Do you check the polymorphic form/crystalline purity in the final product?

According to ICH Q6A “It is generally technically very difficult to measure polymorphic changes in drug products. A surrogate test (e.g., dissolution) can generally be used to monitor product performance, and polymorph content should only be used as a test and acceptance criterion of last resort.” 

Has your dissolution method been validated to reveal slight polymorphic changes?  – changes that could potentially influence the product behaviour in vivo. It implies that the dissolution method should be sensitive enough to reveal changes in dissolution rate in vivo (e.g. at various pH values and in biological relevant media). Of course the potential risk depends highly on the API in question (solubility/dose etc) and risk assessment should be based on such considerations.

It is stated in the guideline that it is “technically very difficult” to measure changes but using XRD or FTIR it is possible to detect down to 3-5% of “another form” in a product (depending on the dose etc.)  This could be somewhat “easier” that to validate a surrogate method?

It could be argued that if you use the stable crystal form in the final product, the risk of transformation is limited – thus the need for control is reduced. However, the stability of the API “alone” does not reflect the interactions in the final product – and we have in more cases observed drastic changes in the crystal form – either polymorphic transformation or de-salting that were not detected in the standard dissolution set-up.

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