FDA Requirements for the "Worst Case" Product during Cleaning Validation

Bracketing approaches are certainly allowed in the context of cleaning validation. First, for the products themselves, so that a "worst case" substance can be used for validation. Second, for equipment of the same design, the effort can be reduced by bracketing. In this way, an equipment can be selected. So how to define these "worst cases"? Here you can read FDA's view on this.

FDA's views on GMP issues can be found, for example, in the Guides to Inspections and Guidances for Industry - as well as in Warning Letters. In a current Warning Letter, the FDA criticises inadequate cleaning validation in relation to the topic of cleaning (21 CFR 211.67). With regard to filling lines, the FDA criticises the statement in the validation protocol that one filling machine would be representative of all other filling machines.


No identical equipment is used in the filling machines - and there is no evidence or scientific justification that the chosen filling machine is really representative.

Yet the "worst case" product that the Verde company had selected for the cleaning validation was also not accepted by the FDA. Here, too, the FDA lacked a scientific justification as to why the selected "worst case" product should really be assessed as a "worst case". Especially as there were other products with the same API but higher API contents than that of the selected "worst case" product.

In short: worst-case considerations in the area of cleaning validation must be supported by scientific justification according to the FDA. 

The FDA's comments on the topic of equipment qualification and process validation are also interesting. The FDA criticised the lack of qualification of filling equipment as well as the lack of process validation in the production of medicinal products. Interestingly, with regard to the lack of qualification, the FDA also emphasised that the corrective measures should also include a description of how personnel are "retrained" and how it is ensured that new personnel will also be included in the qualification requirements.  

Retrospective validation as a substitute for the missing process validation is once again not accepted by the FDA. Here, the FDA expects a much more determined approach that shows that the process validation cycle will be adhered to in the future.

You can find the complete Warning Letter on the FDA website.

Go back


Stay informed with the GMP Newsletters from ECA

GMP Newsletter

The ECA offers various free of charge GMP newsletters for which you can subscribe to according to your needs.

To subscribe, please click here.