4.2.5.1. Setting Acceptance Criteria for Swab Limits 对擦拭限度设定可接受标准
For each item tested, the following acceptance criteria (AC) apply.
以下可接受标准适用于各测试项目：
AC1. The cleaning result of an individual part should not exceed the maximum expected residue.
单个设备清洁结果应不超过最大可接受残留量。
AC2. For the total equipment train the MACO must not be exceeded.
总设备链的MACO不得超过。
In determining acceptance limits, all possible cases of following products in the relevant equipment shall be taken into account. It is proposed that a matrix be set up in which the limits for all cases are calculated. Either acceptance criteria for each product in the equipment can be prepared or the worst case of all product combinations may be selected.
在制订可接受限度时，要考虑在相关设备中可能生产的所有后续产品。建议画出矩阵图，在其中对所有情况下的限度进行计算，然后针对在该设备中生产的每个产品分别制订可接受标准，也可以对所产品选择最差情况下的可接受标准。
4.2.5.2. Evaluation of results 结果评估
When all surfaces have been sampled and the samples have been analyzed, the results are compared to the acceptance criteria. Companies may find it easier to evaluate against the MACO. However, it is advisable to have a policy for swab limit as well. Especially because analytical methods are validated within a certain range for swab results. Another reason is that some pieces could be very contaminated, and it is not good practice to clean certain pieces very thoroughly in order to let others be dirty. Thus, limits for both MACO and swabs should be set.
在对所有表面取样后，对样品进行分析，将结果与可接受标准进行比较。公司可以发现采用MACO来评估会比较容易。但是，还是建议对于擦拭限制订一个原则，主要是因为擦拭样品分析方法的验证是在一定的浓度范围内进行的。另一个原因是有一些部件的污染可能会比较严重，没有理由让一些部件清洁的非常彻底而让另一些部件很脏。因此，应同时设定MACO限度和擦拭限度。
4.2.6. Rinse Limit 淋洗限度
The residue amount in equipment after cleaning can also be determined by taking rinse samples. During equipment qualification it should be established that all direct content parts of the equipment is wetted / reached by the rinsing solvent. After the last cleaning cycle (last rinse), the equipment should be assessed as ‘clean’. In some cases it may be advisable to dry the equipment in order to do a proper assessment. Thereafter, the rinse cycle can be executed, and a sample taken (sampling rinse). The procedure for the rinse cycle and sampling should be well established and described to assure repeatability and comparability (cycle times, temperatures, volumes, etc.). The choice of the rinse solvent should be established during cleaning validation, taking into account solubility of the contaminations, and reactivity of the rinse solvent towards the contaminants (saponification, hydrolyses, etc). Method validation is needed.
设备清洁后的残留量也可以采用淋洗样来检测。在设备确认时，应该识别出设备中所有可以被淋洗溶剂淋到的部件。在最后清洁（最后淋洗）结束后，设备状态应评估为“清洁”方可取样。有时，需要对烘干设备以便进行适当的评估。之后，对设备进行淋洗，取样（淋洗样）。应制订书面程序描述淋洗和取样操作，以保证其可重复性和可比较性（重复次数、温度、体积等）。在清洁验证时应对淋洗用溶剂作出选择，选择时应考虑污染物的溶解度，以及淋洗用溶剂与污染物之间的反应活性（皂化反应、水解反应等）。淋洗方法要进行验证。
In a worst case approach, the amount of the residue in the equipment can be assumed to be equal to the amount determined by analysis of the rinse sample. This can be supported by rinse studies that show a strong decay of a residue in a piece of equipment.
如果采了最差情形方法，可以假定设备中的残留量与对淋洗样品的检测结果相等。这个假设可以通过对一个设备部件上淋洗前后残留物急剧减少来支撑。
The MACO is usually calculated on each individual product change over scenario according to the procedures outlined above and individual acceptance criteria are established using the following equation:
通常根据上述所列的方法，针对各个产品更换的情况计算MACO。采用以下公式，可以计算出单个可接受标准：
Target value (mg/L) = MACO (mg) / Volume of rinse or boil (L)
目标值 = MACO/淋洗溶剂体积
For quantitation a solvent sample (e.g. 1 L) is taken, the residue in the sample is determined by a suitable analytical method and the residue in the whole equipment is calculated according to the following equation:
对于一定的取样体积（例如1升），采用适当的分析方法测定样品中的残留量，根据以下公式计算整个设备中的残留量：
M = V*(C-Cb)
M | Amount of residue in the cleaned equipment in mg | 已清洁设备中的残留总量 |
V | Volume of the last rinse or wash solvent portion in L | 最后淋洗或冲洗溶剂的体积 |
C | Concentration of impurities in the sample in mg/L | 样品中杂质浓度 |
Cb | Blank of the cleaning or rinsing solvent in mg/L. If several samples are taken during one run, one and the same blank can be used for all samples provided the same solvent lot was used for the whole run. | 空白淋洗或冲洗溶剂 如果在一个轮次中取了几个样品，则可以采用其中一个空白用于该轮中所有样品的计算 |
Requirement: M < Target value.
要求：M < 目标值
The requirement is that M < target value. If needed, the sample can be concentrated before analysis.
要求是M < 目标值。那天要时，样品在检测前可以浓缩。
The choice for swab or rinse sampling usually depends on the type of equipment. Areas to be swabbed are determined during equipment and cleaning validation (‘hard to clean areas’), and are preferably readily accessible for operational reasons,e.g. near the manhole. If swabbing of the indicated area is not easy, rinse sampling is the alternative. The advantage is that the whole surface of the equipment is sampled for contamination, being provided that during equipment qualification, surface wetting testing was taken into account. Thus equipment used for milling, mixing, filters, etc. are usually swabbed, whilst reactor systems are usually sampled by rinsing.
选择擦拭样品还是淋洗样品通常取决于设备的类型。擦拭取样点应在设备验证和清洁验证中确定（难以清洁点），最好还要易于操作，例如接受人孔处。如果要取样的地方很难采用擦拭取样，可以采用淋洗取样。淋洗取样的优点是设备的整个表面都能被取样测试污染程度。淋洗取样时，要考虑表面润湿测试，该测试应在设备确认期间完成。鉴于此，用于粉碎、混合、过滤等的设备一般采用擦拭取样，而反应釜系统一般采用淋洗取样。
4.2.7 Rationale for the use of different limits in pharmaceutical and chemical production 在药品和化学生产中使用不同限度的合理性
Unlike in pharmaceutical production, where residues on the surface of equipment may be 100 % carried over to the next product, in API production the carry-over risk is much lower for technical and chemical manufacturing reasons. Thus higher limits may be acceptable in chemical production compared to pharmaceutical production. For example chemical processing steps often include dissolution, extraction and filtration steps that are likely to reduce significantly any residue left from previous production and cleaning operations. A factor of 5-10 could be applied to the MACO calculated using the Acceptable Daily Exposure Limit or the secondary criteria defined in the previous sections.
在药品生产中，设备表面残留可能会100%被带入下一产品。与之不同的是，在原料药生产中，由于技术和化学生产原因，残留带入风险要低很多。因此，与药品生产相比，在化学生产中采用较高的残留限度是可以接受的。例如，化学工艺步骤经常包括溶出、提取和过滤，这些步骤可能会显著降低上一产品和清洁操作所残留的东西。如果采用ADEL值计算MACO，则可以使用5-10的安全系数，或者采用上述部分中界定的中等标准。
In all cases, the limits should be justified by a competent chemist with detailed knowledge about the equipment and the chemical processes, following Quality Risk Management Principles and the limits should be approved by Operations and Quality Assurance Managers.
在所有情况下，所有的限度均应由具备资质的化学家进行论证。他应该具备关于设备和化学工艺的知识，遵守质量风险管理原则。所制订的限度应由操作和质量保证经理批准。
The following description shows an example where the carry-over risk for a residue in chemical production equipment is much lower than in pharmaceutical production equipment.
以下例子说明了在化学生产设备中，其残留的带入风险比药品生产设备要低很多。
Assuming that the common criteria (ADE, 1/1000th dose, LD50 NOEL/ADI with SF 100-1000, 10 ppm) represent the state of the art for pharmaceutical production and are considered sufficiently safe, then the calculation of limits in API manufacture must reflect the different processes in pharmaceutical production and in the chemical production of active pharmaceutical ingredients to allow comparable risk analyses to be undertaken.
假定常用标准（ADE，1000分之一剂量，LD50 NOEL/ADI安全系数100-1000，10ppm）代表药品生产理想状态，被认为是足够安全的，这时原料药生产中的限度计算必须反映化学原料药生产与药品生产工艺的不同，使得可以进行风险分析比较。
Pharmaceutical production, Chemical production physical process 药品生产、化学生产的物理处理
In pharmaceutical production a residue remaining on the surface of equipment after cleaning is, in the next production cycle, distributed in a mixture of active substance and excipients if it does not remain on the surface. In the worst case it will be 100 % transferred to the first batch of next product.
在药品生产中，清洁后残留保存在设备表面，在下一个生产循环中，如果这些残留不再停留在设备表面，则会分布在原料药和辅料的混合物中。最差情况是这些残留100%地被带入下一产品的第一个批次。
Chemical production/processing 化学生产/工艺
In chemical production a 100 % carry-over of residue from the equipment surface to the next product to be manufactured is very unlikely based on the way the process is run and on technical considerations. The residue remaining on the equipment surface can, during the next production cycle, be carried over into the reaction mixture consisting of solvent and raw materials. In most cases, however, any residue in solution will be eliminated from the process together with the solvent, and insoluble residue by physical separation processes (e.g. filtration), so likely carry over into the end-product will be low.
在化学生产中，考虑到工艺运行的方式，以及技术问题，残留物被100%地从设备表面带入下一产品中的情形不太可能发生。残留在设备里的东西，在下一生产循环中，会被带入溶剂和原料所组成的混合反应液中。在大多数情况下，所有溶液中的残留都会与溶剂一起被从工艺中去除，不溶性残留会被物理分离工艺（例如过滤）减少，因此，可能被带到最终产品中的残留会很低。
The final step in a multi-step chemical synthesis is selective purification of the API (e.g. by crystallization), during which contaminants are removed from the process and/or insoluble residues are removed by physical separation). From the original reaction mixture of educt, agent and solvent there remains only a fraction of the original mass as API at the end of the chemical process.
在多步化学合成的最后一步，一般是原料药选择性精制（例如，通过结晶方式）。在精制过程中，污染物被从工艺中去除，不溶性残留被物理分离所去除。在经过这些化学工艺后，原来那些由离析物、试剂和溶剂所组成的混合反应液只剩下一些原来物质的片断，在最后成为原料药。
【译者：第一句有一个半括号，原文如此】
It is also to be noted that, during subsequent pharmaceutical production, the API is further diluted through the excipients that are added.
还要注意的一点是，在后续的药品生产过程中，原料药通过加入辅料被进一步稀释了。
Conclusion: 结论
Assuming that there is no intention to impose more stringent yardsticks during API production than in pharmaceutical production but that they should be approximately the same, the logical conclusion is that the limits in chemical production should be set higher than in pharmaceutical production. Based on this rationale, a factor of 5 - 10 compared to the established pharmaceutical production limits is both plausible and, in terms of pharmaceutical risk, acceptable.
假定我们并无意将比药品生产更严格的标尺强加给原料药生产，而只是要将它们保持大致相同，则从逻辑上得到的结论就是在化学生产中的限度应该设定得比药品生产中的限度要高。基于此理论，相比于已建立的药品生产限度，对原料药生产采用5-10的安全系数既貌似合理，从药品风险角度来说，也是可以接受的。
Chemical production “physical processes” (drying, mixing, filling, ...)化学生产的“物理处理”（干燥、混合、充填……）
Apparatus and equipment that is used for physical end-treatments such as drying, mixing or milling may either be operated together with the previous synthesis equipment or generally be used separately. During separate physical end-treatments of APIs, there is no decrease of contaminants compared to the aforementioned chemical process. Consequently, we recommend in this case that the calculation methods applied should be those normally used in pharmaceutical production, (ADE, 1/1000th dose, LD50 NOEL/ADE with SF 100-1000, 10 ppm). The Limits for carry over into the final API should be the same as those calculated in the previous sections.
用于最终物理处理，如干燥、混合或磨粉，的设备仪器，可以与之前的合成设备一起使用，通常是单独使用。在原料药单独的物理最终处理过程中，与之前提到的化学过程相比，其污染物不会减少。因此，我们推荐在这种情况下，应采用制剂产品中常用的计算方法（ADE、千分之一剂量、半数致死量、NOEL/ADE和安全系统 100-1000、10ppm）。带入最终原料药的残留量限度应与之前各部分所计算的相同。
ANNEX 1: Examples of MACO calculations.
附录1：MACO计算的例子
Example 1: ADE calculation
例1：ADE计算
Product A has a NOAEL70kg of 100 mg/day human oral dose. Uncertainty factors applied to calculate the ADE are an UFS of 3 (extrapolation from an acute dose to subchronic/chronic dosing) and UFH of 8.13 (the inter-individual variability based upon a PK (kinetic component) of 2.54 and PD of 3.2 (dynamic component)). The MF is 10 (extrapolation from a ‘generally healthy’ population to a more susceptible sick patient population). Product B is an oral product (PK = 1).
A产品NOAEL70kg人类口服剂量为100mg/天，用于计算ADE的不确定因子UFS为3（从急性剂量到亚慢性/慢性给药外推得到），UFH为8.13（根据PK（动力学组成）为2.54和PD为3.2（动力学组成）所得的内在个体变化）。MF为10（从“一般健康”人群外推至易感人群）。
产品B为口服产品（PK = 1）.
ADE = | 100（mg/day） | = 410（μg/day） |
3×8.13×10×1 |
Result: ADE oral is 410 μg/day
结果：口服ADE值为410μg/天
If product B is a parenteral product and the PK is 62.5 (based upon an oral bio-availability study in human after parenteral).
如果产品B是一个注射产品，PK值为62.5（基于人体注射后的口服生物利用度研究）
ADE = | 100（mg/day） | = 6.6（μg/day） |
3×8.13×10×62.5 |
Result: ADEparenteral is 6.6 μg/day
结果：注射ADE值为6.6μg/天
Example 2: ADE calculation
例2：ADE计算
A teratogenic product A has a LOAEL of 1 mg/kg.day human oral dose (BW is 70 kg). Uncertainty factors applied to calculate the ADE are an UFL of 3 (extrapolation from LOAEL to NOAEL), an UFH of 10 (the inter-individual variability) and a MF of 10 (severity of effect: teratogenicity). Product B is an oral product (PK = 1).
ADE = | 1（mg/kg day）× 70kg | = 231（μg/day） |
3×10×10×1 |
Result: ADEoral is 231μg/day.
结果：口服ADE值为231μg/天。
Example 3: Acceptance criteria based on Acceptable Daily Exposure
例3：根据可接受日暴露值计算可接受标准
Product A will be cleaned out. The product has an ADE of 2 mg and the batch size is 200 kg. The next product B has a standard daily dose of 250 mg and the batch size is 50 kg. Calculate the MACO for A in B.
产品A要被清洁，其ADE值为2mg，批量为200kg。
下一产品B标准日剂量为250mg，批量为50kg。
计算A在B中的允许最大残留量。
MACO = | 0.002（mg）× 50 000 000 (mg) | = 400(mg) |
250 (mg) |
Result: MACO is 0.4g (400mg).
结果：允许最大残留值为0.4g（400mg）。
Example 4: Acceptance criteria based on Therapeutic Daily Dose
例4：根据日治疗剂量计算可接受标准
Product A will be cleaned out. The product has a standard daily dose of 10 mg and the batch size is 200 kg. The next product B has a standard daily dose of 250 mg and the batch size is 50 kg. Both A and B are administrated orally and SF is set to 1000. Calculate the MACO for A in B.
产品A要被清洁，其标准日剂量为10mg，批量为200kg。
下一产品B标准日剂量为250mg，批量为50kg。
A和B都是口服摄入，安全系数SF设定为1000。
计算A在B中的最大允许残留量MACO。
MACO = | 10（mg）× 50 000 000 (mg) | = 2000(mg) |
1000 × 250 (mg) |
Result: MACO is 2g (2000mg).
结果：允许最大残留值为2g（2000mg）。
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