent residues in accordance with analytical protocol — 根据分析方案检测清洁剂残留

Swab samples should be tested for: 擦拭样要检测

— Product residues in accordance with analytical protocol — 根据检验方案检测产品残留

— Cleaning agent residues in accordance with analytical protocol — 根据分析方案检测清洁剂残留

Microbiological test samples should be tested for: 微生物试样要检测 Total germ number 总菌数

Note the limits of quantitation and detection as well as the % recovery for the tests being performed.

注意要验证检测方法的检测限和定量限及回收率。

The analytical protocol should include a calculation to convert the amount of residue detected in the sample to 100% (i.e. if the analytical validation results indicate that only 50% of spiked active / cleaning agent is recovered using the swabbing / rinse method of choice, the amount of active cleaning agent recovered per sample should be multiplied by 2 to bring result to 100%).

检测方案要包括将样品中残留结果进行折算至100%的方法（即，如果方法验证结果显示采用擦拭/淋洗方法时加入的活性成份/清洁剂只有50%被回收，则样品中活性物质/清洁剂测得结果要乘以2使回收率达到100%）。

All data generated should be attached to this study and returned to the Validation department where calculations and adherence to acceptance criteria is determined. 所有生成的数据要附入本研究，交回验证部门，由验证部门计算并与可接受标准进行比较。

9.7 Acceptance criteria 可接受标准

? The Visual cleanliness of the equipment must be checked and verified after cleaning according to the procedure xxx: 必须目视检查设备清洁度，在清洁后根据程序XXX进行确认。

Equipment is visually clean: Signed (manufacturing): _______ Date: _______ 设备经目视检查清洁：签名（生产部） 日期： Verified (QA): ______ Date: _______ 审核（QA） 日期

The swab / rinse sample acceptance criteria for product and cleaning agent residues as well as the microbiological test acceptance criteria should be detailed along with a rational for the figures quoted.

擦拭/淋洗样品中产品和清洁剂残留物的可接受标准与微生物检查的可接受标准应与引用数值的理由一起进行详细描述。

(Unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low), detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning. Thus they should be easily removed. Otherwise a different detergent should be selected.)

（与产品残留不同，清洁剂在清洁后应没有残留（或特别灵敏的分析方法----非常低）。清洁剂不是生产工艺的一部分，只是在清洁时加入设备中的物质，因此应该易于清除，否则要重新选择清洁剂。）

Reference: Please see chapter 4 of this guidance document for examples of calculating acceptance criteria.

参考：请参见本指南的第4章，其中有计算可接受标准的例子。

In addition a sample calculation detailing how the residual levels of active ingredient / cleaning agent for the entire equipment are computed should be given.

另外，要给出一个计算的样例，详细写出如何计算整个设备中的活性成分/清洁剂的残留水平。

POINTS TO CONSIDER: 要考虑的问题

Surface area calculations should be performed, verified and kept on file for all equipment evaluated (photos may be incorporated into the protocol to ensure samples are taken from the correct position).

要对所有设备表面积进行计算、验算并保存在文件中（可以将照片放入方案中，以保证从正确的位置取样）。

When the worst case result recorded is less than the limit of quantitation but greater than the limit of detection for the test method, the value denoting the limit of quantitation should be used to perform the calculations.

如果所记录的最差情况结果低于检测方法的定量限，但大于检测限，则应将定量限值作为样品结果用于计算。

When the worst case result recorded is less than the limit of detection for the test being performed the value denoting the limit of detection should be used to perform the calculations.

如果所记录的最差情况结果低于测试方法的检测限，则应将检测限值作为样品结果用于计算。

Dirty Hold Times and Clean Hold Times 清洁前保存时长和清洁后保存时长

The period and when appropriate, conditions of storage of equipment before cleaning, commonly referred to as The Dirty Hold Time (DHT) and the time between cleaning and equipment reuse, prior to additional cleaning, commonly referred to as The Clean Hold Time (CHT), should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow potential for build up of degradation products that may not be removed by the standard cleaning procedure and does not allow potential for microbial contamination of equipment and to ensure that these potential risks are properly assessed and controlled.

清洁前设备可以放置的时长，适当时包括放置的条件，一般称为清洁前保存时长（DHT），以及设备在清洁后再次使用前，进行重新清洁之前，一般称为清洁后保存时长（CHT），应该作为清洁程序验证的一部分。该验证证明对设备的常规清洁和存放不会使得标准清洁程序未能清除的降解产物增加，以保证这些潜在风险经过了适当的评估和控制。

TABLE 1: SAMPLE REFERENCE TABLE Sample Swab sample Swab sample Swab sample Swab sample Swab sample Swab sample Swab sample Swab

To be tested Area for swabbed Active Cleaning agent Active Cleaning agent Active Cleaning agent Active Cleaning

Total

Sample

surface

ref.

area (cm2)xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

Signed/date

sample agent Swab Active sample Swab Cleaning sample agent Sample Rinse sample Rinse sample Sample

Xxx Xxx

Signed/date

Signed/date

To be tested Sample for volume Active Cleaning agent

To be tested for

Microbial contamination Microbial contamination

Sample ref.

Total

Sample

volume of ref.

rinseXxx xxx

Swab sample Swab sample

表1：样品对照表 样品 擦拭样品 擦拭样品 擦拭样品 擦拭样品 擦拭样品 擦拭样品 擦拭样品 擦拭样品 擦拭样品 擦拭样品 样品 淋洗样品 淋洗样品 样品 擦拭样品 擦拭样品

测试项目 活性成分 清洁剂 活性成分 清洁剂 活性成分 清洁剂 活性成分 清洁剂 活性成分 清洁剂 测试项目 Active Cleaning agent 测试项目 微生物 微生物

擦拭面积 样品体积 样品编号

总面积

样品编号

(cm2)xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Total

volume of 样品编号 rinseXxx xxx

签名/日期

签名/日期

签名/日期

9.8 Deviations 偏差

Please indicate whether deviations occurred during the completion of this Validation Protocol and give details especially with regard to impact on the effectiveness of the cleaning validation and with regard to corrective and preventive actions.

在此说明在完成此验证方案的过程中是否有偏差发生，特别要详细说明偏差对清洁验证效果的影响，以及相应的纠正预防措施。 9.9 Revalidation 再验证

Define the Revalidation strategy for cleaning processes 确定清洁工艺的再验证策略。

Signed: __________________ Verified: _________________ 签名： 确认： 10.0 Validation Questions 关于验证的问题

Question 1: When should a company validate/ revalidate cleaning procedures? When is validation not required? Advice: Ref. Section 7.0 and 10.0

Companies should look at each situation individually and determine the need for validation. Section 7.0 provides a basic template, which may be used as a starting point in this evaluation. The necessity to revalidate cleaning procedures should be determined under change control parameters - See Section 10.0.

If routine verification procedures are used, these should be monitored to ensure that the procedure is in control. Companies should consider a periodic evaluation of cleaning procedures, which are subject to variation (i.e. manual procedures etc.), as an additional precaution to assure that the procedures are still valid.

问1：公司在什么情况下对清洁程序进行验证/再验证？什么时候不需要验证？ 建议：参见7.0和10.0部分。

公司应检查单独检查每一种情形，决定是否需要验证。在7.0部分中提供了一个基本模板，可以用来开始此项评估。是否需要对清洁程序进行再验证应在变更控制下进行评估---参见10.0部分。

如果使用了日常确认程序，则需要进行监测以保证程序受控。公司应考虑对可能会有变化（即人工操作程序等）的清洁程序进行定期评估，作为额外的预防措施来保证清洁程序仍然有效。

Question 2: When is it appropriate to use Prospective, Concurrent or Retrospective Validation Advice: Ref. Section 9.0

Retrospective Validation of cleaning is not condoned by regulatory Authorities Prospective Validation is the ideal method of validation.

In situations where very few runs are manufactured in any given period and/ or a business decision has been taken to release the next material manufactured after cleaning based on a high level of testing of the equipment (i.e. Validation level,) concurrent release of material may take place.

问2：什么时候应该使用前验证、同步验证和回顾性验证？ 建议：参见9.0部分。

药监当局不认可对清洁方法进行回顾性验证。 前验证是理想的验证方法。

如果在给定的时间段内只生产较少的轮次，且/或已从业务角度决定了清洁后的下一生产物料将在对设备较高水平测试（即，验证水平）后才放行，则可以在验证同时放行物料。

Question 3: What level of testing is needed after cleaning validation? Advice: Ref. Section 5.3

The answer to this question depends on individual situations. Typically, companies perform visual inspection and take rinse samples to monitor the effectiveness of the cleaning in pre-defined intervals (time or number of batches).

If after validation company decides to perform always cleaning verification non-specific scientifically sound analytical methods may be used.

A practical approach for monitoring the effectiveness of cleaning after completion of cleaning validation in an effective, scientific sound and inexpensive way is given below:

1.) Visual inspection of the cleaned equipment. Only after this check is considered satisfactory, proceed with the next step.

2.) Take a rinse and/or swab sample (one litre of rinsing liquid is usually required) 3.) Determine the dry residue by evaporating about 500 ml to dryness in a small flask using a rotary evaporator. This unspecific test covers also inorganic salts, known or unknown organic products and will detect the total residues. (this test might be omitted for the drying equipment, in this instance we have a pure API or intermediate and typically no potential for side products, degradation, etc.)

4.) If the result meets the specification, proceed to specific (chromato-graphic) technique. Start with a TLC-limit test (inexpensive and fast to validate, broad detection range – UV and specific derivatisation – if these techniques are combined, the method is very specific for the different impurities potentially present in the sample. Apply 2 samples: the last washing liquid (to see all potential residues), the rinsing liquid (to look for the residue) and two standards: one of the suspected residual product at a concentration that is the limit accepted, and a 1:2 dilution of the

standard. If the main spot in the rinsing liquid has lower intensity than the standard, the equipment is clean. The second standard is for confirmation of detection. 5.) If TLC is not the appropriate technique, revert to HPLC or GC. 问3：清洁验证后的检测要求是怎样的？ 建议：参见5.3部分。

对此问题的回答取决于各不同情形。一般来说，公司先进行目视检查，然后以预定的间隔（时间或批次）取淋洗样品检查清洁的有效性。

如果公司决定在验证后一直实施清洁检查，可以采用非专属性且科学合理的方法。 以下给出了清洁验证完成后，较为实用的对清洁有效性进行监控的有效且科学合理的便宜方法：

1）对清洁后的设备进行目视检查。此检查符合要求后，方可进入下一步。 2）取一个淋洗样和/或擦拭样品（一般使用一升淋洗样）

3）使用旋转蒸发器将约500ml样品在小烧瓶中蒸干检测蒸发残留。该非专属方法包括了无机盐、已知或未知有机产品，可以检出总残留。（烘干设备不需要做此项测试，此时，设备中只有纯的原料药或中间体，一般没有潜在的副产物、降解产物等）。

4）如果结果符合标准，则可以采用特定的技术（色谱法）。从TLC限度测试开始（便宜且易于验证，具有较宽的检测范围----紫外和特定衍生产品---如果将这些技术合并，方法会对可能出现在样品中的不同杂质具有专属性），测试2个样品，一个是最后洗涤液（检查所有潜在残留物），一个是淋洗液（检查实际残留），测试2个标准品，一个是认为可能残留的产品，浓度为可接受的限度，另一个是1：2稀释的标准品。如果淋洗液中的主斑点不深于标准，则认为设备已清洁。第二个标准品是用来确认检测限的。 5）如果TLC不适用，改成HPLC或GC。

Question 4: What critical parameters need to be looked at during cleaning validation?

Advice: Ref. Section 8.2 for details

It is vital that the equipment design is evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and the cleaning techniques. Also the ruggedness and reproducibility of the cleaning procedure should be covered.

问4：在清洁验证过程中，要查看哪些关键的参数？ 建议：参见8.2部分。

在设备设计中，要结合需要清除的产品残留、可以获得的清洁剂和清洁技术进行评估。还要包括清洁程序的耐用性和可重复性。

Question 5: What number of cleans should be run in order to validate a cleaning procedure?

Advice: Ref. Section 9.0

A validation program generally encompasses three consecutive successful replicates. However, companies should evaluate each situation individually. 问5：要验证一个清洁程序，需要重复几轮清洁？ 建议：参见9.0部分。

一个验证程序一般是经过三次连续成功的重复。但是，公司应对各种情形进行单独评估。

Question 6: Is it acceptable for a validated cleaning procedure to be continued until the analytical results demonstrate it is clean? Advice: Regulatory authorities do not condone this practice.

When the analytical result does not meet the acceptance criteria an investigation to determine the possible root cause should be performed. If needed re-training of the operators should be performed and/or adjustment of the cleaning procedure to solve the issue.

问6：是否可以重复一个经过验证的清洁操作直至分析结果显示其已清洁？ 建议：药监当局不接受这种方法。

如果检测结果不符合可接受标准，则需要进行调查，找出可能的根本原因。必要时，应对操作人员进行再次培训，和/或对清洁程序进行调整以解决问题。 Question 7: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be dirty before cleaning?

Advice: Companies should have SOPs in place, which require cleaning to be performed immediately after production has stopped. This scenario should be validated.

However, if for some reason immediate cleaning is not always possible, companies should consider the effect of time on the material deposited on the equipment. It may be possible to ‘Group’ or ‘Bracket’ products, and validate a worst case scenario. 问：公司是否需要验证在清洁前，脏的设备可以放置的最长时间？

建议7：公司应制订SOP，其中说明生产结束后应立即对设备进行清洁。这种情况是需要验证的。

但是，如果因为某些原因，使得没法总是立即清洁，公司应考虑放置时间对设备中存留物料的影响。可以考虑对于“一组”或“一类”产品，验证其最差情形。 Question 8: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be left clean before re-use?

Advice: Companies should have SOPs in place to ensure that pieces of equipment are adequately protected from any contamination after cleaning has taken place i.e. ensure that the equipment is adequately covered, closed from dust etc.

If the company feels that there is any risk of contamination during ‘idle time’ after cleaning, validation should be considered.

问8：公司是否需要验证在清洁后，已清洁的设备在使用前可以放置的最长时间？

建议：公司应制订SOP，保证清洁后的设备受到充分的保护，不受到污染，例如保证设备被遮盖、关闭防止灰尘进入等。

如果公司觉得在清洁后的“闲置时间”内还是有被污染的风险，则需要考虑验证。 Question 9: Is it necessary to establish time limits for cleaning if equipment is not used frequently?

Advice: Please see previous advice to question 8.

问9：对于不经常使用的设备，是否需要设定清洁时间限制？ 建议：请参见问8的回答。

Question 10: What is the maximum time allowed after cleaning with water as last rinse?

Advice: Equipment should not be left with water in it after cleaning. The last step of the cleaning procedure involve drying with solvent or flushing with Nitrogen, thus ensuring that there is no opportunity for microbial growth. 问10：用水最后淋洗后，可以放置的最长时间是多少？

建议：清洁后不应有水留在设备内。清洁程序的最后一步应是采用溶剂干燥或氮气吹干，这样保证微生物没有机会滋生。

Question 11: Is it possible that a deterioration of equipment may take place over time, thus invalidating the original validation results?

Advice: Materials used to manufacture equipment for the pharmaceutical / chemical industry is of a very high standard. However, equipment materials used should be evaluated to ensure their durability over time as part of the preventative maintenance programme. The possibility of surface roughness and any possible effects that it may have on cleaning should be considered.

Companies employing verification methods after validation should monitor analytical data generated as part of this process.

问11：是否有可能经过一段时间，设备情况会变差，这样原来的验证结果不再有效？

答：用于药品/化学行业生产的设备的材质一般都有很高的标准。但是，所用的设备材质应经过评估，保证其能经受一段时间的使用，这应该是预防性维保计划的一部分。要考虑表面粗糙的可能性，以及可能对清洁产生的影响。

Question 12: If a company has validated a worst case scenario (grouping or bracketing regime), should they also need to validate a ‘less’ worst case? Advice: When grouping products and determining worst case situation scenario for validation, companies should determine whether or not the worst case being validated is one, which is appropriate for routine manufacture. For operational reasons it may be beneficial to validate a ”less” stringent cleaning procedure for some products. 问12：如果一个公司已经验证了最差情形（分组或分类），是否还需要验证“较差”情形？

答：如果将产品分组，并确定了最差情形用于验证，公司应决定所验证的最差情形适用于日常生产。由于操作原因，可能需要对某些产品的“其次”严格的清洁程序进行验证。

Question 13: In a case of a dedicated plant with no degradants, is there a need to validate?

Advice: Ref. Section 7.0

Companies should consider each situation individually and validate where there is a potential for contamination. In the above situation, there may not be a need. However, consideration should be given to the number of runs being performed prior to full cleaning.

问13：如果使用的是专用车间，且没有降解产物，是否还需要进行验证呢？ 建议：参见7.0部分。

公司要单独考虑每种情形，如果有潜在污染时则需要验证。在上述情形下，可能不需要验证。但是，要考虑在进行全面清洁前可以生产的轮次。

Question 14: Should cleaning validation be part of a development programme? Advice: While it is not a requirement of ICH that cleaning validation be performed during development phase the following should be considered:

If the equipment being cleaned after the development product in question is used to manufacture commercial product or product for human use for example clinical trials, it is essential to verify the appropriate cleanliness of the equipment prior to re-use. Development of the Cleaning procedure for the product should take place at development phase for validation when the product becomes commercially available. The cleaning procedure validation should be performed or at least should start with the process validation campaign.

问14：清洁验证是否应该作为研发计划的一部分？

建议：ICH并没有要求在研发期间进行清洁验证，但要考虑以下内容： 如果设备在用于研发产品生产后，又用于生产商业化产品，或用于人用药品例如临床试验药品生产，则需要确认设备再次使用前已被适当清洁。

产品清洁程序应该在产品研发，可以商业化生产时建立。清洁程序验证应在工艺验证周期时进行，或至少开始。

Question 15: Is it necessary to include microbiological testing / aspects in the cleaning validation programme? Advice: Ref. Section 8.1

Yes, if the following product needs to have a low microbiological load, also depending on the cleaning agent used, if there is any risk for microbiological contamination of the subsequent product (e.g. if water is used for final cleaning). 问15：清洁验证计划中是否要包括微生物测试？ 建议：参见8.1部分。

是的，如果下一产品对微生物负载有要求，另外也取决于所用的清洁剂，以及之后的产品是否有微生物污染的风险（例如，如果最后清洁用的是水）。 Question 16: Which analytical methods should be used in cleaning validation studies (is only HPLC -testing acceptable?) and to which extend should these methods be validated?

Advice: Ref. Section8.0 of this “Guidance on Aspects Document”

Any analytical method suitable for its intended use could be used. In general limit tests are performed in cleaning validation studies which result in less stringent validation requirements. (as outlined in ICH-Q2A and Q2B).

However, if a company decides to validate analytical methods, suitable for the determination of the residue over a certain range (e.g. decay-curve, to prove the success of cleaning during proceeding of a defined cleaning procedure consisting of individual cleaning steps) also less stringent validation requirements for e.g. linearity and accuracy could be established compared with figures typically required in the validation of API release testing methods.

问16：什么样的检验方法可以用于清洁验证检测（只能用HPLC吗）？这些检验方法要验证要什么程度？ 建议：参见8.0部分。

所有适用的检验方法都可以使用。清洁验证一般所用的检测方法为限度检测，方法验证要求较低（如ICH-Q2A和Q2B所列）。

但是，如果公司决定要验证一个检验方法，用于一定范围内残留量的检测（例如，清除曲线，证明某个清洁步骤是否成功），其验证要求比起原料药放行检测方法的验证来说要低，例如可以建立线性和准确度。

Question 17: Do we have to wait for swab and rinse samples to be approved prior using the equipment for production?

Advice: During cleaning validation studies it is recommended to wait for completion of all planned tests prior to release equipment for further use (to be able to perform an investigation if tests fail). In routine operations (after validation has been completed) the release of equipment pending testing results (verification, monitoring status of the tests) could be done. Responsibilities and circumstances for using equipment pending release should be defined within the company.

问17：在将设备用于生产前，是否需要等擦拭样品和淋洗样品被批准？ 建议：在清洁验证研究期间，建议等所有计划的测试完成后再放行设备，用于后续使用（这样如果检测失败可以进行调查）。在日常运行中（验证完成后），可以在检测结果（核查、测试监控状态）未出来前将设备放行用于后续使用。公司应界定使用未放行设备的责任人和条件