Formulation development is a critical step in the production of a drug to ensure that it is safe, effective, stable, and suitable for administration. Companies that provide formulation development services are experts in applying best practices to achieve optimal results. GEN sought the perspectives of experts from four leading companies to describe the considerations they make when working with customers on developing new formulations.
GEN asked two questions: How would you approach formulation development for a customer’s specific molecule, and what key risks would you evaluate first? How do you determine that you have found a robust formulation rather than just the best-performing formulation under your initial test conditions?
Abzena
Initially, we would perform a developability assessment to understand how the molecule behaves under platform manufacturing stresses, including low pH, freeze-thaw, shear, and hold conditions. This establishes the early-risk profile, including aggregation, fragmentation, oxidation, and deamidation risks, and identifies any molecule-specific liabilities before formulation screening begins.
Head of Formulation
We would then align with the customer on the target product profile (TPP), including intended dose, concentration, route of administration, and presentation requirements, so the formulation strategy is driven by clinical and product needs rather than screening performance alone.
Once the TPP is agreed, we would confirm compatibility with platform analytical methods and run focused formulation screens assessing pH, ionic strength, excipient compatibility, and thermal stability. For subcutaneous products, we would also evaluate high-concentration feasibility, including solubility, viscosity, and aggregation risk.
Lead formulations would then be challenged through thermal and freeze/thaw stability studies using orthogonal analytical methods. Robustness is demonstrated when the selected formulation performs consistently across relevant stresses, analytical readouts, and small variations in formulation or process conditions, rather than simply being the best performer in the initial screen.
For Phase I/first-in-human (FIH) supply, the final formulation should provide an acceptable stability margin, support scale-up and manufacturing, and generate data suitable for Investigational New Drug (IND) filing.
Good Manufacturing Practices (GMP) batches would be placed on International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)-compliant stability studies, typically for up to four years, to confirm long-term performance and further justify the formulation selection.
BioAgilytix
When approaching formulation development, I would start by understanding the molecule itself: what makes it unstable, which quality attributes matter most, and what conditions are most likely to cause problems. That means looking at physical and chemical stability, aggregation or particle formation, potency and purity, as well as sensitivity to things like pH, temperature, oxidation, agitation, and freeze-thaw. I would also look closely at the excipients, because stabilizers and other formulation components can affect both the molecule and its degradation pathways.
Scientific Officer
From the analytical side, an important question is whether we have the right assays to detect those changes. A formulation may alter how a drug degrades, and an assay that works well for the drug substance may not tell the whole story once that molecule is in its final formulation. We need stability-indicating methods that can distinguish the intact drug from degradation products and detect meaningful changes in the critical quality attributes without interference from the formulation itself.
The bigger question then becomes more than which formulation performs best in an initial screen. We need to understand why it performs well and whether it continues to perform when challenged.
For me, that is the difference between a formulation that looks good and one that is truly robust. It should tolerate normal variability in formulation parameters, manufacturing, handling, and storage. If performance falls off as soon as you move away from the exact conditions used in the initial study, you probably haven’t found a robust formulation yet. Confidence comes from analytical and stability data showing that the formulation continues to protect the molecule under the conditions it is likely to encounter.
Curia Global
Director of Formulation R&D
We take a bespoke approach to formulation development, where we don’t make assumptions on behavior based on the type of molecule, but rather we use a process to efficiently and pragmatically identify critical quality attributes and understand why a molecule behaves the way it does. First, the Curia team would characterize the molecule across a wide formulation space, systematically mapping pH vs. ionic strength, the two parameters that most strongly influence how molecules present themselves to their environment. This broad physicochemical space allows us to force a molecule down the various degradation pathways it could encounter, and doing this across a range of temperatures allows us to understand the temperature-dependency of these pathways. Many biologics do not follow Arrhenius-type kinetics with regard to degradation activation energies, so understanding which degradation pathways are most relevant at the intended storage temperatures is critical in weighting formulation space performance.
Once this baseline understanding of molecule behavior is established, we can then pointedly mitigate remaining issues. For example, if we achieve good physical stability but are still encountering some chemical degradation such as oxidation, we can then screen antioxidants and have the background data to justify why we are adding such excipients.
Eventually, with enough stability data to have confidence in a final formulation space, we would utilize DOE studies to refine each variable in the formulation. The gold standard for us is long-term stability, so to definitively show the formulation is robust, we run long-term stability studies on a small selection of bracketed formulations around our sweet spot.
Quotient Sciences
Formulation development should start with the target product profile and the molecule itself, including the required dose and exposure, route of administration, dosage form, and the API’s physicochemical, solid-state, and biopharmaceutic properties. The first priority is to identify the risks most likely to compromise clinical performance or create downstream development barriers. Depending on the molecule, these may include solubility and dissolution relative to dose, permeability, solid-form and chemical stability, excipient compatibility, dose feasibility, and manufacturability.
Vice President, Global Commercial and Scientific Consulting, Drug Product
The objective is not to select the most sophisticated technology, but rather the simplest formulation capable of delivering the required clinical performance while remaining viable through scale-up, transfer, and later-stage manufacture.
A robust formulation should be understood, not simply selected. Critical material attributes and process parameters should be challenged across justified ranges, including relevant interactions and boundary conditions, to determine where performance is maintained and where it begins to fail. The formulation choice should then be confirmed through reproducibility across batches, stability over time, performance on representative equipment, clinically relevant in vitro testing, and, where appropriate, human data.
A formulation is robust when normal variability is understood, controlled, and does not materially affect product quality or intended clinical performance.
