Things have progressed nicely for Ruby Casareno, Vice President, Chemistry, Manufacturing and Controls (CMC), Allakos Inc. For biotech executives who wish the same prognosis for your CMC leadership and organization, there are some lessons on why that’s the case.
Those lessons also recall for Casareno an earlier experience where progression traversed a rockier road. Both experiences provide us some best practices for the CMC function at biotechs, particularly when it comes to outsourcing drug development and manufacturing.
Look Before You Leap
Allakos, a clinical stage antibody-based therapeutics biotech focused on inflammatory diseases, was founded in 2012. It outsources drug substance and drug product manufacturing. After a successful IPO this year, it currently employs about 50 full time employees. The company is conducting phase one and two clinical studies for its lead candidate.
Casareno says this opportunity at Allakos (she’d previously worked at Johnson & Johnson, Seattle Genetics, OncoMed and Portola), was “like a dream job,” the enumeration of which starts us on the path to advice for CMC organizations.
Allakos tasked Casareno with establishing a CMC group – including responsibility for drug substance, drug product, analytical, QC, supply chain and CMC project management. She has contract-manufacturing oversight, and at the same time building internal development capability is another major responsibility. While CMC was starting “more or less from scratch,” project management existed via two people. Two others – a bioassay expert and a purification senior scientist – were recent hires.
What these four had in common, says Casareno, is they’d all worked together at prior companies. “Even though Allakos found me through a different route, I inherited people I know and trust from the past. That lent me the confidence to take this on.” Casareno then hired heads of upstream, downstream, drug product manufacturing, and of analytical development / QC, and continues to build from there.
Her plans had been well telegraphed. “During the job interview when I outlined the CMC org chart,” she explains, “I saw that senior management was aligned with my thinking. I needed that support. I was extremely pleased when I realized they fully understood the importance of manufacturing – that clinical and manufacturing go hand-in-hand when you file a BLA [biologics license application].”
Another key for her: The contract development and manufacturing organizations (CDMOs) that Allakos are closely partnering with are ones that Casareno knew well, and very much approved. “That’s part of the reason I joined; if they weren’t reputable CDMOs, I would have thought twice,” confesses Casareno. Since she’d worked with the CDMOs before, there was a familiarity with their systems and how their project teams operate.
Still, she had to prepare her new team for the interactions she intended. “I always want to ensure clear, concise communication with the CDMOs,” she explains. “To prepare for our weekly conference calls, internally the project team members get together on a weekly basis to vet topics for joint team discussion. We achieve internal alignment before we discuss with the CDMO.”
Early this year, Casareno traveled with her team to the drug substance CDMO site “for a risk assessment exercise prior to process characterization” – and stayed on site for a week. “It is best practice for new teams to conduct face-to-face meetings, tour the facility and laboratories to establish rapport, and have an appreciation of each other’s capabilities,” she states.
And when we spoke, Casareno had just come back from face-to-face meetings for the drug product process transfer. “Since that location is ex-US, we made the effort to meet at the CMO site. It’s now a different culture that's an added factor we need to take into consideration.” Yes, she and her team stayed there a week as well.
Taken together, here’s what Allakos and Casareno have going for them. Obviously, these aren’t factors or circumstances every executive looking to hire a CMC head can simply materialize – nor every person looking to join a company as a CMC head can expect. But it can’t hurt to enumerate them … and shoot for as many as you can get.
1. Hire a CMC candidate experienced in development and manufacturing.
2. Give the CMC hire autonomy and a real leadership role at the company.
3. Hire a CMC candidate who is familiar with your current external partner(s), or heavily involve them in the selection process.
4. Give full executive leadership approval and support of the CMC’s plans – learn about those plans in the job interview.
5. Allow the CMC head to bring in her own hires, or bring in a CMC head who has worked in the past with some of your current employees.
6. Ensure that the CMC team leads a “high communication / visitation” operation with external partners.
When You’ve Already Leapt
Now on to that other experience Casareno recalled, starting when she joined a new company: “I joined a CMC team, where regarding the specific outsourced program, let’s just say it felt like the train had left the station. I came on board just after they’d received a CRL [complete response letter]. With my manufacturing experience, I hoped to help the team turn things around to resubmit a successful BLA.”
However, this time Casareno had to work with a CDMO unfamiliar to her – and one it turns out was part of the problem the company was facing. “They were already doing commercial batches, but there was a big gap between the two sides; the relationship with the CDMO was not on solid ground,” she recalls.
Casareno tried to re-establish rapport and build trust. She was at the CDMO site every other week to conduct meetings, and gain insight on how they conducted business. “That helped position us to move forward, but there were limitations. There were certain things due to how they operated.”
Casareno argued for changes to the manufacturing process from a data-driven perspective, she says. “We presented why we needed to look at things from a different angle, compiled manufacturing data, and investigated the failures and proposed root causes. My team avoided finger-pointing. I tried to drive home the message that our success is the CDMO’s success.”
In the meantime, Casareno had a persuasion job to do internally. “I tried to make the team aware that from my experiences, there’re good reasons why the regulatory agency has its stance. I helped drive the message that there are things that the agency is looking for, and currently some of these are missing from our submission.”
Casareno recalls a particular situation. “The CDMO had failed multiple times to perform a study required by the regulatory agency. The protocol for the repeat study had already been in motion when I came on board. Upon completion of the study, senior management asked for my opinion. Knowing that regulatory approval hinged on this study, I had to give the honest verdict of ‘not acceptable.’ It was hard for me to deliver that message knowing that it is not what the company wants to hear as it means a delay in the resubmission. However, I proposed a strategy that would address the agency’s concerns.”
Personal validation for Casareno came the next day, when without her knowledge, the executive team had a meeting with its manufacturing advisory board (MAB). The board expressed the same opinion; they should not submit the study as is.
“That’s the kind of intensity that can exist,” sums up Casareno. “Eventually, the BLA was resubmitted and the drug was approved.”