This article is an online exclusive bonus to the Pharmaceutical Technology October 2010 cover story, Vaccine Manufacturing Reborn.
PharmTech: Novartis recently built a plant for cell-based manufacture of influenza vaccine in Holly Springs, North Carolina. What will be produced at the facility?
Stober: Novartis opened its Holly Springs, North Carolina facility in November 2009 in collaboration with the US Department of Health and Human Services (HHS). The opening of the Holly Springs manufacturing facility is part of our continued commitment to address urgent healthcare needs for our patients.
The facility has been designed and constructed with the support of the US government to produce seasonal flu cell-culture vaccine, pre-pandemic [H5N1] and pandemic [H1N1] influenza vaccine. The facility will be ready to respond to an influenza pandemic as early as 2011 if licensed in an emergency. The plant is expected to be running at full scale and approved for commercial production in 2013. Additionally, the site will have a fill/finish facility capable of producing both flu and non-flu products.
PharmTech: Does Novartis also have an egg-based manufacturing program? If not, why not? If so, what are the challenges/limitations of producing vaccine in eggs? Are those challenges/limitations alleviated in cell-based systems? Are there challenges inherent in cell-based manufacture that are not challenges in egg-based systems?
Stober: Yes, Novartis uses both egg and cell-culture technology to produce vaccines in order to provide the greatest amount of vaccine. While egg-based technology is still the most widely used, cell-culture manufacturing offers several advantages over traditional egg-based manufacturing, such as the ability to more rapidly respond to time-critical situations, since there is no need for chicken eggs. Other advantages include more rapid and scalable manufacturing, enhanced consistency and reliability, and cell-culture-derived vaccines can be administered to patients who are allergic to eggs.
PharmTech: Please give me a sense of the relative yields of egg- versus cell-based systems.
Stober: Novartis sets high standards for all its products and aims to achieve the highest yield possible using both egg-based and cell-based technologies. As demonstrated from last year’s A(H1N1) pandemic, yields are a biological process and cannot always be guaranteed. Producing high enough yields was one of the main challenges in developing the H1N1 vaccine because the volume of vaccine produced depends on how well the virus can replicate. However, cultivating viruses using a cell line offers the possibility of a more robust virus production and seed-strain development that more closely matches circulating viruses, which could potentially translate into a more immunogenic and effective response.
PharmTech: Please give me a sense of the start-up times for egg- versus cell-based paradigms. Scale-up?
Stober: A major advantage of using next-generation influenza manufacturing where eggs are no longer used is that the lead time to order and take delivery of eggs is eliminated. The Novartis proprietary cell line also allows for manufacturing flexibility. Because the lead time is eliminated, cell-culture-derived influenza vaccine can be produced more quickly and efficiently in emergency situations such as pandemics. For example, Novartis was able to produce the first monobulk vaccine for the A(H1N1) pandemic in only 60 days.
PharmTech: How do you purify your cell-based vaccines? How does this compare with egg-based purification paradigms?
Stober: The Novartis cell-derived influenza vaccines are purified in a way that is similar to that used for egg- based vaccines, though there are additional purification steps. For example, host-cell proteins are removed during purification. In egg-based vaccines, some egg proteins remain in the vaccine.
PharmTech: Many people have said the cost of manufacturing vaccines in cells is prohibitive without government subsidies. The Holly Springs plant was built with a $485 million grant from the government. If the government had not bestowed this grant, would Novartis have built a cell-based manufacturing facility on its own?
Stober: New technologies are initially more expensive due to preliminary investment. Cell-based technology is an example of an innovation that required this type of investment. Once the technology is further developed and put into effect, the increased productivity makes the overall cost savings more apparent, which is why the partnership with the government was so important when building the facility. Additionally, cell-culture technology is beneficial because it provides a foundation for future biotechnology innovations.
PharmTech: If vaccine production is seasonal, how will the plant be used in the off season?
Stober: The facility in Holly Springs, NC, was designed to be capable of producing seasonal flu cell-culture vaccine, pre-pandemic vaccine, and 150 million doses of pandemic vaccine within 6 months of an influenza pandemic declaration. Additionally, the site will have a fill/finish facility capable of producing both flu and non-flu products.
PharmTech: Many companies are exploring the use of recombinant technologies for influenza vaccines. Does Novartis have such a program? If yes, please describe. If no, why not?
Stober: As a leader in innovative science and technology for vaccine development, Novartis Vaccines is not using only cell culture technology, but is also applying additional scientific breakthroughs such as adjuvants and reverse vaccinology to develop the most efficacious vaccines possible.
Reverse vaccinology is a method by which viruses such as influenza are generated from segments of DNA. For prospective pandemic influenza vaccines, reverse vaccinology can be a useful technology because the process does not require manufacturers to work directly with potentially highly infectious pandemic strains, rather only segments of the virus's genome.
PharmTech: I understand that Novartis has a proprietary adjuvant. Could you describe what this adjuvant is and how it stimulates the immune system?
Stober: Novartis’s proprietary adjuvant MF59 has an established safety profile. It is the only oil-in-water adjuvant supported by more than 12 years of post-marketing clinical safety data and more than 45 million doses of commercial use. The adjuvant has also been studied in randomized clinical trials and observational studies involving 124,000 individuals including children, adults, and elderly, and has been licensed for use in individuals 65 years of age and over in the seasonal influenza vaccine, FLUAD, since 1997 in the European Union.
Benefits of vaccines produced with the MF59 adjuvant include established safety, immunogenicity, cross-reactivity, long-term boost-ability, T-cell immune memory, and antigen-sparing properties.