Forced Degredation Accepance Criteria

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Hi,
We have studied forced degredation with drug product. Assay and related substances methods are differ from each other. Assay result is 93%, but total impurities are 3.4%. Difference between results is 3.6%. Authorities haven't accepted the difference. How can we explain mass balance? What should be acceptance criteria for forced deg.?

Thanks
Hello.
There are several explanations:
* assay method isn't suitable for forced degradation product, try to increase ultrasound and/or shaking time f.e.
* there are not eluting degradation products, try add more time for isocratic elution or extend gradient f.e.
* there are not detectable degradation products: f.e. CO2 & H2O.
Best regards,
Dmitriy A. Perlow
Thank you Dmitry. You're right. But I have to explain the difference to authority. What can I justify?

Thanks again
The degradation products might not have the same UV response as your main compound. Or you drug might have reacted with the excipients. Or the degradation products don't elute from the column or elute so early that you don't detect them. There are many things that can happen.

The authority has a valid question here, you need to demonstrate a better mass balance but I don't think there is a fixed limit for the mass balance. An assay method typically has an error of +/- 2% so I would guess that a 98% mass balance would be "passable"
We did some attempts at forced degradation in our validation studies, but most times we were unable to cause any measurable degradation under the "usual" conditions. We tried more acidic, more basic, longer exposures, etc., as well. Our consumer products were pH controlled and monitored over their 3-year ambient and elevated temperature studies, and our QA department felt that we would be able to detect degradation.

For example, we had a sunscreen active that was found not stable with the chosen preservative, so that preservative was changed.

Another active was confirmed reacting with an excipient as product development had been warned, so that project was ditched. Early in my career I confirmed similar in another product, product developer tried to blast me with "his PhD" but it turned out that I was correct.

Not a drug issue, but an enzyme in a laundry detergent was shown to be unstable due to degradation caused by a different enzyme.

Unfortunately, the company I worked for seemed to enjoy killing the messenger too often.....
Only Brazil's ANVISA requires 'forced degradation', but they don't explain the necessary conditions of acid, base, heat, light, oxidation. This is up to you! You must understand the chemistry and physics of this molecule. In my experience esters (used to increase the stability of the API) will breakdown. Molecules like Calcium Carbonate or Magnesium Carbonate (used in Tums) will not degrade since they are already elements.

You do not want the molecule to undergo secondary degradation. Thus, your SOP should specify that the API not degrade more than 20% in less than 5 days.

If you want a more specific answer you must tell us your API, formulation (including concentrations of other excipients).
Calculate Mass Balance by the following formula and share the value,

(Assay + Total impurities of degraded sample)
Mass Balance = ---------------------------------------------------- x 100
(Assay + Total impurities of as such sample)

The value obtained should be more than 95%
There is NO requirement to have 95-100% 'mass balance'. In fact, there are a lot of common molecules like water and carbon dioxide that do not appear in chromatograms.

Be sure your calculations are in moles, mmoles, nmoles, or pmoles, and not mass (mg...).

If your mass balance is still low it means you have an undetected degradant which elutes in the solvent front, may be completely retained under your chromatographic conditions, or may not be detectable...
I agree to your comments regarding the requirement of mass balance, however if by using this formula we get to know whether we need to look out for any missing impurities (could be not detected in chromatographic technique).
Thanks to everyone.
Hi Mahesh Acharya
Is there any document for this criterion (95%)? We have to answer to authorities and we can't change our methods now.

Thanks again
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