Jonathan Knight, VP New Product Development, Cambrex06.06.17
Reviewing the manufacturing process of an active pharmaceutical ingredient (API) or key intermediate as a project moves towards commercialization can offer significant gains in terms of innovation, process improvement and reduced cost of goods. This article discusses how innovation and the adoption of new technologies by a contract manufacturing organization (CMO) can bring down the costs of an API, and also how collaborative risk and cost sharing approaches between a CMO and customer can benefit both parties.
As an API progresses from early clinical development through clinical trials and on to commercialization, the original synthetic route may not always be the most efficient, sustainable or cost-effective process as the scale of manufacturing increases. Furthermore, complicated or hazardous chemistries, or expensive key intermediates may prevent outsourcing or insourcing of production, or may even make the process too uneconomical to allow the development program to continue.
Process improvement opportunities are often driven by the in-licensing activity of late stage projects from small biotech companies to large and medium sized pharma companies. In-licensing takes place at Phase IIb or even Phase III, but because the small biotech companies have been able to commit only limited resources to this development, and have little experience in commercial manufacture, the processes are frequently not fully developed, very expensive, non-sustainable from an environmental standpoint or very difficult to scale up and make into a commercial process.
By reviewing compounds that are entering Phase III or above and examining the available data to ascertain the potential competitiveness of the published synthetic routes, a CMO can try to identify opportunities to create significant technical advantage, thereby offering potential customers the benefits of significant cost reductions, sustainable robust processes and additional intellectual property.
There are many opportunities in the marketplace where a CMO could bring innovation to bear on existing processes, but while the potential rewards may be great, these opportunities also entail a high degree of technical and commercial risk, as well as requiring significant resources. For this reason, good project selection as to which to commit potential time and resource is critical.
The three key selection criteria are technical evaluation, market assessment and customer interaction. The technical evaluation will involve a full and comprehensive literature search and a freedom to operate (FTO) study to ensure that any new process development is non-infringing. A cost simulation will also need to be carried out, for both the existing manufacturing process and the proposed innovative process to assess the level of possible cost savings.
The potential market is assessed by gathering information relating to the target product and any potential competitive products in the pipeline that may significantly influence the market dynamics. The risks and rewards for each product are then evaluated.
For projects where a CMO is manufacturing a product for a customer, and is in a position to propose alternative routes, open discussion with the customer is vital. From the customer perspective, a cheaper route of manufacture must be weighed up against the cost of change, and the regulatory consequences that change brings. In such a situation, customers who are willing to share clear development targets, long-term costs and specifications is preferable for a CMO, so that quick, informed decisions can be made. The different potential supply strategies and business models will be considered, such as the supply of the API or key intermediates or perhaps a licensing model.
Customers will need a good reason to switch from their current synthesis or supply chain to the one offered by the CMO, and this is primarily achieved by offering a significant reduction in the cost of goods (CoG). For instance, Cambrex, which set up a dedicated Innovative Product Group in 2012, sets a target in this regard of a minimum saving of $5m or a 25% CoG reduction. All these evaluations need to be carried out prior to any laboratory work being undertaken by the CMO.
Once a project has been identified that is suitable for developmental work, the next step is undertaking a proof of concept study. This would typically focus on the critical step in the proposed new process and could take several weeks to complete. If this is successful, and the market and customer information has been reconfirmed, a proof of scalability study is the next appropriate step, during which the CMO will work to develop a robust and commercially appropriate manufacturing process. This could take several months, depending on the complexity of the project.
The key elements to consider when developing an innovative process and/or cost improvement project are:
These considerations are clearly illustrated in a project to develop an alternative synthesis method for the manufacture of lacosamide as a generic drug. There were already a number of synthetic methods existing in the literature, but all had significant drawbacks, including the use of an expensive, unnatural amino acid that is not readily available as a starting material, the need for an expensive catalytic system, and multiple, linear chemical steps, as well as health and safety issues.
The main challenge in the project was to introduce chirality, and initially an enzymatic approach was used. This resulted in a conversion of up to 90% and an enantiomeric excess (ee) of 80-85%. Although the enzyme was expensive, it could be recycled at least 10 times, but the major drawback of the step was a process time of typically 24 hours, or even longer depending on the catalyst load. In addition, there was a difficulty associated with product isolation that was due to incomplete conversion and moderate enantioselectivity that resulted in low overall yield.
However, a good racemization system was developed that converted the remaining amine enantiomer into racemate, and this system was then successfully used in the next generation approach, which was resolution by crystallization.
It was known from the literature that the desired (R)-enantiomer of the amine precursor could be selectively crystallized using N-Acetyl-D-leucin, but this resolving agent is an unnatural amino acid and therefore expensive. However, during salt screening tests a very similar resolving agent, N-Formyl-L-leucine, was tested. This resolving agent is a natural amino acid and is therefore easily accessible commercially at a much lower price. In the investigation, N-Formyl-L-leucine exhibited superior selectivity compared with N-Acetyl-D-leucin: in particular, the typical purity of crude diastereomeric salt was 90% compared with 80-85%, and the typical crude yield from racemate was >45% compared with 30-40%.
After some optimization work, a five-step telescoped process with only one isolated intermediate was achieved. The overall yield was 57%, with a purity of greater than 99%, and an ee in excess of 99%. The new route used easily accessible materials and simple processes in standard processing equipment. Thanks to the novelty diastereomeric salt and innovative dynamic resolution system, the route developed was patentable, and offered considerable cost savings over published routes.
Case Study 2
Another case study demonstrates how it is possible to dramatically reduce the cost of goods to a customer by examining the key variables in an existing process. Using proprietary technology, Cambrex was the sole supplier to the innovator of a key intermediate through the entire clinical development program of a drug. When the Phase II clinical readout showed that the company needed to increase the dosage ten-fold, this presented a significant CoG issue as the intermediate was a major cost driver in the whole process. The customer therefore wanted to see whether it was possible to achieve a major reduction in the price of the intermediate; if not, the entire clinical program would have to be terminated. The company was looking to pay a commercial price of between $300 and $400/kg (at a scale of greater than 50 metric tons), which represented a reduction of up to 87% from the current price of $2450/kg.
Cambrex’s technical team looked at both the process and the capacity of facilities, and examined eight key variables that would enable it to put together a realistic scenario that would see an achievable price of approximately $640/kg. Presented with the simulation and supporting documentation, the customer decided to proceed with the clinical trial program. Over the course of five subsequent delivery periods, the price was reduced by between $150/kg to $500/kg.
By reviewing the plant capacity and throughput, Cambrex engineers demonstrated that an investment of $2.3 million would enable the weekly throughput to be increased from the current 500kg, to 2000kg, which would give significant cost improvements. This allowed a long-term projection to be offered to the customer of $320/kg, based on a commercial supply agreement that included an investment payback.
Unfortunately, however, this investment was not made due to the termination of the project by the customer in the wake of poor Phase III clinical trial data.
In conclusion, there are a number of aspects to managing the API life cycle to take advantage of the growing opportunities in the market. However, there are certain factors that are crucial if the benefits are to outweigh the risks; the first and foremost of these is initial project selection. Clear project goals should be established at the outset and referred to frequently, and existing patent landscapes should be investigated and understood.
To achieve process improvements, a good understanding of the process and the facilities is important, as well as looking to reduce waste costs by good waste management. Parallel processing and process telescoping give significant benefits with regard to capacity utilization and product throughput.
Both process and capacity should also be considered when looking to improve the cost of goods. The identification of the key drivers is critical to ensure that valuable development time is focused on where the most significant cost savings can be realized.
Jonathan Knight is vice president of new product development at Cambrex.
As an API progresses from early clinical development through clinical trials and on to commercialization, the original synthetic route may not always be the most efficient, sustainable or cost-effective process as the scale of manufacturing increases. Furthermore, complicated or hazardous chemistries, or expensive key intermediates may prevent outsourcing or insourcing of production, or may even make the process too uneconomical to allow the development program to continue.
Process improvement opportunities are often driven by the in-licensing activity of late stage projects from small biotech companies to large and medium sized pharma companies. In-licensing takes place at Phase IIb or even Phase III, but because the small biotech companies have been able to commit only limited resources to this development, and have little experience in commercial manufacture, the processes are frequently not fully developed, very expensive, non-sustainable from an environmental standpoint or very difficult to scale up and make into a commercial process.
By reviewing compounds that are entering Phase III or above and examining the available data to ascertain the potential competitiveness of the published synthetic routes, a CMO can try to identify opportunities to create significant technical advantage, thereby offering potential customers the benefits of significant cost reductions, sustainable robust processes and additional intellectual property.
There are many opportunities in the marketplace where a CMO could bring innovation to bear on existing processes, but while the potential rewards may be great, these opportunities also entail a high degree of technical and commercial risk, as well as requiring significant resources. For this reason, good project selection as to which to commit potential time and resource is critical.
The three key selection criteria are technical evaluation, market assessment and customer interaction. The technical evaluation will involve a full and comprehensive literature search and a freedom to operate (FTO) study to ensure that any new process development is non-infringing. A cost simulation will also need to be carried out, for both the existing manufacturing process and the proposed innovative process to assess the level of possible cost savings.
The potential market is assessed by gathering information relating to the target product and any potential competitive products in the pipeline that may significantly influence the market dynamics. The risks and rewards for each product are then evaluated.
For projects where a CMO is manufacturing a product for a customer, and is in a position to propose alternative routes, open discussion with the customer is vital. From the customer perspective, a cheaper route of manufacture must be weighed up against the cost of change, and the regulatory consequences that change brings. In such a situation, customers who are willing to share clear development targets, long-term costs and specifications is preferable for a CMO, so that quick, informed decisions can be made. The different potential supply strategies and business models will be considered, such as the supply of the API or key intermediates or perhaps a licensing model.
Customers will need a good reason to switch from their current synthesis or supply chain to the one offered by the CMO, and this is primarily achieved by offering a significant reduction in the cost of goods (CoG). For instance, Cambrex, which set up a dedicated Innovative Product Group in 2012, sets a target in this regard of a minimum saving of $5m or a 25% CoG reduction. All these evaluations need to be carried out prior to any laboratory work being undertaken by the CMO.
Once a project has been identified that is suitable for developmental work, the next step is undertaking a proof of concept study. This would typically focus on the critical step in the proposed new process and could take several weeks to complete. If this is successful, and the market and customer information has been reconfirmed, a proof of scalability study is the next appropriate step, during which the CMO will work to develop a robust and commercially appropriate manufacturing process. This could take several months, depending on the complexity of the project.
The key elements to consider when developing an innovative process and/or cost improvement project are:
- An understanding of the CoG for the competitive processes;
- A knowledge of the patent landscape to ensure freedom to operate;
- An understanding of the key cost drivers within the innovative process;
- An understanding of the cost and availability of raw materials;
- Opportunity to increase the yield;
- Opportunity to improve processing times, to telescope the process where possible and thus reduce the number of isolated intermediates;
- Opportunity to develop robust and reproducible processes, thus ensuring that the specification is met every time;
- Ensuring a limited and manageable waste stream;
- Recycling solvents, where possible, within a tight regulatory framework; and
- Using standard equipment where possible to avoid additional capital investment.
These considerations are clearly illustrated in a project to develop an alternative synthesis method for the manufacture of lacosamide as a generic drug. There were already a number of synthetic methods existing in the literature, but all had significant drawbacks, including the use of an expensive, unnatural amino acid that is not readily available as a starting material, the need for an expensive catalytic system, and multiple, linear chemical steps, as well as health and safety issues.
The main challenge in the project was to introduce chirality, and initially an enzymatic approach was used. This resulted in a conversion of up to 90% and an enantiomeric excess (ee) of 80-85%. Although the enzyme was expensive, it could be recycled at least 10 times, but the major drawback of the step was a process time of typically 24 hours, or even longer depending on the catalyst load. In addition, there was a difficulty associated with product isolation that was due to incomplete conversion and moderate enantioselectivity that resulted in low overall yield.
However, a good racemization system was developed that converted the remaining amine enantiomer into racemate, and this system was then successfully used in the next generation approach, which was resolution by crystallization.
It was known from the literature that the desired (R)-enantiomer of the amine precursor could be selectively crystallized using N-Acetyl-D-leucin, but this resolving agent is an unnatural amino acid and therefore expensive. However, during salt screening tests a very similar resolving agent, N-Formyl-L-leucine, was tested. This resolving agent is a natural amino acid and is therefore easily accessible commercially at a much lower price. In the investigation, N-Formyl-L-leucine exhibited superior selectivity compared with N-Acetyl-D-leucin: in particular, the typical purity of crude diastereomeric salt was 90% compared with 80-85%, and the typical crude yield from racemate was >45% compared with 30-40%.
After some optimization work, a five-step telescoped process with only one isolated intermediate was achieved. The overall yield was 57%, with a purity of greater than 99%, and an ee in excess of 99%. The new route used easily accessible materials and simple processes in standard processing equipment. Thanks to the novelty diastereomeric salt and innovative dynamic resolution system, the route developed was patentable, and offered considerable cost savings over published routes.
Case Study 2
Another case study demonstrates how it is possible to dramatically reduce the cost of goods to a customer by examining the key variables in an existing process. Using proprietary technology, Cambrex was the sole supplier to the innovator of a key intermediate through the entire clinical development program of a drug. When the Phase II clinical readout showed that the company needed to increase the dosage ten-fold, this presented a significant CoG issue as the intermediate was a major cost driver in the whole process. The customer therefore wanted to see whether it was possible to achieve a major reduction in the price of the intermediate; if not, the entire clinical program would have to be terminated. The company was looking to pay a commercial price of between $300 and $400/kg (at a scale of greater than 50 metric tons), which represented a reduction of up to 87% from the current price of $2450/kg.
Cambrex’s technical team looked at both the process and the capacity of facilities, and examined eight key variables that would enable it to put together a realistic scenario that would see an achievable price of approximately $640/kg. Presented with the simulation and supporting documentation, the customer decided to proceed with the clinical trial program. Over the course of five subsequent delivery periods, the price was reduced by between $150/kg to $500/kg.
By reviewing the plant capacity and throughput, Cambrex engineers demonstrated that an investment of $2.3 million would enable the weekly throughput to be increased from the current 500kg, to 2000kg, which would give significant cost improvements. This allowed a long-term projection to be offered to the customer of $320/kg, based on a commercial supply agreement that included an investment payback.
Unfortunately, however, this investment was not made due to the termination of the project by the customer in the wake of poor Phase III clinical trial data.
In conclusion, there are a number of aspects to managing the API life cycle to take advantage of the growing opportunities in the market. However, there are certain factors that are crucial if the benefits are to outweigh the risks; the first and foremost of these is initial project selection. Clear project goals should be established at the outset and referred to frequently, and existing patent landscapes should be investigated and understood.
To achieve process improvements, a good understanding of the process and the facilities is important, as well as looking to reduce waste costs by good waste management. Parallel processing and process telescoping give significant benefits with regard to capacity utilization and product throughput.
Both process and capacity should also be considered when looking to improve the cost of goods. The identification of the key drivers is critical to ensure that valuable development time is focused on where the most significant cost savings can be realized.
Jonathan Knight is vice president of new product development at Cambrex.