The pandemic has prompted drug developers and regulators to develop and approve new medicines and vaccines in record time. Importantly, it’s not just traditional medicines using established technologies and processes but new drug modalities, such as RNA therapeutics, reaching clinical trials within two years of development. So, how has this been possible? One of the key factors facilitating these unprecedented development timelines has been leveraging innovative advanced analytical technologies to ensure regulatory compliance in the development and production of these novel vaccines.

Dr. Susan Darling, Ph.D., Senior Director of Biopharma Market and Product Management within the Global Biopharma and CE Business Unit at SCIEX, shares insight into what’s fueling the growth of new drug modalities, key factors facilitating rapid development timelines, and the role of advanced analytical technologies. –KB

Contract Pharma: What is fueling the growth and rapid advancement of new drug modalities?

Susan Darling: Pre-COVID demands for more rapid, accurate, and automated methods was growing. An evolution towards semi- or fully continuous and flexible processes was already happening, but it was going at a slow pace, which is common in pharma, an industry averse to change. COVID hit the fast forward button, making the need for speed a necessity for vaccine development. The results that have been achieved have shown that timelines can safely and effectively be optimized using next generation methods. 
 
Traditional vaccines are based on weakened or attenuated viruses that stimulate the production of antibodies that bind to the virus in question and prevent it from invading host cells. While they provide good immune responses, it generally takes many years to develop and commercialize them. More modern vaccines are derived from recombinant simulants of the relevant disease antigen in special forms that enable effective delivery, such as virus-like particles. These approaches, which have included new vaccines for Ebola and Dengue, have shorter development times (1–2 vs 4–5 years).
 
Newer genetic vaccines take a different approach to production and eliminate the need to work with live viruses. Approaches including those based on naked (plasmid) DNA, viral vectors, and messenger RNA (mRNA) cause the production of viral proteins inside cells, using native protein translation and post-translational modification machinery within the cells.
 
DNA and mRNA vaccines are typically delivered in the form of a lipid nanoparticle that enters human cells, which then produce the antigens that generate the desired immune response. With viral-vector vaccines, the engineered virus delivers the nucleic acid encoding the viral antigen to the cells.
 
CP: What are the key factors facilitating rapid development timelines?
 
SD: Once the genetic sequence of the infectious agent has been identified, genetic vaccines can be rapidly designed and processes for their expression developed and scaled for clinical and commercial production. No cell bank or viral seed bank must be developed, and genetic vaccines require much lower doses. Production therefore can be achieved in a smaller footprint employing single use technologies, and scale up is typically quicker than for traditional viral vaccines.
 
Importantly, unlike with attenuated and subunit vaccines that require development of a new process for each vaccine, with these genetic technologies only creation of the genetic sequence for the parts of the virus being targeted is required to generate a new vaccine. The formulation, production, packaging and even the safety profiles are nearly identical across different vaccines. The ability to use robust, scalable platform processes that are nearly identical from one vaccine product to the next greatly reduces development timelines.
 
CP: What role do advanced analytical technologies play in drug development?
 
SD: Access to robust and scalable analytical processes for DNA, viral vector and mRNA vaccines is a challenge today given the short turnaround time for obtaining analytical results. The functional cell-based assays and infectivity studies that have been used for traditional vaccine development can take days to weeks to generate results. The decision to progress a batch must often be made within 24 hours or less, however; manufacturers must use limited information for the decision to move ahead with a process and thus risk losing time and costly product.
 
The development of consistent, scalable, rapid functional analytical methods is critical for improving the manufacturing of genetic vaccines. Without speedy assays, the ability to fully understand all the relevant process parameters and how they impact product quality attributes is limited, which prevents the development of robust processes.
 
Advances in automation and data analysis have the potential to reduce analysis times as well as simplify analyses while increasing consistency and accuracy. These assays must also have greater sensitivity and precision given the often-low production volumes for genetic vaccines.
 
CP: How is this different from more traditional drug development methods?
 
SD: To overcome the challenges associated with the development of robust analytical solutions for genetic vaccines, many analytical technologies initially developed for protein therapeutics have been modified to address the assessment needs for genetic vaccines. Experience is also being drawn from the gene therapy field. Other methods have been developed to meet the unique analysis needs presented by these novel technologies.
 
Instrument manufacturers and software developers are committed to both modifying existing methods and developing new techniques that simplify and reduce the time required for analysis of novel modalities.
 
The goal is to provide high-throughput, robust platform methods with high specificity, precision and resolution for the detection and quantification of biologic compounds, even in the most complex and challenging samples so that novel medicines such as genetic vaccines can be safely brought to market as rapidly as possible.
 
CP: How is advanced analytical technology being leveraged to ensure regulatory compliance in development and production?
 
SD: New robust assays based on mass spectrometry (MS) and capillary electrophoresis combined with laser-induced fluorescence (CE-LIF) and other detection methods rapidly provide accurate and reproducible results for both the protein and genetic components of DNA and viral-vector vaccines (plasmid isoform, recombinant DNA sequencing, etc.) Liquid chromatography-MS/MS methods are valuable for sequence confirmation and rapid and reproducible detection, separation and sizing of mRNA, high-resolution analysis of important 5’ cap and 3’ poly-A tail fragments and confirmation of LNP composition.

Acoustic Ejection Mass Spectrometry (AEMS) eliminates tedious sample preparation, time-consuming liquid chromatography method development and chromatographic run times while providing access to the compound tuning and specificity of MS at the high-throughput speeds associated with plate readers.

Similarly, the direct coupling of capillary Isoelectric Focusing (cIEF) charge variant analysis with high-resolution MS enables rapid analysis of intact viral vector capsid proteins, allowing users to make more informed and timely decisions when they are needed.

All these methods contribute to the acceleration of critical decision-making and in turn reduction of developmenttimelines and costs, both of which are essential for successful drug development today.
 

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Susan Darling is the Sr. Director of Biopharma Market and Product Management within the Global Biopharma and CE Business Unit at SCIEX. She is responsible for driving growth in the Biopharma segment, development and execution of strategic direction, as well as new product and workflow development.