A common misconception in regulatory submissions is that if one strength fails biowaiver criteria, all strengths must undergo in vivo bioequivalence (BE) studies. This is not correct as biowaiver eligibility is assessed per strength. Each strength must independently meet all applicable biowaiver criteria, such as proportional formulation, same manufacturing process, same release mechanism, and comparable dissolution behavior.
BCS based biowaivers are accepted only for specific dosage forms, primarily immediate-release, solid oral dosage forms and they are not applicable to:
- Modified release products
- Complex dosage forms
- Products not meeting BCS and dissolution criteria
Which regulatory agencies accept biowaivers?
Major regulatory authorities that accept BCS based biowaivers, under defined scientific conditions are EMA/EU Member States, US FDA, Health Canada, PMDA (Japan), TGA (Australia), WHO (Prequalification Programme). Acceptance is case-by-case, strength-specific, and dependent on BCS class, dosage form, formulation, and dissolution data.
What if one strength fails a criterion?
If a specific strength does not meet one or more biowaiver conditions (e.g. non similar dissolution or non-proportional composition) ... Biowaiver is denied only for that specific strength, in vivo BE is required only for the non compliant strength and other strengths may still be biowaived if they fully comply.
But don’t companies always keep formulations proportional?
In practice, most companies aim for proportional formulations. However, non-proportionality can still arise, particularly in: Low-dose strengths (minimum functional excipient levels),
manufacturing feasibility or robustness requirements, use of functional excipients (e.g. disintegrants, surfactants) and fixed tablet size or patient acceptability considerations. So when proportionality is lost, API excipient ratios change, which can influence tablet microstructure, disintegration, and dissolution behavior increasing uncertainty in bioavailability.
Biowaiver decisions are strength-specific and dosage-form dependent. They apply only where scientific justification and BCS criteria support predictable bioavailability.
Understanding this nuance is critical for regulatory strategy, development timelines, and cost optimization.
Read also: Challenges in BCS Based Biowaivers
Resource Person: Chetan Rajak
