Designing Robust Lyophilization Processes for Biologicals

Approximately one-third of the unique biologicals in the FDA’s purple book are lyophilized, according to a recent paper. That includes (in 2020) nearly a quarter of monoclonal antibodies. Trends suggest interest in this freeze-drying process is growing among biologics developers.

Variability in the lyophilization process itself, as well as among lab-scale and commercial-scale equipment can introduce differences that cause product failures. And, because the products aren’t monitored during freeze-drying, “it is a blind processing strategy,” Brecht Vanbillemont, PhD, senior scientist, Coriolis Pharma, tells GEN.

“Due to poor heat transfer in a vacuum environment, subtle changes in interactions between the product container (such as vials or dual chamber syringes) and the freeze-drying equipment can have a substantial impact on the process dynamics and, consequently, product quality attributes,” he says.

Quality-by-design is vital

“The main cause of process failures is developers not following a quality-by-design approach during lyophilization process optimization and process transfer,” he says. “Often, the rationale is lacking on how the freeze-drying process was established. Biologicals require many excipients that often depress these temperatures, limiting the lyophilization process.”

Vanbillemont recommends characterizing the lyophilization equipment using specific experiments “to establish processing limits and to understand the interactions of the product container with the equipment, under different process conditions.” A model based on those experiments, then, can be used to predict variability in the freeze-dryer for various shelf temperatures and chamber pressures at various time intervals throughout the process.

Focus on the primary drying phase, he advises. That constitutes approximately 70% of the drying time and is the source of many product failures.

For example, although hundreds of thousands of vials may be lyophilized simultaneously, their position in the freeze-dryer affects outcome.

“Vials near the edge of the pack can easily run 5 °C higher in product temperature during their sublimation phase and finish their sublimation 35% earlier than vials in the center of the pack,” he points out. “These differences are very related to the equipment configuration and are one of the main reasons why freeze-drying protocols cannot be transferred without proper equipment characterization.”

“The next big source of variation comes from the freezing phase. Since ice nucleation is a stochastic event, nucleation temperature and timepoint will vary greatly between unit doses. Every unit dose in the lyophilizer will therefore form its ice crystals in a slightly different way,” he says, which affects their microstructure.

Therefore, Vanbillemont concludes, “A primary drying process model that includes the various sources of process variability can guide the process optimization and transfer,” and adhere to quality-by-design (QbD) principles.

Brecht Vanbillemont will discuss developing robust lyophilization processes for biopharmaceuticals during the  AAPS PharmSci 360 conference in October.