清洁验证:最长生产周期验证及专用设备考虑点

本文发布于Pharmaceutical Technology，《Cleaning of Dedicated Equipment: Why Validation is Needed？专用设备清洁：为什么需要验证？》作者Cristina Baccarelli, Paola Bernard, Teresa Cortellino, Oscar Cruciani, Rita Pacello, Chiara Parisi, Luisa Stoppa, Isabella Marta，主要阐述关于专用设备清洁验证的考虑点，此外还谈到关于最长生产周期的验证考虑点，作者提到在意大利AIFA于在一个专用生产设施进行的一次审计中，AIFA发现清洁验证研究并未对适宜的生产周期进行验证（如，设备清洁前连续生产的时长和/或批数）。此外，该公司也未设置生产周期内控制以确认设备潜在降解残留物在一个生产周期内的水平可以被维持在最低水平，不会超出预定的标准。

如果不是逐批清洁而是阶段性清洁的话，则需要对最长生产周期进行验证（根据时长、批数和批量）以说明连续多批生产而不进行批间清洁不会导致不良残留物的累积至在生产结束时不能被所选择的清洁程序有效去除的情况。

原文摘译如下：

Generally speaking, when one thinks of cleaning validation, the first thing that comes to mind is “prevention of cross-contamination”, which obviously applies only when equipment is used for manufacturing more than one product. So why is cleaning validation talked about with regard to dedicated equipment? Section 12.70 of the guideline ICH Q7, states that, “Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality…” (2). Table I highlights the differences between the approach to clean shared and dedicated equipment.

一般来说，当想到清洁验证时，第一个念头就是“防止交叉污染”，这显然只适用于多产品生产所用的设备。那为什么还要对专用设备进行清洁验证呢？ICH指南Q7第12.70章说道：“一般需要对清洁程序进行验证。通常，在物料的污染或携带对原料药质量有最大风险的情况或工序应进行清洁验证......”。表1给出了共用设备和专用设备清洁方法的不同。

For dedicated plants/equipment, there is no risk of cross-contamination among different active substances; nevertheless, a wide range of possible contaminants must be evaluated on a case-by-case basis (3), taking into consideration the type of process (i.e., chemical synthesis, extraction from natural sources, fermentation, physical steps, etc.), the final product, and the materials used during the manufacturing process (i.e., starting and raw materials, solvents, and reagents). As for cleaning validation of shared manufacturing plants, even for dedicated plants/equipment, it is necessary to identify all possible sources of contamination. Some key points to be considered are summarized in Table II.

对于专用厂区/设备，虽然没有不同原料药之间的交叉污染风险，但需要根据工艺类型（如，化学合成、自然来源提取、发酵、物理步骤等）、最终产品、生产工艺中所用到物料（如，起始原料、原料、溶剂和试剂）具体分析可能的污染物。对于共用生产厂区的清洁验证，即使是专用设备，也需要识别出所有的可能污染源。表II总结了一些关键考虑点。

Companies manufacturing only one product use dedicated equipment by default. In addition, companies must use a dedicated facility, line, or equipment, if:

公司仅生产一个产品则必然是使用专用。此外，在下列情况，公司也必须使用专用设施、专用生产线或专用设备：

• The calculated limits of undesirable residues are too low and therefore the potential residues would not be detectable with the available analytical methods (2).

  残留物的计算限度太低从而导致现有分析方法不能检测出可能的残留。

  
  

• The acceptance criteria are too low and cannot be achieved (i.e., for some high potency active substances).

  可接受限度太低而不能达到（如，有一些高活性原料药）。

  
  

• The data to calculate safe threshold levels for toxic or sensitizing substances are not yet available or not sufficient (4).

  用于计算毒性或敏感物料安全限度的数据不充分或不可获得。

Planning for cleaning validation

清洁验证计划

Visual examination is not acceptable as the only test to check residue during initial validation studies. Even if some literature data report proposed visual limits, this test does not meet ICH Q7 expectations, as it may depend on too many variables that are difficult to standardize (5) and validate. After the cleaning validation has been performed, visual examination could be used to detect “gross contamination” of the equipment immediately before use (2).

仅用目视检查残留水平在首验证中是不被接受的。即使有一些文献报导了提议了目视检查限度，但目视检查不符合ICH Q7的期望，因为目视检查所依赖的变量太多从而难以标准化和验证。目视检查可以用于清洁验证后，在设备使用前来发现“明显的污染”。

As for non-dedicated facilities, equipment should be of appropriate design and adequate size and suitably located for its intended use, cleaning, and sanitation (2). Design and technical aspects of equipment are covered by good engineering practices (6) and some technical references; practical guidelines for equipment design are also provided by food industry regulation (7). Equipment can be considered as “cleanable” if it is constructed using adequate materials such as stainless steel or polymeric materials that are compatible with the process to be carried out. Finished surfaces should be smooth and properly polished, and equipment should be appropriately designed and assembled in a way that facilitates cleaning and prevents microbial growth (i.e., no dead legs, not too many horizontal pipelines or excessive instrumentation, and ancillary components such as shafts, bearings, and agitators should be easy to disassemble). Finally, the equipment should be easy to inspect.

对于非专用设施，设备应根据其用途有适宜的设计和充足的大小，及适宜的定置，清洁和消毒。设备设计和技术方面可以参见良好工程规范（GEP），及一些技术文献，食品行业法规也提供了一些设备设计的实用指南。如果一设备使用了不锈钢或聚合材料等与工艺相兼容的材质的话，该设备会被视为是“可清洁的”。设备表面应是光滑并经适当抛光的，设备应有适宜的设计且其组装应便于清洁和防止微生物滋生（如，无盲管、没有太多的水平管道或多余的仪器设备，辅助配件如转轴、轴承和搅拌等应易于拆卸）。最后，设备应易于检查。

Sampling method selection (swabbing and/or rinsing or other means [8]) is essentially related to type and design of the equipment, nature of the residues, residues acceptance limits, and the analytical methods used for residues quantification; the approach to sampling is the same for dedicated and shared facilities.

取样方法的选择（擦拭法和/或淋洗，或其它方法）必须结合设备类型和设计，残留物性质，残留可接受限度，及残留定量分析所用分析方法等因素。取样方法对于专用设备和共用设备是一样的。

Cleaning validation of dedicated production equipment

专用生产设备的清洁验证

• There are three main aspects to consider when performing cleaning validation of dedicated production equipment: campaign length, clean hold time (CHT), and dirty hold time (DHT).

  在进行专用生产设备的清洁验证时需要考虑的三个主要方面包括：生产周期、清洁有效期（CHT）和滞脏时间（DHT）

  
  

• If cleaning of equipment dedicated to one API production is not carried out after each batch but on a campaign basis, it is necessary to validate the maximum campaign length (in terms of duration, number of batches, and batch size) by demonstrating that manufacturing consecutive batches with no cleaning between them does not lead to a build-up of undesirable residues that cannot be properly removed at the end of the campaign with the selected cleaning procedure.

  如果对于专用于某一原料药生产的设备不是逐批清洁而是阶段性清洁的话，则有必要对最长生产周期进行验证（根据时长、批数和批量）以说明连续多批生产而不进行批间清洁不会导致不良残留物的累积至在生产结束时不能被所选择的清洁程序有效去除的情况。

  
  

• Recent inspection results show that lack of cleaning validation related to the maximum campaign length is still an issue that is worth clarifying. During an inspection of a dedicated manufacturing facility, conducted by the Italian Medicines Agency, Agenzia Italiana del Farmaco AIFA in 2015, it was observed that no validation studies were performed to determine an appropriate campaign length (i.e., duration and/or number of batches that can be manufactured before having to clean the equipment). Moreover, the company failed to put in place intra-campaign controls aimed at verifying that during a production campaign the level of potential degradation residues in the equipment was maintained to a minimum and below pre-established specifications.

  最近的审计结果表明缺乏对最长生产周期的验证是个值得说明的问题。在意大利AIFA于2015年在一个专用生产设施进行的一次审计中，AIFA发现清洁验证研究并未对适宜的生产周期进行验证（如，设备清洁前连续生产的时长和/或批数）。此外，该公司也未设置生产周期内控制以确认设备潜在降解残留物在一个生产周期内的水平可以被维持在最低水平，不会超出预定的标准。

  
  

• CHT is defined as the time between the completion of cleaning and the beginning of the next manufacturing operation. Clean equipment will not remain clean indefinitely depending on the length of the storage period and the condition of the storage environment. Cleaning validation studies, therefore, should demonstrate that storage conditions do not contribute to growth of microorganisms. Evaluations need to be performed on a case-by-case basis; a CHT might not need to be defined if, for example, the equipment is always cleaned just prior to use.

  清洁有效期指的是自清洁结束至下次生产开始的时间。清洁设备不会无限期地保持清洁，其清洁状态取决于储存周期和储存环境。因此，清洁验证需要说明储存条件不会导致微生物的滋生。因此需要逐一进行评估，不过，如果一设备总是清洁后即投入使用则无需建立清洁有效期。

  
  

• The CHT also must be determined for dedicated equipment/facility. During an inspection conducted by FDA, it was observed that tanks used for the manufacture of a single API, carried out a few months before, were not cleaned since the last campaign. The interior of the equipment had accumulated approximately half an inch of a white substance and contained a shallow pool of liquid at the bottom.

  专用设备/设施也必须建立清洁有效期。在一次FDA审计过程中，发现一些用于单一原料药生产的罐自上次几个月前的生产后一直未清洁。设备内部已经积累了半英寸厚的白色物质，在罐底还有一滩液体。

  
  

• DHT is defined as the time between the end of manufacturing and the beginning of cleaning procedure. A residue easy to remove, if cleaned immediately after use of equipment, could maybe be difficult to remove when applying the same cleaning procedure if the cleaning was not performed immediately after use. This could occur, for example, for the residues in a crystallization tank; the “wet” residues might be easy to remove while the “dried” residues could require a different cleaning procedure. As for CHT, evaluations need to be performed on a case-by-case basis. A DHT might not need to be defined if, for example, the equipment is always cleaned right after use.

  滞脏时间是指从生产结束到开始清洁之间的时间。若设备使用结束后即立即进行清洁，则残留物易于去除；但若未能在使用结束后立即进行清洁，则使用同样的清洁程序去去除残留物会存在困难。比如，对于结晶罐内的残留物，“湿”残留物可能易于去除，而“干”残留物则可能需要不同的清洁程序。有时也可以不制订滞脏时间，比如设备总是在使用后即进行清洁的情况。

  
  

For the reasons mentioned previously, it can be concluded that it is crucial to conduct cleaning validation for dedicated equipment. The quality of an API is intrinsically related to the cleaning procedure employed; therefore, this aspect needs to be adequately addressed by the manufacturers and deeply reviewed by regulatory authorities during GMP inspections.

基于上述理由，可以得出专用设备进行清洁验证是非常重要的。原料药的质量与清洁程序有着本质的相关性，因此生产厂家应对这方面作详实的阐述，在GMP检查时药政官方也会进行深入的审核。