1. FREEZE DRYING OF VACCINES- CURRENT TRENDS AND FUTURE SCOPE
Dr Gaurav Gupta
Vaccine Technology Center,
Zydus Cadila, Ahmedabad. India

2. Contents Classification of vaccines Freeze drying scope in Vaccines
Basics of lyophilization
Practices of Lyophilization in use
Challenges & Future scope in Lyophilzed products

3. CLASSIFICATION OF VACCINES
VIRAL VACCINES– LIVE OR KILLED
Lyophilized:
live - MMR, Varicella
Killed- Rabies
Liquid:
Live –Polio, rota
Killed-Hepatitis A, B & E, influenza ,Rabies, Japanese encephalitis
BACTERIAL VACCINES
Lyophilized: Hib
Liquid: DPTHiB- Hep B, typhoid, meningiococcal

5. SCOPE OF FREEZE FRYING
Most of vaccines are temperature sensitive and thermolabile.
But few of them are very unstable in liquid state therefore Lyophilized like live viral vaccines.
Due to enhanced regulatory stability requirements (37 degree C for 7 days) need to be lyophilized.

6. VACCINE PRODUCTION PROCESS FLOW
Upstream (production of antigen)
Downstream
(Purification of antigen from impurities )
Formulation
Blending
Filling and /or Lyophilization

7. LYOPHIZATION DEVELOPMENT STEPS FOR VACCINES
Selection of stabilizing agents combination of cryoprotective & bulking agents
Running placebo cycles to optimize moisture content (less than 2 %) and acceptable cake appearance
Optimizing lyophilization process to meet the regulatory requirements of product based on accelerated stability (37 degree C for 7 days)
Testing for critical quality parameters especially potency and stability

8. LYOPHIZATION DEVELOPMENT STEPS FOR VACCINES
5. If required changing formulations by optimizing stabilizer further and lypophilization accordingly to meet stability parameters.
It takes about 6-18 months and even longer for lyo cycle development
The process duration ranges from 3-7 days typically.

9. What is the goal of Lyophilization Development?
• Design an optimized cycle that can consistently produce product with acceptable quality and stability • Scale up and transfer the cycle to a production facility • Show consistency between development, clinical, and commercial batches • Demonstrate reproducibility

10. Critical Parameters in Freeze-Drying
Shelf temperature
Chamber pressure
Length of each phase
Thermal fluid heating/cooling rates
We strive to control all of the factors that effect these critical parameters

11. Development Pilot Studies
Characterize the Drug Product
DSC, DTA, Freeze-dry microscopy to determine Tg,Te, Tc
XRPD to determine crystalline/amorphous character
Target moisture content
Cycle Development/Optimization

12. Development Pilot Studies
• Cycle Development/Optimization - Optimized equilibration, freezing, annealing, primary drying, and secondary drying protocols • Determine container closure system and preparation - Type, formulation, coatings, washing, sterilizing, drying protocols

13. RANGE OF FREEZE DRYING PARAMETERS

14. CHALLENGES IN LYOPHILIZATION
At large scale due to long duration of process time while filling and loading leading losses
Maintenance of critical parameters (deeper cooling/ slower heating rates) due to lyophiliser performance over a period of time
Uniformity of process in different shelves
Inprocess monitoring of lyophilization process based on product probes

15. CHALLENGES IN LYOPHILIZATION
Excipients batch to batch variation (bulking agents like gelatin)
Lyophilization losses are tremendous sometimes and lead to loss of productivity ( ) up to 90 %
But It seems to be possible by controlling better our lyophilization process using modern analytical tools

16. FUTURE SCOPE Technologies to bring down time of cycle development
Facilitating scale up from between different make lyophilizers based on software instead of trial & error
Analytical tools & programmed software to monitor and control online shelf temperature & vaccum from cycle to cycle consistently
Integration of new inprocess monitoring tools in existing lyophilizers

17. THANK YOU