Regulatory Issues: Pandemic Preparedness Pacing Up - Challenges and opportunities for facilitating the development and licensure of pandemic influenza vaccines - BioPharm International


Regulatory Issues: Pandemic Preparedness Pacing Up
Challenges and opportunities for facilitating the development and licensure of pandemic influenza vaccines

BioPharm International

Enabling New Approaches and Technologies

Manufacturers and researchers actively study new manufacturing methods for influenza vaccines, such as cell-culture-based and recombinant technologies, along with adjuvants and other dose-sparing techniques.


Adjuvants have been used in a number of vaccines against other bacterial and viral pathogens, and are being investigated for use in influenza vaccines. The purpose of formulating vaccines with adjuvants is to increase the immune response to the vaccine, thus allowing either a decrease in antigen dose, a greater efficacy, or both. Alum is the only adjuvant used in influenza vaccines in the US, and has been used extensively. MF59, an oil and water emulsion, has been used in influenza vaccines in Europe since 1997.5 Small studies of inactivated nonadjuvanted pandemic influenza vaccines have demonstrated that more antigen per dose and more than one dose will probably be necessary to elicit immune responses comparable to those elicited following a single dose of an annual seasonal inactivated influenza vaccine.6

If a new adjuvant is added to the vaccine formulation, the result is considered a new product and requires the submission of a new BLA. Data supporting the safety of the adjuvanted formulation and the added benefit over the unadjuvanted formulation must be included in the BLA. Early studies should demonstrate the rationale for adding the adjuvant, e.g., evidence of enhanced immune response, antigen-sparing effects, or other advantages, and data supporting selection of the dose of the adjuvant itself. If the vaccine is a hemagglutinin-based product, the HI antibody assay may be appropriate to evaluate the immune response. The FDA recommends that if proof-of-concept and other studies are favorable, Phase 3 studies should be pursued in the interpandemic period.

For initial dose and formulation selection, a comparative clinical study of adjuvanted versus nonadjuvanted vaccines that both contain the same amount of antigen should demonstrate that the immune response elicited by the adjuvanted antigen is better than that elicited by the same antigen alone. For differences in HI antibody titer and seroconversion rates, the lower confidence limit on the appropriate point estimate excluding equality (i.e., the value 1 for the ratio parameter or 0 for the difference parameter) may be sufficient to demonstrate the added value of the adjuvant.

Cell Culture Technology

Cell culture and recombinant influenza vaccines are also under development, and may eventually replace the use of chicken eggs to produce influenza vaccines. Although egg-based manufacturing has been successful and cost effective, non-egg based manufacturing has potential advantages in affording more flexibility, and may allow greater yield of product. The FDA considers the use of a new cell substrate as a new product, and therefore, influenza vaccines manufactured in cell cultures require the submission of a new BLA. Cell-culture technology is used in the manufacture of other vaccines, and product characterization is important in using this technology for influenza vaccine manufacture. FDA recently published a draft guidance on the characterization and qualification of cell substrates and other biological starting materials used in the production of viral vaccines for the prevention and treatment of infectious disease.7 This guidance outlines FDA's current recommendations.

FDA is evaluating other technologies under investigation for potential use in the development of seasonal and pandemic influenza vaccines, such as alternative delivery systems and routes of administration, and use of immune stimulators. These technologies are at different stages of development, and they all present unique challenges to regulatory authorities.

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