Technical expertise and access to state-of-the-art equipment and facilities are necessary but insufficient for successful completion of small molecule API technology transfer projects. Contract development and manufacturing organizations (CDMOs) must have a collaborative culture that encourages open and transparent communication among internal team members, client representatives and other external partners.
Strong Technical Foundation is a Start
The complexity of small molecule APIs is growing rapidly. Many drug substances contain multiple heterocyclic rings and functional groups and are designed with ever-increasing specificity in mind. While these novel compounds targeting cancer and other diseases are enabling increasingly personalized treatments, they pose immense challenges from a manufacturing perspective.
Production of most of these molecules requires multiple process steps involving sophisticated chemistries. A thorough understanding of the pitfalls of these chemistries is needed to enable effective implementation at a large scale. Tight control of process conditions is essential to ensure acceptable yields and to minimize impurities. Often, these large compounds have poor solubility in typical reaction solvents and require unique synthetic strategies. For example, most modern processes employ powerful cross-coupling reactions that are mediated by precious metal catalysts for which the controlling factors are often quite subtle. These reactions frequently require development of unique purification protocols for removal of the catalytic metal, as required by the new ICH Q3D Guidelines on elemental impurities. In another common example, amide coupling reactions often must be performed in the presence of highly sensitive substituents while avoiding unwanted side reactions, which again requires development of a specifically tailored process.
Established Scale-up Strategy
A strategy for process development and scale-up is essential to the implementation of robust, reliable processes. Albemarle Fine Chemistry Services (FCS) encompases a GMP manufacturing site in South Haven, Michigan and a non-GMP manufacturing site in Tyrone, Pennsylvania. This allows for domestic production of regulatory starting materials (RSM) and improves our ability to control the supply chain.
In a new project, our process R&D group focuses first on route development, or familiarization, at the 50-mL to 1-L scales. As development continues, high-throughput equipment (<100 mL) is used for design-of-experiment studies to enable multivariate parameter analysis.
In the next phase, we run a lab demonstration batch at the 2-L scale using a jacketed reactor to ensure that we evaluate the reaction under conditions similar to those that will exist in the plant. Throughout this process, we evaluate the technical risks, working closely with process engineers to identify and investigate any necessary safe hold points and to determine process robustness. This work focuses on the reaction and workup steps. At plant scale, these processes generally take much longer than in the lab. It is important to determine the stability of the product under the separation/purification conditions to ensure that it will not degrade.
Frequently, the next phase of tech transfer/scale-up occurs in the kilo lab (25–100 L). Here, a small-scale process demonstration run is performed, allowing identification of any scale-up issues that were not discovered in the lab. In many cases, customers use this material for toxicology testing. We can also produce small GMP batches, which can be used for phase I or smaller phase II trials.
These runs provide significant value to customers, because the R&D chemists involved in the 2-L process demonstration carry their experience directly into the kilo lab and continue to engage with the engineers to evaluate all aspects of the process. In addition, the glass equipment in the kilo lab offers plant operators and engineers the opportunity to view the process and see firsthand how it will behave. This visual experience contributes greatly to successful scale-up.
Throughout the phases of scale-up, our process chemists and engineers apply their experience and knowledge to ensure that the right elements needed for successful validation are built in from the start. They establish process understanding to identify the key points that define the optimal control strategies, including analytical methods, that will be effective as the process scale increases.
At Albemarle FCS, we pursue phase-appropriate application of process understanding, because we recognize that there are always time and cost elements to consider. Once the weak points in a process are identified, we communicate them and our risk-mitigation strategy to our clients.
Demonstrated Successes
The culture, teamwork and integrated strategy for technology transfer and process scale-up at Albemarle have benefited numerous customers.
In one example, our non-GMP site in Tyrone was supplying an RSM for an API made at South Haven. A new impurity was observed during the development phase of the API, and the structure was rapidly determined using LCMS and NMR analysis techniques. This allowed us to trace its origins to the key raw material for the RSM. Albemarle was able to work with the supplier and set the appropriate specifications on that particular raw material to ensure that the impurity was well controlled.
In another instance, an unstable reaction mixture was discovered while preparing for a kilo lab campaign. A weight percent analysis for this reaction showed product decomposition after reaction completion; this decomposition was not detected in the area percent analysis. Implementing an expedited reaction quench and workup after reaction completion resulted in increased isolated yield from 50–60% to nearly 80%.
Our commitment to teamwork and gaining deep process understanding often leads to improved processes. For example, an existing multistep purification process involving repeated crystallizations and an overall 51% yield was eliminated after the performance of parallel solvent screening studies and LCMS work revealed the identity of the problematic impurities. Minor process changes were implemented to facilitate removal of these impurities, leading to a streamlined process workup and a well-understood crystallization system that resulted in high-purity product and afforded an 87% yield.
Our constant consideration of regulatory agency expectations also enables us to anticipate and manage potential issues before they become real problems. For one customer, analysis of the synthetic route for an intermediate identified the potential for the generation of a genotoxic/mutagenic impurity (GTI). Communication with the analytical group allowed for expedited development of a method to detect the GTI down to its ICH limits. The customer was notified and agreed to a course of action. Screening of the raw material and intermediate revealed that the potential impurity was not present.