Kristin Brooks, Managing Editor, Contract Pharma01.27.21
The CDMO Division of Lubrizol Life Science Health (LLS Health) is a pharmaceutical contract development and drug product manufacturing organization that offers a range of technical capabilities, multiple technology platforms, and expertise in complex drug delivery.
LLS Health offers R&D formulation and clinical/commercial drug product manufacturing supported by analytical testing, ICH stability programs, and HPAPI/controlled substance handling. Its technology-agnostic team offers expertise in solubility and bioavailability enhancement, sterile and aseptic manufacturing, and long-acting injectables and implantables.
Contract Pharma recently caught up with the president of LLS Health, Rob Lee, and talked about the CDMO’s continued growth alongside the rise of biologics and parenteral drug delivery and technology trends in general.
Contract Pharma (CP): In what services areas are you seeing the most growth?
Rob Lee (RL): Currently, drug delivery is a significant area of growth, particularly parenteral drug delivery. We have seen a lot of advancement in pre-filled syringes, continuing the trend in healthcare for the past decade towards home healthcare and self-administration of injectables. The rise in insoluble small molecules and biologics is also driving this trend towards parenteral drug delivery.
At LLS Health, we have seen a lot of interest in companies looking for small batch size commercial manufacturing capacity. This may not be a sweet spot for larger CDMOs who have traditionally designed their manufacturing lines to serve high volume, blockbuster drug products. LLS Health, in contrast, has designed unique manufacturing facilities to accommodate small batch commercial manufacturing and flexible systems to serve the growth of biologics, orphan drug products, and personalized medicine, as well as traditional drug products.
CP: What are some of the latest technology platforms being leveraged in these service areas?
RL: Linked to the rise in parenterals, we have seen an increased market interest in more patient centric dosage forms such as infusion-type wearable devices. We have seen growth in highly viscous liquid products that are used in these devices, particularly for biologics, which has led us to re-examine and reconfigure existing technologies that we run in filling operations. These changes meant we had to look at the allotment, filtration, and dosing to retool from an operational and validation standpoint to ensure a consistent product.
We selected equipment that utilizes tub-filling to accommodate flexible GMP manufacturing. This technology allows us to fill many different types of primary packaging such as vials, syringes, cartridges, and bottles.
In addition, there continues to be growing interest in long-acting injectables that can help cut down the number of injections that a patient requires for a given treatment. These are lyophilized products that are reconstituted to form a depot in the body and rely on much of the same expertise as viscous biologic formulations.
CP: What are the key considerations in designing and executing aseptic processes?
RL: It is preferable to use closed systems as much as possible. Even when working with an open system and executing manual aseptic processes, it is essential to understand the process and have an experienced, proven engineering team in place to design it and ensure the use of appropriate validation methods to support it. Otherwise the risk of failure due to microbial contamination increases.
And, of course, aseptic process simulations or media fills must take place prior to an aseptic fill. Media fills involve challenging an aseptic process using a sterile microbiological growth medium to ensure a process prevents contamination during actual production. During a media fill for a new process, the fill is performed three consecutive times to check sterility assurance across the totality of the process, including personnel, equipment, packaging, and manufacturing steps. Any change to an aseptic process may require revalidation, so partnering with a CDMO that has experience and media fill strategy helps ensure aseptic validation does not end up being a drain on project funds and resources.
CP: What are the main challenges when performing aseptic lyophilization and how can they be overcome?
RL: A major consideration when dealing with a sterile lyophilized product that is manufactured aseptically is maintaining an ISO 5, Grade A environment for the partially stoppered vials to avoid contamination. This either requires a lyophilizer that is maintained in an ISO 5, Grade A area or the use of isolator technology. At the LLS Health facility, to maintain the greatest amount of flexibility, we have opted to build an ISO 5 Grade A room for our lyophilizer allowing us to incorporate many different technologies.
Another challenge centers on formulation considerations related to the continued growth of mixed solvent systems and the use of organics, such as t-butanol. Attempting to remove these solvents and organics during lyophilization poses a challenge, as most lyophilizers are designed to remove water as the primary solvent. To address this challenge, we elected to modify our lyophilizer to include an inline condenser unit to remove the solvent so that the solvent doesn’t liquify in the main condenser or leave the system.
CP: What kind of growth are you seeing for aseptic lyophilization for biologics and complex drug products?
RL: We are seeing significant growth in small batch size complex parenteral drug products, including biologics and nanoparticulate suspensions. The key here is to understand and control the formulation and lyophilization process.
For biologics, it is critical to ensure that molecules maintain their three-dimensional structure/conformation and avoid aggregation upon reconstitution. This requires strict control over processing parameters during manufacturing steps such as mixing, filtration, and filling. A well-designed process ensures that large molecule APIs maintain their biological activity and can be properly administered from devices like pre-filled syringes.
For nanoparticulate suspensions, the key is maintaining the same particle size pre- and post-reconstitution. Developing particulate-based products often requires specialized formulation and analytical techniques to characterize particles and ensure they are unchanged by the lyophilization process. Therefore, it important to work with an organization that has experience in nanoparticulate suspensions and who has worked on many nanomilled products over the years.
LLS Health has experience working with biologics and nanoparticulate suspensions, giving us access to the formulation techniques, excipients, and characterization tools to specifically address stability and aggregation challenges in a manufacturing setting. For example, a customer who was developing a challenging nanoparticulate-based ophthalmic product approached LLS Health for process optimization and scale-up support. LLS Health’s experience with nanoparticulate suspensions guided formulation development, resulting in a reproducible, highly concentrated, and stable nanoparticulate intermediate. Our team then designed a scaled-up, aseptic manufacturing process and is currently working with the customer to validate the process. This project required LLS Health’s unique nanoparticulate knowledge and our experience with sterile product manufacturing—a rare, but valuable, combination of CDMO services that enabled success.
Dr. Rob Lee is president of the CDMO Division of Lubrizol Life Science Health (LLS Health) where he is responsible for product and business development along with providing strategic direction. Before joining LLS Health, Rob held senior management positions at Novavax, Lyotropic Therapeutics and Imcor Pharmaceutical. He has over 30 years of experience in pharmaceutical research and development of both therapeutic drugs and diagnostic imaging agents and has published more than three dozen articles and five book chapters plus holds 11 issued patents and 15 provisional or PCT patent applications.
LLS Health offers R&D formulation and clinical/commercial drug product manufacturing supported by analytical testing, ICH stability programs, and HPAPI/controlled substance handling. Its technology-agnostic team offers expertise in solubility and bioavailability enhancement, sterile and aseptic manufacturing, and long-acting injectables and implantables.
Contract Pharma recently caught up with the president of LLS Health, Rob Lee, and talked about the CDMO’s continued growth alongside the rise of biologics and parenteral drug delivery and technology trends in general.
Contract Pharma (CP): In what services areas are you seeing the most growth?
Rob Lee (RL): Currently, drug delivery is a significant area of growth, particularly parenteral drug delivery. We have seen a lot of advancement in pre-filled syringes, continuing the trend in healthcare for the past decade towards home healthcare and self-administration of injectables. The rise in insoluble small molecules and biologics is also driving this trend towards parenteral drug delivery.
At LLS Health, we have seen a lot of interest in companies looking for small batch size commercial manufacturing capacity. This may not be a sweet spot for larger CDMOs who have traditionally designed their manufacturing lines to serve high volume, blockbuster drug products. LLS Health, in contrast, has designed unique manufacturing facilities to accommodate small batch commercial manufacturing and flexible systems to serve the growth of biologics, orphan drug products, and personalized medicine, as well as traditional drug products.
CP: What are some of the latest technology platforms being leveraged in these service areas?
RL: Linked to the rise in parenterals, we have seen an increased market interest in more patient centric dosage forms such as infusion-type wearable devices. We have seen growth in highly viscous liquid products that are used in these devices, particularly for biologics, which has led us to re-examine and reconfigure existing technologies that we run in filling operations. These changes meant we had to look at the allotment, filtration, and dosing to retool from an operational and validation standpoint to ensure a consistent product.
We selected equipment that utilizes tub-filling to accommodate flexible GMP manufacturing. This technology allows us to fill many different types of primary packaging such as vials, syringes, cartridges, and bottles.
In addition, there continues to be growing interest in long-acting injectables that can help cut down the number of injections that a patient requires for a given treatment. These are lyophilized products that are reconstituted to form a depot in the body and rely on much of the same expertise as viscous biologic formulations.
CP: What are the key considerations in designing and executing aseptic processes?
RL: It is preferable to use closed systems as much as possible. Even when working with an open system and executing manual aseptic processes, it is essential to understand the process and have an experienced, proven engineering team in place to design it and ensure the use of appropriate validation methods to support it. Otherwise the risk of failure due to microbial contamination increases.
And, of course, aseptic process simulations or media fills must take place prior to an aseptic fill. Media fills involve challenging an aseptic process using a sterile microbiological growth medium to ensure a process prevents contamination during actual production. During a media fill for a new process, the fill is performed three consecutive times to check sterility assurance across the totality of the process, including personnel, equipment, packaging, and manufacturing steps. Any change to an aseptic process may require revalidation, so partnering with a CDMO that has experience and media fill strategy helps ensure aseptic validation does not end up being a drain on project funds and resources.
CP: What are the main challenges when performing aseptic lyophilization and how can they be overcome?
RL: A major consideration when dealing with a sterile lyophilized product that is manufactured aseptically is maintaining an ISO 5, Grade A environment for the partially stoppered vials to avoid contamination. This either requires a lyophilizer that is maintained in an ISO 5, Grade A area or the use of isolator technology. At the LLS Health facility, to maintain the greatest amount of flexibility, we have opted to build an ISO 5 Grade A room for our lyophilizer allowing us to incorporate many different technologies.
Another challenge centers on formulation considerations related to the continued growth of mixed solvent systems and the use of organics, such as t-butanol. Attempting to remove these solvents and organics during lyophilization poses a challenge, as most lyophilizers are designed to remove water as the primary solvent. To address this challenge, we elected to modify our lyophilizer to include an inline condenser unit to remove the solvent so that the solvent doesn’t liquify in the main condenser or leave the system.
CP: What kind of growth are you seeing for aseptic lyophilization for biologics and complex drug products?
RL: We are seeing significant growth in small batch size complex parenteral drug products, including biologics and nanoparticulate suspensions. The key here is to understand and control the formulation and lyophilization process.
For biologics, it is critical to ensure that molecules maintain their three-dimensional structure/conformation and avoid aggregation upon reconstitution. This requires strict control over processing parameters during manufacturing steps such as mixing, filtration, and filling. A well-designed process ensures that large molecule APIs maintain their biological activity and can be properly administered from devices like pre-filled syringes.
For nanoparticulate suspensions, the key is maintaining the same particle size pre- and post-reconstitution. Developing particulate-based products often requires specialized formulation and analytical techniques to characterize particles and ensure they are unchanged by the lyophilization process. Therefore, it important to work with an organization that has experience in nanoparticulate suspensions and who has worked on many nanomilled products over the years.
LLS Health has experience working with biologics and nanoparticulate suspensions, giving us access to the formulation techniques, excipients, and characterization tools to specifically address stability and aggregation challenges in a manufacturing setting. For example, a customer who was developing a challenging nanoparticulate-based ophthalmic product approached LLS Health for process optimization and scale-up support. LLS Health’s experience with nanoparticulate suspensions guided formulation development, resulting in a reproducible, highly concentrated, and stable nanoparticulate intermediate. Our team then designed a scaled-up, aseptic manufacturing process and is currently working with the customer to validate the process. This project required LLS Health’s unique nanoparticulate knowledge and our experience with sterile product manufacturing—a rare, but valuable, combination of CDMO services that enabled success.
