Imagine a single resource supporting your organization’s drug development and manufacturing programs who is described this way:
“Twenty-five years’ experience working in positions at Big Pharma and biotechs in process development, technical operations, CMC, supply chain and lifecycle management, manufacturing sciences and engineering, and all aspects of outsourcing and managing CDMOs. An industry-recognized expert in quality by design (QbD). International experience, including positions in Canada, Europe, and the U.S. Accomplishments include successful development and commercial manufacture of small and large molecule products (as well as generics).”
Actually, you’ve just met Jana Spes.
Unfortunately, she isn’t for hire at the moment. After working at companies such as Pfizer, J&J, and Ferring Pharmaceuticals, at the end of 2018 she planted her multifarious flag at Ironwood Pharmaceuticals in Boston. Ironwood is a biotech focused on gastrointestinal diseases, with a commercial product (LINZESS) and two development programs (IW-3718 and MD-7246) targeting highly symptomatic conditions with significant unmet needs.
Here, Spes provides us with some uniquely qualified analysis and guidance on the outsourcing industry and working with CDMOs. Don’t be surprised if you come away thinking for your next outsourcing operations hire, specialization is out, and the Spes model is in.
A Woman For All Phases
Over the years, two industry trends converged to increase the need for multi-experienced outsourcing professionals. First, the industry embraced the virtual — or at Big Pharma, streamlined — development model. At the same time, CDMOs began to offer a continuously wider variety of services to support those models.
Says Spes, “When you look back, it’s a chicken or egg calculation: Did CROs and CMOs have the foresight to anticipate which way outsourcing was heading? Or was it the actual evolving to the virtual model by biotechs, and Big Pharma’s new desire to work with strategic partners, that advanced the industry? We’ll never know who the genius exactly was at the given moment.”
We do know that as a result of these changes, this is happening: While on the one hand drug development and manufacturing, per se, dashes toward narrower and deeper specification (e.g., antibody-drug conjugates [ADCs], monoclonal antibodies [mAbs], cell and gene therapies, personalized medicine, orphan-disease markets, etc.), the actual “art of outsourcing,” as Spes describes it, stands in bleak contrast, it now benefits from a broader brush of experience.
“I’ve been fortunate to gain commercial experience early on and also have a career on the interface between ‘r’ and ‘d,’ including technical operations and lifecycle management,” says Spes. “I can fully understand the end game from the earliest points of a drug program’s departure. And that end game today requires recognizing as early as possible the needs for flexible drug product manufacturing, whether it’s capacity, quality, analytical testing, packaging, supply chain distribution, or lifecycle management.”
Spes provides an example: “Let’s say you discover you need to qualify a second manufacturing partner because projections indicate your capacity will run out two years after launch. You must identify a CMO and perform a tech transfer. First, this need might have been avoided with more foresight. However, I can now seamlessly translate all of these current and future needs into the required development activities, including understanding who the correct new manufacturing partner should be.
“So, given there is this broad adoption of the virtual model and ‘end-to-end development,’ ‘tech ops’ expertise is becoming an amassed group of specialties needed to work with CDMOs effectively. I can tell you there is a huge demand for people with end-to-end experience to match the services at the CDMOs.”
She continues: “I believe it’s unprecedented how recruiters are trying to get individuals with this experience to jump from company to company. There’s this high demand for those who have an entwined experience. Today you must see the consequences of all your early program decisions in Phase 1 and 2. Many of those decisions you are making now are not reversible later. Those are the strategies — the analytical, sourcing, manufacturing strategies — that will stay with you throughout your filing and launch of the product.”
I ask Spes if there’s been one prevalent piece of advice, an admonition perhaps, she’s had to repeat most over the years. “First, on the plus side,” she replies diplomatically, “my current company is quite sophisticated. And I think the tide is changing throughout the industry. People understand early on that the products they’re developing are intended for commercial scale, and all their decisions have consequences.
“However, over the years I have seen where a biopharma’s R&D group is strictly focused on their mission and employs the suppliers that they want to work with. But after minor scale-ups, neither they nor their vendors can now imagine manufacturing on the required commercial scale. It’s not in their realm of experience. So I always advocate breaking down those internal silos, if they exist. But again, while we are not there yet, I think both the drug sponsors and service providers are evolving.”
When We Do Specialize
Of course, credit for some of that evolution goes to people like Spes. However, we should interject here: Even multi-experienced professionals do tend to acquire particular areas of expertise and focus. As that’s also a positive attribute.
QbD can be defined simply as a systematic approach to pharma development and manufacturing. Its full detail and implementation, though, are anything but simple. It was formally introduced to our industry under ICH Q8 Guidance published by the FDA in 2006. As updated guidance on QbD continued to flow from the agency, Spes was working with a pharma development team on an early implementation strategy. But it was her second “teaching” of that QbD strategy that planted her firmly on the path to becoming a recognized leader in the discipline.
“We were working with an established service provider in southern Europe, but we realized they had no knowledge or experience with QbD. This was not unusual at the time,” she recalls. “So we began to patiently walk them through the process, considered them as our team members, and involved them in every aspect of how we were developing our QbD processes.
“Fast forward to 2019, and this CDMO now uses its experience in QbD as a selling point to attract biopharma customers and hence can command premium services [and pricing]. Now they claim they are best-in-class in QbD tools and experience.”
Spes more broadly reminds us here that the “teaching” experience has been part of the mosaic of our outsourcing industry, one that lays out the narrative of how science and strategies have been transmitted from entity to entity.
At the advent of outsourcing, pharma companies employed CMOs to perform rote tasks under strict supervision. After some years, though, Big Pharma started to behave more like teachers of the “arts” of drug development and manufacturing. Then CDMOs began transferring that know-how to their smaller customers: the startups and virtual biotechs. And in the final arc of this cycle, those smaller companies have begun guiding bigger pharma on how to be more productive in their outsourcing via concepts such as enhanced virtual management and program flexibility. In fact, Spes says there have been cycles within cycles over the past decades.
“Previously, pharma companies had to employ multiple CROs and CMOs and perform various transfers. That was a tremendous financial and timeline burden, with added technical and supply risks. This contributed to tension inside the pharma companies between the R&D and commercial-supply organizations, which had very different priorities and deliverables.
“Now, CROs and CMOs, to quite an extent, have morphed into CDMOs by adding development capabilities or by M&A. They advertise and position themselves with ‘end-to-end’ offerings, specifically when it comes to final development and manufacturing.”
For some perspective on these changes, Spes recalls working years ago at Pfizer (she was there during the Viagra launch) when “It required a small army of internal resources with varying specialties and responsibilities for process development, engineering equipment design, formulation, and packaging. But the point, she says, is that the contractors employed to help were only executing on specific orders. All the work and designs were done first by the sponsor. “Today those activities can be accomplished with much smaller teams at the sponsor because the expertise resides within the CDMOs. Moreover, the CDMOs can — and should — take more project ownership. They are tooled up to deliver various products; hence, efficiencies have increased in the pharma companies’ development organizations. You just don’t need such large internal teams.”
What you do need — both at pharma and bio organizations — are resources who understand and can oversee those growing CDMO operations.
Experience In Action
Spes recalls her first day at a new company some years ago. The production team was engaged with a key Canadian supplier, which had just been deemed unreliable. Immediately, Spes says, experience informed her “things are never so simple.” She helped catalyze an effort to further evaluate the situation before any decisions to leave that supplier were taken.
“In a global business,” she explains, “you have to do many filings with regulatory agencies; exiting a supplier can become a multiyear project.” Additionally, this CMO was producing an essential life-saving medicine. The product was highly sensitive to temperature and required strict refrigeration protocols to maintain shelf life. Any potential manufacturing variability could cause serious production problems. In fact, the manufacturer had experienced several batches that trended out of specification. Spes’ new employer was facing a potentially devastating drug shortage.
“It was like a status-quo black hole,” she recalls. “Our quality and process teams were not able to identify the probable cause. Things would temporarily get better, and then we’d return to out of trend.” Spes and others at the company decided to take a new tack. They held face-to-face meetings at the supplier to discuss how to conduct other kinds of investigations into the issues.
“This was around the time when the CDMOs themselves were starting to employ experienced individuals and particularly people who were Six Sigma Black Belt trained,” recalls Spes. “Once we agreed on using a structured Six Sigma approach, dug into the data, and investigated more systemically, we were able to elucidate the situation and identify the root cause, which it turns out, was a single piece of equipment causing minute contamination impacting product shelf life.
“It’s actually quite a typical story,” muses Spes. “It comes down to communication and building trust to start with. It’s still the best approach in my opinion. Then, with the better utilization of data, a certain sophistication around the data was needed. It required modeling, whether it’s looking retrospectively at the process performance or the modeling of future performance.”
Spes still recognizes this as an area where CDMOs can further improve. “They’re generating so much data on our behalf. They should increase their intellectual muscle so they can apply the product and process data in a value-added way. The end of the story, in this case, was that the product was subsequently reformulated to maintain stability at room temperature. It continues to play a critical role in saving lives, especially in developing countries around the world. That’s what this should always be about.
“And a most salient point is this,” she says after a slight pause. “Years of multiple experiences allow you to see things from many angles. You can foresee what ‘good’ looks like and know how to get to that state. You can think through some of the changes and tweaks, whether they’re systems or people.”
So does Spes look for resources as well rounded as she is at the CDMOs she selects for her projects?
“Yes,” she replies, “I’m definitely looking for people who are first very current on industry practices and who can speak the QbD language and understand QbD-based development. Then, I’m looking for teams that know how to model and apply data for process control and improvements and those that have various experiences.
“I’m also looking for those CDMOs that take shared accountability. Unfortunately, that component is still difficult to come by. If the final responsibility lies solely with sponsors, then I don’t believe we can outsource as much as we like. There still needs to be more joint accountability, one that I can feel from the CDMO … it’s a kind of trust.”
“I’m still dreaming about meeting that perfect partner,” Spes adds with a smile.