Late-Stage Formulation Is A Different Ballgame. Insights From An Allstar
By Louis Garguilo, Chief Editor, Outsourced Pharma
The art and science of late-stage/commercial formulation compared to early-phase formulation is a different ballgame, says Dileep Boinipally, Director, Drug Product Formulation at Metsera, a clinical-stage biopharma utilizing CDMOs to advance a pipeline of oral and injectable candidates, including GLP-1 RA drugs.
Boinipally earlier described what’s needed scientifically and operationally in that early stage, but as candidates move to later phase development, he says you’ll need a new playbook, and maybe new players.
“When it comes to CMC and drug product - critical quality attributes and target product profiles are areas the agencies scrutinize along with the safety data,” he says
As a drug-product developer, you’ll need to provide more insight into:
- how you arrived at what will become your commercial-level formulation
- changes you made based on the risk assessment of components in relation to the drug substance itself, and how each of those perform
- the defined role of each excipient in the formulation, and
- how you arrived at your specific (now) large-scale manufacturing process
A Formulator’s Journey
There are various manufacturing processes for drug products, especially in solid dosages, Boinipally says.
“You have traditional wet and dry granulations, direct compression, film/functional coatings, and cumbersome extrusion and spheronization, drug layering, spray drying, solid dispersions etc.
“It’s important to show how and why you selected your specific unit operations, how you control the critical quality attributes, typically the assay, the impurities, the dissolution, and then uniformity for every dose.”
Your message to the regulators should be:
“Yes, I understand the drug product performance, and its in-vivo behavior as we are increasing the number of subjects and obtaining further information – for example dosing in a single ascending dose versus multiple ascending dose placebo-controlled trials.”
This progression can be viewed as the formulation specialist’s journey.
Boinipally has progressed programs from animal studies to commercial drug in several instances. An example is the drug Aumolertinib, which works as a tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR), when he was at EQRx International (acquired by Revolution Medicines in 2023).
“That was on an MHRA application for the UK,” he explains. “We had to validate formulation and process, author the whole development journey, justify risks, explain CMC data in the submission’s quality module [Module 3].”
“But even after we submit," Boinipally adds, "I'm still involved. The agencies take about a year to 18 months for approval. You get questions periodically regarding your CMC section during this review period.”
An Example Of Internal Partnerships
As a formulation specialist, most likely you work with a core team from various disciplines, such as drug substance, drug product, analytical, quality, and project management.
Boinipally details a typical situation:
“Whenever I’m selecting a CDMO, most all of us go on an audit."
"It’s also a team effort to review and approve the documents for GMP activities, for example batch release of clinical material – and that’s where QA comes in place; there’s little QC until we go commercial.
"Mostly, though, it’s analytical development. Obviously, this is now a new drug substance. We need to figure out the analytical methods to test the drug product.
I’m in close discussions with analytical teams looking at a particular formulation. I have an idea about how it releases and why I designed the way I did.
Based on that, I provide prototypes for testing that analytical would usually use to start working on methods. These eventually need to be modified, qualified, and validated as formulation gets to a finished stage.
I talk to drug substance colleagues along the way. Physico-chemical attributes of drug substance is one of the important criteria for drug products, i.e., how stable is it, what's the particle size, how it flows and degrades, what are the sensitivities, does it have different polymorphs?
Understanding the molecule itself is important for me to understand what kind of manufacturing process I need to use. For example, if the drug degrades under humidity, under light, I might want to stay away from spraying water in aqueous granulations during drug product manufacturing.
I do all the stress studies to understand how to effectively move that into a drug product with the same stability at initial stage, and then study overall over time.
My interactions with project management are regarding schedules and appropriate milestones. But my technical interactions are with drug substance and analytical colleagues, and our counterparts at the CDMOs.”
CDMO Selection
Boinipally says CDMO selection often works out nicely.
If what he is working on does not require a specialized formulation-service organization, he’ll work with the CDMO his drug substance colleagues might be leaning towards, provided they have capabilities to manufacture drug product. “It keeps it simple,” he says.
Regarding supporting those important analytical services, he says, “I like to go with the CDMO’s internal capabilities if it’s a larger organization, for example a Thermo Fisher, Catalent or WuXi site.”
“It's easier to understand how various formulations behave in vitro quickly, and it is faster to react to analytical variations on drug product and/or manufacturing process, or variability in formulation iterations, if we are at the same service provider.”
Nonetheless, Boinipally will at times end up at one CDMO while the drug substance work is at another.
The main reason – what he considers utmost important in working with external formulations providers – is flexibility.
“When a CDMO team comes on board, you want to share information upfront. Both parties need to determine whether the molecule is suitable for their facility, depending on, for example, occupational exposure limits and material handling – EHS details.”
He advises discussing all their capabilities as you share in detail what you have in mind for formulation and drug properties. Also talk to your service provider about potential evolution of the relationship.
Don’t think: ‘I'm going to make five formulations, they cost this much, and I’ll be done with them.’
A better mindset is: ‘As we work together, we’ll interpret data and adjust, execute new experiments, we may want to widen the scope or conversely, go directly into manufacturing.’
“Especially for a smaller biotech in a competitive space,” says Boinipally, “that kind of flexibility – the ability to pivot, change scopes and timelines, quickly issue change orders that are fairly priced, are all vital elements.”
Did someone mention price? That’s where we’ll go in an upcoming editorial.