In general, how has the lyophilization market changed over the last five years? How have these changes allowed LSNE to better assist your clients?
Lyophilization development has evolved to take a more comprehensive approach to understanding the formulation of the drug product to be lyophilized. A few of the primary tools LSNE uses to develop pharmaceutically elegant lyophilized dosage forms are modulated Differential Scanning Calorimetry (mDSC) and Freeze Dry Microscopy (FDM). We also use a ‘vial thief’ which allows our scientists to remove samples during the course of the lyophilization cycle development run and obtain real time information about the product as it is going through the lyophilization process. We utilize a Quality by Design (QbD) approach to reduce the number of iterations required during the formulation and lyophilization cycle development phase to plan our development pathway to save our clients time and money while providing the best drug product presentation possible. The time spent obtaining a comprehensive understanding of the thermal profile of the formulation and its freezing point, glass transition temperature, collapse temperature, and eutectic temperature, allows LSNE to develop a robust/optimized lyophilization cycle. By optimizing the lyophilization cycle at an early stage of clinical development, a cost savings is realized by having a reduced lyophilization cycle time which will save our clients’ money throughout the product’s lifecycle. In addition to the reduced lyophilization cycle time, the optimized drug product has greater stability and this can be demonstrated at an earlier stage by conducting the required ICH Stability Studies with an advanced lyophilized Drug Product.
Are there significant differences between R&D lyophilization scale-up processes and larger scale GMP processes? What should a pharmaceutical manufacturer keep in mind when scaling up a lyophilization process?
Yes, transferring a lyophilization process from small scale development to a large scale clinical or commercial lyophilizer has some challenges. LSNE uses proprietary algorithms to transfer projects from lyophilization cycle development to large scale cGMP manufacturing. We have a vast amount of experience in efficiently developing and optimizing lyophilization cycles in our development scale lyophilizers (down to 4.6 square feet) and transferring the lyophilization process to our largest cGMP lyophilizer (270 square feet). First and foremost it is critical to understand the capabilities of the large production lyophilizers and the parameters that can be obtained. These provide specific design attributes critical to a successful transfer of the cycle. LSNE uses several types of equipment and tools to evaluate this lyophilization process transfer, including thermocouples, capacitance manometers, Pirani gauges, and extensive analytical testing, to name a few.
For lyophilization cycles that have been developed by our clients or another CDMO, LSNE prefers to use a stepwise approach for the process transfer to ensure an efficient process at one of our three cGMP manufacturing facilities. During the transfer of a new lyophilization cycle developed by a 3rd party, a small scale non-GMP technical transfer run is conducted. As API or BDS is so valuable to our client’s development and clinical programs, we develop a plan with the client to minimize the amount of Drug Substance or API used. A preferred method is to add active vials to various areas of the development lyophilizer for testing; a standard approach is to place active vials in the front, back, left, right, top, middle, and bottom. To ensure the lyophilizer is simulating a full lyophilization run, we will add dunnage to load the rest of the lyophilizer’s shelves. The dunnage is typically the formulation without the active (placebo) or WFI. The info from this transfer run is discussed with the client and we may offer suggestions for further development/optimization. After the initial small scale technical transfer run has been successfully completed, LSNE will use its scale-up algorithms to develop a cycle for the larger production lyophilizers. Next, we will perform an engineering run, using the same Production units that will be utilized in the cGMP batches. This engineering run reduces risk and ensures an efficient and cGMP compliant process is in place prior to the cGMP batch run. During the engineering run, not only is the lyophilization cycle itself evaluated, but all aspects of the process are assessed; from formulation to filtration, to the filling of the vial to ensure no product adheres to the sides of the vial or near the stopper.
In particular, can you tell me how LSNE’s technologies, services and experience can help a pharmaceutical manufacturer develop a robust lyophilization scale-up process that can be quickly and economically transferred to a GMP manufacturing operation with little risk?
LSNE is an industry leader as a CMO with the largest number of lyophilizers in service in North America. We have multiple development lyophilizers ranging in size from 4.6 square feet to 14 square feet. We have the ability to run multiple formulations in identical development lyophilizers which greatly speeds up the formulation and lyophilization cycle development process. LSNE also has almost 20 years of experience in successfully developing over 400 lyophilization cycles for our clients. We have seen many complex formulations and families of molecules and have faced many technically challenging development projects.
Upon launching a lyophilization development program, LSNE will review the current formulation of the product to evaluate whether it is amenable to lyophilization. LSNE can develop a formulation de novo or optimize the current formulation and evaluate different buffering systems, bulking agents and/or cryoprotectants. By using multiple lyophilizers, we can perform the lyophilization development runs in parallel, which not only provide our clients with a cutting edge development process to rapidly identify a suitable process, but a cost saving is realized as well.
LSNE works with our clients to improve lyophilization processes at all stages, from developing a formulation and lyophilization cycle in-house, to optimizing a commercial stage lyophilization cycle to reduce its length and again reduce cost. Recently, LSNE was transferring a manufacturing process to our cGMP aseptic drug product facility for a late stage product that had obtained commercial approval. The lyophilization cycle for the product, which was a monoclonal antibody, was reviewed and the lyophilization time seemed lengthy. We coordinated a meeting with the client and LSNE’s Formulation and Lyophilization Development team and, thereafter, performed a lyophilization optimization program to reduce the lyophilization cycle time. The lyophilization development program was a success and the lyophilization cycle was reduced by 18% which realized an immediate impact on the client’s cost of cGMP manufacture of the product. The client achieved an immediate ROI and paid for the cost of development after just a few cGMP manufacturing runs. This is an example of our success with a mature commercial product. Our optimization programs for earlier stage products typically yield dramatic decreases in the cycle time and improvements in the overall product profile.
To support our client’s lyophilization development programs, we evaluate the shelf-life of the product under various accelerated storage conditions with a short-term stability program. Once the product has demonstrated sufficient stability and moves to cGMP manufacturing, LSNE can perform a long-term ICH stability study on the Drug Product.
LSNE’s R&D team works closely with the manufacturing team to ensure a process developed by LSNE is transferrable to LSNE’s GMP Operations Group and cGMP equipment.
Can you elaborate on LSNE’s facilities and capabilities? What sets you apart from other companies that operate in the same market segment?
LSNE has been developing lyophilization cycles and providing manufacturing for the last 20 years. We have three commercially approved cGMP compliant manufacturing sites with different areas of expertise. I think what really sets us apart is that if a product can be lyophilized, we’ve probably handled it. I’d be hard pressed to name another CDMO with our breath and depth of experience. Our experience ranges from diagnostics, medical devices, bulks, intermediates, APIs, as well as drug product. Additionally, we’ve worked with some very complex lyophilized dosage forms that were suspensions/emulsions or liposomal formulations. In addition to our standard ISO 7 formulation room where we formulate products to be sterile filtered into our ISO 5 fill suite, LSNE has a dedicated ISO 5 formulation suite that we can use to aseptically process products that cannot be sterile filtered or terminally sterilized. This has been beneficial to a large number of our clients developing microparticle and nanoparticle products that cannot be sterile filtered.
LSNE is a worldwide supplier that has been inspected by the MHRA. As a result of the inspection, we received a letter of GMP compliance to aseptically manufacture both liquid and lyophilized drug product. Additionally, we host multiple QP audits per year. We also support our clients’ programs globally, including Asia and Israel.
To protect our clients’ valuable drug product, all of LSNE’s manufacturing equipment are on redundant systems and linked to our backup generator. LSNE’s facilities team offers fast and reliable maintenance which allows us to be self-reliant and not dependent on outside technical service organization to support our equipment. This in-house expertise gives us the ability to work with formulations containing organic solvents, which is a capability that very few of our competitors can accommodate.
Looking ahead, can you describe some of the technologies and capabilities that will be needed for scaling-up and processing future pharmaceuticals that might fall into categories such as potent/ toxic compounds, or products that have very high dollar values, and products that might be stored in containers other than glass? Is LSNE actively looking at these issues and ready to offer solutions to the industry and their clients?
As the biologics market continues to mature and new products enter the clinic, LSNE’s techniques for minimizing line-loss continue to gain efficiency. We have a large percentage of clients developing monoclonal antibodies and with each new client we have discussions about the high expense of the product and how we will work to maximize the use of every drop. LSNE has seen a significant increase in the number of companies developing RNAi or siRNA products and the cost of the oligonucleotide drug substance is very high as well. With our years of working with monoclonal antibodies we are extremely well positioned to work with oligonucleotides in an efficient and cost effective manner.
LSNE systematically reviews business metrics to consider and then decide what areas to add to our capabilities or target drug types for our existing capabilities. We evaluate new therapeutic advancements that currently fit into our existing capabilities or what systems or capabilities we may need to enhance or add-on for new novel technologies being developed. LSNE also has the ability to expand our current manufacturing facilities to support the specific needs of new larger scale projects.
As more companies are developing therapeutics with Orphan Drug Designation, LSNE is working with our clients and potential clients to expeditiously move their product into and through clinical development. LSNE batch sizes are perfect for drugs that will be receiving or have received Orphan Drug Designation. Our Quality Team stays abreast of the latest regulatory changes to stay compliant and streamline support activities. Such efficiencies include in-house regulatory writing support and having a Type V DMF on file with the FDA.
To support the growth in the outsourcing industry, LSNE is continuing to expand our facilities as well as our employees. LSNE’s staff has grown significantly over the last couple of years and we are continuing to add key employees such as industry Subject Matter Experts in many fields. We are continually adding staff with industry experience to increase competitive advantage over other CMOs.