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Accelerated development of new preventives raises challenges for efficient CMC evaluation and production.
A lethal influenza outbreak this past winter has spotlighted the importance of improving and accelerating vaccine discovery and production. Reports that this year’s flu vaccine was only 36% effective have raised concerns about continued use of egg-based production systems that appear outdated and less reliable. And the imperative to combat infectious disease outbreaks and deadly conditions such as malaria and tuberculosis emphasizes the need to modernize and streamline vaccine testing and manufacturing.
A source of optimism is continued development of new, more effective inoculations. In 2017, FDA’s Center for Biologics Evaluation and Research (CBER) approved GlaxoSmithKline’s new Shingrix vaccine against shingles and a new recombinant hepatitis B preventive from Dynavax Technologies featuring a new adjuvant to boost immune response. A report from the Pharmaceutical Research and Manufacturers of America (PhRMA) in late 2017 lists 264 vaccines in development, including 137 for infectious diseases and more than 100 for cancer (1). And while vaccines are expensive in the United States, costs in low- and middle-income countries are dropping as regional producers such as India’s Bharat Biotech gain World Health Organization (WHO) prequalification for important preventives.
Vaccine discovery, however, remains challenging and unpredictable for the biomedical research community and industry. Even though increasingly effective vaccines are eliminating diseases such as polio and diphtheria and helped stem the Ebola outbreak three years ago, promising candidates often fail. Sanofi recently halted distribution of its dengue fever vaccine in the Philippines after some patients developed the disease following injection (2).
Such setbacks fuel anti-vaccine campaigns around the world, as seen in attacks on inoculation programs to combat a yellow fever outbreak in Brazil and on measles vaccines in the United States and Europe. Rumors of health risks continue to discourage vaccination of teens against human papillomavirus (HPV) despite evidence that it can prevent cancer.
FDA Commissioner Scott Gottlieb, MD, voiced strong support for vaccines at his Senate confirmation hearing in April 2017, where he dismissed as groundless claims of a causal link between vaccines and autism, distancing himself from earlier challenges to vaccine safety by President Trump. In an announcement of spending priorities for 2019, Gottlieb highlighted the importance of advancing manufacturing technologies for drugs and biologics, including vaccines. He noted that continuous manufacturing platforms can help ramp up vaccine supply on short notice and that FDA clarification of its requirements and standards should encourage industry investment in new technologies and opportunities (3).
FDA support is important in maintaining an efficient development and review process to deliver vaccines that meet high standards to ensure product safety and quality. FDA is applying lessons learned from Ebola to streamline vaccine development, noted Philip Krause, deputy director of CBER’s Office of Vaccine Research & Review (OVRR), at the January 2018 WCBP symposium in Washington, DC. Krause emphasized how FDA strives to review and approve submissions and manufacturing supplements in a “sensible” way that emphasizes good science. CBER also encourages manufacturers to meet with FDA staff to address chemistry, manufacturing, and controls (CMC) issues before filing an application.
Robin Levis, deputy director of OVRR’s Division of Viral Products, further described how FDA’s Fast Track and priority review programs facilitated development of Ebola vaccines and other preventives. To keep pace with accelerated clinical testing of potential Ebola preventives, FDA collaborated with other regulatory authorities and WHO to gain convergence on key issues, such as exceptions to product characterization and testing procedures, and where certain aspects of process validation could be abbreviated. While FDA licenses only those vaccines supported by adequate and well-controlled studies and able to be manufactured in a consistent manner, Levis noted that there may be flexibility when combating epidemics, such as accepting supportive CMC data from platform-related products and specifications based on related products. Test vaccines also may be used prior to obtaining real-time stability data, especially for early clinical trials.
An accelerated pathway for vaccine testing, however, “puts the squeeze on the CMC window” for process definition, characterization, and qualification, commented Natalie Christian, integrated development and supply team lead at Merck, at the January WCBP symposium. Vaccine development may be even more challenging, she observed, due to limited platform technologies for these products, potential for process change during technology transfer, scale-up difficulties, and a need for additional qualification lots. Similarly, Cristiana Campa of GSK Vaccines in Italy emphasized that the complexity of vaccine development makes it important to define a control strategy for identifying critical quality attributes as early as possible to help screen and select adjuvants and to identify attributes to be tested in clinical studies.
Advances in designing small footprint, single-use bioreactors will provide vaccines quickly at greatly reduced cost, predicted Benjamin Damien, director of business development at Belgium-based Univercells. He said these developments will “transform the biopharmaceutical industry” by boosting local production and supply of high-quality vaccines in developing countries, while also expanding capacity for rapid response to epidemics and global threats.
Many of these initiatives have support from the Bill & Melinda Gates Foundation, which has led efforts for the past decade to spur vaccine development to combat global diseases. To enhance the process, Gates established the Medical Research Institute (Gates MRI) in Boston to work closely with scientists and biopharma companies on identifying, selecting, and optimizing production of novel vaccine candidates. Gates veteran Penny Heaton is building the MRI with the aim to eradicate malaria, accelerate the end of the tuberculosis epidemic, and prevent diarrheal deaths in children through developing new drugs, vaccines, biologics, and diagnostics. Heaton outlined plans at the WCBP symposium for supporting early clinical testing of products that then can be passed on to manufacturers for late-stage development and commercialization. She anticipates a strong focus on CMC issues, which she described as often the “number-one bottleneck” in vaccine development.
Meanwhile, the race is on to discover a universal flu vaccine that doesn’t require reformulation every year. A dozen candidates are undergoing preclinical and clinical testing at research institutions and commercial labs. This coincides with efforts to shift from egg-based to cell-based and recombinant DNA production technologies. In commenting on the effectiveness of this year’s flu vaccine, Gottlieb noted that products made with cell-based methods appear more effective in protecting against the H3N2 virus than egg-based products (4).
Seqiris, a unit of Australia’s CSL, plans to produce 20 million flu vaccine doses this year using cell culture at its North Carolina facility, and Sanofi has linked with South Korean vaccine maker SK Chemicals to tap its cell-based vaccine production technology. A live attenuated intranasal FluMist vaccine from AstraZeneca’s MedImmune division, an alternative to painful sticks, is back on the US recommended list after a two-year suspension due to data indicating low efficacy.
Despite the shortcomings of annual flu vaccination, health authorities continue to stress the importance of regular immunization to prevent thousands of deaths from influenza each year, particularly in children and the elderly. Hopefully, the research community will devise a more reliable and effective universal flu vaccine before the next, much-feared influenza pandemic strikes.
1. A. Powaleny, “New Report and Event Examine the New Era of Vaccines,” The Catalyst, Nov. 9, 2017.
2. Sanofi, “Sanofi Updates Information on Dengue Vaccine,” Press Release, Nov. 29, 2017.
3. FDA, Statement from FDA Commissioner Scott Gottlieb, M.D., on Administration’s Request for New FDA Funding to Promote Innovation and Broaden Patient Access through Competition, Feb. 13, 2018.
4. FDA, Statement from FDA Commissioner Scott Gottlieb, M.D. on the Efficacy of the 2017-2018 Influenza Vaccine, Feb. 15, 2018.
Vol. 31, No. 4
When referring to this article, please cite it as J. Wechsler, "Modern Manufacturing Key to More Effective Vaccines," BioPharm International 31 (4) 2018.