Out of the Lab: Operationalizing Cell and Gene Therapy

Nicholas (Nico) Crudele
  • 0.0 (0)
  • Medicine

In Cell & Gene Therapy, opportunity created by openly discussing operational reality far outweighs the micro-risk of looking unpolished. By building a safe, unscripted space where experts can talk naturally about real work, we stop pretending everything is fine and start building the solutions needed to actually fix the system. Explore our Solution: https://www.methodmade.ca/?utm_source=podcast&utm_medium=show_notes&utm_campaign=out_of_the_lab

  1. 1d ago

    Designing for Resilience: Why CGT Supply Chain Begins Years Before Tech Transfer | Mehran Bhatti

    How do 1 in 16 cell and gene therapies fail, not because of the biology, but because of the supply chain? In this episode of Out of the Lab, host Nico sits down with Mehran, a seasoned Cell & Gene Therapy supply chain consultant, to dissect why operational resilience must be engineered into your product long before tech transfer ever takes place. From CDMO selection gaps to un-addressable spend and non-standard Bill of Materials (BOM) choices, Mehran exposes the hidden operational traps that trigger FDA Complete Response Letters (CRLs) and derail launches. In this episode, we cover: Who Owns Resilience? Why supply chain expertise must intersect with early CMC and process development. The CDMO Bottleneck: Unpacking why 40% of manufacturing-related FDA hurdles stem from partner selection and process optimization gaps. Addressable vs. Non-Addressable Spend: Why 42% of materials get locked in filings and how to optimize raw material selection up front. Real-World Harmonization: Lessons from J&J’s Carvykti pipeline on managing apheresis variability and standardizing network supply. The Future of Orchestration: How AI and predictive analytics are transforming patient slotting, scheduling, and apheresis quality. Timestamps & Chapters: 00:00 – Introduction: Supply chain resilience in Cell & Gene Therapy 02:03 – Who owns resilience? Bridging CMC, process development, and supply chain 04:57 – CDMO partner selection & commercial readiness 06:21 – The cost of failure: CRLs, manufacturing quality, and CDMO gaps 08:05 – Process ownership vs. CDMO lock-in: Lessons from J&J and apheresis 12:21 – Addressable vs. non-addressable spend in biomanufacturing 16:38 – The 50 mL Syringe Example: Why process engineers need supply chain optics 20:15 – Geopolitical risk, tariffs, and global facility harmonization 24:18 – Built-in network resilience: Lessons from radiopharmaceuticals 28:20 – Logistics, cold-chain, and patient orchestration in Europe vs. US 34:34 – The role of data, AI, and predictive analytics in apheresis quality

  2. Aug 11

    You Can’t Test Quality Into a Product: FDA Import Alerts & GXP with Wynngate Consulting

    What happens when a foreign manufacturer gets put on an FDA import alert? Or when a single undocumented ingredient turns a harmless dietary supplement into an unapproved drug? In this episode of Out of the Lab, host Nico sits down with Dan and Binh from Wynngate Consulting. Bringing decades of insider FDA experience from compliance enforcement to foreign facility inspections, they pull back the curtain on the operational realities of GXP manufacturing. We explore the massive regulatory shifts brought on by the Food Safety Modernization Act (FSMA) and why the FDA's Foreign Supplier Verification Program has changed the game for importers. In this episode, we cover: The Overlapping 50%: The surprising similarities and critical differences between dietary supplement GMPs (Part 111) and pharmaceutical GMPs (Part 211). The "Checking the Box" Trap: How an inadequate response to an FDA 483 observation can escalate into an Import Alert and a 10-year remediation nightmare. Intentional vs. Accidental Adulteration: From shared line cross-contamination to companies secretly lacing weight-loss supplements with active pharmaceuticals to dodge clinical trials. The Old FDA Adage: Why you can never test quality into a product once underlying GMP violations exist. Supply Chain Resilience: Why vetting your foreign CDMO's quality management system is the ultimate risk mitigation technique for drug sponsors. Dan and Binh consult on GxP compliance at Wynngate Consulting.Connect with them: Dan Simonsen, Vice President: https://www.linkedin.com/in/danjsimonsen/ Binh Nguyen, President: https://www.linkedin.com/in/binh-nguyen-a77046190/ Visit their website:https://www.wynngateconsulting.com/

  3. Jul 28

    Why Yield Isn't King: Analytics & Tech Transfer Lessons with Forge Biologics CTO David Dismuke

    What are the hidden operational mistakes early-stage drug developers make before ever selecting a CDMO? In this episode of Out of the Lab, host Nicholas Crudele sits down with David Dismuke, Chief Technology Officer at Forge Biologics. Drawing on over 20 years of experience across both academic CDMOs, corporate CDMOs, and therapeutic developers, David breaks down why yield should not be your only metric, how host cell DNA and empty/full ratios impact clinical timelines, and why a low-CV potency assay is your ultimate insurance policy during tech transfer. In this episode, we cover: The Yield Trap: Why focusing solely on viral titer masks critical quality attributes (CQAs) that can derail regulatory filings. Empty vs. Full Capsid Ratios: Managing host cell DNA trade-offs and understanding route of administration impacts. Potency Assays as Comparability Anchors: How high-throughput, sound analytical methods allow you to innovate safely in GMP environments. Two-Sided Tech Transfer: Why you should never "throw the process over the wall" and how to execute proper gap analyses with your CDMO. Single-Use Equipment: Navigating downstream chromatography hurdles and eliminating multi-product contact risks.

  4. Jul 28

    The Holy Grail of MES: Why Paperwork Isn't Process Control | Robert Perks

    Why do biomanufacturing execution systems fail despite multi-million dollar investments? In this episode of Out of the Lab, host Nicholas Crudele sits down with biopharma automation and manufacturing execution system (MES) consultant Robert Perks to unpack the realities of digitizing biomanufacturing workflows. From early R&D data integration to navigating the FDA’s shift toward Computer Software Assurance (CSA), Robert shares what it actually takes to achieve release by exception. Key Topics Covered: Cross-Functional Ownership: Why MES implementations fail when controlled by a single department. CSV to CSA Shift: Moving away from binders of paper to risk-based critical thinking. Designing for the Operator: Eliminating duplicated data entry and friction on the cleanroom floor. Bridging R&D and Manufacturing: Leveraging early KPI and CQA data to build standardized Master Batch Records (MBRs). Release by Exception: What infrastructure is required to make automated batch release a reality. Timestamps: 00:00:00 – Introduction & Operational Scope 00:01:14 – What is an MES & Who Needs a Seat at the Table? 00:03:12 – When Should Early Biotechs Engage with MES? 00:07:55 – Operator Optimization & Reducing Data Duplication 00:11:46 – The Regulatory Paradigm Shift: From CSV to CSA 00:18:48 – Integrating R&D Data into Scale-Up Master Batch Records 00:26:44 – The Holy Grail: Achieving Release by Exception

  5. Jul 14

    The Outsourcing Trap: Why Pharma Needs to Reclaim Manufacturing | Hedley Rees

    Has the pharmaceutical industry outsourced its way into a supply chain crisis? In this episode of Out of the Lab, host Nicholas Crudele sits down with repeat guest Hedley Rees to uncover the systemic risks embedded in the modern pharmaceutical manufacturing model. For decades, the industry has relied on outsourcing to CDMOs and offshoring to lower costs, but this shift has resulted in a devastating loss of internal critical assets and manufacturing capability. Drawing on powerful analogies—from Apple's tight grip on iPhone manufacturing to Boeing's multi-billion-dollar Dreamliner outsourcing disaster—Hedley explains why pharmaceutical companies must bring clinical and manufacturing expertise back in-house. We also explore the historical success of process-driven drugs like Penicillin, and how current patent laws prioritizing molecule claims over scalable processes are driving massive phase-three failure rates. In this episode, we cover: The Boeing Dreamliner Analogy: The hidden costs and massive delays caused by fragmented supply chains. Why CDMOs now own the "critical assets" of drug development, and how that strips product owners of competitive advantage. The case for process patents over compound claims to reduce late-stage clinical failures. Why early-stage CMC (Chemistry, Manufacturing, and Controls) must be at the center of IP and commercialization strategies. The urgent need to reintegrate physicians and engineers directly into the early stages of drug supply chain design.

  6. Jul 7

    Shoehorning Living Cures into Dead Supply Chains | Hedley Rees

    What happens when the biopharmaceutical industry tries to force living, hyper-perishable cell therapies into a legacy supply chain built for shelf-stable small molecules? The entire system breaks down. In this episode of Out of the Lab, host Nico sits down with Hedley Rees, Managing Director of PharmaFlow and a 40-year biopharma supply chain veteran, to pull back the curtain on why advanced therapies are hitting an operational dead end. Hedley details the immense logistical dangers of circular, "vein-to-vein" CAR-T workflows, the vulnerabilities left unaddressed by major wholesale distributors, and why the current industry model is built entirely on a structural paradox. We pull apart: The Evolution of Tech Friction: Why modern manufacturing architectures were never truly re-engineered to survive deep cryogenic and cold chain realities. The 99% Attrition Trap: How archaic patent laws incentivize companies to claim molecules before establishing repeatable, scalable manufacturing processes. Post-Contractual Moral Hazard: The commercial reality check of what happens when private-equity-backed CDMOs hold all the leverage, leaving asset owners to face regulatory scrutiny alone. Back to the Future: Leveraging the collaboration model of Penicillin to integrate clinicians and engineers directly back into early-stage drug development. Timestamps & Chapters: 00:00 – Introduction: Discussing operational complexity in cell and gene therapy. 01:44 – Alka-Seltzer vs. Monoclonal Antibodies: The failure to re-engineer legacy logistics. 03:34 – CAR-T Realities: Demystifying the highly volatile, circular "vein-to-vein" supply chain. 07:07 – Handover Hazards: Real-time tracking, temperature excursions, and runway failures. 13:26 – The Penicillin Blueprint: Why the earliest breakthrough required process over molecule. 19:39 – Changing the Rules: Redesigning patent law to solve structural asset attrition. 29:46 – The CDMO Leverage Trap: Navigating post-contractual moral hazard on the floor. 46:15 – Shared Risk Alliances: The future of integrated manufacturing capability.

  7. Jun 30

    Fixing the Broken Business Model of Rare Disease Gene Therapies | Craig Martin

    What happens when a life-saving gene therapy is developed for a patient population of only 30 people? The traditional pharmaceutical business model completely breaks down. In this episode of Out of the Lab, host Nico sits down with Craig Martin, CEO and Founder of the Orphan Therapeutics Accelerator, to dissect the radical operational and financial shifts required to bring advanced therapies to ultra-rare disease communities. Craig shares how his non-profit accelerator is rewriting the playbook, from rescuing and "ring-fencing" shelved pharma assets to establishing a shared clinical development network (Orphan ClinDevNet) that spreads infrastructure costs across multiple therapies. They dive deep into the gritty operational realities of advanced therapies: the staggering financial burdens placed on caregivers, the ethical dilemmas of placebo-controlled arms in pediatric trials, and why a reimbursement system built for chronic, recurring pills fundamentally fails a one-time cure. Discussion Points: The Shared Infrastructure Fix: Discover how the Orphan ClinDevNet partners with specialized CDMOs and CROs to build a repeatable framework, avoiding the need to reinvent the manufacturing wheel for every single ultra-rare indication. The Non-Profit Win-Win for IP: Learn how biotech companies can safely out-license or ring-fence shelved rare disease assets to a non-profit accelerator without losing the commercial upside for larger, subsequent indications. The $1 Trillion Problem: Why leaving rare diseases untreated costs the US healthcare system over $1 trillion annually, and why a high one-time cure price tag is actually a collective macroeconomic win. The Logistical Nightmare of Patient Access: An inside look at the hidden friction points of advanced therapies—from navigating state-by-state Medicaid reimbursement hurdles to seeking OIG opinions for travel and lodging support for economically disadvantaged families. Timestamps: 00:00 - Introduction & The Rare Disease Market Failure 02:14 - Scaling Efficiencies: What is the Orphan ClinDevNet? 05:30 - Rescuing Shelved IP via a Non-Profit Accelerator Model 08:45 - The Operational and Regulatory Bottlenecks (CMC Batches & Placebos) 12:15 - The Real Cost of Caregiving: Travel, Lodging, and OIG Regulations 15:40 - Why Our Reimbursement System Fails One-Time Cures 19:10 - Platform Approvals & The Future of "Plausible Mechanism" Access

  8. Jun 23

    Applying Lean Principles to Cell & Gene Therapy

    "Cell and gene therapy developers are contending with the same problems the early pioneers of lean production contended with. Specifically, a frugal environment with scarce resources."  — Andrew, ScaleReady.  In this episode of Out of the Lab, we sit down with Andrew from ScaleReady to discuss the operational parallels between historical manufacturing revolutions and the current challenges in cell and gene therapy. We explore how "lean" manufacturing principles originally developed by Toyota for resource-scarce environments can be applied to modern cell therapy development to solve the industry’s most pressing operational hurdles. Andrew shares insights into why adopting these established frameworks can help developers streamline processes, reduce waste, and overcome the "frugal" environment many pioneers currently face. Topics covered: The relevance of the Toyota Way in modern biotech. Navigating resource scarcity in cell therapy manufacturing. Why lean methodologies resonate with cell and gene therapy pioneers. Timestamps & Key Takeaways: 00:00 – 03:00 | Introduction: Setting the stage for the operational challenges in cell and gene therapy. 03:00 – 08:30 | Defining the "Frugal" Environment: A discussion on the current macro-economic pressures facing developers and why efficiency is no longer optional. 08:30 – 15:45 | The Lean Parallel: Exploring the historical origins of lean production (Toyota Way) and why those original, resource-constrained conditions mirror the current challenges in cell therapy development. 15:45 – 22:10 | Operational Hurdles: Why the "widget" approach in manufacturing is often misunderstood or misapplied in early-stage biotech. 22:10 – 30:00 | Scarcity as a Catalyst: How resource scarcity can actually force better innovation and rigorous process design. 30:00 – 37:30 | Lean Discipleship: Andrew shares his journey into becoming a "lean disciple" and the value of reading foundational texts like The Toyota Way to solve modern biotech bottlenecks. 37:30 – 42:00 | Closing Thoughts: Final advice for cell and gene therapy developers looking to align their internal operations with the high stakes of commercialization.

See All (39)

About

In Cell & Gene Therapy, opportunity created by openly discussing operational reality far outweighs the micro-risk of looking unpolished. By building a safe, unscripted space where experts can talk naturally about real work, we stop pretending everything is fine and start building the solutions needed to actually fix the system. Explore our Solution: https://www.methodmade.ca/?utm_source=podcast&utm_medium=show_notes&utm_campaign=out_of_the_lab

Information