3.3   Design Considerations

3.3设计考虑

3.3.1Location of Cleaning

3.3.1清洁位置

Equipmentmay be cleaned at its installed location, or it may be disassembled and movedto a central location for cleaning.

设备可以在其安装的位置清洁，也可以被拆卸并移动到一个清洗间进行清洁。

3.3.1.1In-Place Cleaning

3.3.1.1在线清洁

Thecleaning of large pieces of equipment may be performed in the equipment’spermanent location, generally in a configuration very similar to that in whichit is utilized for production. In this document, in-place cleaning can beeither for automated or manual cleaning processes.

大型设备的清洁可以在设备的安装位置进行，一般与其用于生产时的布局非常相似。在本文档中，在线清洁可以是自动或手动清洁工艺。

3.3.1.1.1Clean-in-Place (CIP) Systems

3.3.1.1.1在线清洁（CIP）系统

Theterm ‘‘Clean-in-Place’’ usually refers to an automated system that consists ofa system which uses various tanks and piping to deliver a cleaning solutionthrough the equipment to be cleaned. There may be a pre-rinse tank and a finalrinse tank. The CIP system utilizes spraying devices to provide coverage andphysical impingement of the cleaning solution on the process equipmentsurfaces. The spray- balls may be stationary or moving (e.g., rotating,oscillating). These systems are commonly used to clean large pieces ofequipment, such as manufacturing tanks, blenders, fluid bed dryers, reactorsand fermentation tanks. The CIP system may be a recirculation system or it maybe a single-pass system.

术语“在线清洁”通常是指一个自动化的系统，该系统使用各种罐和管道输送清洁液至待清洁的设备。也许还有一个预淋洗罐和一个最终淋洗罐。该CIP系统利用喷洒装置将清洁液覆盖工艺设备表面并通过物理冲击除去污物。喷淋球可以是静止的或运动的（例如，旋转、摆动）。这些系统通常被用来清洗大件的设备，如制造罐，混料机，流化床干燥机，反应器和发酵罐。该CIP系统可能是一个再循环系统，或者它可以是一单程系统。

CentralizedCIPsystems can provide a single location for handling cleaning agents and reducethe plant requirements for cleaning-related equipment (pumps, tanks) andinstrumentation. However, centralized systems often require interconnectedpiping designs and may complicate desires to segregate parts of the process.Some process equipment may require special cleaning agents that are differentthan those used for the rest of the process equipment. For these situations,dedicated CIP systems that are integrated into the process skids may bedesirable.

中央CIP系统：可以提供一个单独位置处理清洁剂，并降低企业对清洁有关的设备（泵，罐）和仪器仪表的需求。然而，集中式的系统往往需要相互连接的管道设计和复杂的工艺分隔。某些工艺设备可能需要不同于其他工艺设备的特殊清洁剂。对于这些情况，建议采用集成到工艺设备模块中的专用CIP系统。

Designof centralized CIP systems should consider the potential for carryover ofproduct residues between process steps; between products being manufacturedconcurrently in multiproduct facilities; and between different products after aproduct changeover. To address the potential for product carryover, central CIPsystems are often dedicated to one part of the manufacturing plant.Non-recirculating systems also reduce the potential for product carryover viathe CIP equipment itself.

中央CIP系统的设计应考虑产品残留转移的潜在可能性，例如：在不同工艺步骤之间、多产品车间中同时生产的产品之间、在产品切换后不同产品之间。为了应对产品残留转移的潜在可能性，中央CIP系统通常专用于生产厂的某一部份。非循环CIP系统亦能减低产品残留经CIP系统转移的可能性。

Pipingof the equipment being cleaned and of the CIP skid should be slopedcontinuously to a physical low point to ensure acceptable draining of thelines. If supply and/or return loop headers are used, the loop must be designedsuch that liquid flows in both parts of the loop at adequate speeds. If this isnot achieved, one part of the loop may become a functional deadleg. Thepressure drop in the piping also needs to be considered. The CIP skids areoften located remotely from the process area, and the length of thedistribution piping results in a total pressure drop that can be significant.The greatest challenge is sizing the distribution piping when the supply flowrates in the system have high variability.This has been addressed in somefacilities by installing pumps in distribution piping before major equipment tocontrol flow rates. For CIP systems, diameters of drains should be adequate toensure adequate drainage without a buildup of cleaning or rinse solution in thevessel.

需要清洁的设备管道和CIP模块应具有一定坡度，以确保管路可以排空。如果使用了供给和/或回流回路总管，回路的设计应确保两个回路的具有足够的流速。如果流速不够，回路中的部份管路可能会变成死角。也需要关注管道中水压的下跌，CIP模块通常远离生产区，分配管道长度所造成的总压降会很大。当系统供水流速变化很大时，则很难制订分配管路流速限度。有些工厂会在主要设备前的分配管路中加入泵，以控制流速。对于CIP系统，应有足够的排水管的内径，确保充分排水，避免清洁溶剂或冲洗液积聚集在容器内。

3.3.1.1.2Solvent Reflux Cleaning

溶剂回流清洁法

Forsmall-molecule API manufacture by organic synthesis, cleaning may involveboiling a volatile solvent(such as methanol) in the reactor vessel. This is atype of in-place process (but not a CIP systemas defined in 3.3.1.1.1). Thesolvent vapors rise to other portions of the equipment, and condense on thosecooler surfaces. The condensed solvent may dissolve residues on those othersurfaces, and carry the dissolved residue back to the boiling solvent in thebottom of the reactor vessel. Such a process is called solvent reflux cleaning.Key issues in solvent reflux cleaning are to make sure that the residues aresoluble in the chosen solvent, and the solvent vapors contact and condense onall intended surfaces.The cleaning should also provide an effective rinse ofthe reactor vessel that held the boiling solvent.

对于一些经有机合成制造的小分子API，可以在反应罐中煮沸一些挥发性溶剂（例如甲醇）。这是一种在线操作的过程（但不是在3.3.1.1.1中定义的在线清洁系统），当溶剂的蒸汽上升到设备的其他部份，并在设备上较冷的表面凝结，这些凝结的溶剂可以溶解这些表面上的残留物，把残留物带回反应罐底部的溶剂中。这种操作过程称为溶剂回流清洁法。使用这种方法的关键是：确保选用的溶剂能溶解相关残留物，溶剂的蒸汽能接触并凝结于所有目标表面。该清洁方法还应对装有煮沸溶剂的反应罐进行有效冲洗。

3.3.1.1.3Placebo Batches as a Cleaning Method

安慰剂清洁法

Placebocleaning is another type of in-place cleaning. For certain highly viscousointments or products, it may be feasible to use a placebo run as a method of cleaningequipment. This approach requires the use of a placebo that has no detrimentalquality impact on the next product manufactured in the equipment. The principleof using a placebo batch for cleaning is that the action of the placebo runningthrough the equipment would clean the equipment of drug residues or processresiduals from the previous batch. The advantage for this type of cleaning isthat the placebo is processed through the equipment in the same fashion as themanufactured product. Therefore, the material would touch the same surfaces andin the same manner as the next product batch. Disadvantages of this method includethe cost of cleaning and the difficulty of demonstration of the effectivenessof the process.

安慰剂清洁法是另一种在线清洁方法。对于一些黏性非常高的软膏或其他产品，可以采用安慰剂批次作为清洁设备的一种方法。这种方法需要选用一种不会对设备的下批产品质量造成不利影响的安慰剂。这种方法的原理是当安慰剂在设备中流动时，会将上批产品的药物残留或工艺残留物清除。这种方法的好处是安慰剂在设备中加工过程与实际生产的产品一样，因此，安慰剂与下批产品以同样的接触方式接触相同的表面。这种方法缺点是成本高，而且难以该清洁工艺的有效性。

3.3.1.2Out-of-Place Cleaning

离线清洁

Smallerequipment items and portable process equipment that are difficult to clean asinstalled are often disassembled and transported to a designated cleaning orwash area where the cleaning procedure is performed, either manually orautomated. The additional activities involved with transport of equipment toand from the wash room, component identification, and the elimination of thepotential for cross-contamination during transfer, reassembly, and storageprior to use makes the validation of these procedures somewhat more complexthan the comparable in-place activity. Care should be exercised for routes andmeans of soiled equipment entering a washing area and routes and means of cleanequipment exiting the washing area, as well as storage of cleaned equipment inthe washing area. Care should also be used to assure contact and/or flow of thecleaning agent through all parts of the equipment, such as for lumens or hoses.The need for manual manipulation is an integral part of out-of-place procedures,and generally requires both more detail in the procedures and appropriatetraining. The manual manipulation makes these concerns similar to those ofmanual in-place cleaning.

对于安装后较难清洗的设备小部件及便携式工艺设备，通常拆卸后转移到一个指定清洗间进行自动或手动清洁。这种清洁方法还涉及以下操作：将设备运送往返清洗间，设备组件的标识，并确保在运送过程中不会造成交叉污染，重新组装设备，使用前储存。因为离线清洁涉及这些操作，使得离线清洁验证比在线清洁更为复杂。需要特别注意未清洁设备进入清洗间的路径和方法、已清洁设备离开清洗间的路径和方法以及已清洗设备的储存。同时亦要确保清洁剂能充分接触/冲洗到设备的所有部位，例如内腔和软管。手工操作是离线清洁中不可或缺的一环，一般需要在文件中进行详细描述，并进行适当培训。这种手工操作的注意事项与在线清洁中手工操作的注意事项类似。

3.3.1.2.1Clean-Out-of-Place Systems

离线清洗系统

Clean-out-of-place(COP) equipment includes items such as wash tanks used to clean small parts or partsremoved from large equipment. Examples include a recirculating bath used forcleaning small parts, pump components, gaskets and other parts removed fromlarger equipment. COP systems may also include dishwasher type cabinets wheresmall manufacturing vessels, drums, filter housings or hoppers can be loadedinside the cabinet and cleaned. The placement of the parts, disassembly of equipmentand loading patterns are critical to the success of cleaning when using COPsystems. The use of these systems significantly reduces the differences betweenCIP cleaning and COP cleaning, although issues related to disassembly andtransport of equipment to the parts washer are still present.

离线清洁(COP) 设备包括用来清洗小部件／从大型设备拆卸下来的部件的清洗槽。例如以循环水浴来清洗细小部件、泵组件、垫圈、其他拆卸自大型设备的部件。COP系统亦包括类似洗碗机的清洗柜，可以将小容器、桶、过滤器外壳、料斗等组件放到柜中清洗。在使用COP系统时，部件的摆放位置、设备的拆卸、装载方式会直接影响清洗的效果。即使使用COP系统仍需要拆卸设备和运送设备，但已能大大减低CIP和COP清洁的差异。

3.3.2Automated vs. Manual Systems

自动 /手动系统

Threebroad definitions of cleaning processes follow, although it should berecognized that they represent points on a continuum. The distinctions betweenthese processes are important to the establishment of an appropriate cleaningprocess.

对清洁工艺有以下3种广泛定义，虽然这3种清洁方式其实代表一个连续体中的不同点（译按:意指这3种方式并不是完全独立分开的）。这些清洁方式的差异对于建立适当清洁工艺是很重要的。

3.3.2.1Manual Processes

手动清洁

Manualcleaning is typically defined as the direct cleaning of equipment by a trainedequipment operator using a variety of hand tools and cleaning agents. Althoughsome process parameters maybe monitored by gauges, the regulation and controlof these parameters is the responsibility of the cleaning personnel.

由经培训的操作员直接用手动操作的工具和清洁剂清洗设备。虽然有些清洁参数是可以用仪表测量的，但对这些参数的实际控制还是由操作员负责。

Importantcleaning parameters for manual cleaning may include:

重要的手动清洁参数包括：

·Volume of cleaning agents

清洁剂的体积

·Volume of rinse water

淋洗水体积

·Temperature of wash and rinse solutions

清洗和淋洗溶液的温度

·Sequence and duration (contact time) of soaking, wash and rinse steps

浸泡、清洗、淋洗的次序和时间（接触时间）

·Scrubbing action

擦洗动作

·Pressure of solutions

水压

·Detergent concentration

洗涤剂的浓度

Itis important to specify in writing the extent of the equipment disassembly toensure the reproducibilityof the cleaning process. Consistency of manualcleaning over time is accomplished by operator training, adequate supervision,and a well-defined, documented cleaning procedure.

为了确保清洁程序的重现性，需要建立文件规定设备的拆卸程度。操作员的培训、充分的监控、清晰的书面清洁程序有助于确保手动清洁的一致性。

3.3.2.2Semi-Automated Processes

半自动清洁

Asopposed to manual cleaning, semi-automated cleaning includes various levels ofautomatic control. At one extreme, this could consist of simply manuallyremoving gaskets/fittings for manual cleaning prior to the automated CIP of atank, or disassembly of a pump or filter housing prior to cleaning in anautomated COP system. At the other extreme, the operator may use a highpressure spray device to clean a surface or may simply open and close valvessupplying spray balls inside a vessel.This type of cleaning is intermediatebetween fully automated and fully manual cleaning.

相对于手动清洁，半自动清洁涉及不同程度的自动化控制。以一个极端例子来说，这包括在对罐子进行CIP自动清洗前，进行一些简单的垫圈/配件拆除，进行手动清洁；或是放入自动COP系统进行清洁前，将泵或过滤器外壳拆下。再以另一个极端例子来说，操作员在使用高压喷淋装置对一表面进行清洁或仅仅是开关容器内喷淋球供水阀门。半自动清洁就是全自动和全手动中间的一种清洁方式。

3.3.2.3Automated Processes

自动清洁

Automatedcleaning typically does not involve personnel intervention (except perhaps toselect a cycle and the start/stop of the operation). The system is usuallyprogrammable for the various cleaning cycles. Use of automation providesconsistent and robust control and monitoring of theautomated cycles and parameters (such as time, flow rate or pressure, cleaningagent concentration, and temperature).

自动清洁通常不涉及人员介入（除了选择清洁程序/开始或结束运行时）。清洗系统通常可对不同清洗行程进行编程。采用自动清洁方式可对自动清洗行程和参数（如时间、流速、压力、清洁剂浓度、温度）进行一致、稳健地监控。

Importantcleaning parameters for automated cleaning may include the volume of cleaningagents, volume of rinse water, flow rates and temperature of wash and rinsesolutions, duration of wash and rinse cycles, pressure of solution, operatingranges and detergent concentration. Disassembly of equipment may still benecessary to allow for complete cleaning or to allow for the separatecleaningof delicate parts.

使用自动清洁时重要的清洁参数包括：清洁剂体积、淋洗水体积、清洗和淋洗溶液的流速和温度、清洗和淋洗的时间、溶液压力、操作范围、清洁剂浓度。自动清洗可能仍需要进行部件拆卸，以达到完全清洗的目的，或将专用部件分开清洗。

Inan automated cleaning system, the cleaning may be controlled through relaylogic, a computer or programmable logic controller (PLC). The control system isan integral and critical part of the overall cleaning process. The controlsystem regulates the cleaning cycles, addition of cleaning agents, temperature,time and other critical cleaning parameters.

在自动清洁系统，清洗程序可以由继电器逻辑控制器、计算机或可编程控制器(PLC)来控制。这些控制系统是整个清洁工艺中的关键部份。它们控制了清洗行程、清洁剂的加入、温度、时间和其他关键的清洁参数。

Theremay also be a control interface or operator interface terminal (OIT) to startthe process, stop the process, monitor various stages of the process and changethe process sequence. Given the increased complexity of the newer PLC andcomputer interfaces, training and validation are important issues that impact theability of the system to provide consistent cleaning. The validation of controlsystems is critical to the success of automated cleaning processes.

可通过控制界面、操作者终端界面(OIT) 来启动/结束程序、监视不同清洁阶段、改变程序次序。基于现在的PLC和计算机界面比以往复杂，培训和验证对清洁的一致性是很重要的。控制系统的验证是自动清洁程序成功的关键。

3.3.3Soil Evaluation and Categorization

污物评价与分类

3.3.3.1Soil Categories

污物分类

Thereare a large variety of substances that contact process equipment surfacesduring the manufacture of pharmaceutical products. They include manufacturedproducts, degradation products, process aids, solvents, and cleaning agents.Cleaning processes and cleaning validation should be designed and tested toaddress this wide variety of potential process soils. These tasks may besimplified by creating categories of soils and selecting representative soilsfor testing and tracking during the development and validation of cleaningprocesses.

生产药品时接触工艺设备表面的物料有很多，它们包括生产物、降解物、工艺助剂、溶剂、清洁剂。设计清洁过程和进行清洁验证时需要考虑这些不同的潜在污物。在清洁工艺开发和验证过程中，可通过将污物分类并选择有代表性的污物进行测试和追溯，以简化工作。

Thefinal selection of a representative soil within a process stream should bebased on the similarity of the physiochemical properties of the soils. In manycircumstances, categories may be combined and the number of representativesoils used for development activities further reduced.

在生产线中选择具代表性的污物需要基于污物的理化性质类似性。多数情况下，可将分组合并，进一步降低工艺开发使用的代表性污物数量。

3.3.3.2Soil Removal

污物的去除

Soilsmay be removed by physical and/or chemical means. Physical removal may beaccomplished by putting energy into the cleaning process through use of highpressure spray, high velocity flow, manual scrubbing, or vacuuming in order toremove soils from the equipment. Physical removal maybe dependent onsolubility, soil amount and its degree of adhesion to the equipment surface.

残留物可由物理和/或化学方法移除。物理方法可采用高压喷淋，高流速的水流、手动擦洗、真空吸尘等将污物从设备上去除。使用物理方法时需考虑污物的溶解性、数量、及其在设备表面的粘附程度。

Chemicalcleaning mechanisms include solubility, emulsification, wetting, chelation,dispersion, hydrolysis and oxidation. Cleaning agents are generally chosen fortheir ability to remove process soils by one or more of these mechanisms. Insome cases, multiple cleaning steps may be used in order to take advantage ofdifferent chemical cleaning mechanisms. For instance, alkaline detergent for solubilizationand emulsification may be followed by a sodium hypochlorite solution foroxidation of protein soils. It should always be kept in mind that the moreaggressive the cleaning solutions are (e.g., solutions with high concentrationsof sodium hypochlorite), the more corrosion may occur.The right choice ofmaterials for cleaning purposes is part of the development phase.

化学清洗机制包括溶解、乳化、湿润、螯合、分散、水解、氧化作用。可根据清洁剂去除工艺污物能力选择清洁剂，清洁剂可通过一种或多种清洗机制发挥作用。在某些情况下，为了利用不同的化学清洗机制，可使用多种清洗步骤。例如，在使用碱性溶液来进行溶解和乳化后，可使用次氯酸钠溶液来氧化蛋白质污物。可。必须记住，使用愈强烈的清洁剂（如高浓度次氯酸钠溶液），对设备的侵蚀可能愈严重。在清洁工艺开发时，便应该选择正确的清洁剂。

Factorsaffecting “cleanability”also include the surface geometry, the surface type, the soil type, and thesoil level. The ease with which a soil is released from the equipment surfaceby one of the mechanisms described above determines its cleanability. Soilresponse to a particular cleaning mechanism may influence the choice ofcleaning agent and cleaning conditions. Attachment to surfaces can be by acombination of van der Waals forces, electrostatic effects, and other forces.The time that the soil resides on the equipment can also influence thedifficulty of soil removal. Fresh soils are generally easier to remove thansoils that have been allowed to dry on the surface. The time between soilingand cleaning must be considered when designing the cleaning studies to simulatethe dirty hold time, if applicable.In some cases, difficulty of cleaning doesnot change with increased dirty hold time. If this is the case and any dirtyhold time can be used in a protocol, it must be clearly justified anddocumented.

可清洁性亦会受以下因素影响：设备表面几何结构、污物类型和污染程度。当使用以上其中一种清洁机制清洗残留物时，将残留物带离设备表面的难易度，决定了该污物的可清洁性。选择清洁剂和清洁条件时，应考虑污物对特定清洁机制的反应。表面的污物可以通过范德华引力、静电作用、或其他力组合而成。污物附着在设备表面的时间同样会影响清洗的难易度。新鲜的污物通常会比干了的污物更易清洗。在设计清洁程序模拟“生产后保持时间”时，必须考虑将设备弄脏至清洁设备的间隔时间，在某些情况下，间隔时间的增加对清洗的难易度没有影响，如果情况的确如此，方案中可采用任何“生产后保持时间”，但必须有书面理由。

Highsoil amounts can complicate removal by saturating the cleaning solvent ordepleting surfactants or other components of the cleaner (such as oxidizers oremulsifiers). This may impact the minimum cleaning solution volumes and shouldbe considered in the cleaning cycle design when high soil amounts areanticipated.

大量污物可能会使清洁变得困难，它们可能会使清洁剂饱和，或者耗尽表面活性剂或清洁剂的其他组分（如氧化剂或乳化剂）。这可能影响最低清洁溶液体积，因此当预料有大量污物时，在开发清洁程序时便应予以考虑。

3.3.4Equipment Considerations

设备相关考虑

Equipmentusage during production is another important aspect to consider in designing acleaning process. It is important to understand the role that the equipmentplays in the production train. Equipment design characteristics, as establishedduring product development, are often driven by equipment functionality and therequirements of the process. With the current emphasis on cleaning validation,it makes sense that “cleanability” be an important criterion in the design ofequipment. Equipment should be free-draining and have limited intricate orcomplex parts. Sanitary designs employing principles such as appropriatelyfinished surfaces, lack of crevices, absence of dead legs and suitableconstruction materials are recommended.

在开发清洁程序时亦应考虑生产过程中设备的用法。了解设备在生产线中的作用是很重要的。在开发产品时建立的设备设计特性，通常取决于它的功能和工艺要求。鉴于目前对于清洁验证的重视程度，设备的“可清洁性”应作为设计生产设备时重要标准之一。设备应为自排水式、尽量减少复杂部件。建议采用卫生设计原则，例如应有适当的表面加工、无裂缝、死角，具有合适的材质。

Cleaningequipment should be designed to ensure adequate coverage of all process equipmentsurfaces to be cleaned, and to not contribute possible contamination. Intankage and enclosed piping systems, the volume of cleaning solution availablemust be sufficient to clean all interior surfaces of the pipe. For spray ballor nozzle spray apparatus, all equipment surfaces should be available forcontact with the spray. The concern here is that areas can be ‘‘shadowed’’by the presence of dip tubes and mixer baffles, blades, and shafts. Spraypatterns may be originally designed by computer simulation, but should beconfirmed by a spray coverage test, such as one using a dilute solution ofriboflavin.

清洁用设备的设计应确保充分清洗所有生产设备待清洁表面，并且不会带来潜在污染。在水槽和密闭管系统中，清洁溶液必须足够用于清洗管路的所有内表面。使用喷淋装置时，应确保设备表面与喷洒液接触。应关注有些位置可能会被导管、混合挡板、搅拌桨叶、搅拌轴。可通过计算机模拟进行喷淋模型的设计，但应使用稀释的核黄素溶液进行喷淋覆盖测试。

3.3.4.1Dedicated – Nondedicated Manufacturing Equipment

专用 /非专用生产设备

Dedicatedequipment is used solely for the production of a single product, or in somecases, of a single product line (e.g., containing the same active ingredient). Concernsover cross-contamination with other products are markedly reduced. However,consideration must be given to residues of cleaning agents, degradants,bioburden, and endotoxin.

专用设备仅用于生产一个产品，或单一产品线（即拥有相同API的产品）。对于这些设备，对产品间交叉污染的忧虑显著地减少。但是，必须要考虑清洁剂残留、降解物、微生物负载、内毒素。

Wherethe same piece of equipment is utilized for different product formulations(i.e., nondedicated equipment), the prevention of carryover of activeingredients between products becomes a major focus of the cleaning process. Fornondedicated equipment, a design consideration is whether a unique cleaningprocess will be developed for each manufactured product, or whether onecleaning process will be designed to address all (or a group) of manufacturedproducts.

当一个设备用于生产不同处方的产品（即非专用设备），清洁工艺的重点是避免API在产品间转移。对于非专用设备，在开发清洁程序时，应考虑是否对于每种产品使用不同的清洁程序，还是对所有产品（或一组类别的产品）使用一种清洁程序。

Certainproducts (such as beta-lactams) may require segregated production areas. Arisk-based analysis should be performed on other products which may be highlyhazardous (e.g., mutagenic active ingredients) in order to determine whetherdedicated facilities should be used. For other products, dedication ofequipment may be made not on a patient risk basis, but rather as a practical businessdecision.

有些产品（例如β-内酰胺类药物）可能需要独立生产区域。对其他可能高危险性的产品（例如致突变的活性成分），应进行风险分析来决定是否需要独立的厂房。对于有些产品，设备的专用不一定基于患者风险，而是基于业务考虑。

3.3.4.2Nonproduct Contact – Product Contact Surfaces

非产品接触部位 /产品接触部位

Validationof cleaning has focused on product contact surfaces. However, indirect productcontact surfaces (“nonproduct contact”surfaces with close proximity to open product) may be included in a cleaningvalidation program. An example of an indirect product contact surface for whichcleaning validation is commonly done is a lyophilizer shelf used inlyophilization of vials. Nonproduct contact surfaces such as floors and wallstypically have cleaning processes, but those cleaning processes are lower risk,are controlled consistent with GMPs, and are outside the scope of a cleaningvalidation program. However, cleaning of floors and walls may be addressedas part of an overall cross-contamination program, particularly for highlyhazardous drug active ingredients.

清洁验证集中于产品直接接触的部位。但是，清洁验证计划中也可以包括非产品接触部位（邻近产品暴露的非产品接触表面）。其中一个非产品接触的例子是清洁验证通常包括用于冻干机搁板。其他非产品接触部位包括地面和墙身，它们也有清洁程序，但一般风险较低，而且按照GMP要求进行控制，亦不在清洁验证计划的范围内。但是，地面和墙身的清洁可以作为整个交叉污染控制计划的一部分，尤其是对于一些高危险性活性成分来说。

3.3.4.3Low-Risk Sites – High-Risk Sites

低风险-高风险区域

Riskis a function of the identification of hazard, the ability to detect thathazard, and the potential exposure of the hazard on product quality and patientsafety. Those locations where there is the danger of a residue affecting asingle dose with a high level of contamination are high-risk sites. Examples ofsuch sites are a filling needle and a tablet punch. Sites which are difficultto clean are also high-risk sites. Those difficult-to-clean sites may includeports, drains, baffles, and the undersides of agitator blades. These high-risksites may require special disassembly, cleaning, and/or inspectionemphasis.Other sites which are easier to clean and uniformly transfer residueto the next product are generally considered lower risk.

风险是由危害的识别、危害的可检测性以及危害对产品质量和患者安全的影响所决定的。有些位置可能会使单剂量药物受到残留严重污染的，例如灌装针头和压片机冲头，都属于高风险区域。一些难清洗的位置的风险也较高，例如接口、排水口、挡板、搅拌叶的底部等。这些高风险位置可能需要特别拆卸和清洗，和或重点检查。对于其他较易清洗，并将残留物均匀地带到下批产品的位置，一般认为其风险较低。

Thedistinction between “major” and “minor” equipment is not a definitive one. TheGood Manufacturing Practices (GMP) (6) make mention of “major” equipment,but are silent on the subject of “minor” equipment except with regard to itemsdescribed as utensils. Major and minor designations do not generally reflectthe challenge of cleaning, nor define whether the equipment surfaces are a loweror higher risk for cleaning processes. Both major and minor product contactequipment items require cleaning verification or validation for multiproductequipment.
“主要”和“次要”设备的区分不是决定性的。GMP（6）提及了“主要”设备，除了定义为器具的设备，GMP没有涉及到“次要”设备。主要和次要的称谓一般不反映清洁方面的挑战，也没有确定清洁过程中设备表面具有低风险还是高风险。对于多产品共用设备，与产品直接接触的主要和次要设备均需进行清洁效果确认或验证。

3.3.4.4Materials of Construction

材质

Factorsaffecting “cleanability”include the surface type and the surface finish. The most common surface typesencountered are stainless steel and glass, but surface types may include othermetals and a variety of plastics and elastomers. Surface finish also affectsthe removal of soils. Rough surfaces provide more area for soil contact and maycontain cracks and crevices that are difficult for the cleaning agent to penetrate.The interior surfaces of stainless steel process equipment may be modified tosmooth and/or polish rough surfaces. The materials of construction of theequipment should be considered carefully when designing a cleaning validationprogram.

影响“可清洁性”的因素包括表面的类别和表面处理。最常见的表面为玻璃和不锈钢，但有些表面可能含有其他金属和一些塑料、橡胶。表面处理同样会影响污物的去除。粗糙的表面为污物提供了更大接触表面，同时亦可能有裂缝和裂纹，使得清洁剂难易渗入。工艺设备的不锈钢内部表面应调整为光滑的和/或对粗糙表面进行抛光。在设计清洁验证计划时应仔细考虑到设备材质。

Porousmaterials may require special cleaning processes. Items such as filter bags andfilter membranes are typically dedicated to a given product.

多孔性物质可能需要特别的清洁程序。如过滤器待和膜过滤器等物品通常为一特定产品专用。

3.3.5Operational Considerations

操作相关考虑

Operationalissues such as the use of campaigns, the utilization of equipment, and thecomplexity of the equipment impact the design of the cleaning validationprogram.

阶段性生产、设备的使用和设备的复杂程度等操作问题将影响清洁验证计划的设计。

Acampaign is a series of batches of the same product manufactured one after theother. Consideration should be given to the need to clean, and the extent of cleaning,between batches in a campaign.Depending on the product, there may be nocleaning between batches or some level of cleaning is done between batches. Ifthe cleaning between batches is simply a vacuuming (for solid products)or asolvent or water rinse (for liquid products), such cleaning is sometimes called“minor”cleaning or “in-process”cleaning. Such minor or in-process cleaning steps do not require separatevalidation.However, consideration should be given to the effect of such minoror in-process cleaning steps on the efficiency of the “full”cleaning process done at the end of a campaign for changeover to a new productor campaign.

阶段性生产是指连续地生产多批同一产品。应考虑批间是否需要清洁，以及清洁的程度。根据产品要求，批间可能不需要清洁，或是只需要一定程度的清洁。如果批间的清洁是简单地用吸尘机（对于固体产品）或用溶剂/水来冲洗（对于液体制剂），这种清洁一般称为“小清洁”或“中间过程清洁”。这种清洁程序是不需要单独验证的。可是，要考虑这种“小清洁”或“中间过程清洁”是否会影响其后“大清洁”（在阶段性生产结束进行的清洁，用于切换生产另一产品或连续生产另一产品）的效果。

Ifonly the cleaning process at the end of the campaign is to be validated,consideration should also be given to the number of batches and/or the totalelapsed time for a campaign. For example, elapsed time might be critical if theactive ingredient left on equipment surfaces degrades over time due to exposureto heat or light. Furthermore, the repetitive production of a single productwithout validated cleaning between batches might also result in the penetrationof materials into a location where single lot production might not present aproblem.

如果只对“大清洁”进行验证，还应考虑可连续生产的批数／可连续生产的时间。例如，有些残留在设备表面的有效成份可能会因为遇热和光照而随着时间降解，这时制定可连续生产的时间便变得很关键。再者，重复地生产同一种产品，而没有使用经验证的方法进行批间清洁，可能会使物料渗入某些部位，而这对于仅生产一批产品则不是问题。

3.3.6Cleaning Agent Selection

清洁剂的选择

Cleaningagent selection should be based on a scientific rationale. Cleaning agentsshould be selected for their suitability to remove the product residues; their compatibilitywith equipment; their ease of cleaning agent removal; and low toxicity.Solvents, formulated detergents, and commodity chemicals should be acceptablefor the process and for use with pharmaceutical products. Water alone ororganic solvent alone may be used as the cleaning agent, particularly forreadily soluble soils.

清洁剂应根据科学原理来选择。选择时应根据它们去除产品残留的能力、与设备的兼容性、清洁剂本身是否容易移除、低毒性。溶剂、配方洗涤剂和日用化学品应可用于清洁工艺和药品。水或有机溶剂可以单独作为清洁剂，尤其对易溶解的污物。

Atthe time of design of the cleaning process, it is important to review anddocument information about any cleaning agents to be used. The establishedcleaning agents should be reviewed against the vendor’scurrent specification sheets and descriptions, including material safety datasheets. Those documents should be available as a minimum requirement for use ofthose cleaning agents before evaluating the cleaning process. When selecting anew cleaning agent or utilizing an established cleaning agent for a newprocess, it is important to know all of the ingredients, as well as thepercentage each constituent comprises, that are in the cleaning agent. Thisallows for the establishment of the consistency of cleaning agent formulationover time, as well as for selecting a possible marker component for analysis ofcleaning agent residues.

在设计清洁工艺时，应重点审核并记录所有使用到的清洁剂的相关信息。对于已确定使用的清洁剂，应对照供货商所提供产品规格书和使用说明，包括物料安全数据表，进行检查。在评估清洁工艺之前，至少应获得这些清洁剂的相关文件。当使用新的清洁剂或将清洁剂用于新的工艺时，必须了解清洁剂中所有成份，包括每个成份的含量百分比。这使得清洁剂的配方可以保持一致性，同时有利于在进行清洁剂残留检测时选取指标组分。

Cleaningagents and their vendors should be qualified in much the same way as a rawmaterial and raw material vendor is qualified. Change control of the cleaningagent formulation, as well as notification of significant changes, should berequired of the cleaning agent vendor.

清洁剂和清洁剂供货商应经过确认，正如对原材料和原材料供货商进行确认一样。清洁剂供应商应有变更控制系统管理清洁剂处方变更，并应将重大变更告知用户。

Duringthe development of the cleaning cycle, quantities of cleaning agents, theirconcentration and their addition mode should be studied. Methods of storage,expiration dating, inventory control, and change control of the cleaning agentswill help establish and maintain a reproducible process.

在开发清洗程序时，应研究清洁剂的用量、浓度、加入的方式。清洁剂储存的方式、有效期、存量控制和变更控制，均有助于建立并维持一个可重现的工艺。

Waterused to prepare cleaning agents and for equipment rinse should be of suitablequality (7). Generally, water used for final rinse should be thesame grade as used for the manufactured product, e.g.,parenteral productsshould utilize WFI and oral products should employ purified water.

用于制备清洁剂和淋洗设备的水应符合适当标准（7）。一般来说，最终淋洗水应与工艺用水级别一致，例如注射剂要使用注射用水(WFI)，口服制剂则使用纯化水。

3.3.7 Product Considerations

产品相关考虑

Chemicaland physical attributes of the product should be taken into account whenestablishing a cycle development program for a specific product.Characteristics such as the solubility, concentration, physical properties ofthe active ingredients and excipients, possible degradation products and the effectof the cleaning agent are important factors in establishing that the cleaningmethod is appropriate.The interaction of the product with all surfaces withwhich it will come into contact is critical.

在建立特定产品的清洁程序时应考虑产品的物理和化学性质。一些特性例如活性成分和辅料的溶解度、浓度、物理性质，可能出现的降解物、清洁剂效果都是建立合适清洁方法的重要因素。产品与其接触表面之间的相互作用也是很关键的。

3.3.7.1Product Risk Considerations

产品风险的考虑

Thecleaning of equipment is closely tied to the type of materials being removedfrom the surface.The product formulation (including the active ingredients andexcipients and formulation aids), including the nature of the product atvarious intermediate steps of manufacture, should be considered.

设备的清洁与从表面待去除的物料类型是紧密相关。产品配方（包括原料药、辅料、配方助剂）、不同阶段中间产品的性质，都应予以考虑。

Becauselimits for highly hazardous drug active ingredients (e.g., those with seriousallergenic, cytotoxic and mutagenic properties) are generally more stringent,more robust cleaning processes may have to be designed. Such highly hazardousdrug active ingredients may be manufactured on nondedicated equipment providedan appropriate risk analysis and cleaning validation is performed. Some firmsmay choose to use dedicated facilities and/or equipment for such highlyhazardous drug activeingredients even though that might not be a regulatoryrequirement. Another approach for such highly hazardous drug active ingredientsis to include in the cleaning process a deactivation or degradation step suchthat residues from the active ingredient do not have those properties that makethe active ingredient highly hazardous. In addition, any unusual hazards ofdegradation products (either unintended or intended degradation products)should be considered.

对于高危险性活性成分（例如高致敏感、细胞毒素、致突变性的药物），残留的限度更严格，因此需要设计一个可靠的清洁程序。如果经过适当风险分析和清洁验证，这些高危险性药品可以在非专用的设备上生产。有些药厂会直接使用专用厂房和/或设备生产这些高危险性产品，纵使法规没有如此要求。对于这种高危险性药品，另一种方法是可以在清洁过程中加入一个去活性或降解的工序，使残留物不再具有高危险性。另外，降解物的任何异常危害（不论是预期或非预期的降解产物）都应该加以考虑。

Theroute of administration of a product may affect the acceptable residue limits,and may therefore affect the nature of the cleaning process. Generallyspeaking, injectable products, intra-ocular formulations,and some inhalantswhich provide direct access to the systemic circulation systems of patients area much greater concern if cross-contamination occurs.

产品的给药途径也会影响残留的可接受限度、并因此影响清洁工艺的特性。一般来说，注射剂、眼用剂、部分吸入剂这种会直接进入患者循环系统的药物，如果发生交叉污染将会更需要关注。

Anotherrisk factor to consider is the amount or extent of information available on theproduct to be cleaned. For example, the amount of information available for amarketed product may be much more extensive than information on a new drugactive ingredient being manufactured for human clinical trials. In addition, insuch early clinical manufacturing, a cleaning verification approach maybeutilized. With such an approach, the cleaning process may be significantlyoverdesigned so that after the cleaning process, residue levels are well withinacceptance limits.

另一个需要考虑的风险因素是对待清洁产品信息的数量和程度，举例来说，一个已在市场上销售的产品，应该会比仍然处于临床试验阶段的产品，有更多相关信息。对于一些早期临床生产阶段的产品，可采用清洁效果确认的方法。采用该方法，清洁工艺的设计更有保障，使清洁后的残留水平远低于可接受限度。