Bioequivalence Study Requirements for Multiple Strengths in UK and EU Submissions
For multiple strengths, one well-designed bioequivalence study is often sufficient for both the UK and EU, provided the remaining strengths qualify for a biowaiver. The number of BE studies is determined by formulation proportionality, pharmacokinetic linearity, manufacturing process and comparative dissolution—not merely by the number of strengths.
For immediate-release tablets or capsules, the BE study is generally conducted using the highest strength when all strengths have the same dosage form, are manufactured at the same site using the same process, have qualitatively identical and quantitatively proportional compositions, show linear pharmacokinetics and demonstrate similar dissolution profiles. For example, if 5 mg, 10 mg, 20 mg and 40 mg strengths meet these conditions, one pivotal BE study using the 40 mg strength may support biowaivers for the lower strengths.
When exposure increases more than proportionally with dose, the highest strength is generally selected because it usually represents the greatest safety and exposure challenge. When exposure increases less than proportionally, strength selection depends on the cause. If the non-linearity results from saturable absorption or uptake rather than limited solubility, a study using the lowest strength or a strength within the linear range may be appropriate. If the non-linearity is associated with limited solubility or its cause is uncertain, studies at both the highest and lowest or another relevant strength may be required.
Additional BE studies may also be necessary when the formulations are not proportionally similar, excipient differences could influence gastrointestinal transit or absorption, different manufacturing processes are used, the dissolution profiles are not similar or the release mechanism changes between strengths.
Modified-release, narrow-therapeutic-index and other complex products require a product-specific assessment and may need more extensive BE evidence.
Therefore, for a conventional proportionally formulated immediate-release product with linear pharmacokinetics and comparable dissolution, the usual strategy is one pivotal BE study at the highest strength, with biowaivers for the remaining strengths. Depending on the product and its food instructions, both fasting and fed BE assessments may still be required at the selected strength.
Relevant Online Courses:
- Bioequivalence Study Strategy Design: A Practical Approach
- Global Regulatory Requirements for Bioequivalence Studies
- Fundamentals of Biopharmaceutics and Pharmacokinetics
Resource Person: Moinuddin Syed , Ph.D , MBA, PMP®
