I have one equipment that i use for liquid product and semi-solid product (ointment, cream, gel). After worst case matrix calculation, i found that liquid product is worst case than semi solid product. If i use the same cleaning process for the both kind of product, could i validate the cleaning process for semi-solid product by liquid product? or i have to separate the 2 categories of product, and make two independant validations? one for liquid and another for semi-solid?
It is possible to validate cleaning of cosmetic product by liquid form and vice versa?
Since you have 1 cleaning procedure you will have to demonstrate that it is effect in cleaning both drug forms. Thus you will have to have 2 separate validations but your carryover acceptance criteria can be different (one liquid and the other semi-solid).
What criteria did you use to determine the worst-case cleaning? Did you just look at potency, or did you also look at the solubility of the liquid and semi-solid in your cleaning solution? I would really challenge the result that the liquid is the hardest to clean. I’ve done worst-case evaluation, and one thing we did was a solubility review (on paper) and also a soil removal test in a laboratory in a cleaning bath.
I have many criteria in the determination of the worst case. I have solubility of all ingredient in the product formula, the toxicicity (LD50), the type of ingredient (if it is actif or excipient) and the cleanability of final product (by experience of manufacturing personal). I multiply the note of all the criteria to obtain the score of the final product. For example : Ingredient 1: solubility x toxicity x type of ingredient. I do the same for ingredient 2, 3, 4 and so one. I sum the result for all ingredients and multiply this sum by the note of cleanability of final product.
After that, i compare the score of all product (liquid and semi-solid) and find the wort case.
For your liquid drug product the carryover acceptance criteria should be based on the molecule’s toxicity (ADE or PDE, not LD50 were you kill half the population). In addition solubility has nothing to do with your carryover risk analysis but rather developing the cleaning procedure.
You MUST be compliant with Eudralex’s chapters 3 and 5!
Thank you,
Do you mean than we cannot use Acceptance criteria based on LD50 for liquid drug product?
In my example above, i was explaing how i do my risk analysis. After this risk analysis, i determine the wort case product. With this worst case product i determine the acceptance criteria base on therapeutic, toxicologic (LD50) and 10 ppm. And finally i choose the lowest result.
How do you do you risk analysis for determine your wort case product? Can you explain by an example please?
because
How do you do in the cases where data like ADE or PDE are not available and only LD50 data is
available?
That is correct. The ADE or PDE (permissible daily exposure) is the only way allowed to measure toxicity. It is even used for topicals. You have not updated your regulations? Where is it required to do 3 calculations?
Thank you very much for this precision. I will update my regulation, i think i missed something in update. Do not hesited to send me links for more information about this discussion.
Note; ICH has no guidance on cleaning validation while the ISPE was scheduled to issue a guidance but ran into political problems (many plants were not compliant already).
I understand the conversation about toxicity and potency and establishing cleaning limits.
Playing the other side of the argument. What would happen if you had a potent product that is super easy to clean (in water lets say), but a less potent product which is very very difficult to clean (in a biofilm lets say)? If you show the water product gets clean, you still haven’t demonstrated the biofilm product gets clean.
Also, there are a ton of discussions on this forum regarding cleaning validation. Lots of good discussions.
True. This is the reason why the ‘hardest to clean formulation’ is secondarily used in the risk analysis and carryover acceptance criteria.
This criteria is common for dietary supplement manufacturers that have non-toxic API’s and promise their products can make you ‘healthy, wealthy, wise, and beautiful instantly’. An example would be
beta-Carotene.
Theoretical “worst-case” based on random scale of “difficult to clean” does not equal real world cleanability. I’ll stand by my argument that a semi-solid is probably harder to clean than a liquid, despite the carryover limit calculation based on ADE or MACO or any other toxicity calculation. If you clean based on a liquid product you could find yourself questioned by regulatory authorities and also find yourself with a residual for semi-solid.
In the least a visual verification of cleaning of the semi-solid should be done.
Yes, I agree. I recall ‘a harder to clean though non-toxic relatively’ black gum on a piece of equipment that we had to scrap 1st. Thus, I include work instructions as well preparation of a cleaning solution.
The worst case approach based on matrix is acceptable considering these
two materials of synthetic category. Ensure that the allowed limit of
rinse/swab sample is less than 10 ppm for vice versa combinations, if the MACO
as per worst case arrived as more than 10 ppm.
The only thing to remember is to select the appropriate SF value while
calculating the MAC value, based on the type of product application.