Real-time Sequencing by FTIR in GMP Oligonucleotide Synthesis

04th March 2020 | 10.00 am EST | John-David McElderry, Scientist at Biogen and Dominique Hebrault, Science & Technology Business Development at Mettler-Toledo International, Inc |WATCH FOR FREE

Biogen uses a novel approach for identity release testing its antisense oligonucleotide (ASO) drug substance which leverages in-process data to confirm the sequence of phosphoramidites in the output. Drug substance identification must discriminate between compounds of closely related structures, which, in the case of ASOs, may require sequence confirmation. In this case, the sequence is determined by the raw material inputs which are each individually identified in real-time as they are pumped into the synthesizer. Spectral information from flowing raw material phosphoramidites is collected using an inline ATR-FTIR sensor, which is then processed using a PLS-based classification technique for discriminating among the various possible phosphoramidite types. To ensure robustness and long-term use in a GMP environment, a risk-based approach to model design was taken, which included variable factors such as flow, concentration, raw material mixing, and instrument calibration. Modifications to the oligonucleotide backbone (i.e. phosphate or phosphorothioate diester) are confirmed by in-line conductivity measurements on the input downstream from the sulfurization/oxidation step. Most abundant mass measurement by LC-UV-MS on the pre-diluted drug substance serves as additional identity confirmation. These independent measures comprise a strategy for confirming identity for ASO drug substance.

With acknowledgements to Dan Hill, Jessica Stolee, Elliott Schmitt, Xiaoye Su.

Presented by John-David McElderry, Scientist at Biogen

John-David McElderry graduated from University of Michigan with his PhD in 2012 and has been an analytical scientist and PAT expert in the Pharma/Biotech industry for seven years. He started his career at Vertex Pharmaceuticals creating PAT applications for the first continuous DP manufacturing rig and helped develop the first real-time release strategy in the industry. He is currently at Biogen where he has developed PAT-based control strategies for continuous flow chemistry of small-molecule drugs and continuous synthesis of oligonucleotide drugs. He is interested in enabling real-time control of quality attributes in pharmaceutical manufacturing through the application of smart sensors and machine learning.

Followed by Dominique Hebrault, Science & Technology Business Development at Mettler-Toledo International, Inc

• M.Sc. Chemical Engineering, Ph.D. Synthetic Chemistry (France / Germany),
• 12 years’ experience chemical development in Pharma in France, U.K., USA (Boston), with Successful scale-up of API’s at 100’s kg manufacturing scale
• 13 years’ experience as a trusted Science & Technology advisor for global pharmaceuticals accounts,
• Subject matter expertise in leading-edge process technologies (PAT, R&D automation, lab to plant) to enable QbD and enhance R&D productivity, and a passion for taking these technologies to the pharma market,
• Invited to speak at more than 25 international conferences across NA, Europe, and Asia, and authored approximately 20 publications and patents

Sponsored by Mettler Toledo

Our goal is to engage scientists to fully understand the challenges facing the organizations that produce the world’s medicines & advanced materials. The result is a set of strategic initiatives that innovative companies are leveraging to transform chemical development programs: Develop a Culture of Safety, Gain Insight into Every Reaction, Improve Organizational Productivity, Take Control of Particles, Modernize Synthesis, & Supply from Lab to Plant. We believe knowledge & control in the modern lab lead to innovative development. With safe & unattended experiments, precise controls, and continuous measurements, researchers quickly understand the effect of changing parameters and make informed decisions.
Key Applications: Chemical Synthesis, Crystallization, Chemical Process Development & Scale-up, Process Analytical Technology, Pharmaceutical Formulations, Fermentation & BioProcessing, Continuous Flow Chemistry


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