Four CDMOs Detail How Robust Formulations Are Actually Proven

CDMO formulation programs should expect ICH-compliant stability studies running up to four years before a formulation choice is fully justified, according to Gary Watt, PhD, Head of Formulation at Abzena. Watt's comment anchors a four-company roundup published by GEN, in which Abzena, BioAgilytix, Curia Global and Quotient Sciences describe how they approach customer molecules and how they distinguish a robust formulation from a screen performer. The piece is vendor commentary rather than peer-reviewed data, and readers should weigh it accordingly: no sample sizes, study results or client outcomes appear in any of the four accounts.

What comes before screening?

Watt said Abzena begins with a developability assessment that subjects the molecule to platform manufacturing stresses — low pH, freeze-thaw, shear and hold conditions. The goal is an early-risk profile covering aggregation, fragmentation, oxidation and deamidation before any formulation screening starts.

Only after that does Abzena align with the customer on a target product profile covering dose, concentration, route of administration and presentation. "The formulation strategy is driven by clinical and product needs rather than screening performance alone," Watt said in effect, describing subsequent screens of pH, ionic strength, excipient compatibility and thermal stability. For subcutaneous products, the company also evaluates high-concentration feasibility: solubility, viscosity and aggregation risk. Lead candidates are then challenged through thermal and freeze-thaw studies using orthogonal analytical methods.

For Phase I and first-in-human supply, Watt said the final formulation must provide an acceptable stability margin, support scale-up and generate data suitable for an IND filing. GMP batches then go on ICH-compliant stability studies, typically up to four years — roughly the full length of a typical Phase I-to-III development arc.

Can your assays see the degradation?

Jessica Weaver, Scientific Officer at BioAgilytix, framed the analytical gap as the central risk. A formulation may change how a drug degrades, and an assay validated for the drug substance may not detect what happens in the final formulation. She argued for stability-indicating methods that distinguish intact drug from degradation products without interference from excipients.

"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," Weaver said. Her definition of robustness is a formulation that tolerates normal variability in formulation parameters, manufacturing, handling and storage — a standard that initial screens cannot meet by construction.

Why Arrhenius kinetics fail for biologics

Tyler Jones, PhD, Director of Formulation R&D at Curia Global, offered the most technically specific account. Curia characterizes molecules across a wide formulation space, systematically mapping pH against ionic strength — the two parameters that most strongly influence molecular behavior — across a range of temperatures.

The rationale is blunt: many biologics do not follow Arrhenius-type kinetics for degradation activation energies. Accelerated-temperature data, in other words, may not predict real storage behavior. Jones said Curia forces molecules down each degradation pathway to determine which pathways dominate at intended storage temperatures, then weights formulation performance accordingly. Only then does the team screen targeted interventions, such as antioxidants against residual oxidation, with background data to justify each excipient. Final refinement uses design-of-experiments studies, and the gold standard is long-term stability testing on a bracketed selection of formulations around the chosen operating space.

Simplest formulation that works

Asma Patel, PhD, Vice President of Global Commercial and Scientific Consulting, Drug Product at Quotient Sciences, began with the target product profile and API properties — physicochemical, solid-state and biopharmaceutic. First-priority risks include solubility and dissolution relative to dose, permeability, solid-form and chemical stability, excipient compatibility, dose feasibility and manufacturability.

"The objective is not to select the most sophisticated technology, but rather the simplest formulation capable of delivering the required clinical performance," Patel said. Her test for robustness is challenging critical material attributes and process parameters across justified ranges to find where performance fails, then confirming through batch reproducibility, long-term stability, representative equipment, clinically relevant in vitro testing and, where appropriate, human data.

All four accounts converge on one claim worth noting for budget planning: robustness is demonstrated only under stress and time, which places multi-year stability commitments — and their cost — inside any formulation development contract. None of the four companies disclosed failure rates, timelines or pricing, leaving buyers to verify those numbers during due diligence.