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。
Level | | | |
| |
| Carryover of the previous product is critical. Cleaning required until predetermined stringent carry over limits are met. High risk. | | | |
| Carryover of the previous product is less critical. Cleaning should reduce the potential carry over to a less stringent limit as required for level 2. Medium risk. | | | |
| Only gross cleaning if carryover of the previous product is not critical. Low risk. | | | |
水平 | | | |
| |
| 上一产品的残留很关键。要求清洁直至符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。中等风险。 | | | |
| 如果上一产品的残留并不关键，则只需要粗清。低风险。 | | | |
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 notspecified 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：
l Easiness of cleaning
l 清洁难易程度
l Toxicological / pharmacological activity of the previous product, its side products or degradants
l 上一产品的毒性/药物活性，其副产物和降解产物
l Maximum daily dose of the following product
l 下一产品的最大日剂量
l Microbiological growth
l 微生物滋长
l Batch size of the following product
l 下一产品的批量
l Solubility, experience, difficult to remove previous product
l 溶解度、经验、上一产品清除难度
l Chemical interactions
l 化学相互反应
l Campaign lengths should be evaluated and determined as part of the risk assessment.
l 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：
l visual inspection or
l 目视检查或
l visual inspection and analytical verification (e.g., swabbing and/or rinsing).
l 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：
l Discoloured surfaces, worn or torn parts;
l 部件表面褪色、磨损或破损
l 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));
l 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。
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发表于 2014-10-15 12:49:17
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