Considerations for Ensuring Safety and Efficacy of Vaccines and Therapeutic Proteins Manufactured by Using Platform Approaches Summary of a Workshop (2010) / Chapter Skim
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INTRODUCTION/PLATFORMS FOR LARGE-SCALE MONOCLONAL ANTIBODY PRODUCTION/PLATFORMS FOR VACCINE PRODUCTION/SUMMARY OF KEY POINTS
INTRODUCTION/PLATFORMS FOR LARGE-SCALE MONOCLONAL ANTIBODY PRODUCTION/PLATFORMS FOR VACCINE PRODUCTION/SUMMARY OF KEY POINTS
Pages 1-15
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From page 1... ...
The TMTI's condensed timetable is likely to drive countermeasure developers to pursue regulatory review at the same time as product-development efforts that include scaling up production. With respect to the likely review of TMTI countermeasures, it is instructive to look at how FDA officials annually evaluate changes in the trivalent influenza vaccine, which is reformulated to optimize activity against currently circulating variants of the influenza virus.
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From page 2... ...
There is less uniformity because of the wide array of vaccine types, including live attenuated or killed viruses, killed bacterial cells, purified polysaccharides and proteins, glycoproteins, conjugate molecules, and vaccines that consist of DNA molecules that encode specific proteins. TMTI Case For Versatile Production Platforms Brian Reinhardt, TMTI discovery deputy, and Darrell Galloway, director of the Defense Threat Reduction Agency Chemical and Biological Technologies Directorate, described a key goal of the TMTI program as fostering development and production of broad-spectrum countermeasures against genetically modified and other novel biological threats.
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From page 3... ...
Some participants suggested that the latter approach provides an advantage -- instead of relying on stored products, the TMTI program could specify short-term production of an alternative, possibly upgraded countermeasure, allowing for adjustments that take into account recent technical or scientific advances -- and likened the adjustments to what happens each year when the seasonal influenza vaccine is produced. However, Harry Greenberg, senior associate dean for research at Stanford University, said that the analogy does not fit the situation that the TMTI faces in that experience with the influenza vaccines covers at least 40 years of regular use in human populations, whereas the substitution of a new countermeasure for one that is only slightly older could not have built up a comparable clinical record.
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PLATFOMS FOR LARGE-SCALE MONOCLONAL ANTIBODY PRODUCTION Brian Kelley, senior director of bioprocess development at Genentech, and Dane Zabriskie, vice president of process development at Amgen, described similar processes for producing MAbs on an industrial scale for human health applications. Kelley said that large-scale MAb production processes are consistent and reliable, so they are more likely than an altogether novel approach to be used for producing therapeutic materials to meet the timetable specified by DOD under the TMTI.
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From page 5... ...
During this period, a producer would also need to be working with FDA officials for the purpose of evaluating and licensing the final product, and also for certifying the production process insofar as is necessary. Kelley stated, in part because of such regulatory issues, it seems preferable to keep to the current, fully vetted approach to producing MAbs instead of switching to an alternative process.
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Although the largest known bioreactor for growth of mammalian cell lines is thought to be the 25-kL vessel at Genentech, Zabriskie predicts that efficiency gains at the cell level and at other stages of MAb production between now and 2014 could mean that smaller bioreactors will be sufficient to meet TMTI-specified production goals. The overall yield of 10 MAbs that Amgen had in development as of 2005 varied from 40% to 80%; it was about 70% for most of them.
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From page 7... ...
The next eight-year phase depends in large part on clinical development and evaluation and is very much "clinically driven." If TMTI products will not be subjected to traditional clinical-efficacy trials, the required safety and pharmacokinetic clinical trials could be completed in 7–12 months, according to Zabriskie. Nevertheless, determining the appropriate molecular targets for effective use of MAbs as countermeasures against particular biothreat agents is a timeconsuming step -- one that could take up to six years to complete, according to Zabriskie.
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Most of the discussion centered around using mammalian cells to produce MAbs, but the group also discussed whether production timelines could be condensed by 8
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Placing the discussion of mammalian cell efficiencies in perspective, Kelley estimated that time savings from implementing even several of the refinements would be around 10–20%, not 50%, for overall production of MAbs. Manufacturing Production Capacity Moving beyond the discussion of whether MAb platforms in general are capable of meeting the TMTI's needs, participants discussed manufacturing facilities.
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From page 10... ...
Because postproduction regulatory issues might slow the approval process for countermeasures that the TMTI is seeking, several participants suggested that DOD consider investing in research that addresses the CQA issues outlined by Zabriskie above. Participants also noted that the FDA sponsors workshops that include exercises in which product sponsors submit mock IND filings to the agency as a way of gaining experience that can be used in shepherding real products through regulatory reviews.
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From page 11... ...
Marks, of the University of California, San Francisco, raised the possibility of using polyclonal instead of monoclonal antibodies for counteracting pathogens. However, that approach could complicate regulatory reviews, particularly if a bank of several dozen MAb-producing cell lines were used to make the polyclonal-antibody mixture, according to Kelley.
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Vaccine developers are immersed in determining efficacy, but Robinson stated that they also need to be developing appropriate bioassays that will later be used as surrogate markers of clinical efficacy. Discussion Participants discussed platform technologies, manufacturing, and regulatory and efficacy issues.
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From page 13... ...
Contract manufacturers could help in meeting vaccine-production needs, but building production capacity among producers of specialized vaccines seemed preferable to at least one participant. The construction of multipurpose vaccine facilities is feasible; Merck has a pilot vaccine facility that is capable of running different platforms, and its versatility encompasses several production platforms, including adenovirus, E
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From page 14... ...
This participant noted that gaining regulatory acceptance of novel approaches, such as one that depends on baculovirus for production, would prolong initial reviews of vaccines that were intended to serve as TMTI countermeasures. For example, the first reviews of DNA-based vaccines drew heightened scrutiny from FDA.
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From page 15... ...
Galloway pointed out that the TMTI is not committed to developing conventional vaccines and is seeking novel ways to induce protective host responses. SUMMARY OF KEY POINTS Patriarca reviewed what was discussed at the workshop, namely the prospects of producing adequate supplies of safe and effective MAbs and vaccines to meet TMTI needs to provide US military forces with countermeasures against biothreats.
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