"Phase-Appropriate" Drug Development The New "Time And Place"

By Louis Garguilo, Chief Editor, Outsourced Pharma

Parents today still caution children with the phrase, “Everything in its time and place.” For me, it just took “the look” for my parents to convey: This wasn’t the right time or place.

In our biopharma industry that axiom gets replaced with, “Everything in its time and phase.” And “the look” might come from veteran project managers, outsourcing providers, or consultants regarding scale-up strategies.

Four such industry veterans led a free-flowing discussion on “phase appropriate” decisions at the inaugural Outsourced Pharma West (OPW) conference and exhibition in San Francisco last November. They had a common message directed at established pharma: “To find out whether the CDMO has exactly what you’re looking for and understands what you’re asking at each phase of your project, you need to forge a good relationship from negotiations.” This requires both sides fully understanding the long-term strategies that will guide step-by-step decisions throughout the business partnership.

Our experts also had a consolidated message for virtual and smaller biopharmaceutical companies. Just as the inexperience of youth makes it hard to judge appropriate actions and timing, you need real-world experience to advance drug development projects from phase to phase. As one of the panelists said: “If there’s no one in your organization experienced with CDMOs, you’ll definitely want to bring expertise or a consultant in-house. If not, you’ll be sending somebody out to build a dam with no engineering background. It’s going to leak.”

What’ll leak is money and time, and at worst the chances your drug makes it to commercial success.

Therefore, experience and the ability to forge relationships with CDMOs form the ground beneath phase-appropriate decision making. Let’s meet our “Fab Four” (or maybe that’s “Lab Four”) to see how to build on that, and then take a closer look at what goes into making scale-up decisions.

THE EXPERTS IN TIME-AND-PHASE
The Outsourced Pharma West discussion was moderated by Bikash Chatterjee, president and CSO, Pharmatech Associates, which provides consulting and services to the regulated and global life sciences industry. In a conversation with Chatterjee just prior to the conference, this comment regarding novice outsourcers stuck with me: “First of all, brace yourself for things taking longer than you are used to in your own labs. It’s a scientific and business process working with a CDMO, so you must build that into your project timelines.”

Ulrich Ernst is senior vice president for manufacturing & quality operations at Amunix, a biotech focused on the design and preclinical development of protein pharmaceuticals with extended serum half-lives. Perhaps his most memorable comment at OPW was a sports analogy.

“If you’re coaching a football team, you want your first 10 plays all mapped out to march down the field and score a touchdown. It’s no different in drug development. To avoid variability, you want your detailed plan set ahead of time. You really want to get to the goal line.”

Patrick Murphy is vice president, manufacturing, at Versartis, Inc., an endocrinefocused biopharmaceutical company developing recombinant human growth hormones for the treatment of growth hormone deficiency. Murphy raised to a higher level the notion of understanding your own business and management strategy when selecting a CMO.

“You need to pick a CDMO appropriate to your company philosophy,” he says. “Do you want a potential commercial process put in place right at Phase I, or are you just looking for a quick Phase I acceptable process? These are definitely different. It’s a conscious decision for your management team. Based on that you should select a CMO that aligns with that direction.”

Last and certainly not least on our panel is James Henshilwood, senior director, API process development and manufacturing for biotech InterMune, now a wholly owned subsidiary of Roche. InterMune is focused on therapies in pulmonology and orphan fibrotic diseases.

Henshilwood is a veteran of the industry since the 1980s and has seen a number of drugs make it from discovery to commercial. He touches on a topic often left out of discussions on provider-sponsor approaches — the provider’s pitch.

“Generally, it should be recognized there’s an opportunity cost for a CDMO to accept your business,” he says. “What are the chances of the molecule you’re working on actually making it to the next stage of the market? I’ve always gone into a CDMO understanding what phase of the project we are in, and with the attitude that I need to pitch my company, to explain why I think it’s wise for them to work with us.”

We can discern another axiom from all these comments: Know thyself (and thy project). It’s incumbent upon the biopharma to understand its own preferred course of advancement, methodology, goals, and overall strategy. And then go out to the outsourcing industry to find a good fit and learn more.

The OPW discussion brought into the open perhaps the biggest tension point between CDMO and project owner: the question of batch size.

TIME, PHASE … AND (BATCH) SIZE
“CMOs tell you their clients think the biggest waste of time is what can be an elaborate discussion during scale up regarding batch size,” is how one OPW participant phrased it. “The sponsor says, ‘You just made 10 grams, so now make this next one a 10-kilo batch.’”

If only scaling up chemistry or biology were so easy; in most cases it just is not. A small “demonstration batch” for a newly transferred project to show process robustness and control — as well as provide material — rarely becomes a strong enough jumping board to spring to a successful multikilo run at a CDMO (or anywhere). At this juncture, there are still risks and potential unknowns; even should a multikilo batch pass this (one) time, you may miss gathering crucial insight about how the process behaves, starting materials, and what might be the most appropriate equipment for production.

“We’ll say, ‘Maybe we should make a couple more batches in between,’” explains a representative of a CDMO. “But try discussing with a customer at this stage that we should only scale up to a one-kilo run. All the customer hears is we’re somehow trying to get more money to do more batches, and we’re wasting time. It’s really a back-and-forth, and from this side of the business, hard to negotiate.”

Moreover, should a larger scale-up encounter issues, who takes the blame and financial hit? That negotiation is even less pleasant.

On the other side, sponsors (big pharma and virtual biotech alike) may indeed have a well-developed, robust process born from thorough internal investigation (and investment of additional time and money). They naturally look askance upon the need – or logic – in additional “development work,” which is what these scale-ups can amount to. “If your internal folks are capable and competent,” says one of the experienced attendees, going back to the point above about in-house expertise, “wherever you’re transferring a process should be a reasonable fit in the first place because you made the appropriate selection of CDMO.

“To be clear,” he continues, “what you want out of this initial scale-up phase is confidence that the process is going to work in the CDMO’s hands. You don’t want some sideshow where the CDMO is telling you how this or that in-house technology is applicable to your project. You really don’t want your process drifting during a tech transfer. I’ve seen that happen, and it becomes an arm wrestling contest. You really want to avoid that. If you feel confident that what you’re bringing in is robust enough, and is a good enough fit, you’re going to question additional work or change.”

That’s quite an admonition of some CDMOs. Perhaps it’s not stretching a metaphor to say if the sponsor-provider relationship hasn’t “scaled up” to a point of mutual trust, there could be difficulties at this and potentially each new phase that comes along. Our experts say that to a degree it can be expected some further development will enhance a process, and that is a good thing. But more importantly, the appropriate technical counterparts should be talking and helping management map out a realistic strategy for getting to a higher degree of confidence on both sides that the scaling up will work and the best path to the ultimate endpoint is taken.

Before leaving this debate and going back briefly to the specific decision for batch size, sometimes bigger is better. This is particularly true heading toward Phases 2 and 3 when the need and the cost for cGMP material both rise. To flip our earlier bias for “smaller is better,” a best practice for sponsors is to allow the CDMO to make additional material when that opportunity makes sense.

For example, if a biotech requests a quote for three kilos, but that amount will fill up only half of the equipment train at the CDMO, it might reconsider. One of our panelists put it this way: “A better idea is to also ask for a quote for all the material to fill up the equipment train to its reasonable capacity.” Maximizing output can save money on running more batches in the future, and the cost differential for running large batches per se might be pleasantly surprising. That’s because most times the biggest contributor to the cost of goods is the labor or equipment time at the plant. Regarding the extra material itself, as somebody at OPW remarked, “Trust me, the additional material will get used. There’s always somebody chomping at the bit for material, so they will use it. It’s quite a benefit to suddenly have more material at relatively little extra cost.”

cGMP AND MORE DECISIONS
Our “batch-sized drama” above has provided a clear example of time-and-phase decisions in drug development. It is one of the most crucial elements for successful project progress for small molecule and perhaps even more for the burgeoning biologics industry. Of course, the wise know there are many more examples, including the timing for production of an initial cGMP batch. Unsuccessful cGMP batches are not only costly from a financial standpoint but also create a batch history for your drug that you’d rather not have documented.

As one participant at OPW said, “The cGMP profile of product development change is dramatic and important as we go from early preclinical GLP [Good Laboratory Practices] through all the phases.” Our four experts say this is an area where sponsors, particularly inexperienced companies, need that close relationship and advice with a CMO who has been through the process many times.

“Biotechs particularly should ensure they understand the fact that it is step-by-step going from research to full commercial,” advises our panel. “It’s key to know when to go from Phase 1 appropriate material to a Phase 2 to a Phase 3 registration. Having an internal understanding, but also with your CDMO advising you up front, is critical. If you haven’t got that, then you’ve got an enormous problem.”

At least one decision on the drug development continuum, then, seems straightforward: If you are utilizing outsourcing services, it’s always the “time and phase” to be actively engaged with your CDMO.