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For pandemic vaccine processing, single-use filter cartridges and membrane chromatography technologies could offer significant time- and cost-reduction advantages.
In today's seasonal influenza market, vaccine manufacturers must match supply to a conservatively estimated annual demand; this estimate is typically lower than what is needed, and so it can represent lost profits. The threat of an influenza pandemic presents an unprecedented vaccine manufacturing situation in which scalability, speed, and biosafety would be key issues. An avian flu strain could mean additional biocontainment challenges. Hence, alternative technologies are being developed to address the drawbacks of traditional platforms. The ideal vaccine manufacturing facility would handle multiproduct campaigns and would include a range of production and process platforms. Vaccine manufacturers should consider how to make a good business case for new production and facility concepts.
The increasing attractiveness of the influenza vaccine market, with its high-growth potential, is proving to be a key driver in planning and building new vaccine manufacturing facilities. The interest in new facilities is heightened by international initiatives focused on the need for ramped-up vaccine production in the event of a World Health Organization (WHO) pandemic Phase 6 declaration. (Phase 6 is a red alert signalling increased and sustained transmission of a virus in the general population, following previous confirmation of the onset of a pandemic [Phases 1, 2, and 3], in localized small clusters [Phase 4], and continuing toward limited transmission across larger clusters [Phase 5]). Although in the short term, new facilities could provide vaccine manufacturers with "the best equipped can best respond" strategies towards pandemic preparedness, the long-term commercial advantages of multipurpose facilities should be evaluated for return on investment and mitigation of financial risks.
The seasonal influenza industry of today can be viewed as the result of an imperfect market. Manufacturers match supply to a conservatively estimated demand for seasonal flu vaccines annually; this estimated demand is far lower than what would prevent or reduce related mortalities, and it results in lost economic productivity. Often seen as fickle, this low estimated seasonal influenza demand has not offered vaccine manufacturers the incentives to develop more efficient processes, and as the consequence of an underfunded market, it has resulted in a manufacturing system based on an antiquated process. This situation is now changing. Because it is expected that seasonal flu facilities will be modified to manufacture pandemic vaccines in a time of crisis, manufacturers' ability to deliver is belied by a global capacity shortfall. This shortfall will occur because the market size for a pandemic vaccine is potentially the entire world population. If represented as the "global influenza superset," this market has little or no relationship to current seasonal demand, yet it is wholly dependent on the supplies of "local subsets" of seasonal flu resources. Currently available capacities would be insufficient in a pandemic crisis, and new investments are driven toward building seasonal influenza manufacturing facilities. However, the key issue being raised is whether there is a good economic case for these new facilities, especially in markets with little or no demand for seasonal vaccines.
The US influenza market (Table 1) illustrates the "current pandemic shortfall–projected seasonal surplus" scenario. This model, when applied to the rest of the world, especially to the latent seasonal vaccines industry in developing countries, shows that the "current shortfall–future surplus" gap is even wider than might be expected. Manufacturers must, therefore, consider a different approach and question whether the surplus capacities planned for preparedness can be used for other programs.
Table 1. The US influenza market overview
The "on your mark, get set, go" manufacturing challenge for pandemic vaccine production is unique and unprecedented. The simplified timeline in Figure 1 illustrates key activities, starting from declaration of a Phase 6 pandemic alert and continuing to production and release of the first batch, leading to first vaccinations.
Figure 1. A timeline for manufacturing vaccines in response to a pandemic
It is expected that following a Phase 6 alert, there would be a lead time of about 3 to 4 weeks for the WHO to generate a master bank of the pandemic strain, which would subsequently be issued to manufacturers. From this point, it would take an estimated development period of about 6 weeks—which would include process adaptation or optimization of the cell-line to the new strain and generation of the master seed and working virus banks—to begin production. On a realistic schedule, these 6 weeks of development with concurrent bulking up of cells, plus an optimistic 2- to 3-week quality assurance (QA) release post-production, allows for a 17- to 18-week manufacturing campaign to produce enough doses to cover 100% of the target population. This is the best-case scenario, based on a 26-week timeline. In the worst-case scenario, the manufacturing campaign should be able to produce sufficient doses to cover the first dose of vaccinations before the second wave erupts.
A key challenge in meeting such a demand will be the capability to develop scalable manufacturing processes that are capable of rapidly deploying a surge production campaign in a facility designed to handle high-risk pathogens (such as H5N1), which require satisfactory biocontainment. Thus, three design factors—scalability, speed, and biocontainment—would typically form the conceptual basis of any multipurpose vaccine facility.
The influenza vaccine industry has traditionally manufactured seasonal vaccines using an embryonated egg–based process that has not changed fundamentally since the 1950s. Although an egg-based vaccine offers some advantages and is considered to be the best strike-back option at hand in the event of an immediate pandemic, production at scale has two significant drawbacks: aseptic processing limitations from a good manufacturing practice (GMP) point of view, and inefficient process scale-up issues from an engineering point of view.
In addition, with highly pathogenic avian flu strains that require operating classification levels of laboratory biosafety level 2 or higher (BSL2+), there would be limitations to biocontainment. These limitations increase with scale for egg-based processes, and they conflict with operator-environment safety. In addition, demand for a pandemic flu vaccine would have a surge characteristic, and it would pose an impractical case for responsive egg supply to meet the target of millions of doses in a very short time. Egg-based production also runs the risk of severe shortfalls in sourcing eggs from biosecure flocks and of culling of at-risk chicken populations. Also, if the pandemic strain were to target the chicken population (which is highly possible), egg-based manufacturing may not be feasible, because the eggs themselves might have antibodies against the circulating strain.
Cell-culture–based and alternative technologies currently in development aim to address drawbacks of the traditional egg-based platform for influenza vaccine manufacturing. By eliminating the constraints on egg supply, and by drawing on the benefits of large-scale bioprocessing with enhanced process control and quality assurance, cell-culture–based processes can be ramped up responsively. Traditional vaccine purification processes based on (ultra)centrifugation techniques are not easily scalable, and they are operationally difficult when closed processing conditions are required. Filtration and chromatography-based processes, on the other hand, can be engineered to scale with relative ease. In addition, with single-use units available today that are capable of handling high throughput, it is possible to have a purification train comprising partially enabled or completely disposable units for up to 8 out of 10 steps. Disposables-enabled unit operations are central to offering flexibility of scale to multipurpose facilities designed for meeting fluctuating market demands.
Global demand for influenza vaccine doses cannot be translated into cell-culture fermentation capacities, because they are largely dependent on varying productivity levels of different cell-lines and varying yields of different influenza strains. Moreover, in the case of a pandemic vaccine, the optimum dose required for effective immunity is unknown. These factors, when combined, pose a tricky proposition for vaccine developers between expanding capacity versus improving efficiency of their corresponding product platforms. Table 2 provides a summary of the current types of influenza vaccines in development and current production platforms being used to develop an avian or pandemic vaccine prototype.
Table 2. Current platforms for avian/ pandemic product candidates in development
Although several prototype pandemic candidates are in development based on mammalian cell-culture processes (Madin-Darby canine kidney [MDCK], Vero, Per.C6, and EBx), other alternative platforms are being developed that offer the potential for improved productivity per liter and hence, lower capacity requirements. Protein Science's and Novavax's insect-cell-culture–based processes are novel approaches with the potential to deliver low-cost options. VaxInnate's fusion product expressed in a bacterial system offers the promise of exceptionally high productivity levels per manufacturing volume. Manufacturing processes based on bacterial and yeast-based platforms, which are easy to scale up, are cost-efficient and tend to offer better and more consistent yields over cell-culture–based processes.
DNA-based vaccines in development also hold great potential, as they involve rapidly scalable processes that can produce high doses per manufacturing volume. Dry formulated DNA vaccines being developed by UK-based PowderMed offer the potential for a low-dose vaccination using a proprietary needleless epidermal drug delivery. GlobeImmune's yeast-based engineered whole-cell product, based on a simplified manufacturing process, offers the promise of a highly immunogenic vaccine.
The strain that would cause the next pandemic is uncertain, yet the threat is real. The impact market is global, production facilities are local, and the time to deliver the vaccine is a window of 24 to 26 weeks. Historical data suggests that pandemic influenza attacks follow a pattern, with the first wave at time zero and the second wave after a period of about 6 months; this attack pattern has historically contributed to the biggest percentage of mortalities. A third wave, if it happens, can be expected within 18 to 24 months from time zero.
These timelines, along with the very limited resources available today, make pandemic influenza vaccine manufacturing unique in the pharmaceutical industry. Although a combination of several pre-pandemic measures—involving stockpiling of antivirals and inter-pandemic vaccines—would serve as the first lines of defense, manufacturing for a pandemic vaccine would start only after a Phase 6 outbreak had been confirmed. Subsequently, the first batches of product that become available 4 to 6 months post-outbreak would offer hope for immunizations before the fatal second wave erupted (Figure 1). The race to deliver the vaccine on time would put demands on reducing turnaround times, performing labor-intensive support functions (with concerns about business continuity issues), and maintaining quality assurance. All of these requirements are achievable by integrating disposable technologies into the manufacturing process as much as possible.
Although it has been easy to realize the benefits that disposable technologies offer to simple unit operations such as mixing, buffer and media hold, and aseptic fluid transfer (all of which are carried out in fermentation), applying disposables with functional groups for separation of biomolecules has been a process challenge downstream. For a pandemic vaccine, reducing downstream purification steps on a risk-to-benefit basis by simplifying processes developed around single-use filter cartridges and membrane chromatography technologies could offer significant time- and cost-reduction advantages. Such disposable-based processes may provide a low-cost manufacturing option, especially in markets where affordability is as important as availability. However, this situation should be considered with complementing developments in adjuvant technologies that have potential for dose-sparing strategies that can further improve the cost-per-dose.
An incomplete list of single-use disposable options that can be integrated at various stages in manufacturing is shown in Table 3. Although by no means comprehensive, some of these technologies are available today, and many more are currently in development. These improved or novel methods are aimed at increasing throughput, improving aseptic intermediate operations, and improving containment.
Table 3. Single-use, disposable options across the production train
When designing production and laboratory facilities for higher biosafety levels (i.e., BSL2+ or BSL3), due consideration must be given to opposing biocontainment design principles with good manufacturing practices. Although GMPs keep contaminants "out of the manufacturing space" and thereby ensure the quality of the end product, they do not ensure safety for operating personnel and the environment. Biosafety guidelines, in turn, identify the product (such as a novel pandemic strain) as a high risk to the environment in the event of release, and hence, the guidelines label the product itself as a "contaminant" that is required to be "fully contained within the manufacturing space." While working with a low-biological-risk product, good manufacturing practices would assume highest priority; however, when working with highly pathogenic organisms, biosafety measures would have to take precedence over GMPs. This factor adds complexity to the operations and layout of a standard multiproduct manufacturing space (Table 4).
Table 4. The key opposing facility design principles
Manufacturing flexibility translates into optimal facility utilization to handle multiproduct campaigns. This approach would have to account for a broad range of production or process platforms, and thus the conceptual design of such a facility begins with the product(s) and the manufacturing process(es) (Figure 2).
Figure 2. A top-down facility design approach
Early stage process development and engineering assess the scalability and feasibility of disposable or novel technologies for potential process improvements; these features become the basis for a large-scale manufacturing strategy. Although resulting recommendations could significantly affect the facility design and layout, segregation of production lines in a multiproduct facility is critical to avoiding the risk of cross-contamination. Operating to the recommended biosafety level classification for biocontainment becomes important with increasing biological risk of the micro-organism in the event of release or accidental exposure. Flow considerations of raw materials, personnel, finished goods, and waste according to good manufacturing practices, plus biosafety measures, define the conceptual layout of the facility.
Scenario analyses and iterative approaches are then needed to test the requirements of scalability, speed, and biocontainment (Figure 3) before the conceptual project moves into the engineering phase. Fast-tracked project execution based on modular engineering principles can typically deliver such a facility in 12 to 14 months from the start of the detailed design to the end of commissioning.
Figure 3. Design triangle for a multipurpose, multiproduct facility (MPP)
New funding as a result of the global pandemic influenza action plan to increase supply has spurred vaccine industry initiatives in planning manufacturing capacity. Given uncertain factors and the potential surge capacity requirement involved in the avian or pandemic influenza vaccine market, preparedness could come at a high cost. Although such a pre-emptive measure is the right step forward, a key question the vaccine manufacturing community must ask is "What production and facility concepts should be applied to provide a good business case?"
Aeby Thomas is a process engineer at NNE Pharmaplan, Søborg, Denmark, +45 4444 7777, firstname.lastname@example.org. At the same company, Niels Guldager is a specialist, business consulting services, and Klaus Hermansen is a senior specialist, business consulting services.
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