Optimizing Vaccine Production to Meet Increasing Demand
By Björn Lundgren, PhD, Marketing Manager, GE HealthcareExplore how biopharmaceutical manufacturers can meet Asia's vaccine demand.
Friday, August 01, 2008
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The challenges posed by vaccine development and manufacture are similar to those faced in the production of other biopharmaceuticals, including escalating demands for:
• Increased speed in the transition from research and development (R&D) to clinical trials,
• Increased cost-effectiveness of manufacturing processes, and
• Reduced time-to-market.
The production of vaccines, however, presents additional issues: the need to produce high volumes of vaccine in short timelines; improved safety measures when with working with pathogens and pathogenic antigens; and meeting US Food, Drug and Administration (FDA) and European regulatory standards. This article looks in more detail at some of these challenges and considers a selection of the resources that are being designed to support vaccine developers and manufacturers, particularly in Asia.
Supply and demand
To effectively protect a target population, a vaccine must be developed for production and delivery in large volumes. When faced with the threat of seasonal and pandemic influenza, vaccine manufacturers face the challenge of scaling up production to deliver large batches of product in the shortest possible time. According to The Bridge, in the event of a pandemic, existing global manufacturing capacity would provide sufficient influenza vaccine for only around 4.6% of the world's population. Previous influenza vaccine shortages serve as a reminder that manufacturing issues play an important role in accessibility to vaccines, a factor crucial to the Asia region where the majority of the population does not have access to even the most basic of medicines.
The influenza vaccine has traditionally been produced by injecting millions of fertilized chicken eggs with a variety of viral strains. Generally three strains are used, each strain being grown separately. The eggs are then incubated for several days to allow the virus to accumulate in the fluid surrounding the embryo. The virus-loaded fluid is then harvested and undergoes a series of purification steps and chemical inactivation treatment. Viral fragments are then collected from batches with different virus strains and combined upon completion of quality control tests to produce the vaccine.
On average, between one and two eggs are needed to produce one dose of vaccine and the entire production process takes at least six months. The whole process is labor-intensive, time-consuming, difficult to automate, and subject to contamination. This manufacturing process may not be fast enough to react to a pandemic and thus would not protect a larger population - given Asia's population of approximately 3.9 billion (United Nations' figures in 2008). This could have significant consequences.
Vero cells
The industry requires new, alternative manufacturing processes that are robust, fast and cost-effective. A novel technology being considered for this is the replacement of the egg-based production method with a cell-based approach. Influenza viruses can be propagated in cultured cell lines, and Baxter has developed a process using Vero cells (Figure 1). Vero cells are derived from kidney epithelial cells extracted from the African green monkey (Cercopithecus aethiops), and have been used for more than 20 years for manufacturing the licensed human vaccines for polio and rabies.
In Baxter's process, the adherent Vero cells have been adapted to grow in a serum and protein-free medium formulation that has been designed for large-scale operation. A single ampoule of Vero cells with a defined passage number is thawed and passaged in T-flasks and roller bottles to produce sufficient cells to inoculate a bioreactor using Cytodex 3 microcarriers from GE Healthcare.
Traditional techniques to intensify cell densities typically require frequent media changes, followed by perfusion to separate the cells from spent media. However, Baxter's method uses Ctyodex microcarriers, cross-linked dextran beads that provide a large surface area for the Vero cells to bind to and a stable environment for optimal cell growth.
Used as part of this method, microcarriers may increase productivity by enabling scale-up to larger volumes or by intensifying the process in smaller volumes, but with higher cell densities. Further advantages include easier washing and changing of culture media prior to viral infection and possible modification of reactors to grow other organisms. In addition, lower fermentation volumes and tank size may be necessary when using microcarriers, leading to reduced or lower engineering expense.
The major strength of the cell-based vaccine manufacture approach compared with egg-based production is the easy expansion and scaling up in times of emergency. The system also allows for stockpiling, as batches of the cells can be frozen and stored, then quickly multiplied when needed. Capacity can also be increased simply by adding fermentation equipment. Data produced from this large-scale approach has confirmed that the rapid high-yield production of pandemic vaccine is possible within a short time frame. Scale-up to multiple 6000 L bioreactors offers the consistent high-yield production of interpandemic virus and the ability to quickly respond to emerging variant pandemic virus strains (Figure 2).
Lower prices for Asia
In Asia's developing countries, the mortality rate as a result of infectious diseases is extremely high, as even the most basic vaccines are too costly for those most at risk. Vaccine developers and manufacturers are facing a need to lower process and production costs to provide inexpensive yet safe and effective vaccines.
The purification of modern biological molecules generally involves both membrane and chromatographic separations. Membrane separations complement chromatography and offer a number of benefits including speed, robustness and increased effectiveness at key stages of bioprocessing. For example, membrane separations allow for concentration and washing of feed streams before chromatography.
Pressure to increase throughput of candidates in process development at increasingly lower operational costs has led to demand for high throughput instruments. One tool that has been designed to enable high throughput process development is the microtiter plate (e.g., GE Healthcare's PreDictor 96 well plates), which can be used to identify the most appropriate chromatography conditions for a process by running many series of experiments in a very short period of time.
Microtiter plates may also be used in conjunction with robotic automation to further enhance throughput. At the Bioprocess International Conference held in Berlin in 2005, experts said this approach is also used to select the most appropriate media resins for each step in process development for chromatography. It is also used to screen for optimal purification conditions. They said another way to eliminate bottlenecks in process development is to use technology platforms that have a standard set of conditions and methods that are applied to all molecules in a given class.
Improving delivery times
At present, it takes nearly nine months to produce currently licensed influenza vaccines. There is little room for manufacturing error and no potential to scale up the process if there is increased demand. There is a need for shorter development and delivery times to enable the production of sufficient vaccine within the required timeframe.
Hardware with single-use components is one answer to the issue of timeliness in vaccine production. Disposable pump heads, bags to replace tanks and tubing to replace piping can contribute to simpler cleaning and validation process in a pilot facility. In addition, installation lead times are minimized and hardware may be moved around the facility or between facilities as required.
Adaptability is another key advantage of switching to single-use systems. "Many of our customers are switching to systems with single use components as a more flexible option, allowing the user to quickly change the target molecule, and providing some flexibility in batch volume," says Catarina Flyborg, vaccines program leader at GE Healthcare.
Single-use components offer many additional benefits besides increased speed, including reduced risk of contamination, minimized downtime for cleaning sterilization and corresponding validation procedures, reduced operation costs and minimal maintenance.
Keep it safe
As vaccines are a preventative therapy, administered to healthy patients, they must be completely safe with a low risk of side effects. At the production level, the health of employees must also be taken into account. All aspects of vaccine production and evaluation must, therefore, meet with the highest standards, as defined in FDA guidelines.
Surface plasmon resonance (SPR) technology (Figure 3), as used in Biacore systems, provides rapid protein characterization to support critical decisions at every step of vaccine development and manufacturing. In biotherapeutic development, for example, Biacore systems are used during early stages to select therapeutic antibody candidates by kinetic screening of hybridoma samples. The same system can perform high-resolution kinetic characterization during the optimization process, as well as during clinical trials to monitor and characterize unwanted immune responses which may significantly reduce efficacy or present serious safety issues. Label-free interaction analysis is also used in the final manufacturing process to provide quality control of proteins.
For example, in the field of HIV/AIDS vaccine development, hundreds of studies have used biosensor data. After many years of intensive HIV vaccine research, it is now generally accepted that classical vaccines based on inactivated viruses, live attenuated viruses or recombinant envelope proteins will not succeed in eliciting an immune response that will protect against HIV infection. Instead a number of novel vaccine approaches are currently being pursued that aim to slow the progression of AIDS in infected individuals rather than conferring full protective immunity. In this area also, SPR measurements have been used for predicting vaccine efficacy.
FDA Approval
Vaccine manufacture requires established, validated equipment and highly skilled, fully-trained individuals to perform the procedures. Production must meet standards as set out by FDA approval guidelines and International Organization for Standardization (ISO) standards, including complying with Current Good Manufacturing Practice (cGMP) biocontainment requirements for aseptic production, and biosafety regulations.
These standards must be maintained throughout all stages of the development process to ensure that the vaccine product remains the consistent and retains high quality. Development of systems and standard operating procedures are vital to promote stability, reduce costs and ensure quality. Companies can ensure regulatory compliance in production by engaging the services of an asset management organization to provide consistency in equipment maintenance and validation.
Conclusion
The challenge faced by vaccine manufacturers over the next few years will be to address the safety, scale-up and regulatory issues, within tightening budgets. As Asia's population continues to grow, so will demand for vaccines - particularly during times of pandemics. Advancements such as micro carriers, single-use components and improved analytical technologies are being developed to support manufacturers in achieving this goal.
However, an industry reportedly worth $10 billion (Kalorama Information) will need to focus on integrated solutions to address and optimize the entire workflow, from research to manufacture, to improve the total economics of production and ensure preparedness for rapid scale-up, reliability and security of supply.
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