Process Development: Stuck In The Middle With You

By Louis Garguilo, Chief Editor, Outsourced Pharma

Not news to OutsourcedPharma.com readers is the relentless pressure to accelerate programs out of research and into development. I’m told it feels like a virtual overlapping of the two disciplines instead of a fluid handoff.

Development gets squeezed on the other end as well.

Despite the complexity of new drugs, therapies and technologies, process development chemists are asked to quick-step to clinical grade and then commercial-ready material.

For their part, CDMOs need to react to it all.    

“Actually, this has evolved over the years,” says Matthew Johnson, Executive Director, Process Development, who joined Astex Pharmaceuticals (US) three years ago after decades as a chemist at CDMOs.

“Some 20 years ago there was the initial push to get development teams involved in the discovery process to allow for a quicker manufacturing start time – with no red flags.”

Not as easy as it sounds, if in fact it sounds easy.

“Trying to bring too much process chemistry back to that stage with medicinal chemists is ineffective for generating a lot of  hit-to-lead compounds for testing,” Johnson says.

Start With Tox

Johnson believes the sweet spot for intersecting disciplines is during “lead development, where you're progressing through to the first tox batches – people can bring process chemistry expertise in.”

Tox batches are often the first time you are looking to develop a scalable manufacturing route. There’s still a balance to be managed – fast delivery of material is a priority, but smart process decisions at this stage can yield significant time savings later in development.

A key component to this is the amount of material needed for clinical trials.

Astex, for example, is focused on oncology, where often the volumes of required material are much smaller than other programs. “It’s quite a wide spectrum,” Johnson points out.

Along with volumes, answers to these questions form a development decision-tree:

• How much budget and time do we want to allot to development overall?
• What are the immediate and long-term goals?
• How much material is needed for scale-ups, trials, and should you go commercial?
• Is this process fit for purpose? Will it take us through the clinical development we need?
• Will we be able to make material reliably? Are we not necessarily trying to answer this completely at the moment, or worry now about the most efficient process?

With these questions answered to the degree possible, next is clearly conveying the answers to all your internal questions, and the mission-critical elements of your program, to your partner.

It’s also sound advice to solicit your CDMO’s feedback. They may have seen similar programs, and can help guide the development process.

Finally, here, Johnson says process development can carry different meanings with it.

“It can be looking to optimize or change the process in significant ways. Or concentrated on gaining enhanced process knowledge and a better understanding of how the process works and how it's controlled.

“I’d say process development continues through the validation batches, which is typically the endpoint, but then as part of continuous life-cycle management, we still continue to do some work optimizing yields, maybe look at further scale-up depending on quantity needs.”

Flowing Technologies

Johnson says the technology he’s been exposed to more now than in the past is engineering software for mixing/distillation modeling, related mostly to scale-up and process performance.  

“I've run into this over the past few years. At Asymchem, there was a lot more chemical engineering being added as I was leaving [in early 2020]. I’m aware of this today when considering our CDMO partners,” he says.

“It's something we push them on. There's an expectation they have knowledge and capabilities in chemical engineering technologies that are becoming more widespread, such as flow technologies.”

On that subject, Johnson has more to say without elicitation.

“Every CDMO likes to say they have and are doing flow,” he offers, “but I think it's one of those challenging times when it's still a niche area. There are only a few companies actually capable of doing flow very well.”

What that might mean from a developer’s point of view is that, unless it's absolutely necessary, continuous may not be a highly viable (or valuable) option.

“Flow [or continuous manufacturing] is something that can actually lock you into a supplier," says Johnson. "It can also narrow the pool of candidates for secondary supply.”

However, he does predict flow technology will continue to be rolled out, and improved. He understands the many professionals who believe it is in fact the way of the future.

“Some processes without flow technology would be difficult to scale up, so it is a real enabler in that way,” he says.

As people get more exposure to continuous manufacturing, “they’ll see flow in terms of nitration or highly exothermic processes that are difficult to operate from a safety perspective. They will look for CDMOs to help them.” (also see: Safety Led Lilly To Leadership In Continuous Manufacturing)

When that help is forthcoming, the feeling at biotechs will be, ‘Okay, that works really well. What can we apply it to next?’

“It’s one of those new technologies, like combinatorial chemistry for lead discovery 25 years ago,” Johnson says.

That didn't turn out quite the way people expected, but it was “the seed for the development of a lot of new beneficial techniques.”

He foresees a similar path with flow – it’ll never be appropriate for everything, but there are times it will significantly improve manufacturing efficiency, and in other cases enable chemistry which would be inaccessible without it.

Regarding another technology in the news – artificial intelligence and machine learning – Johnson has these final, although this time somewhat hesitant, comments.

“It's easy to see how AI can be used in discovery, with genetic sequencing, looking at various genes, all the data mining involved, crystal structure data, fragment-based screening, and so on. There's so much data and so much computing.

“That might be applied within process development. I'm sure somebody smarter than me will figure out a way.”