Introduction to Vaccines - CMC Regulatory and Quality Aspects

This course provides a solid foundation to understand scientific, global regulatory principles and approval strategies of Cell & Gene Therapies. It allows to coAt the end of the three-day course attendees will:

• Gain a solid understanding of the regulatory framework for vaccines for prophylactic (infectious disease) and therapeutic indications, incidents that have prompted regulation, and an understanding of the differences and commonalities of vaccine regulation versus small molecule drugs and other biologics. 
• Understand the structure of CBER within FDA and its historical evolution, and the processes in place in EU for review and authorization of new vaccines. 
• Understand the fundamental bioprocess steps in production of bacterial and viral (cell-based) vaccines and control testing requirements/strategies, including a basic understanding of Master Cell Banks, Master Viral Seeds, upstream and downstream processes, and testing/characterization of process- and product-related impurities and adventitious agents.
• Gain an understanding of the elements of the immune system and its response to vaccines, and the use of basic immunological methods used in the quality control and characterization of vaccines.
• Gain an understanding of the different types (classes) of prophylactic vaccines in commercial use, including live attenuated vaccines, inactivated bacterial and viral vaccines, subunits/toxoids, recombinantly produced vaccines and gene-based (mRNA) vaccines, and an understanding of approaches (vaccine types) being evaluated as potential therapeutic vaccines for conditions such as cancer.  
• Understand the rapid development of COVID-19 vaccines through government funding (OWS, BARDA) and the current FDA requirements for Emergency Use Authorization (EUA) and full approval (BLA) of COVID-19 vaccines. Gain an understanding of different approaches undertaken by companies globally to develop COVID-19 vaccines and real-word safety experience, and understand the quality control strategies applied to these vaccines.

Historical Development of Vaccines

• From smallpox vaccination to today’s new mRNA vaccines for COVID-19
• Classes of vaccines (live attenuated, inactivated bacteria and viruses, toxoids and subunit vaccines, recombinant proteins/viruses, gene-based vaccines)
• High level view of vaccines in commercial distribution today
• Progression of vaccines recommended for routine use: 4 pediatric vaccines (1940s) to 15 vaccines today.

Development of Vaccine Regulation

• Early regulation of vaccines/biologics in the US – a horse named Jim 
• Regulations evolve in parallel with traditional drugs: The Public Service Health Act (PHSA) and the Food Drug and Cosmetic Act (FD&CA)
• The “Cutter Incident” and other disasters spur regulation
• Vaccine regulatory authority moves from NIH to FDA; more than just an administrative shift
• What is a vaccine, anyway?
• Current organization of CBER within FDA; Office of Vaccines Research and Review, Office of Tissues and Advanced Therapies 
• MAA pathways in EU for vaccines (Centralized Procedure, Decentralized and Mutual Recognition procedures)

Immunization policy in the US and EU

• Roles of CDC and ACIP, and FDA and VRBPAC in the US
• Decentralized vaccination policy within the EU (vaccines used, routes of administration, vaccination schedules)

Vaccine Production Overview – Basic Production Processes for Bacterial and Viral Vaccines 

• Fundamental process steps for vaccine production
• Upstream and downstream vaccine production processes – a high level view 
• Examples of manufacturing process flows for a bacterial conjugate vaccine and an inactivated influenza vaccine
• Master Cell Banks and Master Virus Banks for vaccine production; ICH Q5B and Q5D, FDA Guidance on Viral Vaccines
• Cell substrates used to produce licensed vaccines
• Vaccine purity/impurities:  process related impurities, product related impurities and adventitious agents; regulatory and quality considerations; ICH Q5A    

Vaccine Production Overview – Basic Production Processes for Bacterial and Viral Vaccines - continued 

Requirements and Testing Strategies for Vaccines

• Requirements imposed by PHSA and FD&CA
• Review of 21 CFR 600-680 requirements pertinent to vaccines:  Biological Production Deviation Reports, establishment inspection and “Team Biologics”, VAERS reporting, vaccine lot release, biological potency testing and potency tests employed for different classes of vaccines  
• Requirements for vaccines and other drugs alike:  21 CFR 200s, 300s, and more 
• Overview of ICH Guidelines and companion FDA Guidance relevant to vaccine development
• Examination of ICH Q6B (Test Procedures and Acceptance Criteria) as applicable to vaccines
• Some typical QC release testing plans for vaccines (bacterial, viral/cell culture based)  

Basic Vaccine Immunology

• Elements of the immune system:  innate and adaptive immune systems
• Immune response to a vaccine:  characteristics of the immune response, factors affecting the response to a vaccine
• Measuring the response to a vaccine in clinical trials and potency assays:  serum neutralization, antibody titer by ELISA
• Other immunological tests for vaccines:  Lf test to quantitate toxoids, SRID for flu vaccine potency 
• Adjuvants:  purposes, classes of adjuvants in vaccines; regulatory assessment of novel adjuvants (EU Guidance)   

Therapeutic vaccines

• Distinction between therapeutic and prophylactic vaccines
• Approaches to development of therapeutic vaccines for cancer: some hits and misses so far 

A focus on COVID-19 vaccines:  vaccine development approaches to the pandemic

• Overview of SARS-CoV-2 virus and COVID-19 disease; recent history; development of “variants”
• Operation Warp Speed funding of vaccine development; BARDA
• FDA Guidance on development of COVID-19 vaccines:  requirements for EUA and BLA approval
• Vaccine development approaches:  inactivated whole viruses, subunits, mRNA, DNA, viral vectors 
• A deeper look at mRNA vaccines:  the basic science of this new vaccine approach; structure of mRNA vaccines, in vitro transcription production, nanoparticle formulations
• QC control strategies applied to mRNA vaccines