March 19, 2020 PAP-Q1-20-CL-008
Albemarle FCS manufactures high-quality APIs for a range of custom and generic products at the South Haven, Michigan site. Our success in production is a result of our robust R&D, analytical services, engineering, quality, and operations teams. These capabilities are further bolstered by the integration of operations between our cGMP manufacturing facility in South Haven, which produces APIs, and our ISO fine chemical facility in Tyrone, Pennsylvania, which is able to produce regulatory starting materials (RSMs) incorporated in the manufacture of our APIs. This integration simplifies the supply chain and provides an unparalleled level of transparency into starting materials, which gives us the ability to secure the logistics and identify and control impurities earlier in the API manufacturing process. This collaboration also allows us to implement process optimizations that will improve the quality of the API. The teams at the South Haven and Tyrone sites work together to identify process opportunities, set production schedules and address logistical issues — these benefits are all available to our sponsor companies.
The South Haven facility has a fully GMP kilo lab for the manufacture of preclinical, toxicology, and phases I and II clinical material, as well as commercial manufacturing of small-volume orphan drugs. The kilo lab suite is equipped with 25–100 L glass vessels, Nutsche and Aurora isolation equipment, which are well suited for isolations in the 1–5 kg range.
Additionally, South Haven features a pilot plant equipped with a range of glass-lined steel and stainless steel vessels with volumes ranging from 50 to 500 gallons, each essentially a scaled-down version of the commercial-scale equipment in our main plant. The pilot plant isolation equipment includes a basket centrifuge, tray dryer, 1 m2 Hastelloy-C Nutsche filter drier, and a 0.5 m2 Hastelloy-C Nutsche filter dryer that is equipped with high containment, glove-box enclosed unloading capabilities. Seamless scale-up from the pilot plant to the main plant is further facilitated by mixing and heat transfer elements that mimic the process at larger scales and by implementing the same utilities in both the pilot and large-scale production plants.
The Tyrone pilot plant utilizes reconfigurable process equipment that can be reoriented quickly to suit individual processes. This pilot plant is typically configured with 3–5 process vessels, depending on current needs. A representative configuration would include one or two 100-gallon glass-lined steel reactors, a 50-gallon Hastelloy-C-276 reactor, and various support tanks, equipped with agitators and overhead condensers and capable of operating at temperatures from –10 °C to 150 °C. The pilot plant also has a 0.35 m2 Hastelloy-C-276 agitated Nutsche filter dryer, which mimics the 5 m2 Hastelloy-C filter dryers in the production facilities.
The kilo, pilot plant, and production facilities at the South Haven GMP API site are all within the same building, so physical transfer is as simple as a short walk across the aisleway or down the hall.
The operators and engineers involved in each of the units cooperate closely and share information. At the South Haven facility, pilot plant operators often assist plant operators and provide coaching support during the initial scale-up of runs in the plant. At our Tyrone site, both operators and technical teams work in full scale production units and the pilot plant. Because operators are cross-trained to work in both areas, they have intimate knowledge of the needs of commercial-scale processes when involved in pilot-scale work.
Accelerated development projects also require flexibility, which is facilitated by the configurability of our kilo labs and pilot plants. At our Tyrone facility, we can rapidly reconfigure the pilot plant and change operating conditions to meet specific
customer needs and ensure full compliance. We also have the resources and organizational agility to acquire additional assets to meet specific customer needs.
For pharma customers, the close working relationship between the two facilities has resulted in a greater understanding of GMP requirements at the Tyrone site, even though it is not a GMP facility. For products that are produced at Tyrone for South Haven, we have implemented a new, higher-level MOC system that includes communication between the two facilities.
As a U.S.-based company with a proven track record of scaling up for foreign and domestic clients, Albemarle FCS provides the highest standards of quality while remaining maximally accessible to our customers, which helps assure peace of mind. Customers appreciate that they can freely and easily visit the site, meet the technical team, be present for start-up and production activities, and return for multiple visits or audits. Frequent face-to-face interaction coupled with regular conferences with the entire technical team ensures better communication and alignment than might be possible when working with a CDMO in Asia, where more than a single visit may not be practical. This physical proximity of our sites to those of our customers — in addition to simple but important factors like sharing the same or proximal time zones and the lack of a language barrier — make communication at every stage of a program simpler. This is particularly critical during technology transfer or troubleshooting and solving any challenges that may arise over the life cycle.
The actual path a project takes depends on the specific needs of the process involved. Highly developed processes that have been run at scale elsewhere may go straight to large-scale production. Nascent projects that require extensive process development work begin in the kilo lab and move through the pilot plant to production. Some projects may only involve process development work and are tackled in the kilo lab exclusively.
In other cases, such as for early-phase APIs or low-volume orphan drugs, the GMP pilot plant at South Haven is used to manufacture new chemical entities (NCEs) for the formulation of clinical trial materials or commercial products, respectively. The kilo lab is often used to produce materials for toxicological and other preclinical studies. The processes developed for these applications often transfer directly to the pilot plant for the production of large clinical trial quantities. The range of reactor volumes in the kilo lab and the pilot plant allows Albemarle FCS to respond quickly to customer needs when trial situations change. In many cases, a particular compound may require increased batch sizes to accommodate increased dosage in trials or when additional trials are launched. The ability to quickly scale-up and effectively mitigate risk is extremely valuable to our sponsors.
We always seek phase-appropriate solutions throughout a program, with a quality and technical team assigned at every scale for every project. These teams include chemists experienced in scaling up from bench through kilo scale and on to commercial validation who are prepared to tackle any pitfalls that may arise from early development through commercial production, and can make the most of small-scale manufacturing.
We have implemented GMP protocols in our South Haven GMP and pilot facilities that are identical to those in the production plant, enabling rapid tech transfer. Risks associated with process scale-up and new process implementation is evaluated by performing a formal Process Risk Assessment following a FMEA protocol. As a result, we are well-positioned to support accelerated projects as they move from preclinical to early- and later-phase development stages.
Mitch Kenyon is a Senior R&D Chemical Engineer at Albemarle Corporation with over ten years of experience in GMP scale-up and process safety. Currently, he functions as site reactive hazard evaluator for all products and serves as the final reviewer of all relief calculations needed on site. Mitch received a BS in chemical engineering from Calvin College.