Publication of the WHO Document on Limits in Cleaning Validation

The issue of (cross-) contamination and, in this context, cleaning validation have played an important role in the GMP environment for decades. For some years now, health-based exposure limits have been added as a possible alternative. In a draft guideline, the WHO has addressed this topic.

The draft document entitled "Points to consider on the different approaches - including HBEL - to establish carryover limits in cleaning validation for identification of contamination risks when manufacturing in shared facilities" contains 22 pages with the following chapters:

• Introduction and background
• Scope
• Glossary
• Traditional approach
• New approaches

The document is completed by references and further literature, together with an Annex; whereby the first three chapters comprise only two and a half pages.

Traditional Aproach in Cleaning Validation

In the chapter Traditional Approach, half a page points out that one of these traditional approaches (with reference to "older" GMP regulations) may no longer be acceptable and justifiable, as they do not take health-based exposure limits into account. Therefore, when using these "traditional acceptance criteria", their application should be discussed and justified. However, with regard to risks due to (cross) contamination, the new approaches should be implemented as soon as possible. 

The aim of the document is to discuss different approaches, including health-based exposure limit values, regarding (cross-) contamination in multi-product facilities. It addresses both APIs and finished medicinal products. Moreover, it provides guidance on cleaning validation and specifies aspects to be considered when evaluating current cleaning validation schemes.

On a page, Annex 1 shows an example of the calculation of "maximum safe carry over" (MSC) and "maximum safe surface residue" (MSSR) values based on health-based exposure limits.

New Approaches in Cleaning Validation

Many traditional cleaning validation approaches lack development and cleanability studies for the cleaning procedures. Often, only the cleaning process itself is considered.

The new approaches focus more on "scientific evidence" and should include:

• Cleanability studies
• Risk assessments and risk controls
• Technical and organisational controls (design of equipment, dedicated facilities, campaign production)
• Health-based exposure limits settings
• Analytical procedures, and
• Cleaning verification with proven capability through statistical evaluation.

These are precisely the topics covered on the following nine pages. Here are a few of them.

Interestingly, an independent Cleaning Validation Master Plan and a company-wide "policy" for setting health-based exposure limits in shared facilities is being requested. There should be written instructions on how to collect scientific data and toxicological information on health-based exposure limits. If such data comes from third sources, the data should be reliable and take into account GMP requirements regarding "outsourced activities" (supplier qualification, contract, etc.). The 16 subitems to be included in a report on the collection of health-based exposure limits are also mentioned. The report should be reviewed by a team for completeness and suitability. The team members should have appropriate qualifications and experience in toxicology. These PDE reports should be regularly reviewed and updated.

Reference to a WHO draft document on data integrity is made explicitly mentioning the need for data integrity. If no health-based exposure limits are used, this should be scientifically justified.

Cleaning Verification

Furthermore, a regular verification of the effectiveness of the validated cleaning process is required. Test results on a routine basis should be subjected to statistical trending. In the document it is then added that process capability calculations could be helpful for this purpose.

Visually clean Criterion

The visually clean criterion has a high priority in this draft document and should be one of  the acceptance criteria used on a routine basis. However, visible residue limits should be documented (SOP, protocol) and quantitatively determined. A "Visual Detection Index" (VDI) may be calculated using the MSSR. The combination of at least two sampling methods is also recommended. These include swab and rinse tests as well as a visual inspection.

Aspects for the determination of health-based exposure limits, cleaning studies, cleaning validation, cleaning verification should be monitored with regard to quality metrics with performance criteria.  

The deadline for comments is end of June 2020. The document is available on the WHO website.