ISPE：清洁验证

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2021-03-22   环球过滤分离技术网   guolvfenlitech6

在制药行业中，清洁验证的实施已经进行了数十年。尽管对于每个药企，达到清洁要求而使用的清洁工艺会有所不同，但在一些共同领域都存在着不小的挑战。

今年8月，ISPE发布了清洁验证方面新的指南，名为“清洁验证生命周期——应用、方法和控制”。在该指南中对于这些共同领域进行了总结，并表示在制定全面的清洁计划时，应考虑这些领域。

1. 基于健康的暴露限度（HBEL）

Health-Based Exposure Limits (HBEL) – The establishment of cleaning limits using a HBEL approach is the recommended guidance for setting safe residue limits . However, there are several situations where alternate approaches for scientifically based limits are required. For example, actives manufactured from biological processes are usually inactivated, denatured, or degraded when strong cleaning processes are used. An appropriate HBEL may not be available to describe the safety risks of the resulting fragments or degradation products.  In addition, development of an Investigational Medicinal Product (IMP), or during early clinical batch production, may lack HBEL-specific information. Furthermore, legacy facilities may not use HBELs as part of their cleaning programs. The transition from traditional approaches to a HBEL-based cleaning program needs to be achieved.

使用HBEL方法建立清洁限度是设置安全残留限度的建议指导。但是，在某些情况下，需要采用替代方法来实现基于科学的限度。例如，当使用强力清洁工艺时，由生物工艺生产的活性物质通常会灭活、变性或降解。可能没有合适的HBEL来描述所得片段或降解产物的安全风险。此外，研究用药品（IMP）的开发或在早期临床批生产过程中，可能缺少HBEL特定信息。此外，传统设施可能不会将HBEL用作其清洁计划的一部分。需要实现从传统方法到基于HBEL的清洁计划的过渡。

2. 腐蚀管理

The corrosion of metal surfaces may reach a point where the established cleaning process is affected. Corrosion may also affect the formation of biofilms, as an increase in roughness may reduce the cleanability of the surface and promote biofilm formation. Each company should have a system to manage metal corrosion (e.g., rouge issues). Corrosion levels that can affect the performance of the validated cleaning process are those that release metal particles into the process, change the color of the rinse/swab samples, cause a failure of visual inspection, or change the equipment surface characteristics making it harder to clean. Monitoring vessel product contact surfaces and using visual inspection criteria to identify corrosion on surfaces should be part of the controls to manage this issue. Other preventive measures (e.g., periodic passivation or chemical treatments) should be considered for corrosion prone or critical equipment.

金属表面的腐蚀可能会影响已建立的清洁工艺。腐蚀还可能影响生物膜的形成，因为粗糙度的增加可能会降低表面的清洁性，并促进生物膜的形成。每个公司都应该有一个系统来管理金属腐蚀（例如，锈蚀问题）。可能影响已验证清洁工艺性能的腐蚀水平是指：将金属颗粒释放到工艺中、改变冲洗/擦拭样品颜色、导致目检失败或改变设备表面特性使其难以清洁的腐蚀水平。监测容器产品接触表面、并使用目检标准识别表面腐蚀，这应作为控制措施的一部分，以管理该问题。对于易腐蚀或关键设备，应考虑采取其他预防措施（例如，定期钝化或化学处理）。

Furthermore, plastic surfaces may be impacted by chemical attack causing cleaning surface degradation, and glass surfaces may be subject to oxidative attack and delamination. Similar controls to the ones in place for corrosion management should be applied where necessary to ensure consistent and effective cleaning.

此外，塑料表面可能受到化学侵蚀的影响，导致清洁表面降解；玻璃表面可能受到氧化侵蚀和发生分层现象。必要时，应采用与腐蚀管理相似的控制措施，以确保清洁一致和有效。

3. 手工清洁工艺

The reproducibility of manual cleaning processes represents a challenge to validate due to the variability of manual steps. Manual processes should be described in detail and designed in a robust way to ensure that the cleaning objectives are reached despite the variability in application. Operators should be trained and periodically assessed to prevent drifting of manual cleaning techniques or skills that may impact the final residue levels. Approaches such as alternating cleaning agents, extended cleaning times, or increased concentration of cleaning agents should be considered during the development of the cleaning process to improve process robustness. The reproducibility required for manual cleaning is more achievable with higher PDE/ADE products than with lower ones. It may not be possible to validate manual cleaning processes at the levels required for low PDE/ ADE products, or at least extensive (and potentially prohibitive) work may be required. As such, consideration should be given to automated cleaning to allow greater consistency, or to dedicated equipment for these products.
由于手动步骤的变异性，手动清洁工艺的重现性成为验证的挑战。应详细描述手动工艺，并以稳健的方式设计，以确保尽管应用存在变异性，但仍可达到清洁目标。应对操作人员进行培训、并定期进行评估，以防止可能影响最终残留水平的手动清洁技术或技能出现波动。在清洁工艺开发过程中，应考虑交替使用清洁剂、延长清洁时间或增加清洁剂浓度等方法，以提高工艺耐用性。与较低的PDE / ADE产品相比，较高的PDE / ADE产品更可实现手动清洁所需的重现性。可能无法以低PDE / ADE产品所需的水平来验证手动清洁工艺，或者可能至少需要进行大量的（且可能是不可行的）工作。因此，应考虑自动清洁以提高一致性，或考虑这些产品的专用设备。手动清洁程序参数设置示例参见附录6。

4. 生物残留物的积累

Clean in Place (CIP) systems may require occasional manual scrubbing of surfaces or the use of alternate cleaning agents to remove residues deposited from some biological processes. If left unattended, the residues may accumulate and affect the cleaning performance. Users should assess the risk of biological residue removal techniques and consider the formation of persistent residue deposits during cleaning process development, and ensure the process and frequency of residue removal is properly documented. Appropriate visual inspection criteria to determine the presence of biological residues should be included in the cleaning procedures of equipment impacted by these types of residues. Enzymatic degradation or manual cleaning steps should be considered in the cleaning process procedure [8].

在线清洁（CIP）系统可能需要偶尔手动擦洗表面，或使用替代清洁剂去除某些生物工艺中沉积的残留物。如果无人关注，残留物可能蓄积并影响清洁性能。用户应评估生物残留物清除技术的风险，并在清洁工艺开发过程中考虑持久性残留物的形成，并确保正确记录残留物的清除工艺和频率。在受这些类型残留物影响的设备的清洁程序中，应包括适当的目检标准，以确定是否存在生物残留物。清洁工艺程序中应考虑酶促降解或手动清洁步骤[8]。

5. 生物膜的形成

Biofilms can be a persistent problem in GMP water systems, facilities, and some processes based on continuous manufacturing. Biofilm is the accumulation of microbial cells to a surface forming a film or layer of extracellular material. Prevention of biofilms, as well as their formation and removal from equipment surfaces, need to be considered during cleaning process development. Biocides and other sanitizing agents are used to prevent biofilm formation.

在GMP水系统、设施和一些基于连续生产的工艺中，生物膜可能是一个持续存在的问题。生物膜是指微生物细胞聚集到表面，形成细胞外物质的膜或层。在清洁工艺开发过程中，需要考虑防止生物膜的形成，以及从设备表面清除。使用杀菌剂和其他消毒剂防止生物膜形成。

6.气/液界面

Many processes leave residues at the air/liquid interface of vessels. If these residues are not removed, they will start to accumulate and affect the cleaning validation status of the equipment. Removal of air/liquid interface residues should be considered during the development of cleaning processes. These residues should also be removed manually when first detected, and until a validated effective cleaning process is implemented.

许多工艺会在容器的气/液界面留下残留物。如果不清除这些残留物，它们将开始积累并影响设备的清洁验证状态。在开发清洁工艺时，应考虑去除气/液界面残留物。第一次检测到这些残留物时也应手动清除，直到实施经过验证的有效清洁工艺为止。

7. 复杂系统的维护

Highly automated systems require all components to work properly. System reliability becomes a challenge if individual components considered single points of failure start to fail (e.g., steam traps, gaskets use life). A risk assessment is recommended to evaluate which components should be emphasized in the maintenance reliability program and maintenance schedules (frequency of failure of components, useful life of gaskets in contact with product, etc.).

高度自动化的系统要求所有组件正常工作。如果认为单个故障点的单个部件开始失效（例如，蒸汽捕集器、垫圈使用寿命），则系统可靠性将成为挑战。建议进行风险评估，以评价维护可靠性计划和维护计划中应强调哪些组件（部件故障频率、垫圈与产品接触的使用寿命等）。

8. 排水性能

Complex systems need to ensure full drainability of liquids after cleaning to ensure adequate Clean Hold Times (CHTs) and appropriate bioburden controls. Cleaned equipment intended for storage should be dried, usually accelerated by the use of Clean, Dry Air (CDA) (filtered air or nitrogen) after draining the system. Manual methods are commonly employed such as using a cloth or alcohol wipes, although these may be less reliable or not feasible for hard-to-reach surfaces.

复杂系统需要确保清洁后液体的完全可排水性，以确保足够的清洁放置时间（CHT）和适当的生物负荷控制。用于储存的已清洁设备应干燥，通常在系统排空后，使用洁净干燥空气（CDA）（过滤空气或氮气）加速干燥。采用手动方法，如使用布或酒精擦拭布，是非常常见的，尽管这些方法对于难以触及的表面可能不太可靠或不可行。

9. 法规的一致性

The developments in MRA between major regulatory agencies should drive toward greater harmonization of requirements and expectations. Cleaning validation can benefit from further alignment regarding the establishment of cleaning limits and overall management
of a compliant cleaning program. During 2015, the PIC/S GMP Guide Annex 15  was harmonized with EudraLex Annex 15  to adopt HBEL as the basis for scientifically justified safe residue limits.

主要监管机构之间互认协议（MRA）的发展将推动对监管要求和期望的更大协调。这将有助于清洁限度的确定和合规清洁程序整体管理的进一步调整，清洁验证可受益于此。2015年，PIC / S GMP指南附录15 与EudraLex附录15 保持一致，采用HBEL作为科学合理的安全残留限度的基础。

参考：

Cleaning Validation Lifecycle Applications, Methods, and Controls. August, 2020. International Society for Pharmacoepidemiology (ISPE).


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