From The Editor | October 7, 2020

Is Biopharma Suffering From Thalassophobia? FDA Regulator Says Yes

Anna Rose Welch Headshot

By Anna Rose Welch, Director, Cell & Gene Collaborative
Subscribe to my blog ARW on CGT here!


A couple of weeks ago, I attended Xconomy’s Xcelerate Keynote Series at Biotech Week Boston. I was particularly interested to hear the opening presentation from Jeff Baker, deputy director of the FDA’s Office of Biotechnology Products, entitled: “Discuss, Deploy, or Defer: New Technologies in Real World Biopharmaceutical Manufacturing.” Over the past few months, I have been familiarizing myself more with discussions occurring on the manufacturing side of the biopharma industry. In addition to the increasing focus on cost of goods in the biosimilar industry, it has also been an interesting time to be in the innovative biotech industry. Not only have huge strides been made in the race for COVID-19 therapies, but the industry is embracing the challenges of cell and gene therapies, drug antibody conjugates, and a wide variety of therapeutic peptides and proteins (and yes, biosimilars).

That impressive list of product classes may suggest that such R&D innovation also translates into more innovative manufacturing. But as Baker explored in his presentation, manufacturing has, surprisingly, not kept pace with R&D. In fact, the industry, Baker worries, is currently suffering from a case of Thalassophobia, or a fear of the sea. To quote Isaac Newton: “What we know is a drop; what we don’t know is an ocean.”

“I fear that, as a community, we’re intent upon analyzing the heck out of a few drops more and more rather than seeking to understand the dynamic diversity and impact of the ocean as a whole,” Baker said.

Here, he shares several thoughts on why this may be the case, offering a call-to-action for the industry to reevaluate its notions of value to encourage greater manufacturing innovation.

Where Is The Innovation Disconnect Happening?

I’m always drawn to presentations from regulators because they’re in a great position to see across an entire industry and highlight the trends impacting that space. For example, in looking at the scores of 351(a) and 351(k) applications submitted over the years, Baker remarked that the technology used to manufacture these products has not evolved as much as we may have anticipated.

Now, in the biosimilar space, this statement requires a bit of clarification. We know that the analytical technologies enabling characterization and greater understanding of both reference and biosimilar molecules have improved immensely. As critical literature from earlier this year emphasized, knowledge of certain process-related impurities and the development of more sensitive and selective assays have ultimately improved manufacturing control design for biosimilar development.

As Baker confirmed, “state of the art” often means something different depending on the technologies’ functions. For example, “The analytics that we have for comparing a biosimilar to a reference product are in a very different place from your process analytical technology (PAT),” he offered. Though the FDA receives many supplemental applications — which could demonstrate the industry’s growth and continuous learning — he shared that these rarely document the deployment of a new, innovative manufacturing technology.

Your mind likely jumped to a couple of different reasons as to why this is the case — for example, perhaps the molecule, company size, or access to the necessary talent or equipment are to blame. But Baker dismissed these all, citing small and large companies’ talents for more rapidly identifying potential therapeutic targets and candidates and proceeding to the clinic.

Another popular argument you’ve likely heard (or made yourself) is that the regulators are partially to blame. Baker acknowledged this could perhaps be the case, but it remains a complicated assertion given the number of FDA initiatives undertaken to encourage manufacturing innovation. Almost 20 years ago in 2001, the agency’s commissioner released a strategic plan to improve drug product manufacturing and quality and offered grants to willing parties to explore innovative strategies of doing so. In 2015, CDER announced the Emerging Technologies Program (ETT), finalizing guidance on the program in 2017. As recently as 2019, CBER launched the advanced technologies team to work with those in the cell and gene therapy space. Long story short, there is a lot of interest at the agency in seeing more innovative strides made in the manufacturing realm.

To ensure that the agency wasn’t missing something, The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIMBL) launched a survey to determine why we haven’t seen as much creativity in the manufacturing realm. The results of this survey led to an “active listening session” between NIMBL, industry representatives (i.e., quality and regulatory affairs professionals), and the FDA. During this session, these experts engaged in active dialogue on regulatory changes that would enable a company to deploy innovative technology for continuous improvement in manufacturing.

However, as the industry representatives shared quite candidly at the meeting, it’s not necessarily that the agency isn’t doing enough to encourage innovation; there just isn’t a business case for investing and implementing new manufacturing technologies.

“Prelaunch, new technologies post a risk to the development timeline,” Baker acknowledged. “Post-launch change management — especially globally — is a big hurdle. There is a huge aversion to being the first to deploy new technology. Even being the second out the gate can concern companies because of the perception that they may face a lot of questions and concerns from the regulatory agency. The industry representatives at this active listening session were very open and honest: there is just no ROI for investing in innovative manufacturing technology.” 

Reevaluating Value: What Experience Should Biopharma Be Seeking?

To illustrate his understanding of ROI, Baker walked us through a few basic analogies that have informed the way he approaches this equation. For example, he showed pictures of two different types of chairs — one a very simple, three-legged stool, and the second an office desk chair. “The stool is stable, sturdy, easily reproduced, and is a tried-and-true design,” he explained. But the work chair on the other hand, provides a very different experience than the one where design and development costs were minimized. The same can be said for cellphones. New models of smartphones are typically released every year, but their basic functions — making calls, sending texts, and using the Internet — don’t change. Baker put it best: “The new phone makes calls just as well as one from two years ago. The difference is the experience that the person has. This is a very important representation of the elements of value as opposed to the elements of cost.” 

If you compare the “experiences” sought in R&D and manufacturing, Baker sees several differences in attitudes toward risk. Taking chances and diving into the unexpected are a natural part of the R&D process. To some extent, as well, the regulatory landscape acknowledges that there will always be some level of residual uncertainty and that not everything can be known. (Totality of the evidence, anyone?)   

Despite the fact that residual uncertainty is a core tenet of the biotech industry, manufacturing remains centered around predictability and control — in particular, standardized platforms, processes, and what Baker refers to as a “vocabulary of specificity that excludes uncertainty.” Such specificity reinforces discomfort over the unknown, in turn leaving the industry unwilling to invest in something that may change the manufacturing experience and its overall value. Hence Baker’s quote from Newton about being obsessed with droplets and fearing the sea.

Of course, cultural changes are hardly efficient, especially in a high-stakes, high-risk industry like biopharma. Baker argues that the first step is to embrace the mindset that, “Uncertainty is neither good nor bad — it simply exists and is an attribute to be understood and managed as opposed to avoided,” he offered. This means the industry needs to shift away from the specification mindset and make the clinical and community experience a more central part of risk-assessment in biopharma manufacturing.

“I hope that we’re not looking at a situation where it’s all about minimizing risk,” he concluded. “If it is, I worry that we’re moving into a situation where we’re responding to the sum of our fears. It is far better to respond to the sum of our vision and to capture the creativity, the innovation, and the energy that is occurring in target identification and product development. If we can translate that to the commercial manufacturing floor, that will really bring us into the 21st century of commercial biopharmaceutical manufacturing.”