Companies developing lifesaving therapeutics often address the challenge of product stability and cold-chain management by developing a lyophilized dosage form for their drug product. The advantage and goal of a lyophilization cycle development program is to increase product stability at more favorable storage conditions; for example, developing a lyophilized dosage form with storage at 2-8°C or ambient for a liquid formulation where previously -20°C storage was required. LSNE receives development requests for a wide variety of products from the biotechnology, pharmaceutical, and medical device industries, and one question that is asked frequently from prospective clients is:
“Is there any kind of standard lyophilization cycle that we could use for our product?”
Being mindful that each drug product has unique properties and sensitivities makes tailored development critical to efficient production of your drug product. Throughout LSNE’s history we’ve developed or optimized over 600 lyophilization cycles for our clients and found that ‘One Size Does Not Fit All’ in terms of pharmaceutical development. Our approach is to develop a lyophilization cycle that is transferrable from small scale R&D lyophilizers to large scale commercial lyophilizers, a more appropriate statement may be ‘One Cycle Does Not Fit All Products and Equipment.’ To develop a robust lyophilization cycle it is critical that one spend the time in the early stages of the development project to fully understand the product’s physical characteristics and thermal properties.
Having an in-depth understanding of the formulated product’s thermal profile prior to developing a lyophilization cycle is the first step. The use of methods such as Modulated Differential Scanning Calorimetry (mDSC) and Freeze-Dry Microscopy (FDM), help us to define and understand the physical characteristics of the formulated product; such as a product’s freezing point, glass transition, eutectic temperature, and collapse temperature in order to customize a lyophilization cycle that will produce a stable pharmaceutical product.
Furthermore, our R&D team will use a ‘sample thief’ to collect multiple samples during development lyophilization runs to assess moisture content or residual solvents in real-time to establish an efficient secondary drying cycle and fully characterize the lyophilization process parameters.
Prior to developing a lyophilization cycle specifically for your product, we must decide whether the current liquid formulation developed by you or a third-party laboratory is amenable to lyophilization. We will first determine if it is beneficial to perform a formulation development project based on the nature of the API’s profile and the product’s degradation pathway. LSNE has experience with very challenging and unique products, such as polymeric nanoparticles, liposomal formulations, drug products formulated in organic solvents, as well as experience with developing lyophilization cycles for thermo-reversing gels that will start to solidify once at room temperature.
As new solubilization technologies and delivery methods become available, many low solubility APIs have entered the market. A CDMO needs to stay abreast of developing technologies to support liposomal formulations, emulsions, suspensions as well as drug products being formulated with a variety of complexing agents. LSNE has kept pace with companies who have developed platform technologies by initiating the program with a comprehensive development plan for the primary platform product and then performing an assessment of subsequent molecules using the optimized platform technology.
CDMOs working collaboratively with the developer on complex and aseptically processed projects are driving the business towards longterm partnerships rather than a single manufacturing batch.
Regarding one size fits all, some of our clients have come to LSNE for their cGMP manufacturing campaigns with a lyophilization cycle that was developed by a third-party CDMO or by using a lyophilization development software package. Some of these lyophilization cycles are not suitable for cGMP manufacturing at scale, as the software package may not consider the shelf temperature and vacuum ramp up or ramp down times required for a commercial sized freeze-dryer or variations in vial heat transfer coefficients (Kv) between different freeze-dryers.
Due to the mass of product in a large lyophilizer, shelf ramp rates must be considered during development. For instance, ramping a research freeze-dryer at 5°C/min may be possible and could minimally reduce cycle times. However, when attempting to ramp a commercial scale freeze-dryer at this rate there will undoubtably be variation in shelf temperature uniformity across and between shelves. Ultimately this could impact the cycle efficiency, appearance, reconstitution time, and residual moisture/solvent within the finished product. The one-sizefits-all model will cause technical transfer issues and delays whether at LSNE or another commercial scale lyophilization manufacturing site.
To help you develop a comprehensive plan for your development project, here are guidelines you can keep in mind prior to initiating your lyophilization cycle development program:
- What clinical stage is your product? At LSNE, we take great care to ensure phase appropriate development to expedite progress and minimize API or BDS loss. For early stage programs you may be able to proceed to the clinic with an abbreviated development program. If the clinical program is successful, you can spend some more time and money on further development as the product matures. If your time or budget is limited, ask your CDMO about a lyophilization development program with a limited number of development runs for your early clinical needs. You may be able to save time and money for your early stage clinical trial(s) by using a conservative lyophilization cycle and then further optimizing the cycle once you’ve completed your dose ranging studies. It will be essential to optimize your cycle as you approach Phase III/Registration and Process Validation batches. A robust lyophilization cycle that is optimized for your product will greatly reduce risk during manufacturing and save you costs over the life of the product.
- Leverage any pre-formulation data you have. Leveraging existing data will allow the development team to assess how much initial work will need to be performed and develop a plan for an efficient development program. The more information you can share with the CDMO on your compound's solubility, stability, acceptable pH range, intended route of administration, and degradation pathway the more the development team can streamline your project.
- How much material do you have available for cycle development? Lead times are increasing for both bulk drug substance/API vendors as well as drug product manufacturers. You will want to ensure you have enough material to complete your development experiments in a timely manner. Without proper planning, you could end up with delays waiting for additional BDS or API to be manufactured to support development. If material is limited, talk to your CDMO about strategies to conserve material by using placebo, dunnage, or scaling down the presentation while maintaining the target concentration for the final presentation during the development program.The amount of material required for testing over the course of development will also need to be taken into consideration. A mature CDMO has procedures in place to provide you with a robust development program while limiting the amount of API required for experimental runs and the supporting analytical testing.
- Ensure you have a stability indicating analytical method(s) available at the start of development. The ability to perform analytical or bioactivity testing quickly after each experiment or lyophilization cycle will allow the program to move as efficiently as possible through the experimental design plan. Outsourced testing could become a bottleneck for your development program if turnaround times to receive test results take longer than originally anticipated. Planning ahead is critical.
Talk with your CDMO early to ensure your stability indicating methods are optimized. Most CDMOs have the capability to develop methods in-house and can work with you to execute multiple development activities in parallel.
- Do you have a unique compound? If your finished product doesn’t present as the standard white pharmaceutically elegant cake, there may be additional development efforts required to be able to successfully visually inspect the product. Your CDMO may also be able to help develop visual inspection standards and test kits during the development phase to support the technology transfer process for your GMP manufacturing campaign.
As you reflect upon the guidelines shared, the take away message is that it is never too soon to start planning. As stated above, there will always be several factors to consider with any development project. To develop a pharmaceutically elegant lyophile it’s worth the upfront time to fully understand your compound as you plan the early stages of development. Take the time to find a CDMO partner that will be able to grow with you as your product progresses, to truly optimize your product’s manufacturing process there is no one-size-fits-all lyophilization cycle that is suitable for all products.
Author Biography
Jeff Clement joined LSNE in 2014 and he manages the Business Development team and oversees marketing. Jeff has over twenty five years in the biotech and pharmaceutical industries and his career includes experience in the pharmaceutical discovery sciences, high throughput automation, clinical formulation development, and cGMP analytical and manufacturing contract services. All of his business development experience is in the aseptic manufacturing and analytical fields. Jeff received a B.S. in Biology from Keene State College and a M.S. in Quality Systems from The New England College of Business.