At TAPI, our Contract Development and Manufacturing Organization (CDMO) capabilities are designed to address the complex challenges of developing oligonucleotide APIs. These advanced modalities require specialized expertise to ensure quality, regulatory compliance, and process efficiency from early-stage development to full-scale production. Our proven track record in overcoming technical challenges enables us to provide high-quality, flexible solutions tailored to our customers’ needs.
A prime example of our expertise in action is our work on Nusinersen, a complex oligonucleotide API. Our recent discussions at TIDES Europe highlighted the intricate challenges of achieving regulatory compliance while maintaining the highest standards of quality and efficiency.
Expertise in Oligonucleotide Development: The Nusinersen Case Study
TAPI’s experience in oligonucleotide development was demonstrated at TIDES Europe, where our R&D team presented critical insights:
- Michael Tikhonov, R&D Analytical Group Manager, discussed the analytical challenges of developing generic oligonucleotides, particularly in impurity profiling.
- Daniel Pinchuk, Group Leader Chemical R&D, gave an in-depth presentation on the development of Nusinersen API, emphasizing how TAPI ensures quality and regulatory sameness with the Reference Listed Drug (RLD).
Daniel and Michael’s talk explored key factors such as phosphorothioates diastereomeric composition, and cost considerations, while also showcasing the advanced statistical tools TAPI employs to ensure similarity.
Watch the Full Presentation: here
Challenges of Generic Oligonucleotide Drug Substance Development
Developing a generic version of Nusinersen presents unique challenges due to its complex structure. In 2022, the FDA issued product-specific guidance recommending that generic versions establish diastereomeric composition sameness with the RLD. This is no small feat—Nusinersen is a mixture of approximately 130,000 stereoisomers!
At TAPI, we take a rigorous approach to ensuring quality and sameness, from manufacturing process development to analytical characterization. Our methodologies focus on key parameters that influence the final diastereomeric ratio, ensuring regulatory compliance while maintaining high-quality standards.
FDA Recommendations for Diastereomeric API Sameness
The FDA guidance outlines several key recommendations for achieving sameness:
- Selecting and controlling reagents and reaction conditions carefully
- Measuring the R/S ratio at each elongation cycle using appropriate methods
- Comparing the diastereomeric composition of the generic API to the RLD
TAPI’s Approach
At TAPI, we leverage advanced analytical techniques to ensure diastereomeric consistency in our generic Nusinersen API. Our approach includes:
✔️ Evaluating the R/S ratio at each elongation step using LC-MS
✔️ Carefully selecting fractions during purification to optimize the diastereomeric ratio and impurity profile
✔️ Using ³¹P NMR fingerprinting, combined with PCA, correlation algorithms, and R/S ratio analysis, to demonstrate diastereomeric sameness
By combining cutting-edge analytical tools with our expertise in complex API development, we ensure that our generic oligonucleotide APIs meet the highest standards of quality and regulatory expectations.
CDMO Capabilities in Action: What This Means for Our Partners
The challenges of developing Nusinersen illustrate the depth of TAPI’s CDMO expertise and our ability to tackle complex problems to deliver high-quality solutions for our selected partners. Our expertise will be at your disposal to:
- Overcome complexity: Navigating the challenges of large stereoisomeric mixtures and ensuring regulatory compliance.
- Innovate solutions: Implementing analytical and manufacturing techniques that enhance process control and optimize outcomes.
- Ensure regulatory success: Adhering to FDA and EMA guidelines to guarantee product safety and efficacy.
- Control isomer ratios and process stability: Managing chiral purity through purification, scale-up, and stringent process monitoring.
- Optimize manufacturing from development to commercial production: Understanding process parameters that influence quality, ensuring smooth scalability, and implementing state of the art equipment.
- Improve efficiency and quality: Process Analytical Technology (PAT) is implemented. PAT enables real-time, quality-based adjustments to the process.
By leveraging these capabilities, we provide our partners with confidence in their oligonucleotide projects, ensuring a seamless path from development to commercialization.
Customized CDMO Solutions at TAPI
At TAPI, we offer tailored CDMO solutions for every stage of your API journey. With over 85 years of API development and manufacturing expertise, we provide flexibility and innovation to meet your unique needs. Our global presence, advanced technologies, and unwavering commitment to quality and compliance enable us to deliver solutions across a wide range of modalities.
Our extensive experience spans advanced oligonucleotide modalities such as Antisense Oligonucleotides (ASO), small interfering RNA (siRNA), and Conjugated-Oligonucleotides. This breadth of expertise further reinforces our position as a leader in the oligo CDMO space, ensuring that we meet the evolving needs of our partners.
Whether your project involves peptides, oligonucleotides, fermentation products, steroids, or small molecules, we are equipped to support you every step of the way.
- Peptides & Oligonucleotides: Tailored manufacturing from research to commercial production, with reactor sizes ranging from 100 L to 2,000 L for peptides.
- Wide Range of Capabilities: Offering regulatory starting materials, intermediates, and APIs for a diverse set of products.
Whatever your project needs, TAPI is ready to deliver.
