Regulatory Open Forum

We have a monoclonal antibody drug product undergoing long-term stability studies. The stability specifications for all quality attributes were initially set to match the release specifications. However, the 36-month real-time data indicates an out-of-specification (OOS) result for A280. Considering that the product is still in clinical development, is it possible to relax these specifications? If so, what justifications could be provided to support this change?

Hi Anon,

More information is needed to answer your question.

1. What phase of clinical development are you at with this drug?
2. how many batches have been made at the scale of the batch in question?
   1. Have there been any OOT results in other attributes at the 36-month point?
3. Did the lab investigation conclusively show that this is an actual OOS result? 
   1. Was there any trend in the A280 results prior to this OOS?
   2. Were there any deviations during manufacture that could be related to the OOS?
4. What is the shelf-life you are targeting - 24 months or 36 months?
5. How much of a range do you have on your A280 acceptance criteria? I have often seen A280 ranges set unrealistically narrow too early in development.

The best justification for any change in specifications is data. If your A280 results showed any downward trend during stability on this and other batches, you may have a valid argument to support reducing the A280 criteria for stability after a specified time point. This depends on how significant a change is being observed. 

If this is a one-off OOS with no observed trends, I would wait and see what data you get from other batches before doing anything as drastic as changing stability specs. MAbs are rugged things, and it is possible this was a one-time OOS.

Best of luck, 

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Arvilla Trag RAC
Principal Consultant
CMC Compliance Services
Iron River MI
United StatesCMC Compliance Services LLC
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