Nixing Nitrosamines

INTRODUCTION

Dear Community,

Welcome to Issue 4 of Synthesis.

Last month, we shared a great interview with Cornell University’s Song Lin – catch up here, if you missed it.

This month, we turn inward to feature one of our own innovators in THE LEAD REACTION.

Unlike Professor Lin, Daniel Kirschner was a natural-born fisherman and not a natural-born chemist. Nevertheless, they both ended up sharing the same infectious love of chemistry.

Daniel now heads up our Durham, NC site, which boasts state-of-the-art instrumentation – or “eye candy,” as he calls it – and a fantastic team of experts to run it all. He’s incredibly proud of what they’ve built.

Amongst many other things, Daniel dips into nitrosamine analysis – a topic that has seen continued emphasis over the last couple of years, especially with regard to risk management. His advice: “Consider conducting nitrosamine risk assessments as soon as [you] start locking down [your] manufacturing to avoid delays down the line.”

It seemed fitting to stay with the nitrosamine theme for ANALYZE THIS, which summarizes a technical paper on risk management and analytical testing co-authored by Technical Director Erik Feldmann, Ph.D. Jump down to the bottom to meet him, too.

Until next time,
Matt Bio

THE LEAD REACTION

Falling for Chemistry – Hook, Line, and Sinker

Synthesis sits down with Daniel Kirschner, Vice President Analytical Services & General Manager at Durham, NC.

Where does your love of chemistry stem from?

Unlike quite a few people in this field, I wasn’t a “science nerd” as a kid; growing up in the rural Pacific NW, I was an avid outdoorsmen and happy fisherman. But I grew up in a mechanically-minded family that liked to create stuff, and I was always excited to learn new things – whether that was fishing, welding or changing the transmission in the old truck.

At college, I had no real desire to pursue chemistry (I had my sights set on a literature & a creative writing major). To be honest, I only took a general chemistry course at the onset to gain some quality study habits, but I was fortunate to be taught by an inspiring professor who really sparked my interest. Despite my initial lack of aptitude, I worked hard and learned a great deal in a short period of time – and chemistry started to come easy to me. All the while, my professor passionately introduced more complex topics and areas of specialism that brought the topic to life, further motivating me. I took an advanced course the following semester, and I was hooked.

Many years on, and I’m still hooked. I love chemistry, and I love solving complex puzzles. (And I’m still a happy fisherman.)

You recently stepped up to General Manager at the Durham site. Can you tell us about your journey into that role?

When I joined the Durham site 10 years ago, it was a relatively small group of a dozen or so analytical chemists. Since then, I’ve helped grow and design the analytical chemistry business, taking on increasing responsibilities as we evolved and expanded our client reach. We’ve had many ‘firsts’ at the site, where we take on and solve a new scientific challenge, and then build a business around it. Over the years, the whole site has gravitated towards the analytical space. You can feel the excitement in the air here for what we’ve created and continue to build.

Though my current role remains technical in nature, I now have additional bandwidth to initiate new projects and rapidly implement changes across the site to support both current and future client needs. I’m very much focused on growing our business the right way.

You previously worked in small biotech and big pharma. How does that experience and insight feed your approach?

To move programs forward at those companies, I worked with several CDMOs that, candidly, did not always meet my high expectations. I guess I would have been considered a tough client! But in reality, I simply knew what I wanted, and I wasn’t afraid of holding partners to account.

So, first and foremost, I aim to exceed my own high expectations! Put another way, I know what clients in the pharma space want, and I focus on delivering a wide-ranging capability that matches their needs and ambitions. This has allowed the analytical business lines to consistently grow every year. I’m always asking myself tough questions: “Why would I bring my business to Cambrex? Why would I trust Cambrex with my programs?”

Where does Durham sit within the wider Cambrex ecosystem?

As a premier API manufacturer, I suppose it’s natural that Cambrex has developed analytical expertise to match. At Durham in particular, we are able to focus almost solely on analytical and (associated) chemical development services, which allows us to provide our standalone clients and the wider Cambrex network not only with advanced and dedicated capability but also robust commercial-phase QC testing to match, as and when needed. For example, if a client at a sister site requires more rapid onboarding of an analytical program to meet critical Phase III timelines, we are on hand, aligned to the goal, and can provide the speed and quality to ensure success. We routinely support release and stability testing for several Cambrex sites and have built a robust strategic reference standard management business supporting many clients in late phase and commercial.

As the Cambrex Analytical Services Center of Excellence, we are at the vanguard of analytical technology and business innovations, investing in new but proven solutions that help us build new capabilities for our clients.

When it comes to analytical technology, how do you keep a finger on the pulse?

We collaborate closely with several hardware and software vendors in the analytical instrumentation space, who regularly give us updates on the latest, greatest technology. We even have vendors in chromatography who are quite familiar with our robust column screening platform and often send us their latest columns so we ‘try it out’ in our method development workflows.

In specific application areas – nitrosamine analysis being a great example – we strive to continually innovate, which means digging into relevant literature for new approaches and platform methods that could be modified and adopted.

My group in analytical and chemical development also gathers for biweekly technical meetings that feature presentations from team members on new topics and exciting progress on client programs. This activity keeps us all informed while encouraging scientific communication more broadly.

Analytical Quality by Design (AQbD) is an ever-evolving topic for us, and we’re always on the lookout for solutions that can support our ambitious goals in this area. Over the next few years, I think we’ll see a continuing conversation on the role of artificial intelligence/machine learning in this space.

You mentioned nitrosamine analysis. What does the 2024 finalized guidance mean for Cambrex and your clients?

The FDA requires a risk assessment of both drug substance and drug product, and that’s where a lot of the initial focus has been for pharmaceutical companies. And it’s certainly something we can help with. Interestingly, we’ve found that around a third of clients with a medium risk for standard nitrosamines or nitrosamine drug substance-related impurities (NDSRIs) ultimately require some routine testing in commercial. Notably, the FDA has set very stringent requirements for nitrosamine levels. At Cambrex, we’ve witnessed firsthand the pressure faced by clients who have found themselves behind the eight ball, with us needing to react rapidly to analytical method development, validation and testing requests. I would gently encourage pharma companies to consider conducting nitrosamine risk assessments as soon as they start locking down their manufacturing routes to avoid delays down the line.

What gets you up in the morning?

I get excited by the prospect of meeting clients, especially when I have the opportunity to walk them through our facility to showcase what we’ve built here (people and capability). I have to constantly clock-watch to avoid getting too deep into the tech, which is probably because I still can’t quite believe all the analytical eye candy myself! I joke with my team that I’ll retire from management someday so I can be on the bench in these labs.

On a related note, capital projects typically kick off in early spring. It’s always super fun to discuss how we will invest in our labs to build out additional capability. We’re constantly trying to push the status quo in our space.

Is there one project that stands out in your mind as a real win?

The first project that comes to mind actually started with a lost bid for a contract. The client required redevelopment of an analytical method for a complex separation in late phase that demanded a ternary gradient and mobile phase additives, among other challenges. We had the skills, expertise and experience, and put forward a compelling proposal. When we lost the bid, we thought, “Well, shoot. That would have been a good opportunity.”

Four months later, the client returned to our proposal, having failed with their initial partner. We were able to completely redevelop the method using our platform approach for column screening. We ended up validating the method. And then the client brought their entire CMC program on site for us to provide analytical testing for drug substance and drug product. Two years on, and they successfully filed and the drug is now a commercial product saving lives. This particular project is not only memorable but also a testament to my belief that we’ve built something that you won’t find at most CDMOs.

In fewer than 10 words, how would you describe your team at Durham?

A highly agile, client-centric team able to tackle tough challenges at any development stage. Sorry, that’s 14 words.

ANALYZE THIS

Navigating nitrosamines with a well-travelled team

The presence and risks of nitrosamines in processed meats and tobacco products have been known for many decades. But the real wake-up call for the pharma industry came in 2018 with the first drug recall. Ever since, regulators have been updating guidance to help the pharma industry tackle this complex chemical challenge. The FDA’s 2024 guidance cemented robust risk assessment expectations and set ppb limits for analysis – with neither being entirely straightforward to achieve.

In terms of risk assessment, the list of potential nitrosamine sources is long (even common excipients may contain nitrosamines or reactive nitrites at trace levels). Moreover, nitrosamines may also form via drug product formulation interactions with packaging components.

In terms of testing, the low-level limits set by the FDA for individual and total nitrosamine analytes demand not only specialized analytical instrumentation but also experienced analytical scientists.

Erik Feldmann and talented colleagues helpfully penned a technical article that includes a deeper dive into potential sources of contamination, explanations of Nitrosamine Scoring Systems, and smart approaches to analytical method development and validation.

For insight from a different brand of experts, read the technical article here…

…or watch this related webinar.

THE CATALYST

What Daniel is reading

We are constantly looking for new and innovative ways to solve analytical challenges. A few months ago, I was hunting within the patent literature for innovations in universal detectors for chromatography – one of my favorite topics. Universal detectors offer chemists tools to tackle quantitative analysis across wider ranges of analytes, many of which may lack UV-absorbing chromophores. Charged aerosol detection (CAD) is arguably the most advanced approach in this space. It has seen significant commercialization in pharma QC laboratories thanks to its sensitivity, broad linear range and near universal detection. CAD also overcomes many of the limitations of evaporative light scattering detection (ELSD) and refractive index detection (RID). But it is not without its own drawbacks; notably, like many nebulization-based techniques, CAD is a destructive detector, and coupling it with mass spectrometry for information-rich identification is not straightforward.

Therefore, I was very interested to see a patent by Waters Corporation (https://patents.justia.com/patent/20240345037) with claims towards a non-destructive CAD. Of course, only time will tell if this advancement can be realized as a commercial instrument, but it has the potential to open up new exciting areas for accurate quantitative analysis. Coupling universal detectors directly to information-rich detectors (such as mass spectrometry) would streamline accurate quantitative profiling of pharmaceutical impurities across a diverse range of compounds, particularly in early clinical development impurity and forced degradation screening.

In short, a non-destructive CAD would turn some of the most advanced mass spectrometry LC instruments into universal quantitative powerhouses!

THE SIDEBAR

Precision through teamwork and technology

When it comes to analytical methods, you need to achieve high-quality standards while remaining efficient. To hit those goals, you need: 1) a dedicated team of talented scientists, and 2) a very well-equipped laboratory. I’m delighted to say we have both!