Dan Bowles and Michael Tracey, Cambrex 10.11.17
In the past century, small molecules drugs have revolutionized human healthcare. From antibiotics to anticancer drugs, allied to medicines designed to treat chronic conditions as diverse as epilepsy and diabetes, the skills of the organic chemist have had a huge impact on both life expectancy and quality of life. Despite the successes, bringing a new small molecule drug to market is far from a trivial exercise. It typically takes 15 years and costs in excess of a billion dollars, and the attrition rate is high—one estimate is that just one in 5,000 promising chemical entities will actually reach the market (see Figure 1).
But the reward is worth the risk: the size of the global pharmaceutical market topped $1 trillion in 2016 (see Figure 2). In the 40 years from 1977-2016, the U.S. FDA approved around 4,000 small molecule products for commercialization. Annual fluctuations aside, there is a constant supply of new drugs to the market, and with many unmet medical needs remaining, the potential for success is great if these hurdles can be overcome.
Once a new biological target has been identified that might have potential for altering the course of a disease, medicinal chemists can get to work on creating a molecule that might interfere with that target’s activity. Only small amounts of these molecules are required for early biological assays and screens, and through an iterative cycle of design–make–test, an optimized compound is identified for further progression.
At this point, the project has usually been up and running for a number of years, and it is only at this stage that larger quantities of prospective active pharmaceutical ingredient (API) will be required. The medicinal chemistry route to the molecule is rarely appropriate for large-scale manufacturing—medicinal chemists are more interested in speed than cost, because time is of the essence when determining its potential biological activity. The sooner a molecule gets into clinical trials, the sooner it will reach the market if it proves efficacious and safe.
Medicinal chemists will, therefore, routinely use reagents and reactions that process chemists try to avoid, because they allow a new molecule to be accessed quickly. These might be organolithium bases that must be used at very low temperatures, perhaps, or a reaction that gives a complex mix of products that require separation using solvent-heavy column chromatography.
This is the first point along the development pathway for a small molecule drug that a contract manufacturing organization (CMO) is likely to get involved. Scale up and route optimization is an art in itself, and if in-house expertise is not available, the skills of the CMO can be invaluable. The CMO can be a complement to a Big Pharma company’s own process development team and, in the case of a biotech company with no in-house capabilities, can offer the means to design an appropriate large-scale synthesis.
It is also important to get a good synthetic route early on in the development cycle. It is rarely altered past phase IIa, but where the demands for API increase throughout the clinical stages, and then further into commercial manufacturing, the synthetic route is scrutinized, and process chemists and engineers look to adapt it.
Route evaluation is common for CMOs once the market has been established for a drug, as late as a number of years after launch. Although there are regulatory costs involved in changing the route post launch, there are occasions when it can be worthwhile. This is particularly the case if the new route is very much faster or very much cheaper, and may even help to reduce the impact of generic competition once patent expiry occurs.
Early stage support
The following two case studies illustrate support provided for API manufacturing demand across the drug development spectrum.
Case Study No. 1: Early process development and rapid progression to first GMP bulk manufacture. A client had developed a 13-step route for a new molecule and initially required sub-kilogram quantities to be manufactured under non-GMP conditions, followed by a scale up to 5kg batches that would be manufactured in accordance with cGMP.
Cambrex was able to design a new route to replace that original medicinal chemistry route, and at the same time increase the overall reaction yield significantly from 2% to 18%. In addition, downstream development was completed in parallel with plant production of the API to minimize the timeline for the process.
Two steps were shaved off the route, bringing the total number down to 11. Furthermore, a hazardous diazotization step was evaluated and risk-mitigated, and solubility and final form issues were resolved to provide the desired polymorph.
Case Study No. 2: Process development and process validation studies. In some cases, full time equivalent (FTE)-based R&D is a more appropriate way to approach a problem. In this example, Cambrex provided FTE-based R&D to support a client’s medicinal chemistry/structure-activity-relationship studies. The result was a second-generation process that was developed in collaboration with the client, and sufficient API was delivered to satisfy an early toxicity study program. This was quickly followed up by the first kilogram-scale GMP batch of API to meet the demands of clinical trials.
During the development process, an issue with water sensitivity was identified. To meet the stringent purity requirements, refinements to the process were made, in collaboration with the client, to ensure its robustness at scale. Further process improvements resulted in an efficient and streamlined route that also dramatically reduced the cost of the API. Full analytical and process validation was successfully completed, enabling the API to be manufactured at a 40kg batch scale.
Supporting API demand at late clinical phase and commercial launch
Late-stage development requires specific skills that a CMO may be better placed to provide than a company’s in-house team. Biotech companies are unlikely to be able to do these tasks themselves, and therefore will look for a CMO with extensive experience in supporting API manufacturing for late-stage development and commercial launch.
Case Study No. 3. Internal development and transfer. A customer synthesis project for a generic API project was originated by Cambrex at the company’s R&D site in Tallinn, Estonia, and a number of scouting runs performed to establish the synthetic route and initial development procedures. The development and technical transfer teams from the company’s Charles City site became involved early on in the project to help direct development, which included design of experiment (DoE) studies.
The process transfer was undertaken in Estonia, so the U.S. staff were able to see the process being implemented and discuss progress with the Estonian development team. This early involvement resulted in very little process development being required after the campaign was transferred back to Cambrex Charles City for full-scale commercial manufacture.
Case Study No. 4: Process development. A client approached Cambrex with an 8-step process that required further development and CMO support for production and commercial launch of an API. A previous CMO had made 50kg of the API with an overall yield of 9%. By understanding and optimizing two key reaction steps, Cambrex was able to develop a process that gave a substantially improved overall yield of 49%. DoE being used to determine a proven acceptable range (PAR) for each critical process parameters (CPP), and fate/purge of impurities. Analytical method development and validation included chiral chromatography and UPLC-MS.
Case Study No. 5: Technology transfer. A U.S. client that had developed a complex 4-step process was looking for a domestic supplier of the product. Cambrex had considerable knowledge of the client’s process, having previously manufactured it at pilot scale, and developed a suite of analytical methods that enabled the chemical process to be monitored.
Cambrex committed to building and qualifying a new large-scale manufacturing facility for the process in Charles City. This was achieved in less than one year, and only one laboratory-scale run was required before the process was transferred to the pilot plant. Furthermore, just two validation pilot runs were required prior to the scale up of the process to 15,000-litre equipment. The application of Six Sigma techniques has allowed an increase in production year-on-year, and more than 60 tons of this API have now been manufactured by Cambrex over the past four years.
What makes a good small molecule CMO?
For a partnership with a CMO to succeed, there are multiple factors that will be important. The CMO should have extensive expertise in process chemistry and engineering, with a reputation for quality and reliability in its manufacturing operations. As well as a strong safety record, it should offer advanced chemical manufacturing technology, and flexibility that allows it to manufacture small molecules from milligram through to ton scales, and be able to adapt as the molecule moves through the development pipeline.
Perhaps the most critically important factor, however, is that the CMO should offer dedicated support throughout the whole route through development, from compound selection to commercial launch and beyond. Speed is of the essence, and any delay in the development process will shave weeks, months or even years off the time a drug will have on the market before it is subject to generic competition on patent expiry. A good CMO will play a key role in getting the drug to the market in a timely fashion, so it can start to recoup those huge development costs.
About the Authors: Dr. Dan Bowles is senior director of chemical development at Cambrex High Point, North Carolina. Dr. Michael Tracey is principal scientist for new product development at Cambrex Charles City, Iowa.
But the reward is worth the risk: the size of the global pharmaceutical market topped $1 trillion in 2016 (see Figure 2). In the 40 years from 1977-2016, the U.S. FDA approved around 4,000 small molecule products for commercialization. Annual fluctuations aside, there is a constant supply of new drugs to the market, and with many unmet medical needs remaining, the potential for success is great if these hurdles can be overcome.
Once a new biological target has been identified that might have potential for altering the course of a disease, medicinal chemists can get to work on creating a molecule that might interfere with that target’s activity. Only small amounts of these molecules are required for early biological assays and screens, and through an iterative cycle of design–make–test, an optimized compound is identified for further progression.
At this point, the project has usually been up and running for a number of years, and it is only at this stage that larger quantities of prospective active pharmaceutical ingredient (API) will be required. The medicinal chemistry route to the molecule is rarely appropriate for large-scale manufacturing—medicinal chemists are more interested in speed than cost, because time is of the essence when determining its potential biological activity. The sooner a molecule gets into clinical trials, the sooner it will reach the market if it proves efficacious and safe.
Medicinal chemists will, therefore, routinely use reagents and reactions that process chemists try to avoid, because they allow a new molecule to be accessed quickly. These might be organolithium bases that must be used at very low temperatures, perhaps, or a reaction that gives a complex mix of products that require separation using solvent-heavy column chromatography.
This is the first point along the development pathway for a small molecule drug that a contract manufacturing organization (CMO) is likely to get involved. Scale up and route optimization is an art in itself, and if in-house expertise is not available, the skills of the CMO can be invaluable. The CMO can be a complement to a Big Pharma company’s own process development team and, in the case of a biotech company with no in-house capabilities, can offer the means to design an appropriate large-scale synthesis.
It is also important to get a good synthetic route early on in the development cycle. It is rarely altered past phase IIa, but where the demands for API increase throughout the clinical stages, and then further into commercial manufacturing, the synthetic route is scrutinized, and process chemists and engineers look to adapt it.
Route evaluation is common for CMOs once the market has been established for a drug, as late as a number of years after launch. Although there are regulatory costs involved in changing the route post launch, there are occasions when it can be worthwhile. This is particularly the case if the new route is very much faster or very much cheaper, and may even help to reduce the impact of generic competition once patent expiry occurs.
Early stage support
The following two case studies illustrate support provided for API manufacturing demand across the drug development spectrum.
Case Study No. 1: Early process development and rapid progression to first GMP bulk manufacture. A client had developed a 13-step route for a new molecule and initially required sub-kilogram quantities to be manufactured under non-GMP conditions, followed by a scale up to 5kg batches that would be manufactured in accordance with cGMP.
Cambrex was able to design a new route to replace that original medicinal chemistry route, and at the same time increase the overall reaction yield significantly from 2% to 18%. In addition, downstream development was completed in parallel with plant production of the API to minimize the timeline for the process.
Two steps were shaved off the route, bringing the total number down to 11. Furthermore, a hazardous diazotization step was evaluated and risk-mitigated, and solubility and final form issues were resolved to provide the desired polymorph.
Case Study No. 2: Process development and process validation studies. In some cases, full time equivalent (FTE)-based R&D is a more appropriate way to approach a problem. In this example, Cambrex provided FTE-based R&D to support a client’s medicinal chemistry/structure-activity-relationship studies. The result was a second-generation process that was developed in collaboration with the client, and sufficient API was delivered to satisfy an early toxicity study program. This was quickly followed up by the first kilogram-scale GMP batch of API to meet the demands of clinical trials.
During the development process, an issue with water sensitivity was identified. To meet the stringent purity requirements, refinements to the process were made, in collaboration with the client, to ensure its robustness at scale. Further process improvements resulted in an efficient and streamlined route that also dramatically reduced the cost of the API. Full analytical and process validation was successfully completed, enabling the API to be manufactured at a 40kg batch scale.
Supporting API demand at late clinical phase and commercial launch
Late-stage development requires specific skills that a CMO may be better placed to provide than a company’s in-house team. Biotech companies are unlikely to be able to do these tasks themselves, and therefore will look for a CMO with extensive experience in supporting API manufacturing for late-stage development and commercial launch.
Case Study No. 3. Internal development and transfer. A customer synthesis project for a generic API project was originated by Cambrex at the company’s R&D site in Tallinn, Estonia, and a number of scouting runs performed to establish the synthetic route and initial development procedures. The development and technical transfer teams from the company’s Charles City site became involved early on in the project to help direct development, which included design of experiment (DoE) studies.
The process transfer was undertaken in Estonia, so the U.S. staff were able to see the process being implemented and discuss progress with the Estonian development team. This early involvement resulted in very little process development being required after the campaign was transferred back to Cambrex Charles City for full-scale commercial manufacture.
Case Study No. 4: Process development. A client approached Cambrex with an 8-step process that required further development and CMO support for production and commercial launch of an API. A previous CMO had made 50kg of the API with an overall yield of 9%. By understanding and optimizing two key reaction steps, Cambrex was able to develop a process that gave a substantially improved overall yield of 49%. DoE being used to determine a proven acceptable range (PAR) for each critical process parameters (CPP), and fate/purge of impurities. Analytical method development and validation included chiral chromatography and UPLC-MS.
Case Study No. 5: Technology transfer. A U.S. client that had developed a complex 4-step process was looking for a domestic supplier of the product. Cambrex had considerable knowledge of the client’s process, having previously manufactured it at pilot scale, and developed a suite of analytical methods that enabled the chemical process to be monitored.
Cambrex committed to building and qualifying a new large-scale manufacturing facility for the process in Charles City. This was achieved in less than one year, and only one laboratory-scale run was required before the process was transferred to the pilot plant. Furthermore, just two validation pilot runs were required prior to the scale up of the process to 15,000-litre equipment. The application of Six Sigma techniques has allowed an increase in production year-on-year, and more than 60 tons of this API have now been manufactured by Cambrex over the past four years.
What makes a good small molecule CMO?
For a partnership with a CMO to succeed, there are multiple factors that will be important. The CMO should have extensive expertise in process chemistry and engineering, with a reputation for quality and reliability in its manufacturing operations. As well as a strong safety record, it should offer advanced chemical manufacturing technology, and flexibility that allows it to manufacture small molecules from milligram through to ton scales, and be able to adapt as the molecule moves through the development pipeline.
Perhaps the most critically important factor, however, is that the CMO should offer dedicated support throughout the whole route through development, from compound selection to commercial launch and beyond. Speed is of the essence, and any delay in the development process will shave weeks, months or even years off the time a drug will have on the market before it is subject to generic competition on patent expiry. A good CMO will play a key role in getting the drug to the market in a timely fashion, so it can start to recoup those huge development costs.
About the Authors: Dr. Dan Bowles is senior director of chemical development at Cambrex High Point, North Carolina. Dr. Michael Tracey is principal scientist for new product development at Cambrex Charles City, Iowa.
