The vaccine production- using fermenters

Introduction: The most effective prevention of diseases worldwide is vaccines, it is proven that vaccines have benefited target humans (including pregnant women and infants) and animals. Especially after the coronavirus pandemic in 2019 people are more alerted to viruses and immunization. Scientists in most of the countries in the world are working on the vaccine process and now there is more scope for its development. For more than 27 diseases or viral agents, vaccines are available, and many causative agents are being used for the development of vaccines for their respective causes.

But, as per the recent nationwide survey data, only 26 million+ people or approx. 62% have received all due vaccines in India. This is the problem in developing countries, the majority of people do not receive vaccines. Vaccine manufacturing is the basis of this problem, cost-effective vaccines reach each, and every person is a challenging task. India should focus on more vaccine policies and immunization programs in the country. This blog’s motive is to provide a context and perspective on the more and more production of cost-effective vaccines that focus on broader events and help people who are unable to access these services.

Vaccines are produced by biological processes. In the past, scientists made vaccines by growing bacteria or a virus in a fermenter. killing the microorganism to attenuate it or heat-killed. But now, instead of simply mixing chemicals to make a small molecule, pharmaceutical companies grow vaccines in a series of steps, including fermentation. These biological processes are very difficult to characterize and control. Therefore, they are part science and part skills.

Types of vaccines:

• Virus based

• Vector based

• DNA vaccines

• Protein vaccines

• Recombinant vaccines

Vaccine process development: The production and development of vaccines are difficult, complex, highly risky, and costly. Therefore, one must understand the biology and the nature of the organism to be used. Scientists generally try to combine multiple components in vaccines and sometimes multiple strains. So, strain selection should be in such a way that it does not react to human/ animal immune systems. It should be ensured that the strain is safe to use and will not act as an antigen to the host body.

We all know that clinical development (which contains 3 phases) is an essential part of vaccine testing on animals. This step is very risky and costly. The risk is high because most vaccine candidates fail in pre-clinical or early clinical development.

So, vaccine development requires strong project management systems and controls, and requisite skill sets among scientists and engineers. A good process development needs well-defined research, manufacturing, clinical, regulatory, and senior management, with a clear statement of the desired outcome of the product development.

The vaccine development process can be broadly divided into two categories: Upstream and downstream-finishing operations. Upstream includes cell culture- fermentation- downstream processing. The finishing operations include formulations- lyophilization- labeling- packaging- controlled storage.

Modern vaccines: While traditional platforms remain in use, modern vaccines are more complicated processes than traditional vaccine production. One latest process includes genetic transduction into bacterial and yeast strains. Yeast cells multiply in a fermenter, they make virus-like particles that look like a real virus but have nothing inside. After harvesting, the yeast cells are ruptured and collected to release virus-like particles. Later they are controlled purified and then use as a vaccine.

New highly significant innovations, technologies, and delivery systems are the reasons we have made it this far.

Antigen products antigenic structures are very valuable nowadays, these are new approaches and diverse platforms and are appreciated for good results. E. coli to yeast to fungi to animal cells and now antigenic components yield good cell-based vaccine products. antigenic proteins, attenuated or subsequently inactivated viruses, virus-like particles (VLP), vectors or delivery packages such as extracellular vesicles (EV), and bacterial or bacterial vectored vaccine production needs to keep up as better results are observed.

Fermenter- A method of production: Two most common reactors used in the production of vaccines are batch reactors and fed-batch reactors. Fed-batch mode has shown better results than batch mode, with high yield cell densities and higher volumetric productivity of cells. Later, it was suggested that if a salt-supplemented medium is applied to batch mode, high productivity can be easily achieved. But, fed-batch is advantageous because the cells stay stable for a longer period and this stable feature helps in terms of downstream processing at a large scale where harvesting occupies longer periods.

Carbon and nitrogen play a very important role in the growth of strains, a definable balance of these components can increase the overall yield of the cells. High oxygen demands lower the need for repetitive feed intake and promote high growth. All these conditions can be achieved by equal attention to the construction of the strain, the medium, and fermentation conditions.

A fermentation condition for the production of vaccines required:

• The use of low power number impellors is desirable

• There should be several feed points into well‐mixed regions around the distal end of one or more impellers. Agitators mustn't be underpowered such that they are slowed by the high viscosity.

• Baffles must stand free of the vessel sides to avoid dead zones.

• Fermentation, biochemical, and analytical processes had to be integrated and managed across sites.

Crossflow microfiltration: This method has become increasingly common in both biopharmaceutical and antibiotics plants. In each case, it is used near the front end of the process so that it should have the capacity for cell harvesting. It is used to concentrate cells and then diafiltrate using buffer solutions. It is observed that ultrafiltration membranes gave higher flux rates with E. coli than microfiltration membranes. More detailed studies have shown that this method is the best option after harvesting fermentation broth and helps in easy downstream processing.

Production facility and manufacturing: It takes almost crores and crores to construct expensive manufacturing plants for vaccine production in India on a large scale. These estimates consider all costs, including R&D costs of products, licensing, clinical trials, and improvements in manufacturing facilities. Depending on the dose requirements, cleaning requirements, and process validation activities according to good manufacturing practices (GMP) add to an additional expenditure of approximately 20% more on construct crores.

Every different vaccine requires a different plant because of the unique strain, unique manufacturing requirements, and regulatory difficulties associated with it. Some strains are scalable, and it is easy to increase their numbers with the size of the manufacturing unit. Scalable strains are profitable, with the increase in yield the unit cost will decrease. Then there are other strains, dependent on viral growth in eggs or cell lines- not scalable. Non-scalable strains create a mess and are unlikely to be produced in large numbers. Therefore, every single strain must be produced in different plants to increase the throughput, so the unit cost does not decrease with an increase in the volume.

Established vaccines with a limited number of suppliers can generate very high-profit margins over the product life cycle. Otherwise, it is difficult to spend years in immune studies first. The immune studies help in bridging the product used in the efficacy trial to material manufactured in the commercial factory. Sometimes immune studies do not help, are not always high reproducible, and pose large financial risks. Product development can fail and access to large amounts of cost. This kind of commitment is hard, and one must know it.

But today technologies and high throughput and robust manufacturing facilities have made the procedure easier. Automation and control systems in the fermenters enable ease and flexibility in modern plants. Electronic production records, process control systems, data history, and laboratory information management systems are new digital technologies for better planning of the process. Such digital platforms streamline product manufacturing, testing, and release. They also enable robust data management to support process development, characterization, and transfer.

Scale-up and current challenges:

• One of the ultimate challenges is to make tens of millions of doses.

• Sterility- the challenge is to overcome contamination chances. After production also, it is difficult to assure the sterility of the specific vaccine lots.

• A very small change in the reagents can produce large changes in the efficacy of the resulting vaccine and the efficiency of producing it. The changes in minor components of raw materials can result in significant changes in the vaccine-manufacturing process.

• Vaccine production can be sensitive to time. At the end of the year, there is a possibility of strain to change. So, every time in need we must make a new product- a disadvantage.

What we need to do is minimize all the challenges above mentioned to obtain effective vaccination doses for the ones who are in need. India is a populated country; all should have access to these preventable measures. To get success in this scenario our motive and vision are to create awareness about cost-effective vaccines. All the above challenges need solutions and Amerging is always there to promote sustainable discoveries. Hope you like our blog and please visit our site to see what we offer for vaccine development, or you can contact our designated personnel at info@amergingtech.com.

References:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151793/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161863/

https://www.drugdiscoverytrends.com/pumping-up-vaccine-production/

https://cellculturedish.com/mrna-vaccine-production-and-facility-design/