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

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

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

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.

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

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

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.

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

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

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

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

RANGE OF FREEZE DRYING PARAMETERS

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

CHALLENGES IN LYOPHILIZATION Excipients batch to batch variation (bulking agents like gelatin) Lyophilization losses are tremendous sometimes and lead to loss of productivity (100.5-101.0 ) up to 90 % But It seems to be possible by controlling better our lyophilization process using modern analytical tools

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

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