2 i. v+ r9 u: c) b; u+ KGMP News
11/06/2014
APIC publishes Guidance on Cleaning Validation in Active Pharmaceutical Ingredients Plants
APIC颁布原料药工厂清洁验证指南
An APIC multinational working group has compiled a new guidance on cleaning validation with the title "APIC Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredients Plants". Publication date is May 2014 and the document can be downloaded from the APIC website. The following is a summary description of the document. The document contains 55 pages and is subdivided into 13 chapters.
APIC多国工作组汇编了新的清洁验证指南，题为“APIC原料药工厂清洁验证指南面面观”。颁布日期为2014年5月，文件可以从APIC官网下载。以下是该文件的摘要。文件包括55页，分为13章。
Foreword 前言
Objective 目的
Scope 范围
Acceptance Criteria 可接受标准
Levels of Cleaning 清洁水平
Control of Cleaning Process 清洁工艺控制
Bracketing and Worst Case Rating 括号法和最差情况分类法
Determination of the Amount of Residue 残留量的检测
Cleaning Validation Protocol 清洁验证方案
Validation Questions 验证问题
References 参考文献
Glossary 术语
Copyright and Disclaimer 版权和声明
The topic cleaning validation gained new importance in the EU with the publication of the EMA Guideline "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities" and with the chapter Cleaning Validation in the draft of the revision of Annex 15. The foreword refers to the integration of cleaning validation within a quality system supported by quality risk management processes in order to protect the patients. According to the authors the document is aligned with ISPE Risk-MaPP and it recommends the revised PDA Technical Report 29 as a valuable guidance document. The document is supposed to assist companies in cleaning validation and to serve as a starting point for internal discussions. It should in no way be considered as a technical standard. The document addresses six topics:
清洁验证主题在欧盟EMA指南
前言指出了清洁验证应与质量体系结合，由质量风险管理过程支持，以保护患者利益。根据文件作者们所言，该文件与ISPE的药品风险管理是一致的，并推荐将修订后的PDA第29号技术报告作为参考文件。该文件意在清洁验证方面给公司提供帮助，作为内部讨论的基础，而不应作为一个技术标准。文件阐述了以下6个主题：
Acceptance criteria 可接受标准
Levels of cleaning 清洁水平
Control of the cleaning process 清洁工艺的控制
Bracketing and worst case rating 括号法和最差情况分类法
Determination of the amount of residue 残留量的检测
Cleaning validation protocol 清洁验证方案
Acceptance Criteria (Chapter 4) 可接受标准（第4章）
The acceptance criteria preferably should be based on the acceptable daily exposure (ADE) calculations whenever this data is available. Alternatively, occupational exposure limits (OEL) are recommended as acceptance criteria. The document then presents examples for the calculation of acceptance criteria. Based upon the ADE the maximum allowable carryover (MACO) is calculated by way of example.
如果可以得到可接受日暴露（ADE）值，则可接受标准应优先采用ADE进行计算。另外，也推荐采用职业暴露限度（OEL）值作为可接受标准。文件举出了可接受标准的计算实例，例中采了ADE计算允许最大残留（MACO）值。
As (further) examples for acceptance criteria and their calculation the document lists:
文件中给出了可接受标准及其计算样例：
Acceptance criteria using health-based data (ADE, MACO)
采用健康的数据（ADE、MACO）计算可接受标准
Acceptance criteria based on the therapeutic daily dose (TDD)
采用日治疗剂量（TDD）计算可接受标准
Acceptance criteria based on LD50
采用半数致死量计算可接受标准
Acceptance criteria based on a general limit (ppm value)
采用通用限度（ppm值）计算可接受标准
The same chapter addresses the calculation of acceptance criteria by means of swab and rinse tests. The chapter closes with a rationale for the use of different limits in pharmaceutical and chemical production of active pharmaceutical ingredients. A competent chemist should accompany the finding of a rationale. It is mentioned expressly that in the production of active pharmaceutical ingredients the risk of carry-over of contaminants because of manufacturing processes (such as extraction or filtration ...) can be much lower than in the manufacture of medicinal products. Based on this consideration limits could be set higher. Naturally, these considerations do not apply to physical manufacturing processes (drying, milling). In this case, the methods applied should be those normally used in pharmaceutical production. Annex 1 contains five examples of MACO calculations according to the acceptance criteria mentioned above.
在同一章中，还说明了采用擦拭和淋洗取样方式如何计算可接受标准。该章结尾阐述了在原料药生产中，采用与药品生产所不同的限度的合理性。需要有一名具备资质的化学家审核限度的合理性。文件中提到，在原料药生产中，由于生产工艺的特点（例如萃取或过滤），污染物被带入下一产品的风险比起制剂生产过程来，要低的多。基于该考虑，可以将限度设定在较高数值。当然，这些考虑并不适用于物理生产过程（干燥、磨粉），这些步骤中应使用制剂生产中的常规方法。附录1包括了5个根据上述可接受标准计算MACO的实例。
Levels of Cleaning (chapter 5) 清洁水平（第5章）
Depending on the step of manufacture and/or the use of multi-purpose equipment the cleaning intensity varies. The document recommends that at least three levels of cleaning (level 0-2) are implemented according to the difficulty of cleaning. Depending on the level different activities are required as concerns visual inspection, analytical verification and cleaning validation. An example presents different product changeover scenarios. In that case the number of cleaning validation activities is defined with at least three consecutive runs. In cases in which it takes some time to finalize the cleaning validation cleaning verification has to be performed in the meantime. In the course of cleaning validation the dirty hold time should also be determined.
根据生产步骤和/或设备是否为多用途情况，清洁的程度会有很大差异。文中推荐根据清洁的难度，至少将清洁分为3级（0-2）。在不同水平，要求实施不同的操作，如目视检查、检测验收和清洁验证。文中给出一个更换产品的例子。在这种情况下，清洁验证活动的次数被界定为至少3个连续轮次。如果需要较长时间来对清洁验证做出结论，则在同时要进行清洁验收。在清洁验证中，还要确定未清洁前状态保持时长。
The whole process is divided into: 整个过程分为
Cleaning process design (understanding the cleaning process residues and establishing a strategy for the cleaning process control;
清洁工艺设计（对工艺残留清洁的了解，建立清洁工艺控制的策略）
Cleaning process qualification (demonstrates that the cleaning procedure works as expected. This includes qualification of specific equipment, cleaning operational parameters, training of operators, identification of critical cleaning locations);
清洁工艺确认（证明清洁方法能达到预期目标。这包括对特殊设备确认、清洁操作参数、操作者培训、识别关键清洁点）
Continued cleaning process verification (demonstrating that the cleaning process remains in control throughout the product lifecycle);
持续清洁工艺验收（证明清洁工艺在整个产品的生命周期中保持受控）
Part of the continued cleaning process verification is also the monitoring after conclusion of the validation, called "post validation monitoring" (such as pH measurements) to confirm the validation status, change control and a periodic management review.
在对验证做出结论后，对清洁所做的监控（称为“验证后监控”，例如pH值测量）是持续清洁工艺验收的一部分，以确认验证状态、变更控制和周期性管理评审
Control of Cleaning Process (chapter 6) 清洁工艺的控制（第6章）
The document gives indications concerning the minimum content of cleaning instructions for manual cleaning and for cleaning with automated systems in chapter 6.
文中在第6章给出了关于手动清洁和自动清洁系统的清洁指令基本内容要求。
Bracketing and Worst Case Rating (chapter 7) 括号法和最差情况分类法（第7章）
At the very beginning of chapter 7 it is pointed out that a grouping of substances and the use of a worst case product can be used in order to simplify the cleaning validation. It is important in any case that a documented scientific rationale for the chosen worst case exists. The basis for a bracketing procedure should be defined in a company policy, or an SOP. A fictive example then shows a way of implementation as concerns the equipment train, substances and cleaning procedures. Again by way of example, a worst case rating study/risk assessment is presented. Criteria to be taken into consideration:
第7章一开始就指出了可以对物质进行分组，采用最差情况产品计算来减少清洁验证。不管在什么情况下，对于最差情况的选择均需要具有科学合理性，并有书面记录。括号法的基础要在公司方针或SOP中定义。文中给出了一个虚构的例子，说明如何在一个设备链上多个物质情况下实施括号法。对于最差情况分类研究/风险评估也使用了一个例子来说明。其中要考虑的标准包括：
Hardest to clean (experience from production);
清洁难易程度（生产经验）
Solubility in used solvent;
在所用溶剂中的溶解度
Concept of acceptable daily exposure (if possible);
可接受日暴露值的概念（可能时）
Lowest therapeutic dose (or toxicity data).
最低治疗剂量（或毒性数据）
The single criteria are rated according to their risk. For this the guidance makes proposals of categorization (for instance concerning cleanability) and of classification concerning solubility, ADE concept, therapeutic dose (1-3 oder 1-5). A table summarises the single data and identifies worst case products for the cleaning validation. Explicit reference is again made to change control which might make necessary a new worst case calculation.
根据其风险，对单个标准进行分类。在本指南中，提议按类别（清洁难易程度），以及按溶解度、ADE概念、治疗剂量（1-3 细分1-5）进行分类。文中给出了一张表，概括了个数据以及对清洁验证中最差情况产品的识别。这里再次明确批出要对可能需要计算新的最差情况的变更进行控制。
Determination of the Amount of Residue (chapter 8) 残留量的检测（第8章）
At the beginning of chapter 8 a practical guidance is provided concerning the validation of analytical methods in the course of a cleaning validation; regulatory requirements (for example FDA) and guidelines are indicated (such as ICH Q2 R1). The second part addresses sampling methods (swab/rinse). A combination of the two methods is described as being generally the most desirable. Interestingly, the subchapter swab sampling mentions the analysis of the first production batch of the following product for impurities as "may" option. In its cleaning validation guidance FDA is critical as concerns this procedure. For swab sampling as well as for rinse or solvent sampling equations are given.
在第8章开头就给出了关于清洁验证中分析方法的验证实用指南，指出了法规要求（例如FDA）和指南（例如ICH Q2R1）。第二部分写的是取样方法（擦拭取样/淋洗取样），以及两方法并用的方式。通常两法并用是实际所需要的。有意思的是，关于擦拭取样的章节中提到对下一产品第一个生产批次的杂质分析“可能”是一种选择。在FDA的清洁验证指南中，FDA对此相当关注。在文给出了擦拭取样、淋洗取样及溶剂取样的计算公式。
There is also mentioned a third method which is rather unknown - the so-called "stamps" or "coins". These elements are placed on appropriate sampling points in the equipment and remain there during the manufacture of the previous product and during cleaning. After cleaning, the contamination on the coins is analysed and the overall contamination is calculated.
文中还提到第3种较少为人知的方法，称为“印章”或“硬币”法。该方法是将一个“硬币”贴在设备取样点，进行上一产品的生产和清洁，在清洁后，对“硬币”上的清洁物进行分析，计算整体污染水平。
Cleaning Validation Protocol (chapter 9) 清洁验证方案（第9章）
In chapter 9 you can find a cleaning validation protocol which is six pages long and divided into 9 chapters:
在第9章中，你会看到一份6页的清洁验证方案，分为9个部分：
Background 背景
Purpose 目的
Scope 范围
Responsibility 职责
Sampling procedure 取样程序
Testing procedure 检测方法
Acceptance criteria 可接受标准
Deviations 偏差
Revalidation 再验证
In Chapter 10 "Validation Questions" frequently asked questions are answered in the style of a Q&A paper. In this document "A" is short for "advice". The questions are answered with references to the single chapters/subchapters in the document.
在第10章“验证问题”中，以问答方式对常见问题进行了回答。在本文件中，“A”是建议“ADVICE”的缩写。问题回答中参考了文件中相关章节。
The document is completed with the chapters 11 (References), 12 (Glossary) and 13 (Copyright and Disclaimer).
文件结尾是第11章（参考文献），第12章（术语）和第13章（版权和声明）。
Conclusion: 结论
In spite of the many pages the document can be read very well. The many practical examples (such as calculations, cleaning validation protocol,...) may be helpful. The document addresses the ADE concept very intensively. This is a question which confuses industry at the moment. But the document also addresses acceptance criteria already known (dose criterion, amount criterion). It is striking that the document still adheres to the three batches concept. Although the document addresses active pharmaceutical ingredients plants it will surely find readers among manufacturers of medicinal products.
除了一些页面之外，整个文件还是非常易读的。许多实用性例子（例如，计算、清洁验证方案……）很有帮助。文件对目前困扰企业的ADE的概念进行了非常深入的阐述。但是，文件仍在说明大家已知道的可接受标准（剂型标准、数量标准）。令人注目的是该文件还是坚持3批的概念。尽管该文件已说了是针对原料药工厂，但无疑也会有一些制剂生产商参考它。
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