As the pharmaceutical industry focuses on complex, potentially life changing biologics, lyophilization, or freeze-drying, has become essential for the successful development and commercialization of a wide array of therapies.
As noted in the LyoHub 2023 Annual Report, submissions for lyophilized drugs approvals have increased by an average of 15% in the past decade. From 2012 to 2022, a total of 336 lyophilized drugs were approved by various regulatory agencies, constituting 59% of all lyophilized drug filings since 1954. While this is a testament to advancements in lyophilizer technology and design strategy implementation, it is also representative of the number of novel, temperature labile drug molecules, such as biologics, reaching the market.
In 2022 alone, the US FDA approved 32 lyophilized drug products, of which oncology and infectious diseases represented 82% of approvals.
This sophisticated drying process offers a way to stabilize drugs, ensuring their efficacy and longevity. From monoclonal antibodies and peptides to vaccines, lyophilization supports the preservation of biologics that are often too delicate for other stabilization and preservation techniques.
The Growing Importance of Lyophilization
For biologics and other sensitive compounds, lyophilization is not just a practical choice; it is often a necessity. The ability to remove solvents through sublimation without exposing the product to harmful levels of heat makes it an ideal option for maintaining the structural integrity and therapeutic efficacy of delicate molecules, according to pharmaceutical contract manufacturer PCI, a specialist in sterile fill-finish and lyophilization processes. PCI Pharma Services is currently involved in a $100 million expansion project installing fully-automated twin lyophilizers, complete with a large scale, Annex 1 compliant isolator vial filling line within a new 50,000-square-foot plant at its Bedford, New Hampshire sterile manufacturing campus.
鈥淟yophilized products demonstrate and exhibit improved thermal stability, eliminating the need for costly frozen storage and reducing risks during transportation,鈥� says Matt Bourassa, senior manager of process development at PCI.
鈥淭his advantage is particularly important for products shipped to regions with challenging environmental conditions, such as tropical climates, where cold-chain infrastructure may be limited.鈥�
Mastering the Lyophilization Cycle
Bourassa explains that lyophilization involves a series of steps to achieve optimal product stability and quality. These can be broadly categorised into three primary phases: freezing, primary drying (sublimation), and secondary drying (desorption). Each phase plays a pivotal role in the successful stabilization of the drug product, and careful control of the parameters in each step is crucial.
- Thermal treatment. This initial step involves freezing the product to create a solid matrix. It is essential to control the freezing rate to ensure uniform ice crystal formation, which directly impacts the efficiency of subsequent drying stages. Cryoprotectants and bulking agents may be added during formulation to protect the product from damage caused by freezing stresses. PCI uses advanced technologies, including heat-flow analysis and crystal-sizing techniques, to hone in on the intricacies of the product during this phase.聽 PCI is also investing in nucleation on-demand capabilities within the Process Development space, which can achieve greater uniformity across batches, enhancing the quality of the final product.
- Primary drying. This is the core of the lyophilization process, where the majority of the solvent is removed under vacuum via sublimation. Precise control of pressure and temperature is essential to drive the sublimation process efficiently without compromising product integrity. PCI employs process analytical tools such as Pirani gauge analysis and thermal characterization techniques to monitor and adjust conditions, ensuring optimal results during development and well into GMP manufacturing. By balancing drying time with product stability, PCI minimizes processing costs while safeguarding product quality.
- Secondary drying. This step involves the removal of bound moisture from the product. By increasing the temperature under controlled conditions, PCI ensures that any residual moisture is desorbed without damaging the drug鈥檚 active ingredients. This phase is particularly delicate, as any mishandling could lead to degradation or structural collapse of the lyophilized product.聽 PCI can assess the residual moisture by sampling product within the lyophilizer during development runs, providing an acceptable range of secondary drying times and drug product residual moisture and stability considerations in real time.聽
Overcoming scale-up challenges
Scaling up the lyophilization process from laboratory to commercial manufacturing presents a host of challenges. Each drug product has unique characteristics that must be considered when developing a lyophilization cycle, and these variables often become even more complex at scale. Factors such as chamber design, vacuum capability, and shelf temperature uniformity can introduce variability that threatens product consistency. To mitigate these risks, PCI invests in state-of-the-art equipment and rigorous process validation of equipment, with product-specific considerations in mind. The company鈥檚 facilities are equipped with some of the industry鈥檚 largest lyophilizers, capable of producing commercial-scale quantities without compromising on quality.
One of the critical aspects of successful lyophilization is ensuring that the product鈥檚 Critical Quality Attributes (CQAs) are maintained throughout the cycle. PCI鈥檚 experience in handling large-scale lyophilization projects enables the company to anticipate and address potential issues early in the development process, and are continuously improved over the product lifecycle during clinical trials. By employing advanced process analytical technologies (PAT) and adhering to the principles of Quality by Design (QbD), PCI can fine-tune cycle parameters to create a robust, scalable process.
Tailored solutions for diverse drug modalities
No two drug products are the same, and the flexibility of the lyophilization process is one of its key advantages. PCI鈥檚 scientific team works closely with each client to understand the specific requirements of their drug product, whether it be a monoclonal antibody, oligonucleotide, peptide, or other biologic. This collaborative approach ensures that the lyophilization cycle is tailored to meet the exact needs of the product, optimising its stability, efficacy, and reconstitution time.
In one case, PCI assisted a small biotech company facing stability issues with a monoclonal antibody in the preclinical phase. By developing a quickstart lyophilization program, PCI was able to create a viable lyophilized product for Phase I clinical trials in a fraction of a standard cycle development time, despite the limitations of the client鈥檚 initial formulation. Even with challenges present, the PCI team utilized a comprehensive team of experts from development to manufacturing to translate scale-up considerations for formulation, lyophilization, and sterile fill finish, leading to clinical success for the client. The success of this program not only enabled the client to progress through clinical trials but also laid the groundwork for a scalable solution that could support future commercialization efforts.
PCI as a strategic CDMO partner
PCI is uniquely positioned to support pharmaceutical companies in bringing these life changing therapies to market. With more than 25 years of experience in lyophilization, PCI鈥檚 expertise spans early-phase clinical trials through to large-scale commercial manufacturing. The company has successfully developed more than 675 lyophilisation cycles, making it a trusted partner for pharmaceutical companies seeking reliable, scalable solutions.
For any pharmaceutical company navigating the complexities of lyophilization, the choice of a CDMO partner is crucial. PCI offers not only the technical expertise and state-of-the-art facilities necessary for success but also a commitment to collaboration and flexibility. From cycle development to full commercial production, PCI stands as a leader in the field, dedicated to helping its clients deliver therapies that improve patient outcomes.
Explore the dynamics of the lyophilization development cycle in the free whitepaper below.
