Not All Fills Are Equal — Stability Can Shift with Volume.
Tip: Evaluate both lowest and highest fill volumes in multi-dose products during stability to identify potential differences in headspace interaction, microbial risk, or physical settling.
Why Fill Volume Affects Stability
In multi-dose containers like oral suspensions, syrups, or reconstituted injectables, the fill volume directly impacts headspace, dosing accuracy, re-dispersion behavior, and preservative effectiveness. Stability studies using only a nominal fill may miss variations that occur in extreme fill scenarios — leading to surprises in real-world use.
Risks with Volume Variation
- Increased headspace promotes oxidation or microbial ingress
- Lower fill may cause under-dosing or higher air-liquid ratio
- Overfill could affect re-dispersion or cause cap leakage
Applicability
- Oral liquids and suspensions in PET or HDPE bottles
- Reconstituted antibiotics or injectables in vials
- Ophthalmic and nasal multi-dose dropper bottles
Recommended Testing Strategy
- Include both minimum and maximum fill volumes in stability protocol
- Evaluate for appearance, pH, assay, impurities, and microbial control
- Test after shaking/re-dispersion at each time point
Regulatory Perspective
WHO, EMA, and USFDA expect fill volume variation to be considered in multi-dose products. Justifying stability only on nominal fill may result in regulatory queries or post-marketing complaints.
Best Practices
- Ensure packaging lines can consistently maintain fill range
- Document fill volume in sample logs and batch records
- Include fill-related discussion in CTD Module 3.2.P.7 and P.8
Conclusion
Volume matters — not just in dose, but in degradation. Testing both ends of your fill range ensures your stability story is complete, compliant, and confidently packaged.