Formulation Change Is Inevitable
It is the rare pharmaceutical development programme that reaches Phase III with exactly the same formulation that entered Phase I. Scale-up changes, stability-driven modifications, bioavailability improvements, and the practical realities of manufacturing optimisation all result in formulation differences between the early clinical and the intended commercial product.
This is not a problem in itself. Regulators understand that development involves iteration. What they need to be confident of is that the clinical data generated with earlier formulations is still relevant to the product being developed, and that any changes have been characterised, controlled, and disclosed appropriately. Bridging studies are the mechanism for providing that confidence.
When a Bridging Study Is Required
The requirement for a bridging study depends on the nature and magnitude of the formulation change, and the stage of development at which it occurs. FDA’s guidance on INDs and EMA’s guidance on clinical trial authorisations both address formulation changes, though the specific triggers and requirements differ between jurisdictions.
| Change Type | Likely Bridging Requirement | Bridging Approach |
| Minor composition change (same formulation concept, adjusted ratio) | Comparative dissolution in multiple pH media | In vitro dissolution comparison; statistical evaluation |
| Bioavailability-enhancing technology change (e.g. crystalline to ASD) | In vivo pharmacokinetic bridging study | Crossover PK study in healthy volunteers or patients |
| Dosage form change (e.g. capsule to tablet) | Comparative dissolution; potentially in vivo PK | In vitro first; in vivo if dissolution differences identified |
| Manufacturing site or scale change | Comparative analytical data; potentially dissolution | Batch analysis comparison; process validation data |
| Excipient change (novel excipient or significant level change) | Regulatory assessment; potentially safety bridging | Toxicology assessment of new excipient if required |
In Vitro Dissolution as a Bridging Tool
For many formulation changes where the mechanism of absorption is not fundamentally altered, comparative dissolution testing in multiple pH media is the first-line bridging tool. Dissolution testing at pH 1.2, 4.5, and 6.8 captures the range of conditions encountered in the gastrointestinal tract and provides evidence that the modified formulation will deliver the drug at a comparable rate and extent.
The statistical approach to comparing dissolution profiles, using the f2 similarity factor or more sophisticated modelling approaches, is addressed in FDA’s dissolution guidance for industry and the EMA’s guideline on dissolution. An f2 value of 50 or greater indicates similarity for most formulation types, though this criterion does not apply to highly variable drugs or drugs with narrow therapeutic windows.
In Vivo PK Bridging Studies
When an in vitro approach is not sufficient to bridge a formulation change, an in vivo pharmacokinetic study in human subjects is required. The design of a PK bridging study depends on the objectives: for a change that may affect rate of absorption but not extent, a crossover study in healthy volunteers measuring Cmax and AUC is typically the most efficient approach. For changes where the effect on bioavailability is expected to be small, a two-period crossover with a 90% confidence interval approach is standard.
Planning PK bridging studies as part of the CMC development strategy, rather than as a reactive response to a regulatory question, avoids the scenario of needing to design and execute a clinical study under time pressure at a critical programme milestone.
Practical Considerations for Formulation Change Management
Document the Scientific Rationale
Every formulation change should be accompanied by a written scientific rationale that explains why the change was made, what data supported the decision, and how the bridging approach was selected. This documentation is both good practice and a regulatory requirement for programmes operating under an active IND or CTA.
Engage Regulators Early
For changes that are likely to require in vivo bridging, early engagement with the relevant regulatory agency, through a Type B meeting request to the FDA or a scientific advice procedure at the EMA, can clarify the bridging expectations before the study is designed. This avoids the risk of executing a study that does not satisfy the agency’s requirements.
Consider the Phase of Development
A formulation change at Phase I is far easier to manage than the same change at Phase III. The earlier a formulation is locked, or a deliberate development path to the intended commercial formulation is established, the less bridging work will ultimately be required.
How Ardena Supports Formulation Change Management
Ardena’s integrated CMC teams manage formulation change programmes across its development and analytical sites. The analytical teams in Ghent and Assen develop and execute comparative dissolution studies and provide the bioanalytical support for in vivo PK bridging studies. The regulatory team advises on jurisdiction-specific requirements and can prepare the CMC change documentation needed for IND amendments or CTA updates.
