Question Received:
I need your input, colleagues. I’m working on an oral solid dosage product with three strengths: 200 mg, 400 mg (bio-strength), and 600 mg based on a look-alike formula.
- For the US, dissolution equivalence has been demonstrated in QC media, and the waiver is filed.
- For the EU, multimedia f2 comparison is required.
Here’s the challenge:
600 mg vs. 400 mg:
- Match in QC media and 0.1 N HCl
- Not matching in pH 4.5 and 6.8 – slower and incomplete release (up to ~50%) for 600 mg
- RSD is low, so statistical approaches are not helping
- Sink conditions not achieved at higher pH due to pH-dependent solubility
- Multi-unit approach isn’t feasible due to the odd strength (600 mg)
What alternative strategies or justifications can be explored to meet EU requirements for the biowaiver?
Key Suggestions from Development Perspective:
1. Use of Surfactant-Based Media:
- Add 0.5%–1% SLS in pH 4.5 and 6.8 to simulate in vivo solubilization.
- Often accepted in EU filings if scientifically justified with solubility data.
2. Reformulate for Dose Proportionality:
- Ensure API-to-excipient ratio in 600 mg matches 400 mg.
- Investigate if lower excipient content is limiting wetting/disintegration.
3. Disintegrant and Buffer Optimization:
- Increase super disintegrant concentration.
- Add internal pH modifiers (e.g., citrate) to improve local solubility.
4. Solubility & Dose/Sink Justification:
- Conduct solubility studies at relevant pH.
- Provide evidence that poor release is solubility-limited, not formulation-dependent.
5. Model-Independent Approaches:
- Use dissolution efficiency (DE%), bootstrap f2, or multivariate techniques if f2 fails.
- Consider PBPK modeling for supportive evidence, if facility is available.
This case reflects a common hurdle in biowaiver strategies for pH-dependent BCS Class II drugs. Ensuring scientific justification and regulatory alignment is critical, especially when dissolution at higher strengths doesn't mimic the bio-strength under non-sink conditions.
I’d love to hear thoughts from fellow formulation scientists, biopharmaceutics experts, or regulatory professionals. Have you encountered similar challenges? What worked for you?
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