- Email: [email protected]
Industry Perspectives on the Development of Biologics
Biologics Supplement Editor’s note: Industry has unique constraints in the development of novel biologic therapies, and understanding the issues that face our industry collaborators will facilitate more fruitful interactions and increase the potential for translation and implementation of our research in this area. Because industry has enormous capacity in biologics research and development, it is to our advantage to partner with industry early and often to ensure that the priorities of our patients are incorporated during the development process. Gwendolyn Sowa, MD, PhD
Industry Perspectives on the Development of Biologics Brian C. Kramer, PhD The goal of every pharmaceutical company in business today is to improve the quality of life for patients. This is accomplished by generating or leveraging scientific knowledge and technology to maintain a robust pipeline and release safe and efficacious products into the market. To accomplish this goal, it is imperative that the pharmaceutical industry invest a significant amount of capital into its research and development (R&D) endeavors. According to the Pharmaceutical Research and Manufacturers of America, the industry spent a record $65.3 billion discovering and developing new medicines in 2009 [1]. With record high R&D budgets, one might expect a plethora of new drugs to reach the market every year, but, in reality, this is not the case. In fact, only 1 in 10,000 new pharmaceuticals ever makes it from the bench to the patient, and it can take upward of 15 years of R&D time and costs of over $800 million dollars to do so [1]. Keep in mind that the $800 million dollars only covers the costs associated for that 1 in 10,000 that makes it to market. It does not account for money invested on the other 9,999 that do not make it through the pipeline. The other 9,999 will either die on the bench or during preclinical efficacy and toxicology testing or in the clinic during human safety and efficacy trials, or due to insurmountable technical or manufacturing challenges along the way. They might even gain approval by the U.S. Food and Drug Administration, make it to market and then be recalled due to some unforeseen adverse effect. Needless to say, the further along a drug goes in the process before a no-go decision is made, the more money that is lost on the investment. The bottom line is that the road from an idea in the laboratory to a product in the market is a long, arduous, and expensive one. Pharmaceuticals are composed of both “active” and “inactive” ingredients. The active ingredient is the component of a drug that has biologic activity, whereas the inactive ingredients are inert and are related to the physical characteristics (ie, tablet or liquid) of the drug. Generally speaking, there are 2 broad categories of pharmaceutical actives that enter into the industry pipeline; chemically derived, small-molecule active ingredients and biologically derived, large-molecule active ingredients. Although both chemical- and biologic-based actives are very important; biologic-based actives have truly revolutionized the pharmaceutical industry and provided powerful drugs for unmet medical needs. The development of high-impact, targeted biologics offers some very unique therapeutic opportunities to treat or prevent illness and is a critical component in the battle to fight disease and improve the quality of life for patients. A pharmaceutical product is considered a biologic when it contains an active ingredient that is derived from a mammalian cell, a microorganism, recombinant DNA, or recombinant protein. These types of products fall into a wide range of categories and complexity. Antibodies and therapeutic proteins are prime examples of actives that have been biologically derived. Products such as Activase (tissue plasminogen activator) (Genentech, Inc., San Francisco, CA), Genotropin (human growth hormone) (Pfizer, Inc, Franklin, OH), Epogen (erythropoietin) (Amgen, Inc, Thousand Oaks, CA), Neupogen (granulocyte coloPM&R
S132
1934-1482/11/$36.00 Printed in U.S.A.
B.C.K. Department of Cell and Molecular Biology, Advanced Technologies and Regenerative Medicine, LLC an affiliate of Johnson & Johnson, CMB, U.S. Route 22 West, Somerville, NJ 08876. Address correspondence to: B.K.; e-mail: [email protected] Disclosure: 2B, full time employee of Advanced Technologies and Regenerative Medicine The opinions expressed in this article are those of the author and do not necessarily represent those of Advanced Technologies and Regenerative Medicine, LLC and its affiliates. Disclosure Key can be found on the Table of Contents and at www.pmrjournal.org Submitted for publication May 3, 2011; accepted May 4 2011.
© 2011 by the American Academy of Physical Medicine and Rehabilitation Vol. 3, S132-S135, June 2011 DOI: 10.1016/j.pmrj.2011.05.006
PM&R
ny-stimulating factor) (Amgen, Inc, Thousand Oaks, CA), Remicade (infliximab) (Centocor Ortho Biotech, Inc, Horsham, PA), and Stelara (ustekinumab) (Centocor Ortho Biotech, Inc, Horsham, PA) are just some examples of biologics in this category. These biologics have fundamentally changed the way we approach and treat disease, and, undoubtedly, many new biologics of this category are in the industry’s pipelines. The next generation of biologics that is now being actively pursued by the industry is in the field of regenerative medicine. This cutting edge technology explores the use of direct injection of cells and tissues to treat and manage disease. In this case, the transplanted cells themselves act as polypharmacies or factor factories, and secreting numerous active factors into the host, which may provide therapeutic solutions to many of the chronic diseases for which few other options currently exist. All pharmaceuticals (biologic and chemical) will work their way through the product development process, which can be divided into 3 major stages. The first stage of the process is known as the discovery phase. This phase can last about 3-6 years and covers the period of time from when an idea is generated, the prototype of the drug is generated, the efficacy of the drug is confirmed in the appropriate preclinical model, and all necessary toxicology studies are completed. Essentially, the discovery phase concludes when an application is filed with the appropriate regulatory agency to begin clinical trials. During the early phase of discovery one can test research-grade material for early proof-of-principle and efficacy studies, however, in latter phases of discovery, such material might no longer be appropriate. Regulatory requirements state that, for a preclinical study to be useful in assuring the safety of humans in clinical trials, the drug being tested in preclinical toxicology studies must be comparable with the drug that is being used in the clinical trials. If any changes (ie, in chemistry or manufacturing process) are made to the drug between preclinical toxicology testing and clinical testing, the sponsor is required to comply with regulatory requirements and justify why they should be allowed to continue with the human clinical studies without conducting additional preclinical toxicology testing to determine safety. Due to regulatory requirements, every effort will be made to conduct toxicology studies by using materials that closely resemble both the clinical supply and the final product. Therefore, it is always important to begin the development process with the end product in mind because ultimately the product is the process. The final product is not only defined by what the drug is composed of (eg, active and nonactive ingredients), but by the process used to manufacture it, and it is crucial to devise this strategy as early as possible. It is one thing to be able to generate relatively small amounts of material for a proof-of-principle study, but it is a completely different thing to generate large quantities of GLP/GMP (good laboratory practice/good manufacturing practice) grade material suitable for preclinical toxicology and subsequent clin-
Vol. 3, Iss. 6S, 2011
S133
ical trials. The key at this stage is to figure out how to take the process that you have developed at the bench to generate small quantities of material and scale it up to produce enough material to satisfy the needs of clinical trials and product launch. The second phase of the product development is called the development phase, which can last 5-10 years. Most of this time is spent conducting the human safety and efficacy trials. In addition, a significant amount of work is done in parallel to improve the manufacturing process that was begun in the discovery phase. Keep in mind, however, that most of the manufacturing plan should really be well vetted before this stage of the product development process. Commercialization, the third and final phase can last anywhere from 5-12 years. It is during this phase when the product is marketed, sold, and distributed. Long-term efficacy and safety are also monitored. This phase begins when the U.S. Food and Drug Administration approves the product for sale and essentially ends when the patent expires. Once the patent expires, other companies can then produce generics or “biosimilars” and the innovators will lose their exclusivity. In the United States, under current patent law, the life of a patent is 20 years from the date the application is filed. Although that might seem like a long time to have patent protection, it is important to put this time frame into the context of the product development process. It is quite common for a patent to be filed very early on in the development process. In fact, a patent is often filed as soon as proof-of-principle data are obtained. For argument’s sake, let us assume that it takes 12 years before a drug garners agency approval and can be brought to market. This means that the company invested all of that time and capital only to have 8 years of patent protection (and, therefore, market exclusivity) before a generic or biosimilar version of that drug floods the market. The reality, in this scenario, is that the innovators only have 8 years to recoup all of their R&D investment, although, at the same time, generate revenue to fund further R&D efforts. Remember that only 1 in 10,000 new pharmaceuticals ever make it to market, so the one drug that does make it to the market also has to generate enough revenue to fund the R&D of the other 9,999 that do not. Without this continued income stream, pharmaceutical R&D would be unable to continue. The bottom line is that, the more complex the molecule, the more complicated, risky, and costly the development process will likely be. Due to their nature, biologics are inherently complex, difficult to mass produce, and present the industry with some very significant challenges. First off, biologic actives are usually much larger than a compound-based active. A typical compound based active, for example, tends to have a molecular weight of approximately 100-600 Da (eg, acetaminophen, 151 Da; acetylsalicylic acid, 180 Da; Sudafed (pseudoephedrine) (McNeil-PPC, New Brunswick, NJ), 165 Da; Risperdal (risperidone) (Janssen, Titusville, NJ), 410 Da;
S134
Kramer
INDUSTRY PERSPECTIVES ON THE DEVELOPMENT OF BIOLOGICS
Motrin (ibuprofen) (McNeil-PPC, New Brunswick, NJ), 206 Da), whereas a typical biologic active has a molecular weight upward of 200 kDa (eg, Epogen, 30.4 kDa; Genotropin, 22.1 kDa; Remicade, 149 kDa; Simponi (golimumab) (Centocor Ortho Biotech, Inc, Horsham, PA), 147 kDa; Stelara, 145 kDa). Second, biologic actives are made from proteins, sugars, nucleic acids, or a combination of these components, which are all created from a biological process, usually in situ. Biologics can also be actual living cells or tissue as well. As a result, biologics are typically generated in an aqueous environment by using large-scale bioreactors in volumes upward of 20,000 L. In spite of the large volume used to generate these actives, the overall product yield is relatively low (0.5-5 g/L). Traditional chemical-based compounds, however, are generally made through multiple chemical reactions and isolations in primarily organic environments in reactor volumes of 5,000-10,000 L and the relative product yield is quite high (100 g/L). The relatively low yield of a biologic is one factor that contributes to a higher cost to market compared with its small-molecule counterpart. The relatively low yield is not the only thing that contributes to the higher cost of a biologic product. The manufacturing process of a biologic is also a major undertaking. Assume that a company has developed an antibody to treat a particular illness. This antibody must be produced in a living cell and that cell must be grown in a certain media, which may require the use of serum. The cells must be grown at a certain temperature, in an appropriately sized vessel to generate the quantity of material required. Before a company could even begin to generate significant amounts of material for testing purposes, no less the actual product, a significant capital investment would have to be made to build a suitable bioprocessing facility. In addition to the physical space that would be required for such a facility, millions of dollars of specialized equipment would need to be purchased and installed, quality systems put in place, and personnel hired to run such a facility. Now let us consider some challenges related to the growth media for the host cells. Consider a scenario in which you need to use 20% fetal bovine serum (FBS) to grow your host cells. Now assume that you need to run a 20,000-L bioreactor to generate enough material to treat a certain number of patients. This means that 4,000 L of FBS would be required for this run. If we assume that the cost of serum is somewhere around $600-$800 a liter, the cost just to purchase FBS for this run would be upward of $3,200,000. This amount does not take into consideration the cost of the other raw materials that you would need to have on hand and ultimately source to grow your cells. Cost of the serum is not the only consideration though. One also has to decide where to source the FBS that will be used to grow the host cells used to generate the antibody. This decision is based on a variety of factors, but, most importantly, it will be driven by what source would be most acceptable to the most agencies that will have regulatory
authority over the product. As one might imagine, once this decision is made, it is very difficult to change course. Say that the decision is made to buy FBS from the United States. What will you do if there is an outbreak of mad-cow disease and you can no longer use that FBS source? What will happen to your ability to meet product development timelines or consumer demands and produce your biologic if your source of FBS dries up? All of this uncertainty and cost, and yet all we have examined is FBS! Another issue that must be considered is whether or not to use antibiotics in your cell culture media, and if so, at what point. Although antibiotics are widely used in research-grade cell culture, their use in manufacturing of the final product is minimized. If you choose to use antibiotics, you might receive limited approval to use the product due to issues related to antibiotic allergies in the patients who use the product. If you do not use antibiotics, bacterial contamination may occur. If this happens, the bioreactor run has to be terminated, its contents discarded, and the time and monetary investment that was made on that run literally goes down the drain. Once the media components have been worked out, one has to consider how to grow the cells themselves. If the cells are adherent, it is likely that you will need to grow them on some sort of microcarrier. A decision will need to be made as to what microcarrier to use. This decision is based on a variety of factors, including cost, availability, and composition, as well as the effect that the microcarrier will have on the cells and media, just to name a few. Regardless of whether the cells are adherent or not, one also has to figure out how to grow them in a large bioreactor, ensure that the cells do not settle, and that there is adequate gas and nutrient exchange. Once all of the growth conditions have been worked out, one has to figure out the best way to collect and purify the antibody that has been generated. Although this does not begin to cover all of the manufacturing issues that must be considered, one cannot help but see the inherent challenges to developing a manufacturing plan that does not make the cost of goods itself become prohibitive to development. Ultimately, cell culture, which is a relatively simple thing to accomplish in the laboratory, becomes a very complex and involved process when you are considering large-scale GLP/GMP manufacturing. As you can imagine, the high cost and complexity of these processes help to drive additional R&D efforts to reduce the cost and increase efficiency of these processes. Manufacturing is a main contributor to the cost of a biologic, however, extensive testing requirements for setting product specification for safety and efficacy is also costly. Once a pharmaceutical is manufactured, it is necessary to have a way to test the final product to ensure that your product meets the specifications set out with respect to safety and efficacy. In the case of a small molecule, this might be a relatively simple and inexpensive assay in which you examine the purity of your compound by using chromatography. In the case of a biologic, the testing might be much more
PM&R
complex and require numerous assays. If your product is cell based, for example, you might have to examine a variety of cell surface markers or perhaps look at the level of growth factor release. You would also have to ensure proper karyotype and that there are no biologic and or viral contaminants in the product, just to name a few. Once you have determined that you have produced the active you intended, it is also necessary to be able to confirm the biologic activity of that active. In the case of a small molecule, this might be a simple receptor-binding assay to ensure that your molecule binds to its target appropriately. In the case of a biologic, one might not necessarily have a complete understanding of the mechanism of action. This might result in having to test each new batch of a biologic in a preclinical model, for example. Alternatively, you might need to use one or more cell-based assays to show that your biologic is having a desired effect. This can be further complicated by the fact that in vitro biologic systems can be
Vol. 3, Iss. 6S, 2011
S135
inherently difficult to consistently reproduce. Regardless, a considerable amount of effort and money generally goes into determining the best course of action in these complex situations. Although the complexities and scenarios described here are by no means exhaustive, they were meant to illustrate some of the challenges that the industry faces when developing biologics. Realistically, these challenges will only increase over time as groundbreaking advancements in the biological sciences and regenerative medicine are made. Ultimately, overcoming these challenges will result in the development of more sophisticated and precise biologics that can treat a variety of diseases and improve the quality of life of our patients.
REFERENCE 1. Pharmaceutical Research and Manufacturers of America. Research. Available at: http://www.phrma.org/research. Accessed May 16, 2011.
Industry Perspectives on the Development of Biologics Brian C. Kramer, PhD The goal of every pharmaceutical company in business today is to improve the quality of life for patients. This is accomplished by generating or leveraging scientific knowledge and technology to maintain a robust pipeline and release safe and efficacious products into the market. To accomplish this goal, it is imperative that the pharmaceutical industry invest a significant amount of capital into its research and development (R&D) endeavors. According to the Pharmaceutical Research and Manufacturers of America, the industry spent a record $65.3 billion discovering and developing new medicines in 2009 [1]. With record high R&D budgets, one might expect a plethora of new drugs to reach the market every year, but, in reality, this is not the case. In fact, only 1 in 10,000 new pharmaceuticals ever makes it from the bench to the patient, and it can take upward of 15 years of R&D time and costs of over $800 million dollars to do so [1]. Keep in mind that the $800 million dollars only covers the costs associated for that 1 in 10,000 that makes it to market. It does not account for money invested on the other 9,999 that do not make it through the pipeline. The other 9,999 will either die on the bench or during preclinical efficacy and toxicology testing or in the clinic during human safety and efficacy trials, or due to insurmountable technical or manufacturing challenges along the way. They might even gain approval by the U.S. Food and Drug Administration, make it to market and then be recalled due to some unforeseen adverse effect. Needless to say, the further along a drug goes in the process before a no-go decision is made, the more money that is lost on the investment. The bottom line is that the road from an idea in the laboratory to a product in the market is a long, arduous, and expensive one. Pharmaceuticals are composed of both “active” and “inactive” ingredients. The active ingredient is the component of a drug that has biologic activity, whereas the inactive ingredients are inert and are related to the physical characteristics (ie, tablet or liquid) of the drug. Generally speaking, there are 2 broad categories of pharmaceutical actives that enter into the industry pipeline; chemically derived, small-molecule active ingredients and biologically derived, large-molecule active ingredients. Although both chemical- and biologic-based actives are very important; biologic-based actives have truly revolutionized the pharmaceutical industry and provided powerful drugs for unmet medical needs. The development of high-impact, targeted biologics offers some very unique therapeutic opportunities to treat or prevent illness and is a critical component in the battle to fight disease and improve the quality of life for patients. A pharmaceutical product is considered a biologic when it contains an active ingredient that is derived from a mammalian cell, a microorganism, recombinant DNA, or recombinant protein. These types of products fall into a wide range of categories and complexity. Antibodies and therapeutic proteins are prime examples of actives that have been biologically derived. Products such as Activase (tissue plasminogen activator) (Genentech, Inc., San Francisco, CA), Genotropin (human growth hormone) (Pfizer, Inc, Franklin, OH), Epogen (erythropoietin) (Amgen, Inc, Thousand Oaks, CA), Neupogen (granulocyte coloPM&R
S132
1934-1482/11/$36.00 Printed in U.S.A.
B.C.K. Department of Cell and Molecular Biology, Advanced Technologies and Regenerative Medicine, LLC an affiliate of Johnson & Johnson, CMB, U.S. Route 22 West, Somerville, NJ 08876. Address correspondence to: B.K.; e-mail: [email protected] Disclosure: 2B, full time employee of Advanced Technologies and Regenerative Medicine The opinions expressed in this article are those of the author and do not necessarily represent those of Advanced Technologies and Regenerative Medicine, LLC and its affiliates. Disclosure Key can be found on the Table of Contents and at www.pmrjournal.org Submitted for publication May 3, 2011; accepted May 4 2011.
© 2011 by the American Academy of Physical Medicine and Rehabilitation Vol. 3, S132-S135, June 2011 DOI: 10.1016/j.pmrj.2011.05.006
PM&R
ny-stimulating factor) (Amgen, Inc, Thousand Oaks, CA), Remicade (infliximab) (Centocor Ortho Biotech, Inc, Horsham, PA), and Stelara (ustekinumab) (Centocor Ortho Biotech, Inc, Horsham, PA) are just some examples of biologics in this category. These biologics have fundamentally changed the way we approach and treat disease, and, undoubtedly, many new biologics of this category are in the industry’s pipelines. The next generation of biologics that is now being actively pursued by the industry is in the field of regenerative medicine. This cutting edge technology explores the use of direct injection of cells and tissues to treat and manage disease. In this case, the transplanted cells themselves act as polypharmacies or factor factories, and secreting numerous active factors into the host, which may provide therapeutic solutions to many of the chronic diseases for which few other options currently exist. All pharmaceuticals (biologic and chemical) will work their way through the product development process, which can be divided into 3 major stages. The first stage of the process is known as the discovery phase. This phase can last about 3-6 years and covers the period of time from when an idea is generated, the prototype of the drug is generated, the efficacy of the drug is confirmed in the appropriate preclinical model, and all necessary toxicology studies are completed. Essentially, the discovery phase concludes when an application is filed with the appropriate regulatory agency to begin clinical trials. During the early phase of discovery one can test research-grade material for early proof-of-principle and efficacy studies, however, in latter phases of discovery, such material might no longer be appropriate. Regulatory requirements state that, for a preclinical study to be useful in assuring the safety of humans in clinical trials, the drug being tested in preclinical toxicology studies must be comparable with the drug that is being used in the clinical trials. If any changes (ie, in chemistry or manufacturing process) are made to the drug between preclinical toxicology testing and clinical testing, the sponsor is required to comply with regulatory requirements and justify why they should be allowed to continue with the human clinical studies without conducting additional preclinical toxicology testing to determine safety. Due to regulatory requirements, every effort will be made to conduct toxicology studies by using materials that closely resemble both the clinical supply and the final product. Therefore, it is always important to begin the development process with the end product in mind because ultimately the product is the process. The final product is not only defined by what the drug is composed of (eg, active and nonactive ingredients), but by the process used to manufacture it, and it is crucial to devise this strategy as early as possible. It is one thing to be able to generate relatively small amounts of material for a proof-of-principle study, but it is a completely different thing to generate large quantities of GLP/GMP (good laboratory practice/good manufacturing practice) grade material suitable for preclinical toxicology and subsequent clin-
Vol. 3, Iss. 6S, 2011
S133
ical trials. The key at this stage is to figure out how to take the process that you have developed at the bench to generate small quantities of material and scale it up to produce enough material to satisfy the needs of clinical trials and product launch. The second phase of the product development is called the development phase, which can last 5-10 years. Most of this time is spent conducting the human safety and efficacy trials. In addition, a significant amount of work is done in parallel to improve the manufacturing process that was begun in the discovery phase. Keep in mind, however, that most of the manufacturing plan should really be well vetted before this stage of the product development process. Commercialization, the third and final phase can last anywhere from 5-12 years. It is during this phase when the product is marketed, sold, and distributed. Long-term efficacy and safety are also monitored. This phase begins when the U.S. Food and Drug Administration approves the product for sale and essentially ends when the patent expires. Once the patent expires, other companies can then produce generics or “biosimilars” and the innovators will lose their exclusivity. In the United States, under current patent law, the life of a patent is 20 years from the date the application is filed. Although that might seem like a long time to have patent protection, it is important to put this time frame into the context of the product development process. It is quite common for a patent to be filed very early on in the development process. In fact, a patent is often filed as soon as proof-of-principle data are obtained. For argument’s sake, let us assume that it takes 12 years before a drug garners agency approval and can be brought to market. This means that the company invested all of that time and capital only to have 8 years of patent protection (and, therefore, market exclusivity) before a generic or biosimilar version of that drug floods the market. The reality, in this scenario, is that the innovators only have 8 years to recoup all of their R&D investment, although, at the same time, generate revenue to fund further R&D efforts. Remember that only 1 in 10,000 new pharmaceuticals ever make it to market, so the one drug that does make it to the market also has to generate enough revenue to fund the R&D of the other 9,999 that do not. Without this continued income stream, pharmaceutical R&D would be unable to continue. The bottom line is that, the more complex the molecule, the more complicated, risky, and costly the development process will likely be. Due to their nature, biologics are inherently complex, difficult to mass produce, and present the industry with some very significant challenges. First off, biologic actives are usually much larger than a compound-based active. A typical compound based active, for example, tends to have a molecular weight of approximately 100-600 Da (eg, acetaminophen, 151 Da; acetylsalicylic acid, 180 Da; Sudafed (pseudoephedrine) (McNeil-PPC, New Brunswick, NJ), 165 Da; Risperdal (risperidone) (Janssen, Titusville, NJ), 410 Da;
S134
Kramer
INDUSTRY PERSPECTIVES ON THE DEVELOPMENT OF BIOLOGICS
Motrin (ibuprofen) (McNeil-PPC, New Brunswick, NJ), 206 Da), whereas a typical biologic active has a molecular weight upward of 200 kDa (eg, Epogen, 30.4 kDa; Genotropin, 22.1 kDa; Remicade, 149 kDa; Simponi (golimumab) (Centocor Ortho Biotech, Inc, Horsham, PA), 147 kDa; Stelara, 145 kDa). Second, biologic actives are made from proteins, sugars, nucleic acids, or a combination of these components, which are all created from a biological process, usually in situ. Biologics can also be actual living cells or tissue as well. As a result, biologics are typically generated in an aqueous environment by using large-scale bioreactors in volumes upward of 20,000 L. In spite of the large volume used to generate these actives, the overall product yield is relatively low (0.5-5 g/L). Traditional chemical-based compounds, however, are generally made through multiple chemical reactions and isolations in primarily organic environments in reactor volumes of 5,000-10,000 L and the relative product yield is quite high (100 g/L). The relatively low yield of a biologic is one factor that contributes to a higher cost to market compared with its small-molecule counterpart. The relatively low yield is not the only thing that contributes to the higher cost of a biologic product. The manufacturing process of a biologic is also a major undertaking. Assume that a company has developed an antibody to treat a particular illness. This antibody must be produced in a living cell and that cell must be grown in a certain media, which may require the use of serum. The cells must be grown at a certain temperature, in an appropriately sized vessel to generate the quantity of material required. Before a company could even begin to generate significant amounts of material for testing purposes, no less the actual product, a significant capital investment would have to be made to build a suitable bioprocessing facility. In addition to the physical space that would be required for such a facility, millions of dollars of specialized equipment would need to be purchased and installed, quality systems put in place, and personnel hired to run such a facility. Now let us consider some challenges related to the growth media for the host cells. Consider a scenario in which you need to use 20% fetal bovine serum (FBS) to grow your host cells. Now assume that you need to run a 20,000-L bioreactor to generate enough material to treat a certain number of patients. This means that 4,000 L of FBS would be required for this run. If we assume that the cost of serum is somewhere around $600-$800 a liter, the cost just to purchase FBS for this run would be upward of $3,200,000. This amount does not take into consideration the cost of the other raw materials that you would need to have on hand and ultimately source to grow your cells. Cost of the serum is not the only consideration though. One also has to decide where to source the FBS that will be used to grow the host cells used to generate the antibody. This decision is based on a variety of factors, but, most importantly, it will be driven by what source would be most acceptable to the most agencies that will have regulatory
authority over the product. As one might imagine, once this decision is made, it is very difficult to change course. Say that the decision is made to buy FBS from the United States. What will you do if there is an outbreak of mad-cow disease and you can no longer use that FBS source? What will happen to your ability to meet product development timelines or consumer demands and produce your biologic if your source of FBS dries up? All of this uncertainty and cost, and yet all we have examined is FBS! Another issue that must be considered is whether or not to use antibiotics in your cell culture media, and if so, at what point. Although antibiotics are widely used in research-grade cell culture, their use in manufacturing of the final product is minimized. If you choose to use antibiotics, you might receive limited approval to use the product due to issues related to antibiotic allergies in the patients who use the product. If you do not use antibiotics, bacterial contamination may occur. If this happens, the bioreactor run has to be terminated, its contents discarded, and the time and monetary investment that was made on that run literally goes down the drain. Once the media components have been worked out, one has to consider how to grow the cells themselves. If the cells are adherent, it is likely that you will need to grow them on some sort of microcarrier. A decision will need to be made as to what microcarrier to use. This decision is based on a variety of factors, including cost, availability, and composition, as well as the effect that the microcarrier will have on the cells and media, just to name a few. Regardless of whether the cells are adherent or not, one also has to figure out how to grow them in a large bioreactor, ensure that the cells do not settle, and that there is adequate gas and nutrient exchange. Once all of the growth conditions have been worked out, one has to figure out the best way to collect and purify the antibody that has been generated. Although this does not begin to cover all of the manufacturing issues that must be considered, one cannot help but see the inherent challenges to developing a manufacturing plan that does not make the cost of goods itself become prohibitive to development. Ultimately, cell culture, which is a relatively simple thing to accomplish in the laboratory, becomes a very complex and involved process when you are considering large-scale GLP/GMP manufacturing. As you can imagine, the high cost and complexity of these processes help to drive additional R&D efforts to reduce the cost and increase efficiency of these processes. Manufacturing is a main contributor to the cost of a biologic, however, extensive testing requirements for setting product specification for safety and efficacy is also costly. Once a pharmaceutical is manufactured, it is necessary to have a way to test the final product to ensure that your product meets the specifications set out with respect to safety and efficacy. In the case of a small molecule, this might be a relatively simple and inexpensive assay in which you examine the purity of your compound by using chromatography. In the case of a biologic, the testing might be much more
PM&R
complex and require numerous assays. If your product is cell based, for example, you might have to examine a variety of cell surface markers or perhaps look at the level of growth factor release. You would also have to ensure proper karyotype and that there are no biologic and or viral contaminants in the product, just to name a few. Once you have determined that you have produced the active you intended, it is also necessary to be able to confirm the biologic activity of that active. In the case of a small molecule, this might be a simple receptor-binding assay to ensure that your molecule binds to its target appropriately. In the case of a biologic, one might not necessarily have a complete understanding of the mechanism of action. This might result in having to test each new batch of a biologic in a preclinical model, for example. Alternatively, you might need to use one or more cell-based assays to show that your biologic is having a desired effect. This can be further complicated by the fact that in vitro biologic systems can be
Vol. 3, Iss. 6S, 2011
S135
inherently difficult to consistently reproduce. Regardless, a considerable amount of effort and money generally goes into determining the best course of action in these complex situations. Although the complexities and scenarios described here are by no means exhaustive, they were meant to illustrate some of the challenges that the industry faces when developing biologics. Realistically, these challenges will only increase over time as groundbreaking advancements in the biological sciences and regenerative medicine are made. Ultimately, overcoming these challenges will result in the development of more sophisticated and precise biologics that can treat a variety of diseases and improve the quality of life of our patients.
REFERENCE 1. Pharmaceutical Research and Manufacturers of America. Research. Available at: http://www.phrma.org/research. Accessed May 16, 2011.