By Louis GarguiloChief Editor, Outsourced Pharma
Follow Me On Twitter @Louis_Garguilo
It never hurts to start with fundamentals: CMC stands for chemistry, manufacturing and controls, part of any new pharmaceutical product application to the FDA. In glorious detail, here is how the FDA lays it out for drug owners. How virtuals, biotechs, and pharma companies get through the nicely arrayed acronym is another story.
David Hennings has some advice. He’s a pharmaceutical industry veteran, and just-named head of CMC and senior director at (San Francisco) Bay Area biotech Cortexyme, Inc.
Intro To Interdisciplinary CMC
“CMC should kick off at nomination of a candidate,” Hennings tells me from his office in Loveland, Colorado.
Some might consider that an early start. I ask him, then, if CMC has an endpoint. “No,” he replies. “It stays through post-approval and beyond. CMC can contribute to profitability adjustments, and even marketing, sometimes driven by the cost of goods or margin erosions.”
“CMC,” he concludes, “lives with the product forever.”
If you are going to be doing something forever, you might as well do it well. Hennings says he’s found that way through the practice of “interdisciplinary CMC.” I ask him to explain.
“When people think of CMC, they don’t consider the full extent of the network they have to interact with. It’s more than the process chemistry, analytical chemistry and pharmaceutics/formulations groups. There’s the strategic management component, quality and regulatory, interfacing with discovery, and dealing with toxicology because you are identifying and controlling impurities. CMC is not a silo. It’s a network within the entire development organization.”
Hennings started building his theory at Bristol-Myers Squibb (BMS), but most of his experience came from his 15 years with Array Biopharma, where among other things, he established interdisciplinary CMC teams to manage the development of clinical candidates, and was team leader for projects including Varlitinib (ARRY-543) and a p38 inhibitor (ARRY-797).
“So yes, fundamentally,” says Hennings, “you do have the three main groups: process chemistry, the formulation group – what some call pharmaceutics, whether that is pre-formulation or the actual clinical or commercial formulation team – and analytical chemistry. But there is also the regulatory aspect, and interaction with the quality groups to make sure that you are filing INDs and updates, putting specs and SOPs in place, and staying current with all regulatory guidance. You also reach back into the discovery arm, because there’s overlap with some knowledge and history with the synthesis of the molecule, and that is usually your starting point for moving forward.”
The Interdisciplinary Team
Who makes up the CMC team, and how many people do you need to be effective?
“You probably need more people than you get,” says Hennings, “but it’s a different answer depending on the size and situation for each company.” If a drug owner has internal capabilities, a leader from each functional group should be chosen to join the CMC team, and one of those is selected as the overall CMC lead. “Someone from senior management should also be included on the team,” adds Hennings. “It’s important not to leave out this connection to senior management. You have to get that strategic support to accomplish your mission.”
In a more virtual setting, the team might consist of a person in charge of CMC, and the CEO. “You also leverage consultants,” Hennings says. “For example, currently I have experts in formulation and analytical validation to help us navigate difficult technical issues. I’m responsible for the activities, but this external consultant is a subject matter expert, and forms part of our CMC team.”
In the biotech setting, where each person wears multiple hats, the CMC “lead” still sits on top of the functions, managing activities and reporting to the CEO, and “is often thinking in terms of ‘how can we get into the phase one trial, establish proof of concept for the therapy, and beyond that, present this for due diligence to fund further development or potentially out license the asset?’”
At Big Pharma, CMC representatives may be accountable to an overall development unit – which could be run by a marketing group. This doesn’t diminish importance, but now “CMC is one chair at the larger inter-organizational table, discussing how the company is going to develop, and market, the compound.”
Critical Ties To Management
What are the best practices for managing the CMC team? Hennings starts with the example of a mid-sized pharma, with the team consisting of representatives from each functional group, and a level of senior management support. There’s also a role played by outside SMEs and consultants. (We’ll focus on the contract development and manufacturing aspect in part two of this article.)
“If you boil it down, because by necessity you include as many groups as possible, both internal and external, it’s about levels of project management,” explains Hennings. “First, you ensure you lay out the deliverables for the different groups, and have somebody accountable for each of those deliverables – whether it’s an analytical method development or major material delivery. Ultimately, the goals of a CMC team are driven by the requirements for an IND or NDA submission.
But what if “Joe” and the analytical team are holding up “Joanne” and the development team? How do you manage that?
“Good question,” Dave says. “As the CMC leader, that’s where your tie to management comes in. Anyone who’s been involved with leading a CMC team has experienced this problem on some level. Team members from different arms of the organization don’t report to you, might not even be within your organizational structure, and may have four or five different projects that they are working on simultaneously. It’s your job to be the advocate for your program, and get prioritization for resources within the organization.”
However, if situations can’t be resolved within the team, CMC is obligated to get the management participation within the group, “whether it’s directly to the CEO or your VP, to get the support to make it happen. That’s when having involvement, or at least a tie to, executive management is critical.”
And that is also when you learn just how critical your project is to your organization. “Every molecule has an advocate,” says Hennings. “But in your corporate landscape, you might have a pipeline and only so many resources. Being tied in to management to know where your project stands in the first place is very important.”
The Interdisciplinary Leader
But who has the skills as the CMC leader to pull this off?
“In early stage development, somebody with a process chemistry background may be the most effective CMC team leader,” begins Hennings. “Many challenges are related to the synthetic chemistry. As the project moves towards phase two and beyond, then somebody who has more of an understanding of the drug product becomes important. So the leadership can change.”
In larger organizations – or as smaller organizations grow – you have people with project management certifications, more managing experience, and broad technical backgrounds. “Now you have leaders specialized in performing the management function throughout the life of the program.”
Above all, sums up Hennings, the CMC head must be highly organized, and have or quickly obtain people skills. “I’ve seen the technically gifted but less organized fail badly at leading a CMC team. Does your CMC leader have the ability to consider all the moving parts, monitor all the areas of expertise both in house and external? Is he or she capable of identifying when a problem is developing? Can they get you to that successful regulatory submission? Those are the questions for all-sized companies looking for effective interdisciplinary CMC leadership.”
Next up: Part 2 with David Hennings, head of CMC and senior director at Cortexyme Inc., on successful tech transfer and working with CDMOs and other service providers.