How To Build Clinical Supply Into Drug Development From The Start
By Hedley Rees and Angeliki Kotsianti, MD
Clinical supply is often brought into a program when the pivotal scientific and clinical decisions have already been made. At that point, teams are asked to make the selected dose, formulation, presentation, and protocol work across sites and countries. They can frequently do so, but late involvement reduces the opportunity to influence the decisions that drive stability, kit design, packaging, comparability, site burden, distribution, and future scale.
The consequence is familiar. A program can be scientifically compelling yet operationally difficult to execute. Short dating, complex dosing, late packaging changes, temperature constraints, and unplanned resupply may be managed as individual supply chain problems, even when they are signals that the medicine, its clinical use, and its supply model were not designed together.
There is a more productive approach. Clinical supply should be treated as an early development partner, contributing operational evidence while the product and trial design can still change. We call this the Penicillin Protocol:1 a practical, integrated model in which discovery, CMC, clinical development, medical, operations, manufacturing, and supply learn from one another throughout development.
The model is not an argument against outsourcing or specialist partners. It is an argument against treating the development system as a sequence of disconnected handoffs — and against leaving the clinical consequences of supply constraints without an owner.
Why The Handoff Model Creates Avoidable Risk
Specialization has delivered valuable expertise, but it can produce a series of local optimizations. Discovery selects for biological promise. CMC develops the product and process. Clinical operations focuses on study execution. Manufacturing prepares to scale. Clinical supply makes the plan work at sites.
Each function can perform well and still leave the program exposed. A formulation decision may restrict shelf life. A presentation selected without site input may create training or administration burdens. A protocol amendment may change demand assumptions after packaging is established. A process change may have implications for comparability, labeling, and release that only become visible as the trial progresses.
The usual response is to improve coordination at the handoff. That helps, but it addresses only half the problem. Shared decisions need to be made earlier, using supply knowledge before product and protocol choices become expensive to revisit. The other half is accountability. A supply constraint stops being a logistics question the moment it reaches a site, and in most programs nobody has been named to answer what it becomes instead.
Why Penicillin Remains A Useful Case Study
Penicillin is often presented as a discovery story. It is more accurately a development-system story.
Alexander Fleming observed antibacterial activity from a Penicillium mold in 1928. A clinically useful medicine emerged only when the Oxford group led by Howard Florey, with Ernst Chain, Norman Heatley, and colleagues, joined purification, potency testing, animal studies, clinical use, and production development in an iterative program.2
Production capacity was not a downstream consideration. The Oxford team had to develop a way to grow the organism, extract and concentrate the unstable product, measure potency, and generate enough material for its first patients. During the 1941 trials, approximately 2,000 liters of culture fluid could be required to treat a single case of sepsis.3
The clinical consequences of limited supply were immediate. The first Oxford patient, Albert Alexander, initially improved, but there was insufficient penicillin to complete treatment. The team recovered penicillin from his urine because each usable amount was valuable. He relapsed and died.4
That is read as a supply story. Read it again as a clinical one. The Oxford team started Albert Alexander on a course of treatment they knew they might not be able to finish, and somebody decided that was the right thing to do. Every physician who has practiced through a shortage has made a version of that decision. You are weighing an incomplete course against no course at all, for a person whose name you know, on evidence that does not exist yet. The moment the material ran short, it stopped being a production problem and became a clinical one.
Four Ways To Apply The Penicillin Protocol
Start with the intended patient experience
At candidate selection, teams should ask more than whether a molecule has the desired biological profile. They should ask what must be true for the eventual medicine to be administered, handled, stored, and supplied reliably to the intended patient population.
That brings route of administration, dose flexibility, care setting, storage expectations, patient adherence, site capability, and likely distribution conditions into the target product profile. Clinical supply can identify practical constraints early, before they become protocol commitments. Medical can say which of those constraints will land on the patient and the investigator, and which are clinically tolerable when they do.
Develop the product and process together
Process development should be a continuing part of product design, not a later industrialization activity. Candidate and formulation decisions should be reviewed against process maturity, material availability, stability, presentation, packaging, and the evidence needed to support future change.
The purpose is not to demand certainty too early. It is to expose the pivotal unknowns while there is still time to design experiments, reserve options, and make informed trade-offs.
Treat clinical supply data as development evidence
Clinical supply teams see how a product and protocol perform in the real conditions of a study. Their data may include site feedback, temperature excursions, resupply patterns, unused product, dosing queries, and deviations. Too often, that information is used only to keep the study running.
It should also be reviewed as design evidence. A repeated site handling issue may point to the need to change the pack, instructions, training. or protocol. A resupply pattern may challenge demand assumptions. A temperature excursion trend may reveal a gap between intended and achievable distribution conditions.
Plan scale before it becomes urgent
Scale-up should test a coherent package, not uncover a series of disconnected decisions. Early cross-functional planning should identify the process attributes, materials, presentation options, and supply conditions that are most likely to constrain development or patient access.
The questions will evolve as data emerge. The value of the approach is that the team knows which questions must be answered before change becomes slow and costly.
The goal is not to make clinical supply responsible for every development decision. It is to make sure its operational knowledge reaches the decisions that supply will ultimately have to execute while there is still time to change them.
That is the first shift the Penicillin Protocol asks of development teams: treat clinical supply as a source of development intelligence, not simply the function that delivers the decisions made by everyone else.
Editor's note: You can read part two of this article series here.
About The Authors:
Hedley Rees is a pharmaceutical supply chain consultant and author specializing in drug development, CMC, and supply-chain strategy. He is the author of Supply Chain Management in the Drug Industry (Wiley, 2011) and Transforming the Pharmaceutical Supply Chain (Wiley, 2025). The accompanying explainer, The Penicillin Protocol: Taking Medicines Back to the Future, introduces the integrated development model behind this article.
Angeliki Kotsianti is a physician-scientist and molecular pathologist. She spent nineteen years at Pfizer, where she chaired benefit-risk and held the final medical judgement on the company's medicines, including decisions on manufacturing, reformulation, recall and supply. She built Pfizer's global Medically Necessary Products strategy and co-led the company's representation in the EU Critical Medicines Alliance, whose work informed the Critical Medicines Act. She now advises on medical governance and regulatory strategy as a consultant with PharmaFlow Ltd, working on how decisions taken early in development determine whether medicines reach patients. Her specialist interest is the governance of evidence, including the validation of AI-derived findings. She is an inventor on eight patents in machine-learning diagnostics and co-founder of Oncolyze Inc.
Editor’s source notes
Historical claims are supported by the American Chemical Society’s history of penicillin, the Oxford History of Science Museum’s account of the original penicillin culture, and the University of Oxford’s history of the first human trial. The Penicillin Protocol is a framework proposed by Hedley Rees and is not a historical term of art. Accounts of shortage response and impurity response governance draw on the professional experience of the co-authors.
References:
- Explainer video — The Penicillin Protocol: Taking Medicines Back to the Future: https://youtu.be/RP8mJCQAMU4
- American Chemical Society — Fleming’s discovery of penicillin: https://www.acs.org/education/whatischemistry/landmarks/flemingpenicillin.html
- Oxford History of Science Museum — original penicillin culture and specimen: https://www.hsm.ox.ac.uk/original-penicillin-culture-and-specimen
- University of Oxford, Primary Care Health Sciences — on this site, penicillin: a historic first: https://www.phc.ox.ac.uk/blog/on-this-site-penicillin-a-historic-first