The industry needs asingle standard cleaning limit at 25 mg/ m2.
行業(yè)需要一個(gè)單一的標準清潔限度，每平米25毫克
Sep 01, 2017
By Michel Crevoisier, Thomas Peglow
Pharmaceutical Technology制藥技術(shù)
At home, when washing the dishes,do we ever consider what meal they will be used for next? When plates andcutlery are taken out of the cupboard to set the table, do we ever ask whatthey have been used for and whether they are clean enough for the gourmetcourse about to be served?
在家里洗盤(pán)子的時(shí)候，我們是否想過(guò)這些盤(pán)子下次會(huì )被用在什么餐中？當盤(pán)子和餐具從櫥柜中取出來(lái)放到桌子上時(shí)，我們是否問(wèn)過(guò)它們之前被用來(lái)做過(guò)什么？對于準備提供的美食它們是否足夠干凈？
Are there different levels ofcleanliness used for the dishes depending on the food served or the guests weentertain? Silly questions, apparently, but the industry’s current approachesto pharmacutical cleaning validation can often seem just as random. Cleaninglimits for pharmaceutical manufacturing equipment are computed based on theprevious and next products for every product change. As a result, it is oftendifficult to explain the cleaning and cleaning validation concept.
根據供應的食物或招待的客人，這些盤(pán)子有不同的清潔級別嗎？顯然，這是個(gè)愚蠢的問(wèn)題，但是目前行業(yè)用于藥物清潔驗證的方法似乎很隨意。藥品生產(chǎn)設備的清潔限度是基于每個(gè)產(chǎn)品更換的前一個(gè)和下一個(gè)產(chǎn)品計算的。因此，通常難以解釋清潔和清潔驗證概念。
This article is about combiningthe simplicity of the household cleaning concept with the science needed toprotect patients’ safety. To reach this goal, it may be necessary to revisit afew traditional ideas about cleaning validation and to establish new principles.The focus will be on API manufacturing of small molecular weight substances(i.e., with industrial organic chemistry and the corresponding traditionalplant equipment such as reactors, separators, crystallizers, centrifuges,filters, dryers, mills, and blenders, plus all the connecting pumps, pipes, andhoses). The size of the vessels typically ranges from 250 to 10000 L, and amanufacturing line can have up to several hundred square meters of productcontact surface.
本文將家庭清潔概念的簡(jiǎn)單性與保護患者安全所需的科學(xué)相結合。為達到這個(gè)目標，可能需要重新審視一些關(guān)于清潔驗證的傳統觀(guān)念，并建立新的原則。重點(diǎn)將集中在小分子量物質(zhì)的API生產(chǎn)（即用工業(yè)有機化學(xué)和相應的傳統工廠(chǎng)設備，比如反應器，分離器，結晶設備，離心機，過(guò)濾器，干燥機，粉碎機和混合機，以及所有連接泵，管道和軟管）。容器尺寸通常在250-10000L之間，生產(chǎn)線(xiàn)與產(chǎn)品接觸的表面積可高達的幾百平方米。
The change from product A to product Bis not a frequent case
從產(chǎn)品A到產(chǎn)品B的轉換并不是頻繁事件
APIs are usually produced inmultipurpose equipment. Several individual modules are concatenated to build aproduct- specific production line or train. After a campaign, the line usuallygets disconnected and the individual modules, not always all of them, are reconfiguredinto a new line for the next product. Some products may use exactly the sameproduction line as others, but most of the time, every product uses a somewhatdifferent configuration of modules. Some equipment is used for many products;other parts are practically dedicated to a few or to only one product.
APIs經(jīng)常在多用途設備中生產(chǎn)。連續幾個(gè)單獨的模塊被連接到一起以構建一個(gè)產(chǎn)品-特定產(chǎn)品線(xiàn)或生產(chǎn)鏈。經(jīng)過(guò)一系列活動(dòng)之后，該產(chǎn)品線(xiàn)通常斷開(kāi)，并且單個(gè)模塊（并不是總是這些）被重新配置為下一個(gè)產(chǎn)品的新生產(chǎn)線(xiàn)。一些產(chǎn)品可能使用與其他產(chǎn)品完全相同的生產(chǎn)線(xiàn)，但是大多時(shí)候，每個(gè)產(chǎn)品使用一些稍微不同的模塊配置。一些設備被用于多個(gè)產(chǎn)品；其他部分實(shí)際上專(zhuān)門(mén)用于幾種或僅一種產(chǎn)品。
When a line is set up for productB, some parts will indeed have been used for product A right before; otherparts, however, may have been in contact with product X, and mobile parts maybe taken from the storeroom and have been used for product Y or Z monthsbefore. There is rarely a pure product changeover from A to B; in reality, thechanges are from products A, X, Y ... to product B.
當為產(chǎn)品B建立生產(chǎn)線(xiàn)時(shí)，某些部件事實(shí)上在之前已經(jīng)被用于產(chǎn)品A；但是，其他部件可能已經(jīng)與產(chǎn)品X接觸，從儲存室中所取的移動(dòng)部件，幾個(gè)月之前已被用于產(chǎn)品Y或Z。很少有純粹從產(chǎn)品A到產(chǎn)品B的轉換；實(shí)際上是從產(chǎn)品A,X,Y…到產(chǎn)品B。
Similarly, when cleaning a pieceof equipment, it is not always known what the next product will be. The changecould be from A to the next products B, C, or D. This is particularly the casewith interchangeable mobile equipment such as flexible hoses, filters, or tanksthat go back to the storeroom after cleaning. Under such circumstances, anumber of questions will arise, including the following:
類(lèi)似地，當清潔一件設備時(shí)，通常不知道下一個(gè)產(chǎn)品是什么?？赡軓漠a(chǎn)品A到下一個(gè)產(chǎn)品B,C或D。這種情況尤其適用于可互換的移動(dòng)設備，例如柔性軟管，過(guò)濾器，或清潔后返回儲藏室的儲罐。在這種情況下，會(huì )出現很多問(wèn)題，包括：
What was the previous product manufactured at the facility, and what will be the next one?
設備以前生產(chǎn)的產(chǎn)品是什么？下一個(gè)產(chǎn)品會(huì )是什么？
How can one make sure that allparts are clean, to the right level for making the next product(s)?
如何確保所有部件都是清潔的并到達生產(chǎn)下一個(gè)產(chǎn)品所需的正確水平呢？
Can the cleaning validation conceptbe built and the cleaning limits computed based on the ideal product. changefrom A to B?
可以建立清潔驗證的概念并基于理想產(chǎn)品計算的清潔限度從A轉換到B嗎？
The following principles aim toanswer these questions.
以下原則旨在回答這些問(wèn)題。
The cleaning procedure is independent ofthe following product(s)
清潔規程應獨立于以下產(chǎn)品
Equipment cleaning should bethought as a reset function. The equipment is reset to a clean ground stateform where it can be used for any product. Every piece of equipment labeledclean must be ready for use, no questions asked.
設備清潔應視為重新設置功能。設備重新設置為干凈的基態(tài)，可用于任何產(chǎn)品。標識為清潔的每件設備必須準備就緒，沒(méi)有任何問(wèn)題。
Consider the analogy with thehousehold: doing the dishes, one doesn’t ask what will be cooked the next day,and when taking clean plates out of the cupboard, it doesn’t matter what the lastmeal was. A clean plate is a clean plate.
與家庭日常相類(lèi)似：洗餐具時(shí)不會(huì )問(wèn)第二天做什么飯，當把干凈的盤(pán)子從櫥柜拿出來(lái)時(shí)，跟上一餐就沒(méi)關(guān)系了。干凈的盤(pán)子就是干凈的盤(pán)子。
Cleaning without asking whatthe next product will be implies that setting the cleaning limit must be a comprehensiveexercisethat includes all products of amanufacturing unit. Quite often, the “cleaning validation runs” and thecorresponding plans and protocols only consider the actual product change A toB, which leads to cleaning à la carte, asking: How clean does it have to betoday?
不問(wèn)下一個(gè)產(chǎn)品是什么的清潔意味著(zhù)設置清潔限度必須是包括生產(chǎn)單元的所有產(chǎn)品的綜合性考量。通常，“清潔驗證運行”和相應的計劃和方案僅考慮從產(chǎn)品A到B的實(shí)際轉換，這導致了清潔按需進(jìn)行按菜單點(diǎn)菜，問(wèn)：今天需要什么樣的潔凈程度？
Using the same cleaningprocedure for different cleanings, it can happen that different limits must bemet from one cleaning to the next, because the limits get recalculated eachtime for the actual, ideal product change. With such moving targets, it isimpossible to properly validate a cleaning process.
使用相同的清潔步驟進(jìn)行不同的清潔，可能會(huì )發(fā)生從一個(gè)清潔到下一個(gè)清潔滿(mǎn)足不同的限度，因為每次實(shí)際和理想產(chǎn)品的變化，其限度都要重新計算。由于這樣的移動(dòng)目標，不可能對清潔過(guò)程進(jìn)行合理驗證。
Establishing a standard cleaning limit (SCL) for all the equipment is thecore element of the cleaning concept (1). The SCL is the level of cleanliness(expressed in mg/m2) that a production unit must maintain with everycleaning process, every time. The SCL applies to every piece of equipment,fixed or mobile, large or small, independently of the product changes.
為所有設備建立標準清潔限度（SCL）是清潔概念中的核心要素（1）。SCL是生產(chǎn)單元在每一次清潔過(guò)程中必須保持的清潔水平（用mg/m2表示）。SCL適用于每件設備，固定的或移動(dòng)的，大的或小的，與產(chǎn)品轉換無(wú)關(guān)。
Most production units willhave collected cleanliness data, typically results of swab tests, over quite along period. An example of such a data set is given in
Figure 1. Theexample is from a relatively old manufacturing unit (Unit A), which usestraditional equipment for industrial organic chemistry. The cleaningproceduresconsist mainly of flushing and boil outs with solvents and manualscrubbing with water and a detergent.
大多數生產(chǎn)部門(mén)將在相當長(cháng)的時(shí)間內收集清潔數據，通常是棉簽測試結果。圖1列舉了這種數據集的例子。該實(shí)例來(lái)自相對老的生產(chǎn)單元（單元A），其使用傳統的設備來(lái)生產(chǎn)工業(yè)有機化學(xué)物質(zhì)。清潔程序主要包括用溶劑回流和沸騰，并用水和洗滌劑進(jìn)行手動(dòng)洗滌。
Figure 1: Graph of morethan 250 swab results collected over a period of 18 months in multipurpose APIunit A. Swabs were taken after using different cleaning procedures, aftercampaigns of different lengths, making different products, and from differentpieces of equipment made of different material. The lowest values were oftenlimited by the limit of quantitation of the analytical methods. (All figurescourtesy of authors.)
圖1：18個(gè)月期間，在多用途API單元A中搜集的超過(guò)250個(gè)擦拭結果的圖表。在使用不同的清潔程序，不同的生產(chǎn)活動(dòng)時(shí)長(cháng)，生產(chǎn)不同的產(chǎn)品，以及擦拭不同材質(zhì)的設備后，進(jìn)行擦拭取樣。最低限度通常受限于分析方法的定量限。（所有圖表由作者提供）
Figure 1 gives a good idea of thelevel of cleanliness this particular production unit can achieve. The valuesvary a great deal and the level of cleanliness that can reasonably beguaranteed is limited by:
圖1給出了特定生產(chǎn)單元可以實(shí)現的清潔度水平的好主意。數值差異很大，可以得到合理保證的清潔水平受以下限制：
Physicochemicalproperties of the process residues 工藝殘留物的物理化學(xué)性質(zhì)
Equipmentdesign設備設計
Cleaningmethods 清潔方法
The conclusion from Figure 1 wasthat this particular production unit could be reliably cleaned down to 25 mg/ m2 . Although much lower values than 25mg/m2were often obtained (see Figure 2), 25 mg/m2 is considered the unit’s standardcleaning performance and so, for this unit, the SCL was set at 25 mg/m.2
圖1得到的結論是特定生產(chǎn)單元可以可靠地清潔到25 mg/ m2 。雖然經(jīng)常得到低于25 mg/ m2 的值（見(jiàn)圖2），但是25 mg/ m2 被認為是該單元的標準清潔性能，因此對于本單元，SCL被設定在25 mg/ m2 。
Figure 2: Histogram withcumulated frequency of swab results from Figure 1. 75% of swabs gave ≤1mg/m2,95%≤10 mg/m2.
圖2：來(lái)自圖1的擦拭積累頻率的直方圖。75%的擦拭檢測結果為≤1mg/m2,95%為≤10 mg/m2。
Setting the SCL in this simple and pragmatic way,solely based on experimental data, without any theoretical considerations,reflects acceptance of the variability and limitations inherent in currentcleaning practice. However, this approach represents a radical change fromtradition. Previously, the limit was calculated in the validation protocol thatonly considered the effective product change. The quality assurance (QA)department determined to what limit the equipment was to be cleaned at this onetime, without considering the big picture of years of cleaning experience.
以簡(jiǎn)單實(shí)用的方式設置SCL，僅僅基于實(shí)驗數據，而沒(méi)有任何理論考慮，反映了當前清潔規范中內在的變異性和局限性。然而，這種方法代表了從傳統方式的根本性轉變。以前，在驗證方案中計算限度時(shí)只考慮有效的產(chǎn)品轉換。質(zhì)量保證（QA）部門(mén)計算該次設備應被清潔的限度，而不考慮多年清潔經(jīng)驗的整體情況。
The theoretical safetyrequirements for a changeover from product A to B are known. Based on thepermitted daily exposure (PDE) of A, the maximal safe carryover (MSC) ofproduct A into product B can be determined by using Equations 1. Dividing the MSC by the product contactsurface used to make B gives the maximum safe surface residue of A (MSSRA) onequipment used for B.
從產(chǎn)品A到B的轉換的理論安全要求是已知的?；?/span>A的允許日暴露量（PDE），產(chǎn)品A到產(chǎn)品B的最大安全殘留量（MSC）可以通過(guò)公式1來(lái)確定。將MSC除以用于生產(chǎn)B的產(chǎn)品接觸表面得出用于B的設備的A的最大安全表面（MSSRA）殘留。
Applying Equations 1 and 2 to all the theoretically possible product changes in a definedmanufacturing unit yields the MSSR matrix. The MSSR matrix is the matrix of allpossible required levels of cleanliness for a defined portfolio of products.See reference 2 for an example of a computed MSSR matrix.
在確定的生產(chǎn)單元中將公式1和2應用于所有理論上可能的產(chǎn)品轉換得到MSSR矩陣中。 MSSR矩陣是確定的產(chǎn)品組合的所有可能要求的清潔水平的矩陣。有關(guān)計算的MSSR矩陣的示例，見(jiàn)參考文獻2。
Figure 1 shows a graph of more than250 swab results collected over a period of 18 months in multipurpose API unitA. Swabs were taken after using different cleaning procedures, after campaignsof different lengths, making different products, and from different pieces ofequipment made of different material. The lowest values were often limited bythe limit of quantitation of the analytical methods.
圖1展示了在多用途API單元A中18個(gè)月內收集的超過(guò)250個(gè)擦拭擦拭結果的圖表。使用不同清潔程序后，在不同長(cháng)度的活動(dòng)之后，生產(chǎn)不同的產(chǎn)品，以及從由不同材料制成的不同的設備上進(jìn)行擦拭取樣。最低值通常受限于分析方法的定量限度。
The risk of carryover contamination can be assessed bycomparing the level of cleanliness that can be reasonably expected (the SCL) withthe cleanliness required by the MSSR matrix (2). During risk assessment, thefollowing should be addressed:
可以通過(guò)將可合理預期（SCL）的清潔水平與MSSR矩陣（2）所要求的進(jìn)行比較來(lái)評估殘留污染的風(fēng)險。在風(fēng)險評估過(guò)程中，應解決以下問(wèn)題：
Arethe cleaning processes good enough to ensure safe changeovers? If not, is itreasonable to simply conclude that the cleaning procedures should be improved?Maybe there is room for improvement; but chances are that the cleaningprocesses have already reached their limits. If this is the case, can risk ofthe worst changeovers be mitigated by other means than cleaning?
清潔過(guò)程是否足以確保安全轉換？如果不能，那么簡(jiǎn)單地得出清潔程序應該改進(jìn)是合理的嗎？也許有改進(jìn)的余地；但很可能清潔工藝已經(jīng)達到了極限。如果是這種情況，是否可以通過(guò)其他方法來(lái)減輕最差情況轉換的風(fēng)險？
Can afew theoretical changeovers be eliminated from the MSSR matrix because they donot share any common equipment?
能否因為它們不共享任何常用設備就可以從MSSR矩陣中消除一些理論上的轉換嗎？
Can manufacturing campaigns be planned in a way to avoid criticalchangeovers?
生產(chǎn)活動(dòng)的計劃可以避免重大轉換嗎？
Docertain products call for partially of fully dedicated equipment?
某些產(chǎn)品是否需要部分完全用專(zhuān)用設備？
Such considerations shouldbe summarized in a risk assessment document, which should be part of thecleaning validation master plan. Additional risk assessment can be done basedon analysis of the swab results shown in Figure 2. The SCL of 25mg/m2 is a safe limit, because theprobability of a cleaning giving a swab result >25 mg/m2 is <1%. should="" a="" failure="" risk="" of="" 5%be="" deemed="" acceptable,="" the="" scl="" could="" even="" be="" lowered="" to="" ≤10="">2. Figure 3 showsswab data, as does Figure 1, but, in this case,they were measured in a different manufacturing unit (B) of the samecompany.
The data for unit B are very similar to those for unitA and the SCL was also set at 25 mg/ m2 for unit B. Because units A and B bothmanufacture small organic molecules, use similar equipment and very similarcleaning processes, it is not really a surprise that similar cleaning resultsare obtained.
應將這些考慮因素在風(fēng)險評估文件中進(jìn)行總結，并作為清潔驗證總計劃的一部分。另外的風(fēng)險評估可以基于圖2所示擦拭的分析結果25mg / m2的SCL是一個(gè)安全限度，因為擦拭結果> 25mg / m2的清潔概率<>％。如果5％的失敗風(fēng)險被認為是可接受的，則SCL甚至可以降低到≤10mg / m2。圖3和圖1一樣展示了擦拭數據，但是在這種情況下，它們是在同一公司的不同生產(chǎn)單位（B）中進(jìn)行測量。單位B的數據與單位A的數據非常相似，單位B的SCL也設定為25mg / m2。由于A和B單位都生產(chǎn)小的有機分子，均使用類(lèi)似的設備和清潔過(guò)程，獲得相似的清潔結果沒(méi)什么驚奇的。
Introducing an SCL opensthe possibility of having a single cleaning limit for many differentmanufacturing units, which can help to further standardize cleaning validation.In fact, the SCL of 25 mg/m2 waseventually introduced in five different manufacturing units.
引入SCL可以為許多不同的生產(chǎn)單元提供單一的清潔限度，有助于進(jìn)一步使清潔驗證標準化。事實(shí)上，25mg / m2的SCL最終被引入五個(gè)不同的生產(chǎn)單元。
With its general applicability and ease of use, theSCL concept can be compared to the classification system for cleanrooms, wherethe room class is independent of the room size or the nature and quantity ofproduct that is handled in the room. The SCL is, similarly, independent ofequipment size, products, or batch size.
由于其一般適用性和易用性，可以將SCL概念與潔凈室的分類(lèi)系統進(jìn)行比較，其中房間級別與房間尺寸或室內處理的產(chǎn)品的性質(zhì)和數量無(wú)關(guān)。類(lèi)似地，SCL與設備尺寸，產(chǎn)品或批量大小無(wú)關(guān)。
Via the SCL, one can imagine a classification of APImanufacturing equipment (e.g., in class 5, 25, and 50 mg/m2). Such equipmentclasses, which in fact would reflect validated cleaning commitments, could becriteria to consider when allocating new products to manufacturing sites oroutsourcing API manufacturing. Comparing the SCL and the MSSR matrix is astraightforward way to start a cleaning risk assessment and to implement thenew EMA guideline on shared facilities (3). In addition, adopting the SCLoffers a number of benefits. For example, it:
通過(guò)SCL，可以想象API生產(chǎn)設備的分類(lèi)（例如，5級，25級和50 mg / m2）。實(shí)際上將反映經(jīng)驗證的清潔承諾的這種設備分類(lèi)可能是將新產(chǎn)品分配到生產(chǎn)基地或外包API生產(chǎn)時(shí)考慮的標準。開(kāi)始清潔風(fēng)險評估并在共享設施（3）上實(shí)施新的EMA指南，比較SCL和MSSR矩陣是一種直觀(guān)方法。此外，采用SCL提供了許多好處。例如：
Allowsfor a consistent level of cleanliness to be enforced over a whole productionunit
允許在整個(gè)生產(chǎn)單元執行一致的清潔度。
Simplifiescleaning validation because there is no need to compute and justify thecleaning limit in every single validation plan; the limit can instead bejustified once in an appropriate document, (e.g., in the cleaning validationmaster plan)
簡(jiǎn)化清潔驗證，因為在每個(gè)驗證計劃中都不需要計算和證明清潔限度；相反，在適當的文件中（例如清潔驗證總計劃），限度只需被證明一次。
Allowsmanufacturers to standardize validation activities in the analyticallaboratory: Specifications for swab tests are constant, as are the workingranges of high-performance liquid chromatography (HPLC) methods and whenspiking coupons for recovery studies.
允許生產(chǎn)商在分析實(shí)驗室中對驗證活動(dòng)進(jìn)行標準化：擦拭測試的標準是恒定的，高效液相色譜（HPLC）方法的工作范圍以及用于回收率研究的尖峰試劑盒也是如此。
Last but not least, the SCL is a simple concept thatis easy to understand and to explain.
最后但很重要的一點(diǎn)是，SCL是一個(gè)易于理解和解釋的簡(jiǎn)單概念。
Acknowledgements致謝
The authors would like to thank SébastienSchuehmacher,Michael W?lfle, and Markus Schaefer for their relentless cleaning efforts andtheir support in the development of the SCL concept, and to Ian Udri forcompiling all the data.
作者要感謝SébastienSchuehmacher，MichaelW?lfle和Markus Schaefer的不懈的清潔努力及其對SCL概念發(fā)展的支持，以及Ian Udri編譯所有數據。
1.M. Voaden, A Leblanc, RJ.Forsyth, Pharmaceutical Technology, 31 (1)pp. 74-83, 2007.
2.M. Crevoisier et al, Pharmaceutical Technology 40 (1) pp. 52-56, 2016.
3. EMA, Guideline on Setting Health Based ExposurelLmits for Use in Risk Identification in the Manufacture of Different MedicinalProducts in Shared Facilities, (EMA,2014).
Michel Crevoisier is former senior quality expert forNovartis Pharma AG, and Thomas Peglow is senior cleaning validation expert atNovartis Pharma AG, Switzerland. The views expressed in this article are thoseof the authors and not necessarily of their employers.
Michel Crevoisier是Novartis Pharma AG的前高級質(zhì)量專(zhuān)家，Thomas Peglow是瑞士Novartis Pharma AG的高級清潔驗證專(zhuān)家。本文所表達的觀(guān)點(diǎn)只是作者的觀(guān)點(diǎn)。
來(lái)源：制藥技術(shù)
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