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Clinically relevant dissolution specifications: selection and assessment

Setting specifications for new oral products can be challenging. Too lenient, and there is a risk of passing batches of inadequate quality; too stringent, and there is a risk of rejecting acceptable batches.

One reason for this is that they are often based on the data from a limited number of batches. The Food and Drug Administration favour setting clinically relevant specifications (CRS).1 This approach is evolving as it is starting to be more widely used and there is an increase in knowledge and regulatory thinking.

CRS are about test methods and acceptance criteria that identify and accept/reject drug product batches that are likely to perform adequately/inadequately in the indicated populations.

Historically, dissolution development and assessment has often been independent of in vivo behaviour. The data used to set specifications was generally based on a limited set of clinical, development and commercial batches. Most of the data generated assessed only the in vitro performance of the product. The clinical relevance of the specification was often unknown, as limited clinical data is generated prior to approval making it difficult to assess whether changes in dissolution have any impact in vivo. The in vitro dissolution methodology can be either over- or under-discriminating to changes in vivo.

There are many benefits to having clinically relevant tests and acceptance criteria. These include being able to:

  • Reject batches that are not bioequivalent to pivotal clinical batches 
  • Indicate product changes that might impact bioavailability 
  • Ensure that batch-to-batch variability is limited to acceptable levels for commercial product compared to clinical material.

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