Having commercial-scale manufacturing in North America is driving business for many large CDMOs in the pharmaceutical sector; Manufacturing Chemist recently visited the first CPhI North America show to find out more
The key technology trends driving the API market cited by US CDMOs are familiar ones: high potency APIs (HPAIs), including controlled substances, and continuous manufacturing. Alcami’s most recent investment has been in HPAIs and it is just completing a $6 million build-out at its Germantown (Wisconsin, USA) API facility. The firm has dedicated two of the five GMP kilo labs to HPAIs and the target is to get to 30 ng containment, mainly through engineering controls and equipment.
Although the facility still makes tonnes of API, Millar said: “The growth and profitability is being driven by high potency. We are investing in infrastructure and technology and we have our own toxicologist on site, so when we get a process in we do a two-headed evaluation, looking at the final product but also a risk assessment for each step.”
In some cases, an intermediate is highly potent but not the final product, so Alcami will look at all the steps to see which are highest risk and which need containment. The company has also invested in infrastructure for controlled substances at the same site; it recently had its analytical registration approved by the DEA and expects its manufacturing licence to be approved shortly.
“So, yes, we have metric tonne capacity, but what we are really looking at is what our customers are going to keep in the US for manufacturing and that tends to be highly potent, controlled substances and complex chemistry,” Millar said. The first projects are due to start in September, once the ongoing investment is completed.
Millar added that Alcami is also looking at continuous flow chemistry, specifically hydrogenation. “We have capabilities in the field and it tends to be a rate-limiting aspect, so we would be interested in the right technology. We have started thinking about it and putting feelers out to equipment suppliers, customers and other CDMOs,” he said.
Haitz said that Cambrex is also seeing a lot of demand for HPAI capacity, particularly regarding oncology projects. Ultimately, he added, you need to prove you can control the chemistry and exposure. This factor is also driving the growing interest in continuous manufacturing, which is now going beyond investing in microreactors and tube reactors to the concept of moving from batch to continuous, reducing waste and improving speed.
“I don’t see the whole industry switching,” Haitz added. “There is no blanket approach to continuous manufacturing, but there are certain elements wherein it fits well. The future in my mind is batch when batch is best and continuous when continuous is best, rather than percentage targets.” Cambrex is also finding more and more customers asking for solid state capabilities, owing to the low bioavailability of modern drugs. Although it is not a drug product company, it can use its skills in API manufacturing to change to solid state properties at the crystallisation stage and sees this as a capability it would like to enhance.
JM is also not active in drug product but is looking at it because some customers want it. “We do have some preformulation capabilities and are developing some capabilities both internally and externally,” said Dilley. “Johnson Matthey is strongly committed to pharma; we see a lot of unmet needs there.”
The CDMO is on the path to becoming yet another pharma industry cliché, one that is often confused with the even hoarier clichés of the one-stop shop or end-to-end services. Yet, all clichés are based on truth. The drive for large suppliers to integrate services across a network or even a single site or network is undoubtedly real — and there are undoubted benefits in terms of time saving and risk reduction. The more important question is how far the trend has to go.
Alcami is one company that bridges the gap between drug substance and drug product, and currently has about ten end-to-end projects and expects more. However, Millar added that this is still a relatively small part of the overall portfolio and tends to be either/or when it comes to API and drug product. There is a fine balance between being excellent at too few things and being good enough at too many.
“We are trying to focus on small molecules on the API side, we don’t do fermentation or ADCs,” he said. “On the drug product side, we do oral solid and sterile injectable doses but have not gone into topicals or other formulations. We have wide expertise but it is not too broad-based. When they are needed, we know third parties we can work with.”
Berger of Catalent said that, despite the company’s ever-growing array of capabilities, he too is “not a big fan of the one-stop shop concept.” Cambrex’s Haitz was more emphatic still, saying that the way forward for the company is to retain its focus on small molecules while looking at adding enabling technologies as they emerge — rather than trying to be everywhere.
“The one-stop model is very popular at the boardroom level and very unpopular at the working level,” he said. “Our clients want to choose the best solution, so they may want to go with us to make a high-energy compound but to another formulation company for something else.”
The array of technologies is too vast for any company to come even close to having them all, Haitz added. “No one has the answer to everything or ever will. Even the apparent bonus of getting one invoice is illusory — the work takes years and no supplier will wait 3 years and send one invoice at the end. The model sounds good but when you look at it, it doesn’t really work. We want to be excellent at what we do and that will channel business to us, whether there is a one-stop model or not.”