Sustainability in the pharmaceutical industry is not only about setting ambitious goals. It is about embedding responsible practices into the everyday environments where science happens.

At TAPI, this includes the laboratories where our teams develop, improve, and support complex API and CDMO solutions. As part of our commitment to responsible innovation and continuous improvement, TAPI is advancing sustainable laboratory practices through My Green Lab® Certification.

What is My Green Lab® Certification?

My Green Lab® Certification is an independent, third-party verified program that assesses laboratories across 14 sustainability categories, including energy, water, waste, chemicals, procurement, and culture.

The certification program is widely recognized as a leading standard for sustainable laboratory operations and is used by many of the world’s top pharmaceutical and biotechnology companies. Laboratories are assessed and awarded certification levels based on their performance, from Bronze to Silver, Gold, Platinum, and Green.

Achieving certification reflects a laboratory’s commitment to reducing environmental impact while supporting safer, more efficient, and more responsible operations.

For TAPI, this recognition is more than a certificate. It reflects our commitment to responsible science, operational excellence, and sustainable progress across our global network.

Why Sustainable Laboratories Matter

Laboratories are essential to scientific progress, but they can also be resource-intensive environments. By adopting more sustainable practices, labs can reduce energy consumption, improve waste and chemical management, conserve water, and strengthen awareness around responsible daily operations.

These improvements support both environmental performance and operational quality. More efficient use of resources, better inventory control, responsible chemical handling, and stronger lab engagement contribute to safer, more reliable, and more controlled R&D environments.

For our partners, this provides additional confidence that TAPI is working to align scientific excellence with responsible operations and evolving ESG expectations.

Building a Culture of Sustainable Science

Sustainable laboratory practices require more than process changes. They depend on awareness, engagement, and consistent action from the people working in the lab every day.

Through My Green Lab® Certification, our teams are encouraged to assess current practices, identify opportunities for improvement, and embed sustainability into daily routines. This includes actions such as switching off idle equipment, optimizing energy use, reducing waste, improving chemical inventory management, and encouraging greener procurement decisions.

These efforts reflect TAPI’s broader commitment to doing the right thing for our customers, our communities, and the planet.

Recognized TAPI Labs

As part of this ongoing journey, TAPI is proud to recognize the laboratories across our network that have achieved My Green Lab® recognition. Each lab’s progress reflects local ownership, strong engagement, and a shared commitment to advancing sustainable science.

TAPI Rho Chemical R&D Lab Achieves My Green Lab® Platinum Certification

TAPI’s Rho Chemical R&D Lab has achieved My Green Lab® Platinum Certification, in recognition of their sustainability efforts.

The certification reflects a comprehensive effort by the Rho team to evaluate, improve, and embed sustainable practices across daily laboratory operations. Each requirement of the My Green Lab® program was analyzed and addressed, ensuring that the necessary actions and policies were in place.
Key focus areas included energy efficiency, waste and chemical reduction, greener laboratory operations, and employee engagement.

The lab implemented energy-saving practices such as switching off idle fume hoods and instruments, optimizing ventilation and cold storage settings, and encouraging more energy-conscious daily routines.
The team also improved waste management practices by expanding recycling efforts and reducing hazardous and chemical waste where possible. Better inventory control, greener experiment planning, and efforts to minimize expired chemical disposal helped support more responsible use of laboratory materials.

In addition, the lab integrated green chemistry principles and sustainable procurement practices into R&D operations. This included efforts to substitute or reduce hazardous reagents when possible, purchase more sustainable lab consumables, and conserve water through practical improvements such as recirculating cooling systems and leak prevention.

A dedicated Green Lab team at Rho guided these efforts, with strong leadership support and broad lab engagement. Employees participated in training, surveys, idea generation, and daily sustainability actions, helping create a culture of continuous improvement.

Achieving Platinum Certification provides independent validation of the Rho Chemical R&D Lab’s environmental performance and reinforces TAPI’s commitment to responsible innovation, safer operations, and sustainable progress.

TAPI Czech Republic R&D Receives My Green Lab® Platinum Recognition

TAPI is also proud to recognize TAPI CZ R&D for receiving My Green Lab® Platinum recognition.
This achievement reflects the team’s commitment to embedding sustainable practices into daily laboratory work and contributing to TAPI’s broader efforts to advance responsible science across our global R&D network.

By reaching Platinum level, TAPI CZ R&D demonstrates strong performance in sustainable laboratory practices and reinforces the importance of local engagement, continuous improvement, and operational responsibility.

Together with the Rho Chemical R&D Lab, this recognition marks another important step in TAPI’s journey to expand sustainable laboratory practices across our sites.

Continuing Our Green Lab Journey

The recognition of these labs is part of an ongoing effort to strengthen sustainability across TAPI’s laboratory network. As more labs advance through the My Green Lab® Certification process, we will continue to share their progress, achievements, and practical actions.

Each recognition reflects the work of dedicated teams who are helping make sustainability part of everyday scientific practice.

Through these efforts, TAPI continues to advance responsible innovation, safer operations, and sustainable progress across our global network.

At TAPI, scientific excellence is demonstrated through the way we design, optimize, and scale complex chemical processes. A newly published peer-reviewed paper from our R&D colleagues in Czechia, featured in Organic Process Research & Development (OPRD), highlights this approach through the development of a scalable synthetic route toward a key intermediate in Cantharidin. 

The publication showcases TAPI’s capabilities in advanced chemistry, crystallization development, and data-driven process optimization, applying Design of Experiments (DoE) and Quality-by-Design (QbD) principles to deliver a robust and industrially viable process. 

Why Cantharidin—and why now? 

Cantharidin is a highly potent natural terpenoid historically sourced from blister beetles. In recent years, interest in reliable synthetic manufacturing has grown—especially as pharmaceutical demand increases and supply chains seek reproducible quality, controlled impurities, and scalable production routes. 

In 2023, U.S. Food and Drug Administration announced approval of YCANTH (cantharidin) as the first treatment indicated for molluscum contagiosum, further reinforcing the need for robust manufacturing approaches to meet rising demand.  

What the paper demonstrates 

The team reports a lithium iodide (LiI)–mediated Diels–Alder cycloaddition that achieves: 

• High conversion efficiency under practical conditions 

• Excellent stereoselectivity (exo-selectivity)—reported as the highest to date in the paper’s context 

• Operational robustness, with conditions described as water- and air-tolerant 

• A process that was successfully scaled to the hundred-gram level using straightforward reactions and work-ups  

DoE-driven optimization to support QbD 

Rather than relying on one-factor-at-a-time optimization, the work applies a structured DoE approach to evaluate key parameters and interactions—supporting a QbD development mindset: 

• Identifying which factors most strongly influence conversion and process operability 

• Balancing conversion and selectivity with practical considerations like agitation parametersEnabling greater confidence in robustness and reproducibility when moving toward larger scale 

This is a strong example of how TAPI R&D brings data-driven process understanding into early development—setting the stage for smoother tech transfer and scale-up. 

A standout: crystallization-based isolation (no chromatography) 

One of the most practical highlights is the crystallization-based isolation protocol reported for the first time for this intermediate: 

• Enables isolation of a pure exo-isomer 

• Removes byproducts and residual salt without relying on chromatography 

• Provides a scalable approach aligned with industrial manufacturing expectations 

This crystallization strategy is a strong demonstration of our capabilities in solid-state understanding, isolation development, and impurity control—all essential for building scalable, manufacturable routes. 

Built with sustainability and cost efficiency in mind 

Beyond performance, the process development choices reflect modern process expectations: 

• Avoiding less desirable systems that require large excesses of certain salts 

• Using conditions designed for industrial operability 

• Introducing the possibility of recovering lithium iodide to improve overall cost efficiency 

This work reflects TAPI’s ability to translate deep scientific understanding into scalable, reproducible, and manufacturing-ready processes, supported by strong solid-state and crystallization expertise. 

Read the full article in Organic Process Research & Development to explore the complete methodology, data, and process insights. 
Scalable Synthesis of Cantharidin: Lithium Iodide as a Stereoselective and Efficient Catalyst in the Diels–Alder Reaction toward a Key Intermediate | Organic Process Research & Development

TAPI will only be able to offer and supply this pharmaceutical ingredient in the countries and exclusively for uses that are exempt from infringement of any exclusive rights(such as patents and/or supplementary protection certificates or extensions) in accordance with applicable law. TAPI requires adequate confirmation of the exempt use upon ordering. 

At TAPI, advancing health from the core means more than scientific excellence. It also means protecting people, preserving resources, and building a safer, more sustainable future across our global organization. 

That is the idea behind the first-ever TAPI EHS&S Awards 2025 — a new global initiative created to recognize exceptional contributions in Environment, Health, Safety and Sustainability across TAPI. 

Launched in mid-October 2025 and highlighted during TAPI EHS&S Week in November, the awards were created to celebrate individuals and teams whose work goes beyond compliance and creates real, lasting impact. Whether through innovation, leadership, collaboration, or continuous improvement, these are the people helping strengthen TAPI every day. 

The program also reflects TAPI’s principles in action: A community more than a company, We love to win, Beyond is where we begin, and We crave science and technology. 

Why These Awards Matter 

In their first year, the EHS&S Awards drew 43 applications from across TAPI in categories including Environment & Sustainability, Safety, Health, Culture, and Other. 

Each submission was reviewed by the Global EHS&S team based on clear criteria: 

• Innovation and originality 

• Magnitude of impact 

• Sustainability and long-term applicability 

• Measurable results and quality of data 

• Replicability across sites 

Following the review process and alignment with top management, four winning projects were selected and announced during the TAPI Q4 and FY2025 Town Hall on January 29, 2026. 

Together, the winners show what EHS&S excellence looks like at TAPI today: practical, people-centered, measurable, and forward-looking. 

Netanel Hakimi 

“Community more than company – doing it together” 

TAPI Israel, Abic 

As TAPI continued strengthening its independent EHS&S practices, the Abic site identified a need for a simple and effective way to report safety observations, hazards, and near misses in its dynamic R&D environment.

The answer was GOARC, a digital safety platform installed on employees’ phones, enabling real-time reporting and immediate follow-up. With strong training, communication, and leadership support, the tool quickly became part of daily work. 

Since launch on July 1, 2025, the site has recorded more than 100 hazard reports and over 50 observation reports, with a closure rate above 90%. Just as importantly, the initiative has helped strengthen trust, accountability, and collaboration across departments. 

This project stood out for turning safety reporting into a shared cultural practice — making prevention more visible, more accessible, and more effective. 

Engineering and Energy Utilities Team 

“Utilization of Waste Heat from WWTP Blowers” 

TAPI Czech Republic, Opava 

Pavel Stehlik’s team focused on finding a smarter use for energy already being generated on site. 

At the Opava wastewater treatment plant, heat produced during air compression for biological aeration was being wasted. The team identified an opportunity to capture that heat and redirect it to the neighboring main warehouse building. 

After system design, cost assessment, and equipment installation, the project delivered clear and measurable results. In its first year, it saved 714 GJ of heat and reduced natural gas consumption by 19,000 m³, generating approximately USD 17,400 in heating energy savings. 

The environmental impact was just as significant, with a reduction of 40 tons of CO2 emissions and additional savings linked to avoided emission allowance costs. 

This project is a strong example of how practical engineering can create value on multiple levels — reducing emissions, lowering costs, and improving energy efficiency at the same time. 

Anantha Rajmohan M 

“Smart Science for a Safer Tomorrow: AI and Automation Elevating EHSS Standards in Polymorph search ” 

TAPI India R&D, Greater Noida 

In TAPI’s polymorph search activities, Anantha Rajmohan M and the Greater Noida team rethought traditional workflows through the lens of EHS&S, combining AI, automation, advanced equipment, and improved engineering controls. 

Polymorph screening is strategically important, but it can also be resource-intensive. The team introduced a smarter model that reduced solvent handling, minimized exposure to hazardous chemicals, lowered waste generation, and improved ergonomics for scientists. 

Among the key improvements, solvent storage was significantly reduced, experiment scale was lowered, and advanced systems such as Genevac, Polar Bear, and high-throughput screening tools enabled more efficient, lower-waste experimentation. AI-driven calculation tools also helped reduce zero-yield experiments from 35–40% to around 10%, generating up to 25% savings in API use, solvent consumption, and man-hours. 

Beyond operational efficiency, the shift also reduced repetitive manual work and physical strain, allowing scientists to focus more on planning, analysis, and innovation. 

This project stood out for showing how science and technology can directly improve safety, sustainability, and research quality — all at the same time. 

Teva Tech Team 

“From Risk to Resilience – Setting a New Benchmark for Managing Acutely Toxic Chemicals” 

TAPI Israel, Teva Tech 

The Teva Tech Team project addressed a major safety challenge: managing acutely toxic non-API chemicals in the absence of formal best-practice standards. 

At Teva Tech, the team identified a gap in how substances with severe acute toxicity — such as Hydrazine Hydrate, DIC, and TBHP — were managed across their lifecycle. In response, they developed a comprehensive risk management strategy that created a new benchmark for safe handling. 

The project introduced improvements across storage, transport, transfer, sampling, emissions treatment, and disposal. These included minimizing packaging sizes, defining dedicated storage requirements, eliminating unnecessary sampling, implementing strict transportation guidelines, and establishing closed transfer systems with leak-tight engineering controls and early leak detection. 

The result was a significant reduction in exposure risk, improved industrial hygiene and process safety, and stronger control over hazardous emissions and waste. 

This project stood out because it did not simply improve an existing framework — it created one. It is a clear example of proactive safety leadership in action. 

Building a Stronger TAPI, Together 

The first TAPI EHS&S Awards highlight the depth of talent, commitment, and innovation across our global network. 

From strengthening reporting culture in Israel, to recovering energy in the Czech Republic, to transforming laboratory workflows in India, to setting new standards for chemical safety in Israel, each winning project reflects a different side of what responsible progress looks like at TAPI. 

Together, they show that EHS&S excellence is not only about reducing risk. It is about enabling innovation, supporting resilience, and reinforcing the culture that helps TAPI move forward — safely, responsibly, and sustainably. 

In pharmaceutical development, the race to bring medicines to patients faster—without compromising on quality—is more critical than ever. At TAPI, we’re answering that challenge head-on with an innovative platform that transforms how solid forms are identified and developed. By integrating computational tools with high-throughput laboratory automation, we’re not just streamlining solid-state R&D—we’re reshaping it. 

Rethinking Polymorph Screening 

Solid form matters. Polymorphs, hydrates, solvates, and amorphous structures may influence a drug’s solubility, stability, manufacturability, and regulatory path. Traditionally, uncovering these forms has relied on labor-intensive, trial-and-error methods. Our bespoke platform reimagines this process by combining computational tools modeling with smart experimental design. 

We leverage tools like Crystal Structure Prediction (CSP), lattice energy ranking, and targeted screening algorithms to identify different solid forms. Our unique approach allows us to creatively design the experimental plan before we even step into the lab—saving time, materials, and energy. 

From Prediction to Precision: Smart Experimentation in Action 

Our software-based systems are fully integrated with  automated high-throughput polymorph screening (HTPS). This means that parallel experimentation with multiple crystallization conditions can be conducted faster and more systematically than ever before. Using tools like PXRD, DSC, TGA, and microscopy, we can rapidly identify and characterize different solid forms with scientific rigor. 

And thanks to a closed-loop feedback system, experimental data feeds back into the AI models—making them smarter over time and improving accuracy with every iteration. 

Impact That Scales 

This is more than a lab breakthrough—it’s a platform with real-world impact. By enabling earlier identification of optimal solid forms, we help pharmaceutical partners minimize late-stage surprises, improve formulation robustness, and accelerate regulatory submission. It’s a smarter, safer, and faster way to advance drug development. 

A New Standard for Solid-State Innovation 

At TAPI, science is strength—and our innovative platform embodies our passion for advancing health from the core. By combining digital intelligence with expert intuition, we’re enabling our partners to make better decisions, faster. It’s not just innovation—it’s transformation. 

Whether you’re formulating a first-in-class therapy or optimizing a generic molecule, our AI-powered solid form platform is ready to support your journey. 

Let’s move beyond what’s expected. Let’s redefine what’s possible. 

At TAPI, we are dedicated to advancing sustainable pharmaceutical manufacturing by harnessing the power of cutting-edge science—particularly biocatalysis. One of our recent successes exemplifies this commitment: the development of a scalable, environmentally responsible biocatalytic process for the production of a complex chiral intermediate used in the synthesis of Avacopan. This achievement not only overcomes long-standing challenges in stereoselective synthesis; it also demonstrates the broader potential of enzyme-based technologies to streamline pharmaceutical production. 

By integrating biocatalysis into our development workflows, we offer innovative, greener alternatives to traditional chemical routes—delivering benefits in efficiency, selectivity, and sustainability. These capabilities are now a core part of our value proposition, both for our internal portfolio and for partners through our CDMO services. Whether optimizing existing processes or designing new synthetic pathways, we are helping to redefine what’s possible in pharmaceutical manufacturing through biocatalytic innovation. 

The Challenge: Double Stereocontrol with High Yield and Low Waste 

The synthesis of 2,3-disubstituted cyclic amines — especially with full control over two adjacent stereocenters — has historically been a significant challenge in API development. Traditional chemical synthesis routes for Avacopan’s (2R,3S)-2-arylpiperidine-3-carboxylate intermediate rely on diastereomeric crystallization, a process that discards nearly half of the material and yields only 42%. 

We saw an opportunity to develop a cleaner, more efficient alternative. Inspired by the principles of green chemistry, our team sought a stereoselective, biocatalytic solution that could reduce waste and improve scalability. 

The Solution: Enzyme-Catalyzed Amine-Imine Transformations 

Through extensive enzyme screening, we developed two innovative routes using imine reductases (IREDs): 

1. Oxidative kinetic resolution of the racemic amine, followed by catalytic hydrogenation for enantiomer recovery — successfully scaled up to kg scale. 

2. Dynamic kinetic reduction using enantiocomplementary IREDs — demonstrated at lab scale, showing strong potential for further development.

These pathways hinge on the reversible imine-enamine tautomeric equilibrium, which allows for efficient recycling of undesired stereoisomers and high selectivity toward the desired (2R,3S)-configured intermediate. 

Key Innovations 

• Enzyme Selection and Cofactor Regeneration 

We identified four commercial IREDs capable of enantioselective oxidation and two others for dynamic kinetic reduction. However, to make the process robust and scalable, we also needed an efficient system for cofactor regeneration. 

Traditionally, NADPH oxidases (NOx) were used for this role but posed challenges due to their sensitivity to solvents. Our breakthrough came with the application of alcohol dehydrogenase (ADH) enzymes — specifically from Lactobacillus brevis — as a more stable and scalable alternative for cofactor regeneration. This was the first reported use of ADHs in IRED-catalyzed oxidations, marking a significant step forward in biocatalysis. 

• High Selectivity and Improved Yields

Our enzymatic process achieved exceptional selectivity: 

• Oxidative route: >99.5% ee and >99.9% de 

• Reductive route: 98.3% ee and >99.9% de 

The oxidative route also significantly improved overall yield. By coupling it with a catalytic hydrogenation recovery step, we reached 72% yield across cycles — a dramatic improvement over the 42% achieved by conventional crystallization. 

• Scalable, Safe, and Sustainable 

Safety and scalability were paramount. Unlike earlier methods using monoamine oxidases and hazardous reducing agents (like boranes), our enzymatic routes avoid incompatible chemicals. The oxidation process was safely scaled to kg levels, with a high space-time yield of 37.2 g/L/day — a strong metric for industrial viability. 

In terms of sustainability, the use of biodegradable enzymes, mild conditions, and minimized waste supports our commitment to environmentally responsible API production. 

A Model for Future Development 

Our biocatalytic model provides a practical framework for innovation in pharmaceutical manufacturing, tackling issues that rise from a standard chemical synthesis approach: 

• It illustrates how the stereo controlled synthesis of complex amines can be achieved efficiently using green chemistry, addressing a long-standing synthetic challenge. 

• It expands the perceived role of ADHs by demonstrating their effectiveness in oxidation reactions, opening new avenues within biocatalysis. 

• It highlights how enzyme-driven processes can achieve both economic scalability and environmental responsibility—two critical priorities for the industry. 

Partnering for Innovation: CDMO Services at TAPI 

This breakthrough in the synthesis of Avacopan API exemplifies how targeted innovation, grounded in green chemistry principles, can transform pharmaceutical manufacturing. With better yields, reduced environmental impact, and strong scalability, this process is not just a milestone for TAPI — it’s a glimpse into the future of sustainable use of biocatalysis in pharmaceutical manufacturing. 
 
This achievement reflects more than scientific innovation—it demonstrates what’s possible when advanced technologies meet end-to-end CDMO support. At TAPI, we offer integrated CDMO services across every stage of development, from route scouting and process design to scale-up, GMP production, and commercial supply.  

Our global network spans 13 manufacturing sites and 5 R&D centers, supported by ~450 scientists and a deep toolbox of enabling technologies—from biocatalysis and flow chemistry to particle engineering and ultrafiltration. Whether your program involves small molecules, peptides, oligonucleotides, fermentation products, or HPAPIs, we’re ready to tailor solutions that accelerate your success. 

At TAPI, innovation drives everything we do—from early development to commercial scale. Crystallization is one of the most critical steps in API manufacturing, and gaining control over this process is key to achieving consistent critical quality attributes (CQAs), such as polymorphic form and particle size distribution. 

Traditionally, crystallization monitoring has depended on offline sampling, a time-consuming and complex approach that limits real-time insights and hinders process optimization. To overcome this, our R&D team implemented in-line process analytical technology (PAT) tools to solve a specific and scientifically challenging crystallization issue during the development of a novel API sulfonate salt. 

The challenge? A late-appearing polymorphic form—an industry-recognized risk with major implications for product consistency and performance.  

Leveraging Blaze high dynamic range (HDR) process microscopy in tandem with Raman spectroscopy, our scientists achieved rapid root-cause identification and developed a robust new crystallization process—demonstrating the power of real-time PAT integration. 

From Insight to Impact: Background & Approach 

During the first kilo-lab scale-up of the sulfonate salt, a new polymorphic form unexpectedly emerged—despite extensive prior screening. To tackle this, our team deployed advanced PAT tools, including HDR microscopy and Raman spectroscopy, for in situ monitoring of particle statistics and polymorphic transitions. 

This data-driven approach allowed rapid, informed decision-making and accelerated the development of a new crystallization process. 

Why PAT Makes the Difference 

The Blaze 900 system integrates HDR microscopic imaging, turbidity measurement, and Raman spectroscopy into a single, multi-functional probe. Its advanced image analysis algorithm provides accurate particle statistics—significantly outperforming conventional tools like PVM and FBRM. 

This capability enables real-time tracking of key crystallization phenomena, including nucleation, growth, attrition, oiling out, and polymorphic transformations—driving deeper process understanding and control. 

Overcoming the Polymorphism Challenge 

Lab investigations revealed that the anhydrous form of the compound could rapidly convert into either a monohydrate or a newly discovered methanolate, depending on the solvent system. These two novel forms, each with distinct crystal habits and thermal behaviors, were shown to be in an enantiotropic relation. 

With direct crystallization of the anhydrous form no longer feasible, our team pivoted to explore seeded cooling crystallization to obtain the monohydrate.  

This was followed by extensive Raman-supported solvent screening to enable a solvent-mediated polymorphic transformation into the desired anhydrous form—unlocking valuable insight into conversion kinetics. 

A Smarter, Faster Path to Process Development 

The integration of HDR microscopy and Raman spectroscopy enabled precise identification of transition points and streamlined the development of a robust crystallization pathway. This not only reduced development time but also improved product quality and ensured more reliable process control—highlighting the strategic value of in-line PAT. 

The combination of Blaze 900 in-line process microscopy with Raman spectroscopy marks a significant step forward in crystallization process development. By enabling real-time, in-depth process insight, these tools reduce reliance on offline analytics, accelerate development, and strengthen product robustness. 

At TAPI, we continuously invest in advanced technologies to drive smarter, faster, and more reliable API development—empowering our partners with solutions that deliver measurable impact. 

We’re proud to share our recent peer-reviewed scientific article, published in the prestigious ACS Organic Process Research & Development journal, titled “Imine Reductase-Catalyzed Synthesis of a Key Intermediate of Avacopan: Enzymatic Oxidative Kinetic Resolution with Ex Situ Recovery and Dynamic Kinetic Reduction Strategies toward 2,3-Disubstituted Piperidine.”

This milestone underscores the strength and innovation of our R&D team and marks TAPI’s presence in the global scientific community as a thought leader in process chemistry.

In this article, our scientists demonstrate the ability of proprietary imine reductases (IREDs) to control the configuration of two vicinal stereogenic centers in avacopan API via oxidative kinetic resolution. The system involves selective oxidation and tautomerization of the undesired enantiomer into a corresponding enamine. This byproduct is then either recycled via catalytic hydrogenation back to the racemic starting material or transformed through a dynamic kinetic resolution using another proprietary IRED with excellent diastereoselectivity. 

The process was successfully scaled to the kilogram level, with outstanding selectivity and yield. It’s an excellent example of how TAPI combines biocatalysis and process innovation to deliver efficient, sustainable solutions to complex synthetic challenges. 

Access the full article here.

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. 

Going the Extra Mile for a Greener and Safer R&D 

The TAPI R&D team developed an innovative ozonolysis in flow synthesis process that offers a selective and environmentally friendly solution to a challenging, synthetic step in our route of synthesis. A prototype of an in-house developed flow ozonator was created and subsequently applied to the design of reaction equipment, enabling larger scale synthesis.  

In this blog, you’ll see how this approach resulted in minimizing the environmental impact, improving product quality, and ensuring high process safety.    

 

Background    

The oxidative C=C bond has been identified as a critical chemical transformation in the manufacturing process of the API Voclosporin. Traditionally, heavy metal-based catalysts are employed for this type of reaction. However, these catalysts often lead to over-oxidation and impurity formation.   

The use of heavy metals presents several challenges in terms of:   

• Product contamination, as heavy metals can contaminate the final product, affecting its purity.    
• Environmental impact, as catalyst leakage into the environment poses risks to ecosystems.    
• Waste disposal and recycling, as proper disposal of heavy metal-containing waste is complex and costly.   

  

The Advantage of Ozonolysis   

Although various oxidative reactions can be considered for this purpose, only a limited number of transformations are compatible with the sensitive molecular scaffold of Cyclosporine, requiring high selectivity and process robustness. One such reaction meeting these criteria is ozonolysis.   

Ozonolysis offers a selective and clean alternative to heavy-metal based oxidative double bond cleavage. In ozonolysis, side reactions and impurity formation are significantly suppressed, resulting in a conversion rate exceeding 99.9%. Moreover, using proper equipment design, any excess ozone is catalytically decomposed back into oxygen.   

 

The Ozonolysis Challenge  

However, ozonolysis has significant drawbacks from an environmental, health and safety (EHS) perspective. There is an inherent toxicity and potential explosion hazard associated with the ozone, especially when mixed with flammable solvents, so precautionary measures are critical during the process design.   

 Large-scale batch ozonolysis is considered too hazardous, prompting the exploration of an alternative flow approach.   

  

The Flow Ozonator   

We set about to build an industrial flow reactor for ozonolysis, starting with a simple prototype based on 3D printing technology. This conceptual shift of reactor design aims to enhance safety while maintaining the desired reaction selectivity, product quality and process robustness. It also represents a unique solution since flow ozonator systems are not commercially available and therefore need to be designed as tailor made systems.   

A prototype of the flow ozonator was developed in-house in our R&D department. The first proof-of-concept system was 3D printed to verify basic functionality and perform feasibility lab studies. 3D printing technology was also used to improve the design of a larger scale, nGMP prototype that allowed us to overcome several technological challenges.    

The final design was subsequently applied to the production equipment, which met all Atex requirements of a production environment.   

The industrial equipment enabled successful production of GMP validation batches and will enable sufficient capacity. Notably, this approach minimizes environmental impact, improves product quality, and ensures high process safety.    

Side reactions and impurity formation are significantly suppressed, resulting in a conversion rate exceeding 99.9%. Additionally, any excess ozone is catalytically decomposed back into oxygen, minimizing any EHS risk.   

9 Key features, functionalities, and unique properties of TAPI’s flow ozonator are as follows:   

• Ozone is produced and consumed in the same close reactor zone.   
• Excess ozone is continuously decomposed to oxygen in the same close reactor zone via an implemented catalytic ozone destructor.  
• Low amount of ozone at any point in the reaction – less than 100 mg.   
• High level of operator protection.    
• Low amount of flammable methanol actively mixed with ozone in the air – less than 50 mL.  
• Very short residence time – less than 10 s therefore overoxidation / formation of by-products suppressed.   
• Low reaction temperature used – reduced solvent vapour well below the flash point of methanol in air.   
• Very low accumulation of reactive intermediates.    
• Since synthetic process in production is continuous and there are no interruptions or delays, predicting and managing production times and costs becomes easier for businesses.   

The implementation of this creative in-house ozonolysis flow technology significantly enhances process safety, robustness and mitigates the environmental footprint associated with chemical processes and optimizes product purity profile and quality.   

It also represents a remarkable example of the benefit of continuous manufacturing applied to a challenging transformation of a complex API.   

For the avoidance of doubt, TAPI is not offering Voclosporin and will not sell Voclosporin, if such offer or sale infringes valid patents, unless in accordance with conditions permissible under applicable law.