Designing More Sustainable Small Molecule API Manufacturing Processes

Designing More Sustainable Small Molecule API Manufacturing Processes

September 16, 2021PAO-09-21-CL-05

Sustainable synthetic routes to pharma intermediates and active pharmaceutical ingredients (APIs) that avoid hazardous materials and reaction conditions provide more robust and reliable manufacturing processes that help ensure the continued supply of critical pharma products. Fermion has the chemistry knowledge and experience to address these concerns from the outset. This approach is combined with fully automated, best-in-class facilities and advanced particle engineering, impurity control, and highly potent API (HPAPI) production capabilities to position Fermion as a one-stop shop for both API development and manufacture and formulation.

Financially Stable, Reliable CDMO with Comprehensive Capabilities and Specialized Expertise

Fermion Oy has been producing cGMP-compliant active pharmaceutical ingredients since 1970, when it was established as a 50:50 joint venture between Rikkihappo Oy (now Kemira Oy) and Orion. Today, generic APIs (approximately 25) and proprietary active ingredients for both Orion and external customers are produced at its facilities in Finland, which have been U.S. FDA inspected and approved since 1979.

A wholly owned subsidiary of a public pharmaceutical company founded in 1917, the financial strength of Fermion is assured. As a key supplier of APIs to Orion, we are committed to contract manufacturing and continually invest in state-of-the-art technologies. As a manufacturer of generics, we have gained extensive experience in the development and continual improvement of highly efficient processes, which allows us to provide our customers with high-quality products and services at very competitive prices.


Working in close partnership with Orion, Fermion offers end-to-end drug development, manufacturing, and formulation services. Since 2020, Fermion has marketed all of the contract manufacturing services of the Orion group, including both APIs and drug products. In addition to synthesis development and process engineering, analytical development and testing, scale-up, validation, and lab- to commercial-scale production services, we offer our customers fully automated, best-in-class facilities combined with advanced particle engineering, impurity control, and HPAPI production capabilities. Fermion offers drug product manufacturing for hormonal and non-hormonal semisolids, as well as oral solid dose.  We can handle HPAPIs for all dosage forms, as well as cytotoxic oral solids.

The safety of Fermion employees and our ultimate customers — the patients that depend on medicines made with active ingredients produced in our facilities — is of paramount importance. At our multipurpose facilities, the potential for contamination (mechanical, microbiological, or cross-contamination) is minimized through the use of strict, established standard protocols built into the procedures for all production and final handling operations. Sustainability is also a primary concern at Fermion, and we have made significant progress in the reduction of our environmental impact.

Dedicated life cycle management engineers provide a further value-added service — continuous improvements in cost efficiency and product quality. As a result, Fermion is ready to be a strategic partner with innovative pharmaceutical companies looking to leverage our advanced technologies and expertise to achieve both high quality and cost competitiveness.

To date, a total of 12 innovative APIs, including oncology products, have been commercialized worldwide (regulatory filings in the United States, Canada, the European Union, Japan, Taiwan, China, Brazil, and Australia) or are currently awaiting regulatory approval. As a strategic partner to innovative pharmaceutical companies, our focus is on providing cost-efficient, well-engineered synthesis, process development, and life cycle management solutions.

Avoiding Highly Hazardous Chemistry

Regardless of whether intermediates and APIs are highly potent, traditional synthetic routes for their production have often involved highly hazardous chemistry — highly toxic ingredients or by-products, large quantities of flammable solvents, highly reactive raw materials, and/or highly energetic processes.

Fermion is committed to avoiding these types of synthetic routes — and routes that pose potential environmental concerns — wherever possible. We take a comprehensive approach to route development that factors in potential environmental, health, and safety concerns from the outset. Our highly skilled chemists apply their knowledge, expertise, and years of experience in pharmaceutical development to the identification of efficient and sustainable processes.

As one example, a customer recently brought a process to us that involved an intermediate bearing a chloroacetyl substituent that generated a red flag in our simulations. Laboratory tests changing the reaction conditions showed that the less troubling traditional acetyl group would work in a similar fashion. In this manner, we avoided producing and handling a compound that was not desirable due to its possible mutagenicity and challenges for the impurity profile.

Leveraging Green Chemistry from the Start

Green chemistry principles have been applied at Fermion for over 20 years using a highly structured and standardized approach for all applicable projects. (It generally is not possible to make changes to late-stage and commercial processes). 

For projects in which the customer has provided an initial synthetic route, the route is first screened to identify opportunities to substitute less toxic chemicals (solvents, catalysts, reagents). If it is not possible to avoid some hazardous materials, because the chemistry will only work in certain solvents or with a certain catalyst, we seek to reduce the amounts of those materials required to generate the desired products in high yield and purity. Opportunities to recover and recycle materials are also explored.

Meeting Customer Supply Concerns

Sustainability and avoiding hazardous chemistry might not seem at first glance to have a significant impact on the supply of important pharmaceutical intermediates and APIs. Aggressive pursuit of sustainable synthetic routes can, however, play an important role in assuring the supply of these critical compounds.

A careful approach to process development that involves the application of green chemistry and sustainable approaches can ensure that processes are robust, reliable, and scalable and do not result in the generation of harmful (e.g., allergenic or mutagenic) impurities that can cause problems for operators and patients.

Therefore, in addition to meeting expectations for delivery time, cost, and quality, many drug developers are seeking contract development and manufacturing partners like Fermion that focus on developing green, sustainable processes. This trend is reflected in the increase in environmental, health and safety/sustainability audits that clients are performing in addition to traditional GMP audits.

Expanding Capacity for High-Volume HPAPIs

It can be particularly important to apply green chemistry principles when developing synthetic routes to highly potent intermediates and HPAPIs. Fermion has extensive experience in this area. The development and manufacturing of OEB class IV (1–10 µg/m3) and V (0.1–1 µg/m3 ) HPAPIs (cytotoxic and noncytotoxic) in quantities from grams to tens of metric tons proceeds in dedicated, state-of-the-art facilities.

Indeed, Fermion’s ability to perform highly potent manufacturing at relatively large scales is a differentiator for us. While most HPAPI manufacturers can produce OEB class V substances in at most 1,000- to 2,000-L reactors, Fermion has several 6,300-liter reactors designed for the safe production of highly potent, OEB 5 substances at our Hanko, Finland, facility.

That capacity will soon be increased notably with the addition of two 6.3-m3 reactors and infrastructure, which will be integrated with a filling and packaging line, all in a containment area appropriate for OEB 5 compounds — an investment of €10 million. With this capability, we will be able to produce HPAPIs that require batch sizes of several hundreds of kilos.


Supporting More Challenging NCEs

Growing numbers of drug candidates suffer from poor solubility and bioavailability; they are only highly efficacious when properly delivered in the body. In addition to the application of green chemistry principles during synthetic route development, particle engineering has therefore become increasingly important as a means for improving the performance of formulated small molecule drug products. 

At Fermion, effective particle engineering has been achieved by developing a thorough understanding of crystallization processes combined with implementation of full automation in production. Crystallization and particle engineering issues are considered at the very earliest stages of each project. The extensive crystallization knowhow and wide range of particle engineering technologies, combined with the use of detailed R&D studies and a variety of milling capabilities, allows Fermion to rapidly develop processes that not only provide high yields, but also highly desirable properties (e.g., stability, processability) and impurity control.

Micronization is an important particle engineering technique that Fermion is well versed in and already provides as a service to many of our customers. With demand for this type of service increasing due to the trend toward more challenging APIs, we are further expanding our micronization capabilities to ensure our continued ability to meet our customers’ needs going forward, extending our one-stop-shop position into the future.

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