All of the basic research and early development behind a biotherapeutic, as well as the preclinical and clinical testing, go for naught without a successful final drug formulation. To benefit patients, all of the research and development must be combined in an actual product. In comparison to a small-molecule therapy, a biotherapeutic final drug formation is more challenging.
According to Daniel Joseph Price, PhD, head of excipients business at the life science business of Merck KGaA, Darmstadt, Germany, “Final formulation of biotech drugs and antibodies poses several unique challenges due to the complexity and sensitivity of these macromolecules.”
For one thing, the proteins in these biotherapeutics must stay stable. Unfortunately, that’s not what proteins tend to do. “Proteins are inherently prone to aggregation, denaturation, and chemical degradation,” says Price. “These changes can compromise therapeutic efficacy and safety, particularly for parenteral applications where aggregates can provoke immune responses.”
Beyond the natural tendency of proteins to change, the environment can accelerate that problem. “During manufacturing, filling, or transportation, proteins encounter stresses, such as air-liquid interfaces or agitation that can unfold proteins and lead to irreversible aggregation,” Price says.
A drug manufacturer can improve protein stability and other features of a biotherapeutic by adding excipients from salts and sugars to preservatives and surfactants. Like the active component in a biotherapeutic, the excipients must be carefully controlled. For example, they “must meet extremely high purity standards due to the high concentrations needed—up to 100 milligrams per milliliter—and the risks associated with injectable routes,” Price explains. “Endotoxin load, nanoparticulate impurities, and batch consistency are also critical quality concerns.”
To stabilize liquid formulations of therapeutic proteins, Merck KGaA optimized its Poloxamer 188 Emprove Expert. “This version of Poloxamer 188 features a high molecular weight and increased hydrophobicity, enabling it to better stabilize proteins against mechanical and interfacial stress,” Price says. “In head-to-head forced degradation studies, this product significantly reduced particle formation and protein aggregation across various monoclonal antibodies and fusion proteins, offering performance equal to or better than traditional polysorbate-based formulations.”
The main challenge in developing Poloxamer 188 Emprove Expert was controlling its complex and heterogeneous structure. “As a polymeric surfactant, its molecular weight and composition can vary significantly between batches and suppliers, affecting performance,” Price says. So, Merck KGaA carefully controlled the material’s characteristics, developed a manufacturing process that kept batches consistent, and added 70 parts per million butylated hydroxytoluene as a stabilizer to produce what Price calls a “precision-engineered excipient.”
Compared to biotherapeutics in general, antibodies pose some unique challenges. During fill and finish, for example, developers must pay special attention to the antibody’s “viscosity or levels of excipients used for stability,” says Christy Eatmon, global subject matter expert of sterile drug products for pharma services at Thermo Fisher Scientific. “As antibodies are concentrated to achieve small injection volumes required for subcutaneous delivery, the viscosity goes up, as well as the propensity for aggregation.” A manufacturer of an antibody-based therapeutic must also optimize the level of excipients, such as polysorbate, for stability and minimize the formation of bubbles during filtration and filling. “Another challenge in the filling process is to reduce waste and line losses as much as possible, as these materials are often very expensive,” Eatmon says.
The formulation of a drug product is developed for a specific application, such as these
pre-filled syringes. [Thermo Fisher Scientific]
Recently, Thermo Fisher introduced excipients or processes that allow for ultra-concentration—above 200 milligrams per milliliter—while keeping the viscosity relatively low, below about 25 centipoise. “The ability to ultra-concentrate will allow for lower dose volumes and the opportunity to deliver these therapies subcutaneously, filling them into a syringe rather than a vial,” Eatmon says. “Along with the shift to pre-filled syringes, we are making advancements in the long-acting injectable space, which will reduce dosing frequency and make treatment more convenient for patients.”
Given the large size and complexity of therapeutic antibodies, potential for aggregation and precipitation, and the non-linear viscosity increase as concentration rises, Thermo Fisher keeps many factors in mind during production to develop and manufacture a product that works in a syringe. As Eatmon says, “We need to ensure that the syringeability profile of these molecules is within acceptable limits, as many are used in combination with auto-injectors.”
No matter what kind of drug a company is developing, the steps taken at the start play crucial roles in negotiating the entire path to produce a final product. Even when a formulation is being developed from scratch, “you have to make sure that you check all of the regulatory boxes, because there are expectations for specific studies and data,” says Travis Webb, CSO at Pharmaceutics International, Inc (Pii), which works primarily on small-molecule drugs. “That minimizes the number of additional requests that come back from regulators.”
In many cases, Pii—recently acquired by Jabil, a global expert in engineering, manufacturing, and supply-chain solutions—works on “formulations that other people don’t really want to deal with,” says Webb. To produce a successful final drug formulation, Pii started using machine learning in the early stages of drug development, such as optimizing a drug’s solubility. “So, instead of trying iterative bench trials, we have a standard list of solvents that we use that kind of fill out the 3D space that we map in,” he says. In this way, Pii can screen hundreds of solvents or combinations of them in a day. This type of information is used to develop a formulation that can be manufactured at a commercial scale.
When asked to assess the value of such modeling, Webb says, “I always make the joke that the best models in the world are 90% correct 80% of the time, and that’s not too bad.”
Nonetheless, finding the best final formulation for any therapy rarely comes from computation alone. “There’s a degree of art that comes with it,” Webb says. “The model may tell you something, but based on your knowledge of formulation and formulation components, you can predict how something might vary, especially in scale-up.”
Another thing to keep in mind early when developing a drug is what will be in the final formulation and how it will be sourced. “If we have a component come in from a client that’s from a single-source provider, we look into that,” Webb says. “We may recommend to them that we start doing some work to evaluate a second source because, as COVID taught us, something can happen tomorrow that throws a wrench into everything.”
All manufacturers of biotherapeutics aim to make products more robust to stay safe and effective in patients. To that end, scientists at Lonza applied a design of experiments (DoE) approach to assessing the robustness of final drug formulation development.
“One of the key challenges was clearly defining the quality target product profile and selecting relevant formulation parameters that could impact product quality,” says Virginie Le Brun, associate director of drug product services formulation development, Lonza. “Identifying these factors early was essential to designing a meaningful robustness study and establishing a reliable design space.”
Then, Lonza used a DoE approach to test the composition and concentration of formulation components across a defined design space to assess robustness. “These robustness studies evaluated product stability at the formulation’s boundaries, supporting specification settings and ensuring the ability to tolerate minor manufacturing variations—reducing the risk of deviations, delays, or batch rejections,” Le Brun says. “This additional knowledge is highly valuable to show robustness in support of the dossier for submission, but also to refine the specifications as well as to understand and support deviations to the target composition during manufacturing.”
In addition, interactions between a formulation’s parameters must be considered to understand the impact of each one on a product’s stability. “This can be addressed using a statistical approach,” Le Brun says. “Following this strategy, we developed and implemented a statistically optimized DoE designed to characterize the individual effects of formulation variables and their interactions, using a limited number of formulations to reduce material needs and timelines.”
For a thorough understanding of a product, though, these tests must also gather long-term stability data at different stability conditions and time points to identify statistically relevant factors, variations, and interactions and their impact on critical quality attributes.
Based on all of this work, Lonza defined “a more reliable and resilient formulation design space, ultimately improving risk management, and supporting regulatory submissions,” Le Brun says.
As biotherapeutics evolve, so too will the steps in final drug formulation. As an example, Price says, “Looking ahead, we aim to expand our portfolio of high-performance stabilizers tailored to next-generation biologics, including bispecifics, fusion proteins, and mRNA delivery systems.”
In particular, scientists at Merck KGaA focus on several improvements. For instance, Price says that the company plans to develop multifunctional excipients “that combine stabilizing, buffering, and antioxidant properties.” Plus, enhanced analytics will be used “to provide deeper insight into excipient-protein interactions and predict formulation stability early in development,” he says.
Beyond testing existing formulations, Merck KGaA also plans to use digital predictive technologies “that can use first principles chemical and biological information to predict optimal formulations of biologics,” Price says. “So far, we have focused our digital-information platforms on small-molecule formulation, but we are already starting to develop solutions with our mPredict digital product for large molecules too.”
Other companies also envision improved approaches to developing the final formulation of biotherapeutics. “Further optimization of predictive modeling and high-throughput screening tools tailored to the needs and complexity of new molecular formats will be crucial,” says Le Brun. “These advancements will help reduce material requirements and accelerate formulation development timelines, benefiting drug developers and their patients.”
The post The Final Formulation: Last Step in the Drug Development Journey appeared first on GEN - Genetic Engineering and Biotechnology News.
According to Daniel Joseph Price, PhD, head of excipients business at the life science business of Merck KGaA, Darmstadt, Germany, “Final formulation of biotech drugs and antibodies poses several unique challenges due to the complexity and sensitivity of these macromolecules.”
For one thing, the proteins in these biotherapeutics must stay stable. Unfortunately, that’s not what proteins tend to do. “Proteins are inherently prone to aggregation, denaturation, and chemical degradation,” says Price. “These changes can compromise therapeutic efficacy and safety, particularly for parenteral applications where aggregates can provoke immune responses.”
Beyond the natural tendency of proteins to change, the environment can accelerate that problem. “During manufacturing, filling, or transportation, proteins encounter stresses, such as air-liquid interfaces or agitation that can unfold proteins and lead to irreversible aggregation,” Price says.
A drug manufacturer can improve protein stability and other features of a biotherapeutic by adding excipients from salts and sugars to preservatives and surfactants. Like the active component in a biotherapeutic, the excipients must be carefully controlled. For example, they “must meet extremely high purity standards due to the high concentrations needed—up to 100 milligrams per milliliter—and the risks associated with injectable routes,” Price explains. “Endotoxin load, nanoparticulate impurities, and batch consistency are also critical quality concerns.”
Keeping proteins stable
To stabilize liquid formulations of therapeutic proteins, Merck KGaA optimized its Poloxamer 188 Emprove Expert. “This version of Poloxamer 188 features a high molecular weight and increased hydrophobicity, enabling it to better stabilize proteins against mechanical and interfacial stress,” Price says. “In head-to-head forced degradation studies, this product significantly reduced particle formation and protein aggregation across various monoclonal antibodies and fusion proteins, offering performance equal to or better than traditional polysorbate-based formulations.”
The main challenge in developing Poloxamer 188 Emprove Expert was controlling its complex and heterogeneous structure. “As a polymeric surfactant, its molecular weight and composition can vary significantly between batches and suppliers, affecting performance,” Price says. So, Merck KGaA carefully controlled the material’s characteristics, developed a manufacturing process that kept batches consistent, and added 70 parts per million butylated hydroxytoluene as a stabilizer to produce what Price calls a “precision-engineered excipient.”
Addressing viscosity in antibodies
Compared to biotherapeutics in general, antibodies pose some unique challenges. During fill and finish, for example, developers must pay special attention to the antibody’s “viscosity or levels of excipients used for stability,” says Christy Eatmon, global subject matter expert of sterile drug products for pharma services at Thermo Fisher Scientific. “As antibodies are concentrated to achieve small injection volumes required for subcutaneous delivery, the viscosity goes up, as well as the propensity for aggregation.” A manufacturer of an antibody-based therapeutic must also optimize the level of excipients, such as polysorbate, for stability and minimize the formation of bubbles during filtration and filling. “Another challenge in the filling process is to reduce waste and line losses as much as possible, as these materials are often very expensive,” Eatmon says.
The formulation of a drug product is developed for a specific application, such as these
pre-filled syringes. [Thermo Fisher Scientific]
Recently, Thermo Fisher introduced excipients or processes that allow for ultra-concentration—above 200 milligrams per milliliter—while keeping the viscosity relatively low, below about 25 centipoise. “The ability to ultra-concentrate will allow for lower dose volumes and the opportunity to deliver these therapies subcutaneously, filling them into a syringe rather than a vial,” Eatmon says. “Along with the shift to pre-filled syringes, we are making advancements in the long-acting injectable space, which will reduce dosing frequency and make treatment more convenient for patients.”
Given the large size and complexity of therapeutic antibodies, potential for aggregation and precipitation, and the non-linear viscosity increase as concentration rises, Thermo Fisher keeps many factors in mind during production to develop and manufacture a product that works in a syringe. As Eatmon says, “We need to ensure that the syringeability profile of these molecules is within acceptable limits, as many are used in combination with auto-injectors.”
The start impacts the finish
No matter what kind of drug a company is developing, the steps taken at the start play crucial roles in negotiating the entire path to produce a final product. Even when a formulation is being developed from scratch, “you have to make sure that you check all of the regulatory boxes, because there are expectations for specific studies and data,” says Travis Webb, CSO at Pharmaceutics International, Inc (Pii), which works primarily on small-molecule drugs. “That minimizes the number of additional requests that come back from regulators.”
In many cases, Pii—recently acquired by Jabil, a global expert in engineering, manufacturing, and supply-chain solutions—works on “formulations that other people don’t really want to deal with,” says Webb. To produce a successful final drug formulation, Pii started using machine learning in the early stages of drug development, such as optimizing a drug’s solubility. “So, instead of trying iterative bench trials, we have a standard list of solvents that we use that kind of fill out the 3D space that we map in,” he says. In this way, Pii can screen hundreds of solvents or combinations of them in a day. This type of information is used to develop a formulation that can be manufactured at a commercial scale.
When asked to assess the value of such modeling, Webb says, “I always make the joke that the best models in the world are 90% correct 80% of the time, and that’s not too bad.”
Nonetheless, finding the best final formulation for any therapy rarely comes from computation alone. “There’s a degree of art that comes with it,” Webb says. “The model may tell you something, but based on your knowledge of formulation and formulation components, you can predict how something might vary, especially in scale-up.”
Another thing to keep in mind early when developing a drug is what will be in the final formulation and how it will be sourced. “If we have a component come in from a client that’s from a single-source provider, we look into that,” Webb says. “We may recommend to them that we start doing some work to evaluate a second source because, as COVID taught us, something can happen tomorrow that throws a wrench into everything.”
Building in robustness
All manufacturers of biotherapeutics aim to make products more robust to stay safe and effective in patients. To that end, scientists at Lonza applied a design of experiments (DoE) approach to assessing the robustness of final drug formulation development.
“One of the key challenges was clearly defining the quality target product profile and selecting relevant formulation parameters that could impact product quality,” says Virginie Le Brun, associate director of drug product services formulation development, Lonza. “Identifying these factors early was essential to designing a meaningful robustness study and establishing a reliable design space.”
Then, Lonza used a DoE approach to test the composition and concentration of formulation components across a defined design space to assess robustness. “These robustness studies evaluated product stability at the formulation’s boundaries, supporting specification settings and ensuring the ability to tolerate minor manufacturing variations—reducing the risk of deviations, delays, or batch rejections,” Le Brun says. “This additional knowledge is highly valuable to show robustness in support of the dossier for submission, but also to refine the specifications as well as to understand and support deviations to the target composition during manufacturing.”
In addition, interactions between a formulation’s parameters must be considered to understand the impact of each one on a product’s stability. “This can be addressed using a statistical approach,” Le Brun says. “Following this strategy, we developed and implemented a statistically optimized DoE designed to characterize the individual effects of formulation variables and their interactions, using a limited number of formulations to reduce material needs and timelines.”
For a thorough understanding of a product, though, these tests must also gather long-term stability data at different stability conditions and time points to identify statistically relevant factors, variations, and interactions and their impact on critical quality attributes.
Based on all of this work, Lonza defined “a more reliable and resilient formulation design space, ultimately improving risk management, and supporting regulatory submissions,” Le Brun says.
Seeking a more stable future
As biotherapeutics evolve, so too will the steps in final drug formulation. As an example, Price says, “Looking ahead, we aim to expand our portfolio of high-performance stabilizers tailored to next-generation biologics, including bispecifics, fusion proteins, and mRNA delivery systems.”
In particular, scientists at Merck KGaA focus on several improvements. For instance, Price says that the company plans to develop multifunctional excipients “that combine stabilizing, buffering, and antioxidant properties.” Plus, enhanced analytics will be used “to provide deeper insight into excipient-protein interactions and predict formulation stability early in development,” he says.
Beyond testing existing formulations, Merck KGaA also plans to use digital predictive technologies “that can use first principles chemical and biological information to predict optimal formulations of biologics,” Price says. “So far, we have focused our digital-information platforms on small-molecule formulation, but we are already starting to develop solutions with our mPredict digital product for large molecules too.”
Other companies also envision improved approaches to developing the final formulation of biotherapeutics. “Further optimization of predictive modeling and high-throughput screening tools tailored to the needs and complexity of new molecular formats will be crucial,” says Le Brun. “These advancements will help reduce material requirements and accelerate formulation development timelines, benefiting drug developers and their patients.”
The post The Final Formulation: Last Step in the Drug Development Journey appeared first on GEN - Genetic Engineering and Biotechnology News.