发布时间 : 星期五 文章APIC 201405原料药厂清洁验证指南：4.0可接受标准更新完毕开始阅读
(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 V Volume of the last rinse or wash solvent portion in L C Concentration of impurities in the sample in mg/L 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.
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。
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 样品中杂质浓度 最后淋洗或冲洗溶剂的体积 已清洁设备中的残留总量 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.