As small molecule APIs become increasingly complex, the development of robust, high-yielding, and cost-effective synthetic routes becomes more challenging. Strategies that emphasize a high level of process understanding facilitate more effective route design and analytical method development.
Increasing Complexity
Complexity is increasing across pharmaceutical API development. A common trend with small molecule drug candidates is that they often contain multiple heterocycles with many nitrogen atoms and, in some cases, they have increased in size. These types of molecules present challenges with respect to synthetic route design and process details as a result of their lower solubility in common solvent systems. The former has been addressed with advances in homogeneous catalysis with respect to ligands, and process conditions have led to wider use of these reactions in small molecule intermediate and API synthesis. At Albemarle Fine Chemistry Services (FCS), we have gained extensive expertise in homogeneous cross-coupling reactions. Solubility issues during work-up operations or crystallizations have been routinely addressed via solubility studies, which leads to implementation of clever solvent systems. Both approaches have been successfully scaled to our manufacturing assets.
There is also an increasing expectation, from both regulators and drug manufacturers, for more robust analytical methods. In addition, customers are seeking validation of analytical methods for raw material testing and in-process monitoring, and not just for the final API release methods. At Albemarle FCS, our approach to satisfying these increased expectations starts during the analytical method development stage and method transfers. When designing, for example, an HPLC-related substance test for incoming advanced regulatory starting materials (RSM), our technologists consider whether the method can satisfy the rigors of ICH method validation criteria, while ensuring that the resulting method is suitable for control of relevant impurities. The increased functionality of more complex molecules provides the opportunity for more impurities that need to be resolved and quantitatively determined. The analytical chemists work closely with the process R&D chemist to identify the observed process impurities, using advanced technologies, such as LCMS, GCMS and NMR, and then demonstrate that the impurities are accurately reported. This may lead to assigning response factors when appropriate.
Greater Expectations for Process Understanding
Adding to these growing challenges is an additional layer of complexity — the need to develop a high level of process understanding. It is no longer sufficient to develop a process with limited understanding of process variables, as there is significant risk when scaling up to manufacturing assets. Albemarle recognizes the need to thoroughly understand processes, which minimizes the scale-up risk and adds value for the customer.
The increasing use of accelerated approval pathways, such as the Breakthrough Therapy and Priority Review designations, is adding complexity and leading to more aggressive development timelines. An efficient strategy must be established in order to tackle these projects with the necessary level of proficiency.
Similarly, increasing expectations with respect to analytical requirements — such as the recently updated ICH guidelines for elemental impurity analysis — are also driving the need for more process understanding. Homogeneous catalysis involves the use of transition metals dissolved in the reaction mixture. It is essential that the concentration of metal in the isolated product be reduced below an acceptable limit. It is critical to both have a strategy for removing metals and an understanding of what conditions will impact their removal and provide an explanation of how and where the metal was removed and how the process is controlled. At Albemarle, we had the required analytical instrumentation (inductively coupled plasma with mass spectrometry) and methods in place before the regulation took effect, ensuring that our customers would be prepared for these changes.
During the phase I project, it is important to identify potential areas for optimization and improvement in the event the project moves through later development stages.
Expertise and Experience are Essential
When facing the increasing complexities of small molecule drug development, the best weapons are experience and expertise, not only in route design and organic synthesis, but in all phases of drug development, from R&D, to the kilo lab, to the pilot plant and commercial production.
At Albemarle in South Haven, MI, our scientists have on average 20 years experience in the pharmaceutical industry. The engagement and commitment of our experts is reflected in very low staff turnover. The chemists that start work on a phase I project will continue to support that project through all development phases, bringing their project-specific knowledge with them, ensuring the continued success of a program as it scales through process validation and enters commercialization.
Keeping Scale-up in Mind
Since the goal of any new early-phase development project is commercialization of the drug candidate, it is essential to develop synthetic routes and processes with scale-up in mind when the work begins. As a result of the extensive manufacturing experience within the process R&D group, we have a strong track record in accomplishing this goal. Bringing process engineers into the discussion early on with continuing collaboration throughout the entire development cycle helps ensure a smooth tech transfer to the plant.
Understanding the impact of longer reaction times is also important. Unit operations typically take much longer to complete on a larger scale. In preparation for process scale-up, it is thus necessary to understand the impact of the extended cycle times on product quality. A laboratory reaction may provide a good yield and acceptable quality when the process time is limited and the workup is performed immediately following the reaction. However, the longer cycle times in the plant may lead to unexpected product decomposition, reducing the yield and potentially generating product that fails to meet the critical quality attributes. At Albemarle FCS, we routinely perform stress studies and evaluate reaction mixtures using HPLC weight percent assays. This approach is invaluable, because degradation products may not always be observed via HPLC impurity profiles alone. Understanding an unstable reaction mixture makes it possible to develop an alternate process or identify appropriate engineering controls for the process at plant scale in advance.
Longer-term Focus
Having a longer-term focus is as important as keeping scale-up in mind from the start. It is possible to develop a route and produce a phase I batch without any other considerations. However, that approach does not provide the greatest benefit to the customer. During the phase I project, it is important to identify potential areas for optimization and improvement in the event the project progresses to later stages of development.
At Albemarle FCS, while we are generating toxicology lots and phase I batches, we also assess our client’s projects with them, planning ahead with respect to the process and analytical methods. An area that can present challenges is the production of acceptable crystalline material in multi-heterocyclic compounds. These compounds often generate poorly behaved crystals or material that is amorphous. Albemarle FCS has significant expertise in developing robust crystallization systems with these types of molecules and has successfully implemented them at scale.
We also recommend additional analytical method development work to ensure that the methods used in early phases can be validated with little effort later on. Projects that involve accelerated approval timelines often move quickly from phase II to the production of phase III registration batches. Access to methods capable of undergoing validation helps keep projects on track. Once a program enters phase III, the ability to quickly validate methods can be critical to the program timelines. Albemarle has recognized the application of a quality-by-design (QbD) approach to analytical method development as a growing trend in the pharmaceutical industry. The power that is gained in process development by better defining the design space can also be obtained in analytical development. Such an approach provides the data needed to support the development of more robust methods.
Collaborating for Success
Collaboration and transparency are two keys to successful completion of projects for any custom manufacturer. At South Haven, we emphasize the collaboration that takes place among our experts on-site and at other FCS sites and, more importantly, with our customers. Each new project is supported by a team with representatives from R&D, analytical services, engineering and quality. The team and program manager stay together throughout the development cycle.
Customers are encouraged to participate at all phases. We encourage transparency and prefer to bring customers into the conversation if an issue occurs, because they often possess the expertise needed to help identify a solution. We find that collaboration is always the best approach to a process as challenging as scale-up.
This approach extends to collaboration with other sites within the Albemarle network. The Tyrone facility has begun producing some of the RSMs we use at the South Haven GMP site. Recently, there has been significant focus on pharmaceutical supply chain security and the need for greater knowledge of how RSMs are made and how the processes used to produce them are controlled. Close collaboration between the RSM supplier and drug substance producer offers a unique advantage in our marketplace.
Working in close collaboration with the Tyrone site has made it possible to gain this knowledge, in addition to achieving process optimization. We also have a better understanding of the impurity profiles for our raw materials, allowing us to head off potential problems sooner rather than later. This will remain essential as the role of RSM quality in controlling final API purity profile increases.
With our strong emphasis on process understanding at all production phases, Albemarle FCS can not only take on a broad range of projects, but we can also crucially anticipate future needs and collaborate with our customers to plan process solutions in advance to reduce time to market.
