REGULATORY CHALLENGES
Despite the advances in vaccine manufacturing across the globe, regulatory hurdles still stand in the way of companies seeking
to take a candidate product to the clinic and eventually to market. Identifying a suitable vaccine candidate, appropriate
antigens, adjuvants, and delivery methods are just the beginning of vaccine development (12). Vaccines are usually injected
into healthy people, hence the emphasis on having well characterized, safe vaccines (13). Additionally, because process development
provides a technological foundation for manufacturing, analytical methods and assay development for characterization and potency
determination must be included (12).
Major regulatory considerations in development and manufacturing of vaccines include use of adequately characterized, homogenous
starting material of defined origin and acceptable quality including cells and production seeds; adequate validation of the
production process to demonstrate that the conditions are reproducible for different production lots; demonstration of consistency
of production to the satisfaction of the regulatory authority; and adequate pre- and postmarketing surveillance of the behavior
of the product in the target population to demonstrate safety and efficacy.
Clinical testing plays a key role in establishing the safety and efficacy of the product. Vaccine-specific issues include
determining correlations of protection necessary for evaluating efficacy, improving assays for potency, or finding animal
models that can be used for the evaluation of efficacy when human clinical trials are not feasible or unethical (14). Because
vaccines are generally given to healthy individuals, particularly children and infants, large-scale efficacy and immunogenicity
studies to prove safety and efficacy are required before an approval is granted (13).
Risks versus benefits of vaccines are closely examined during the review process. Special considerations may apply. For example,
it may be easier for a National Regulatory Authority (NRA) of a developing country to approve a product if the product has
already been approved by a regulatory authority in a developed country. All NRAs need to also follow a process of continuous
improvement with respect to their approval process. Tests that are outdated because of developments in technology and advances
in understanding should be removed. On the other hand, expectations related to compliance with GMPs need to be maintained
to ensure product consistency and safety. Further, novel analytical technologies for product characterization need to be put
in practice. Newer regulatory initiatives such as quality by design (QbD) and process analytical technology (PAT) need to
be implemented for vaccine manufacturing as well (15, 16).
The World Health Organization (WHO) has developed a major role in collaborating with and facilitating knowledge-sharing among
the NRAs. WHO's prototype GMP guidelines have been adopted by more than 100 countries. WHO prequalification or recommendation
is essential for many international tenders of UN agencies and other such large buyers. Other major regulatory agencies also
have mechanisms of supporting product licensure in countries outside their jurisdiction. The European Medicines Agency (EMA)
has a provision under Article 58 of giving scientific opinion on products with sponsors or manufacturers in Europe that will
not be marketed in Europe (17). The process is as rigorous as the usual Marketing Authorization. Many times, experts in the
endemic countries are included in the group that gives the scientific opinion. In the US, a similar kind of procedure is
the FDA Global Disease Approach for vaccines (18).
For many vaccine products, the need is greatest in poor and developing countries. In such cases, besides the safety and efficacy
of the products, affordability becomes another criterion of significance. NRAs of the endemic country can initiate a joint
review of applications for which one or more regulatory authorities work with the local NRA to provide a comprehensive review
process. Health Canada has participated in such a file review with the Drugs Controller General (India) to enable timely
registration and approval of a certain vaccine (19).
Timeliness for approval may be an issue for the cases of pandemic vaccines. The prevailing strains of the flu virus change
often and manufacturers have to use the prevailing strains for the season based on WHO recommendations. Selection of the strain
for the development of a vaccine in such cases needs extensive research to study the prevailing wild type and the feasibility
of that strain for use in a vaccine. Hence, influenza vaccines have a registration procedure which includes rapid reviews
of annual strain updates so that the vaccine is available before the flu season starts. When the pandemic influenza vaccine
of H1N1 was the need of the hour, many manufacturers and regulators worked together to develop, approve, and bring it to the
market in a short time (20).
Today's vaccine manufacturers, whether manufacturing in-house or as a contract service, have to strive to reduce overall timelines
for development and production and manage with limited resources. Meeting global demand while conforming to very strict quality
and regulatory controls is an ongoing challenge requiring proper planning during the development of a vaccine. Key regulatory
issues need to be thought of and a presubmission check list should be developed. Manufacturers should be ready for inspections
and interactions with the health authorities. They should plan the registration strategies for various countries by gathering
adequate information regarding the regulations and risks.
VACCINE SUSTAINABLITY
Figure 2: Development of Meningitis vaccine through a consortium of government and industrial partners.
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The vaccine industry is changing dramatically. Vaccine manufacturing technologies are changing, creating a push to produce
newer products. Companies are working rapidly with new combinations where they can. There is tremendous competition at the
technical and manufacturing levels. Market uncertainties are high, especially for those vaccines that will be largely used
in public-sector programs. Government pricing policy poses another obstacle to vaccine development. Furthermore, for manufacturers
in developing countries, challenges for vaccine development also include cost and lack of access to technology. Thus, the
vaccine industry globally is looking for ways forward to counter these challenges. Various global initiatives based on push
and pull strategies are being implemented. One type of initiative is a public private partnership, involving consortia between
governments, industry, the international health community, and funding agencies. The best example of such an approach is the
recent development and launch of a meningococal conjugate vaccine A in sub-Saharan Africa at an innovative pricing of less
than 50 cents a dose (see Figure 2). The timely launch of this vaccine has been reported to have had a significant health
impact in the meningitis belt of sub-Saharan Africa. Such consortium approaches need to be encouraged to target key challenges
in vaccine development to encourage innovation and improve the chances of success.
ANURAG S. RATHORE* is a biotech CMC consultant and a faculty member in the department of chemical engineering, Indian Institute of Technology,
New Dehli, as well as a member of BioPharm International's editorial advisory board; SURESH JADHAV is an executive director in the Serum Institute of India, Pune; MAHESH BHALGHAT is a vice-president at Biological E, Hyderabad; SHIRAZ KANDAWALLA is a senior manager at Sanofi Pasteur, Mumbai; SUMA RAY is a process development scientist, viral clearance and cell line development, Global Purification Technologies Group at Sartorium
Stedim, Bangalore; and ASHOK KUMAR PATRA is a group leader at Panacea Biotech, New Delhi. *To whom correspondence should be addressed, asrathore@biotechcmz.com
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