Points to consider when including Health-Based Exposure Limits (HBELs) in cleaning validation
1. Introduction and background:
The World Health Organization (WHO) has published the guideline entitled Good manufacturing practices for pharmaceutical products: main principles in the WHO Technical Report Series, No. 986, Annex 2, 2014 (1).
The WHO Supplementary guidelines on good manufacturing practice: validation were published in 2006 and were supported by seven appendices. The main text (2) and its appendixes (3, 4, 6, 7, 8, 9) were revised between 2006 and 2019. Appendix 3, relating to cleaning validation (5), was not updated at that time. Its revision, however, was discussed during an informal consultation held in Geneva, Switzerland, in July 2019. The outcome of the discussion was presented to the WHO Expert Committee on Specifications for Pharmaceutical Products (ECSPP) meeting in October 2019. The ECSPP acknowledged the importance of harmonization in regulatory expectations with regards to cleaning validation approaches. The Expert Committee recommended a “Points to consider” document be prepared in order to describe the current approaches used in cleaning validation and highlighting the complexities involved in order to establish a common understanding. A revision of the relevant appendix would then be considered by the Expert Committee thereafter.
Some of the main principles of good manufacturing practices (GMP) include the prevention of mix-ups and the prevention of contamination and cross-contamination. Multi-product facilities in particular, have a potential risk of cross-contamination. It is therefore important that manufacturers identify all risks relating to contamination and cross-contamination and identify and implement the appropriate controls to mitigate these risks.
These controls may include, for example, technical and organizational measures, dedicated facilities, closed systems, cleaning and cleaning validation.
It is strongly recommended that manufacturers review their existing technical and organizational measures, suitability of cleaning procedures and appropriateness of existing cleaning validation studies.
Technical controls, such as the design of the premises and utilities (e.g. heating, ventilation and air-conditioning [HVAC], water and gas), should be appropriate for the range of products manufactured (e.g. pharmacological classification, activities and properties). Effective controls should be implemented to prevent cross-contamination when air is re-circulated through the HVAC system.
Organizational controls, such as dedicated areas and utilities, dedicated equipment, procedural control, and campaign production, should be considered where appropriate as a means to reduce the risk of cross-contamination.
Measures to prevent cross-contamination and their effectiveness should be reviewed periodically in accordance with authorized procedures.
It should be noted that the above examples are described in more detail in other documents. The focus of this document is on Health-Based Exposure Limits (HBELs) setting in cleaning validation.
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Table of Contents
1. Introduction and
background
4. Historical approach
in cleaning validation
5. New approach using
HBELs in cleaning validation
5.7 Guidance for
Health-Based Exposure Limits (HBELs) setting
5.11 Cleaning validation
and cleaning verification
5.13 Cleaning process
capability
Appendix 1 Using Health-Based Exposure Limits (HBELs) to assess risk in cleaning validation
WHO TRS (Technical Report Series) 1033, 2021 Annex 2:
