The complexity of small molecule APIs is growing rapidly. Many drug substances contain multiple heterocyclic rings and functional groups; they are designed with ever-increasing specificity in mind. While these novel compounds targeting cancer and other diseases enable more and more personalized treatments, they also pose immense challenges from a manufacturing perspective.
Producing most of these molecules requires multiple process steps that involve sophisticated chemistries. A thorough understanding of the pitfalls of these chemistries is necessary for effective implementation at a large scale. Tight control of process conditions ensures acceptable yields and minimizes impurities. These compounds often have poor solubility in typical reaction solvents and require unique synthetic strategies.
For example, most modern processes employ powerful cross-coupling reactions 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 for implementing robust, reliable processes. Grace Fine Chemical Manufacturing Services (FCMS) comprises 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 enhances our supply chain control.
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 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 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 separation and purification conditions to ensure that it will not degrade.
Frequently, the next phase of tech transfer and scale-up occurs in the kilo lab (25–100 L). Here, we run a small-scale process demonstration to identify 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 collaborate with the engineers in the kilo lab to evaluate all aspects of the process and continue to engage with the engineers to evaluate all aspects of the process. Glass equipment in the kilo lab also allows plant operators and engineers the opportunity monitor the process closely and ensure successful scale-up.
At Grace FCMS, we pursue phase-appropriate application of process understanding, because we recognize that there are always time and cost elements to consider. Once we have identified the weak points in a process, we communicate them and our risk-mitigation strategy to our clients. Through robust process understanding, our experienced process chemists and engineers ensure the right elements for successful validation are built in from the start of each scale-up phase. They identify key points that define optimal control strategies, including analytical methods that will be effective as the process scale increases.
Grace FCMS’s culture, teamwork, and integrated strategy for technology transfer and process scale-up have benefited countless customers. In one example, our non-GMP site in Tyrone supplied an RSM for an API made at South Haven. A new impurity was discovered during the development phase of the API, and we rapidly determined the structure using LCMS and NMR analysis techniques. This helped us trace its origins to a specific raw material used in the RSM. Grace FCMS was able to work with the supplier and set the appropriate specifications on that raw material to ensure that the impurity was well controlled.
In another instance, we discovered an unstable reaction mixture while preparing for a kilo lab campaign. A weight percent analysis for this reaction showed product decomposition after reaction completion, which had not been detected in the area percent analysis.
Implementing an expedited reaction quench and workup after reaction completion produced an 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, we eliminated an existing multi-step purification process involving repeated crystallizations and an overall 51% yield after parallel solvent screening studies and LCMS work revealed the identities of some problematic impurities. We implemented minor changes to remove these impurities, creating a streamlined process workup and a well-understood crystallization system that resulted in a high-purity product and an 87% yield.
Through our constant consideration of regulatory agency expectations, we 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 generation of a genotoxic/mutagenic impurity (GTI). Our analytical group expedited development of a method to detect the GTI down to its ICH limits. The customer was consulted before we proceeded with screening of the raw material and intermediate, which revealed that the potential impurity was not present.