A continuous and controlled pharmaceutical freeze-drying technology for unit doses
Among the list of over 300 FDA and EMA approved biopharmaceutical products, around 50% are freeze-dried – indicating that freeze-drying is the preferred way of stabilising biopharmaceutical drug products that are unstable in aqueous solution, despite the high cost and long processing time linked to this manufacturing technique.1,2
Freeze drying is a low-temperature drying process, based on the principles of heat and mass transfer, employed to convert aqueous solutions of (heat-)labile materials into solids with sufficient stability for distribution and storage.3 Many biopharmaceuticals have limited stability in aqueous solution and are subject to a number of degradation pathways mediated by water, which might result in a lower potency or even in toxicity of the drug molecule. A pharmaceutical freeze-drying process consists of three consecutive steps:
- During freezing most of the water crystallises to ice, thus concentrating the solutes between the ice crystals. Some of the solutes crystallise during freezing, while those that do not are transformed into a rigid glass
- The ice crystals are removed under vacuum by sublimation (primary drying). Heat is supplied to the frozen product for sublimation, but the product temperature is kept below the collapse temperature to avoid structural product collapse, hence ensuring a solid and rigid dried cake after freeze-drying
- A secondary drying step where most of the unfrozen water (ie, water dissolved in the amorphous phase) is removed by diffusion and desorption.
The most important critical quality attributes evaluated after freeze-drying on randomly selected samples using off-line analytical techniques are: (i) the API state (eg, protein conformation) and stability; (ii) the residual moisture content; (iii) the freeze-dried product cake appearance; (iv) the reconstitution time.
For more than 80 years, pharmaceutical freeze-drying has been performed using an unchanged batch-wise approach, although the handling equipment before (filling) and after (capping and packaging) freeze-drying is continuously operated by nature. A typical pharmaceutical freeze-dryer consists of a vacuum drying chamber in which the pharmaceutical unit doses (vials) are placed on temperature controlled shelves…