Smart Biotech Scientist | Master Bioprocess CMC Development, Biologics Manufacturing & Scale-up, Cell Culture Innovation

David Brühlmann - CMC Development Leader, Biotech C-level Advisor, Business Strategist
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The Go-to Podcast for Biotech Scientists Who Want to Master Biopharma CMC Development and Biomanufacturing. **TOP 10 LIFE SCIENCES PODCAST** Are you ready to simplify bioprocess development and scale with confidence to reduce time to market? Are you feeling overwhelmed by the complexity and guesswork of biologics development and biomanufacturing? Do you wish you had more time to enjoy the beauty of science, without worrying about failing your cell culture process development and commercialization? There's a way to simplify and streamline so you can remove complexity, skip trials and errors, deliver your groundbreaking therapy to clinics and market without delay, and still enjoy every single step. I'm David Brühlmann, a biotech entrepreneur and strategic advisor who partners with C-level biopharma leaders to tackle one of our industry's biggest challenges: reducing manufacturing costs to make lifesaving therapies accessible to more patients worldwide. Through engaging conversations with industry pioneers and practical insights from the trenches, this podcast tackles the critical challenges in bioprocess CMC development and manufacturing of recombinant proteins and cell and gene therapy products. We cut through the complexity so you can: Master bioprocess development with confidence and clarity Excel at scale-up and manufacturing of biologics Transform your innovative therapy and manufacturing technology into market-ready solutions faster Optimize manufacturing costs without compromising quality Make data-driven decisions that reduce the risk of failure I can’t wait to help you do biotech the smart way. Grab a cup of coffee and your favorite notebook and pen. Now is the time to take your bioprocessing game to the next level. Ready to transform your biomanufacturing journey? Let's dive in! Next Steps: Book a free call to reduce biomanufacturing costs and make lifesaving therapies more accessible: https://bruehlmann-consulting.com/call 🧬 Ready to accelerate your IND timeline? Get the proven CMC Dashboard that's guided successful mAb programs from chaos to submission: https://stan.store/SmartBiotech/p/cmc-dashboard-for-biotech-founders Accelerate biologics development with expert guidance: https://bruehlmann-consulting.com For sponsorship opportunities, contact us at hello@bruehlmann-consulting.com Visit the Website: https://smartbiotechscientist.com Email us: hello@bruehlmann-consulting.com

  1. 17H AGO

    228: Media-Based Glycan Engineering for Biosimilars: Your Rapid Implementation Guide

    How early in process development should you address glycosylation? This episode presents the case for co-optimizing glycan profiles with productivity from initial process characterization. Deferring glycosylation characterization until after titer targets are met introduces risk: quality attribute gaps discovered late in development force process re-optimization, extended timelines, and potential cell line reselection. Media supplementation enables earlier intervention—tuning glycan distribution as a process parameter from the beginning of cell line and media development rather than as a remediation strategy. David Brühlmann outlines the experimental protocol for validating raffinose supplementation, including decision criteria for proceeding or terminating at each development stage. The discussion addresses process design space requirements, analytical monitoring strategy, and the experimental variables that determine when media-based glycan tuning is appropriate versus when alternative approaches are needed. Highlights from the episode: When to use (and not use) raffinose in your development program, including limitations and effectiveness windows (00:30)Essential protocol: three experiments over eight weeks to validate raffinose for your process, with clear go/no-go criteria (04:09)Why individualized mannose tracking (Man5, Man6, Man7, Man8) is crucial for meaningful results (01:06)Managing osmolality: why it matters and how to control it in your experiment (04:36)Advice on scaling up: moving from small-scale screens to benchtop bioreactors and stress-testing your process (07:48)Three key mistakes to avoid when implementing raffinose, including lessons from analytical oversight, incomplete design mapping, and feed interference (09:08)Integrating glycosylation as a core part of process design, not just a secondary consideration after titer optimization (13:10)Strategic insight: Sequential optimization of productivity followed by glycosylation introduces development risk: quality attribute deviations discovered after process lockdown require costly re-optimization cycles. Parallel development of titer and glycan specifications from initial cell line characterization reduces this risk by establishing feasible operating windows early in the development timeline. Are you planning your next recombinant protein scale-up? Hear how David’s rule-of-three protocol and battle-tested lessons can help you optimize faster and avoid painful late-stage surprises. Resources: Journal of Biotechnology, 2017, volume 252, pages 32 to 42 Next step: Need fast CMC guidance? → Get rapid CMC decision support here Support the show

    16 min

  2. FEB 10

    227: Media-Based Glycan Engineering for Biosimilars: Achieving Reference Product Match

    When your biosimilar analytical data shows 1.4% high mannose against a 6% reference product specification, you face limited options: process temperature shifts that compromise titer, kifunensine supplementation that requires extensive regulatory justification, or 12-18 months to reclone and revalidate. Media supplementation offers an alternative pathway—tuning glycan profiles through formulation adjustments rather than cell line or process re-engineering. In this episode, David Brühlmann presents the experimental development of a media supplementation strategy that achieved 2.8-fold increases in high mannose glycans across multiple CHO cell lines. Drawing from research published in the Journal of Biotechnology (2017, 252:32-42), the discussion covers the mechanism of raffinose-mediated glycan processing arrest, the experimental variables that initially obscured the effect, and the process development considerations for implementing media-based glycan tuning. The episode examines N-glycan biosynthesis in CHO cells, regulatory comparability requirements for biosimilar glycosylation profiles, and the experimental framework for evaluating media supplementation as a glycan control strategy. Highlights from the episode: The unexpected link between dietary raffinose and reduced athletic performance, and its connection to bioprocessing (01:11)A clear primer on the importance of glycosylation for biosimilar drugs and regulatory approval (02:43)Common challenges when glycan profiles don't match reference products, and why high mannose glycans matter (04:19)A review of industry strategies (temperature shifts, enzyme inhibitors, cell line reengineering) and their pitfalls (05:33)Mechanistic insights into how raffinose alters glycan processing in CHO cells (07:05)Key experimental findings on raffinose concentration, osmolality control, and practical lab troubleshooting (09:48)Application stories and regulatory considerations for implementing raffinose-based media adjustments (13:47)Closing thoughts on process optimization, regulatory impact, and what to expect in Part 2 (15:11)Strategic insight: Implementing raffinose as a media supplement is straightforward, regulatory-friendly, and cost-effective. It does not involve genetic engineering or enzyme inhibitors and is easily sourced as a GMP-grade material. For programs approaching submission with glycan comparability gaps, media-based tuning offers a process optimization pathway that maintains existing cell lines and manufacturing platforms while addressing critical quality attribute specifications. Listen to this episode of the Smart Biotech Scientist Podcast to learn David’s best strategies for rapid, regulatory-friendly glycosylation control. If you want to transform your glycoengineering workflow, keep an eye (and ear) out for the next episode of the Smart Biotech Scientist Podcast. Your path to regulatory success might be as simple as a pinch of raffinose. Resources: Journal of Biotechnology, 2017, volume 252, pages 32 to 42 Next step: Need fast CMC guidance? → Get rapid CMC decision support here Support the show

    17 min

  3. FEB 5

    226: Mastering Radiopharmaceutical Development: Preclinical Model Selection for Clinical Success with Bryan Miller - Part 2

    Hard-to-treat cancers like pancreatic ductal adenocarcinoma (PDAC) have long defied conventional therapies. Radiopharmaceuticals, combining targeted therapy with diagnostic power, are creating new opportunities in precision oncology. Host David Brühlmann speaks with Bryan Miller of Crown Bioscience, who explains how Crown's strategic partnerships, rigorous quality standards, and adaptive study design are shaping radiopharmaceutical development—delivering speed, safety, and real clinical impact. In this episode, you'll learn: The promise and practical implications of theranostics—agents used for both diagnosis and treatment (02:44)Definitions and distinctions between CDX (cell line-derived xenograft) and PDX (patient-derived xenograft) models, and why PDX models better recapitulate tumor heterogeneity (05:11)Strategies for building more predictive, clinically relevant research models (06:09)Balancing rapid innovation with rigorous quality standards—why robust QC systems enable speed without compromising safety (08:01)Key advice for scientists entering radiopharmaceutical development, including how to choose the right research partners (09:53)Why effective collaboration between biotech companies and CROs is akin to a well-chosen partnership (10:50)The future outlook for radiopharmaceuticals and their impact on hard-to-treat cancers (12:21)Strategic insight: Focusing on theranostic radiopharmaceuticals—agents that combine diagnostics and therapy—offers a high-impact strategy for hard-to-treat cancers like PDAC. By enabling simultaneous patient stratification and targeted treatment, theranostics can accelerate development, improve clinical outcomes, and create a competitive advantage in areas where traditional therapies are limited. Where do you see radiopharmaceuticals and advanced preclinical models making the biggest impact in oncology or beyond? Explore the full conversation to learn how Bryan Miller and Crown Bioscience are scaling innovation for the next generation of cancer therapies. Connect with Bryan Miller: LinkedIn: www.linkedin.com/in/bryan-miller-148344aa Crown Bioscience: www.crownbio.com Next step: Need fast CMC guidance? → Get rapid CMC decision support here Support the show

    16 min

  4. FEB 3

    225: Mastering Radiopharmaceutical Development: Preclinical Model Selection for Clinical Success with Bryan Miller - Part 1

    Imagine treating cancer with the precision of a guided missile—delivering radioactive payloads directly to tumor cells. Radiopharmaceuticals are reshaping cancer diagnostics and therapy by pairing tumor-targeting molecules with radioisotopes for diagnosis or therapy. But what does it really take to develop these therapies, and why is interest from scientists, biotech companies, and pharma accelerating? In this episode, we're joined by Bryan Miller, Director of Scientific and Technical Operations at Crown Bioscience UK. From a PhD in cardiac disease to leading preclinical oncology and radiopharmaceutical programs, Bryan brings hands-on insight into building advanced cancer models and translating innovative therapies from bench to clinic. Topics discussed include: Bryan Miller's path from cardiac disease research to leading preclinical cancer model development (03:03)Crown Bioscience's comprehensive cancer model platforms, from organoids to PDX and humanized in vivo models (04:05)How radiopharmaceuticals differ from traditional chemotherapies in terms of safety and speed, including the concept of theranostics (07:32)The reasons behind the surge of interest in radiopharmaceuticals within science and industry (09:04)The importance of selecting the right preclinical model for success—and how AI and data-driven approaches will shape future workflows (10:11)Critical pitfalls and unique technical challenges in radiopharmaceutical drug development (12:46)Crown Bioscience's collaborative approach with Medicines Discovery Catapult to navigate the complexities of radiopharmaceutical research (13:35)The diverse client needs, from small startups to global pharma companies, and how mature their development programs can be (14:20)Strategies for scaling preclinical and translational capabilities to meet growing demand in radiopharmaceutical studies (16:04)Strategic insight: Radiopharmaceutical success requires integrated design from the start—combining precise model selection, targeting strategy, isotope choice, linker chemistry, and rigorous QC. Programs that establish this comprehensive foundation early move faster and with higher translational confidence than those addressing these elements sequentially or treating any aspect as a downstream refinement. If you're curious about the real challenges of drug development, the rise of theranostics, and how data-driven approaches (including AI) are shaping preclinical workflows, this episode delivers actionable strategies and insider perspectives for scientists and biotech innovators alike. Connect with Bryan Miller: LinkedIn: www.linkedin.com/in/bryan-miller-148344aa Crown Bioscience: www.crownbio.com Next step: Need fast CMC guidance? → Get rapid CMC decision support here Support the show

    18 min

  5. JAN 29

    224: From Cultivated Meat to Chocolate: Rethinking Cellular Agriculture Scale-Up with Steven Lang - Part 2

    The cultivated meat industry has captured headlines and struggled with economics. Meanwhile, plant cell biomanufacturing is quietly solving the cost equation and approaching commercial launch. The question isn't whether cellular agriculture can work at scale. It's which applications will get there first, and what bioprocessing innovations will make it possible. In Part 2, we dive into the commercialization challenges that separate laboratory curiosity from market-ready products. Steven Lang tackles the hard questions: How do you replicate chocolate's complex flavor profile without traditional fermentation? What analytical infrastructure ensures product consistency and safety? And how do you build the right team and data foundation to navigate the journey from premium launch to commodity-scale production? Steven's background spanning Johnson & Johnson, Genentech, and Upside Foods gives him a unique perspective on what works and what doesn't when translating biopharma rigor to food applications. At California Cultured, he's applying those lessons to launch high-flavanol cocoa powder in 2026, with a clear roadmap to commodity cocoa and coffee thereafter. In this episode: The challenge of replicating chocolate’s taste and fermentation in the lab (02:39)How plant cell culture differs from conventional farming and its advantages for safety and scalability (03:03)Analytical methods and equipment needed for consistent, safe, and high-quality cultured cocoa products (05:05)The potential for cell-based food to minimize heavy metals and other contaminants in chocolate (06:09)Environmental implications: tackling climate change, deforestation, and the realistic timeline for widespread adoption of lab-grown foods (06:50)Emerging opportunities beyond cocoa and coffee—saffron, ginseng, echinacea, and even lab-grown wood (08:40)Key advice for scientists and entrepreneurs interested in entering the cellular agriculture field (10:12)Building successful teams and robust data foundations in biotech startups (11:43)Key takeaway: Cellular agriculture's future isn't a single technology replacing conventional food production. It's multiple parallel approaches creating resilience in global food systems. The opportunity is clear: the technical principles you've mastered in biopharma translate directly to food applications, but the faster commercialization timelines and novel business models require rethinking what "stage-appropriate development" means. The question for bioprocess leaders is whether you'll help build the solutions to bridge the food production gap, or watch from the sidelines as food security becomes the defining challenge of our generation. Here is the previous conversation with Steven Lang: Episodes 55-56: Cultivated Meat: A Promising Future or an Inevitable Bubble? with Steven LangConnect with Steven Lang: LinkedIn: www.linkedin.com/in/steven-lang-b003406 California Cultured Inc.: www.cacultured.com Next step: Need fast CMC guidance? → Get rapid CMC decision support here Support the show

    17 min

  6. JAN 27

    223: From Cultivated Meat to Chocolate: Rethinking Cellular Agriculture Scale-Up with Steven Lang - Part 1

    What if the chocolate industry's reliance on equatorial farms—and the deforestation that comes with it—could be eliminated entirely? Plant cell bioreactors are doing that, producing real cacao without a single tree. But this isn't just about chocolate. It's about fundamentally rethinking how we manufacture food at scale, and the bioprocessing innovations emerging from this shift have implications far beyond the food industry. Steven Lang, Head of R&D at California Cultured, spent two decades mastering mammalian cell culture at biopharma giants like Johnson & Johnson and Genentech. Then he made a radical pivot: applying those same bioprocessing principles to cultivate plant cells for food production. His mission? Prove that cellular agriculture extends far beyond the cultivated meat narrative, and that plant cell manufacturing offers a faster, more economical path to market. At California Cultured, Steven's team is scaling cacao and coffee production using innovative low-cost plastic bioreactors instead of expensive stainless steel vessels. They've engineered plant cell media formulations that operate at a fraction of typical bioprocessing costs. And they're preparing to launch their first commercial product—high-flavanol cocoa powder—in 2026. What you'll discover in this episode: Why cellular agriculture ≠ cultivated meat (07:16) – Steven's frustration with the narrow definition that's holding the industry back, and why plant cell culture deserves equal attentionPlant vs. animal cell culture fundamentals (09:26) – Technical comparison: totipotent plant cells, callus formation, adaptation to suspension culture, and how cacao cell lines are developed from explantsAchieving 30-40% pack cell volume in 7-day batches (11:14) – Process parameters: ambient temperature growth, low pH environments, minimal downstream processing, and maintaining product consistency without genetic modificationThe economics that change everything (14:38) – How plant cell media costs and simple raw material requirements create commodity-scale economicsThe Tesla model for biotech (15:58) – Strategic rationale for launching with premium high-flavanol cocoa powder first, then using that revenue runway to optimize for commodity pricingLow-cost bioreactor innovation (18:23) – Why plastic vessels beat stainless steel, contamination management in low-pH cultures, and scale-out strategy over traditional scale-upDecentralized biomanufacturing (23:10) – Converting underutilized office space into production facilities, onshoring food ingredient production, and what this means for emerging markets and supply chain resilienceThe bigger picture beyond cacao (24:23) – Four approved drugs already produced via plant cell culture, the expanding landscape of ingredients (saffron, ginseng, echinacea), and why stage-appropriate models matter for cellular agriculture's futureThe strategic insight: While the cultivated meat industry struggles with cost structures and consumer acceptance, plant cell manufacturing is quietly proving the business model. The lesson for bioprocessing professionals? Sometimes the fastest path to commercialization isn't the most obvious one, and the innovations happening in food manufacturing today could reshape how we think about bioproduction economics across industries. Here is the previous conversation with Steven Lang: Episodes 55-56: Cultivated Meat: A Promising Future or an Inevitable Bubble? with Steven LangConnect One bad CDMO decision can cost you two years and your Series A. If you're navigating tech transfer, CDMO selection, or IND prep, let's talk before it gets expensive. Two slots open this month. Support the show

    28 min

  7. JAN 22

    222: From 2D Cultures to Advanced 3D Cell Models for Preclinical Research with Catarina Brito - Part 2

    What happens when we move beyond oversimplified cell cultures and truly embrace the complexity of human biology? In this episode of the Smart Biotech Scientist Podcast, we explore how advanced 3D cell models are reshaping preclinical research—recreating human tissue microenvironments to better understand tumors, immunotherapies, and gene and cell therapies. David’s guest is Catarina Brito, Principal Investigator at ITQB NOVA and Head of the Advanced Cell Models Laboratory at iBET and ITQB NOVA (Portugal). Her work bridges academia and industry through iBET, a unique partnering organization that integrates cell engineering, bioprocessing, and translational modeling. Catarina’s pioneering models help both pharma leaders and startups predict drug resistance and immunogenicity earlier and more reliably, accelerating the path to safer, more effective therapies—well before clinical trials begin. Topics discussed: Understanding the contribution of stromal and immune cells to therapy outcomes in tumor microenvironments (03:42)Studying immune responses to gene therapy vectors with advanced neural models (04:31)Combining multi-omics and spatial data with AI for predictive biology and patient-specific digital twins (05:16)Catarina’s advice: Start simple, let the biological question dictate model design, and avoid premature overengineering (06:53)Importance of reproducibility, process controls, and standardization in advanced models (08:10)How academic-industry collaborations drive model development, scalability, and real-world relevance (08:42)Common pitfalls: Overengineering, poor cell source selection, insufficient system validation (11:03)Next steps for precision medicine and translational research using advanced cell models (13:08)Want to know how leading scientists make advanced cell models actionable and collaborative for pharma breakthroughs? Tune in for practical strategies, real-world collaborations, and pitfalls to avoid as you scale your own translational research. Connect with Catarina Brito: LinkedIn: www.linkedin.com/in/catarina-brito-ibet Advanced Cell Models Lab – iBET: www.ibet.pt/laboratories/advanced-cell-models-lab Next step: Need fast CMC guidance? → Get rapid CMC decision support here Support the show

    15 min

  8. JAN 20

    221: From 2D Cultures to Advanced 3D Cell Models for Preclinical Research with Catarina Brito - Part 1

    What if the failure rate in clinical trials isn't about picking the wrong drug candidates—but about testing them in the wrong models? When you move cells from a 2D culture plate into a bioreactor, you're not simply scaling volume. You're fundamentally changing the biological context. Cell density shifts. Mass transfer dynamics evolve. Mechanical cues emerge. The cells sense these changes and respond—often in ways that derail strategies built on oversimplified assumptions. Most preclinical research still relies on flat plastic surfaces and animal models that miss critical aspects of human biology. The result? Therapeutics fail late in development because the models couldn't predict how human tissues would actually respond. In this episode, David Brühlmann speaks with Catarina Brito, Principal Investigator at ITQB NOVA and Head of the Advanced Cell Models Laboratory at iBET and ITQB NOVA in Portugal. Catarina's career-defining insight came early: studying glycan-protein interactions in murine versus human cells revealed that species differences weren't just nuances—they were fundamental gaps that could mislead entire research programs. Catarina and her team have developed neural, liver, and tumor models that capture the multicellular complexity and microenvironmental cues that 2D cultures cannot replicate. Her work creates preclinical models sophisticated enough to predict human responses while remaining scalable for drug development workflows. Highlights of the episode: Limitations of traditional 2D cell cultures and animal models in capturing realistic tissue behavior and therapeutic responses (06:27)Catarina Brito's personal scientific journey: from discovering model limitations to pioneering 3D culture systems in neural and liver tissues (04:19)How advanced 3D models recreate cell-to-cell interactions, tissue-specific microenvironments, diffusion gradients, and multicellular complexity (10:35)Regulatory movements toward reducing animal models, and the challenge of validating advanced alternatives for systemic biology studies (09:10)Key differences in designing bioreactors for various cell types, with practical examples from liver and neural models (15:16)The impact of scalable, robust 3D models on accelerating drug development and improving selection of candidate therapies (17:22)Key Takeaway: Bioprocess development starts when you choose the model that validates your therapeutic approach. If that model can't capture the biology that matters, every downstream optimization is built on a flawed foundation. In Part 2, Catarina reveals how 3D tumor microenvironments expose drug resistance mechanisms invisible in 2D cultures, and her vision for AI-powered digital twins enabling personalized medicine. Subscribe & Review: If this conversation changed how you think about preclinical model selection, leave a review on Apple Podcasts. Your reviews help other biotech scientists discover these insights. For more CMC development insights, visit smartbiotechscientist.com. Connect with Catarina Brito: LinkedIn: www.linkedin.com/in/catarina-brito-ibet Advanced Cell Models Lab – iBET: www.ibet.pt/laboratories/advanced-cell-models-lab Next step: Need fast CMC guidance? → Get rapid CMC decision support here Support the show

    20 min
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The Go-to Podcast for Biotech Scientists Who Want to Master Biopharma CMC Development and Biomanufacturing. **TOP 10 LIFE SCIENCES PODCAST** Are you ready to simplify bioprocess development and scale with confidence to reduce time to market? Are you feeling overwhelmed by the complexity and guesswork of biologics development and biomanufacturing? Do you wish you had more time to enjoy the beauty of science, without worrying about failing your cell culture process development and commercialization? There's a way to simplify and streamline so you can remove complexity, skip trials and errors, deliver your groundbreaking therapy to clinics and market without delay, and still enjoy every single step. I'm David Brühlmann, a biotech entrepreneur and strategic advisor who partners with C-level biopharma leaders to tackle one of our industry's biggest challenges: reducing manufacturing costs to make lifesaving therapies accessible to more patients worldwide. Through engaging conversations with industry pioneers and practical insights from the trenches, this podcast tackles the critical challenges in bioprocess CMC development and manufacturing of recombinant proteins and cell and gene therapy products. We cut through the complexity so you can: Master bioprocess development with confidence and clarity Excel at scale-up and manufacturing of biologics Transform your innovative therapy and manufacturing technology into market-ready solutions faster Optimize manufacturing costs without compromising quality Make data-driven decisions that reduce the risk of failure I can’t wait to help you do biotech the smart way. Grab a cup of coffee and your favorite notebook and pen. Now is the time to take your bioprocessing game to the next level. Ready to transform your biomanufacturing journey? Let's dive in! Next Steps: Book a free call to reduce biomanufacturing costs and make lifesaving therapies more accessible: https://bruehlmann-consulting.com/call 🧬 Ready to accelerate your IND timeline? Get the proven CMC Dashboard that's guided successful mAb programs from chaos to submission: https://stan.store/SmartBiotech/p/cmc-dashboard-for-biotech-founders Accelerate biologics development with expert guidance: https://bruehlmann-consulting.com For sponsorship opportunities, contact us at hello@bruehlmann-consulting.com Visit the Website: https://smartbiotechscientist.com Email us: hello@bruehlmann-consulting.com

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