Control Strategy - Testing Frequency

Guidance, Documents, Resources
1

I’m interested to see how varied the responses may be for this. For a drug product which showed results 25-75% of the specification upon confirmatory testing, what was the testing frequency agreed to by the appropriate agency, both on release and stability?

Adding clarity. This is all hypothetical. At expiry, if the nitrosamine is around 50% of the regulatory limit, what strategies have you seen accepted by the regulatory agency? Skip lot testing or all batches? Full stability testing on annual stability commitments only? Only testing at release and end of life?

2

Dear Jason,
our policy, regarding the dossier/exhibit batches, is whenever we have a result >10% of the spec limit to add the testing in the specs of the product for release and end-life. We could follow the ‘’ skip testing’’ policy for results till 30% but we prefer to control the suspicious nitrosamine closely to understand its trend and where would be the plateau (if exists)

Christos

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3

Hi Jason

I think it would depend, do you mean 25-75% by the end of shelf-life? I believe this question cannot be generally responded but a case-by-case evaluation is required. If for example all batches are below 10% at release, I might try to move to skip testing at release while keeping control in all batches placed in stability. But to be honest, 25-75% seems like a huge variability and that something is not under control in the process.

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4

Thanks, added clarification. All hypothetical. Not saying anything about variation, just that the results are in the ballpark of 50%

5

For exhibit batches certainly the nitrosamine will be part of the specification for release as well as stability.
For Commercial products, nitrosamine testing will be part of the specification at release and end point. However this will not suffice. The regulatory agencies have come back to us asking for more appropriate controls (eg nitrite monitoring in critical excipients like MCC or Aerosil)

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6

Thanks all for the very insightful discussion. I truly appreciate you sharing the feedback received from the agencies on these queries. That level of insight is what makes this community unique and rewarding! I just wanted to share my appreciation.

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7

That makes sense. That’s an important added detail.

8

I completely agree. There is nowhere else we could ask this question.

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9

If I may add another control strategy would be to control the precursor to the nitrosamine e.g

  1. Dimethylamine for NDMA ( lot of organizations follow this strategy)
  2. Control the impurity if the nitrosamine is impurity related. Especially if it’s a process impurity…controlling the impurity in the API specification at an appropriate limit may reduce the risk of nitrosamine in the finished product.
    It is widely reported that quality of air plays an important role…it has been our experience as well…Can somebody elaborate about what controls can be used for air monitoring (nox monitoring)
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10

This is a great point. I have not heard this spoken of much, but controlling the des-methyl impurity in dimethyl tertiary amine APIs is critical.

11

For the NDSRI cases it is more often the control of the desmethyl-API in the DP over shelf life which is more challenging than in the API, both for solid and liquid formulations I find.

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