“The failure looks sudden. It almost never is.”
— Lonnie Robarge, CMC Strategy Advisor, Portfolio CMC Advisors
Most manufacturing failures don’t start where you find them. By the time they show up, they’ve usually been building quietly over time.
A process may run smoothly through a handful of early batches, but that doesn’t necessarily mean the process is fully understood. Early success often shows that the process works under a specific set of conditions: with the same team, at the same scale, and at the same site. As the program grows and moves into new environments, gaps in process understanding, robustness, or control can become more visible. At the same time, more is riding on the process as capital is deployed, teams expand, CDMOs are brought in, and regulatory commitments are made.
Scale-up, tech transfer, and execution across different sites and teams are often what reveal the limits of that operating window, and they tend to do so when the organization has less flexibility to absorb unexpected issues.
The Phase 2 Manufacturing Wall
This is the idea behind The Phase 2 Manufacturing Wall™, a framework developed by Lonnie Robarge, Founder of Portfolio CMC Advisors, with Bharat Gurale, Ph.D., Associate Director of Drug Substance, CMC, at Verastem Oncology. It describes the point where two things that can develop at different rates — how well the manufacturing process is understood and how much the organization depends on that process — begin to converge.
The challenge is not simply a lack of process knowledge, but a lack of visibility into how that knowledge is developing. Clinical progress is closely tracked, funded, and reported, while manufacturing and process understanding often mature with less visibility. As a result, a program can advance faster than its process understanding without that gap being obvious. It may only become visible during scale-up, tech transfer, an investigation, or a comparability assessment — at which point the organization may have already made significant investments and commitments around the process, making changes more difficult and costly.
One of the framework’s key points is timing. The best opportunity to identify and close these gaps is earlier than many teams expect. Before scale-up, tech transfer, or filing pressure puts the process under greater scrutiny.
Score your own program
Lonnie also developed a short self-assessment, the Readiness–Exposure Gap™, that applies the framework to an individual program. It compares how well the manufacturing process is understood with the level of organizational, financial, and regulatory commitment that now depends on it.
The assessment is not meant to give a program a grade. It is a quick way to identify whether those commitments may be growing faster than process understanding, and to surface potential gaps while there is still time and flexibility to address them.
You can run it directly below.
htmlTool by Lonnie Robarge & Bharat Gurale, Portfolio CMC Advisors. Having trouble loading it? Open the diagnostic directly →
Full framework — including the “Illusion of Readiness,” why organizations structurally miss the warning signs, and two industry cases (Ritonavir and the valsartan nitrosamine recalls) where this pattern played out is in the white paper, co-authored by Lonnie Robarge and Bharat Gurale, Ph.D.: Read the white paper →
Hear it live at CDMO Live Americas
Lonnie is joining a panel tackling this territory at CDMO Live Americas in Boston (October 21, 2026), in a session called “De-Risking Small Molecule CMC: Decision Gates, Global Capacity, and Supply Chain Strategy.” He’s joined by Rahela Gasparac-Knezic (HeliPharm Consulting), David de Chaves (Keys Associates), Stefanie Roeper (Vertex), Amit Jain (QurAlis), and Ben Locwin (Reliant Life Sciences) for a cross-functional look at the go/no-go gates, developability frameworks, and global capacity trade-offs that separate programs that scale cleanly from ones that hit the wall.
Register for CDMO Live Americas →
