Holodiag and Malvern Panalytical: Advancing pharmaceutical development through small molecule characterization

20	3	99%
years of collaboration	Malvern Panalytical products	time saved for configuration exchange

• Malvern Panalytical was the natural choice for Holodiag – providing superior quality and reliability
• The collaborative relationship, combined with Malvern Panalytical’s customizable products and services, enables Holodiag to adapt seamlessly to every customer’s unique needs
• Empyrean provides accuracy, consistency and precision for every project
• Mastersizer ensures consistent, reproducible data every time

When Pierric Marchand founded Holodiag in 2006, solid-state and crystal structure analysis was viewed by many pharmaceutical companies as little more than a box ticking exercise. Fast forward 20 years, and solid-state characterization of small molecules is now widely recognized as an essential component of drug manufacturing. 

Adopting leading technologies has been a focus for Pierric since the very early days of his CRO (contract research organization) – his first investment was a pioneering X-ray diffractometer from Malvern Panalytical. That marked the beginning of an ongoing relationship between the two companies that has seen Holodiag go from strength to strength. Today, Holodiag owns two Empyreans (Malvern Panalytical’s multi-purpose X-ray diffractometer), along with the company’s flagship particle size analyzer, the Mastersizer. In this case study, Pierric explores the factors driving Holodiag’s growth and the important role his collaboration with Malvern Panalytical has played.

X-ray powder diffraction with the Empyrean is one of the first steps we do when a sample comes into the lab. Without it we do not exist, we cannot work.”

Pierric Marchand, PhD — Founder and General Manager of Holodiag

Active Pharmaceutical Ingredients

Active pharmaceutical ingredients (APIs) are the cornerstone of biopharmaceutical products, responsible for delivering a drug’s therapeutic benefit to patients. 

Understanding the particle-level characteristics of small molecules is crucial for achieving optimal solubility, stability and bioavailability.

Yet, surprisingly, it wasn’t until the late 1990s that pharmaceutical companies paid much attention to solid state and crystallization.

Pierric Marchand, Founder and General Manager of Holodiag, recalls: “People knew it was necessary, but they didn’t really care about it. It took a few famous stories in the 1990s to really ignite this activity.”

These high-profile cases included an unexpected variation in the crystalline form of a drug that cost the manufacturer millions of dollars to resolve, and legal action over patent infringement of a crystal form. 

Pierric says: “It became increasingly clear that pharma couldn’t afford to overlook this area. Today it is strange not to include solid state and crystallization in services and development.”

The importance of future-proof technologies

While the quality and depth of Holodiag’s services have proved a winning formula, Pierric has always ensured that they are underpinned by market-leading technologies.

“Even starting out, I realized that buying the best equipment was important,” explains Pierric. “The first device I bought was an X’Pert Pro X-ray diffractometer from Malvern Panalytical. I was a student, so it was very expensive for me, but I wanted to go straight to the top.”

The X’Pert Pro provided Pierric with highly specific fingerprints of crystal forms – essential for identifying what he was dealing with and determining next steps. “Even today, X-ray powder diffraction is one of the first steps we do when a sample comes into the lab. Without it we do not exist, we cannot work.”

The X’Pert Pro was eventually replaced by two Malvern Panalytical Empyreans, the X’Pert Pro’s successor. One of these Empyreans supports Holodiag’s research and development services for customers, which comprise around 50% of the lab’s work. The second Empyrean supports their quality control and analytics services. Each offers several possible configuration options, but Pierric says it’s the transition mode they rely on daily: “The great thing about it is that it’s fully isolated, which allows us to safely handle highly potent compounds. It protects the user and the sample while offering very good accuracy and resolution.”  He adds: “You can see why the Empyrean is the equipment we use the most.”

Around 10 years ago, Pierric added a third Malvern Panalytical device to the lab, the Mastersizer, which uses laser diffraction to analyze particle size. This makes it a great option for development projects, as well as troubleshooting.

“We chose the Mastersizer because in the pharmaceutical industry, it’s really the gold standard, and it’s enabled us to save projects that looked like they were doomed,” says Pierric. 

He points to the case of a customer that sought the CRO’s help to address variation in the dissolution rate of their tablets. “We identified that every problem tablet came from the same API batch, but even though the main suspect for dissolution rate is always particle size, full characterization didn’t show any differences between the problem batch and a normal one,” he explains. The Mastersizer helped them pinpoint that the issue lay with the ultrasonication method used to prepare the problem batch. “We then worked on the crystallization process to yield smaller particles so that the customer could move on.”

We chose the Mastersizer because in the pharmaceutical industry, it’s really the gold standard, and it’s enabled us to save projects that looked like they were doomed"

Pierric Marchand — Holodiag

His passion for new technology has seen Pierric recently add another instrument to the lab – one that uses electrons instead of X-ray. “It enables us to access the full molecular structure of a crystal from a single particle of crystalline powder, as small as 15 nanometers. It means we don’t have to grow single crystals, which can be a painful process prone to failure. It’s a very powerful piece of equipment.”

The new device also provides “gold nugget” reference data that the Empyrean can use for method development and validation – something Pierric believes will become increasingly important. He explains: “Part of our job is to help customers respond to questions and deficiency letters from regulatory authorities, but these requests are growing ever more complex. This combination of equipment means Holodiag can not only provide regulators with the high-level data they need today, but we are also well prepared for whatever comes in the future.” 

Finding the right collaborative partner

For Pierric, the natural choice for X-ray diffractometers and particle size analyzers was Malvern Panalytical due to the fact its products have always stood apart. 

When he bought the X’Pert Pro from Malvern Panalytical, deciding factors included:

• Its ability to outperform competitors in key areas. “The two products on our final list were both good, but Malvern Panalytical’s was just better.”
• Malvern Panalytical’s willingness to help customize the configuration: “I had very specific requirements, but other companies could only offer what was in their catalogue. Malvern Panalytical was really open to working with me to meet my needs.”

When Pierric was ready to upgrade his X-ray diffractometer, he was immediately drawn to the Empyrean’s consistency and precision. “We need top technologies that are very reliable, so the Empyrean was a natural choice,” he explains. “The accuracy of the measurement allows us to distinguish solid solutions from other impurities – that’s very important for pharmaceutical development. In addition, with the Empyrean we can reach very low levels of detection, which helps us respond to those difficult regulatory questions.”

The Empyrean’s configuration options – and the speed with which they can be changed – was another major plus point. “It’s really easy to change the mode and that kind of flexibility is important. For example, one morning a customer called us to say ‘OK, there’s a sample in a taxi coming to your site and we need the report this afternoon’. We were able to deliver it on time.”

With the former generation of diffractometers, it took several days to change the configuration. With the Malvern Panalytical system, that process takes around 30 minutes, so we can even change it several times in one day!”

Pierric Marchand — Holodiag

With the Mastersizer, the decision-making process was even simpler. 

“More than 90% of the devices on the market are Mastersizers. Because my customers use Mastersizers, buying anything else would have been an issue – they want sample continuity... And the Mastersizer is a very robust and reliable tool.”

Another aspect that drew Pierric to Malvern Panalytical was the company’s collaborative approach. He recalls: “Right from the start, Malvern Panalytical was talking about partnering together.”

He adds: “Today we have a relationship based on trust and collaboration. As we say in French, it’s tu not vous. And we know we can rely on them when we need them – if there is an issue with the device, it will be fixed tomorrow, and that's very valuable for us.”

Holodiag’s relationship with Malvern Panalytical is a 20-year story. We are very happy with both the technologies and the support they provide to us."

Pierric Marchand — Holodiag

It’s a collaboration that Pierric expects to continue as Holodiag expands into new markets like the US and Japan following the CRO’s acquisition by Italian firm ICROM in 2024.

“We may add a third Empyrean in the future. And Malvern Panalytical has recently integrated with Micromeritics – a company with a range of devices we are interested in for a new development that involves surface measurements, porosity and density of powders. It would be very complementary with our existing services, so let’s see....”

Useful links

• Empyrean instrument
• Mastersizer instrument
• X-ray Diffraction