Chugai Pharmaceutical’s strengths lie in its world-leading antibody drug discovery technologies and advanced small-molecule drug discovery research. The role of structural analysis is to thoroughly analyze the structure of mid-size molecule drug substances and related impurities and provide crucial scientific evidence for commercialization. This article examines the appeal and potential of conducting pharmaceutical research at Chugai Pharmaceutical from the perspectives of an expert who has been engaged in structural analysis for many years.

(Interviewee: Ofuji)

*Reproduced from Chugai Pharmaceutical’s official Talentbook page (https://www.talent-book.jp/chugai-pharm) Article details and employee positions are current as of July 2024.

Navigating the maze of chemistry. Structural analysis underpinning the efficacy and safety of pharmaceuticals

Ofuji belongs to the Analytical Development Department of the Pharmaceutical Technology Division. As an expert in structural analysis, he is involved in the elucidation of the molecular structure of candidate compounds and other substances.

‘Our role is to guarantee the chemical structure of promising compounds that have been synthesized by the Research Division so that applications for clinical trials as drug products and applications for approval to sell them as pharmaceuticals that can be adapted for clinical purposes can be filed.

We do not only conduct structural analysis on drug substances. We also analyze intermediates in the manufacturing process, such as molecules with partial structures of the drug substance generated during the pharmaceutical synthesis process, as well as the structures of the raw materials.

Given the nature of the chemical synthesis process, contamination of the drug substances with impurities is unavoidable. We also conduct structural analysis of these impurities to clarify their chemical characteristics.

Based on the analysis results, we provide scientific evidence for setting the tolerable limits of each impurity. This is another of our key duties.’

 

The role of structural analysis does not end at the development stage. It also fulfills a vital role in ensuring the quality and safety of pharmaceuticals when they are launched on the market.

 

‘When aiming to commercialize a promising candidate compound, we must file an application with the regulatory authorities. In that application process, a detailed description of the molecular structure is required as a key piece of information about the characteristics of that compound.

In terms of active substances, a vast array of data is required, including on their efficacy and safety, and similar information regarding impurities may also be required. Impurities, in particular, are often scrutinized from a safety perspective.’

 

Ofuji also analyzes mid-size molecules, which are the third pillar that Chugai Pharmaceutical is focusing its efforts on after small molecules and antibodies. While such analysis presents challenges that conventional methods struggle to address, Ofuji says that it also gives him many opportunities to stimulate his intellectual curiosity.

 

‘While the molecular weight of small molecules is generally up to around 500, in mid-size molecules it can reach to close to 1,500. In structural analysis, we use many diverse analysis methods to decipher the interaction between molecules, so when the molecular weight increases, the structural elements become more complex, increasing the degree of difficulty of the analysis.

Before work began on mid-size molecule peptides in earnest, we did not have enough knowledge in the area of their structural analysis. Today, verification of methods suitable for peptide analysis is under way, and I have sensed the rapid evolution of analysis technologies.

There are times when methods that have previously been seen as the standard no longer apply. In such cases, we start by considering why they do not work and identifying the underlying causes. The resulting expansion of the areas that we need to explore is helping to deepen our knowledge and skills as researchers.

Of course, not everything we try works, but the joy and sense of accomplishment we feel when we overcome a barrier are quite special. The chances of facing difficult situations have increased, but I do feel a great sense of reward in being able to work on challenging issues.’

The concept of patient-centricity provides the strength to overcome difficulties

Ofuji first encountered structural analysis as a university student while doing research in organic chemistry in the faculty of agriculture. After obtaining his doctorate, he joined a foreign-owned pharmaceuticals manufacturer in Japan, launching his career in the field of drug product analysis.

 

‘My job was to analyze and evaluate developed drug products at a facility that researches drug products for administration to patients. Specifically, I analyzed the dissolution of the active ingredients in oral solid drug products, as well as whether there any time-dependent degradation products were generated.

In my third year at that company, through an in-house program, I was seconded to the parent company for about nine months. At that time, that company was one of the world’s largest pharmaceutical manufacturers. Experiencing first-hand its advanced scientific approaches and overwhelming presence in the pharmaceutical industry became an invaluable foundation for my subsequent career.’

 

On his return to Japan, with the downsizing of the research facility where he had previously worked, Ofuji ventured into new territory, choosing Chugai Pharmaceutical. The reason behind that choice was his desire to broaden the range of his career as a researcher.

 

‘When I asked about the details at the interview, I learned that their expectations for me were not in small molecules but the research and development of antibodies. Chugai Pharmaceutical is one of Japan’s leading companies in the development of antibody drugs. Having specialized in small molecules until then, I felt that this challenge of antibody research was the perfect opportunity for me to build new experiences.’

 

Ofuji joined Chugai Pharmaceutical in 2006, and after working in overseas applications for antibody drugs and the development of analytical procedures, he was assigned to small molecules in his fifth year. He recalls an event that became the impetus for his growth as an expert in structural analysis.

 

‘I was involved in the early phases of development of a drug, and we needed to supply large volumes of the investigational product for the clinical trial stage. We were tasked with conducting tests for the shipment of those products, which was an important role for confirming their conformance with specifications. Amid various problems arising in the processes of manufacture and analysis, we needed to ship massive quantities of the investigational product in a short period of time. Supplying products that met stringent quality criteria while dealing with these problems was a task of immense difficulty.

That we were able to overcome this situation without incident was entirely thanks to the dedicated efforts of every team member. By working as a united force, ultimately, we were able to produce significant outcomes.’

 

What supported Ofuji at the times was the mission of “for the benefit of the patients.’ Underlying this was an experience that I have been unable to forget.

 

‘There were great expectations that the compound we were developing would offer innovative efficacy. It had undoubted potential to become an effective treatment option once it was on the market. I believe that this was the source of our team’s motivation.

In fact, because its efficacy in many patients had been confirmed in the clinical trials, it was our fervent wish that this drug be delivered into patients’ hands as soon as possible. It was our great joy to be able to help them to return to a normal life.

I believe that my own personal experience also gave a strong boost to that sentiment. My father died from cancer seven years ago, and while he was fighting the disease, he was helped by drugs made by Chugai Pharmaceutical.

Through this experience, I felt a greater, more earnest affinity with the patients and their families who were eagerly awaiting these drugs. That understanding has, I believe, helped me to continue with my work with passion and commitment until the very end.’

Innovation led by cooperation across barriers. A unique research environment and collaboration with Roche will be the impetus for next-generation drug discovery

Ofuji is now in his 19th year at Chugai Pharmaceutical. He describes the thrill of working in structural analysis in Chugai Pharmaceutical’s Analytical Development Department in the following terms.

 

‘The distinctive aspect of our research facilities is that researchers handling small molecules, mid-size molecules, and antibodies all co-exist in the same premises. Moreover, respective experts in drug substances and drug products that are important in the pharmaceutical development process are also working in the same location.

Because of this, I have opportunities to encounter a wide range of analysis targets, including small and mid-size molecule drug substances, antibody drug substances, small and mid-size molecule drug products, and antibody drug products.’

 

Ofuji says that there are actually many cases in which problems are solved by transcending the boundaries of specializations.

 

‘At many pharmaceutical companies, it is common for research of drug substances and drug products to be conducted at different locations, which may lead to a tendency for opportunities for technology exchange to be limited. At Chugai, on the other hand, we have interactions with experts in other fields on a daily basis.

Certainly, there are times when different areas require completely different approaches, but in analysis that identifies phenomena in isolated areas, it can be effective in some cases to use the same tools for antibody research and for small and mid-size molecule research. There have been numerous occasions when we have cooperated with the antibody research team, using our mutual knowledge and insights to solve issues.

In 2023, a new research laboratory, equipped with leading-edge equipment, was opened in Yokohama. My sense is that we have a highly stimulating and rewarding environment for researchers.’

 

Ofuji also points out that the open workplace environment here and the collaboration with Roche have had a favorable effect on his research activities.

 

‘In addition to being free and open, we have a culture that encourages new technological approaches.

The fact that Chugai Pharmaceutical is a member of the Roche Group is also highly attractive. The interaction and collaboration with Roche delivers immense added value to our research activities, including the opportunity to encounter cutting-edge information that only global pharmaceutical companies know about and innovative approaches that have the potential to become the global standards of the future.’

Aiming for even greater heights as an expert in structural analysis together with new colleagues

Ofuji has built his career as an expert in structural analysis. Even now, as a veteran with a wealth of experience, he continues to hone his expertise.

 

‘The most important aspect of structural analysis is to deliver the required information accurately. Without this, even the most sophisticated analysis will be meaningless. I am always mindful of the process of steadily accumulating reliable and sufficient data, obtaining validation through experiments.

Grasping the latest research trends is also essential. Research findings reported in academic papers and presentations at academic conferences contain information that is filled with insights. I make a point of collecting as many of these as I can and reflecting them in my own research.

I have also participated actively in activities outside the company. I am currently involved in a collaborative research project led by the National Institute of Health Sciences. The aims of this project, titled “Studies on new general tests in Japanese Pharmacopoeia for rational quality control of pharmaceuticals,” are the harmonization and evaluation of regulations on pharmaceuticals and other related products.

I am also an active member of other general incorporated academic societies. Through exchanges with corporate researchers at other companies who were not experts in structural analysis, I have had extremely meaningful and valuable opportunities to exchange information about the latest research trends in the industry and the issues being faced.

 

To continue growing as a member of the Analytical Development Department. Ofuji has a message for his future colleagues.

 

‘At Chugai Pharmaceutical, there are many employees who think for themselves and take action themselves. I believe that it is a workplace that is most suited to people who have initiative and drive and that those are the people who will produce great outcomes in this environment.

What is important is to hold your own convictions and an attitude of working with persistence to realize those convictions. We welcome people who have the will to follow the path that they believe in.’

 

Even with his wealth of experience as an expert in structural analysis, Ofuji’s inquisitive mind shows no signs of weakening. While passing on to those who come after him the knowledge and skills that he has cultivated to date, he will aim for even greater heights with his unwavering curiosity and passion.