(Gaurav Gupta, Vaccine Technology Centre, Zydus Cadila, India) CREATIVE IMPLEMENTATION OF NEW TECHNOLOGY PLATFORMS FOR RAPID PRODUCTION AND MANUFACTURING OF VACCINES & ANTIBODIES (Gaurav Gupta, Vaccine Technology Centre, Zydus Cadila, India)

CONTENTS Current Global trends in production of vaccines and antibodies Key targets for new technologies implementation in Vaccines & antibodies Challenges and future potential in implications

CURRENT GLOBAL VACCINE PRODUCTION TRENDS Cell culture MRC-5 cells- MMR, Varicella, Rabies Vero cells- JEV, Rabies, Influenza, Rota, Polio, Dengue Primary cells- CEF for Mumps, Rabies Fermentation E Coli/Yeast culture- Papilloma, Hepatitis B, Malaria Seed strains (Diphtheria, Pertussis, Tetanus, Hemophilus, Pneumococcal, Meningiococcal) Egg based Allantoic route: Influenza Yolk sac: Rabies Animal based Mice brain: JEV, Congo

CURRENT GLOBAL ANTIBODY PRODUCTION TRENDS Cell culture CHO cells Hybridoma PERC.6 HEK293 fermentation E Coli/yeast - Antibody fragments Animal immunization Mice and rabbits Horse

Information technology KEY TARGETS FOR NEW TECHNOLOGIES IMPLEMENTATION IN VACCINES & ANTIBODIES Production & testing GMP facility Manpower Documentation Information technology Logistics

PRODUCTION AND TESTING METHODS

PRODUCTION PROCESS FLOW Production of antigen or antibodies in suitable substrate system Purification of antigen/antibodies Formulation, filling and lyophilization Inprocess and finished product testing & release to Market Time should be reduced at every step for rapid Manufacturing

Rapid Production of antigens/antibodies 1. Adaptation of seed strain/Clone in substrates of quick production No substrate E coli Yeast mammalian cells Eggs Animals

Bioreactors- disposable/ reusable Rapid Production of antigens/antibodies 2. Selection of rapid production platforms: Cell culture Bioreactors- disposable/ reusable Robotic cell culture system Manual techniques- roller bottles/ cell factories Fermentation Fermenters Shake flask cultures Egg based Automatic inoculation, harvesting Manual techniques Animal based Small animals Large animals

Rapid Purification of Antigen/Antibodies Clarification Continuous centrifugation Batch centrifugation filtration ultrafiltration Precipitation Ammonium Sulphate PEG Column chromatography Ion exchange/Hydrophobic/ affinity gel filtration Ultracentrifugation continuous batch sucrose gradient cesium chloride gradient Ultrafiltration hollow fibres Tangital flow filtration Diafiltration dialysis membranes Filtration cross flow depth filtration

RAPID FORMULATION, FILLING AND LYOPHILIZATION Blending in disposable bags Blending in vessels Use of animal origin free excipients use of animal origin excipients Filling speed Filling containers Single type of vial/PFS for single and multiple doses Different vials/PFS Lyophilization capacity Lyophilization cycle Cycle optimization to reduce cycle time Packing & release Automatic visual inspection, labeling & packing Manual

Rapid Testing Methods Carbohydrate Lipid Host cell protein (Genomics & Proteomics) Characterization methods Seed Drug substance & Drug product Rapid microbiological tools Sterility (Bacterial, Mycotic, Mycoplasma & Mycobacteria) EMP (cell based, Immunoassays) Potency methods In vitro methods In vivo methods Biochemical methods (Kit based) Carbohydrate Lipid Host cell protein Host cell DNA

GMP FACILITY Installation of Flexible modular facility for quick production as per BSL requirements Installation of multiproduct facilities Upgradation with modern instruments for rapid production in existing facilities

INFORMATION TECHNOLOGY Updated softwares for all respective areas in production, quality and regulatory Access to online global knowledge sharing domains Introduction of Project management softwares LOGISTICS Online purchasing of raw materials Robotic dispensing of raw materials Online Inventory management of raw materials and finished products

MANPOWER Training onsite & offsite to Production, QC,QA, engineering & regulatory staff on regular basis for new technologies DOCUMENTATION: Paperless Online system of documentation for production, testing and release

CHALLENGES IN IMPLICATIONS OF RAPID MANUFACTURING Evaluation of need-Market demand & process upgradation Environment concerns due to heavy waste generation Cost implications for process, facility and registration Commercial returns & payback period

FUTURE POTENTIALS Promising for launching new product where no better alternative is available for global unmet health problems (Malaria, Dengue, TB,HIV) High productivity is expected so low cost of production due to efficient infrastructure and organization. Less manpower dependent therefore high consistency can be expected. Lesser time to reach Market

CONCLUSIONS Rapid manufacturing tools and technologies are now available for worldwide use in vaccine and antibodies production. Considering present marketed products, it will be only a mindset question to take forward for execution. Keeping ourselves updated with new technologies will be the key for execution. The national regulatory environment has a lot of impact on the success of introduction for new technologies and products in the relevant country and need to be addressed. For future novel products it will be widely and easily acceptable due to lesser commercial & regulatory challenges.

THANKS