What if the bottleneck in cell line development isn’t how many clones you screen, but how you track them?

Cloning workflows have long relied on brute force: screen more cells, automate harder, and hope that small-scale performance predicts manufacturability. But too often, the “perfect” clone in a 96-well plate turns into a dud when it reaches the bioreactor. That disconnect costs time, money, and promising therapies.

This week, host David Brühlmann welcomes Kent Rapp, Co-founder and CEO of Biolinco, an entrepreneur who’s turning the classic approach to cell line development inside out. Drawing from his background in chemical engineering and his work in biomanufacturing at Johns Hopkins University, Kent teamed up with DNA barcoding experts to pioneer a new workflow: barcode every cell, pool them, and track their true performance in the environment that matters.

Topics discussed:

• The pitfalls of brute-force screening in traditional cell line development (03:05)
• Kent’s background and how he was drawn to combine science, startups, and biomanufacturing (04:37)
• Overcoming discrepancies between small-scale and large-scale screening environments (08:30)
• How DNA barcoding allows for high-resolution, pooled clone screening (10:34)
• Sensitivity advantages of sequencing over plate-based detection (14:21)
• Methodology for tracking and recovering individual high-performing clones from pools (15:13)
• Impact on speed and workflow efficiency in cell line development (17:31)
• Regulatory and safety considerations related to DNA barcodes in cell lines (19:04)

Smart insight: According to Kent, biotech as an industry has a tendency to "automate problems instead of solve them". Rather than addressing the root causes—like lack of meaningful measurements at relevant scales—companies often throw more robots and more plates at the issue, hoping brute force will finally yield the magical clone. But real process improvement requires a rethinking of what is being measured and how those insights are generated—not just a higher throughput of the same flawed assay.

If this got you rethinking how you screen clones, you'll want these next. We've tackled cell line development, high-throughput screening, and the art of spotting manufacturable candidates early from a few different directions — here are four worth queuing up.

• Episodes 117 - 118 : Cell Line Development Secrets: Eliminating Critical Bottlenecks for Faster Timelines with Andrea Gough
• Episodes 09 - 10: Revolutionizing Cell-Line Development: Unleashing the Power of Nanopens and Microenvironments with Tanner Nevill
• Episodes 123 - 124: Manufacturability: Why Most Protein Candidates Fail (And How to Pick Winners Early) with Susan Sharfstein
• Episodes 115 - 116: Revolutionizing Biologics Development with Hyper Throughput Screening and AI with Jeremy Agresti

Connect with Kent Rapp:
LinkedIn: www.linkedin.com/in/kent-rapp
Biolinco website: www.biolinco.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

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Your active ingredient is the nucleic acid. So why does a proteolipid vehicle filing include viral clearance studies, stability data and full characterisation of a membrane protein that is not the drug? Because that protein sits on the particle surface, and a component nobody has filed before is the agency's problem regardless of what you call it.

Proteolipid vehicles (PLVs), the platform Jitendra Kumar works on as Lead Scientist for Chemistry and Process Development at Entos Pharmaceuticals, represent a novel frontier in drug delivery, Instead of being taken up into an endosome and having to escape it, a PLV fuses with the cell membrane and releases cargo straight into the cytosol. That opens targets and patient groups that liver-tropic lipid nanoparticles and viral vectors have struggled to reach, and it leaves Kumar building a regulatory file with nothing on the shelf to copy.

Highlights from the episode:

• Strategies for communicating novel technology with regulatory agencies and ensuring robust science-driven submissions (02:34)
• What differentiates the analytical characterization of PLVs compared to standard recombinant proteins or antibodies (04:03)
• The development plan and regulatory pathway towards clinical and commercial approval for their lead leptin therapy (05:35)
• The evolving role of advanced techniques—such as cryo-EM—in supporting regulatory filings and product understanding (06:56)
• Jitendra Kumar's career journey: from agricultural research in India to protein science and neurodegeneration, and how these experiences inform current PLV technology development (09:00)
• Challenges of early diagnostics and product development in neurodegenerative diseases (14:29)
• Decision-making differences and focus in academic versus industry biotech research (15:32)
• Practical advice on the importance of honest technology assessment, building networks, and understanding both strengths and weaknesses (16:16)

Smart insight: A persistent challenge for groundbreaking delivery systems is the lack of established regulatory playbooks. Jitendra Kumar laid out a science-first approach: let data do the talking, supported by rigorous GLP toxicology studies and transparent communication with agencies. Regulatory bodies like Health Canada are receptive to innovation, provided that sponsors demonstrate safety, efficacy, and scientific rationale for any deviation from standard criteria.

If this conversation got you thinking about how novel delivery vehicles reach the cell — and what it takes to carry one from bench through CMC, scale-up, and regulatory review — these four episodes go deeper:

• Episodes 125 - 126: How to Enhance Cell Engineering Using Mechanical Intracellular Delivery with Armon Sharei
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann
• Episodes 89 - 90: Scale-Up Secrets: Cracking the Code of AAV Production with Ahmed Youssef
• Episodes 71 - 72: Effective Outsourcing: How Small Biotech Companies Can Thrive with Mark Melville

Connect with Jitendra Kumar:

• LinkedIn: www.linkedin.com/in/jkumar2
• Email: jitendra.kumar@entospharma.com
• Website: www.entospharma.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

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Gene therapy only works if the cargo reaches the right cells intact. Adeno-associated viruses (AAV) and lipid nanoparticles have carried the field this far, but both share a constraint: the particle is taken up into an endosome, and the payload has to escape that compartment before it is degraded. Endosomal escape is where a large share of the dose is lost, and it is why delivery, not the genetic construct, is usually the thing that limits the therapy. Lipid nanoparticles carry a second constraint, since they tend to accumulate in the liver, which narrows the diseases they can reach. What if the particle never entered that way at all?

Jitendra Kumar, Lead Scientist for Chemistry and Process Development at Entos Pharmaceuticals, works on a platform that fuses directly with the cell membrane and releases its cargo straight into the cytosol. He came to nanoparticle design the long way, through fifteen years of structural biology on the prion protein in Frankfurt and Edmonton, which is why he thinks about particle size, packaging and diffusion the way he does.

Key topics discussed:

• Jitendra’s career background in structural biology and journey to Entos Pharmaceuticals (03:18)
• The scientific motivation and challenges of working with prion proteins and breaking down complex diseases (04:55)
• Genetic medicine approaches: gain-of-function vs. loss-of-function, and the role of siRNA, ASOs, and gene delivery (06:27)
• The FAST protein platform: origins, function, and advantages for drug delivery (07:56)
• Manufacturing differences compared to LNPs, including the introduction of recombinant membrane protein production and related CMC complexity (09:55)
• Scale-up and production challenges for membrane proteins, and strategies for clinical supply (11:21)
• Clinical development progress: Phase 1/2 studies with the platform, especially for COVID vaccine delivery (12:23)
• Focus areas for the technology, including selective lung delivery and leptin therapy for lipodystrophy (13:12)
• Lessons for small biotech companies in phase 1/2 manufacturing strategy, technology transfer, and the value of an experienced network (14:31)
• Balancing process robustness with speed in new biotech ventures (16:02)
• The importance of identifying “pause steps” and must-have vs. nice-to-have features in early manufacturing processes (17:15)

Smart insight: Jitendra’s takeaway for startups: for early phases, find a partner who genuinely understands your tech and can move at your pace rather than defaulting to a big CDMO, treat your network as infrastructure, and build the ability to run production in-house. The one thing that's never up for negotiation is process robustness. The real question isn't robustness vs. speed, but how many checkpoints and safe pause points you build in so you can have both.

If this conversation got you thinking about how novel delivery vehicles reach the cell — and what it takes to carry one from bench through CMC, scale-up, and regulatory review — these four episodes go deeper:

• Episodes 125 - 126: How to Enhance Cell Engineering Using Mechanical Intracellular Delivery with Armon Sharei
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann
• Episodes 89 - 90: Scale-Up Secrets: Cracking the Code of AAV Production with Ahmed Youssef
• Episodes 71 - 72: Effective Outsourcing: How Small Biotech Companies Can Thrive with Mark Melville

Connect with Jitendra Kumar:

• LinkedIn: www.linkedin.com/in/jkumar2
• Email: jitendra.kumar@entospharma.com
• Website: www.entospharma.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

For decades, drug development has been saddled with costly manufacturing, stringent biosafety requirements, and the limits of conventional carriers. But a new approach—born from cell-derived nanovesicles—could democratize access to advanced therapies and open entirely new doors for oral, topical, and even global vaccine delivery.

This week, David Brühlmann welcomes Christopher Locher, CEO and Co-founder of Versatope Therapeutics. Christopher has shaped the translation of novel vesicle technology from idea to clinical pipeline, navigating both the science and the unstructured realm of first-in-class GMP manufacturing.

Topics discussed:

• Tackling GMP manufacturing challenges and analytics development from scratch (00:34)
• Deciding what to outsource vs. insource as a small biotech, and the value of a robust tech transfer process (02:25)
• Perspectives on partnering with CDMOs versus managing manufacturing and analytics in-house (02:40)
• Geographic expansion goals and considerations for delivering low-cost biologics in underserved markets (04:26)
• Differentiators of Versatope’s platform—endotoxin-free processes and non-pathogenic strains (05:05)
• Key advice on critical quality attributes and early regulatory planning for Phase 1 readiness (06:19)
• Lessons learned as a biotech founder—getting support, leveraging networks, and planning cost-effectively (07:57)
• Understanding end users, leveraging I-Corps™, and customer discovery in early product development (09:04)
• The science and promise of engineered nanovesicles: delivery routes, biological origins, and research applications (10:12)
• Business models for platform out-licensing and potential for co-development partnerships (12:58)
• Practical takeaways for scientists: setting "good enough" standards and focusing on lean, regulatory-aligned development (13:28)

Smart insight: Christopher is honest about his blind spots, learning on the fly from CMC consultants, and the practical importance of “good enough” regulatory solutions delivers sharp advice for anyone charting the long road from discovery to human trials. Think monoclonal analytics, batch consistency, and the art of prioritization, all from someone who’s made it work with a small team and limited resources

If Christopher's vesicle platform has you thinking about building a novel modality on an unconventional host, these four episodes go deeper on alternative production systems, microbial scale-up, and the CMC and cost decisions that get a first-in-class biologic to patients.

• Episodes 217 - 218: Silkworm Biomanufacturing: From Ancient Silk Production to Phase I Vaccine Trials with Masafumi Osawa
• Episodes 239 - 240: Continuous Microbial Manufacturing: From Genetic Instability to 40-Day E. coli Processes with Juergen Mairhofer
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann
• Episodes 267 - 268: Why Affordable Insulin Is a Money Problem, Not a Science Problem with Eric Moyal

Connect with Christopher Locher:
Website: www.versatope.com
LinkedIn: www.linkedin.com/in/christopher-locher-biotech

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What if the best way to unlock durable, broad-spectrum immunity is to rethink the very vessels delivering our vaccines?

While much of the industry focuses on refining existing delivery systems, Christopher Locher is charting a new course—one inspired by nature’s own couriers. Imagine a future where oral vaccines and modular, on-demand manufacturing aren’t just possibilities, but standard practice.

Christopher Locher, CEO and Co-founder of Versatope Therapeutics, brings decades of experience in drug discovery from Vertex Pharmaceuticals, Opsona Therapeutics, and Maxigen. In this episode, he shares his journey from high school science classrooms to the helm of a company pioneering recombinant extracellular transport vesicles—nanovesicles that promise to transform vaccine delivery and immunomodulation.

Topics discussed:

• How basic scientific curiosity and the inspiration from teachers sparked Christopher's career in biotechnology (03:39)
• The unmet needs in vaccine development for infectious and parasitic diseases, especially in regions below the equator (04:17)
• Engineering nanovesicles as immunomodulators and drug delivery vehicles, using microbial bioreactors for production (06:38)
• Co-producing proteins and vesicles in a single process, and the flexibility of the platform (08:28)
• Key benefits of Versatope's platform, such as cost efficiency, stability, and commercial scalability compared to mammalian exosomes (09:53)
• Prospects for multi-specific vaccines and the future direction for scalable bioprocessing (11:47)
• Adapting manufacturing processes and overcoming logistical challenges—from COVID-related shutdowns to supply chain bottlenecks (12:21)
• Strategies for navigating evolving regulatory requirements with agencies like the FDA, and experience with fast IND allowance (14:53)
• Analytical and characterization challenges of complex nanovesicle-based products versus simpler platforms like antibodies (17:30)
• The vision for decentralized or local vaccine manufacturing, especially in resource-limited settings (19:12)

Smart insight: Christopher Locher highlighted that the FDA allowed their IND submission for a universal influenza vaccine in less than a month after review—and notably, with no hold clinical questions—when it was submitted just before the Christmas holidays and allowed on January 19th, 2025. This rapid regulatory turn-around was made possible by a strong regulatory team and collaborative CDMO efforts, showcasing how innovative platforms and well-prepared submissions can accelerate early-stage clinical development in biotech.

If Christopher's vesicle platform has you thinking about building a novel modality on an unconventional host, these four episodes go deeper on alternative production systems, microbial scale-up, and the CMC and cost decisions that get a first-in-class biologic to patients.

• Episodes 217 - 218: Silkworm Biomanufacturing: From Ancient Silk Production to Phase I Vaccine Trials with Masafumi Osawa
• Episodes 239 - 240: Continuous Microbial Manufacturing: From Genetic Instability to 40-Day E. coli Processes with Juergen Mairhofer
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann
• Episodes 267 - 268: Why Affordable Insulin Is a Money Problem, Not a Science Problem with Eric Moyal

Connect with Christopher Locher:
Website: www.versatope.com
LinkedIn: www.linkedin.com/in/christopher-locher-biotech

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How do you take a model that works in process development and get it accepted for use in GMP manufacturing? That question stalls most bioprocess modeling projects before they start. Ignasi Bofarull-Manzano, Senior Data Scientist and CMC Consultant at Körber Pharma, pushes back on the premise: the process you run today is already governed by a mathematical model, fitted once at small scale during process characterization and then left untouched for years, even as the process shifts.

Part 1 separated digital models from digital shadows and digital twins, and made the case for starting with the decision rather than the data. Part 2 goes into the plant: what regulators actually require, what the numbers looked like on a real biologics process, and where a team should start on Monday morning.

Topics covered:

• Core differences—and surprising similarities—between modeling in development versus manufacturing (02:35)
• Regulatory requirements: credibility assessments, model risk, and validation steps for digital twins (05:07)
• Real-world example: How deploying an end-to-end process model led to 35% yield increase for Takeda, and considerations for ROI in manufacturing (08:34)
• Advice for startup leaders on when to invest in modeling and how to scale efforts case-by-case (11:42)
• Steps for scientists new to modeling: identifying bottlenecks, starting simple, and proving value offline before scaling up (12:26)
• The importance of understanding basic statistics before relying on AI-generated models (15:22)
• A stepwise summary for deploying digital modeling effectively in biotech (16:01)

Smart insight: The digital twin is the last step, not the first. Identify the bottleneck, build the simplest model that supports the decision, and concatenate it end to end so you can see how a parameter moves final drug substance quality rather than one unit operation's output. Prove the value offline. Only then connect interfaces, because that is where the cost and the validation burden live. Teams that lead with the twin arrive at the C-level with a proof of concept and no evidence. Teams that lead with the offline model arrive with a number.

Before a digital twin can earn its keep, you need connected data, the right model, and a clear decision for it to support. These four episodes cover that ground — data silos, hybrid and mechanistic modeling, and twins built to survive regulatory scrutiny.

• Episodes 215 - 216: From Data Silos to Autonomous Biomanufacturing: Digital Twins and AI-Driven Scale-Up with Ilya Burkov
• Episodes 05 - 06: Hybrid Modeling: The Key to Smarter Bioprocessing with Michael Sokolov
• Episodes 17 - 18: How Extracting Gold From Your Data Accelerates Process Development with Ioscani Jiménez del Val
• Episodes 263 - 264: Why AI and Automation Tools Won't Deliver Until Your Lab's Data Is Connected with David Hardy

Connect with Ignasi Bofarull-Manzano:

LinkedIn: www.linkedin.com/in/ignasi-bofarull

Körber Pharma website: www.koerber-pharma.com

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Most bioprocess teams believe a digital twin demands vast datasets and sophisticated models. Ignasi Bofarull-Manzano argues both assumptions are wrong, and that the data already sitting in your Excel files, historians and ELNs is probably enough to start.

Ignasi Bofarull-Manzano, Senior Data Scientist and CMC Consultant at Körber Pharma, breaks down what a digital twin actually is, where modeling pays back fastest across the product lifecycle, and how to tell a real business case from an expensive proof of concept.

In this episode:

• Misconceptions about data requirements for digital twins—why quality and context of data matter more than sheer quantity (02:40)
• Ignasi’s journey from curiosity in biology to a career in data science, modeling, and digital twins (04:31)
• Clear distinctions between digital models, digital shadows, and digital twins, explained with real-world analogies (06:42)
• How to approach digital development when faced with legacy data silos and scattered analytics (09:56)
• The importance of starting with a focused business need instead of chasing trends or buzzwords (12:28)
• Insights into where modeling truly delivers value in the product lifecycle—development versus manufacturing (13:11)
• Strategies for small companies to leverage digitalization and data from the ground up (15:56)
• An accessible overview of physics-informed AI, physical AI, and hybrid modeling—and their application in bioprocessing (18:15)
• The comparative advantages of physics-informed AI versus hybrid models in different bioprocessing contexts (24:45)

Smart insight: Do not start with the model. Start with the bottleneck. Identify the business need first, then the decision the model must support, then the minimum data required for that context of use. Build the model offline, concatenate it end to end across unit operations rather than optimizing one in isolation, and prove the value before connecting a single interface. Teams that skip this sequence end up building models because models sound impressive, and those projects get expensive before they get useful.

Before a digital twin can earn its keep, you need connected data, the right model, and a clear decision for it to support. These four episodes cover that ground — data silos, hybrid and mechanistic modeling, and twins built to survive regulatory scrutiny.

• Episodes 215 - 216: From Data Silos to Autonomous Biomanufacturing: Digital Twins and AI-Driven Scale-Up with Ilya Burkov
• Episodes 05 - 06: Hybrid Modeling: The Key to Smarter Bioprocessing with Michael Sokolov
• Episodes 17 - 18: How Extracting Gold From Your Data Accelerates Process Development with Ioscani Jiménez del Val
• Episodes 263 - 264: Why AI and Automation Tools Won't Deliver Until Your Lab's Data Is Connected with David Hardy

Connect with Ignasi Bofarull-Manzano:

LinkedIn: www.linkedin.com/in/ignasi-bofarull

Körber Pharma website: www.koerber-pharma.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

How do you turn a lab-born regenerative medical device into a solution that surgeons actually want to use and investors want to back? The path from academic innovation to clinical adoption is full of practical hurdles and strategic pivots, where compelling science alone isn’t enough.

David Brühlmann welcomes back Eva-Maria Balet, whose journey spans tissue engineering research at EPFL to leading Regenosca through first-in-human trials, fundraising, and an executive MBA completed while running the company. This conversation covers the practical realities behind that journey, from quality control to clinical setbacks to investor pitches.

Topics discussed:

• Defining TissueSpan’s regulatory path and quality control as a medical device (02:49)
• The significance of first-in-human studies and what early clinical experience reveals (04:11)
• Selecting an initial clinical indication and opportunities for technology expansion (05:50)
• Realistic assessment of where soft tissue repair technologies apply—and where they do not (07:18)
• The stepwise progression from in vitro to animal models in product development (08:18)
• Navigating setbacks, including the impact of Covid-19 on clinical trials, and the value of adaptability (10:36)
• Bridging science and business in biotech fundraising and communication (12:15)
• Key takeaways from pursuing an executive MBA alongside building a biotech company (13:42)
• The importance of collaboration, mindset, and meaningful networks in driving biotech innovation (15:19)

Smart insight: The transition from scientist to founder brought its own learning curve. Eva-Maria pursued an executive MBA while running Regenosca, and points to financial and business vocabulary as the skill she'd have built earlier if she could. For a technical founder or CMC lead, the lesson isn't to become a business generalist, it's that the moment you're translating a manufacturing process or clinical dataset into an investor pitch, fluency in the language of accounting, market strategy, and cost structure becomes as load-bearing as the science itself.

This week's episode with Eva-Maria Balet steps out of bioprocessing into MedTech, following a collagen scaffold from EPFL lab bench to first-in-human implant. These back-catalog picks cover similar ground: what it takes to win investor buy-in beyond the science, the discipline of turning a lab process into GMP manufacturing, why regulatory classification shapes a product's whole trajectory, and what it really takes to commercialize a lab discovery.

• Episodes 259 - 260: Why Strong Science Isn't Enough to Get Funded: What Investors Actually Look For with Michael Rome
• Episodes 257 - 258: Why Regulatory Affairs Belongs in Drug Design: 30 Years of CMC Lessons from Discovery to GMP Manufacturing with Milan Tomic
• Episodes 105 - 106: From Proteins to Cell Therapy: Why ATMPs Aren't Just Complex Biologics with Oliver Kraemer
• Episodes 183 - 184: From Lab to Market: Secrets to Commercializing Cutting-Edge Biotech Innovations with Chervee Ho

Connect with Eva-Maria Balet:
LinkedIn: www.linkedin.com/in/eva-maria-balet-72561737
Regenosca website: www.regenosca.com

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