As active pharmaceutical ingredient (API) complexity has increased, so too has the raw material supply chain. Drug manufacturers must ensure that these materials meet strict regulatory guidelines regarding impurity levels, that their quality is well documented to mitigate risk and that they can be traced throughout the supply chain. An integrated supply chain with transparency among sponsors and suppliers ensures that regulatory starting materials (RSMs) are well characterized and free of impurities that can impact the final drug product.
Integrated Manufacturing of RSMs and APIs
Albemarle Fine Chemistry Services (FCS) is a manufacturer of APIs for a range of custom and generic products. We produce high-quality APIs that meet and surpass the updated regulations regarding impurities — including heavy metals and genotoxic compounds. Our success in production is a result of our robust R&D, analytical services, engineering and quality teams. These capabilities are further bolstered by the integration of operations between our cGMP manufacturing facility that produces APIs and our ISO fine chemical facility, which produces many of the 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 identify and control impurities earlier in the API manufacturing process, as well as collaboration for implementing potential process optimizations that will impact the quality of the API.
Albemarle’s site in South Haven, Michigan, is FDA-registered and implements cGMP in the production of more than 40 products — from custom APIs and advanced intermediates to a family of generics. Albemarle’s facility in Tyrone, Pennsylvania performs custom manufacturing and routinely handles highly hazardous materials, such as chlorine, anhydrous ammonia, thionyl chloride, N-butyl lithium and others. Tyrone supplies RSMs ranging from small pilot (10 kg) to commercial (100 metric tons) quantities.
The teams at the South Haven and Tyrone sites collaborate and communicate to identify opportunities for improvement, set production schedules and address logistical issues. Albemarle’s project sponsors benefit from this integration, particularly as it relates to identifying impurities, method development, process development, scale-up, regulatory compliance and speed to market.
The integration of the Tyrone and South Haven operations makes Albemarle FCS one of the most capable and flexible broad-based chemistry operations in North America, which is essential as materials and compounds become more complex. As the chemistries required to synthesize these compounds become more advanced, there is a corresponding increase in the stringency of requirements to identify, characterize and control residual impurities. Albemarle’s integrated supply chain excels in addressing this ever-increasing standard in the APIs we manufacture for our customers. This is possible because we understand our capabilities and chemistries at both facilities and are well positioned to choose the most effective and efficient actions to reduce impurities and run our processes in control.
Core strengths of Albemarle FCS include analytical and R&D capabilities at both sites that allow us to perform development work in collaboration with our customers. We are continually working to develop and refine analytical methods to identify impurities with increasing stringency and to determine the optimal upstream and/or downstream process modifications to control, minimize or eliminate them. The quality of incoming RSMs from the Tyrone site are tightly controlled through the predetermined acceptance criteria; any deviation from those criteria can be quickly addressed because of the integration between the two sites. In addition, when a deeper investigation is required, the two sites can work closely together to determine the root cause and implement the appropriate corrective actions.
Regulatory agencies expect manufacturers to have a comprehensive understanding of the process used to produce the RSMs they use to manufacture drug substances, but it is not typically possible to achieve the necessary transparency with an external supplier. The integration of both of these operations under the Albemarle umbrella, however, achieves a new level of transparency that has far-reaching benefits. When the Tyrone facility considers process optimizations for a particular RSM, the impact of the process change is evaluated by both sites to determine the level of testing required to approve the optimized process. This collaborative environment ensures that any impact to the final API due to optimization of the RSM manufacturing process is fully understood.
Process Development for Safety at Any Scale
Once the chemistry for a given API has been determined, we work on developing optimal processes at both sites, with safety and quality always our primary concerns. Sometimes, we have to suggest alternative chemistries to ensure that we are running a process that is robust enough from a safety design perspective. It is important to address such safety issues up front when approaching scale-up, as it becomes more challenging and costly to change chemistry to optimize operational safety as a new API approaches validation.
Forecasting and Scale-Up
Speed to market is a high priority for many of our customers. Forecasting production schedules is an added advantage of this integrated supply chain. The two sites meet regularly to ensure that the production schedules and quantities are in alignment for meeting the customer’s expectations. In addition, the teams at the two sites can move quickly to respond to changes in customer demand and work with the customer to ensure success in delivering the API.
Fast Track Pathways and Approvals
The communication between the Tyrone and South Haven teams is also beneficial to sponsors who are fast-tracking a product to market. When a product is being fast-tracked, everything moves on a compressed timeline, which makes it even more critical to make the most informed choices and prepare for contingencies from the start. The two Albemarle sites typically coordinate to discuss a fast-track filing and make adjustments as quickly as possible. Without this integration, the process would be delayed as sponsors send out data and wait for feedback.
Regardless of the approval pathway, a product approved in the United States is not automatically approved in Europe, as was common in the past. Being prepared with the proper analytical and R&D expertise and the analytical equipment on-site allows us to anticipate these potential gaps and respond quickly with solutions. Our regulatory teams work with customers to develop processes and methods to ensure the compliance and quality of their APIs, because their products are as important to us as they are to them.