Cleaning of Dedicated Equipment: Why Validation is Needed? 专用设备的清洗:为什么需要验证? Aug 15, 2015 2015年8月15日 By Cristina Baccarelli, Paola Bernard, Teresa Cortellino, Oscar Cruciani, Rita Pacello, Chiara Parisi, Luisa Stoppa, Isabella Marta 作者:克里斯蒂娜-巴卡纳尼、保拉-伯纳德、特里沙-考特里罗、奥斯卡-克鲁西尼、丽塔-帕西罗、基娅拉-帕瑞西、露莎-斯托帕、伊沙贝拉-马塔 Pharmaceutical Technology 制药技术 Volume 2015 Supplement, Issue 3, pg s48–s51 2015第3期 增刊 Cleaning of pharmaceutical equipment is essential to reduce the risk of product contamination and, as stated in relevant guidelines and as recognized by the pharmaceutical sector, this can be achieved only if the cleaning procedure has been validated. International Conference on Harmonization (ICH) guidance ICH Q9 (1) encourages that a quality risk management approach be considered and that, based on the level of risk, cleaning processes may be subject to different levels of validation or verification. 制药设备的清洗对于减少产品污染是必要的,清洗验证需经验证才能得到预期的效果,这是相关指南的要求,也是制药领域的共识。ICH指南Q9鼓励考虑采用质量风险管理方法,基于风险水平可以对清洗程序进行不同水平的验证或确认。 This article covers cleaning validation of equipment dedicated to the production of a single API; equipment used for manufacturing a class of products (e.g., penicillins) should be considered as shared equipment and is not addressed here. 本文讨论的是单一原料药生产所用专用设备的清洗验证;同一类型产品(如:青霉素类)生产所用设备被视为共用设备,本文对此不作讨论。 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,当想到清洗验证时,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谈论清洗验证呢?ICH指南Q7第12.70章说道:“一般需要对清洗程序进行验证。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洗验证......”。表1强调了共用设备和专用设备清洗方法之间的不同。
As indicated in Table I, most points apply to both cases, meaning that great care needs to be given also when planning cleaning validation activities of dedicated equipment. 如表I所示,绝大部分要点适用于两种情况,这意味着在计划专用设备的清洗验证活动时也同样需要投入很大的关注。 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洗验证,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。
Only cleaning procedures that have been validated ensure that any undesirable residues have been effectively removed below a level that has been demonstrated to be acceptable and that does not pose a risk to patients. Cleaning validation is time and resources consuming; however, some companies might prefer not to use shared facilities and, instead, dedicate an entire building, manufacturing line, or piece of equipment for the manufacture of a single product. If they use disposable equipment, such as single-use bioreactors, compatibility of the disposable equipment with the process should also be assessed. 只有经验证的清洗程序才能确保任何残留可以被有效去除至经确认可接受的水平之下,且不会对患者造成风险。清洗验证是要耗时的,也是需要资源的;因此,有些公司可能情愿不使用共用设施,而是选择使用整座建筑、生产线,或设备来生产单个产品。如果他们使用一次性设备,如单次使用生物反应器,则也需要评估一次性设备与工艺之间的兼容性。 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肯定是使用专用。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 · 清洗验证计划 · 仅用目测来检查残留水平在首次验证研究中是不被接受的。即使有一些文献报导了提议了目测限度,但目测不符合ICH Q7的期望,因为目测所依赖的变量太多从而难以标准化和验证。在进行过清洗验证后,可在设备使用前使用目测来发现“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,清洗和消毒。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洗和防止微生物滋生(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 · 专用生产设备的清洗验证 · 在进行专用生产设备的清洗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洗而是阶段性清洗的话,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洗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洗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发现清洗验证研究并未对适宜的生产周期进行验证(如,设备清洗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洗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,清洗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,如果一设备总是清洗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洗。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洗之间的时间。若设备使用结束后即立即进行清洗,则残留物易于去除;但若未能在使用结束后立即进行清洗,则使用同样的清洗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洗程序。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洗的情况。 · 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洗验证是重要的这个结论。原料药的质量与清洗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。 · References · 参考文献 · · Editors’ Note: This article is based on a topic addressed during the 6th Pharmaceutical Inspection Co-operation Scheme (PIC/S) Expert Circle on APIs meeting, held in Rome in May 2014 and hosted by the Italian Medicines Agency (AIFA). PIC/S is a co-operative arrangement between 46 regulatory authorities worldwide active in the field of GMP for medicinal products for human or veterinary use. It aims at harmonizing inspection procedures globally by developing common GMP standards, training inspectors, and facilitating exchange of information and mutual confidence between regulators. · Article Details · Citation:
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