Key Considerations for Development and Production of Vaccine Products - Challenges of vaccine development include regulatory, technical, and manufacturing hurdles in translating a vaccine candidate in

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Key Considerations for Development and Production of Vaccine Products
Challenges of vaccine development include regulatory, technical, and manufacturing hurdles in translating a vaccine candidate into a commercial product.


BioPharm International Supplements
Volume 25, Issue 3, pp. s28-s34

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.
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,
.


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