Challenges and Trends in Vaccine Manufacturing - An evaluation of the technologies and process parameters needed to develop a safe, effective, and economically efficient vaccine. This article is part

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Challenges and Trends in Vaccine Manufacturing
An evaluation of the technologies and process parameters needed to develop a safe, effective, and economically efficient vaccine. This article is part of a special section on vaccines.


BioPharm International Supplements
Volume 24, Issue 10, pp. s3-s11

NEW AND EXISTING TRENDS IN VACCINE MANUFACTURING

The process of vaccine development begins with a good understanding of the underlying biology involved.

Egg-based versus cell-culture based

There has been much debate regarding whether the egg-based method for manufacturing a viral vaccine is more effective than the animal cell-culture based method. A third method using virus-like particles (VLPs) is also in use. This method is similar to the recombinant-vaccine manufacturing process in terms of cloning and expressing recombinant proteins.

Although the egg-based viral vaccine manufacturing process is an old and familiar technology that has been practiced for more than 60 years, it has its own complex issues. Egg-based viral vaccine manufacturing, for example requires a large number of specific pathogen free (SPF) eggs because the virus needs to be propagated inside the fertilized chicken eggs. However, typcially, one can only produce one or two doses of vaccine per egg. Here, the nutrition status of the poultry is also important because changes in their diet can dramatically affect the virus yield from the eggs. The process is labor intensive and highly susceptible to bacterial contamination. In addition, individuals who are allergic to eggs might have allergic reactions to such vaccines.

On the contrary, animal cell-culture driven viral vaccine processes are being encouraged by regulatory authorities, particularly because the process reduces the lead time from laboratory to market. Furthermore, during an emergency, chances of scaling up production capacity of an egg-based vaccine is dismal considering the reliance on SPF eggs, compared with cell culture, which can be propagated multiple times from frozen cellbanks. In addition, the footprint for cell-culture-based production is considerably smaller, and processing takes place in closed systems, thereby reducing chances of contamination.

However, an important issue with cell-culture processes is the tumorigenic and oncogenic potential of the cells in which the virus is propagated. Although highly tumorigenic cell substrates have never been used in vaccine manufacturing, it is important to keep in mind that some Madine-Darby Canine Kidney epithelial cell (MDCK) sublines are highly tumorigenic. Such cell substrates can pose significant regulatory challenges (e.g., if the cell line harbors oncogenic or tumorigenic viruses, that virus could integrate into the recipient's genome and cause a tumor). Other cell-culture concerns include the oncogenic potential of virus producing cells due to the presence of contaminating DNA in the product. Additionally, the use of animal-derived components in the cell-culture media—whether serum-sourced from calf or trypsin-sourced from porcine—could be potential sources of animal viruses. The International Conference on Harmonization (ICH) Q5A guideline on the quality of biotechnology products, therefore, recommends using serum-free, chemically defined media for cell culture and genetically engineered trypsin to ensure the absence of any animal-derived component in the raw materials used in manufacturing.

Use of VLPs in vaccine development

During the past few years, the use of VLPs for the manufacturing of vaccines is becoming more popular. For example, the H1N1 influenza vaccine developed jointly by Novovax and Cadila Pharmaceuticals uses VLPs. The advantages of a VLP-based vaccine platform is that it uses a recombinant-vaccine technology with a baculovirus expression system and, as a result, one does not need to handle a live pathogenic virus. This process rules out the need for a containment facility. There are no safety concerns and the process is easily scalable to large quantities and more economical in terms of facility, materials, labor, and utility costs (6). When using recombinant technology, one can select the exact genetic match for hemagglutinin, neuraminidase, and matrix proteins of the circulating virus strain. The entire process of manufacturing, from cloning to development and release, takes about 12 weeks (6). Other VLP-derived vaccines include Merck's Gardasil, which protects against human papillomavirus types 6, 11, 16, and 18.


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