清洁验证可见残留检查和可见残留标准！

译自2020年8月份发布的《ISPE基准指南：清洁验证生命周期–应用，方法和控制（ISPE Baseline Guide: Cleaning Validation Lifecycle: Applications, Methods, and Controls）》 

6.3   Visual Inspection and  Criteria

清洁验证目视检查和标准

 

Visually Clean (VC) is one criterion used to assess surfacecleanliness. This criterion is significant in that ifthere is visible residue on the surface, then the equipment isnot considered clean. The visual inspection is anactiveobservation of all visually accessible productcontact surfaces of the pharmaceutical manufacturing equipment after everycleaning. It is a GMP requirement [77] and must determine that the equipment isfree from any visibleresidues inorder for the cleaning to be considered adequate. Additionally, GMPs requirecompleting a visual inspection immediately before manufacturing activities cancommence[78].

目视清洁是评价表面清洁的一个标准。这个标准很重要，因为如果表面有可见的残留物，那么设备就不被认为是清洁的。目视检查是在每次清洗后，对所有可视的且接触产品的制药生产设备表面进行主动观察。这是GMP要求[77]，必须确定设备没有任何可见残留物，才能被认为是足够的清洗。另外，GMPs要求在生产活动开始前立即完成一次目视检查[78]。

 

6.3.1  Visible Residue Limit Studies

可见残留限度研究

 

It is possible to conduct Visible Residue Limit (VRL) studies todetermine the level of visible detection of residues for many soilants andsurfaces. A method to determine the detection level is by spiking decreasingamounts ofeach residue onto testingcoupons representative of equipment surfaces, allowing them to dry, and then havingthem viewed by a group of observers. Multiple observers should view theresidues under different light levels, fromdifferentdistances, and from different angles to mimic actual visual inspectionconditions in order to provide a more rugged visuallimit.

可进行可见残留限度(VRL)研究，以确定各污染物和表面的可见残留检测水平。确定检测水平的方法是，将逐步递减的每种残留物喷到代表设备表面的测试样板上，使其干燥，然后由一组观察人员对其进行观察。为了提供更可靠的目视限度，这些观察人员应在不同的光照水平，不同的距离和不同的角度观察残留物，以模拟实际的目视检查条件。

 

“Thelowestresidueamountthatisvisibletoallobserversisthevisualdetectionlimitforthatproduct.”[3]

“所有观察人员都能看到的最低残留量就是该产品的目视检测限度。”[3]

 

If the residues can be consistently observed at a known residue level,and this level is much lower than the cleaning acceptance criteria, then VCprovides a high degree of confidence that the equipment is sufficientlycleaned. Even with a visual limit in place, VC is predominately not consideredadequate by itself for establishing cleaning validation. Direct surfacesampling (e.g., swabs or TOC rinse measures) is also required [17]. However, VCcould be used as a criterion along with periodic sampling in a routinemonitoring program after the cleaning validation is complete [79]. Ifhistorical data shows that the visual limit is higher than what was obtainedvia coupon studies, launch aninvestigationto verify. If the out of specification is correct, then raise theVRL.

如果可以在已知的残留量水平上始终能观察到残留物，并且该水平远低于清洁可接受标准，则目视清洁（VC）可提供较高置信度表明对设备进行了充分清洁。即使建立了目视限度，绝大多数认为目视清洁本身不足以建立清洁验证。还需要直接表面取样（例如：棉签或TOC淋洗水）[17]。然而，在清洁验证完成后，目视清洁可以与定期取样一起作为日常监测程序中的标准[79]。如果历史数据表明实际目视限度高于测试样板研究获得的目视限度，应展开调查以确认。如果确实不符合标准，应提高目视检查限度。

 

For the VRL to have value, the data or results for the margin of safety for VI (distancebetween the safety limit andtheresidue level represented by the VRL) must be sufficiently large to compensatefor the variability between operators performing the VI and also the inherentvariability of the VI itself. Operators performing VRL determinationsshould be qualified in the method. VI for VRL determinations should beperformed by an operator and verified by a second operator prior to theequipment being released for use. In addition, a periodic review of thecontrols is necessaryafter thecleaning process has been qualified to ensure that performance has not beennegatively impacted by increased or new sources of variability and to confirmthat a VRL is still a valid and justifiedapproach.

为了使VRL具有价值，VI（安全限度与VRL所代表的残留水平之间的距离）的安全系数的数据或结果必须足够大，以补偿执行VI的操作员之间的差异和VI本身固有的可变性。在该方法中应对执行可见残留限度检查的操作人员进行确认。可见残留限度的VI应由操作员执行，并在设备放行使用前由第二位操作员复核。此外，在清洁工艺确认后，应定期审查控制措施，以确保性能不受累加的或新的变异性的不良影响，并确认可见残留限度仍是有效且合理。

 

If the VRL is at a level above the cleaning acceptance criteria, thenVC has limited value in determining whetherthe equipment is sufficientlycleaned.

如果可见残留限度VRL高于清洁接受标准，则目视清洁在确定设备是否得到充分清洁方面的价值有限。

VRL studies are determined using well-defined parameters to enable itsuse in cleaning programs and minimize subjectivity. The viewing variablesassociated with studying visible residue must be defined, and thenexperimental parameters for the study canbe established [80]. The parameters consideredare:

可见残留限度研究通过定义明确的参数以供在清洁程序中使用，并将主观性降到最低。应明确与研究可见残留物相关的观察变量，然后可以建立研究的实验参数[80]。考虑参数如下：

• MOC

• 结构材料

• Lightconditions

• 照明条件

•  Viewingdistance

• 观察距离

• Viewingangle
  

• 观察角度

• Observervariability
  

• 观察人员的差异

• Solventeffects
  

• 溶剂影响

 

The MOC must match or represent the ones used in the equipment to becleaned (e.g., SS, polycarbonate, glass, etc.). Conducting VRL studies for allequipment MOCs is not logical. For example, a VRL on a white surface (e.g.,PTFE) would be much higher than on a SS surface [81]. Therefore, VRL studiesshould be coordinated with swab sampling of the equipment to confirm swabresults are lower than the VRL. The swab results would alsodemonstrate equivalent cleaning for allMOCs. After validation, for routine monitoring it could be concluded that ifthe SS surfaces were visibly clean, then all surfaces were cleaned to the sameextent.

结构材料必须与待清洁设备（例如不锈钢，聚碳酸酯，玻璃等）相称或具备代表性。对所有设备结构材料都进行VRL研究是不科学的。例如，白色表面（例如PTFE）上的VRL会比SS表面上的VRL高得多[81]。因此，VRL研究应与设备的擦拭采样相协调，以确保棉签结果低于VRL。擦拭结果还将证明所有结构材料的清洁效果均相同。在验证之后，对于日常监测，可以得出结论，如果不锈钢表面明显清洁，则所有表面都被清洁到相同程度。

 

Lightingconditionsforvisualdeterminationsforcleanlinesswillvaryfromonepieceofequipmenttoanother,andfrom room to room. Lightintensity parameters should be determined for the visual inspection procedureintended to be used. Light intensity levels above 200 lux do not have an impacton visual observations, but light levels below 200 lux inhibit the ability todetect visible residues[80].

目视确定清洁度的照明条件会因为设备和房间的不同而异。应为拟使用的目视检查程序确定照明参数。高于200 lux的照明对目视观察没有影响，但是低于200 lux的照明会抑制检测可见残留物的能力[80]。

 

The viewing distance and viewing angle are based on the manufacturingequipment that is used at the site. Larger pieces of equipment can often beviewed at a distance of no greater than 10 feet and could have a restrictedviewing angle[80].

观察距离和角度取决于现场使用的生产设备。较大的设备通常可以目视检查的距离不超过10英尺，并且视角可能会受限[80]。

 

The variations in observers can be minimized by implementing clearprocedures, training observers on how to conduct visual inspectionsconsistently, and establishing the VRL parameters as controls for VIdeterminations.

可通过执行清晰的程序，培训检查人员如何一致地进行目视检查以及建立可见残留限度参数作为VI确定的控制，以减少观察人员之间的差异。

 

Arecommended training approach for inspectors [78]includes:

检查人员的推荐培训方法[78]包括：

 

• Reviewing SOP for conducting thevisual inspection of cleaned manufacturing equipment, includingproduct contactsurfaces

• 回顾已清洁生产设备包括产品接触面的目视检查SOP

• Reviewing equipment diagrams tounderstand hard-to-clean areas and areas of productbuildup
  

• 回顾设备图纸以理解不易清洁的部位和产品积累的部位

• Reviewing VRLexamples
  

• 回顾可见残留限度示例

• Discussing VRL versus cleaninglimit
  

• 讨论可见残留限度与清洁限度的比较

• Conducting on-the-jobtraining
  

• 进行岗位培训：

  -         Emphasize effects of viewingparameters, especially viewingangle

  重视目视参数的影响，尤其是目视角度

  -         Harmonize on when to use supplementallighting(flashlight/torch)

  理解何时使用辅助照明(手电筒)

  -         Strive for consistency among visualinspections to maintain expectations for visualcleanliness

  保持目视检查的一致性，以保持目视清洁

 

Visual inspections are normally executed by qualified personnel anddocumented in cleaning log booksormanufacturing batchrecords.

目视检查通常由经确认的人员执行，并记录在清洁日志或生产批次记录中。

 

Referto Appendix 3 – Example: Protocol for Development and Establishment of aVisible Residue Limit(VRL).

请参阅附录3 –示例：制定和建立可见残留限度（VRL）方案。

 

6.3.2  Visible Residue Limit and SafetyLimits

可见残留限度和安全限度

 

It can be justified and documented that for chemicals and activeswhere the VRL is significantly (e.g., lower than 20% of the margin of safety)lower than the SL, equipment surfaces cleaned to a VC level following cleaningofthepreviousproduct would ensure with low risk the next manufactured product’s identity, strength,quality, and purityfrom a cleanequipmentperspective.

可以证明和记录，对于可见残留限度显著低于安全限度（例如：低于安全边际的20％）的化学活性物质，在该产品清洁后，设备表面清洁至目视清洁水平可以确保对下一个生产产品的特性，强度，质量和纯度的风险较低。

 

“Assuring adequate removal of non-intrinsic cleaningagents such as surfactants often involves very highhealth- based residual limits and the absence of visible residueis a much more stringent criteria than the health-based residual limit.”[3]

“确保适当去除外在清洁剂（例如表面活性剂，通常具有非常高的基于健康的残留限值），并且没有可见残留是比基于健康的残留限值更为严格的标准。” [3]

 

6.3.3 Non-AccessibleAreasandtheVisualInspectionProcess

不易接近区域和目视检查过程

 

Product quality concernsshould be addressed for areas not accessible to visual inspection. Some methodsincludea cleaning comparisonevaluation or boroscoping. A risk-based approach should be applied when usingeither of these methods, especially for actives with low ADE/PDE (high hazard)values.

对于无法目视检查的区域，应关注产品质量问题。一些方法包括清洁比较评估或浸涂。当使用这两种方法中的任何一种时，都应采用基于风险的方法，尤其是对于具有低ADE / PDE（高风险）值的活性物质。

 

6.3.3.1  CleaningComparisonEvaluation

清洁可比性评估

 

If equipment that is not visually accessible (e.g., a transfer line)is cleaned with a cleaning process as robust, ormore robust than equipment that is visually accessible, it maybe argued that the visually inaccessibly equipment is also clean.

如无法直接目视检查（例如传输管道）的设备的清洁过程与能够目视检查的设备相当稳健或更加稳健，则可认为无法直接目视检查的设备也是干净的。

 

The cleaning of the inaccessible areas needs to be equal to or greaterthan the cleaning of accessible areas. For example, a tank and transfer linewith the same production soil are cleaned using the same cleaning parameters(i.e., cleaning time, cleaning agentconcentration, and temperature). The only difference is the cleaning action.The tank is cleaned using impingement and cascading action, and the transferpipe is cleaned using turbulent flow. If the piping cleaning flow meets theappropriate turbulent flow, it can be rationalized that the transfer line isclean to a visual cleanliness level since the tank areas cleaned via cascadingaction were demonstrated to beVC.

不可及区域的清洁需要与可及区域的清洁相当或更多。例如，清洁具有相同生产污染物的储罐和输送管道使用相同的清洁参数（如清洁时间，清洁剂浓度和温度）。唯一的区别是清洁动作。储罐可以使用冲洗和倾泻清洁，而输送管道则需要使用湍流清洁。如果管道清洁水流满足适当的湍流，则可以有理由认为输送管道清洁达到目视清洁度，因为已证明通过冲洗清洁的储罐区域为目视清洁。

 

Thisrationalecouldalsobeusedforpartsofthesameequipment.Forexample,ifaspoolpiece(i.e.,determinedtobeVC after cleaning) on the transfer line system was cleaned via the samecleaning process and shown to be as difficult or more difficult to clean as therest of the transfer line system, it could represent the whole transfer linesystem.

该原理也可用于同一设备的部件。例如，如果通过相同的清洁过程清洁了传输系统上的管道（即，清洁后确定为目视清洁），并且显示出与其余传输系统一样难以清洁，可以代表整个传输系统。

 

It is not necessary todemonstrate that all visually accessible area cleaning actions (i.e.,impingement and cascading in the case of the tank) are less than or equal tothe visually inaccessible area cleaning action to make theargument. Each situation should beevaluated individually while considering the cleaning process and cleaningdifficulty.

没有必要证明所有能够目视检查的区域清洁活动（即：储罐的冲洗）都小于或等于不能目视检查的区域清洁活动。在考虑清洁过程和清洁难度时，应分别评估每种情况。

 

6.3.3.2  Boroscoping

内窥镜检测

Pipes, transfer lines, and other inaccessible areas can be visuallyinspected using a boroscope. Any remote visual inspection should be qualified.The benefit of boroscoping inaccessible areas should be weighedagainst the equipment maintenance andlongevity risks of routinely breaking line connections and performingintrusive inspections.The decision for or against routine boroscoping for visual inspection should bethoroughly riskassessed.

管道、传输管线和不易接触的区域可以使用内窥镜进行检查。所有远程目视检查都应被确认。应权衡对不易接触区域的内窥镜检查的好处和设备维护和定期打开管路连接进行侵入式检查的寿命风险。允许或反对常规内窥镜目视检查的决定应进行彻底的风险评估。

 

6.3.4     OrganolepticInspection

感官检查

 

The removal of odors or color residues may need to be confirmed aspart of cleaning validation. Where the requirement is not based on safety, andwhere there are no calculated residue limits, the acceptable removal ofthe residue may be performed by using thesense of smell or through visualinspection.

作为清洁验证的一部分，可能需要确认气味或颜色残留的清除。如该要求不是基于安全，并且也没有计算出的残留物限度，则可以通过嗅觉或目视检查来执行可接受的残留物去除。

Visualinspection of the surfaces can be quantified and so may also be used were aresidue limit iscalculated.

表面的目视检查可以量化，因此也可以用于计算残留限量。

 

Detection of odors can be enhanced by sealing the equipment itemovernight. For example, by closing a lidded vessel or containing the equipmentin a bag, any odor is concentrated, giving a greater assurance that no odorwillbe carried over into the nextproduct.

对设备部件进行过夜密封，可以增强对气味的检测。例如，通过盖上容器的盖子或将设备装在一个袋子里，任何气味都被集中，从而更加保证气味不会被带到下一个产品中。

 

Those involved in manufacturing may become desensitized to the odor;therefore, the test is more effective if itis performed by someone not involved in the manufacture of thatproduct.

生产人员可能对气味失去敏感性；因此，如果由不参与该产品生产的人员进行测试，则该测试会更有效。

 

The level of qualification should be risk based. The level of the risk(i.e., business risk or product risk) shouldmatch the level ofqualification.

确认级别应基于风险。风险级别（即业务风险或产品风险）应与确认级别相匹配。

 

The detection of colored products may be enhanced by examining a swabused to sample difficult-to-inspect points where material may gather, forexample seal interfaces. However, detection of residual color during samplingis already too late to prevent a cleaning failure. A more practical approachfor a piece of equipment having a color or dye ingredient is to thoroughly wipethe entire surface of the equipment with solvent (e.g., 70% isopropyl alcohol)as the last step of the cleaning process. This is often done during cleaning toremove residual water, but can alsoserveas a check on color removal before the equipment gets to the visual inspectionand samplingsteps.

有色产品的检查可以通过使用棉签擦拭难以检查的易于累计物料的位置（例如密封接口）。但是，在采样期间检测残留颜色已经太迟了，无法防止清洁失败。对于具有颜色或色素成分的设备，一种更实际的方法是在清洁过程的最后一步中用溶剂（例如70％异丙醇）彻底擦拭设备的整个表面。这通常是在清洁过程中完成的，以去除残留的水，但也可以在设备进入目测和取样步骤之前，对颜色的去除进行检查。

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