制药企业清洁验证中对API生产中清洁的特殊考虑

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制药企业清洁验证中对API生产中清洁的特殊考虑
10.7Cleaning for API Manufacture
API生产的清洁
Equipmentfor multiproduct intermediate and API manufacturing can be exposed to a largevariety of substances and agents (e.g., solvents, reagents, catalysts, cellcultures and processing aids). Detailed written procedures should beestablished to enable effective and reproducible cleaning of these residues andsubsequent release of the equipment for next use. Acceptance criteria forresidues and the choice of cleaning procedures and cleaning agents should bejustified on the basis of being practical, achievable and scientifically sound.For equipment producing later stage intermediates and final APIs, cleaning procedureswill therefore need to be developed and validated to remove manufacturingresidues that may include raw materials, un-isolated intermediates,by-products, degradants and the product itself. It should be noted thatequipment used solely for some raw materials that are Generally Recognized as Safe(GRAS) and for raw materials or intermediates, visual inspection alone may beappropriate if all parts of the equipment are visually inspectable. For APImanufacturing, lack of adequate cleaning may impact not only potential crosscontamination of the next product, it may also impact the processing of thenext product (e.g., if residual materials interfere with subsequent processreactions).
用于生产多品种中间体和API的设备会暴露于不同的物质和试剂(例如:溶剂、试剂、催化剂,细胞培养物和工艺助剂)中。

应该建立详细的书面程序,以有效和重现地清洁残留,并放行设备用于下一次使用。

残留物的可接受标准以及清洁程序和清洁剂的选择,应该具
有实用性、可实现性和科学合理性。

对于用于生产后一阶段的中间体和最终API的设备,需要开发并验证清洁程序,以去除生产残留,可能包括原材料、未分离的中间体、副产物、降解产物和产品本身。

应该注意的是,对于专用于那些通常被认为是安全的原料(GRAS)、其他原料或中间体的设备,如果该设备的所有部分都可以目测检查,则可仅进行目视检查。

对于API生产,缺少合适的清洁会导致下一个产品潜在的交叉污染,还会影响下一个产品的加工(例如,残留物质干扰随后的工艺反应)。

Theneed for limits for residual organic solvents should be evaluated and canutilize a risk assessment. For example, some residual organic solventsevaporate upon drying of the equipment. If there are measures in place (e.g.,equipment drying or flush with next process solvent) that may mitigate the riskfor residues of residual solvents then analytical limits may not be necessary.If necessary, limits for residual organic solvents may be derived from ICH Q3guidance (19). Limits for other residues expected to be presentafter cleaning must also be established. For some residues, such as earlierintermediates, dose, toxicity, or acceptable daily intake information may notbe established or available. For other residues, such as proteins or unstableresidues, degradation may occur to produce multiple other residues, some ofwhich may not be characterized. For these cases, other approaches to the establishmentof limits may be necessary. Industry benchmarking data may be used to determineif there are common limits applied for these cases. For any limits approachused, the rationales and risk assessments used to establish that approachshould be documented and approved.
应采用风险评估评价是否需要建立有机残留溶剂限度。

例如,设备干燥时,一些残留溶剂会挥发。

如果有措施(例如,设备干燥或用
下一种工艺溶剂冲洗)可以减轻溶剂残留的风险,那就没有必要建立分析限度。

如有必要,残留溶剂的限度可根据ICHQ3指导原则(19)得出。

应建立清洁后其他可能存在残留的限度。

对于一些残留,例如,较早的中间体,也许没有剂量、毒性或可接受的日摄入量信息。

对于其他残留,例如,蛋白质或不稳定残留,可能会降解产生其他多种残留,其中一些可能无法鉴别。

对于这些情况,需要采用别的方法建立限度。

工业基准数据可以用于确定这些情况是否可以采用通用的限度。

对于所采用的任何限度建立方法,应记录该方法建立的依据和采用的风险评估,并得到批准。

Facilitiesand manufacturing systems for intermediates and APIs should be designed tofacilitate cleaning as appropriate to the type and stage of manufacture.Equipment used for API manufacturing is often large, closed and complex. Itoften includes a significant amount of process piping and large-scale vessels,dryers, condensers and/or chromatography columns. For this reason, visualinspection of much of the equipment may not be possible due to inaccessibility.Equipment design for cleanability is a significant factor in the ease andreproducibility of cleaning for these types of large closed systems. Designfactors of particular importance can include equipment and pipe sloping fordrainage, elimination or minimization of deadlegs, adequate pump size forturbulent flow of cleaning solutions, and the use of spray coverage devices.
根据生产类型和生产阶段,中间体和API的厂房和生产系统的设计应该便于清洁。

用于API生产的设备通常较大、密闭而复杂。

通常包括大量的工艺管道和大体积容器、干燥器、冷凝器和/或层析柱。

由于无法接近,不太可能对大部分设备进行目测。

对于这类大型密闭系统,设备的可清洁性设计对于清洁的重现性和简易性是非常重要的。

尤为重要的设计因素包括设备和排水管道的坡度、盲管的消除和最小
化、适当的泵体积以使清洁溶液处于紊流状态、以及喷淋装置的使用。

Qualityrisk-assessments should be used to determine the need for microbiologicalspecifications (ifany) after cleaning, if any. The harsh chemical environment(e.g., pH extremes, use of organic solvents, high temperature processes) thatis often associated with small-molecule intermediate and API manufacture mayeliminate the risk to product quality from microbiological proliferation. Wheremicrobiological specifications have been established for the cleaning,facilities should be designed to limit exposure to objectionablemicrobiological contaminants. Equipment cleaning and/or sanitation studiesshould address microbiological and endotoxin contamination for those processeswhere there is a need to reduce total microbiological count or endotoxins inthe API or other processes where such contamination could be of concern (e.g.,aqueous-based processing of non-sterile APIs used to manufacture sterileproducts).
应该采用质量风险评估以确定是否需要建立清洁后的微生物质量标准(如果有)。

小分子中间体和API生产中苛刻的化学环境(例如:极端的pH,有机溶剂的使用,高温处理),可以消除由于微生物繁殖导致的产品质量风险。

如果已经建立了清洁后的微生物质量标准,设施的设计应能避免致病微生物污染。

对于那些需要降低API中微生物总数和内毒素的工艺或其他需要关注此类污染的工艺(例如用于生产无菌药品的非无菌API采用液体工艺生产),设备清洁和/或卫生研究应该包含微生物和内毒素污染的研究。

Cleaningvalidation at product changeover should be directed to situations or processsteps where contamination or carryover of materials poses the greatest risk toAPI quality (34).
Cleaning validation is typically performed onequipment used to produce later stage intermediates and APIs. SeeICH Q7 Table 1for guidance on where cleaning validation may be expected (34).For equipment used in early intermediate production, it may be unnecessary tovalidate equipment cleaning procedures.In these cases, cleaning verificationfor multipurpose equipment is still required. Validated analytical methods usedto verify the equipment cleaning should be used. If product/processing residuesare demonstrated to be removed by subsequent purification steps, this may beconsidered in a documented risk assessment to determine the level of cleaningand cleaning validation necessary.
在更换产品时的清洁验证应该关注那些物料携带或污染会给API 质量带来最高风险的情况或工艺(34)。

清洁验证通常在生产较后阶段中间体和API的设备上进行。

对于何时进行清洁验证,见ICHQ7表1(34)。

对于前一阶段中间体生产的设备,没有必要验证这些设备的清洁程序。

在这些情况下,需要对共用设备进行清洁效果确认。

用于确认设备清洁效果的分析方法应经过验证。

如果产品/工艺残留被证明可以通过后续的纯化步骤去除,应在书面的风险评估中予以考虑,并确定清洁的程度和所需的清洁验证。

Cleaningprocedures should be monitored at appropriate intervals after validation toensure that they remain effective when used during routine changeovers.Depending on equipment design and complexity, it is typical for API equipmentcleanliness to be routinely monitored by analytical testing and/or visualexamination, where feasible, after each cleaning after cleaning validation iscompleted.This is often associated with the higher risk of some API cleaningcircumstances (e.g., large closed equipment that cannot
be easily visuallyinspected and the fact that contamination of one batch of API can oftenimplicate many batches of drug product). This routine cleaning monitoring aftereach campaign for multipurpose equipment is often accomplished via rinsesampling and testing for large closed equipment.
在验证以后应定期对清洁程序进行监控,以确保例行更换品种时,清洁程序仍然有效。

基于设备设计和复杂性,在清洁验证后的每一次清洁后,通常应采用分析测试和/或目测检查,对API设备的清洁状况穾进行例行监控。

这通常关系到较高风险的一些API清洁环境(例如大的密闭设备,不易目测检查,而且每批API的污染会影响很多批的制剂)。

对于共用设备每次阶段性生产后的例行清洁监控通常通过对大型密闭设备冲洗取样和检测来完成。

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