Cleaning validation worst case product selection

Can any one suggest me that we have 10 products to be manufactured in our new facility(oral dosage forms.) in that 1 product is combination product.(Atenolol 50mg and Amlodipine 5mg tablets). We did MAR caluculation based on smallest batch size & strength.

  1. What is the smallest strength for this product?

In our products Glimepiride 1 mg Tablet is the worest case product based on dose creteria. But this product is direct compressible product. This product is not contacting with RMG & FBD. we did validation on this particular product. But Some external auditors asking Cleaning validation report for RMG.
Can any one explain to solve my problem?

Dear venkibt2005,

actually you need to define three worst cases: The worst contaminant, the worst contaminated and the worst contaminating. Our approach for this case is the selection based on the following criteria:

  • Worst contaminant: The active which is the most insoluble one and the most potent one. First criterion is solubility, second criterion potency, which in our case means that the solubility expressed in mg/ml is weighted by a 95% and the potency, expressed in mg, by a 5% (this weighting is absolutely arbitrary!). A last criterion can be applied, which overruns the other two, and which is based on a risk assessment of the physiological action of the active: e.g. Simethicone is extremely insoluble and has a (surprisingly) high potency, but clearly poses a lower risk to the patient’s health than a Domperidone with much higher solubility and less potency.

  • Worst contaminated: The product that has the worst combination of (small) batch size, (high) number of maximum daily takings and (biggest) product exposed surface of manufacturing train.

  • Worst contaminating: The product that contains the highest dosage of the selected worst contaminant (e.g. among Amlodipine 2,5 mg, 5,0 mg and 10,0 mg, it is Amlodipine 10,0 mg). It determines only with which product the cleaning validation is finally carried out.

In the case there are two actives in one product simply the selection criteria for the worst contaminant are applied (as if they were two products). In your case clearly the worst case is the Amlodipine: Lowest solubility (0,0753 mg/ml
http://www.drugbank.ca/drugs/DB00381
), highest potency (smallest strength 2,5 mg [
http://www.pfizer.com/files/products/uspi_norvasc.pdf]
), vs. Atenolol (solubility 26,5 mg/ml , smallest strength 25 mg [
http://www1.astrazeneca-us.com/pi/tenormin.pdf]
).

Regarding the discussion with your auditor, the auditor is right. The worst case is defined per piece of equipment, and thus the Glimepiride may be the worst case for a mixer, a tablet press or a deduster, but not for the RMG and FBD, where the worst case is a product manufactured by wet granulation.

Best regards

Alfred