Medicinal Chemist, Meet Your CDMO
By Louis Garguilo, Chief Editor, Outsourced Pharma
Ben Stevens’ career began at the tail end of 2006 at Merck & Co. He subsequently moved to Pfizer, and then on to a 3.5-year stint at the FDA as a Branch Chief/Chemistry Reviewer. Next, he went back into industry with a few years at Alnylam Pharmaceuticals; and in 2021 alit at GSK, where he has settled in as Director, CMC Policy and Advocacy.
“I've had interactions with CDMOs pretty much all through my career,” he tells me at the start of a recent discussion.
“Even when I was doing med chem,” Stevens explains, “as part of the programs we were spearheading, we worked with a variety of providers to source materials for activities such as animal studies or early-stage clinical trials."
At Pfizer, for example, Stevens worked on peptides, and coordinated closely with a number of CDMOs to generate lead candidates for programs.
Too often sponsors can overlook key interactions between med-chem scientists and research biologists, and contract development and manufacturing organizations.
This despite CDMOs telling anyone who will listen that their services do not begin specifically at the “D,” but overlap, if you will, with the driving of programs from discovery.
Some CDMOs today try signaling as much by squeezing an “R” into their acronym: CRDMO.
It’s a bit unwieldly, and hasn’t taken off. But that segment of the early-stage marketplace has. And it has been catalyzed by the shortened timeframes for bringing early-stage programs to development and the clinic.
Med Chem Lessons
Stevens does fess up to a certain inexperience when it comes to medicinal chemists and researchers having to reach out to external-partner developers for the first time.
“This probably comes across to your readers as naïve," he says, "but because I was a medicinal chemist, I didn’t necessarily have a good initial grasp of all our GMP requirements for materials."
“I was soon schooled on the strong scrutiny pharma like Pfizer pay when they vet their suppliers.”
In one case, Stevens was contracting for material from a well-known CDMO. “A lot of companies use them,” he thought comfortably.
But it turns out Pfizer did not have their “standing agreement” in place with this CDMO.
As Stevens describes the experience, he and team had to then jump through “a lot of hoops” to ensure their vetting process of the CDMO met Pfizer's companywide standards.
“For me it was eye-opening,” Stevens says.
“You think of it as basically, the regulators are the ones who create the quality bar. But it's the potential client as well, with its own audit processes and internal systems to scrutinize and maintain CDMOs, and for example, establish quality agreements.
“In med chem, oftentimes we're not dealing with GMP materials. In this particular case, we needed GMP because there was a strong desire to source material that could be used further down the line for potential clinical studies.
“And in fact, we did run into troubles actually receiving the material from the contract manufacturer.”
Since Pfizer hadn’t prequalified this particular CDMO to receive the material as part of their GMP receipt process, “it created confusion just when the CDMO was on the cusp of sending us the final material and do the final disposition.”
Looking back, and from his current vantage point as a director of CMC and policy at a Big Pharma himself, does Stevens think the requirements/protocols Pfizer had in place were somewhat overblown?
“I came away from that situation understanding that to the extent possible, you have to be clear on what the intent is for the particular material you need,” is Stevens’ reply.
“Ultimately, we didn't run clinical studies with the material, and only utilized it for research purposes. But no, I do not think there's anything wrong with the scrutiny that pharma companies apply.
“I understand today this has become a key part of ensuring requirements are met. We need to perform appropriate and necessary due diligence.”
The challenge, though, Stevens adds, is with the inability at early stages to be clear about what any further intent is for the use of material, and opting for GMP adds costs and time to projects.
Therefore, he concludes here, “My point being it's not that the internal structure is set up too rigidly. Rather, it is that you have to try your best to be less ambiguous about what your plans are – and what your overall organization needs.”
And ensure your service provider understands all that as well.
More Tips For Early-Stage Outsourcers
Stevens, also an Outsourced Pharma Editorial Advisory Board member, provided these further thoughts for readers, which I have edited into bullet points.
- Despite today’s climate for quicker/faster program advancement, resist the urge to move too fast, based on individual stakeholder priority.
- Any move into GMP manufacturing must be carefully planned, and aligned across all key areas of the project team and organization.
- To the extent possible, perceive when you may have a need for GMP, and when you don’t.
- Don’t try to ‘kill two birds with one stone’ as a basic tactic. Base your approach on pertinent facts and carefully determined strategy.
- For emerging biotechs (and others), rely on your internal manufacturing experts, and the CDMOs as well, to provide insights into your plans and strategy for material use.
- “Institutional experience” is invaluable; at times it is worth extending a timeline to mitigate potential risks; other times you can learn how to avoid unnecessary delays.
- Always consider the regulators’ experience with the CDMOs you plan to or are woring with.
- Information is available directly from FDA, EMA and other regulators. They provide insight into the potential risks of using a particular provider or strategy.
- Your QA experts are almost certainly already accounting for this; work closely with them.
- In cases when you can in fact perform lead optimization work and clinical manufacturing at a single CDMO, while this can afford some significant advantages, the benefit always needs to be weighed against the long-term commercialization plan and risk assessments.
- Finally, for all work sent out to CDMOs, it's worth the time to deeply consider the potential impact of recent geopolitical events and government initiatives (e.g., US FDA Unannounced Foreign Inspection Pilot).
Next up, Stevens helps us understand a subject many of us believe we already know well enough, but he says we may want to consider more deeply: The relationship of the FDA, your CDMO, and the drug master files (DMFs) needed to process and manufacture our materials, APIs, and drug products.