CHALLENGES IN PROCESS DEVELOPMENT AND MANUFACTURING
Process development is the technological foundation that underlies the manufacture of new vaccines and is central to successful
commercialization. The key issue related to technology is the evolution and translation from a procedure used for making vaccines
in a basic-research laboratory to a process that can be scaled up and run reproducibly in a manufacturing environment to make
tens of millions of doses per year. Vaccine manufacture is broadly similar to other biotech manufacturing operations, but
with some important differences. Purity is a particular challenge for vaccines, because some vaccine impurities have an immunomodulatory
effect and can act like an adjuvant to the vaccine. Therefore, manufacturers have to scale up their production without losing
the potency of the mixture of the vaccine and the impurity. Several new vaccine manufacturing platforms offer advantages including
more effective vaccines, less costly vaccines, or more rapidly produced vaccines. At the same time, these manufacturing platforms
raise new scientific and regulatory concerns that might potentially affect the vaccine's safety or efficacy.
For example, novel cell substrates raise new questions about potential adventitious viral agents. Vaccines also differ from
conventional drugs in that some vaccines are generally stockpiled and are not used continuously. Therefore, vaccine manufacturing
needs to be flexible, rather than continuous. Meanwhile, cell banks required for vaccine manufacture may become depleted with
time and a new working cell bank may be needed, but the cells may not grow and perform as they did 10 years ago. Growing expertise
in cell-culture technology and bioprocessing is helping manufacturers to overcome these problems.
Therefore, it should be possible to put many new vaccines into robust large-scale production during the next few years. The
challenges of vaccine development are not limited to identification of suitable antigens, adjuvants, and delivery methods,
but also include regulatory, technical, and manufacturing hurdles in translating a vaccine candidate into a commercial product.
A variety of technologies have been used to develop successful vaccines. These technologies include live attenuated bacteria
and viruses such as Bacillus Calmette-Guérin and measles, mumps, and rubella (MMR); inactivated bacteria and viruses such
as whole cell pertussis; proteins such as diptheria and tetanus toxiods; polysaccharides such as PneumoVax (Merck & Co.);
conjugated polysaccharides such as Prevnar (Pfizer), and virus-like particles (VLPs). This variety can be a challenge to the
vaccine manufacturer with respect to standardization of facilities and equipment. Also, while manufacturing processes and
practices have significantly advanced with time, certain critical vaccines are still manufactured by traditional methods because
of lack of suitable technology or lack of incentive for developing improved technology. For example, influenza vaccines are
manufactured by methods fundamentally unchanged over several decades. This has made the manufacturers susceptible to disruptions
in the supply of suitable eggs and to virus strains that do not propagate in the allantoic fluids. Although demand for this
vaccine has increased over time, the motivation to improve the process is neutralized by the seasonal nature of influenza
and the variable risk associated with the antigenic drift and antigenic shift associated with the pathogen. At the other end
of the spectrum is Nesseria meningitis serogroup B vaccine, wherein the natural antigenic elements of the bacteria elicit an autoimmune response. Many newer versions
of this vaccine are presently undergoing advanced clinical trials (4).
Compliance with the principles and guidelines of cGMP is a statutory requirement that applies to all pharmaceutical products
including vaccines. In recent years, a number of novel tools and trends have been pursued in pharmaceutical manufacturing.
These include novel ways of managing the manufacturing operations, such as operational excellence initiatives including lean
manufacturing, total quality management, quality risk management, Six Sigma, and process and analytical technology.
Vaccines are complex and diverse biomolecules ranging from recombinant subunit antigens to live organisms. Therefore, their
manufacturing has traditionally been relatively inefficient and technically challenging. As a result, a range of purification
technologies and specialized development approaches are required to manufacture sufficient quantities of these products. To
date, production of viruses and VLPs is primarily performed by density-gradient centrifugation, a labor-intensive process
that is not readily scalable. An alternative strategy is to apply column chromatography. However, the problem with conventional
porous chromatography resins is low binding efficiency due to the large size of viruses and low flow rate. With the adoption
of membranes and monolithic columns, purification of recombinant vaccines is easier because of low steric restriction to the
active binding channels (5). These formats also offer higher flow rates, resulting in smaller columns and shorter cycle times.
With advances in technology, vaccine manufacturers have access to a greater range of choices. For instance, traditional vaccines,
which are often made through inactivation or crude fractionation of an infectious agent, are now being supplemented by vaccines
based on pure proteins, engineered virus particles, DNA, or even cells. The latter may offer significant advantages in terms
of safety and the ability to generate the required immune response. However, there are challenges in implementing such technologies
as they require more sophisticated and expensive manufacturing technology, which could limit their broad availability and