Abstract
Process understanding is essential to achieving high-yielding, robust, and reliable pharmaceutical manufacturing processes. Albemarle applies a combination of technical expertise, creativity, collaboration, and a culture of continuous improvement to solve difficult process development challenges.
The Importance of Process Understanding
Pharmaceutical manufacturing processes must be robust and reliable to consistently provide the desired registered starting material (RSM), intermediate, or active pharmaceutical ingredient (API) that meets the high yield and purity industry standards. In order for them to do so, they must be carefully designed, controlled, and run by a team with complete process understanding.
Culture of Collaboration and Problem Solving
Deep process knowledge is only gained by teams that have the right values and are able to perform good science. At Albemarle Fine Chemistry Services (FCS), we apply a combination of technical and analytical expertise paired with equipment capabilities to establish process understanding for each project we tackle. This scientific approach is pursued by curious, courageous, and engaged chemists and engineers supported by a culture grounded in collaboration, communication, and trust.
By working collaboratively within and among internal teams and with our customers, Albemarle FCS is able to more rapidly develop the process understanding required to achieve a positive resolution of problems and issues related to process difficulties.
With the scientists and engineers at each of our two facilities in Tyrone, Pennsylvania and South Haven, Michigan all located in the campuses, it is easy for our process and analytical chemists to work closely with chemical engineers and plant production coordinators to correlate performance of lab-, pilot-, and commercial-scale runs and to identify process challenges.
We tackle those challenges by taking a holistic approach. Quality, yield, and cycle time are all interdependent; reducing the cycle time alone, for instance, often leads to higher impurity levels and lower yields. We thus address all three aspects of a process simultaneously, an effort that could not be achieved without effective communication and collaboration.
Constant communication with customers ensures that they are aware of issues, proposed approaches to solving them, and progress on achieving the desired solutions. Often, customers provide additional insights into processes that may confirm or expand our process understanding and facilitate optimal problem resolution. Consultation with customers is also important to confirm that no changes to a process will cause downstream issues.
Phase-Appropriate Application Important for APIs
For APIs, there is another element of process understanding that must be considered: how much process knowledge and process improvement is appropriate. For early-phase projects, the goal is to get material produced for preclinical testing or use in early clinical trials as quickly as possible. While developing processes with manufacturability in mind from the start is the ideal approach, in some cases—particularly for Fast Track and other accelerated approval projects—timelines do not allow extensive exploration of the design space.
The goal for early-phase projects is to address the most pressing detrimental problems, such as significant impurity generation, product degradation, or repetitive steps that are indicative of a lack of process control. Such process weaknesses must be eliminated to avoid the risk of failing validation or ending up with a variable commercial process. Issues that are manageable are not immediately addressed but communicated to the customer with proposed solutions that can be implemented if the candidate moves further along the development cycle.
For phase II projects, there is a greater need to develop process understanding in order to establish a process that is robust, reliable, and scalable. In phase III, extensive process characterization is performed in order to enable process validation.
Tyrone Case Study One: Yield and Cycle Time Improvement
An RSM manufactured at the Tyrone facility initially came to Tyrone with a process that suffered from low yield and extremely long cycle time. To improve the yield, the chemists worked closely with the engineers to make numerous small adjustments in temperature, feed rates, and other parameters. Similarly, several process bottlenecks, including many in the purification process, were attacked to reduce the cycle time.
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A 35% increase in the yield of higher-quality products made it easier to purify the product, providing a synergistic effect that helped to achieve a 60% reduction in the cycle time. As a result, productivity increased from 23 lbs. product/hour to 55 lbs. product/hour and the manufacturing cost greatly reduced.
Overall, a four-step process was developed that required some equipment modifications and installation. Despite these additional challenges, a 6-tonne demonstration campaign in commercial equipment was completed in six months. Continuous improvement efforts are currently focused on converting part of the process to continuous flow.
Tyrone Case Study Two: Improving a Complex Process at Scale
A complex process comprising eight chemical steps and 27 unit operations needed to be upscaled from large laboratory equipment directly to commercial scale. Throughout the implementation, various complications arose, many of which were interconnected.
One of the biggest challenges was posed by a difficult filtration with 50-hour cycle times due to the physical properties of the product. Working closely with the customer’s lab development team, numerous solutions were proposed and evaluated, including the use of alternative filtration units. Ultimately, it was determined that the best way to address the problem was to gain better control of the precipitation process in order to produce the product in a form that could be more readily filtered. After conducting lab- and plant-scale studies, a process was developed with a 50% shorter cycle time.
Throughout the entire process, it was essential to track how modifications in processes (e.g., changing solvent ratios, distillation conditions) have impacted the production of undesirable impurities. A supplied raw material already contained impurities, and it was necessary to determine how they might be transformed and controlled to ensure maximized rejection of undesired compounds so that the final product could meet the established specifications.
The project required a tremendous amount of work and extensive collaboration between Albemarle’s onsite teams. Engineers and production coordinators held daily discussions with chemists, providing feedback regarding process behaviors in the plant in order to determine which aspects of the process were scaling well and which were not. Throughout the process, these teams were also working very closely with the customer’s technical team to understand the process history and what approaches were previously taken.
The combination of our deep technical expertise and collaborative approach to problem-solving made it possible to identify critical quality attributes and successfully modify steps to control the tight purity profile of the final product. The overall result was an improvement in the throughput by 800% over three campaigns. Continued debottlenecking has created opportunities to meet our customer’s growing product demand while building confidence in our company’s ability to handle the toughest challenges.
South Haven Case Study One: Purification Process Enhancement
A process initially developed by another CDMO to generate phase I clinical trial material was brought to Albemarle as a phase II project. The multi-step chemical process relied on repeating the final crystallization four times until all impurities met the final API specifications, resulting in a 51% overall yield for the crystallization.
This repetitive approach suggested that the process was not well controlled, and, at the proposal stage, Albemarle identified this process issue and provided a general approach for solving it. Solvent screening studies provided information about the recovery of the product, while analysis of the remaining liquors from these crystallizations allowed for an understanding of the impurity-purging capabilities of the various solvent systems. In addition, liquid chromatography-mass spectrometry (LCMS) was used to assist in determining the structures of the main impurities. As a result, the team was able to ascertain the mechanisms of formation. With this knowledge, it was possible to develop a process in which several of the impurities were removed chemically.
In this effort, the analytical chemists worked very closely with the synthetic organic chemists to develop an alternative purification approach. The streamlined process that resulted involved only two crystallizations using a new solvent system and provided the API with the required purity profile in an 87% yield.
South Haven Case Study Two: Overcoming Product Instability
An early-stage project was brought to Albemarle for the production of toxicological lots. One of the transformations provided with the existing process involved a homogenous cross-coupling reaction.
While reaction conversion was always observed to be above 95%, the isolated yield of the product was very low.
HPLC analysis of all process streams did not show any significant product loss. Monitoring of the reaction progress using weight percent assay, however, revealed that the product was decomposing under the reaction conditions, and the decomposition products were not detectable using the current HPLC method. The weight percent assay of the reaction progression, in particular how the mass loss was accelerating after completion of the reaction, provided the knowledge needed to avoid significant yield loss. While in most cases product instability can be predicted by the chemical structure, in this case, the instability was not expected.
Our solution for this preclinical, kilo-lab campaign was to minimize the reaction time, check for reaction completion, and then immediately quench the reaction mixture. The result was a >25% increase in yield. When the project progressed to the clinical stage, the chemistry was redesigned, using a different, scalable homogeneous coupling reaction that provides a stable product.