The role of science-led development in de-risking OSD programs 

Author: Balasubramaniam Jagdish, Vice President Formulation Development (PDU)

In early drug development, the next milestone can easily become the immediate focus. A formulation needs to support a clinical study. A process needs to produce the next batch. An analytical method needs to generate the data required to move the program forward. 

But decisions made to solve an immediate development challenge can have consequences much further down the line. 

As an oral solid dose (OSD) program progresses, the formulation and process will need to perform at different scales, on different equipment and under increasingly defined manufacturing conditions. What works during early development therefore needs to provide a foundation for what comes next. 

This makes early scientific understanding particularly important. A strong understanding of the formulation and process can help identify potential risks early and guide decisions with robustness, scale-up and future manufacturing in mind. Having direct access to the scientific and technical experts doing the work can help bring that understanding into development decisions from the outset. 

Complexity in formulation requires an integrated scientific approach 

The importance of early scientific understanding becomes particularly clear when developing products involving APIs with very different characteristics. 

Fixed-dose combinations are a good example. Combining multiple APIs in a single dosage form can offer therapeutic advantages, but it can also introduce competing formulation requirements. Differences in solubility, permeability, pharmacokinetics and release behaviour need to be understood together rather than in isolation. 

In one investigational therapy programme, we supported the development of an extended-release fixed-dose combination tablet containing two APIs with very different physicochemical and pharmacokinetic properties. One API was a BCS class II compound with low solubility and high permeability, while the other was BCS class IV, with both low solubility and low permeability. Their absorption characteristics and half-lives also differed considerably.  

Simply bringing the two APIs together in one tablet was therefore not enough. The formulation needed to control how each was released over time. 

Formulation and analytical development need to work together 

Understanding those differences helped guide the formulation strategy.A matrix-based extended-release tablet using wet granulation was selected, with a hydrogel used as the extended-release polymer.  

Optimising the polymer level was critical to achieving the targeted release profile, while film coating was incorporated to address taste considerations.  However, formulation development was only one part of solving the problem. The contrasting solubility profiles of the APIs also required an appropriate way of assessing their release. A two-stage discriminatory dissolution method was developed, beginning with an acidic stage followed by a buffer stage with surfactant. Different surfactant concentrations and paddle speeds were evaluated as part of establishing the method.  

This illustrates an important principle in OSD development: formulation and analytical development are most valuable when they inform one another.  

Analytical methods are not simply a means of testing whether a formulation passes or fails. The data they generate can help scientists understand why a formulation behaves as it does, refine the development strategy and make better-informed decisions about the process. That becomes increasingly important as complexity increases. 

Scale-up is where scientific understanding is put to the test 

A formulation performing as intended at development scale is an important milestone, but it does not automatically demonstrate that the process is ready for what comes next. 

As scale changes, the relationship between material properties, process conditions and product performance can also change. Development therefore needs to establish sufficient understanding of the formulation and process to support progression beyond the initial experiments. 

In this program, the formulation successfully balanced the release profiles of the two APIs, with comparable results across pilot and scale-up batches. Later in vivo studies demonstrated synchronised release profiles, and the program progressed towards Phase III clinical manufacture and preparation of registration batches.  

Together, these outcomes demonstrate how the scientific decisions made during development supported both the immediate formulation requirements and progression into later development stages. 

Connecting scientific expertise across development 

Strong scientific expertise comes from connecting different disciplines throughout development: understanding the molecule, interpreting analytical data, selecting and refining the formulation, anticipating process behaviour and applying that knowledge as the program progresses.  

It is also why direct interaction with the scientists doing the work matters. When formulation, analytical and technical expertise are connected around the same development problem, emerging information can be interpreted in context rather than passed between isolated activities. 

For companies moving from early development towards later clinical phases, that scientific continuity can help identify technical risks earlier and provide a stronger basis for decisions about formulation, process robustness, scale-up and future manufacturing. 

Building for next stage, not just the next milestone 

Decisions made early in OSD development can influence the program long after the next milestone has been reached.  

A science-led approach helps ensure that formulation and process decisions are based not only on what works today, but also on what the program will need tomorrow.  

Bringing scientific expertise into those decisions early can help reduce risk and build the understanding needed for robust scale-up and future manufacturing.