Early-Phase Formulation Done Right: An Expert Analysis

By Louis Garguilo, Chief Editor, Outsourced Pharma

Dileep Boinipally has extensive experience in formulation, manufacturing process development, and regulatory strategy. He’s adept at explaining all that.

He’s worked on generic and novel drug formulations within education institutions (New Jersey Institute of Technology), at CDMOs (Tedor Pharma), and in Pharma (Boehringer Ingelheim, Upsher-smith, and EQRx). He’s been instrumental in advancing several drug candidates from development to commercialization throughout his career.

Boinipally currently works at Metsera, a clinical-stage biopharma with a pipeline of oral and injectable – and “potentially combinable” – therapeutic candidates, including GLP-1 RA drugs for obesity and related diseases, where he leads the oral formulation stratagems as Director, Drug Product Formulation.

I initially asked Boinipally to talk to us specifically about the ins-and-outs of the practice of early formulation development.

Formulation For The Long Term

“I've been in oral dosage development space for a long time,” he says. “So much has to do with what phase the drug candidate is in.”

Boinipally has ushered drug candidates from pre-IND to commercial manufacture, but his focus has been on the early-phase formulation development for first-in-human studies for the past few years.

“Considering CDMOs, I typically look closely for early-stage capabilities I need now, and then consider where I want to go with that long term,” he explains.

He determines whether he can stick with a CDMO as the asset moves from phase 1 to phase 2 and beyond. “Whether I want to stick with them beyond phase 1 supplies, I keep that outlook in the background,” he says.

Boinipally specifically investigates what kind of manufacturing capabilities and formulation expertise CDMOs have specific to his programs.

He asks questions such as, ‘Have they previously worked in oncology? On small molecules, large molecules, several areas of formulation (like modified release, improving solubility and/or bioavailability, traditional and complex solid dose manufacturing processes)?

“When it comes to developing drug product formulations with significant bioavailability challenges orally, I must be cautious in terms of who I would work. Much depends on the size and the risk of the asset. It’s extremely challenging to get to a phase 2,” he says.

Nonetheless, he does find a number of CDMOs to select from. “I usually stick to a smaller vendor to help me further understand the molecule itself early on,” he adds.

The task, he advises, is to determine exactly what works for you the sponsor, and how best to communicate that. “The sponsor’s scope and funding also need to be considered,” he adds.

“Flexibility” is also a word he uses often. We’ll go into what he means in detail in part two of our conversation.

The Run Down: Early Formulation

In quick summation, this is what you and the CDMO you select will need to be thinking about in early-formulation stages. (We’ll cover the actual CDMO selection process (as well as later-phase/commercial formulation strategy) subsequently.

With a drug product/substance for first-in-human use and to clear the IND, you generate certain toxicology safety data for that molecule itself, and with any novel excipients in the formulation.

You will select multiple preclinical species. Depending on the molecule, you could dose the pure drug, or you might need to formulate a product to dose it, either as a solid dose or liquid.

For example, with drug candidates that are sensitive and unstable in the GI tract, these get “chewed up and destroyed in the stomach.” That's why most peptides are injectables. In that situation, you need to consider a formulation for drug products for your animal studies.

On the other hand, for relatively stable molecules, you might dose API in a capsule to initially estimate the toxicology safety data. These doses are higher than those normally dosed in human clinical trials. “You analyze the readout and adverse effects, which you include as part of your nonclinical development package.”

However, says Boinipally, “as a member of our CMC team, a molecule could stay with me all the way to commercialization, so I prefer to start the drug product formulation work from the get-go.”

Boinipally stresses that all the above is discussed/planned out with your external formulator, and that discussion may influence the external partner you select initially.

From the start, says Boinipally, “the formulator would want to demonstrate they can control their proposed manufacturing processes, and clarify what attributes are being pursued.”

In oral solid dosage forms, “you look for performance, dissolution i.e. the release of the drug from the product, the assay, uniformity, impurities over time on stability.”

Depending on where globally you are sending your application, there are varying regulatory requirements for these attributes.

Boinipally offers the example for a CTA (Clinical Trial Application) in Canada, in which you need to demonstrate stability of drug product for an NOL (No objection letter) to conduct the trial, and a SMP (Study may proceed) in the case of an IND (Investigational New Drug Application) in the United States.

“You expose your material to different temperature and humidity levels, understand impurity levels growing from drug substance into a drug product, show that this preliminary product is not only safe when administered in your preclinical species, but also for later human administration,” he explains.

Additionally, you and your CDMO must demonstrate what you’ve developed is set to “a reasonable manufacturing process where you can control specific parameters, and you can show the impurities are reasonably in limits with ICH guidelines.”

Then it’s on to clinical batches, which need to be packaged, labeled depending on study design, such as blinded/unblinded, configurations with placebo/without placebo … and sent to the clinic.

“Once we get the readout from Phase 1/dose escalation trials, we'll understand where this formulation stands,” says Boinipally. “From there, working with our CDMO, we might want to improve or alter the dose or formulation strategy.”

“Typically,” he continues, “we’ll look at three or four different doses to understand the best output in terms of efficacy and adverse events. From there, we’ll further optimize the manufacturing process and the formulation.”

As you go to Phase 2A/B and Phase 3, you obviously need to be thinking about scaling up formulation and manufacturing processes.

That could mean a tech transfer of your smaller-scale formulation and process to larger scale equipment at a new CDMO, or if you selected a capable CDMO to begin with, transition from pilot into production scale.

Next we’ll go into both selecting CDMOs and progressing to later-stage formulation outsourcing.