Last week I came across a LinkedIn post claiming you can validate one ‘pseudo/ worst-case strength’ because same API = same method performance.
While it’s true that ‘representative’ strengths ARE used in method validation. But for dissolution, this assumption is an oversimplification to the point where it’s not correct.
Why?
- Because dissolution is not assay.
- And same API ≠ same dissolution behaviour.
In multi-strength products, what changes isn’t just the ‘mg’, sometimes it’s the release mechanism. Strength selection for dissolution method validation is a risk decision, and not one of convenience.
So how do you choose the strength(s) for dissolution method validation? (Assuming the dissolution method employed is the same for all the strengths)
𝗦𝘁𝗲𝗽 𝟭: Identify what kind of multi-strength formulation you actually have
Dose-proportional strengths
- Same API
- Same excipients
- Same manufacturing process
- Same qualitative and quantitatively proportional composition (same API-to-excipient ratio) across strengths. Often using a common blend/ granulate in tablets or capsules.
Dose-similar strengths
- Same API
- Same excipients
- Same manufacturing process
- Different strengths keep nearly the same excipient concentrations while changing only the drug load, resulting in a changing drug-to-excipient ratio
Non-similar/ strength-specific formulation
- Different excipients and/ or different processes to make the strength work
𝗦𝘁𝗲𝗽 𝟮: Identify dissolution worst-case mechanistically
For dose-proportional formulations, the highest strength is often your ‘worst-case’ because it stresses solubility, hydrodynamics/ coning, precipitation, filter adsorption.
For dose-similar formulations, the highest and lowest strengths are often your ‘range’ because the changing API-to-excipient interactions can impact overall drug release.
For non-similar/ strength-specific formulation – you obviously need separate method validations. And in some instances, a different dissolution method.
𝗦𝘁𝗲𝗽 𝟯: Prove it with Bridging
‘Dose proportional’ or ‘dose similar’ doesn’t guarantee identical drug release across strengths.
So, you run confirmatory dissolution profiles across all the strengths to show no mechanism shift and comparable release kinetics to the ‘representative’ strength(s).
Then, based on your risk, you may need partial method validation on additional strengths – especially precision.
In summary, whichever option you choose – one strength or two – don’t assume the logic is implied. You must justify your selected strength(s) with data + rationale.
Because unlike assay, dissolution doesn’t just measure the drug concentration It’s drug release from the dosage form and then measurement.
That’s what stands up in a submission and during post approval changes when someone asks: “On what basis did you assume the method validation covered the other strengths?”
Read also: Things Required to Start Analytical Method Validation
Resource Person: Pearl Pereira Nambiar