Department of Pharmaceutical Analysis

Laurens De Meyer

Laboratory of Pharmaceutical Process Analytical TechnologyLaurens.jpg

Ottergemsesteenweg 460
B-9000 Gent (Belgium)
Tel.: +32-9-264.80.82
Fax: +32-9-222.82.36
E-mail: Laurens.DeMeyer@UGent.be
Education: Pharmacist (Master in Industrial Pharmacy)

Continuous freeze-drying concept for biopharmaceutical products

Since large molecules are considered the key driver of growth for the pharmaceutical industry, the focus is shifting from small molecules to biopharmaceuticals. Among the list of Food and Drug Administration (FDA) and European Medicine Agency (EMA) approved biopharmaceutical products (> 300), approx. 50% are freeze-dried products. This indicates that freeze-drying is the preferred way of stabilizing biopharmaceutical drug products that are unstable in aqueous solution (e.g., water mediated degradation pathways), despite the high cost and energy consumption and long processing time linked to this manufacturing technique. The largest fraction of freeze-dried biopharmaceutical products are therapeutic protein formulations and vaccines. Influential biopharmaceutical companies predict a compound annual growth rate (CAGR) of 4.4% for biopharmaceutical products as contrasted to small-molecule products with a growth rate below 1%.

Freeze-drying (lyophilisation) is a drying process that consists of three consecutive steps: freezing, primary drying (ice removal by sublimation) and secondary drying (removal of unfrozen water). Conventional pharmaceutical freeze-drying is performed batch-wise: vials are placed on temperature-controlled shelves in the drying chamber. However, batch wise freeze-drying is associated with significant disadvantages:

  1. The freezing step is uncontrolled which has a significant impact on the consecutive drying steps.
  2. The heat transfer in the freeze-drying chamber is uneven, which results in temperature differences in vials that are placed at different locations on the freeze-drier shelves.
    Both disadvantage 1 and 2 result in an uncontrolled vial-to-vial and batch-to-batch end product variability.
  3. Freeze-drying is a slow, and hence time-consuming and expensive process.
  4. Freeze-drying is a batch process, but the handling equipment before (filling) and after (capping, packaging) the process is continuously operated.
  5. The handling equipment takes up a large area of space which is very expensive because of the high standards of cleanliness and sterility.
  6. A batch freeze-drier is commonly designed and optimized to only process the largest applicable amount of vials.
  7. The installation is subject to various thermal and pressure conditions which can lead to thermal inefficiencies, so the transient conditions may not be well defined.
  8. The course of the freeze drying process cannot be monitored at the scale of the individual vial: the product behaviour (at molecular level) in each vial during freeze-drying is unknown.
  9. Up-scaling requires complete re-optimisation and re-validation of the process.

The aim of this PhD thesis is to perform the fundamental research needed for providing a continuous freeze-drying concept. The main focus will be on the freezing step.

The continuous freeze-drying concept starts with a continuous freezing step where the vials are spin frozen. To achieve this, the filled vials are rotated along their longitudinal axis, creating a thin frozen product layer on the entire vial wall. The surface area will be larger compared to traditional batch freeze-drying.

Some research questions arise with this new freezing method:

  1. Continuous spin freezing allows us to use more and faster cooling rates compared to traditional freeze-driers. It should be examined if these parameters affect the drying processes and the product quality.
  2. To protect proteins during the freezing step, cryoprotectants are added to the formulation. It should be examined if these protectants are still needed, if the stress mechanisms are the same as those in batch freeze-drying or if other protection strategies are needed.
  3. During the spin freezing, the vials are rotated rapidly. It should be evaluated if this can cause protein degradation or aggregation.
  4. Rotation of the vials is expected to trigger the onset of the ice nucleation. This will overcome the supercooling variability in batch freeze-drying. But it should be evaluated if supercooling variability is eliminated and if the degree of supercooling can be controlled.
  5. Traditional formulations contain standard excipients like buffers, cryoprotectans, lyoprotectans, bulking agents,… It should be examined if these excipients are still needed or if other excipients should be added to the formulation.