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.
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.
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.
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].
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.
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.
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.).
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.
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).