Expect the Unexpected in Early Development

INTRODUCTION

Dear Community,

I am just back from CPHI in Milan and reflecting on the conversations with innovators this year vs. past. The diversity of synthetic modalities and the technologies required to deliver those modalities is almost overwhelming. As a synthetic chemist, I am thrilled to see the expanding universe of modalities that rely on synthetic chemistry. We are seeing new modalities such as macrocyclic peptides, oligo-protein conjugates, radioligand-protein and peptide conjugates, polymeric delivery agents, etc. All this makes for exciting times to be in the business of synthetic process development.

One of the joys, but also challenges, of process chemistry is that you don’t get to choose the molecules, but instead get presented with a molecule that you know can be made but you need to figure out how to do that in a safe, scalable, controlled and practical manner. Each of these new modalities comes with a unique set of challenges that threaten to overwhelm the process chemist. At times like that, I reflect on an experience early in my career. My first project in industry was to come up with a process for the manufacture of a carbohydrate. I was really struggling to figure out how to work with this molecule, how to make the bonds I needed to in an efficient manner. When the department head asked me how the project was going, I bemoaned the fact that I did not have any carbohydrate chemistry experience. He looked at the molecule drawn on my hood and said don’t think about it as a carbohydrate, it is just another heterocycle. I think that experience holds an important lesson when facing these new modalities; don’t think of these modalities something foreign and unknown. Instead, fall back on the principles of good process development and apply them to the problem at hand.

At Cambrex, we certainly pride ourselves on dreaming up creative solutions for “unexpected” development challenges. In THE LEAD REACTION this month, our early development experts Cy Credille and TJ Harper discuss some unique challenges. Early-phase projects can be particularly challenging because so much about the process is unknown and new. It is critical to view these challenges through a phase-appropriate lens and to work closely and collaboratively with the client to determine the best way forward.

Until next time,

Matt Bio

THE LEAD REACTION

Expect the Unexpected in Early Development

What we’d tell you about drug development, if we weren’t afraid to hurt your feelings:

Working with a huge range of developers and therapies, Cambrex scientists know a thing or two about how to move a product toward the clinic. Perhaps more importantly, they know how programs fail.

In a recent webinar, Cambrex’s Cy Credille, Ph.D. (Associate Director – Process Chemistry) and TJ Harper (Director of Material Characterization & Operations) talk us through the most common technical and operational failures that can slow or even end programs.

Some problems are unsolvable. When Mother Nature says no, we have no choice but to listen. But even solvable problems can easily become program-ending if not handled promptly and effectively.

Cy and TJ do most of their work at the transition between preclinical and clinical trials. This is a high-pressure point in the pipeline, with critical funding milestones, changes in client stakeholders and the potential for new chemical and physical issues to crop up. Inevitably, most projects run into some difficulties during this period, but by mitigating small problems quickly, we can stop them from snowballing into large ones.

In the webinar, the dynamic duo takes us through a series of case studies showing how the team troubleshoots common (and not so common) problems – from unexpected impurities to finding a 15-inch “meatball” in the reaction vessel. Here are three to whet your appetite:

Case Study 1. Whack-a-mole chemistry

Problem 1: Initial medicinal chemistry route had issues with scalability, purity and chiral control.

Solution: We optimized chemistry to improve chiral control and improve scalability. Purity looked good at bench scale but…

Problem 2: Scale-up led to production of quinazolinone impurities. The desired product could be crystallized out, but the solvents required weren’t suitable for GMP.

Solution: Extensive screening of reaction conditions reduced impurities to a level where more suitable solvents could be used for crystallization.

Problem 3: GMP batches failed elemental impurity analysis for Lithium. This was traced back to changes made to solve earlier problems. A domino effect!

Solution: Emergency development to remove Lithium during form flip. The drug was then able to successfully proceed.

Case study 2: The mysterious case of the nitrosamine-eating formulation

Problem: When developing a nitrosamine method to test a formulated drug product, we were surprised to see an initial recovery of 25 percent. Where was the nitrosamine going?

Solution: First, we spiked each component of the drug separately. All achieved over 95% recovery, except for the tablet coating. It appeared that components of the tablet coating were consuming the nitrosamine – a previously unrecorded phenomenon. Studies are still ongoing to discover the exact mechanism and how this might affect other drugs using the same coating. For now, we needed to find a way to exclude the coating from testing.

After trying more than 20 different methods of varying complexity, the old adage of “keep it simple” proved true. By splitting the tablet and adding acetonitrile to dissolve the contents, the insoluble coating could be mechanically removed, and testing could proceed with a 90% recovery rate.

Case study 3: Let’s get physical

Problem 1: The early process relied on chromatography and spray drying, but was not suitable for large-scale production. We removed chromatography and developed a direct crystallization method without too much difficulty. However, as we scaled up, the substance took on the texture of marshmallow fluff with terrible drying properties.

Solution: We adjusted the crystallization process for faster precipitation, and added a high-shear impeller, to break up the crystals and cut through the fluff.

Problem 2: As the material moved into drug product development, the dissolution profile was a cause for concern, with agglomerates of up to 0.5 mm formed during crystallization

Solution: We added wet milling during the crystallization process and slowed precipitation rate for a more consistent particle size.

For more case studies (the “meatball!”), insights and hard truths drawn from Cy and TJ’s decades of experience, watch the webinar.

THE METHOD

Five Top IND-enabling Tips

We return to Cy Credille and TJ Harper for their top tips for managing chemical and physical challenges during that tricky transition from preclinical to clinical.

1. Expect the unexpected. Things can and often will go wrong in drug development. Whether it’s an unusual contaminant or a promising formulation morphing into marshmallow whip, accept that unexpected problems will arise and equip yourself with the space and expertise to handle them.
2. Do not skip the engineering batch. It’s much easier to fix a problem before you enter GMP.
3. Be prepared for physical problems. Early development tends to be heavily focused on chemistry, but physical properties are more likely to trip you up as you scale. Look beyond bond forming.
4. Be judicious and realistic in your risk assessments. Always adapt your risk assessment to the current stage of development.
5. Communicate with your external partners. Don’t treat them as simply an extra pair of hands; instead, lean on them for their expertise. They want to help you succeed.

Watch “Navigating the Unexpected: Creative Solutions for Early Pharmaceutical Development.”

THE CATALYST

What we are reading…

The September issue of Chemistry World has as its cover article “Honey Laundering: How do we know what’s in the jar is real?” The article focus on the complexity of analyzing honey and determining both its provenance and even whether it is honey at all, or adulterated with sugar syrups from other sources. I was surprised to learn how difficult it is to analyze honey and how complex this food is both in its composition but also in how it is obtained. My first reaction was to wonder what the stuff in the squeeze bottle in my pantry actually is? Am I actually consuming honey on my yogurt or is there a good dose of sugar from other sources in there? When I think about the challenge of understanding what is in a bottle of honey, I am struck by how little we know about the food we eat every day and at the same time how much we know about the drugs we thankfully rarely need.

As a synthetic chemist, I take for granted that I can know, to a high degree of accuracy, exactly what the composition of a reaction product is. I am used to routinely determining the exact structure of a molecule, measuring the metal contents to levels of parts per billion and identifying residual solvents to parts per million. However, as I noted in the intro to this newsletter, we are increasingly being challenged to develop drugs which are less a single thing and more a complex collection of similar molecules; ADCs come to mind. A bit disconcerting to think that this thing called honey, which I consume multiple times a week, is less characterizable than the most complex drug modalities.

THE SIDEBAR

Balancing speed and rigor to keep early-stage programs on track.

TJ Harper

Director of Material Characterization & Operations | Cambrex Longmont

Time is paramount, especially for INDs. Many companies are limited on funding and dependent on hitting tightly spaced milestones. Our true strength lies in our ability to diligently complete everything much faster.

Cy Credille

Process Research and Development Group Leader, Research Fellow | Cambrex Longmont

There are two critical rules as you advance through early-stage development. The first is ‘plan for setbacks.’ Things will always go wrong. The second is ‘don't take bad shortcuts.’ You will have to pay for it eventually.