Maurits Janssen, Head Commercial Development API, Lonza Pharma & Biotech09.16.19
In the development of new cancer therapies, molecules have become more potent, and their structures, physical properties and final dosage forms have simultaneously become more complex. Most of these highly potent oncology small molecule drugs are dosed systematically to patients, thereby affecting non-diseased tissue along with the targeted cancer cells.
The introduction of the antibody drug conjugate (ADC), a relatively new class of cancer therapy compounds that combine cytotoxic small molecule payloads with antibodies, can lessen the impact to non-diseased areas in comparison to systemic administration of highly potent small molecule products. While still systematically admitted, the antibody functionality guides the toxic payload directly to the diseased cells, effectively producing a very focused and concentrated dosing specific to the diseased area. This class of compounds represents a major advance in oncology research and treatment application.
These drugs, combining the potency of highly potent API (HPAPI) and a biologic targeting agent, are now gradually finding their way to the market. The ADC market has grown consistently by double digits since 2012 (17%), according to an analysis by Citeline (July 2017), and there are five ADCs currently approved for commercial use.
Given the commonality of high potency between ADCs and HPAPI products, there will be considerable similarities in their manufacturing and product development best practices. A few examples of these similarities include the importance of operator safety when handling potent chemicals; access to flexible manufacturing assets; and the ability to scale up from drug substance to drug product manufacturing.
However, there are also important differences. ADCs require technologies from the large molecule toolbox including handling, purification and formulation. Furthermore, ADC drug products are often administered via injectable dosing whereas many HPAPI are dosed orally.
These insights will be especially useful for smaller biotech companies, which control around 80% of all new chemical entities (NCEs) in today’s drug development pipeline but often do not have development or production assets of their own. Such companies may benefit from working with an outsourced partner with specialized experience and capabilities, in order to access flexible and phase-appropriate infrastructure to bring the next innovative ADC product from concept to commercialization.
Importance of containment when working with potent compounds
Since HPAPIs and ADCs are very potent compounds, best practices for HPAPI handling and containment can be applied as general lessons for the pharma and biotech industry when it comes to safe manufacturing of ADC products and their toxic payloads.
In the HPAPI small molecule field, the main challenge is to maintain product containment in pharmaceutical production areas within the required low levels, in order to ensure employee safety. However, whereas the containment range for highly potent small molecule APIs typically suffices between 0.1-10 µg/m3 (OEL), ADC payload containment regimes must typically be 10-100 times stricter due to the increased potency of the payload.
Pharmaceutical manufacturers may approach containment in several ways. Most western countries have legislation that requires employees be able to work in normal protective clothing (lab coat & safety goggles). Containment should primarily be achieved by technical (design) measures and, to a lesser extent, by organizational measures to ensure no one relies solely on personal protective equipment.
With plant setup, there are several technical solutions for achieving containment. The primary containment components—including reactors, centrifuge/filter and dryer—have to be tightly closed and robust. Connections between equipment are traditionally hard-piped, though the quality of connections has since improved to the level that flexible connections are gaining use.
Meanwhile, process-related containment challenges generally relate to the addition of raw materials, sampling of reaction mass/product (e.g. during drying) and cleaning of the equipment at the end of production. For the addition or removal of material during production, several packaging solutions and valves are available on the market, and some are easier to use with better quality of containment than others. In addition, any waste stream needs to be managed as strictly as the product itself.
Finally, it is critical that HPAPI and payload handling be performed by a team of experienced and properly trained personnel. Training is crucial for introducing new processes in the facility or new members to a team, but fostering a culture of flawless execution is imperative. Even with the right equipment and best procedures, at least half of performance relates to the workforce in a specific plant or company.
The bottom line is that an integrated employee safety and containment strategy, combined with proactive cleaning and decontamination processes, including during technical transfer—within a culture of flawless execution—facilitates ongoing efficient and safe manufacturing operations and, ultimately, contribute to lower costs for highly potent compounds.
Managing uncertainties with phase-appropriate production scales
Small molecule APIs can be manufactured in a variety of manners to accommodate for scale. Pharma and biotech companies can benefit from choosing an outsourced production partner with a wide and scalable chemical toolbox and able to support the entire product lifecycle from development through market launch, and into efficient commercialization. Working with partners with scalable production assets—inclusive of containment—can lead to time and cost savings during both clinical and commercial production.
In addition, having phase-appropriate manufacturing scales allows pharma companies and CDMOs to anticipate uncertainties encountered during clinical development. It is not uncommon for companies to expect to need extremely large volumes of their drug product, only to have the demand fail to materialize. This is increasingly the case for more specialized products which are becoming the norm in the era of personalized medicine.
This difficulty in projecting demand often means that there is a mismatch between the scale of production equipment expected—defining batch size and thus regulatory relevance—and what is actually necessary. A more realistic challenge of forecasts versus production assets, and especially batch size, will lead to much more economical production costs. Flexibility in assets is increasingly important so that demand swings can be rapidly accommodated.
In such cases that product volumes grow above current production asset capabilities, pharma companies may benefit from working with an external provider that can scale up quickly and seamlessly. In this scenario, validation to a larger concept can be initiated while keeping the same supplier and same production site. This can also substantially lower the risk and costs associated with regulatory change and maintain supply from being interrupted. Of course, this is true for both small molecule APIs as well as for biologics, and especially applicable for highly potent applications where more specialized approaches are required.
A lower-risk option has been demonstrated with dedicated production facilities, e.g. Lonza’s monoplant approach. We developed a dedicated HPAPI manufacturing line for Clovis Oncology for their Rucaparib drug for the treatment of ovarian cancer. By dedicating the line, it allowed a high level of process automation and implementation of real time release testing (RTRT), thus lowering operational costs substantially. In addition, this dedicated line can run 24/7 and 365 days a year and can be achieved with surprisingly smaller scale manufacturing equipment (e.g. reactor size 1’000L)—thereby also lowering capital costs substantially.
By having buffer stock of non-potent intermediates, production can start up immediately upon customer product demand, thus allowing for delivery in record time. Ultimate customer value of security of supply was thus guaranteed, and the possibility of a market shortage has been successfully mitigated. Cost of goods also fell substantiality compared to pre-monoplant production campaigns, due to increased flexibility and the holistic approach.
Formulation: Advantage of integrated services
Following adoption of the optimal manufacturing capacity for the drug substance, the next step is to consider production of the drug product. Particle engineering of HPAPI, e.g. particle size reduction or spray drying, may be required to address dissolution rate or solubility issues. Specialized dosage forms that minimize HPAPI handling during processing and/or better ensure low dose uniformity can come into play, e.g. liquid filled hard capsule technology. Similar considerations as apply to the HPAPI are applicable for these processing steps, i.e. phase-appropriate scale, effective containment, operator experience and culture. Working with a single external provider for drug substance and drug product development to commercialization can introduce synergies and reduce timelines, risk and costs for biopharma companies.
Typically, when working with separate partners, the released drug substance is sent to a drug product manufacturer who performs analyses on the incoming goods and carries the product through further processing. Both transportation and control of incoming goods take time and do not add value, beyond risk mitigation on behalf of the formulator. However, when working with different entities, the time spent on those non-value add activities cannot be avoided as all parties have the responsibility to have proper processes in place.
Other activities where the alignment of drug substance to product manufacturing is rather inefficient include information exchange between different partners in the value chain, alignment and coordination of responsibilities and the respective contractual or quality agreements. The net result is prolonged timelines and costs that can be especially problematic to smaller biopharma companies, especially for drug programs with orphan or break-through designations where speed is paramount.
A Tufts University report concludes that a single source partner has the potential to shorten timelines by an average of 19 weeks for a small molecule through phase I, with an estimated reduction in program costs of nearly $21 million.
Differences to keep in mind between ADCs and small molecule HPAPI
Despite many similarities, there are important differences between ADCs and small molecule HPAPIs which influence manufacturing processes that biopharmaceutical companies need to keep in mind.
First of all, small molecule manufacturing uses a broad toolbox of often aggressive reactions, forcing the need of high capital investment in glass-lined, stainless steel equipment. For ADCs, the manufacturing processes are often water-based or use dilute organic solvent in aqueous-based buffer, and the coupling reaction happens under mild conditions (e.g., to avoid deterioration of the antibody).
However, the main difference for ADCs is the fact that different toxin platforms exist, including maytansines, auristatins, among others where the very strict cleaning requirements (i.e., demonstrating equipment is clean at nano-levels) often lead to the selection of platform-dedicated process equipment. This adds substantial costs to the overall infrastructure, thus impacting the cost of goods.
Because of these high capital costs, there is a growing trend of using disposable, single-use equipment for ADC processing. Although this has not yet become routine for commercial, long-term larger-scale manufacturing, this may change over time for therapeutic indications with small patient populations.
Strengths in ADC production
ADCs are typically produced as bulk drug substance (BDS) that have a similar composition as the final formulation. Therefore, one could think that integration of these would add limited value. However, in this value chain using the same supplier for both intermediates and drug product relieves the drug developer of the risks associated with intermediate supply and management of the integrated timeline.
Lonza is able produce and assemble the separate parts of ADC products at a single facility in Visp, Switzerland. This straightforward setup not only reduces cost and time savings specific to scalable capabilities and reduces material transfer and coordination between separate producers, but it can also lead to easier regulatory processes and filing, since all manufacturing occurs under the same quality systems. The track record from the Visp site includes more than 300 commercial large-scale batches and currently three commercial ADCs.
In addition to providing an integrated model of drug substance and drug product manufacturing across its API and biologic facilities globally, starting in 2020, Lonza will be capable of delivering monoclonal antibodies from the IBEX facility in Visp, the site of drug product manufacturing. That means that all ADC raw materials will be available at the same location, further simplifying the regulatory processes and reducing the manufacturing timeline. Transfer of the antibody from Lonza’s global manufacturing network will no longer be required.
Conclusion
The market for ADCs and HPAPI products in general has more potential than ever, a trend that is bound to continue in the future. That said, there are several important challenges that biopharmaceutical companies will need to overcome. Obstacles include: more complex, highly potent molecules; the ongoing shift to personalized medicine; accelerated timelines to market; and uncertain in-market demand. These challenges can be especially daunting for small and emerging companies.
For companies of all sizes, there may be benefit in working with an adept external partner with a wide set of scalable capabilities. Integrated services and innovative business models are increasingly coming into play. As the ADC market continues to grow, new ways of collaboration will help bring ingenuity and greater efficiencies to the table in order to deliver innovative, life-saving therapies to patients.
Maurits Janssen is Head of Commercial Development, API Manufacturing & Development at Lonza Pharma & Biotech. He is based in Basel, Switzerland.
The introduction of the antibody drug conjugate (ADC), a relatively new class of cancer therapy compounds that combine cytotoxic small molecule payloads with antibodies, can lessen the impact to non-diseased areas in comparison to systemic administration of highly potent small molecule products. While still systematically admitted, the antibody functionality guides the toxic payload directly to the diseased cells, effectively producing a very focused and concentrated dosing specific to the diseased area. This class of compounds represents a major advance in oncology research and treatment application.
These drugs, combining the potency of highly potent API (HPAPI) and a biologic targeting agent, are now gradually finding their way to the market. The ADC market has grown consistently by double digits since 2012 (17%), according to an analysis by Citeline (July 2017), and there are five ADCs currently approved for commercial use.
Given the commonality of high potency between ADCs and HPAPI products, there will be considerable similarities in their manufacturing and product development best practices. A few examples of these similarities include the importance of operator safety when handling potent chemicals; access to flexible manufacturing assets; and the ability to scale up from drug substance to drug product manufacturing.
However, there are also important differences. ADCs require technologies from the large molecule toolbox including handling, purification and formulation. Furthermore, ADC drug products are often administered via injectable dosing whereas many HPAPI are dosed orally.
These insights will be especially useful for smaller biotech companies, which control around 80% of all new chemical entities (NCEs) in today’s drug development pipeline but often do not have development or production assets of their own. Such companies may benefit from working with an outsourced partner with specialized experience and capabilities, in order to access flexible and phase-appropriate infrastructure to bring the next innovative ADC product from concept to commercialization.
Importance of containment when working with potent compounds
Since HPAPIs and ADCs are very potent compounds, best practices for HPAPI handling and containment can be applied as general lessons for the pharma and biotech industry when it comes to safe manufacturing of ADC products and their toxic payloads.
In the HPAPI small molecule field, the main challenge is to maintain product containment in pharmaceutical production areas within the required low levels, in order to ensure employee safety. However, whereas the containment range for highly potent small molecule APIs typically suffices between 0.1-10 µg/m3 (OEL), ADC payload containment regimes must typically be 10-100 times stricter due to the increased potency of the payload.
Pharmaceutical manufacturers may approach containment in several ways. Most western countries have legislation that requires employees be able to work in normal protective clothing (lab coat & safety goggles). Containment should primarily be achieved by technical (design) measures and, to a lesser extent, by organizational measures to ensure no one relies solely on personal protective equipment.
With plant setup, there are several technical solutions for achieving containment. The primary containment components—including reactors, centrifuge/filter and dryer—have to be tightly closed and robust. Connections between equipment are traditionally hard-piped, though the quality of connections has since improved to the level that flexible connections are gaining use.
Meanwhile, process-related containment challenges generally relate to the addition of raw materials, sampling of reaction mass/product (e.g. during drying) and cleaning of the equipment at the end of production. For the addition or removal of material during production, several packaging solutions and valves are available on the market, and some are easier to use with better quality of containment than others. In addition, any waste stream needs to be managed as strictly as the product itself.
Finally, it is critical that HPAPI and payload handling be performed by a team of experienced and properly trained personnel. Training is crucial for introducing new processes in the facility or new members to a team, but fostering a culture of flawless execution is imperative. Even with the right equipment and best procedures, at least half of performance relates to the workforce in a specific plant or company.
The bottom line is that an integrated employee safety and containment strategy, combined with proactive cleaning and decontamination processes, including during technical transfer—within a culture of flawless execution—facilitates ongoing efficient and safe manufacturing operations and, ultimately, contribute to lower costs for highly potent compounds.
Managing uncertainties with phase-appropriate production scales
Small molecule APIs can be manufactured in a variety of manners to accommodate for scale. Pharma and biotech companies can benefit from choosing an outsourced production partner with a wide and scalable chemical toolbox and able to support the entire product lifecycle from development through market launch, and into efficient commercialization. Working with partners with scalable production assets—inclusive of containment—can lead to time and cost savings during both clinical and commercial production.
In addition, having phase-appropriate manufacturing scales allows pharma companies and CDMOs to anticipate uncertainties encountered during clinical development. It is not uncommon for companies to expect to need extremely large volumes of their drug product, only to have the demand fail to materialize. This is increasingly the case for more specialized products which are becoming the norm in the era of personalized medicine.
This difficulty in projecting demand often means that there is a mismatch between the scale of production equipment expected—defining batch size and thus regulatory relevance—and what is actually necessary. A more realistic challenge of forecasts versus production assets, and especially batch size, will lead to much more economical production costs. Flexibility in assets is increasingly important so that demand swings can be rapidly accommodated.
In such cases that product volumes grow above current production asset capabilities, pharma companies may benefit from working with an external provider that can scale up quickly and seamlessly. In this scenario, validation to a larger concept can be initiated while keeping the same supplier and same production site. This can also substantially lower the risk and costs associated with regulatory change and maintain supply from being interrupted. Of course, this is true for both small molecule APIs as well as for biologics, and especially applicable for highly potent applications where more specialized approaches are required.
A lower-risk option has been demonstrated with dedicated production facilities, e.g. Lonza’s monoplant approach. We developed a dedicated HPAPI manufacturing line for Clovis Oncology for their Rucaparib drug for the treatment of ovarian cancer. By dedicating the line, it allowed a high level of process automation and implementation of real time release testing (RTRT), thus lowering operational costs substantially. In addition, this dedicated line can run 24/7 and 365 days a year and can be achieved with surprisingly smaller scale manufacturing equipment (e.g. reactor size 1’000L)—thereby also lowering capital costs substantially.
By having buffer stock of non-potent intermediates, production can start up immediately upon customer product demand, thus allowing for delivery in record time. Ultimate customer value of security of supply was thus guaranteed, and the possibility of a market shortage has been successfully mitigated. Cost of goods also fell substantiality compared to pre-monoplant production campaigns, due to increased flexibility and the holistic approach.
Formulation: Advantage of integrated services
Following adoption of the optimal manufacturing capacity for the drug substance, the next step is to consider production of the drug product. Particle engineering of HPAPI, e.g. particle size reduction or spray drying, may be required to address dissolution rate or solubility issues. Specialized dosage forms that minimize HPAPI handling during processing and/or better ensure low dose uniformity can come into play, e.g. liquid filled hard capsule technology. Similar considerations as apply to the HPAPI are applicable for these processing steps, i.e. phase-appropriate scale, effective containment, operator experience and culture. Working with a single external provider for drug substance and drug product development to commercialization can introduce synergies and reduce timelines, risk and costs for biopharma companies.
Typically, when working with separate partners, the released drug substance is sent to a drug product manufacturer who performs analyses on the incoming goods and carries the product through further processing. Both transportation and control of incoming goods take time and do not add value, beyond risk mitigation on behalf of the formulator. However, when working with different entities, the time spent on those non-value add activities cannot be avoided as all parties have the responsibility to have proper processes in place.
Other activities where the alignment of drug substance to product manufacturing is rather inefficient include information exchange between different partners in the value chain, alignment and coordination of responsibilities and the respective contractual or quality agreements. The net result is prolonged timelines and costs that can be especially problematic to smaller biopharma companies, especially for drug programs with orphan or break-through designations where speed is paramount.
A Tufts University report concludes that a single source partner has the potential to shorten timelines by an average of 19 weeks for a small molecule through phase I, with an estimated reduction in program costs of nearly $21 million.
Differences to keep in mind between ADCs and small molecule HPAPI
Despite many similarities, there are important differences between ADCs and small molecule HPAPIs which influence manufacturing processes that biopharmaceutical companies need to keep in mind.
First of all, small molecule manufacturing uses a broad toolbox of often aggressive reactions, forcing the need of high capital investment in glass-lined, stainless steel equipment. For ADCs, the manufacturing processes are often water-based or use dilute organic solvent in aqueous-based buffer, and the coupling reaction happens under mild conditions (e.g., to avoid deterioration of the antibody).
However, the main difference for ADCs is the fact that different toxin platforms exist, including maytansines, auristatins, among others where the very strict cleaning requirements (i.e., demonstrating equipment is clean at nano-levels) often lead to the selection of platform-dedicated process equipment. This adds substantial costs to the overall infrastructure, thus impacting the cost of goods.
Because of these high capital costs, there is a growing trend of using disposable, single-use equipment for ADC processing. Although this has not yet become routine for commercial, long-term larger-scale manufacturing, this may change over time for therapeutic indications with small patient populations.
Strengths in ADC production
ADCs are typically produced as bulk drug substance (BDS) that have a similar composition as the final formulation. Therefore, one could think that integration of these would add limited value. However, in this value chain using the same supplier for both intermediates and drug product relieves the drug developer of the risks associated with intermediate supply and management of the integrated timeline.
Lonza is able produce and assemble the separate parts of ADC products at a single facility in Visp, Switzerland. This straightforward setup not only reduces cost and time savings specific to scalable capabilities and reduces material transfer and coordination between separate producers, but it can also lead to easier regulatory processes and filing, since all manufacturing occurs under the same quality systems. The track record from the Visp site includes more than 300 commercial large-scale batches and currently three commercial ADCs.
In addition to providing an integrated model of drug substance and drug product manufacturing across its API and biologic facilities globally, starting in 2020, Lonza will be capable of delivering monoclonal antibodies from the IBEX facility in Visp, the site of drug product manufacturing. That means that all ADC raw materials will be available at the same location, further simplifying the regulatory processes and reducing the manufacturing timeline. Transfer of the antibody from Lonza’s global manufacturing network will no longer be required.
Conclusion
The market for ADCs and HPAPI products in general has more potential than ever, a trend that is bound to continue in the future. That said, there are several important challenges that biopharmaceutical companies will need to overcome. Obstacles include: more complex, highly potent molecules; the ongoing shift to personalized medicine; accelerated timelines to market; and uncertain in-market demand. These challenges can be especially daunting for small and emerging companies.
For companies of all sizes, there may be benefit in working with an adept external partner with a wide set of scalable capabilities. Integrated services and innovative business models are increasingly coming into play. As the ADC market continues to grow, new ways of collaboration will help bring ingenuity and greater efficiencies to the table in order to deliver innovative, life-saving therapies to patients.
Maurits Janssen is Head of Commercial Development, API Manufacturing & Development at Lonza Pharma & Biotech. He is based in Basel, Switzerland.
