Other Considerations
其他需考慮因素
The items discussed below are issues that may be considered as part of any evaluation in establishing limit.
以下是設(shè)定限度時，可能需要考慮的問題
1. Multiple Next Products 后續(xù)生產(chǎn)產(chǎn)品的多樣性
In many pharmaceutical manufacturing situations, there is not just one product that could possibly be manufactured after a given product for which limits are being established. If flexibility is desired to manufacture products in any order, calculations should be considered for all “subsequently manufactured products”, and the resulting lowest limit (typically the lowest limit persurface area) should be established for the cleaned product. As discussed previously, relevant factors to consider for the next product are dosing, batch size and shared surface area. In this manner, any of the products considered maybe safely manufactured after cleaning of the first product. In such evaluations, the combination of the specific relevant factors for each next product should be considered. However, it is also acceptable as a worst-case to consider only the most stringent of each of the three relevant factors.
在制藥行業(yè)中，很多時候在一個指定產(chǎn)品（其殘留限度已確定）生產(chǎn)結(jié)束后，后續(xù)生產(chǎn)的可能不只是一個產(chǎn)品。如果希望可以靈活生產(chǎn)任何產(chǎn)品，計算已清潔產(chǎn)品殘留最低限度（通常是每單位表面積的最低限度）時應(yīng)考慮所有“后續(xù)生產(chǎn)產(chǎn)品”。如之前討論，需要考慮的后續(xù)生產(chǎn)產(chǎn)品的相關(guān)因素包括劑量、批量以及共用表面積。這樣，第一個產(chǎn)品清潔之后，可以安全地生產(chǎn)任何其他產(chǎn)品。評估時應(yīng)該綜合考慮每一種后續(xù)生產(chǎn)產(chǎn)品的相關(guān)因素組合。當(dāng)然，采用最嚴(yán)格的三個相關(guān)因素組合作為最差條件也是可以接受的。
Another option is to restrict the order of manufacturing based, for example, on aspecific subsequently manufactured product causing a limit to be very low. In such cases, procedures should be in place to assure that the restricted order of manufacture is consistently followed.
另一種方式是限定生產(chǎn)順序，例如，基于后續(xù)生產(chǎn)產(chǎn)品建立的殘留限度非常低。這種情況下，要有相應(yīng)的規(guī)程以確保嚴(yán)格執(zhí)行限定的生產(chǎn)順序。
A third option is to operate in cleaning verification mode where the acceptability of each specific cleaning event is determining based on a limit for the immediately following next product. In this way, the limit for cleaning a given product may vary depending on subsequently manufactured product. In this verification mode, residues are measured after each cleaning event and compared to the acceptance limit calculated based on the product immediately following.
第三種方式是按照清潔效果確認(rèn)的模式來執(zhí)行，基于后續(xù)生產(chǎn)的第一個產(chǎn)品建立的殘留限度，確定每一清潔活動是否符合要求。這樣的話，指定產(chǎn)品的清潔限度可能會根據(jù)后續(xù)生產(chǎn)產(chǎn)品的不同而不同。在這種清潔效果確認(rèn)模式中，每次清潔后都要測量殘留，并同基于后續(xù)生產(chǎn)產(chǎn)品計算出的殘留可接受限度進(jìn)行比較。
2. Next Product in Verification Approach 清潔效果確認(rèn)方法中的后續(xù)產(chǎn)品
Ina cleaning verification protocol, only the actual immediately following productis required for establishing limits. Particularly in development or clinical manufacturing, where a verification approach is commonly used, the next productmay not be known at the time of the cleaning verification evaluation. Insuch cases, one approach is to measure residues following cleaning, and then not to release the equipment until the next product is determined. At that time, a carryover evaluation is performed to determine whether the residues measured are acceptable. If the measured residues are not acceptable, the equipment may be recleaned and cleaning verification performed again. A second approachis to establish, based on the types of products manufactured, some worst-case values for the relevant factors for the next product. These worst-case values are used for establishing limits, and the equipmentis cleaned to meet those values. When the next product is determined, it is appropriate toverify that the relevant parameters of the next product are within the worst-case values.
清潔效果確認(rèn)方案中，只需要根據(jù)緊接著生產(chǎn)的產(chǎn)品確定殘留限度。尤其是在研發(fā)批或臨床批的生產(chǎn)中，經(jīng)常使用清潔效果確認(rèn)的方法，在清潔效果確認(rèn)的評估時可能不知道后續(xù)產(chǎn)品會是什么。這種情況下，一種方式是清潔后檢測殘留，直到確定了后續(xù)生產(chǎn)產(chǎn)品后才允許設(shè)備的使用。進(jìn)行殘留評估，決定檢測出來的殘留是否可接受。如果檢測出來的殘留無法接受，應(yīng)重新清潔設(shè)備并再次進(jìn)行清潔效果確認(rèn)。第二種方式是基于生產(chǎn)的產(chǎn)品類型，為后續(xù)產(chǎn)品建立一些最差條件。這些”最差條件”數(shù)值被用于設(shè)定限度，同時設(shè)備清潔后需要符合這些數(shù)值。當(dāng)確定了后續(xù)生產(chǎn)產(chǎn)品時，合適的做法是確認(rèn)該后續(xù)產(chǎn)品的相關(guān)參數(shù)沒有超出最條件數(shù)值范圍。
3. Default Limits 默認(rèn)限度
As used in this document, default limits are one of two types. One type is a default limit which is utilized if the default value is more stringent than what is established by the medically safe calculation (as given in Sections5.3 through 5.8). A second type is a default limit where a medically safe limit cannot be established, such as for intermediates in API manufacture.In the latter case, the default limit maybe established on criteria that are specific to the individual situation, based on process understanding and a risk assessment.
本文件有兩種類型默認(rèn)限度，。第一種默認(rèn)限度是默認(rèn)值比通過醫(yī)學(xué)安全計算（如5.3至5.8中所描述）建立的限度更嚴(yán)格。第二種默認(rèn)限度是醫(yī)學(xué)安全限度無法建立時，如API生產(chǎn)過程中的中間體。在后一種情況中，默認(rèn)限度可根據(jù)對工藝的理解以及風(fēng)險評估，建立針對特定情況的限度標(biāo)準(zhǔn)。
One example of the first type of default limit is a default limit used for the ARL. For drug products, the most common default limit for the ARL (thelimit in the next product) is 10 ppm; however, other values may be used. If the ARL calculation (Equation 5A, 5D or 5F) results in a value above10 ppm, then 10 ppm is used as the ARL. If the ARL calculation results in avalue below 10 ppm, then that lower calculated value is used as the ARL. For API manufacture, more common default limits for the ARL are 50 ppm or 100 ppm (18),although other values may be selected and used if they are more stringent than what is established by the medically safe calculation.
第一種情況可以ARL使用的默認(rèn)限度為例。對于制劑來說，ARL（下一產(chǎn)品中殘留可接受標(biāo)準(zhǔn)限度）最常用的默認(rèn)限度為10ppm。當(dāng)然，也可以采用其他數(shù)值。如果ARL計算結(jié)果（公式 5A, 5D或5F）大于10ppm, 則選用10ppm作為ARL。如果ARL的計算結(jié)果小于10ppm，則選擇計算得來的較小的數(shù)值作為ARL。在API生產(chǎn)中，ARL更常用的默認(rèn)限度是50ppm或100ppm (18)，當(dāng)然如果其他數(shù)值比醫(yī)學(xué)安全計算得來的數(shù)值更嚴(yán)格，則也可能被選用。
A second example of this type of default limit is a default limit for the SAL.For either drug product or API manufacture, the most typical default value for the SAL used is 4μg/cm2. This level is commonly cited as the upper limit for what is considered visually clean. If the SAL calculation (Equation5I) results in a value above 4μg/cm2, then 4μg/cm2 is used as the SAL. If the SAL calculation resultsin a value below 4μg/cm2, then that lower calculated value is used as the SAL.
這一情況的第二個例子是SAL的默認(rèn)限度。無論是對于制劑還是API生產(chǎn)，最廣泛使用的SAL默認(rèn)限度是4μg/cm2。這一水平常被作為上限，也就是目檢潔凈。如果SAL計算結(jié)果（Equation5I）大于4μg/cm2，則選用4 μg/cm2作為SAL。如果SAL計算結(jié)果（Equation5I）小于4μg/cm2，則選擇計算得來的較小數(shù)值作為SAL。
It should be understood that in these two examples, the logic is that any value below the medically safe value may be used as it represents a more stringent criterion.
需要理解的是，這兩個示例的邏輯是可采用任何低于醫(yī)學(xué)安全數(shù)值的值作為限度，因為它代表了一個更嚴(yán)格的標(biāo)準(zhǔn)。
4. Use of Different Safety Factors不同安全系數(shù)的使用
The safety factor applied to a minimum daily dose is typically 0.001 (one one-thousandth), regardless of the route of administration. Based on a risk assessment, a more stringent or less stringent safety factor may be applied as appropriate for a specific situation. For example, for clinical trial materials where the dose is not fully established, a more stringent safety factor may be considered. Since the safety factor of 0.001 was originally established for drug product administered chronically, it may be acceptable (again based on arisk assessment) to use a less stringent factor for drug products administered for a short time (such as cold tablets, which may be administered for only 10days).
無論什么類型的給藥途徑，每日最小有效劑量的安全系數(shù)通常是0.001?；陲L(fēng)險評估，在特定的情況，可以適當(dāng)使用一個更嚴(yán)格或不那么嚴(yán)格的安全系數(shù)。例如，對于用于臨床試驗的藥品，其劑量尚未完全確定，則可以考慮使用一個更嚴(yán)格的安全系數(shù)。因為安全系數(shù)0.001本是為長期給藥的制劑而設(shè)定的，那么基于風(fēng)險評估，對于短期給藥的制劑（如治療感冒的片劑，服藥時間可能只有10天），則可以使用一個不那么嚴(yán)格的安全系數(shù)。
5. DifferentRoutes of Administration 不同的給藥途徑
If the cleaned product and the next product are administered by different routes (suchas the first product being an oral dose and the second product being an injectable), a risk assessment should be considered. This risk assessment might include an evaluation of hazards of the oral drug if administered as an injectable,or it might include a review of data for the extent of systemic availability of the oral drug if given orally.
如果已清潔產(chǎn)品和接下來要生產(chǎn)的產(chǎn)品使用不同的給藥途徑（比如第一的產(chǎn)品是口服給藥，第二個產(chǎn)品用于注射），則需進(jìn)行風(fēng)險評估。風(fēng)險評估可能包括對口服給藥的產(chǎn)品如果被用于注射的危害評估，或者可能包括口服制劑口服給藥后的生物利用度的數(shù)據(jù)回顧。
6.Different Doses for Adults and Children 成人和兒童劑量差異
For two products where both products have different doses for adults and for children, it is appropriate to determine the ARL based on both products with the adult dose, and then for both products using the child’s dose. The lower ARL of the two values should be used for subsequent limit calculations.In cases where one product may be dosed only for adults and the next product only dosed for children, then a risk assessment should be considered.
如果兩個產(chǎn)品對于成人和兒童都分別有不同的劑量，比較合適的做法是先基于兩個產(chǎn)品的成人劑量計算ARL，再基于兩個產(chǎn)品的兒童劑量計算ARL。較小的ARL將被采納用于后續(xù)限度計算。如果一個產(chǎn)品只有成人劑量，后續(xù)產(chǎn)品只有兒童劑量，則需要進(jìn)行風(fēng)險評估。
7. Human and Veterinary Products Manufactured on the Same Equipment
同一設(shè)備用于生產(chǎn)人用產(chǎn)品和獸用產(chǎn)品
For this situation, a risk assessment should be considered to set limits appropriately. In addition to the species difference, the body weight difference may also be a significant factor.
在這種情況下，應(yīng)進(jìn)行風(fēng)險評估以設(shè)定適當(dāng)?shù)南薅?。除了物種不同，個體重量差異也可能是個重要因素。
8.Residues of Genotoxic and Other Highly Hazardous Active Ingredients
基因毒性殘留以及其他高危活性成分
One approach to genotoxic residues is covered in Section 5.3.3, which is to utilize the Threshold of Toxicological Concern (TTC) value of 1.5μg/day as the safe daily intake (16), and utilize conventional calculations to set an acceptable limit in an analytical sample. Another approach for genotoxic residues (provided the genotoxic residue is the active ingredient and not a degradant), as well as other residues of special medical concern, is to dedicate equipment to that one product and thus avoid the issue of the genotoxic residue being carried over to a different product. A third approachis to perform cleaning validation, with limits based on a toxicological evaluation related to the genotoxic effect (or other special toxicity concern)using the principles in Section 5.3.2.2. A fourth approach is to set the limit for the genotoxic residue as below the limit of detection of the best available analytical technique. In the latter case, a medical risk assessment should be performed to determine whether residues at that detection limit are acceptable. In this latter case, it may also be possible to include in the cleaning process a step which deactivates or degrades the genotoxic material such that genotoxic properties are no longer present. Such a determination of deactivation or degradation is preferably performed as a laboratory study.These approaches may also be applicable to other active ingredients with special concerns, such as reproductive toxicity hazards, allergenicity,cytotoxicity, and mutagenicity.
5.3.3節(jié)涵蓋了基因毒性殘留限度的一個設(shè)定方法，也就是利用毒理學(xué)閾值（TTC）1.5μg/day作為每日安全攝入量（16），并利用傳統(tǒng)的計算方法設(shè)定分析樣品中殘留的允許限度。對于基因毒性殘留（假如該基因毒殘留是活性成分而不是降解產(chǎn)物）以及其他需特殊醫(yī)學(xué)關(guān)注的殘留，另一個方法，是采用專用設(shè)備生產(chǎn)該產(chǎn)品以防止基因毒性殘留轉(zhuǎn)移到另一個產(chǎn)品中。第三種方法是進(jìn)行清潔驗證，使用5.3.2.2節(jié)的理論，根據(jù)基因毒性（或其他需要關(guān)注的特殊毒性）作用進(jìn)行毒理學(xué)評估并設(shè)定限度。第四種方法是將基因毒性殘留的限度設(shè)置為低于目前最好的分析技術(shù)的檢測限。在最后一個方法中，需要進(jìn)行醫(yī)學(xué)風(fēng)險評估以決定是否是可以接受位于檢測限的殘留水平，同時可能需要在清潔程序中增加一步，使基因毒性的物料因失活或降解而不再表現(xiàn)出基因毒性。基因毒物料的失活或降解方法最好作為實驗室研究進(jìn)行。以上方法可能也適用于其他需特殊醫(yī)學(xué)關(guān)注的活性成分，如生殖毒性、致敏性、細(xì)胞毒性和致突變性。
9.Limits Based on Analytical Detection Limits
基于分析方法檢測限的限度
Limits may be established based on the analytical detection limits providing residues at those analytical detection limits are determined to be safe. It should be recognized that this method is not normally recommended because with ever improving analytical methods, the limits will be driven exceedingly low so as not be practically achievable. The issue is not whether the residue can be measured, but rather whether the residue is medically safe and does not affect subsequent product quality.
如果確定殘留水平位于檢測限是安全，則可以基于分析方法檢測限確定殘留允許限度。需注意的是，通常并不推薦采用該方法，因為檢測方法的不斷改進(jìn)，檢測限度趨于非常低，以至于實際操作中無法達(dá)到該水平。問題不在于殘留是否是可以被測量的，而是從醫(yī)學(xué)的角度來說殘留是否是安全的，且不會對后續(xù)產(chǎn)品的質(zhì)量產(chǎn)生影響。
10.Degradation of the Active Ingredient 活性成分的降解
If the active ingredient degrades during the cleaning process (or after the cleaning process during the time before sampling), it may not be appropriate to measure residues of that active ingredient using a specific analytical procedure in a cleaning validation protocol. The reason is that the relevant residue to measure is the degradant. There are at least two approaches to dealing with this situation. One approach is to set limits for the degradant,and then measure the degradant in the protocol using an appropriate analytical method.This assumes that there is a specific degradant for which limits can be established (e.g., based on a toxicity calculation). Another approach is to set limits for the undegraded active based on its dose. Residues are then measured with a non specific analytical method (such as TOC). The residue as measured by that nonspecific method is converted to an equivalent amount of undegraded active ingredient and compared to the calculated limit. This approach may be acceptable if the safety concerns from residues of the degradant(s) are no more serious than the safety concerns of the active ingredient. There may be other acceptable approaches based on the specific of the situation and a risk assessment.
如果活性成分在清潔過程中降解，或清潔后取樣前這一時間降解，則清潔驗證方案中使用指定分析方法測量該活性成分的殘留是不合適的，因為應(yīng)該測量的是降解產(chǎn)物的殘留。至少有兩個方案可解決這個問題。一個是為降解產(chǎn)物設(shè)定限度，然后在方案中用合適的分析方法測量降解產(chǎn)物。前提是可以設(shè)定一個特定降解產(chǎn)物的殘留限度（如，基于毒性計算）。另一個方案是基于活性成分的劑量，為未降解的活性成分設(shè)置限度，再采用非專屬的檢測方法測量殘留量，如TOC。使用非專屬檢測方法測量出的殘留被轉(zhuǎn)換成相應(yīng)的未降解的活性成分的含量，并同計算得來的限度進(jìn)行對比。如果降解產(chǎn)物殘留的安全危害沒有活性成分的安全危害嚴(yán)重，則可以采用這個方法。根據(jù)特定的情況和風(fēng)險評估，也可采用其他方法。
11.Limits Not Measureable無法測量的限度
If calculations for the limit of the active ingredient in the analytical sample result in values that are not measurable by available analytical methods, there are several options. One option is to dedicate the equipment to that one product,thereby reducing the need to measure the active ingredient except by a visually clean criterion. A second option is to modify the parameters of the next manufactured product such that the limit is higher. For example, raising the minimum batch size of the next product will increase the limit.It may also be possible to restrict the order of manufacture such that certain products, which drive the limit lower, are not manufactured after the cleaned product with the low limit. In such cases, appropriate measures should be put in place to insure that only those approved products are manufactured as the next product. A third option is to modify the sampling parameters. For example, for swab sampling,sampling a larger area (100 cm2 rather than 25 cm2) or extracting the swab witha smaller amount of solvent will result in an increased limit in the analytical sample. A fourth option is lower the rinse volume for rinse sampling. A fifth option is to concentrate the rinse sample by a technique such as vacuum evaporation.
如果計算得來的被檢測樣品中活性成分限度無法采用現(xiàn)有的檢測方法進(jìn)行測量，可有多種選擇。一種是該設(shè)備專用于一個產(chǎn)品，因此減少了測量該有效成分的需要，僅需符合目檢清潔標(biāo)準(zhǔn)。第二個選擇是調(diào)整后續(xù)生產(chǎn)產(chǎn)品的相關(guān)參數(shù)以提高殘留限度。例如，增大后續(xù)產(chǎn)品的最小批量會提高限度。也可能限制生產(chǎn)順序，如果已清潔的產(chǎn)品殘留限度較低，則下一生產(chǎn)產(chǎn)品不能為限度更低的部分產(chǎn)品。這樣的話，需要用適當(dāng)措施來保證只有被批準(zhǔn)的產(chǎn)品才能作為下一生產(chǎn)產(chǎn)品。第三個選擇是更改取樣參數(shù)。例如，擦拭取樣中，通過增大取樣面積（從25cm2增加到100cm2）或者減少拭子萃取的溶劑量來提高被檢測樣品的殘留限度。第四個選擇是沖洗取樣過程中減少沖洗量。第五是通過技術(shù)，如真空蒸發(fā)，對沖洗樣品進(jìn)行濃縮。
12.Limits for Organic Solvents 有機(jī)溶劑限度
For organic solvents that are typically used for cleaning in small molecule API synthesis, limits maybe established based on toxicity calculations. Another approach is to use the values in ICH Q3C (R5), which establishes acceptable levels for solvents in API’s and in drug products (19). It should be recognized that Q3C technically applies to solvents used in the manufactureof API’s. While cleaning processes are sometimes considered manufacturingsteps, they are often considered part of the supporting“equipment and facilities”. Therefore this approach should be carefully evaluated before use.Another approach is not to set limits for volatile organic solvents. One situation where this may applyis if there is an adequate determination (based on process understanding and appropriate studies) that there are adequate conditions for the volatile solvent to evaporate. Note that this latter consideration also applies to use of isopropanol or ethanol used as final rinse or wipe for drug product manufacture.
對小分子原料藥合成的清潔時使用的有機(jī)溶劑，可根據(jù)毒性計算來設(shè)定殘留限度。另一種方式是使用ICH Q3C (R5)中的數(shù)值，建立原料藥和制劑中的溶劑的可接受標(biāo)準(zhǔn)。需要注意的是，從技術(shù)角度來說，Q3C適用于生產(chǎn)API過程中使用的溶劑。雖然有時候清潔過程也會被認(rèn)為是生產(chǎn)步驟，更多的是將其作為對設(shè)備、設(shè)施的支持程序。因此這個方法在使用前需要仔細(xì)評估。另一種方法是不對揮發(fā)性有機(jī)溶劑設(shè)定限度，當(dāng)有充分理由（基于對工藝的理解以及適當(dāng)?shù)难芯浚┐_定可有充分的條件允許該揮發(fā)性有機(jī)溶劑揮發(fā)時，可以采用該方法。注意這一要求同樣適用于制劑生產(chǎn)中使用異丙醇或乙醇進(jìn)行最終的沖洗或擦拭。
Another situation where limits may not be required is where the same solvent is used for the final rinse as for manufacture of the next product.
另一種不需要設(shè)定限度的情況是下一產(chǎn)品生產(chǎn)中使用相同的溶劑進(jìn)行最終沖洗。
13. Dedicated Equipment 專用設(shè)備
For equipment trains dedicated to manufacture of only one product, the concern about carryover of the active ingredient from one batch to the next is minimized. As stated in the U.S. FDA guidance document, visually clean may be appropriate to address such a concern (20). However,cleaning validation may still be required because of concerns about other residues, such as degradants, cleaning agent and bioburden, carrying over tothe next batch of the same product.
對于只用于生產(chǎn)一個產(chǎn)品的專用設(shè)備組，則較少擔(dān)心將活性成分轉(zhuǎn)移至下一批產(chǎn)品中。如美國FDA指南文件所述，目視潔凈即可。但是，考慮到其他殘留可能仍需進(jìn)行清潔驗證，如降解產(chǎn)物，清潔劑和生物負(fù)載，這些殘留可能轉(zhuǎn)移到相同產(chǎn)品的下一批次中。
If only parts of an equipment train are dedicated to one product, then that dedicated part is not considered as part of the shared surface area for calculating limits for an active ingredient. However, the surface area of that part may be relevant for calculating other limits, such as the limit for the cleaning agent.
如果設(shè)備組中只有一部分是專用于一個產(chǎn)品，那么在計算活性成分殘留限度時，這一部分不視為共用表面積。但是，在計算其他限度時，這一部分表面積可能是相關(guān)的，比如清潔劑的限度。
Another approach is to set limits for the active ingredient and measure residues of the active ingredient in a cleaning validation protocol for dedicated equipment for other reasons, such as concerns about batch integrity or certain equipment surfaces may not be easily evaluated by visual examination.
考慮到批的完整性，或有些特定的設(shè)備表面可能不容易通過目檢來評估，另一種方法是設(shè)定活性成分的殘留限度，并在專用設(shè)定的清潔驗證方案中對活性成分殘留進(jìn)行測量。
14. Dividing a Limit among Various Pieces of Equipment 區(qū)分不同設(shè)備的限度
In order to evaluate a processing operation composed of several unit operations,it is important to consider the accumulated residue from each piece of process equipment. The MAC is the sum of all target residues that could be present on the various pieces of relevant shared equipment surfaces. A common practice isto require the same SAL for each and every surface in an equipment train. An alternativeis to apportion the total amount (the MAC) differently among the different equipment items, such that the total amount present still reflects the MAC amount. For example, for an equipment train comprising three separate vesselseach of the same surface area, the SAL limit might be1.0 μg/cm2 ifthe MAC is distributed evenly over all surface areas. In contrast, the MAC might be apportioned such that the SAL was 0.5 μg/cm2 for Equipment A, 1.0μg/cm2 for Equipment B, and1.5 μg/cm2 for Equipment C, provided the total carryover limit was still at the calculated MAC value.
為了評估一個由多個操作單元組成的操作步驟，重要的是計算每一操作設(shè)備中的累積殘留。MAC是可能存在于不同設(shè)備的共用面積上所有目標(biāo)殘留的總和。通常一個設(shè)備組中每一共用表面都采用相同的SAL。另一種選擇是將MAC的總量不平均地分配給不同的設(shè)備，其總量依然可以有效反應(yīng)出MAC。例如，如果一個設(shè)備組包含三個獨立容器，三個容器具有相同的表面積，如果將MAC按照總表面積平均分配，則SAL限度可能為1.0μg/cm2，相反，可以不平均地分配MAC，使設(shè)備A的SAL為0.5μg/cm2，設(shè)備B是1.0 μg/cm2，設(shè)備C是1.5μg/cm2，殘留限度總和仍然等同計算出的MAC值。
15.Limits for Preferential Transfer to a First Portion of the Next Product
向下一個產(chǎn)品前一部分優(yōu)先轉(zhuǎn)移的殘留限度
An equipment train should be delineated to separate those portions in which the residue would be evenly (homogeneously) distributed in the next product (e.g.,blender, granulator) from those in which the residue could be transferred to an individual dosage unit of the next product (e.g., tablet press, vial filler).To address the situation of preferential (non-homogeneous) transfer, the carryover calculations can be adjusted based on the surface area subject to preferential transfer and the portion of the next batch subject to being potentially contaminated with the transferred residue. This will result inusing a different, more stringent limit to the equipment surfaces which can preferentially transfer to the next product, thus restricting potential carryover to an initially manufactured single product dose of the next product.In addition, this preferential transfer can be addressed based on production techniques if an adequate first portion of the next manufactured product (e.g.,filled vials, tablets) is discarded. Another option is to utilize equipmentparts dedicated to one product where this preferential transfer may occur.
設(shè)備組中有些設(shè)備上的殘留會平均的（均勻的）分布在下一產(chǎn)品（如，混合機(jī)，制粒機(jī)）中，有些設(shè)備的殘留會轉(zhuǎn)移至下一產(chǎn)品單個劑量單元（如壓片、裝瓶）中，應(yīng)將這兩類設(shè)備區(qū)分開來。對優(yōu)先轉(zhuǎn)移（不均勻）的情況，可以根據(jù)優(yōu)先轉(zhuǎn)移的設(shè)備表面積以及下一批次中可能受到殘留污染的產(chǎn)品的多少對殘留計算結(jié)果進(jìn)行調(diào)整。這將導(dǎo)致對存在優(yōu)先轉(zhuǎn)移設(shè)備表面采用不同的、更嚴(yán)格的殘留限度，以控制下一產(chǎn)品中最初生產(chǎn)單個劑量單元中殘留量。另外，如果下一產(chǎn)品最初生產(chǎn)的部分（如已灌裝的瓶子、片子）有足夠數(shù)量作報廢處理，則可通過生產(chǎn)技術(shù)控制解決該優(yōu)先轉(zhuǎn)移的問題。另一方法是當(dāng)存在優(yōu)先轉(zhuǎn)移的可能時，就采取產(chǎn)品專用的設(shè)備部件。
16.Limits for Biotechnology Manufacture殘留限度-生物技術(shù)制造
More information on limits for biotechnology manufacture is given in PDA Technical Report No. 49,“Points to Consider for Biotechnology Cleaning Validation” (2).
關(guān)于生物技術(shù)制造中的殘留限度的更多信息，見PDA T49號技術(shù)報告“生物技術(shù)清潔驗證要點”（2）。
17. Products with More Than One Active Ingredient
有不止一種活性成分的產(chǎn)品
In drug product manufacture, there may be more than one active ingredient in the drug product. In such cases, there are at least two options. One option is to set limits for all active ingredients and measure each active ingredient in a cleaning validation protocol. Another option is to determine a “worst case”among the different active ingredients, and to only set limits for that worst-case active ingredient based on the lowest limit of any active ingredientin the group. Considerations for determining the worst-case active ingredient include difficulty of cleaning, solubility in the cleaning solution, and concentration of the active.
制劑中可能存在不止一種活性成分。這種情況下，至少有兩種選擇。其一是對所有的活性成分都設(shè)定限度并在清潔驗證方案中測量每個活性成分殘留。另一種在不同的活性成分中確定“最差條件”，并基于這一組活性成分中最低的殘留限度，只對“最差條件”的活性成分設(shè)定限度。判斷“最差條件”活性成分，需要考慮清潔難易程度，在清潔溶劑中的溶解能力以及活性成分的濃度。
18. BioburdenLimits
生物負(fù)載限度
Inconsidering bioburden limits following cleaning, it is not expected that thecleaning process itself results in sterile equipment. If limits are establishedfor bioburden in a cleaning validation protocol, those limits can beestablished using carryover calculations using the principles in Sections5.3 through 5.6. For non-sterile manufacture, the starting point isan ARL in CFU/g or CFU/mL of the next manufactured product. The starting pointfor that ARL value is the bioburden specification of that next product.However, since there are sources of bioburden other than the cleaned equipment (e.g.,from the raw materials of the next product), an adjustment factor is usuallyapplied to the product specification to lower the bioburden ARL. Thesecarryover calculations typically result in SAL values significantly above 10CFU/cm2 or a rinse sampling solution limit significantly above 100CFU/mL. Arisk assessment should be done to determine the acceptability of such values,includingthe nature of the next product (low water activity, which will notallow proliferation in the productvs. high water activity which, withoutpreservatives, will allow proliferation in the next product). The acceptablebioburden level should also take into consideration effects on bioburdenproliferation during the clean hold time. For this reason, many companies willestablish very conservative bioburden limits, such as 1-2 CFU/cm2 for surfacesampling methods and the typical purified water limit of 100CFU/mL for rinsesamples.
考慮清潔之后的生物負(fù)載限度時，不能期望僅依靠清潔過程本身就使設(shè)備達(dá)到無菌狀態(tài)。如果在清潔驗證方案中需設(shè)定生物負(fù)載限度，則可根據(jù) 5.3到5.6節(jié)中的理論，采用殘留物計算方法確定生物負(fù)載限度。對于非無菌生產(chǎn)，首先是確定下一產(chǎn)品的ARL，以CFU/g或CFU/ml為單位。該ARL值是下一產(chǎn)品的生物負(fù)載標(biāo)準(zhǔn)。當(dāng)然，由于除了已清潔設(shè)備，生物負(fù)載還有其他來源（如，來自下一產(chǎn)品的原料），常采用調(diào)整因子對產(chǎn)品標(biāo)準(zhǔn)進(jìn)行調(diào)整，以降低生物負(fù)載ARL。這些殘留物計算通常導(dǎo)致SAL的值遠(yuǎn)高于10CFU/cm2，或沖洗樣品溶液限度遠(yuǎn)高于100CFU/ml。需要進(jìn)行風(fēng)險評估以確認(rèn)這些數(shù)值是否可接受，包括下一產(chǎn)品的特性（低水分活度：這不利于產(chǎn)品中的微生物的繁殖；高水分活度：沒有防腐劑的情況下，微生物將在下一產(chǎn)品中的繁殖）。允許的生物負(fù)載水平還應(yīng)考慮在清潔有效期內(nèi)對生物負(fù)載的增殖有影響的因素，因此許多公司都采用非常保守的生物負(fù)載限度，如對于表面取樣法采用1-2CFU/m2，對沖洗樣品，則通常采用100CFU/mL純化水限度。
However,even if the process equipment is steamed in place or autoclaved prior tomanufacture of the next product, or even if the next product is sterile-filtered,it is typically the practice to evaluate bioburden to establish that thesubsequent process is not overly challenged. Achievement of typical bioburdenlimits for non-sterile manufacturing (1-2 CFU/cm2) is consideredmore than adequate for surface sampling. For rinse sampling that is performedwith WFI, one approach is to utilize typical WFI values (10 CFU/100 mL), whileanother approach is to utilize a value of either 100 CFU/100 mLor 1,000 CFU/100mL. The rationale for the higher limit is that the equipment will besubsequently steamed. Furthermore the WFI value is the value for the WFI in therecirculating loop; once it is removed from that loop and passed through cleanequipment, there is not necessarily an expectation that it will stillmeet the WFI value.
然而，即使在生產(chǎn)下一產(chǎn)品前對工藝設(shè)備進(jìn)行在線或高壓滅菌，或者即使下一產(chǎn)品是除菌過濾過的，通常會評估生物負(fù)載來確定后續(xù)工藝沒有被過度挑戰(zhàn)。非無菌生產(chǎn)的典型的生物負(fù)載限度（1-2CFU/cm2）被認(rèn)為足以用于表面取樣。對于采用WFI沖洗取樣時，一種方法是使用典型的WFI的值（10CFU/100ml），另一方法是使用100CFU/100 mL或1,000 CFU/100 mL其中的一個。使用更高限度的基本原理是該設(shè)備將會被蒸汽滅菌。而且，該WFI的值是WFI在循環(huán)回路中的允許限值，一旦WFI從回路中移出，并轉(zhuǎn)移到清潔設(shè)備中，沒有必要期待它仍然符合WFI的限值。
An additional consideration for bioburden evaluation is the determination ofobjectionable organisms.Objectionable organisms are not necessarily limited tothe USP specified organisms, but include organisms selected based on anunderstanding of the product and manufacturing situation. What makes anorganism objectionable is not just the species, but also the number. The degreeof identification may be identification down to the species level, or it may justinclude methods to exclude objectionable organisms. Furthermore, one approachis to identify all colonies that are found, while another approach is to onlyidentify colonies if the number is above a certain threshold (e.g., 50% of theacceptance limit).
對于生物負(fù)載，另一個需要考慮的是有害微生物的鑒定。有害微生物沒有必要局限于USP中列出的微生物，而是應(yīng)該結(jié)合產(chǎn)品和生產(chǎn)情況確定有害微生物。而判斷微生物是否是有害的也不應(yīng)以種屬作為唯一標(biāo)準(zhǔn)，也要考慮數(shù)量?？梢允氰b定到“種”（備注：界( Kingdom）、門( phylum)、綱(Class)、目 (Order)、科(Family)、屬( Genus)、種(Species)）的級別，也可能只是排除有害微生物的方法。另外，一種方法是鑒別出所有發(fā)現(xiàn)的菌落，另一種是只對數(shù)量超出一閾值的菌落（如可接受限度的50%）進(jìn)行鑒別。
19. EndotoxinLimits
內(nèi)毒素限度
Endotoxincarryover to the final product is a concern for any product with endotoxinspecifications.In this situation, it is common practice to measure endotoxin inthe final rinse water, with limits typically set at the WFI limit of 0.25EU/mL. If the equipment is depyrogenated by heat, endotoxin will be deactivatedand measurement of endotoxin for cleaned equipment may not be required.
對于任何有內(nèi)毒素限度要求的產(chǎn)品，都需要關(guān)注轉(zhuǎn)移至成品的內(nèi)毒素殘留。通常測量最終沖洗水中的內(nèi)毒素，限度通常和WFI標(biāo)準(zhǔn)（0.25EU/mL）相同。如果通過加熱除去設(shè)備上的熱原，內(nèi)毒素將失去活性，則不需要測量已清潔設(shè)備的內(nèi)毒素殘留。
20. VisuallyClean Criterion
目視清潔標(biāo)準(zhǔn)
Visual appearance of production surfaces is a direct measurement that verifies removalof residuals.The most common use of a visually clean criterion is to supplementswab and/or rinse testing for residues for cleaning validation protocols. Insuch cases, it is common practice not to establish a quantitative visuallimit.
對生產(chǎn)表面的目檢是確認(rèn)殘留去除的直觀方法。通常，目檢在清潔驗證方案中作為擦拭法或沖洗水法檢測殘留的一種補(bǔ)充。此時，通常不需量化目檢限度。
Ifvisual examination is used without swab and rinse sampling, it is requiredto establish a quantitative visual limit for a residue on aspecified surface under specified viewing conditions. If visual examination supplementsswab and/or rinse sampling, such a visual limit determination may bedone to further refine and/or limit what visually clean means. A discussion ofthat methodology for establishing a visual limit is given in Section 7.7.3. Providedthe quantitative visual limit is more stringent than a SAL carryoverlimit (see Section 5.5) and provided that the equipment surfaces can beviewed in the cleaning validation protocol under conditions that are the sameor more stringent than the viewing conditions established for the quantitativelimit, then this visually clean criterion may be used without swab or rinsesampling. If this approach is used, a second-person verification in protocolexecution should be utilized. Typical visual limits reported in the literatureare 1-4 μg/cm2. However, it should be recognized that this limitdepends on factors or conditions such as the nature of the residue, the natureof the surface, the lighting, the distance of viewing, the angle of viewing,and the visual acuity of the operator.
如果沒有擦拭取樣或沖洗水取樣，僅使用目視檢查，則需要量化指定表面上殘留的目檢限度，并說明具體觀察條件。如果目檢作為擦拭或沖洗水取樣的補(bǔ)充，則確定目檢限度可以明確和/或限制目視清潔的具體含義。關(guān)于設(shè)定目檢限度方法的討論詳見7.7.3節(jié)。假如量化的目撿限度比SAL限度（見5.5節(jié)）更嚴(yán)格，同時假如清潔驗證方案中設(shè)備表面的目檢條件同建立量化限度時的目檢條件相同或更苛刻，則可采用該目視清潔標(biāo)準(zhǔn)而無需進(jìn)行擦拭或沖洗取樣。如果采用該方法，在方案執(zhí)行時需要另一個人進(jìn)行目檢的確認(rèn)。通常文獻(xiàn)中的目撿限度是1-4 μg/cm2。當(dāng)然，該限度受許多因素或條件影響，如殘留特性，表面特性，燈光，觀測的距離，觀測角度以及觀測人員的視力情況。
The requirement for “visual cleanness” usually applies to equipment surfaces. It is not necessarily a requirement that swabs be visually clean after a surface is swabbed, due to the fact that residue which is not visible on a larger surfacemay become “visible” when concentrated on the smaller area of the swab head.
“目視潔凈”的要求通常應(yīng)用于設(shè)備表面。沒有必要要求設(shè)備表面擦拭后拭子本身也是“目視清潔”的，因為在更大的表面上看不到的殘留，可能由于聚集在拭子頭部而變得“可見”了。
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