Smart Biotech Scientist | The CMC and Bioprocessing Podcast for Process Development and Manufacturing Leaders

Cardiovascular disease has long been managed by slowing its relentless progression. But Matthew O'Connor, CEO of Scientific Affairs at Cyclarity Therapeutics, is betting on an outright paradigm shift: treating atherosclerotic plaque with therapies designed to actively reverse disease, not simply manage symptoms or risk.

In this episode, David Brühlmann explores the strategy, regulatory journey, and manufacturing realities behind Cyclarity's unconventional cyclodextrin-based approach—a molecule sitting at the crossroads of small and large molecule drug development.

Topics discussed:

• Insights into the company's clinical development progress, including completion of a first-in-human study and what comes next (02:47)
• How the FDA views drugs that don't fit traditional categories and how this influences development pathways (04:35)
• The challenges and considerations in demonstrating efficacy for drugs designed to reduce heart attacks and strokes (05:22)
• Cost considerations in manufacturing the cyclodextrin dimer and how it compares to biologics and GLP-1 drugs (08:14)
• Vision for how cardiovascular disease may be diagnosed and treated a decade from now, including the role of imaging and prevention (10:24)
• Broader implications for treating age-related diseases by targeting toxic metabolites in the body (14:25)
• Why next-generation therapeutics may be built not by sticking to old modalities but by tackling root causes with custom solutions (16:10)
• Reflections on making new drugs both safe and fundamentally beneficial, minimizing side effects (17:10)

Smart insight: Start with the problem, not the modality. Matthew O'Connor argues that instead of defaulting to an antibody, a small molecule or a gene therapy, developers should build a custom solution to the problem they're trying to solve. A drug that suppresses a pathway across the whole body brings side effects you have to manage. A drug that removes something harmful, like oxidized cholesterol, can have side effects that are actually beneficial. His goal for the next generation of drugs is ones that simply make people healthier.

When a drug is too big to be a small molecule and too small to be a biologic, every CMC decision gets harder. These episodes look at what it takes to develop, characterize and manufacture a modality that doesn't fit an existing box.

• Episodes 281 - 282: When Your Delivery Vehicle Contains a Membrane Protein: CMC Decisions With No Regulatory Precedent with Jitendra Kumar
• Episodes 207 - 208: Cryogenic Infrared Ion Spectroscopy: From Mass Spec Limitations to Molecular Precision with Tom Rizzo
• Episodes 197 - 198: Mastering ADC Development: CDMO Strategies for Analytics and Scale-Up with Amanda Hoertz
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann

Connect with Matthew O'Connor:
Website: www.cyclaritytx.com
LinkedIn: www.linkedin.com/in/droki
Email: [email protected]

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show

Why does CMC development still expect every drug to be one molecule with one peak, when new therapeutics don't always fit neatly into existing regulatory or chemical categories?

Matthew O'Connor, CEO of Scientific Affairs at Cyclarity Therapeutics, is developing a drug that sits between a small molecule and a biologic. On the Smart Biotech Scientist Podcast, Matthew shared how his team engineered a cyclodextrin dimer that binds and removes 7-ketocholesterol, an oxidized form of cholesterol that builds up in artery plaque and is linked to a higher risk of heart attack and stroke.

Topics discussed:

• Matthew O'Connor's motivation for focusing on aging and molecular damage (03:39)
• The biological problem of oxidized cholesterol buildup and its role in atherosclerosis (04:42)
• Mechanism of action: how the cyclodextrin binds and removes 7-ketocholesterol (06:23)
• Approaches to designing a highly specific cyclodextrin therapeutic (09:14)
• The "medium-sized molecule" characteristics and the question of regulatory classification (12:16)
• Why cyclodextrin starting material is cheap and not a manufacturing bottleneck (15:37)
• Manufacturing strategies and the role of specialist CDMOs in complex carbohydrate chemistry (17:04)
• Methods for demonstrating identity and consistency in isomeric mixtures (18:43)
• Drug formulation considerations and why an injectable route is necessary (21:46)

Smart insight: Matthew O'Connor's work shows what happens when you start with the problem rather than the drug format. His team's cyclodextrin dimer doesn't fit neatly as a small molecule or a biologic, and that makes manufacturing, analytics and regulatory work harder. But if it can remove oxidized cholesterol from the body, it could help reverse plaque instead of just slowing it down.

When a drug is too big to be a small molecule and too small to be a biologic, every CMC decision gets harder. These episodes look at what it takes to develop, characterize and manufacture a modality that doesn't fit an existing box.

• Episodes 281 - 282: When Your Delivery Vehicle Contains a Membrane Protein: CMC Decisions With No Regulatory Precedent with Jitendra Kumar
• Episodes 207 - 208: Cryogenic Infrared Ion Spectroscopy: From Mass Spec Limitations to Molecular Precision with Tom Rizzo
• Episodes 197 - 198: Mastering ADC Development: CDMO Strategies for Analytics and Scale-Up with Amanda Hoertz
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann

Connect with Matthew O'Connor:
Website: www.cyclaritytx.com
LinkedIn: www.linkedin.com/in/droki
Email: [email protected]

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show

Scale-up doesn't fail because the science was wrong. It fails because a cell's environment in a shake flask has little in common with its environment in a bioreactor. Christian Witz has spent years building the tools to close that gap: simulating exactly what a cell experiences as it moves from bench to plant, before a single liter is wasted finding out the hard way.

Continuing from Part 1, David Brühlmann and Christian Witz, CEO and founder of SimVantage, go deeper into how CFD moves from theory to daily practice: validating simulation results, scaling real cell therapy and Streptomyces processes, and an active FDA-backed project on residence time distribution in continuous bioprocessing.

Topics discussed:

• Why data validation is crucial in CFD simulations and how to interpret and trust simulation results (02:39)
• Real-world examples of scaling up from shake flasks to stirred tank reactors using CFD, including specific collaborations and cell therapy case studies (05:40)
• Technical and validation challenges in simulating fluid dynamics in shake flasks and integrating these results into scale-up strategies (08:14)
• Ongoing FDA-backed project to model residence time distribution in continuous bioprocessing and its regulatory significance (11:49)
• The increasing openness of regulators like the FDA to include CFD data in submissions and relevant guidelines for simulation credibility (13:23)
• Advice for small biotech teams on when and how to start using CFD in CMC development and scale-up planning (15:06)
• Insights on the future of bioprocessing, including virtual scale-up, digital reactor repositories, and the democratization of CFD tools (18:20)

Smart insight: Christian Witz advised that teams begin CFD modeling as early as concept development. CFD not only helps choose the right equipment—even when working with contract manufacturers—but creates a digital process record that reduces experimental burden, shortens timelines, and impresses investors with its risk mitigation.

If this conversation got you rethinking your scale-up strategy, here are a few past episodes that go deeper on the pieces Christian touched on:

• Episodes 91 - 92 : Mass Transfer Secrets: Mastering Bubbles and kLa from Bench to Large-Scale Production with Lars Puiman & Rik Volger
• Episodes 245 - 246: Why Your Shake Flask Culture Doesn't Scale: OTR, Shaking Diameter, and How to Fix It with Tibor Anderlei
• Episodes 173 - 174: Mastering Hybrid Model Digital Twins: From Lab Scale to Commercial Bioprocessing with Krist Gernaey
• Episode 243: Turn Tech Transfer from a Gamble into a Managed Process: The 6-Pillar Biologics Scale-Up Framework

Connect with Christian Witz:
Website: www.simvantage.com
Christian’s LinkedIn: www.linkedin.com/in/christian-witz-84aa9b162/
Christian’s email: [email protected]

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show

You've perfected your process at the bench. Now comes the part that keeps CMC scientists up at night: will it still work at 2,000L? Right now, most teams find out the hard way, through failed runs, wasted batches, and months of delay to patients waiting on a therapy. Christian Witz believes there's a better way: use computational fluid dynamics to see how your cells will actually behave at full scale before you ever run the process, and stop treating scale-up as a guessing game.

On this episode of the Smart Biotech Scientist Podcast, David Brühlmann talks with Christian, founder of SimVantage, about why he treats CFD as a tool every process engineer should use directly, not something you outsource to a specialist. Christian's path into biotech ran through heat pump simulations and GPU-based particle flow modeling before he rebuilt a legacy Fortran bioreactor simulation program in modern C++ and CUDA, work that became the foundation of SimVantage.

Topics discussed:

• Christian’s path from simulating heat pumps and particle flows to pioneering GPU-based bioreactor simulations (03:54)
• The surprising lack of full equipment characterization in the biotech industry compared to fields like oil, gas, and iron & steel (06:40)
• The interdisciplinary challenges and steep learning curve when entering biotech from other industries (08:07)
• Why academic spinouts matter and the practical realities of founding a company based on university-developed software (09:44)
• Reasons behind CFD’s low adoption in bioprocessing—perceived complexity, need for specialists, and historical limitations in algorithms and computing power (11:58)
• How recent advances in GPU power, algorithms, and cloud computing remove barriers for routine use of CFD in process development (14:35)
• Strategies for characterizing and scaling processes across various reactor types, from shake flasks to manufacturing reactors (16:39)
• Practical considerations and limitations when setting up comprehensive CFD characterizations, including simulation parameter choices (19:49)

Smart insight: The degree of reactor characterization depends on a company’s needs. Startups might analyze a scale-up project once, while contract manufacturers—handling diverse products—benefit from comprehensive, reusable characterization across all reactors and operating conditions. Simulations are guided by physics (density, viscosity, surface tension) rather than biological specifics, allowing quick adaptation to new media or cell types.

If this conversation got you rethinking your scale-up strategy, here are a few past episodes that go deeper on the pieces Christian touched on:

• Episodes 91 - 92 : Mass Transfer Secrets: Mastering Bubbles and kLa from Bench to Large-Scale Production with Lars Puiman & Rik Volger
• Episodes 245 - 246: Why Your Shake Flask Culture Doesn't Scale: OTR, Shaking Diameter, and How to Fix It with Tibor Anderlei
• Episodes 173 - 174: Mastering Hybrid Model Digital Twins: From Lab Scale to Commercial Bioprocessing with Krist Gernaey
• Episode 243: Turn Tech Transfer from a Gamble into a Managed Process: The 6-Pillar Biologics Scale-Up Framework

Connect with Christian Witz:
Website: www.simvantage.com
Christian’s LinkedIn: www.linkedin.com/in/christian-witz-84aa9b162/
Christian’s email: [email protected]

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show

Biotech founders often pour everything into building the “perfect” product only to realize their real customers have walked out the door. Chasing perfection can burn money and stall even the most promising CMC innovations.

In this episode, David Brühlmann continues his conversation with biotech entrepreneur and investor John Bonham-Carter. John shares his insights on the realities of building and scaling successful biotools companies, from the challenges of fundraising and the importance of authentic storytelling, to knowing when to stop perfecting a product and start selling.

Topics discussed:

• How fundraising is less about money and more about the story, team, and real commitment behind a startup (02:33)
• Practical advice for founders: obsess over the customer, not just the technology (07:14)
• The dangers of spreading yourself too thin as a startup founder and lessons from parenting applied to startups (07:09)
• Choosing business partners and collaborators whose skills complement your own—and making peace with imperfection (10:10)
• John’s approach to building teams and why accepting mediocrity in some areas can lead to collective excellence (11:16)
• The story behind John joining Stellion Biosystems, and what makes their cell counting technology different in the market (11:51)
• Using creative, low-budget tactics for visibility—why John chose a lizard mascot for Stellion Biosystems (15:19)
• Thoughts on when (if ever) to stop and the value of keeping multiple life and career doors open (17:26)
• John’s main takeaway: “Try everything”—professional advice drawn from experience (and Zootopia) (19:01)

Smart insight: John leaves us with a simple yet powerful credo: “Try everything.” In biotech, that means embracing experimentation not just in the lab, but in business strategy, partnerships, hiring, and technology adoption. By collaborating, iterating, and listening closely to customers, you can grow, succeed, and—perhaps—build something that truly makes a difference. In a field where the only constant is change, remember: launch before you’re ready, find your people, and keep your story genuine.

Some ideas are ahead of their time; a few people make a career of being early. This is part bioprocess history, part founder's playbook: why the best technology doesn't automatically win, how to move a conservative industry, and when to sell rather than scale. To go further on both the technology and the business behind it:

• Episodes 191 - 192: Process Intensification Secrets: A Process Engineer's Decision Framework with Andreas Castan
• Episodes 183 - 184: From Lab to Market: Secrets to Commercializing Cutting-Edge Biotech Innovations with Chervee Ho
• Episodes 259 - 260: Why Strong Science Isn't Enough to Get Funded: What Investors Actually Look For with Michael Rome
• Episodes 165 - 166: Why Your Funding Pitches Fail Despite Brilliant Science (And How to Fix It)

Connect with John Bonham-Carter:
Website: www.stellion-biosystems.com
LinkedIn: www.linkedin.com/in/johnbc

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show

Biotech loves talk of disruptive technology, but few have repeatedly shifted the industry's direction. This episode of the Smart Biotech Scientist Podcast focuses on an idea once dismissed as a fool's game: process intensification through perfusion—now the backbone of leading biomanufacturing platforms.

Meet John Bonham-Carter, a serial entrepreneur whose fingerprints are on some of biotech's most transformative tools. From putting the once-ignored ATF system and perfusion on the global stage to pushing intensified cell therapy bioprocessing with ERBI, John's story isn't about chasing the next big exit. Instead, it's about spotting unmet needs and building and selling biotools companies more than once.

Topics discussed:

• The story behind the ATF system, and how John Bonham-Carter and his collaborators convinced a conservative industry to adopt perfusion (04:43)
• Early career influences, including family ties to bioprocess equipment manufacturing (05:03)
• Reflections on the biotech industry’s culture of collaboration and the dual motivation to deliver medicines and achieve commercial success (07:18)
• Realities of scaling a startup, trading income for equity, and the role of persistence in sales (09:34)
• Lessons learned from global travel and building professional networks in biotech (10:16)
• The importance of recognizing what drives different biotech companies to adopt new technology (12:25)
• The transition from ATF to co-founding Erbi, a bioprocessing startup focused on small-volume cell therapy (19:05)
• Strategic acquisitions: experiences of being acquired by Repligen and Merck Millipore (22:50)
• Advice for founders on whether to build a company for exit or long-term operation (23:07)
• The limits of leading with technology, and why customer understanding is critical to success (26:10)

Smart insight: For founders, John Bonham-Carter offers practical guidance anchored in self-awareness. Should you build a company for the long haul or for acquisition? The answer: “There isn’t really a right answer...it is, what is the life you want to lead?” Some entrepreneurs thrive at the scale of ten-person teams and relish the handoff to a strategic acquirer. Others yearn to build and steer a 200-person enterprise. Regardless, serving customers and employees well, and being attuned to the market’s shifting demands, matter most. Exit opportunities arise from building value and strategic fit—not from fixating on selling out.

Some ideas are ahead of their time; a few people make a career of being early. This is part bioprocess history, part founder's playbook: why the best technology doesn't automatically win, how to move a conservative industry, and when to sell rather than scale. To go further on both the technology and the business behind it:

• Episodes 191 - 192: Process Intensification Secrets: A Process Engineer's Decision Framework with Andreas Castan
• Episodes 183 - 184: From Lab to Market: Secrets to Commercializing Cutting-Edge Biotech Innovations with Chervee Ho
• Episodes 259 - 260: Why Strong Science Isn't Enough to Get Funded: What Investors Actually Look For with Michael Rome
• Episodes 165 - 166: Why Your Funding Pitches Fail Despite Brilliant Science (And How to Fix It)

Connect with John Bonham-Carter:
Website: www.stellion-biosystems.com
LinkedIn: www.linkedin.com/in/johnbc

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show

What if building a world-class biotech company didn’t require owning a single piece of manufacturing equipment or even a lab of your own?

Most startups obsess over bricks, mortar, and stainless steel. Not Sandra Núñez. She’s challenging the status quo as CEO of Amela Biosciences by running a “virtual plant” model: zero in-house production, everything outsourced, and agility baked into every decision. It’s a bold experiment in redefining what a biotech company can look like. One that’s already delivering real, animal-free products to customers today.

Topics discussed:

• Key considerations and pitfalls in tech transfer from academic labs to external CDMO partners (02:34)
• The reasoning behind choosing a virtual plant model with no in-house manufacturing (04:57)
• Criteria for selecting external manufacturing partners, including technical capabilities and cultural fit (06:28)
• Stakeholder communications and managing misconceptions about outsourced manufacturing (07:44)
• Process development challenges when scaling products for commercial use, including impurity profile and scalability of purification methods (08:53)
• Early preparations for future GMP manufacturing and building a foundation for regulatory compliance (11:20)
• The impact of regulatory shifts (like the FDA Modernization Act 2.0) on manufacturing strategy and product reproducibility (12:47)
• Hopes for the company’s future role in the transition to animal-free and regenerative medicine (14:19)
• Practical advice for startup founders considering a leap from corporate biotech to entrepreneurship (15:09)
• Reflections on the importance of addressing batch-to-batch variability and building reproducible systems (16:40)

Smart insight: Don’t accept batch-to-batch variability. Reproducibility is non-negotiable. Batch-to-batch variability, whether in raw materials or process design, is a critical risk that forward-thinking should design out, not accept as inevitable. As Sandra concludes, reproducibility isn’t just a lab problem, it’s a company-building problem, one that shapes strategy, manufacturing partnerships, and regulatory success.

Here are four episodes that pick up the same threads: animal-free matrices, reproducibility by design, and building a biotech without a factory:

• Episodes 271 - 272: From Static Scaffolds to Dynamic Matrices: Hydrogels for Animal-Free 3D Cell Culture with Jan Hunik and Matt Baker
• Episodes 221 - 222: From 2D Cultures to Advanced 3D Cell Models for Preclinical Research with Catarina Brito
• Episodes 275 - 276: From Lab-Scale Molding to GMP: Manufacturing a Collagen Implant for the Clinic with Eva-Maria Balet
• Episodes 279 - 280: Why Nanovesicles Outperform Exosomes: Scalable Drug Delivery Beyond Injectable Vaccines with Christopher Locher

Connect with Sandra Núñez:
Website: www.amelabiosciences.com
Company LinkedIn: www.linkedin.com/company/amela-biosciences-ag
Sandra’s LinkedIn: www.linkedin.com/in/sandra-nunez-ch
Sandra’s email: [email protected]

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show

Batch-to-batch variability isn’t just a minor annoyance in bioprocess development; it’s often a systemic design flaw hiding in plain sight.

That’s the challenge Sandra Núñez, CEO of Amela Biosciences, set out to eliminate. Drawing on 15 years across Lonza, Medinova, Baxalta, and Biogen, she’s engineered a new generation of animal-free, recombinant protein matrices that promise researchers experimental consistency on demand.

Topics discussed:

• The widespread issue of batch-to-batch variability and why Sandra argues it’s a design failure, not the norm (02:49)
• The mechanics and biological tunability of Amela’s engineered protein matrices, and how this technology works (06:34)
• How Amela’s recombinant protein bioinks differ from traditional animal-sourced extracts, enabling reproducibility (08:53)
• Manufacturing insights: why the proteins are relatively straightforward to produce for research use (12:05)
• Engaging with users to optimize and customize protein matrices for diverse tissue and assay applications (13:33)
• The creation and use of protein libraries for specific user requirements and the flexibility this provides (16:20)
• Definitions and roles of ‘bioinks’ in tissue modeling and 3D cell culture (16:52)

Smart insight: Reproducibility remains the cornerstone of reliable science. With innovative platforms like Amela Biosciences’ engineered protein matrices, the future of tissue engineering and in vitro biology looks not just reliable, but radically empowering. If you’re striving for consistency, customizability, and cutting-edge technology in your workflows, the era of animal-free, batch-consistent bioinks has arrived.

Here are four episodes that pick up the same threads: animal-free matrices, reproducibility by design, and building a biotech without a factory:

• Episodes 271 - 272: From Static Scaffolds to Dynamic Matrices: Hydrogels for Animal-Free 3D Cell Culture with Jan Hunik and Matt Baker
• Episodes 221 - 222: From 2D Cultures to Advanced 3D Cell Models for Preclinical Research with Catarina Brito
• Episodes 275 - 276: From Lab-Scale Molding to GMP: Manufacturing a Collagen Implant for the Clinic with Eva-Maria Balet
• Episodes 279 - 280: Why Nanovesicles Outperform Exosomes: Scalable Drug Delivery Beyond Injectable Vaccines with Christopher Locher

Connect with Sandra Núñez:
Website: www.amelabiosciences.com
Company LinkedIn: www.linkedin.com/company/amela-biosciences-ag
Sandra’s LinkedIn: www.linkedin.com/in/sandra-nunez-ch
Sandra’s email: [email protected]

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show

Manufacturability challenges in biotech are becoming more complex as therapies become more potent, formats diversify, and timelines compress across the industry.

On this episode, David Brühlmann sits down with Sigma Mostafa, Chief Scientific and Technology Officer at KBI Biopharma. Sigma brings deep expertise in early-stage CMC decision-making and has guided countless programs—from upstart startups to established pipelines—through the traps and trade-offs of process development. Her ground-floor perspective spans in silico modeling, innovative cell line engineering, and the gritty realities of tech transfer.

Key topics discussed:

• Practical advice for startups on selecting robust cell lines and avoiding long-term lock-in to problematic platforms (03:07)
• Managing risks in process development, such as high oxygen demand and filter loading, before tech transfer to manufacturing (04:47)
• The value of pressure testing bioprocesses at scale and identifying potential failure modes, including filter clogging and narrow feeding windows (07:41)
• Balancing speed, robustness, and regulatory expectations when advancing new molecules (09:23)
• How fast-tracking from transfection to IND is changing timelines, and the associated risks of accelerated development (09:54)
• Trends and caution in applying AI and in silico tools to protein and process modeling, and the limits of digital solutions (12:01)
• What first-time founders need to get right, including early analysis of molecular issues and careful cell line selection (15:48)
• Shifting modality trends—growing numbers of ADCs/XDCs, more complexity, and the move toward smaller scale and more potent molecules (16:55)
• The overarching lesson: invest early in the areas you cannot change later—especially cell line and understanding of molecule challenges (18:23)

Smart insight: Startup founders often wonder which fires to fight first. Sigma’s advice: focus on deep molecular assessment and making informed, scalable cell line choices above all else. These are the “few things you cannot change later” and the investments that separate enduring programs from cautionary tales.

This episode unpacks what that means in practice and where speed and robustness pull against each other. If it resonated, these conversations expand the picture: how to spot manufacturable candidates early, how in silico tools predict stability and aggregation before the lab, and which early CMC decisions quietly become permanent.

• Episodes 123 - 124: Manufacturability: Why Most Protein Candidates Fail (And How to Pick Winners Early) with Susan Sharfstein
• Episodes 213 - 214: From Developability to Formulation: How In Silico Methods Predict Stability Issues Before the Lab with Giuseppe Licari
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann
• Episodes 103 - 104: One-Stop Shop vs. Specialist CDMO: A Scientist's Guide to CDMO Selection with Sigma Mostafa

Connect with Sigma Mostafa:
 Linkedin: https://www.linkedin.com/in/sigma-mostafa-79180817
KBI website: https://www.kbibiopharma.com

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show

A breakthrough in drug discovery can be derailed in an instant if manufacturability is left as an afterthought. Too many biotech programs hit bottlenecks at scale-up because key decisions in cell line and process development get kicked down the road.

On the Smart Biotech Scientist Podcast, David Brühlmann spoke with Sigma Mostafa, Chief Scientific and Technology Officer at KBI Biopharma. She’s spent 25+ years converting early-stage discoveries into commercial biomanufacturing success and she’s adamant: manufacturability decisions belong at the candidate selection stage, not after.

Topics discussed:

• Why manufacturability should be assessed at the candidate selection stage, not later (03:02)
• Sigma’s background in bringing math and biology together and her path into bioprocess engineering (04:18)
• The "art" and complexity of bioprocess development, especially with new molecule types (05:54)
• A case study of how switching cell lines revealed hidden manufacturability issues (07:33)
• Key properties affecting manufacturability, such as aggregation and thermal stability (10:10)
• Reasons companies delay manufacturability assessments—timing pressure, costs, and lack of early deep characterization (11:02)
• Why CMC should be integrated from day one and concerns with treating scalability as 'just' engineering (12:08)
• Critical decisions and pitfalls in cell line development, including robustness, media choices, and adapting after the master cell bank is made (12:48)
• Regulatory aspects of cell line development: demonstrating clonality, avoiding animal source materials, and documentation requirements (15:04)

Smart insight: Manufacturability is not just a box for the CMC team. It’s a proactive mindset, to be embraced from day one. Early, cross-functional scrutiny—examining both molecule and cell line—preempts disasters during scale-up and accelerates timelines to market while minimizing costly surprises.

This episode unpacks what that means in practice and where speed and robustness pull against each other. If it resonated, these conversations expand the picture: how to spot manufacturable candidates early, how in silico tools predict stability and aggregation before the lab, and which early CMC decisions quietly become permanent.

• Episodes 123 - 124: Manufacturability: Why Most Protein Candidates Fail (And How to Pick Winners Early) with Susan Sharfstein
• Episodes 213 - 214: From Developability to Formulation: How In Silico Methods Predict Stability Issues Before the Lab with Giuseppe Licari
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann
• Episodes 103 - 104: One-Stop Shop vs. Specialist CDMO: A Scientist's Guide to CDMO Selection with Sigma Mostafa

Connect with Sigma Mostafa:
 Linkedin: https://www.linkedin.com/in/sigma-mostafa-79180817
KBI website: https://www.kbibiopharma.com

Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here

Support the show