From The Editor | May 9, 2019

Didn't Get The Memo On High Potency And Analytical Services?


By Louis Garguilo, Chief Editor, Outsourced Pharma

Memo on tablet

Didn’t you get the memo? Actually, the series of memos: Biopharma customers need more HP and analytical support. These two services continue to pop up as limiting factors for drug development and manufacturing outsourcing programs.

Now another of these memos has been written, by Doug Bakan, Arena Pharmaceuticals’ Executive Vice President, Technical Operations. Part one starts like this:

“The industry perception regarding the criticality and shortage of analytical services at CDMOs is an accurate assessment of what we experience. I will tell you with every project we’ve done since I’ve been at Arena, a limiting factor has been analytical, or at least that’s always the pinch point.”

Buying or “Borrowing” Support

Bakan describes a situation where one of Arena’s small-molecule programs had a particularly challenging analytical path to travel.

“When we were trying to develop a cleaning verification method, the number of resources it took the CMO to accomplish this was incredible. To their credit, they actually did reallocate some resources and were able to successfully develop and verify a process for us.”

However, even with the good can come another side.

“But I know,” says Bakan softly, “when they put additional resources on our project, they were likely stolen from someone else’s project. I felt badly about that. I said, ‘But what can we do? We can’t continue with the project until we get this cleaning verification done.’”

I ask Bakan to answer his own question for me: What can either the sponsor or service provider do when analytical is stretched at the CDMO?

“One thing I do on a regular basis is try to proactively remove the hurdles these CMOs might have standing in our way. I tell them all the time, ‘Look, if you need me to hire you an analyst – or two or three – part time or full time, for me it’s money well spent.’

“I need to ensure we have dedicated resources to complete the activities we need to get done. I agree with what Outsourced Pharma has been reporting – analytical is the one area where CDMOs always seem short on people. But the parties have to realize that every “simple method” you think you’ve already got well qualified, and should be a slam-dunk validation, can run into challenges, taking up extra time and money, and before you know it, the resources you thought would be adequate are suddenly inadequate.”

Frankly, after so many years of documenting – and experiencing firsthand when working in the industry – this same narrative, I have to ask Bakan again why the analytical roadblocks are still there.

“It’s a question we always ask ourselves as well,” he replies. “But the only solution I have at this time comes in the form of that question I proactively ask the CDMOs: ‘How can we help?’”

For Arena – and we can assume most drug sponsors today – that “proactivity” starts at the job interview. Bakan says when members of his Tech Ops team (for details on the team, see part one) interview potential CDMOs, the assessment of the analytical group and its capabilities is “really high on our priority list.”

He suggests thinking about the situation in these terms:

“If you make a batch of drug substance, there’s basically one campaign, and you have drug substance; the same for drug product. But for both of these, you could have anywhere from three to over a dozen methods that have to be performed each time you test that substance or product.

“There’s that amplification factor. For every given drug product or every batch, you’ve got 8 or 10 times the amount of assays to fulfill the testing for release or stability. And all you need is to have one method with a little hiccup somewhere, or the CDMO say, ‘Gee, my column needs to be replaced,’ and the CDMO throws in week-long delays like there’s no tomorrow. So this has to be an area our scientists keep an extremely close tab on.”

HP Services Evaporate Upon Further Inspection

Regarding high potency needs, Bakan starts with this: “We had an interesting, particular challenge in drug substance and product. The sixty medicinal chemists developing our compounds early on at Arena were so good that nearly all our lead compounds are highly potent. Unfortunately, the number of CDMOs who can handle HP drug substance or drug product is limited.”

Bakan estimates that within this outsourcing space – and to be clear, Arena’s compounds are highly potent but not cytotoxic in nature – there are perhaps a hundred CMOs that might be able to manufacture drug substance or drug product for Arena … or for any other biopharma for that matter.

Then there’s probably only six or seven among those that can “actually effectively handle high-potent compounds in a way that is satisfactory to us,” he says. “You visit them to ask: ‘Are you sure you can handle this compound like you say you can?’ We’ve found the honest answer to that question cuts prospective partners in half again.”

The hyper-selectivity employed by Bakan’s Tech Ops team is also because they want to “neither endanger the employees at the CMO, nor end up with drug product that may expose patients, other family members, or caregivers to the drug before the patient actually ingests the dose.”

But once again, we need the interjecting question: Why is this the case – particularly after many years of HP compounds coming down the pipelines and being commercially approved? Isn’t the situation improving?

“I’m going to say yes and no,” says Bakan. “Yes, because I think people in the industry are in fact recognizing the need out there. A lot of these companies we have spoken with are now making significant investments in both containment engineering solutions as well as training and personal protective equipment. They recognize a lot of the newer compounds in development are quite selective in their targeting, and therefore much more potent.”

“But no, because we’re seeing there are still very few CDMOs who can actually provide these services. And many of those are booked to the hilt. The problem this presents is if you don’t plan accordingly and months in advance, some of these lead times to get into their queue are exorbitant. We had one company with a 19-month wait list to be able to get into their drug-product manufacturing site.

“Then once in the queue, God forbid something goes wrong in your campaign. They’ll either extend your time in the plant at the expense of another client’s timelines, or they’ll abort your campaign and throw you forward five, six … eight months before you get back in the queue again.

“So my final comment is the industry recognizes the need, but we’re not there in terms of having adequate capacity to meet the demand for all the HP work to be done.”

And when you combine the HP needs with the analytical hurdles, Arena and so many other biopharma sponsors are still searching for solutions.

Is anybody reading the memos?