NDMA testing in metformin

[sbasaleh]

I would like to inquire about the appropriate stage for testing NDMA impurities in Metformin for product release specifications. Specifically, should the testing for NDMA be conducted on the finished product prior to primary packaging or after primary packaging?

Additionally, could you clarify the definition of “finished product” according to the regulatory guidance? Is it defined as the bulk product prior to packaging, or does it refer to the product in its final packaged form?

Thank you

[stephanie.snow]

Hi there. The regulatory definition of a finished product is of a drug product in its final container closure system; since stability studies (as per ICH requirements) are performed on the finished product packaged with the container closure system it is preferable to perform NDMA testing (or others) on the final product after packaging unless you have strong justification to use the drug product bulk solution for this test (e.g.: NDMA ruled out as potential degradant of the drug product, no risk with formation or presence of NDMA linked to container closure system…)
I hope it is helpful.

[sbasaleh]

Is there a different between finished product and drug product?

[Naiffer_Host]

You want to read this publication by @schlinjo1975 …

How to avoid NDMA in Metformin? (In press)

Back in October 2020, we saw an increased concern about the potential presence of NDMA in Metformin. @trust_user_a @trust_user_b @trust_user_c “As of October 2020, EMA and the national competent authorities are asking marketing authorization holders for metformin-containing medicines to test their medicines before releasing them onto the market,” said EMA’s Committee on Human Medicinal Products (CHMP) in an update to its post-authorization nitrosamine impurity testing procedures” As a Nitros…

NDMA risk is everywhere in the process!!

[sbasaleh]

Dears ,
For other chemical tests(Assay , RS) for solid dosage form , is it fine to test at release before packaging ?

Any reference please

[Muzaffar]

Although your question is not specifically related to nitrosamine impurities, I will try to share my insights:
It is a general understanding that the chemical tests (Assay, RS etc.) including all those specified on the drug product specifications are performed at release and only the stability indicating tests (such as description, identification, assay, related substances and other degradation impurities etc.) are performed throughout the entire stability program. Therefore, the stability testing is actually performed on the samples which have been packed under the recommended commercial packaging conditions (which includes your primary, secondary and tertiary packaging) albeit on a smaller scale.

Regarding NDMA in Metformin solid oral dosage, I am afraid, as this impurity is a process-cum-degradation product, you will have to test it at release as well as during the entire stability programme.
In fact where a risk of formation is identified, all NDSRIs must be tested throughout the stability programme of the drug product.

I hope this helps.