Outsourced Vaccine Development - Pharmaceutical Technology

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Outsourced Vaccine Development
The authors discuss how strategic outsourcing to contract manufacturing organizations that have technical and regulatory expertise can add further value during vaccine development.

Pharmaceutical Technology
Volume 33, Issue 7

Adding value during vaccine development

Expression technologies. As for all biopharmaceuticals, there are key value-adding stages during vaccine development. However, as vaccines are probably the most disparate of all biological medicines, both in terms of biochemical composition and the methods of production, there are currently only a limited number of platform manufacturing methods applicable to distinct vaccines. Likewise, there is not a single expression system suitable for numerous vaccine candidates, as they range from relatively simple polypeptides to entire cells.

The criteria when choosing an expression system are the same as for any other biopharmaceutical—it is essential that the system produce a product of consistent safety and quality. It is also necessary to ensure that the yield of the production method is fully-optimized, as cost-of-goods for vaccines are critically important, particularly for those medicines intended for supply to developing nations.

The adoption of novel expression systems has to be carefully considered. Although there are benefits in applying innovation to shorten development times and be first to market, the vaccine industry is traditionally relatively conservative. This is because the medicines are typically administered to healthy patients, and there is a resulting strong emphasis on product safety. In addition, the complex nature of many vaccines minimizes the available options for risk-reduction through extensive product characterization.

As vaccines are typically administered in fewer and smaller doses than are therapeutic drugs, market supply may consist of grams rather than kilograms of material per annum, diminishing the net requirement for large-scale production. The drive for large-scale production involving high-titer expression systems has, therefore, been less for vaccine manufacture than for other biological molecules such as monoclonal antibodies. With all of these considerations, there has been reluctance in the vaccine industry to adopt novel expression systems, but rather a preference for working with well established systems of a known and accepted safety profile.

Table 1: Drivers to move from eggs to cell culture when manufacturing influenza vaccine.
There are examples of economic and regulatory influences, however, that are encouraging the adoption of new expression technologies for vaccine development. A high profile example is the move from eggs to cell culture in the production of the influenza vaccine (see Table 1). There is likely to be further adoption of new expression systems, especially those with associated benefits for reducing overall development times.

There are very few expression systems that are specifically targeted toward vaccines, although there are technologies used in protein expression that are particularly adaptable to vaccine manufacturing. These include the PER.C6 cell line, and the associated AdVac/Virosome technology, available from Crucell/DSM (Leiden, The Netherlands), and the avian-derived cell lines from Vivalis (EBx, Nantes, France) and ProBioGen (Berlin, Germany). Another expression technology with potential benefits is the Pfēnex Expression Technology from Dow (Midland, MI), which has been applied to generate high levels of vaccine antigens. Insect cells also represent an alternative system for vaccine production, with examples including production of antigen for the Provenge cellular vaccine (Dendreon, Seattle, WA) and Ceravix (GSK). Protein Sciences Corporation (Meriden, CT). has developed a patented baculovirus protein expression system (BEVS) for production of proteins and vaccines in variant Sf9 cells.

Rational drug design. There are few examples of engineered vaccines, probably because the technology is relatively immature and the approaches of protein engineering are not easily applied to traditionally complex vaccines. There is, however, potential application of protein engineering as subunit recombinant vaccines are further developed (4). One of the main objectives in the rational design of conventional biotherapeutics is to minimize immunogenicity, either through humanization, PEGylation, or by reducing protein aggregation. The opposite is true for vaccines, however, where protein design may be applied to increase the antigenicity of the molecule.

Process development and advances in vaccine production. As described, vaccines are complex and diverse biomolecules ranging from recombinant subunit antigens to live organisms. Correspondingly, therefore, a range of production technologies are required to manufacture sufficient quantities of these products, including the use of eggs, cell factories, roller bottles, shake/tissue culture flasks, and bioreactors. This range of production methods can be problematic, as each method requires specific capital expenditure, specialized development approaches, and operator expertise. As a result, there is a growing trend to lower the number of production platforms by implementing manufacture in suspension culture bioreactors wherever possible. For vaccines manufactured in mammalian-cell culture, it is necessary to establish well-characterized expression permissive cell lines that have been adapted to grow in suspension culture, and (where appropriate) in a serum-free medium. An example of this is the emergence of suspension HEK293 cultures for the production of adenovirus viral vectors, where the development of chemically defined and serum-free formulations has been influential in increasing titers and generating fully scalable processes (5). Similarly, microbial systems are being optimized for the manufacture of vaccines, especially those in which co-expression of two or more proteins is beneficial to provide multivalency.


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