The recent influenza vaccine shortage is a pointer to the fact how problems in supply and manufacturing can deny access to vital vaccines in times of dire needs. The solution to prevent such occurrences lie in the application of new technologies to the discovery, assessment, development and production of vaccines. These may also enable the introduction of new vaccines, like gene-based vaccines, virus-like particles, plant-derived vaccines and novel adjuvants and delivery systems. These represent promising approaches to creating safer and more potent vaccines. Consequently, more people will have faster access to more effective vaccines against a broad spectrum of infectious diseases. However, the increased cost of producing new vaccines and regulatory uncertainty remain challenges for vaccine manufacturers.
Practically all licensed vaccines in the United States are produced by a handful of pharmaceutical companies namely GlaxoSmithKline, Merck, Novartis, Sanofi Pasteur, and Wyeth. With a restricted number of manufacturers and many recommended vaccines produced by only a single company, there will be large fluctuations in the availability of vaccines.
Challenges to vaccine manufacturers
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.
Small biotechnology companies may present challenges to multinational vaccine manufacturers by improving aspects of vaccine development, such as improved delivery systems. More often, however, the high cost of vaccine development requires partnership between these small firms and the major manufacturers, further cementing their central role in the US and international vaccine landscape.
It takes around five to six months for the first supplies of approved vaccine to become available once a new strain of influenza virus with pandemic potential is identified and isolated. These months are required as the process of producing a new vaccine involves many sequential steps, and each of these steps require a certain amount of time to complete.
Precisely speaking, flu vaccine is usually grown in fertilized chicken eggs. As per November 2007 data, both the conventional injection and the nasal spray are manufactured using chicken eggs. The European Union has also approved Optaflu, a vaccine produced by Novartis using vats of animal cells. This technique is expected to be more scalable and avoid problems with eggs, such as allergic reactions and incompatibility with strains that affect avians. In an hawkish scenario of producing pandemic influenza vaccines by 2013, only 2.8 billion courses could be produced in a six-month time period. If all high- and upper-middle-income countries sought vaccines for their entire populations in a pandemic, nearly two billion courses would be required. If China pursued this goal as well, more than three billion courses would be required to serve these populations.
Vaccine manufacturers perform the following activities:
Optimization of virus growth conditions: The vaccine manufacturer takes the hybrid vaccine virus that it has received from the WHO laboratories, and tests various growth conditions in eggs to find the best conditions. This process requires approximately three weeks.
Vaccine bulk manufacture: For most influenza vaccine production, this is performed in nine to 12 -day old fertilized hen's eggs. The vaccine virus is injected into thousands of eggs, and the eggs are then incubated for two to three days during which time the virus multiplies. The egg white, which now contains many millions of vaccine viruses is then harvested and the virus is separated from the egg white. The partially pure virus is killed with chemicals. The outer proteins of the virus are then purified and the result is several hundred or thousand litres of purified virus protein that is referred to as antigen, the active ingredient in the vaccine.
Quality control: This can only begin once the reagents for testing the vaccine are supplied by WHO laboratories. Each batch is tested and the sterility of bulk antigen is checked. This process takes two weeks.
Vaccine filling and release: The batch of vaccine is diluted to give the desired concentration of antigen, and put into vials or syringes, and labelled. This process takes two weeks.
Clinical studies: In some countries, each new influenza vaccine has to be tested in a few people to show that it performs as expected. This requires at least four weeks.
Regulatory approval for vaccines:
Before the vaccine can be marketed, regulatory approval is required. If the vaccine is made with the same processes as the seasonal influenza vaccine, and in the same manufacturing plant, this will take place within one to two days. Regulatory agencies in some countries may require clinical testing before approving the vaccine, which adds to the time before the vaccine is available.
The full process can be completed in five to six months. Now the first final pandemic vaccine lot would be available for distribution and use.
Note: The grey lines indicate the time period required for the first time an activity is done that is then repeated. The blue lines signify that the activity takes place within a finite period.
WHO list of vaccines for purchase by UN agencies as of October 2009:
Some important considerations for vaccine manufacturing
Supply and demand: In order to effectively protect a target population, a vaccine must be developed for production and delivery in bulky 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. In the event of a pandemic, existing global manufacturing capacity would provide sufficient influenza vaccine for only approximately 4.6% of the world's population. The accessibility to vaccines is a crucial factor for 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. 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 labour-intensive, time-consuming and subject to contamination. This manufacturing process may not be fast enough to react to a pandemic. Ultimately, this would not protect a larger population.
Novel technology: The vaccine 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. Vero cells are derived from kidney epithelial cells extracted from the African green monkey, and have been used for more than 20 years for manufacturing the licensed human vaccines for polio and rabies.
The major advantage of the cell-based vaccine manufacture approach over 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.
Curtailing prices for Asia: In Asia, especially the developing nations, 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 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.
* Reducing delivery time: Currently, it takes nearly nine months to produce currently licensed influenza vaccines. There is little scope 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. In a pilot facility, the disposable pump heads, bags to replace tanks and tubing to replace piping can contribute to simpler cleaning and validation process. Additionally, installation lead times are minimized and hardware may be moved around the facility or between facilities as required.
Keeping vaccines secure: As vaccines are a preventative therapy, administered to healthy patients, they must be completely secured with negligible side effects. All aspects of vaccine production and evaluation must, therefore, meet with the highest standards. Improving analytical methods during vaccine development and production can support the optimization of process parameters. The removal of contaminants such as derivatives from the host cell, including Deoxyribonucleic acid (DNA), proteins and leachables, must be documented. The removal or inactivation of adventitious viruses is also a challenge. Improved analytical methods contribute to safety and efficacy during the development and manufacturing of vaccines, and can also reduce batch release times as many of the in vitro and in vivo assays currently applied to vaccine production processes take weeks to run.
FDA approval: Vaccine manufacture requires established, validated equipment and highly skilled, fully-trained individuals to perform the procedures. Their manufacturing must meet standards as set out by Food and Drug Administration (FDA) approval guidelines and International Organization for Standardization (ISO) standards, Current Good Manufacturing Practice (cGMP) and other biosafety regulations. Development of systems and standard operating procedures (SOPs) are cardinal to promote stability, reduce costs and ensure quality.
Future forecast
Presently there has been a concern over influenza in India especially as it has been suggested that in the event of a pandemic, there will be limited management options available. The critical question is that in Indian children with or without underlying conditions (population), does influenza vaccination (intervention) as compared to no vaccination (comparator) result in improved clinical outcomes (outcome)? Vaccine research and development is poised to identify novel vaccine approaches that could produce much greater quantities of vaccine at a price that is affordable to the global population. 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 increase, so will demand for vaccines, and mainly 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.
The author is Team Lead-Drug Safety,Tata Consultancy Services,Mumbai