K. John Morrow, Jr. and Eric S. Langer, BioPlan Associates11.20.19
BioPlan Associates has followed the bioprocessing industry for 30 years, since 1989, and we have taken note and reported on advances and critical issues in this field through our 16th Annual Report of Biopharmaceutical Manufacturing Capacity and Production.1 This annual study provides insights from over 220 global bioprocessing professionals. In this article we point out just a few of the significant trends, changes and developments affecting the industry over the past decades as they affect contract manufacturing and outsourcing. Some of the most noteworthy include:
• Changes and new developments in manufacturing efficiency and productivity;
• The rapid expansion of outsourcing as a viable option for the industry;
• The proliferation of new companies and bioprocessing technologies; and
• The upward trend of FDA approvals for new biopharmaceutical products.
Changes and New Developments in Manufacturing Efficiency and Productivity
Overall improvement in manufacturing efficiency (Figure 1) has allowed the industry to avoid the production bottleneck that was of concern several years ago. An important aspect of the overall trend in increasing efficiency and productivity has been the improvement over the years in expression systems, which has allowed companies to generate more grams of protein per liter without having to increase the size and numbers of their bioprocessors. This was accomplished, in part, by many small yet incremental improvements in cell line performance. Over the years, companies and academics have looked at numerous options to achieve this goal.
Figure 1. Selected responses—SINGLE most important biomanufacturing trend, 2014-2019.1
While there is continuing interest in expanding the menu of mammalian expression systems, for the most part, new candidates have failed to measure up to the venerable Chinese Hamster Ovary (CHO) workhorse, which has come to dominate the industry. But not only is the CHO system the prevailing player among mammalian options, but the industry appears to have little interest in expanding the role of microbial bioprocessing options, which has not increased significantly in the last 20 years. There are many reasons for the decision to concentrate efforts on the CHO expression system, including higher fidelity of transcription and more authentic glycosylation. But paramount is the fact that success breeds success: as more knowledge of the properties and limitations of CHO piles up, investigators have not ventured into uncharted waters. Moreover, there are a wide variety of different strains of CHO available as open resources, without patent restrictions, which have been modified for a wide range of purposes.
A robust CHO system, responding easily to further engineering, and endowed with multiple selective markers is a tempting plum, especially with the ongoing move to single platform manufacturing at commercial scale. Thus the industry is continuing a trend toward the use of a single platform for expression of a wide range of products.
Other areas for innovation improvements in upstream manufacturing have greatly increased titers in recent years. Much of this is due not only to improved cell lines, expression systems and genetic engineering, but also to improved culture media and optimized additives. With augmentations in these and other areas, users have now been expressing desires for comparable upgrades in automation and in bags, connectors, and other equipment. Downstream purification processes, on the other hand, remain little changed and are increasingly a major limiting factor in commercial-scale biopharmaceutical manufacture.
Another area of expansion over the years has been the adoption of single use components in manufacturing. Earlier, single use technology expanded rapidly but may have now reached a saturation point. As noted, the increases are dramatic, in some cases a doubling in the last five years. The single use technologies have greatly increased overall efficiency of the manufacturing process, as they allow manufacturers to avoid laborious cleaning and quality control of reusable and stainless steel devices. For example, in upstream clinical production, on average, 47.5% of facility unit operations substantially involved single-use devices.
Rapid Expansion of Outsourcing as a Viable Option
Outsourcing is becoming an increasingly important component of bioprocessing company strategy. For example, as new technologies are introduced, it can be more cost effective to outsource certain aspects of the process rather than acquire the training and hardware to carry out many of these tasks in house. Figure 2 presents data on a variety of services that are increasingly outsourced; for example analytical testing is now outsourced by a third of the companies surveyed. Other activities such as toxicity testing and fill/finish operations are at the top of the list.
Figure 2. Selected data—estimated average % of activity outsourced, 2019.1
Analytical testing is a leading outsourcing activity in all regions. But as we evaluate these trends regionally, we find that in general, there appears be a trend for U.S. and Western European biomanufacturers to concentrate more on optimization and incremental bioprocessing improvements, while Rest-of-World bioprocessors are more concerned with basic aspects and operations, and availability of support services, such as analytical testing and validation services. This is to be expected. ROW biomanufacturers appear to generally be devoting more effort and are seeing the most improvements in the more basic aspects of process control and development, while U.S. and Western European companies with more mature bioprocessing tend to report improvements in more specific areas and involving optimization rather than the most basic aspects of bioprocessing.
The countries playing a major role in outsourcing are also notable (Figure 3). While the USA remains the predominant preference, China is now viewed favorably by an increasing percentage of respondents, with Germany, a traditional supplier in third place. China’s rise as a potential outsourcing destination is surprising given the fact that just seven years ago, China was essentially not included as part of the industry’s consideration set.
Figure 3. Selected regions considered a likelihood for CMO outsourcing within 5 years.1
The rise of contract manufacturing organizations (CMOs) has proven to be another defining feature of the bioprocessing industry in recent decades. Outsourcing is increasingly viewed as a desirable option, in part due to the increasing complexity of the technology that may require highly trained staff and specialized instrumentation. Thus, in the future not only will routine services and products with smaller markets be outsourced more frequently, but also more specialized technologies such as cellular and gene therapies.
The Proliferation of New Companies and Bioprocessing Technologies
The biopharmaceutical sector of the international economy continues its robust growth, and CMOs track the overall sector at 12% annual growth. This figure is one many staid, reliable industries can only dream of. Total annual biopharmaceutical revenue was $3.4 billion in 2018 and is expected to grow to approximately $3.8 billion in the current year.
And projections of planned future capacity expansion in the next five years paint a rosy picture. Mammalian cell culture, microbial fermentation, and cell and gene therapy are all slated for large scale expansions in the coming years (Figure 4). This expansion drives both the biopharma companies and the CMOs, which are the beneficiaries of the push toward increased outsourcing.
Figure 4. Planned future capacity expansion, Biotherapeutic Developers vs CMOs.1
CMOs play an outsized role in the industry. Currently CMOs produce approximately 30% of recombinant commercial products, with a handful of large companies dominating the sector. These companies provide R&D expertise and early phase support, so the predominant picture today is of the CMOs playing an even larger role in the early aspects of product development than with commercial manufacturing. As bioprocessing technology matures, it gains in sophistication and complexity, so we can anticipate that CMOs will become increasingly advanced in their mastery of highly demanding and complex protocols. Because CMOs have been involved in a wider range of projects, they are likely to have command of a greater range of technologies.
Historically, the well-established pharma giants employed outsourcing as a way of controlling staff and resources. Today they tend toward more compelling decision making, taking into account their core competencies and balancing their internal strengths with the benefits of specific outsourcing needs. In this approach, they scan the nooks and crannies of their operation, so every aspect is evaluated as a viable outsourcing candidate.
With the growing number of biopharmaceuticals in the developmental pipeline, there is substantial effort within CMOs to hone their skills in order to deal with a wide range of molecules, not limited to recombinant proteins and monoclonal antibodies, but also encompassing a plethora of novel products such as highly engineered antibodies with modified cores and backbones, antibody conjugates, cellular and gene therapies and many other unusual and innovative classes of molecules and their derivatives. Any of these new strategies are moving ahead rapidly.
Large scale, commercial development of various biologics will require the use of single-use bioreactors and expansion of new facilities. BioPlan has documented2 around 180,000 L of single use systems with capabilities in excess of 1000 L. There is a probability that the rapid expansion of single systems will take place at the expense of stainless steel-based bioprocessing.
Although the U.S. was for a long time the dominant player in the industry, recent years have seen competitors from all over the world popping up, especially in China and Latin America. Chinese companies in particular have reached out aggressively, with WuXi investing $60 million to build a manufacturing facility in Worcester MA, in addition to plans to construct a $392 million biologics manufacturing facility in Dundalk, Ireland.
Another important trend over the decades has been the increase in average commercial scale titers, from an estimated 1.1g/L as far back as 2003 to a current level of 3 g/L or more. At the same time, the number of FDA approved recombinant therapeutics has increased dramatically, with a record of 31 approvals in 2017.
A description of trends in the bioprocessing industry would be incomplete without mentioning the concern in the early part of this century over a capacity crunch, which was envisioned as an inability of the commercial manufacturing industry to meet the demands of numerous new products coming online. This crunch did not occur for a variety of reasons which were unforeseen at the time by industry analysts. Most significantly, innovation in media, cell lines and equipment, especially the rise of disposables made it possible to increase capacity whiling taking on multiple projects at the same time.
Gene therapy is another important trend within the industry, requiring different areas of expertise. The production of gene therapy reagents is complex and demanding, so CMOs will need to cultivate highly trained staff to produce these potential treatment options. For this reason these companies are in the midst of expanding their capacity and expertise.
The 16th Annual Report recently summarized ongoing trends in the biopharmaceutical industry, summarizing the state of the industry as “dynamic and complex.” The report argues that the coming years will see the extension of current movements within the industry. Bioprocessing productivity will continue to increase, especially at the upstream end. Reports of expression rates of monoclonal antibodies at titers of > 5 g/L in 14 day fed batch production are common. Such robust values enable the use of smaller scale (2000 L) bioreactors for commercial production, and allow smaller firms to be competitive in the CMO marketplace.
Moreover, the proliferation of new biosimilar and biogeneric products entering the world marketplace, with hundreds in development or already in the biotechnology bazaar, combined with new follow-on biopharmaceuticals, opens a vast landscape for exploitation by newly expanding companies. These advances drive the expansion of the industry to meet the current facility constraints that are causing bottlenecks in production. These bottlenecks also factor into the demand among consumers for further innovation in the field of continuous bioprocessing.
A natural outcome of a dynamic industry is the push to reduce manufacturing costs, which traditionally were not considered an important factor since the selling price of the drug was dictated by value added to patients overall quality of life. However, with the rapid expansion of the industry, companies are negotiating harder with CMOs to reduce product costs.
Overall, the 16th Annual Report posits that with strong overall growth we are seeing a substantial increase in facilities bioprocessing budgets, up an average of 8.2% in 2018, hardly surprising when one contemplates the ruddy health of the overall industry.
Given current activities in the industry, it is to be anticipated that that American entrepreneurs would not be left alone in a world demanding their services. So, we see not only Asian companies, with 25% of the market, but also Western Europe with over 33%, mashing in on the U.S., always the major player, with 37% of capacity.
Upward Trend of FDA Approvals for New Biopharmaceuticals
It is noteworthy that approximately 25 new biopharmaceuticals were approved by the FDA in 2018, swelling an already large proliferation of already approved biologics. As patent protection expires on older products, they will morph into biosimilars, available for exploitation, again expanding the growing market.
The changes taking place within the bioprocessing industry have enabled faster, more efficient and more economical development of new biotherapeutics. During the early period in the development of biologics, the process was laborious, and the rate of new approvals was modest. With the passage of time, both the industry and the regulatory sphere have streamlined their administrative arms, and evaluation of new drug entities move ahead much more rapidly than in the past. One of the most recent regulatory changes designed to accelerate the process was the regenerative medicine advanced therapies (RMAT) designation under the 21st Century Cures Act which is now part of the FDA program for moving new cell therapies through an accelerated approval process.
Conclusion
Aside from being buffeted by many broader worldwide and pharmaceutical industry trends, the biopharmaceutical industry is continuously evolving and demanding new and improved bioprocessing technologies to reduce costs, increase efficiencies, and improve weak development pipelines. In fact, most large pharmaceutical companies are now spending 40-50% or more of their R&D on biopharmaceuticals.
Along with and facilitating this trend, incremental innovation in improved manufacturing productivity continues unabated, driving many biopharmaceutical trends. This is exemplified by constant incremental increases in upstream titers. Innovation and expanded options also speed discovery, increase flexibility, and can drive down costs while improving productivity. The current situation in biopharma is exciting, with new technologies, biosimilars, cellular and gene therapies, and other major opportunities in both established and emerging markets.
References
K.John Morrow, PhD, is a long-time collaborator with BioPlan Associates, Inc. He is president since 2005 of Newport Biotechnology Consultants and has written many articles for Genetic Engineering and Biotechnology News, Life Science Leader, and other Biotechnology journals.
Eric S. Langer is president and managing partner at BioPlan Associates, Inc., a biotechnology and life sciences marketing research and publishing firm established in Rockville, MD in 1989. He is editor of numerous studies, including “Biopharmaceutical Technology in China,” “Advances in Large-scale Biopharmaceutical Manufacturing”, and many other industry reports. elanger@bioplanassociates.com, +1 301-921-5979, www.bioplanassociates.com
• Changes and new developments in manufacturing efficiency and productivity;
• The rapid expansion of outsourcing as a viable option for the industry;
• The proliferation of new companies and bioprocessing technologies; and
• The upward trend of FDA approvals for new biopharmaceutical products.
Changes and New Developments in Manufacturing Efficiency and Productivity
Overall improvement in manufacturing efficiency (Figure 1) has allowed the industry to avoid the production bottleneck that was of concern several years ago. An important aspect of the overall trend in increasing efficiency and productivity has been the improvement over the years in expression systems, which has allowed companies to generate more grams of protein per liter without having to increase the size and numbers of their bioprocessors. This was accomplished, in part, by many small yet incremental improvements in cell line performance. Over the years, companies and academics have looked at numerous options to achieve this goal.
Figure 1. Selected responses—SINGLE most important biomanufacturing trend, 2014-2019.1
While there is continuing interest in expanding the menu of mammalian expression systems, for the most part, new candidates have failed to measure up to the venerable Chinese Hamster Ovary (CHO) workhorse, which has come to dominate the industry. But not only is the CHO system the prevailing player among mammalian options, but the industry appears to have little interest in expanding the role of microbial bioprocessing options, which has not increased significantly in the last 20 years. There are many reasons for the decision to concentrate efforts on the CHO expression system, including higher fidelity of transcription and more authentic glycosylation. But paramount is the fact that success breeds success: as more knowledge of the properties and limitations of CHO piles up, investigators have not ventured into uncharted waters. Moreover, there are a wide variety of different strains of CHO available as open resources, without patent restrictions, which have been modified for a wide range of purposes.
A robust CHO system, responding easily to further engineering, and endowed with multiple selective markers is a tempting plum, especially with the ongoing move to single platform manufacturing at commercial scale. Thus the industry is continuing a trend toward the use of a single platform for expression of a wide range of products.
Other areas for innovation improvements in upstream manufacturing have greatly increased titers in recent years. Much of this is due not only to improved cell lines, expression systems and genetic engineering, but also to improved culture media and optimized additives. With augmentations in these and other areas, users have now been expressing desires for comparable upgrades in automation and in bags, connectors, and other equipment. Downstream purification processes, on the other hand, remain little changed and are increasingly a major limiting factor in commercial-scale biopharmaceutical manufacture.
Another area of expansion over the years has been the adoption of single use components in manufacturing. Earlier, single use technology expanded rapidly but may have now reached a saturation point. As noted, the increases are dramatic, in some cases a doubling in the last five years. The single use technologies have greatly increased overall efficiency of the manufacturing process, as they allow manufacturers to avoid laborious cleaning and quality control of reusable and stainless steel devices. For example, in upstream clinical production, on average, 47.5% of facility unit operations substantially involved single-use devices.
Rapid Expansion of Outsourcing as a Viable Option
Outsourcing is becoming an increasingly important component of bioprocessing company strategy. For example, as new technologies are introduced, it can be more cost effective to outsource certain aspects of the process rather than acquire the training and hardware to carry out many of these tasks in house. Figure 2 presents data on a variety of services that are increasingly outsourced; for example analytical testing is now outsourced by a third of the companies surveyed. Other activities such as toxicity testing and fill/finish operations are at the top of the list.
Figure 2. Selected data—estimated average % of activity outsourced, 2019.1
Analytical testing is a leading outsourcing activity in all regions. But as we evaluate these trends regionally, we find that in general, there appears be a trend for U.S. and Western European biomanufacturers to concentrate more on optimization and incremental bioprocessing improvements, while Rest-of-World bioprocessors are more concerned with basic aspects and operations, and availability of support services, such as analytical testing and validation services. This is to be expected. ROW biomanufacturers appear to generally be devoting more effort and are seeing the most improvements in the more basic aspects of process control and development, while U.S. and Western European companies with more mature bioprocessing tend to report improvements in more specific areas and involving optimization rather than the most basic aspects of bioprocessing.
The countries playing a major role in outsourcing are also notable (Figure 3). While the USA remains the predominant preference, China is now viewed favorably by an increasing percentage of respondents, with Germany, a traditional supplier in third place. China’s rise as a potential outsourcing destination is surprising given the fact that just seven years ago, China was essentially not included as part of the industry’s consideration set.
Figure 3. Selected regions considered a likelihood for CMO outsourcing within 5 years.1
The rise of contract manufacturing organizations (CMOs) has proven to be another defining feature of the bioprocessing industry in recent decades. Outsourcing is increasingly viewed as a desirable option, in part due to the increasing complexity of the technology that may require highly trained staff and specialized instrumentation. Thus, in the future not only will routine services and products with smaller markets be outsourced more frequently, but also more specialized technologies such as cellular and gene therapies.
The Proliferation of New Companies and Bioprocessing Technologies
The biopharmaceutical sector of the international economy continues its robust growth, and CMOs track the overall sector at 12% annual growth. This figure is one many staid, reliable industries can only dream of. Total annual biopharmaceutical revenue was $3.4 billion in 2018 and is expected to grow to approximately $3.8 billion in the current year.
And projections of planned future capacity expansion in the next five years paint a rosy picture. Mammalian cell culture, microbial fermentation, and cell and gene therapy are all slated for large scale expansions in the coming years (Figure 4). This expansion drives both the biopharma companies and the CMOs, which are the beneficiaries of the push toward increased outsourcing.
Figure 4. Planned future capacity expansion, Biotherapeutic Developers vs CMOs.1
CMOs play an outsized role in the industry. Currently CMOs produce approximately 30% of recombinant commercial products, with a handful of large companies dominating the sector. These companies provide R&D expertise and early phase support, so the predominant picture today is of the CMOs playing an even larger role in the early aspects of product development than with commercial manufacturing. As bioprocessing technology matures, it gains in sophistication and complexity, so we can anticipate that CMOs will become increasingly advanced in their mastery of highly demanding and complex protocols. Because CMOs have been involved in a wider range of projects, they are likely to have command of a greater range of technologies.
Historically, the well-established pharma giants employed outsourcing as a way of controlling staff and resources. Today they tend toward more compelling decision making, taking into account their core competencies and balancing their internal strengths with the benefits of specific outsourcing needs. In this approach, they scan the nooks and crannies of their operation, so every aspect is evaluated as a viable outsourcing candidate.
With the growing number of biopharmaceuticals in the developmental pipeline, there is substantial effort within CMOs to hone their skills in order to deal with a wide range of molecules, not limited to recombinant proteins and monoclonal antibodies, but also encompassing a plethora of novel products such as highly engineered antibodies with modified cores and backbones, antibody conjugates, cellular and gene therapies and many other unusual and innovative classes of molecules and their derivatives. Any of these new strategies are moving ahead rapidly.
Large scale, commercial development of various biologics will require the use of single-use bioreactors and expansion of new facilities. BioPlan has documented2 around 180,000 L of single use systems with capabilities in excess of 1000 L. There is a probability that the rapid expansion of single systems will take place at the expense of stainless steel-based bioprocessing.
Although the U.S. was for a long time the dominant player in the industry, recent years have seen competitors from all over the world popping up, especially in China and Latin America. Chinese companies in particular have reached out aggressively, with WuXi investing $60 million to build a manufacturing facility in Worcester MA, in addition to plans to construct a $392 million biologics manufacturing facility in Dundalk, Ireland.
Another important trend over the decades has been the increase in average commercial scale titers, from an estimated 1.1g/L as far back as 2003 to a current level of 3 g/L or more. At the same time, the number of FDA approved recombinant therapeutics has increased dramatically, with a record of 31 approvals in 2017.
A description of trends in the bioprocessing industry would be incomplete without mentioning the concern in the early part of this century over a capacity crunch, which was envisioned as an inability of the commercial manufacturing industry to meet the demands of numerous new products coming online. This crunch did not occur for a variety of reasons which were unforeseen at the time by industry analysts. Most significantly, innovation in media, cell lines and equipment, especially the rise of disposables made it possible to increase capacity whiling taking on multiple projects at the same time.
Gene therapy is another important trend within the industry, requiring different areas of expertise. The production of gene therapy reagents is complex and demanding, so CMOs will need to cultivate highly trained staff to produce these potential treatment options. For this reason these companies are in the midst of expanding their capacity and expertise.
The 16th Annual Report recently summarized ongoing trends in the biopharmaceutical industry, summarizing the state of the industry as “dynamic and complex.” The report argues that the coming years will see the extension of current movements within the industry. Bioprocessing productivity will continue to increase, especially at the upstream end. Reports of expression rates of monoclonal antibodies at titers of > 5 g/L in 14 day fed batch production are common. Such robust values enable the use of smaller scale (2000 L) bioreactors for commercial production, and allow smaller firms to be competitive in the CMO marketplace.
Moreover, the proliferation of new biosimilar and biogeneric products entering the world marketplace, with hundreds in development or already in the biotechnology bazaar, combined with new follow-on biopharmaceuticals, opens a vast landscape for exploitation by newly expanding companies. These advances drive the expansion of the industry to meet the current facility constraints that are causing bottlenecks in production. These bottlenecks also factor into the demand among consumers for further innovation in the field of continuous bioprocessing.
A natural outcome of a dynamic industry is the push to reduce manufacturing costs, which traditionally were not considered an important factor since the selling price of the drug was dictated by value added to patients overall quality of life. However, with the rapid expansion of the industry, companies are negotiating harder with CMOs to reduce product costs.
Overall, the 16th Annual Report posits that with strong overall growth we are seeing a substantial increase in facilities bioprocessing budgets, up an average of 8.2% in 2018, hardly surprising when one contemplates the ruddy health of the overall industry.
Given current activities in the industry, it is to be anticipated that that American entrepreneurs would not be left alone in a world demanding their services. So, we see not only Asian companies, with 25% of the market, but also Western Europe with over 33%, mashing in on the U.S., always the major player, with 37% of capacity.
Upward Trend of FDA Approvals for New Biopharmaceuticals
It is noteworthy that approximately 25 new biopharmaceuticals were approved by the FDA in 2018, swelling an already large proliferation of already approved biologics. As patent protection expires on older products, they will morph into biosimilars, available for exploitation, again expanding the growing market.
The changes taking place within the bioprocessing industry have enabled faster, more efficient and more economical development of new biotherapeutics. During the early period in the development of biologics, the process was laborious, and the rate of new approvals was modest. With the passage of time, both the industry and the regulatory sphere have streamlined their administrative arms, and evaluation of new drug entities move ahead much more rapidly than in the past. One of the most recent regulatory changes designed to accelerate the process was the regenerative medicine advanced therapies (RMAT) designation under the 21st Century Cures Act which is now part of the FDA program for moving new cell therapies through an accelerated approval process.
Conclusion
Aside from being buffeted by many broader worldwide and pharmaceutical industry trends, the biopharmaceutical industry is continuously evolving and demanding new and improved bioprocessing technologies to reduce costs, increase efficiencies, and improve weak development pipelines. In fact, most large pharmaceutical companies are now spending 40-50% or more of their R&D on biopharmaceuticals.
Along with and facilitating this trend, incremental innovation in improved manufacturing productivity continues unabated, driving many biopharmaceutical trends. This is exemplified by constant incremental increases in upstream titers. Innovation and expanded options also speed discovery, increase flexibility, and can drive down costs while improving productivity. The current situation in biopharma is exciting, with new technologies, biosimilars, cellular and gene therapies, and other major opportunities in both established and emerging markets.
References
- 16th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, April 2019, www.bioplanassociates.com/16th
- Langer, E., and Rader, R. The outlook for CMO outsourcing in 2019. Biopharma International 32(1):8-10.
K.John Morrow, PhD, is a long-time collaborator with BioPlan Associates, Inc. He is president since 2005 of Newport Biotechnology Consultants and has written many articles for Genetic Engineering and Biotechnology News, Life Science Leader, and other Biotechnology journals.
Eric S. Langer is president and managing partner at BioPlan Associates, Inc., a biotechnology and life sciences marketing research and publishing firm established in Rockville, MD in 1989. He is editor of numerous studies, including “Biopharmaceutical Technology in China,” “Advances in Large-scale Biopharmaceutical Manufacturing”, and many other industry reports. elanger@bioplanassociates.com, +1 301-921-5979, www.bioplanassociates.com
