Discriminatory Power: The Make or Break Factor in Dissolution Methods
In my work with pharmaceutical clients, one of the most common CMC gaps I encounter is dissolution methods that lack discriminatory power. Teams often assume their USP monograph method is sufficient, only to face regulatory questions or delays when reviewers challenge whether the method can truly detect meaningful quality changes. I’ve outlined some key points below to help teams strengthen their approach to dissolution method design and build regulatory confidence through sound scientific justification.
What is meant by discriminatory?
A discriminatory dissolution method detects batches that differ in critical quality attributes which could affect bioavailability. It goes beyond just meeting compendial requirements. The method has to be physiologically relevant and predictive of in vivo performance.
Why do regulators care?
Regulators care about this for good reason. Without discriminatory power, meaningful changes in your formulation or process can go undetected. Non-bioequivalent batches might pass testing anyway. Your quality control loses its clinical relevance in those cases and this goes beyond a technical nicety, It is really a patient safety issue. A non-discriminatory method can give false assurance that a product will perform as expected in patients. Critical changes might have actually compromised bioavailability or therapeutic effect.
How to establish it the evidence-based way.
Link your method to critical quality attributes first. Test formulation or process variants, especially high-risk failure modes like particle size changes, over-granulation, or disintegrant level variations. Use Design of Experiments with 6 to 12 dosage units and include stability testing under different conditions too.
Key regulatory insights.
- FDA expects dissolution methods to demonstrate sufficient discriminatory power during development and in support of post-approval (SUPAC) evaluations.
- The EMA’s 2017 Reflection Paper recommends comparing in vivo bioequivalence data with dissolution profiles. It uses pragmatic time points like 15, 30, 45 minutes and Q values such as 75 percent, 80 percent, 85 percent.
- QbD approaches strengthen the link between your dissolution method and clinical performance.
Common pitfalls.
- Overreliance on USP monograph methods without verification.
- Methods with more than 85 percent release in less than 15 minutes, which is too fast to discriminate.
- Increasing stirring speed just to reduce variability which comes at the cost of discrimination.
- Ignoring how stability affects discriminatory capability.
In conclusion
A physiologically relevant, discriminatory dissolution method is not just a regulatory checkbox, it’s the analytical bridge linking your control strategy to patient outcomes. Sponsors who invest early in designing and documenting a method that truly detects meaningful changes build regulatory confidence. Those who don’t, often face avoidable scrutiny during review.