清潔驗(yàn)證可見(jiàn)殘留檢查和可見(jiàn)殘留標(biāo)準(zhǔn)！

譯自2020年8月份發(fā)布的《ISPE基準(zhǔn)指南：清潔驗(yàn)證生命周期–應(yīng)用，方法和控制（ISPE Baseline Guide: Cleaning Validation Lifecycle: Applications, Methods, and Controls）》?

6.3???Visual Inspection and ?Criteria

清潔驗(yàn)證目視檢查和標(biāo)準(zhǔn)

?

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].

目視清潔是評(píng)價(jià)表面清潔的一個(gè)標(biāo)準(zhǔn)。這個(gè)標(biāo)準(zhǔn)很重要，因?yàn)槿绻砻嬗锌梢?jiàn)的殘留物，那么設(shè)備就不被認(rèn)為是清潔的。目視檢查是在每次清洗后，對(duì)所有可視的且接觸產(chǎn)品的制藥生產(chǎn)設(shè)備表面進(jìn)行主動(dòng)觀(guān)察。這是GMP要求[77]，必須確定設(shè)備沒(méi)有任何可見(jiàn)殘留物，才能被認(rèn)為是足夠的清洗。另外，GMPs要求在生產(chǎn)活動(dòng)開(kāi)始前立即完成一次目視檢查[78]。

?

6.3.1??Visible Residue Limit Studies

可見(jiàn)殘留限度研究

?

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.

可進(jìn)行可見(jiàn)殘留限度(VRL)研究，以確定各污染物和表面的可見(jiàn)殘留檢測(cè)水平。確定檢測(cè)水平的方法是，將逐步遞減的每種殘留物噴到代表設(shè)備表面的測(cè)試樣板上，使其干燥，然后由一組觀(guān)察人員對(duì)其進(jìn)行觀(guān)察。為了提供更可靠的目視限度，這些觀(guān)察人員應(yīng)在不同的光照水平，不同的距離和不同的角度觀(guān)察殘留物，以模擬實(shí)際的目視檢查條件。

?

“Thelowestresidueamountthatisvisibletoallobserversisthevisualdetectionlimitforthatproduct.”[3]

“所有觀(guān)察人員都能看到的最低殘留量就是該產(chǎn)品的目視檢測(cè)限度?！盵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.

如果可以在已知的殘留量水平上始終能觀(guān)察到殘留物，并且該水平遠(yuǎn)低于清潔可接受標(biāo)準(zhǔn)，則目視清潔（VC）可提供較高置信度表明對(duì)設(shè)備進(jìn)行了充分清潔。即使建立了目視限度，絕大多數(shù)認(rèn)為目視清潔本身不足以建立清潔驗(yàn)證。還需要直接表面取樣（例如：棉簽或TOC淋洗水）[17]。然而，在清潔驗(yàn)證完成后，目視清潔可以與定期取樣一起作為日常監(jiān)測(cè)程序中的標(biāo)準(zhǔn)[79]。如果歷史數(shù)據(jù)表明實(shí)際目視限度高于測(cè)試樣板研究獲得的目視限度，應(yīng)展開(kāi)調(diào)查以確認(rèn)。如果確實(shí)不符合標(biāo)準(zhǔn)，應(yīng)提高目視檢查限度。

?

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.

為了使VRL具有價(jià)值，VI（安全限度與VRL所代表的殘留水平之間的距離）的安全系數(shù)的數(shù)據(jù)或結(jié)果必須足夠大，以補(bǔ)償執(zhí)行VI的操作員之間的差異和VI本身固有的可變性。在該方法中應(yīng)對(duì)執(zhí)行可見(jiàn)殘留限度檢查的操作人員進(jìn)行確認(rèn)?？梢?jiàn)殘留限度的VI應(yīng)由操作員執(zhí)行，并在設(shè)備放行使用前由第二位操作員復(fù)核。此外，在清潔工藝確認(rèn)后，應(yīng)定期審查控制措施，以確保性能不受累加的或新的變異性的不良影響，并確認(rèn)可見(jiàn)殘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.

如果可見(jiàn)殘留限度VRL高于清潔接受標(biāo)準(zhǔn)，則目視清潔在確定設(shè)備是否得到充分清潔方面的價(jià)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:

可見(jiàn)殘留限度研究通過(guò)定義明確的參數(shù)以供在清潔程序中使用，并將主觀(guān)性降到最低。應(yīng)明確與研究可見(jiàn)殘留物相關(guān)的觀(guān)察變量，然后可以建立研究的實(shí)驗(yàn)參數(shù)[80]?？紤]參數(shù)如下：

• MOC

• 結(jié)構(gòu)材料

• Lightconditions

• 照明條件

• ?Viewingdistance

• 觀(guān)察距離

• Viewingangle
  

• 觀(guān)察角度

• Observervariability
  

• 觀(guān)察人員的差異

• Solventeffects
  

• 溶劑影響

?

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.

結(jié)構(gòu)材料必須與待清潔設(shè)備（例如不銹鋼，聚碳酸酯，玻璃等）相稱(chēng)或具備代表性。對(duì)所有設(shè)備結(jié)構(gòu)材料都進(jìn)行VRL研究是不科學(xué)的。例如，白色表面（例如PTFE）上的VRL會(huì)比SS表面上的VRL高得多[81]。因此，VRL研究應(yīng)與設(shè)備的擦拭采樣相協(xié)調(diào)，以確保棉簽結(jié)果低于VRL。擦拭結(jié)果還將證明所有結(jié)構(gòu)材料的清潔效果均相同。在驗(yàn)證之后，對(duì)于日常監(jiān)測(cè)，可以得出結(jié)論，如果不銹鋼表面明顯清潔，則所有表面都被清潔到相同程度。

?

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].

目視確定清潔度的照明條件會(huì)因?yàn)樵O(shè)備和房間的不同而異。應(yīng)為擬使用的目視檢查程序確定照明參數(shù)。高于200 lux的照明對(duì)目視觀(guān)察沒(méi)有影響，但是低于200 lux的照明會(huì)抑制檢測(cè)可見(jiàn)殘留物的能力[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].

觀(guān)察距離和角度取決于現(xiàn)場(chǎng)使用的生產(chǎn)設(shè)備。較大的設(shè)備通常可以目視檢查的距離不超過(guò)10英尺，并且視角可能會(huì)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.

可通過(guò)執(zhí)行清晰的程序，培訓(xùn)檢查人員如何一致地進(jìn)行目視檢查以及建立可見(jiàn)殘留限度參數(shù)作為VI確定的控制，以減少觀(guān)察人員之間的差異。

?

Arecommended training approach for inspectors [78]includes:

檢查人員的推薦培訓(xùn)方法[78]包括：

?

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

• 回顧已清潔生產(chǎn)設(shè)備包括產(chǎn)品接觸面的目視檢查SOP

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

• 回顧設(shè)備圖紙以理解不易清潔的部位和產(chǎn)品積累的部位

• Reviewing VRLexamples
  

• 回顧可見(jiàn)殘留限度示例

• Discussing VRL versus cleaninglimit
  

• 討論可見(jiàn)殘留限度與清潔限度的比較

• Conducting on-the-jobtraining
  

• 進(jìn)行崗位培訓(xùn)：

  -?????????Emphasize effects of viewingparameters, especially viewingangle

  重視目視參數(shù)的影響，尤其是目視角度

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

  理解何時(shí)使用輔助照明(手電筒)

  -?????????Strive for consistency among visualinspections to maintain expectations for visualcleanliness

  保持目視檢查的一致性，以保持目視清潔

?

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

目視檢查通常由經(jīng)確認(rèn)的人員執(zhí)行，并記錄在清潔日志或生產(chǎn)批次記錄中。

?

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

請(qǐng)參閱附錄3 –示例：制定和建立可見(jiàn)殘留限度（VRL）方案。

?

6.3.2??Visible Residue Limit and SafetyLimits

可見(jiàn)殘留限度和安全限度

?

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.

可以證明和記錄，對(duì)于可見(jiàn)殘留限度顯著低于安全限度（例如：低于安全邊際的20％）的化學(xué)活性物質(zhì)，在該產(chǎn)品清潔后，設(shè)備表面清潔至目視清潔水平可以確保對(duì)下一個(gè)生產(chǎn)產(chǎn)品的特性，強(qiáng)度，質(zhì)量和純度的風(fēng)險(xiǎn)較低。

?

“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]

“確保適當(dāng)去除外在清潔劑（例如表面活性劑，通常具有非常高的基于健康的殘留限值），并且沒(méi)有可見(jiàn)殘留是比基于健康的殘留限值更為嚴(yán)格的標(biāo)準(zhǔn)?！?[3]

?

6.3.3?Non-AccessibleAreasandtheVisualInspectionProcess

不易接近區(qū)域和目視檢查過(guò)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.

對(duì)于無(wú)法目視檢查的區(qū)域，應(yīng)關(guān)注產(chǎn)品質(zhì)量問(wèn)題。一些方法包括清潔比較評(píng)估或浸涂。當(dāng)使用這兩種方法中的任何一種時(shí)，都應(yīng)采用基于風(fēng)險(xiǎn)的方法，尤其是對(duì)于具有低ADE / PDE（高風(fēng)險(xiǎn)）值的活性物質(zhì)。

?

6.3.3.1??CleaningComparisonEvaluation

清潔可比性評(píng)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.

如無(wú)法直接目視檢查（例如傳輸管道）的設(shè)備的清潔過(guò)程與能夠目視檢查的設(shè)備相當(dāng)穩(wěn)健或更加穩(wěn)健，則可認(rèn)為無(wú)法直接目視檢查的設(shè)備也是干凈的。

?

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.

不可及區(qū)域的清潔需要與可及區(qū)域的清潔相當(dāng)或更多。例如，清潔具有相同生產(chǎn)污染物的儲(chǔ)罐和輸送管道使用相同的清潔參數(shù)（如清潔時(shí)間，清潔劑濃度和溫度）。唯一的區(qū)別是清潔動(dòng)作。儲(chǔ)罐可以使用沖洗和傾瀉清潔，而輸送管道則需要使用湍流清潔。如果管道清潔水流滿(mǎn)足適當(dāng)?shù)耐牧?，則可以有理由認(rèn)為輸送管道清潔達(dá)到目視清潔度，因?yàn)橐炎C明通過(guò)沖洗清潔的儲(chǔ)罐區(qū)域?yàn)槟恳暻鍧崱?/span>

?

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.

該原理也可用于同一設(shè)備的部件。例如，如果通過(guò)相同的清潔過(guò)程清潔了傳輸系統(tǒng)上的管道（即，清潔后確定為目視清潔），并且顯示出與其余傳輸系統(tǒng)一樣難以清潔，可以代表整個(gè)傳輸系統(tǒng)。

?

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.

沒(méi)有必要證明所有能夠目視檢查的區(qū)域清潔活動(dòng)（即：儲(chǔ)罐的沖洗）都小于或等于不能目視檢查的區(qū)域清潔活動(dòng)。在考慮清潔過(guò)程和清潔難度時(shí)，應(yīng)分別評(píng)估每種情況。

?

6.3.3.2??Boroscoping

內(nèi)窺鏡檢測(cè)

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、傳輸管線(xiàn)和不易接觸的區(qū)域可以使用內(nèi)窺鏡進(jìn)行檢查。所有遠(yuǎn)程目視檢查都應(yīng)被確認(rèn)。應(yīng)權(quán)衡對(duì)不易接觸區(qū)域的內(nèi)窺鏡檢查的好處和設(shè)備維護(hù)和定期打開(kāi)管路連接進(jìn)行侵入式檢查的壽命風(fēng)險(xiǎn)。允許或反對(duì)常規(guī)內(nèi)窺鏡目視檢查的決定應(yīng)進(jìn)行徹底的風(fēng)險(xiǎn)評(píng)估。

?

6.3.4?????OrganolepticInspection

感官檢查

?

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.

作為清潔驗(yàn)證的一部分，可能需要確認(rèn)氣味或顏色殘留的清除。如該要求不是基于安全，并且也沒(méi)有計(jì)算出的殘留物限度，則可以通過(guò)嗅覺(jué)或目視檢查來(lái)執(zhí)行可接受的殘留物去除。

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

表面的目視檢查可以量化，因此也可以用于計(jì)算殘留限量。

?

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.

對(duì)設(shè)備部件進(jìn)行過(guò)夜密封，可以增強(qiáng)對(duì)氣味的檢測(cè)。例如，通過(guò)蓋上容器的蓋子或?qū)⒃O(shè)備裝在一個(gè)袋子里，任何氣味都被集中，從而更加保證氣味不會(huì)被帶到下一個(gè)產(chǎn)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.

生產(chǎn)人員可能對(duì)氣味失去敏感性；因此，如果由不參與該產(chǎn)品生產(chǎn)的人員進(jìn)行測(cè)試，則該測(cè)試會(huì)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.

確認(rèn)級(jí)別應(yīng)基于風(fēng)險(xiǎn)。風(fēng)險(xiǎn)級(jí)別（即業(yè)務(wù)風(fēng)險(xiǎn)或產(chǎn)品風(fēng)險(xiǎn)）應(yīng)與確認(rèn)級(jí)別相匹配。

?

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.

有色產(chǎn)品的檢查可以通過(guò)使用棉簽擦拭難以檢查的易于累計(jì)物料的位置（例如密封接口）。但是，在采樣期間檢測(cè)殘留顏色已經(jīng)太遲了，無(wú)法防止清潔失敗。對(duì)于具有顏色或色素成分的設(shè)備，一種更實(shí)際的方法是在清潔過(guò)程的最后一步中用溶劑（例如70％異丙醇）徹底擦拭設(shè)備的整個(gè)表面。這通常是在清潔過(guò)程中完成的，以去除殘留的水，但也可以在設(shè)備進(jìn)入目測(cè)和取樣步驟之前，對(duì)顏色的去除進(jìn)行檢查。

?