Quality by Design
Justin Neway, CSO and vp at Aegis Analytical, is keen on incorporating the principles of quality by design (QbD) into vaccine production. Whereas, Dr. Folmsbee believes that deciding which filter to use for purification must be determined when planning the entire manufacturing process rather than only at the last step, Neway stressed that we need to use data from current manufacturing processes to hone future process development.
QbD requires that companies continuously demonstrate that their process is running as designed so problems can be isolated at the point at which they occur. This way, if the final product is flawed, you don’t have to go through the entire manufacturing process to identify where and when the problem occurred. Vaccine development is among “the most variable life science processes; it is ripe for design,” Neway reports.
QbD, he adds, is “about the outcome you are trying to achieve rather than the technology you are using to achieve it.” Aegis Analytical created Discoverant software, a real-time, self-service data access and contextualization platform, to help life science manufacturers segue into achieving their QbD goals.
John P. Hennessey Jr. has been involved in the process, analytical, and formulation development of vaccines for over 20 years. He is currently vp of research and development of NovaDigm Therapeutics.
NovaDigm is developing NDV-3, a vaccine that has demonstrated preclinical protective efficacy against two very different pathogens; it is directed against Staphylococcus aureus (including MRSA) and the fungal pathogen Candida.
NDV-3 is undergoing a Phase I trial this year, so it is not surprising that Hennessey has potency assays on his mind.
The main factor in choosing an appropriate potency assay is to define what you are trying to accomplish (with vaccines that would be trying to prevent disease by eliciting an immune response). Efficacy studies determine if this is really happening, but once efficacy is established such studies become unethical because an effective vaccine should not be withheld from half of the study subjects.
Thus biomarkers—Hennessey calls them “surrogate markers of efficacy”—must be developed and used. Historically, these biomarkers were usually antibodies, but as knowledge of the immune system has expanded, T-cell responses are now often measured as well.
In addition to assaying biomarkers, the contents of the vaccine are evaluated and correlated with biomarker levels and efficacy. For recombinant protein vaccines, like NDV-3, this is often an ELISA to quantitate the amount of vaccine antigen in the vial. For live vaccines, like attenuated viruses and bacteria, consistent replication must be demonstrated by applying the vaccine to susceptible cells.