PRODUCTION OF VACCINES

PRODUCTION OF VACCINES
3.1 Process of Vaccine Production

Materials for vaccines are generally pathogens, bacteria and virus,
use infectious diseases. The quality control of vaccines is most important and regulated by the Minimum Requirements for Biological Products. Each vaccine is controlled by the standards for biological substance production and specific processes and techniques are requested. Vaccines being used in Japan should clear these regulations and pass the tests by the National Institute of health (N.I.H.). Vaccines are classified into live vaccines, inactivated vaccines, and toxoids, as shown in Table 3.1. Recently, recombinant vaccines have been developed using the DNA recombination technique. Processes of the vaccine production are shown in Figures 3.1, 3.2, and 3.3.

3.1.1 Materials for vaccines

a. Vaccine strain: A specified strain of pathogen is nominated as the vaccine strain by the Standard. Influenza virus, however, mutate easily, so the vaccine strain is decided every year by N.I.H. according to the prevalence strain isolated from patients, antigenic analysis, and antibodies found in the patients' blood. The vaccine strain of the year is distributed by N.I.H. Vaccine strains for the live vaccines are kept as the seed lots in N.I.H. The number of transfers of the culture from the seed lot is limited 5 at the maximum.

Media for Vaccine Production
Cultured cells have long been known to serve as excellent hosts for propagation of many types of viruses. The ability of cell culture systems to produce large quantities of attenuated viral particles has served as the basis for the production of both human and veterinary vaccines. Traditional methods have relied on the production of viral agents in cells cultured in medium supplemented with serum, most commonly fetal bovine serum. The animal serum in cell cultures used in production processes can cause a number of problems for manufacturers. The increased costs of raw materials and post-production processing associated with serum have prompted interest in the development of serum-free media for vaccine production. More recently, the potential for contamination by adventitious agents present in serum has heightened regulatory concerns regarding the use of animal-derived components in media used for pharmaceutical manufacturing. With these factors in mind, Sigma has developed new media for vaccine production with reduced levels or completely devoid of animal-derived components. At the same time, we will continue our commitment to traditional manufacturing methods by maintaining and expanding the range of basal media for use with serum supplementation and serve as the basis for customization into serum-free formulations.
The ability to genetically engineer viral particles for use as therapeutic agents to treat genetic diseases (gene therapy) represents one exciting new avenue that science and technology are bringing to modern medicine. Cultured cells have long been known to serve as excellent hosts for the propagation of many types of viruses. Traditional methods have relied on the growth of viral agents in cells cultured in serum-supplemented media. A great concern is the potential for contamination by adventitious agents introduced into the manufacturing process through the use of animal-derived materials. This has heightened regulatory concerns regarding the use of such components in media employed in pharmaceutical manufacturing, particularly in the case of therapeutic injectables. These concerns have led to recommendations that all animal-derived components be avoided when therapeutic agents are manufactured. It is likely that these recommendations will become rigid requirements in the near future. With these factors in mind, Sigma has developed new media tailored to the needs of two of the more popular cell lines used for the propagation of viral particles employed in gene therapy. These media are formulated without the use of animal-derived components.
Vaccine Production in Cells
For decades, vaccines have provided effective protection from influenza for Americans. While they have traditionally been produced in chicken eggs, a new technology-cell-based vaccine production-could save hundreds of thousands of lives in the event of an outbreak of pandemic influenza, or some other infectious disease.
The new approach would use mammalian cells (kidney cells are often used) to grow the influenza viruses. Cell-based vaccine production could more easily meet "surge capacity needs" because cells could be frozen and stored in advance of an epidemic or developed rapidly in response to an epidemic. Cell-based vaccine production dramatically reduces the possibility for contamination and promises to be more reliable, flexible, and expandable than egg-based methods.
In place of eggs, cell-based vaccine production utilizes laboratory-grown cell lines that are capable of hosting a growing virus. The virus is injected into the cells where it multiplies. The cells' outer walls are removed, harvested, purified, and inactivated. A vaccine can be produced in a matter of weeks. Polio vaccine is currently produced using the cell-based method.
While both methods could produce an equally effective vaccine against a virus such as H5N1, egg-based production is physically limited by the availability of specialized eggs and alone may not be able to meet the accelerated demands of a global influenza pandemic. Cell-based vaccines offer the potential to increase production surge capacity and save lives:
• In order to produce 300 million doses of vaccine, egg-based production would require some 900 million eggs. In the case of an avian flu pandemic, egg-producing flocks could decline, jeopardizing vaccine production capabilities.
• While eggs are perishable, cell lines can be safely kept frozen indefinitely, increasing the capability to rapidly produce vaccines if an influenza pandemic were to occur.
• Vaccine manufacturers are able to bypass the steps needed to adapt the virus strains to grow in eggs
• People allergic to eggs cannot receive vaccines produced from chicken eggs, but can be immunized with a cell-based vaccine.

In March 2005, the Department of Health and Human Services issued a five-year contract to Sanofi-Pasteur for $97.1 million to develop cell-based influenza vaccine technology and conduct clinical trials, with the goal of obtaining an FDA license for this vaccine. Under this advanced development contract, the company has committed to develop a plan to establish a U.S. cell-based influenza vaccine manufacturing facility, capable of producing at least 300 million doses of a pandemic influenza vaccine over a one year period.
In May 2006, HHS awarded five contracts totaling more than $1 billion to accelerate development and production of new technologies for influenza vaccines within the U.S. These five contracts support the advanced development of cell-based production technologies for influenza vaccines and will help to modernize and strengthen the nation's influenza vaccine production by creating an alternative to producing influenza vaccines in eggs. The funds are part of $3.3 billion proposed by the President and appropriated by Congress to HHS for fiscal year 2006 to help the nation prepare for a pandemic. (News release).
There is no H5N1 pandemic so it has not been possible to develop an H5N1 pandemic vaccine; however, "pre-pandemic vaccines" have been created, are being refined and tested, and do have some promise both in furthering research and preparedness for a possible pandemic.