Guillaume Plane, Global Development and Marketing Manager, BioReliance End-to-End Solutions, MilliporeSigma01.25.19
The requirements of pharmaceutical development and manufacturing are in constant flux. To flourish, contract development and manufacturing organizations (CDMOs) must adapt to ongoing changes and seize the opportunities presented by these changes. At the same time, CDMO customers must understand the trends and select CDMO partners equipped for success.
Challenges in this arena abound. Increasingly complex biopharma development processes, the growing pressure from drug payers and the advent of biosimilars exert cost pressures. The variable product demand, unknown of whether a product will be a success and intense competition create uncertainty. Emerging markets and the sputtering global economy add to this concern. And unforeseeable, specialized requirements for manufacturing new product classes, such as novel forms of antibody-drug conjugates (ADCs), along with ever-changing regulations and the vagaries of tech transfer make it seem impossible to plan ahead.
This article will examine these current and forthcoming challenges in drug development and manufacturing—and discuss solutions.
Payer pressure, biosimilars and emerging markets
By 2020, according to the IMS Institute for Healthcare Informatics, over $57 billion per year in biologic sales will be off-patent.1 Though dozens of biosimilars are under development and a few are already on the market, the massive patent die-off hasn’t yet prompted the predicted boom of lower-cost biosimilars that is expected to bring relief and savings to patients all over the world. The reality is that to compete with off-patent reference biologics and competing copies, biosimilar drugs must be manufactured more efficiently. However, developing these therapies, even the second time around, is extremely challenging. They are required to have the same structure, activity, clinical efficacy and safety profile as the reference biologics. Expensive development programs—a significant challenge for biosimilars manufacturers under pressure to lower costs and maximize manufacturing flexibility—diminish these projects’ appeal.
The overzealous actions of payers and policy makers may compound the problem. According to the IMS, in some countries, certain stakeholders are short-circuiting competition by mandating artificially low prices for biosimilars. But unhampered competition is needed to ensure that manufacturers have the incentive to invest in ongoing development and commercialization of biosimilar products, which is what will eventually lead to real cost savings. A premature focus on lowering cost at the risk of volume is a mistake.
As time goes on, more and more biosimilars will break through the barriers and come on the market. A huge breakthrough in production costs could trigger a global revolution spurring biosimilar development.2 Geopolitical factors, such as the changing strength of emerging markets or softening of relevant regulatory requirements, as in India,3 can also cause deep shifts in the competitive landscape. Makers of both biologics and biosimilars will undoubtedly be subject to increasing competition. Though the timing and intensity remain uncertain, the ability to keep costs down and the flexibility to tailor yields to match demand will be key.
Managing biologics production cost
Maximizing process yield. Time, of course, is money but in upstream development, process yield comes first. Why? Upstream, where the object is to optimize recombinant protein expression to achieve the maximum possible titers in line with time and cost goals, the cost of goods is inversely linked to yield and titer. Choices made here have profound consequences on the success of a biologic candidate. Cell line selection, clone selection, media development and process scale-up considerations all have a direct effect on yield, product quality and how a molecule fares in the face of regulation.
While the current cost pressures for biological drugs are directed at the end product rather than the cost of development, it’s important to recognize the process needs for maintaining product quality and titers from the beginning. Early analytics development enables developers to modify initial methods to meet process economics for high performance and consistency when manufacturing at scale.
Process fitting. In addition to developing a robust and high-yield process, such as the CHO cell line producing titers >6g/L as shown in Figure 1 (see the image slider at the top of the page), cost pressures can be managed through process fitting experiments that help reduce a molecule’s manufacturing footprint.
For example, in one case, a cation exchange chromatography process was converted from a “bind/elute” step, to an “flow-through” step.
Increased mass loading capacity and decreased conductivity in the second setup signify better, more efficient aggregate removal performance. The second setup also increases productivity through easier column packing, higher flow-through rates, lack of the need for elution, elimination of dilution before later ion exchange steps (no salt) and reduced overall volume to be processed in subsequent virus- and ultra-filtration steps. The second, more efficient column has a smaller footprint and saves raw materials as it requires less resin and buffer to run. In this case, a technology upgrade has improved aggregate removal, increased productivity, reduced overhead and reduced the cost of raw materials.
Supply and Demand
When handling trending uncertainties in supply and demand, flexibility is key. Future trends in supply and demand are unknown and unpredictable. Demand for a product depends on how successful it is. Market growth is further subject to the local economy, and competing regional manufacturers may also be a factor. For a CDMO, the key to adapting to this fluctuating state of affairs is flexibility.
A flexible biologics manufacturing facility features multi-use spaces that can be quickly and easily adapted from one study type or design to the next. Mobile, small-footprint equipment is easy to move and reconfigure into the next manufacturing assembly. Single-use systems lend themselves to flexible manufacturing, from assorted bags up through complete, GMP-scale systems that include processing equipment and reaction vessels. In addition to added flexibility and a small footprint, benefits of these systems include better operator safety, decreased risk of contamination, scalability, reproducibility, lower cost and time saved through efficiencies such as easy setup and cleanup with no cleaning validation requirement.
Because it requires less preparation time and cleaning, compared with stainless steel, single-use technology, capacity increases by 42% to 100% and achieves a per batch cost savings of 23% to 42% (see Figure 2 in the slider).
Clearly, these are significant benefits toward trimming timelines and lowering the cost of production. CDMOs must realize, however, that adoption of new technologies always carries some degree of burden. In the case of single-use systems, for example, the facility’s flow and work spaces will be impacted; there will be different workflows. There will no longer be a need for clean-in-place but there will be a new need for bag storage space. Thinking through all the outcomes of any changes before implementation is always wise.
Tech Transfer
Tech transfer is important in determining cost and links to a critical need: control. With all the cost pressures previously mentioned—the expense of complex drug development, the unpredictability of market demand or product success, and possible competition from emerging global markets—the ability to scale-up and transfer processes efficiently and effectively is crucial. Wasting time is expensive and can result in missed opportunities. Failure to reproduce any aspect of the original process, from materials to titers, can lead to poor product performance and/or productivity with associated cost consequences.
Process transfer is performed at multiple steps in the product life cycle, from the development lab to the pilot lab and clinical manufacturing to internal or external manufacturing sites. It should be a tightly organized activity in which the sending and receiving teams agree on clear endpoints and exchange specific knowledge regarding methods, raw materials, equipment, facilities and analytics.
Because process transfer is truly a keystone of biomanufacturing, transfer skills make a big difference to success. Selecting a CDMO partner with a significant history of tech transfer success helps safeguard the hard development work that has already been done.
One thing to look for in a potential partner is an effective methodology for obtaining reproducible results in different sizes and models of bioreactors. While bioreactors have similar components—impeller, sparger, reactor, etc.—any change in their size, shape or relationship to other elements will cause variations in reactor temperature gradients, the flow of culture media or the degree of perfusion and mixing. As a result, a cell line will not grow the same way in two different bioreactor models, resulting in altered final batch titers or quality.
However, mass transfer modeling of the different bioreactors in use can help determine the right equipment settings to achieve uniform titers and reliable end products.
Consider three bioreactor parameters:
• Volumetric mass transfer coefficient, KL.a (/hr): a constant function of P/V and Vs ;
• Power per unit volume, P/V (W/m3): a variable mixing characteristic; and
• Superficial gas velocity, Vs (m/s): the variable speed of O2 being pumped into the bioreactor.
Their relationship, for a specific bioreactor, is shown in Figure 3. Different bioreactors exhibit very different relationships among these parameters, resulting in distinctive graphs. The key point, however, is that adjustment of the variables P/V and Vs , in two un-like reactors so that their volumetric mass transfer coefficients are the same, can achieve equivalent cell line growth and titer curves in both bioreactors. A methodology like this helps de-risk tech transfer, maximizing the likelihood of success and minimizing time and cost expenditures.
Process Intensification & Continuous Manufacturing
Continuous and intensified processing can increase capacity and speed, lower cost, shrink footprints and mitigate risk. In recent years, biologics developers and manufacturers—with the general support of regulators—have shown great interest in the evolving techniques of process intensification and continuous manufacturing. Still in early adoption phases across the pharmaceutical industry, these techniques are seen to offer great benefits and are starting to be used for both new and established products.
Continuous processes are far from simple; with so many variables, they must generally be custom-designed for each molecule. And while many companies have adopted elements of intensification and several drug products manufactured with continuous processes have been approved by the FDA, research has shown that few companies consider their processes fully intensified or continuous.4
Perfusion systems increase productivity over fed-batch systems, accelerating upstream processing, shrinking development timelines and increasing productivity. Gamma-irradiated single-use assemblies help reduce the risk of contamination. The latest cell retention devices, combined with a new understanding of chemical growth media, have run times ranging from 30 to 60 days or more, as opposed to 10 to 12 days for fed-batch operations. Most of these are upstream processes, but there is interest in eventually joining them to downstream processes for fully integrated production that will offer competitive time and cost savings for biopharmaceutical manufacturing.
The operative word here is will. As a note of caution, even though one might think adoption of the latest, most advanced technologies will propel a development project forward, the opposite can be true. For one thing, the novel technology’s intricacies may not be fully understood. For another, very new technology may not be widely transferrable, limiting later manufacturing options and success. When selecting development and manufacturing processes, it’s crucial to keep the overall product life cycle in mind.
Navigating Cost Pressures and an Uncertain Market
Flexibility is the key to navigating today’s cost pressures and uncertain market, while new technologies should be adopted judiciously. Today’s unpredictable production demands make project planning difficult, while cost pressures necessitate that CDMO facilities be highly efficient and filled to capacity. The antidote is flexibility, which allows a manufacturer to transition quickly from one project to another and operate efficiently. One way to attain such flexibility is through single-use systems. Moving equipment from the upstream to the downstream suite, for example, or pricing and margin calculations are far easier with a single-use approach. Ultimately, for a CDMO, flexibility prevents waste and, most importantly, may be what keeps the company thriving.
While the latest technologies may offer many benefits and efficiencies, innovation must be adopted thoughtfully. If the level of innovation is too high, tech transfer may be difficult or impossible in Phase III. It’s important to strike a balance. For example, continuous processes offer many advantages, but at this time, they would not be reproducible in the majority of manufacturing facilities. The future freedom to transfer a process wherever good business dictates must be carefully considered and preserved throughout development.
References
Challenges in this arena abound. Increasingly complex biopharma development processes, the growing pressure from drug payers and the advent of biosimilars exert cost pressures. The variable product demand, unknown of whether a product will be a success and intense competition create uncertainty. Emerging markets and the sputtering global economy add to this concern. And unforeseeable, specialized requirements for manufacturing new product classes, such as novel forms of antibody-drug conjugates (ADCs), along with ever-changing regulations and the vagaries of tech transfer make it seem impossible to plan ahead.
This article will examine these current and forthcoming challenges in drug development and manufacturing—and discuss solutions.
Payer pressure, biosimilars and emerging markets
By 2020, according to the IMS Institute for Healthcare Informatics, over $57 billion per year in biologic sales will be off-patent.1 Though dozens of biosimilars are under development and a few are already on the market, the massive patent die-off hasn’t yet prompted the predicted boom of lower-cost biosimilars that is expected to bring relief and savings to patients all over the world. The reality is that to compete with off-patent reference biologics and competing copies, biosimilar drugs must be manufactured more efficiently. However, developing these therapies, even the second time around, is extremely challenging. They are required to have the same structure, activity, clinical efficacy and safety profile as the reference biologics. Expensive development programs—a significant challenge for biosimilars manufacturers under pressure to lower costs and maximize manufacturing flexibility—diminish these projects’ appeal.
The overzealous actions of payers and policy makers may compound the problem. According to the IMS, in some countries, certain stakeholders are short-circuiting competition by mandating artificially low prices for biosimilars. But unhampered competition is needed to ensure that manufacturers have the incentive to invest in ongoing development and commercialization of biosimilar products, which is what will eventually lead to real cost savings. A premature focus on lowering cost at the risk of volume is a mistake.
As time goes on, more and more biosimilars will break through the barriers and come on the market. A huge breakthrough in production costs could trigger a global revolution spurring biosimilar development.2 Geopolitical factors, such as the changing strength of emerging markets or softening of relevant regulatory requirements, as in India,3 can also cause deep shifts in the competitive landscape. Makers of both biologics and biosimilars will undoubtedly be subject to increasing competition. Though the timing and intensity remain uncertain, the ability to keep costs down and the flexibility to tailor yields to match demand will be key.
Managing biologics production cost
Maximizing process yield. Time, of course, is money but in upstream development, process yield comes first. Why? Upstream, where the object is to optimize recombinant protein expression to achieve the maximum possible titers in line with time and cost goals, the cost of goods is inversely linked to yield and titer. Choices made here have profound consequences on the success of a biologic candidate. Cell line selection, clone selection, media development and process scale-up considerations all have a direct effect on yield, product quality and how a molecule fares in the face of regulation.
While the current cost pressures for biological drugs are directed at the end product rather than the cost of development, it’s important to recognize the process needs for maintaining product quality and titers from the beginning. Early analytics development enables developers to modify initial methods to meet process economics for high performance and consistency when manufacturing at scale.
Process fitting. In addition to developing a robust and high-yield process, such as the CHO cell line producing titers >6g/L as shown in Figure 1 (see the image slider at the top of the page), cost pressures can be managed through process fitting experiments that help reduce a molecule’s manufacturing footprint.
For example, in one case, a cation exchange chromatography process was converted from a “bind/elute” step, to an “flow-through” step.
Increased mass loading capacity and decreased conductivity in the second setup signify better, more efficient aggregate removal performance. The second setup also increases productivity through easier column packing, higher flow-through rates, lack of the need for elution, elimination of dilution before later ion exchange steps (no salt) and reduced overall volume to be processed in subsequent virus- and ultra-filtration steps. The second, more efficient column has a smaller footprint and saves raw materials as it requires less resin and buffer to run. In this case, a technology upgrade has improved aggregate removal, increased productivity, reduced overhead and reduced the cost of raw materials.
Supply and Demand
When handling trending uncertainties in supply and demand, flexibility is key. Future trends in supply and demand are unknown and unpredictable. Demand for a product depends on how successful it is. Market growth is further subject to the local economy, and competing regional manufacturers may also be a factor. For a CDMO, the key to adapting to this fluctuating state of affairs is flexibility.
A flexible biologics manufacturing facility features multi-use spaces that can be quickly and easily adapted from one study type or design to the next. Mobile, small-footprint equipment is easy to move and reconfigure into the next manufacturing assembly. Single-use systems lend themselves to flexible manufacturing, from assorted bags up through complete, GMP-scale systems that include processing equipment and reaction vessels. In addition to added flexibility and a small footprint, benefits of these systems include better operator safety, decreased risk of contamination, scalability, reproducibility, lower cost and time saved through efficiencies such as easy setup and cleanup with no cleaning validation requirement.
Because it requires less preparation time and cleaning, compared with stainless steel, single-use technology, capacity increases by 42% to 100% and achieves a per batch cost savings of 23% to 42% (see Figure 2 in the slider).
Clearly, these are significant benefits toward trimming timelines and lowering the cost of production. CDMOs must realize, however, that adoption of new technologies always carries some degree of burden. In the case of single-use systems, for example, the facility’s flow and work spaces will be impacted; there will be different workflows. There will no longer be a need for clean-in-place but there will be a new need for bag storage space. Thinking through all the outcomes of any changes before implementation is always wise.
Tech Transfer
Tech transfer is important in determining cost and links to a critical need: control. With all the cost pressures previously mentioned—the expense of complex drug development, the unpredictability of market demand or product success, and possible competition from emerging global markets—the ability to scale-up and transfer processes efficiently and effectively is crucial. Wasting time is expensive and can result in missed opportunities. Failure to reproduce any aspect of the original process, from materials to titers, can lead to poor product performance and/or productivity with associated cost consequences.
Process transfer is performed at multiple steps in the product life cycle, from the development lab to the pilot lab and clinical manufacturing to internal or external manufacturing sites. It should be a tightly organized activity in which the sending and receiving teams agree on clear endpoints and exchange specific knowledge regarding methods, raw materials, equipment, facilities and analytics.
Because process transfer is truly a keystone of biomanufacturing, transfer skills make a big difference to success. Selecting a CDMO partner with a significant history of tech transfer success helps safeguard the hard development work that has already been done.
One thing to look for in a potential partner is an effective methodology for obtaining reproducible results in different sizes and models of bioreactors. While bioreactors have similar components—impeller, sparger, reactor, etc.—any change in their size, shape or relationship to other elements will cause variations in reactor temperature gradients, the flow of culture media or the degree of perfusion and mixing. As a result, a cell line will not grow the same way in two different bioreactor models, resulting in altered final batch titers or quality.
However, mass transfer modeling of the different bioreactors in use can help determine the right equipment settings to achieve uniform titers and reliable end products.
Consider three bioreactor parameters:
• Volumetric mass transfer coefficient, KL.a (/hr): a constant function of P/V and Vs ;
• Power per unit volume, P/V (W/m3): a variable mixing characteristic; and
• Superficial gas velocity, Vs (m/s): the variable speed of O2 being pumped into the bioreactor.
Their relationship, for a specific bioreactor, is shown in Figure 3. Different bioreactors exhibit very different relationships among these parameters, resulting in distinctive graphs. The key point, however, is that adjustment of the variables P/V and Vs , in two un-like reactors so that their volumetric mass transfer coefficients are the same, can achieve equivalent cell line growth and titer curves in both bioreactors. A methodology like this helps de-risk tech transfer, maximizing the likelihood of success and minimizing time and cost expenditures.
Process Intensification & Continuous Manufacturing
Continuous and intensified processing can increase capacity and speed, lower cost, shrink footprints and mitigate risk. In recent years, biologics developers and manufacturers—with the general support of regulators—have shown great interest in the evolving techniques of process intensification and continuous manufacturing. Still in early adoption phases across the pharmaceutical industry, these techniques are seen to offer great benefits and are starting to be used for both new and established products.
Continuous processes are far from simple; with so many variables, they must generally be custom-designed for each molecule. And while many companies have adopted elements of intensification and several drug products manufactured with continuous processes have been approved by the FDA, research has shown that few companies consider their processes fully intensified or continuous.4
Perfusion systems increase productivity over fed-batch systems, accelerating upstream processing, shrinking development timelines and increasing productivity. Gamma-irradiated single-use assemblies help reduce the risk of contamination. The latest cell retention devices, combined with a new understanding of chemical growth media, have run times ranging from 30 to 60 days or more, as opposed to 10 to 12 days for fed-batch operations. Most of these are upstream processes, but there is interest in eventually joining them to downstream processes for fully integrated production that will offer competitive time and cost savings for biopharmaceutical manufacturing.
The operative word here is will. As a note of caution, even though one might think adoption of the latest, most advanced technologies will propel a development project forward, the opposite can be true. For one thing, the novel technology’s intricacies may not be fully understood. For another, very new technology may not be widely transferrable, limiting later manufacturing options and success. When selecting development and manufacturing processes, it’s crucial to keep the overall product life cycle in mind.
Navigating Cost Pressures and an Uncertain Market
Flexibility is the key to navigating today’s cost pressures and uncertain market, while new technologies should be adopted judiciously. Today’s unpredictable production demands make project planning difficult, while cost pressures necessitate that CDMO facilities be highly efficient and filled to capacity. The antidote is flexibility, which allows a manufacturer to transition quickly from one project to another and operate efficiently. One way to attain such flexibility is through single-use systems. Moving equipment from the upstream to the downstream suite, for example, or pricing and margin calculations are far easier with a single-use approach. Ultimately, for a CDMO, flexibility prevents waste and, most importantly, may be what keeps the company thriving.
While the latest technologies may offer many benefits and efficiencies, innovation must be adopted thoughtfully. If the level of innovation is too high, tech transfer may be difficult or impossible in Phase III. It’s important to strike a balance. For example, continuous processes offer many advantages, but at this time, they would not be reproducible in the majority of manufacturing facilities. The future freedom to transfer a process wherever good business dictates must be carefully considered and preserved throughout development.
References
- IMS Institute for Healthcare Informatics. Delivering on the potential of biosimilar medicines. Report. March 2016. https://www.medicinesforeurope.com/wp-content/uploads/2016/03/IMS-Institute-Biosimilar-Report-March-2016-FINAL.pdf.
- Guillaume Plane. Biosimilars Development – Revolution or Evolution? European Biopharmaceutical Review. Summer 2017. Online. http://www.samedanltd.com/?mod=magazine&id=12&page=article&issid=274&pid=4596&readall.
- Bobby George. Changes in Regulatory Requirements for Biosimilar Development In India. Biosimilar Development. November 22, 2016. Online. https://www.biosimilardevelopment.com/doc/changes-in-regulatory-requirements-for-biosimilar-development-in-india-0001.
- Rapti Madurawe, Eric Langer, Girish Malhotra, Merilee Whitney, Peter Levison and Dave Sternasty. Continuous Processing. American Pharmaceutical Review. April 20, 2018. Online. https://www.americanpharmaceuticalreview.com/Featured-Articles/349412-Continuous-Processing
