Present And Future of Oncology: What Is Needed from API Suppliers? 

Oncology is one of the most important growth markets for the pharmaceuticals industry, partly because of the increasing prevalence of cancer in a world population that is growing and living longer. As some have remarked with grim humor, cancer and cardiovascular diseases are the two most common killers in the developed world “because we live long enough to get them.”  

However, they are also becoming increasingly common in the parts of the less developed world, where lifespans are lengthening the fastest. By some estimates, cancer drugs now account for 30% of the global pharma pipeline and 25% of industry revenues. 

Estimates of the size of the global oncology drugs market by market research companies vary considerably, depending in large part on definitions, but all agree that the market has massive growth potential for the foreseeable future.  

Rise of Niche Therapies 
Alongside the sheer size of the market, oncology therapeutics are seeing rapid advances in technology, enabling previously lethal cancers to be treated and treatment regimens to move away from brutal chemotherapy. There has been much excitement about new biologics such as monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), biospecifics, and cell and gene therapies such as CAR-T therapies, but most of the heavy lifting continues to be done by small molecules, most of them highly potent. In addition, a large proportion of the emerging therapies are precision medicines that are highly specific to subtypes of cancer that affect smaller subsets of the patient population. The blockbuster model, as in much of the pharmaceutical industry as a whole, is in retreat. 

For the Italian-based contract development and manufacturing organization (CDMO) Olon, which has been active in highly potent APIs (HPAPIs), including anti-cancer drugs and cytotoxics, for over half a century, the decline of the blockbuster model in oncology and the rise of niche therapies are combining to create opportunities and challenges at the same time. “We are observing two main trends,” says Roberta Pachera, Vice President of CDMO Small Molecules, at Olon. “The first is smaller volume demand—typically in the range of hundreds of kilos—because of the smaller target applications; the second is greater complexity in design, including more chemistry steps in the manufacture of molecules, which means higher value.”  

Challenge Of Complexity 
For Giorgio Bertolini, Senior Vice President of R&D at Olon, the complex chemical structures and long syntheses of the new compounds form both the main regulatory and the main technology challenge. Defining the registered starting materials (RSMs) is not easy. “The challenge is often to find the right balance between the complexity of the structure and the number of steps you can run under cGMP,” he says. “In some cases, you could be carrying out 10 steps in house from an already very complex starting material, so it is not easy to convince the regulatory authorities that it is the right RSM.” A broad range of technologies is needed to be able to develop and make them.  

“When there are 10, 15, or even 20 chemistry steps you also need to have a very good, sustainable supply chain to be able to source the RSMs,” he adds. “With many of the new chemical entities (NCEs), the starting materials are not available on the market, so we have also to develop some of these as a sort of sub-CDMO activity and be our own supplier. We need to provide to our customers a very broad and comprehensive approach, not only in terms of the technology that we have internally, but also technology that our qualified suppliers have to contribute the starting materials for these products.” 

Through its offices in India and China, Olon has developed in the last decades a network of suppliers so that it can develop the starting materials it needs, as well as acquiring all of the key capabilities necessary. “Customers are looking above all for technology, supply chain, quality, flexibility, sustainability, and reliability,” says Olon’s Bertolini. “Quality is a must, of course, and in that we are at the same level as our competitors but in terms of technology and flexibility I believe we can provide a better service than the others.” 

Rapid Movement Through Phases 
To address that requires a significant footprint—Olon itself has a global network of 11 sites—coupled with the flexibility and agility to move a compound around a plant in order to keep the manufacturing times very tight. In addition, a certain skillset is needed. “You need to have a critical mass in the R&D team and people who, when they are developing a project in Phase I, already have in mind what will be needed to support the customer in Phase III,” says Olon’s Bertolini. 

In the context of fast-moving projects, project-management skills are obvious to the fore but this needs to go more than just having a single contact person managing the whole project internally and coordinating all the activity between the sites; it involves multiple functions working together, including quality, operations, EHS, sourcing, and planning. “Our departments are working all together in synergy on projects. There are no silos; we are working together in a team. This is managed by a project manager, but it is not just any project manager that can guarantee the efficiency of the system,” says Olon’s Bertolini, who likens the project manager’s role to the conductor of an orchestra. 

The ‘one-stop shop’ is a well-worn cliché in the pharmaceuticals industry, but it is clearly relevant in oncology, where the pace of development is so fast. For Olon, Pachera says, this means being totally integrated so that the company can anticipate customers’ future needs from early on in the process. “Having the know-how within the same company is crucial. It means you don’t need to move around from one supplier to another to a third,” she says. “We can serve our clients from milligram-scale for preclinical and throughout Phases I, II and III,” she says. “This enables customers to discharge any risks related to toxicological studies quickly, as well as avoiding tech transfer.” 

What Is High Containment? 
Olon’s website cites ‘high containment’ as a key capability. The term varies in meaning from company to company, but to Olon, this essentially means occupational exposure levels (OELs) of <10 μg/m3. It can also go down as far as 0.1 μg/m3, and the company is now investing in a new plant, due to open next year, that will enable the company to reach levels of 10 ng/m3.  Further recent and planned investments include: new capabilities at the company’s site in Cleveland, Ohio, which mainly makes preclinical and Phase I-II volumes; a new line in Italy to make 20–50 kg batches of high-potency anti-cancer compounds; and a large-scale highly potent plant for 100-kg batches.  

Thanks to recent investments in its integrated manufacturing network, today Olon offers the capacity to develop and produce highly potent APIs, from very small to large scale, along the entire development chain. This is because Olon relies on all types of reactors regardless of required size, as well as its experience in managing high-containment production processes which is among the most extensive worldwide. 

The Company completed the new extremely high-containment production line with reactors that allow us to produce highly potent APIs in large-scale product batches ranging from 30 to 150 kg. This expansion enables us to serve the customer along all the stages of the scale up, in conjunction with our sites. 

Olon is building a new facility which will be entirely dedicated to managing and producing Ultra-Potent compounds, used for example as payloads and payload-linkers for antibody-drug conjugates. The ultra-high-containment production line will produce high-potency and toxic products and will therefore reach containment level OEB6 (target OEL 10 ng/m3). 

Today the Group is one of the few API suppliers to offer the range of specific integrated capabilities necessary to support the customer from the first clinical phase up to industrialization, regardless of the quantity of product needed and batch size required and regardless of the ongoing molecule development phase. From a few grams to hundreds of kilograms. 

The expertise in high-containment processes is evident from the equipment we have at our disposal, but even more so from the in-house know-how that we have developed in recent decades, among the most extensive in the global API manufacturing market. 

“The knowledge in this area goes back a long way: in the 1970s, our plants in Rodano and Settimo Torinese, Italy, were two of the first sites worldwide to operate in containment, for the production of the first cytotoxic anticancer products on the market,” says Olon’s Bertolini. “Since then, Olon has continued to invest in the corporate culture of high containment, and today it makes it available to its Partners.”  

As well as the ‘hardware,” such as gloveboxes and isolators, Bertolini stresses the need for the ‘software’: the human experience needed to handle HPAPIs correctly. “All of our people are trained in how to manage the starting material, how to make the products, how to take out a sample for analysis and so on,” he says. “A lot of companies now say, ‘We have high-potency capabilities’ or ‘We have put up a high-potency plant’, but this is not enough. You need experience, you need knowledge; you cannot just pick this up in a few years. You need a very long journey to build up that knowledge and Olon is one of the companies that has this kind of knowledge in this area.”