Telstar reveals its solution to developing a freeze-drying recipe for a cytotoxic product in a solution of water and tert-butyl alcohol as a solvent, in this case study.
Recipe
Telstar table
The company
Telstar focuses on the design, manufacture, sales and support of high technology equipment solutions for the pharmaceutical, biotech and related industries with a range of product offerings, including GMP lyophilisers with integrated automatic loading/unloading systems.
The challenge
A customer wanted to develop a freeze-drying recipe for a cytotoxic product in a solution of water and tert-butyl alcohol as a solvent but did not have the tools and expert knowledge to successfully perform this task in a cost-effective way while also maintaining the initial product properties.
The solution
The company contracted Telstar’s services to develop the best freeze-drying recipe in accordance with its requirements as well as those of the product, including a solution to the problem of powder ‘blow out’ from the vial and an upper ring of product in the vial wall.
The Telstar’s process to develop and design a freeze-drying recipe consisted of:
1) Differential scanning calorimeter (DSC) study to find out the thermal product properties
Differential scanning calorimeter study
Telstar Figure 1
2) Cryogenic microscopy analysis to seek the critical temperature to freeze dry the product.
Cryogenic microscope product photos (1st figure: good freeze drying of sample; 2nd figure: product collapsing)
Figure 2.1
After gathering this information several freeze-drying tests are performed at the laboratory to optimise the recipe to obtain a good product, as quickly as possible.
Development problems
The freeze-drying study of the product highlights two main process problems.
1) Explosion of product and powder ‘blow out’ of the vial
This effect is a result of the fact that the freeze-dried cake is not cohesive enough to withstand being ejected from the matrix by the water vapour escaping from the sublimation front.1 Product ejection is more common in formulations containing organic solvents such as this product which contains tert-butyl alcohol so, it is believed that the explosion of product corresponds to the dilute solution part of TBT in water.
1st figure: Product ‘blow out’. 2nd & 3rd figures: Exploded product cakes.
Figure 3.1
This fact not only shows the product mass lost in vials, but also an important contamination of the freeze dryer chamber.
Several conditions of temperature and pressure were studied together with a video camera to monitor the explosion moment.
Solution:
Soft temperature and pressure of primary drying at freeze-drying recipe to avoid the aggressive ‘blow out’ of product.
2) Upper ring of product in vials
After the freeze-drying tests some stains and sometimes rings of product appeared on the vial walls. There are various possible reasons for this effect:
- Aggressive manipulation of the vials during the dosing and/or loading the freeze dryer.
- Blow up of frozen cake at the beginning of pulling vacuum.
- The low surface tension of TBT-water solution in contact with vial walls promotes liquid to rise and wet the walls.
Stains and upper-ring of product on vial walls
Figure 4.1
At the beginning of the vials dosage, this effect was observed together with a noticeable concave meniscus. Therefore, the low surface tension was the reason for the product on the walls.
Solution:
Study different treated vials and choose the ones which avoid the defect. Depyrogenated, siliconised, as well as other types of glass material affect the results of ring.
The results
Development defects were solved obtaining good cosmetic cake and cost-effective cycle duration. Product properties were not damaged after being freeze dried.
Good and acceptable cosmetic cake
Figure 5.1
The improvement opportunities
Customer has a robust freeze-drying recipe in which:
- Product does not explode during cycle
- Absence of cosmetic cake defects (upper ring)
- Assure the quality and properties of product (it has been analysed by the client)
- Optimised duration of cycle to achieve the correct product results
- Saving product and money
Reference:
- Lyophilized Drug Product Cake Appearance: What is acceptable?; Journal of pharmaceutical science, 2017