What’s hot in freeze drying? Your lyophilization questions answered

April 23, 2024 by Staff writer (15 minute read)

Category | Large molecule

What’s hot in freeze drying? Your lyophilization questions answered

Lyophilization is a critical process in the sterile fill-finish phase of pharmaceutical manufacturing, particularly for products that require high levels of stability and a longer shelf life. The freeze-drying technique involves removing water from a frozen drug product under low temperature and vacuum without compromising its structural integrity and efficacy. The ability to transform drug products into a dry powder without compromising their structural integrity is particularly crucial for preserving the stability and efficacy of biologic products, such as vaccines, antibodies, and other protein-based therapies.

Over the years, advancements in technology and process optimization have made lyophilization more efficient and reliable for a wide range of pharmaceutical applications. In a recent webinar, Thermo Fisher Scientific's Alessandro Chreim, a global subject matter expert in sterile drug products, provided insights into the latest trends, challenges and innovations in this field. This blog post addresses some of the pivotal questions surrounding lyophilization, shedding light on its current state and future direction.

What makes lyophilization crucial in today's pharmaceutical industry?

Lyophilization plays a crucial role because can provide a solution to stabilize pharmaceutical products that can degrade or lose their efficacy when exposed to liquid or thermal stress. The process encompasses controlled phases of freezing, primary drying, and secondary drying and needs to be designed in order to minimize the stress on delicate molecules and stabilize them under various storage conditions. Converting drugs into a stable, dry form significantly extends their shelf life, which is especially valuable for regions lacking sophisticated refrigeration or where supply chains are long and complex.

What are some of the main challenges in lyophilization?

One of the most pressing challenges is ensuring uniformity and quality of the lyophilized product. Achieving consistency can be difficult due to variability in freeze-drying cycles and differences in vial heat transfer. This challenge is exacerbated by the increased complexity of new drug products, especially biologics. Additional challenges include translating lyophilization processes from lab scale to full-scale production; meeting stringent and often evolving regulatory requirements for drug products; managing the escalating costs associated with the energy intensity of the freeze-drying process; and minimizing the risk of contamination to ensure the sterility of the product.

How are these challenges being addressed?

Recent innovations are reshaping the lyophilization landscape. Examples include automated loading and unloading systems that reduce the risk of contamination and human error; advanced freeze-drying sensors and process analytical technology (PAT) tools that allow for better control of the lyophilization process; controlled nucleation techniques that standardize the freezing step of the process; improvements in energy efficiency and thus cost; equipment and process control innovations that enable efficient and predictable scalability from lab to industrial scale; integration with software and data analytics to support better process understanding and optimization; and the adoption of quality by design (QbD) principles that enable more robust and efficient lyophilization processes.

Together, these advances allow for precise control over lyophilization cycles, facilitating consistent quality across production batches, especially in complex drug formulations.

How does formulation development impact lyophilization?

Drug formulation can impact the stability of the final product and directly affects the lyophilization cycle, particularly the freezing and primary drying phases. An optimal formulation ensures efficient sublimation and reduces the risk of product collapse or degradation during the process. In this regard, the formulation stage is key to ensuring that the final lyophilized product is stable, effective, and safe for use.

Formulation development is the first step of the lyophilization development journey and it’s more than just combining ingredients, formulation is a complex process of understanding and optimizing how each component interacts with the drug and affects the lyophilization cycle. The choice of excipients and stabilizers is integral because these components protect the active pharmaceutical ingredient (API) during the freeze-drying process. For example, sugars like sucrose or mannitol, are often used as cryoprotectants to stabilize the structure of proteins during freezing. They prevent the denaturation or aggregation of the API, which especially important for complex molecules like biologics but on the other hand they can influence the drug product behavior during sublimation and therefore a deep understanding of how formulation can influence lyophilization process is essential.

The characterization step of formulation development in lyophilization is also critical, as it provides the essential information about the physical and chemical properties of the drug product, which in turn influences the formulation and the lyophilization process. Characterization includes understanding the product’s thermal properties, which dictate the freezing and primary drying conditions. It also involves determining the stability of the drug in solution, its pH, solubility, and the behavior of the drug excipient mixture at various temperatures—all of which informs the development of a lyophilization cycle that optimally preserves the drug’s efficacy.

Importantly, different drugs require specific formulation strategies. Proteins, for instance, might need different stabilizers compared to small molecule drugs. The lyophilization process for a protein-based drug might be optimized to preserve its tertiary structure, whereas for a small molecule, the focus might be more on preventing crystallization.

Formulation also impacts the ease of reconstituting the lyophilized powder back into a solution for administration—a well-formulated lyophilized product will dissolve quickly and easily without leaving particulates or causing changes in the drug’s potency—and it affects the long-term stability of the lyophilized product.

What are the regulatory compliance implications?

Compliance with guidelines and standards set by regulatory authorities such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is a critical requirement for market approval and maintaining public trust. In lyophilization, compliance is a multi-faceted, dynamic, and ongoing process, encompassing everything from the early stages of formulation development to post-market monitoring.

One of the primary aspects of regulatory compliance in lyophilization involves maintaining comprehensive and detailed documentation of the entire lyophilization process. This documentation serves as evidence that the lyophilization process consistently produces a product that meets predetermined specifications and quality attributes. Key components include data on formulation development, process validation and monitoring, quality control and testing, Good Manufacturing Practice (GMP), risk management, and post-market surveillance.

What are the strategic benefits of working with a contract development and manufacturing partner (CDMO) partner that has extensive lyophilization experience?

Lyophilization is a nuanced and evolving field within pharmaceutical manufacturing. As technologies advance and regulatory landscapes shift, partnering with a skilled CDMO can be a critical factor in a drug product’s success.

CDMOs with lyophilization expertise and experience are typically equipped with state-of-the-art technology and facilities to support the freeze-drying process for sterile fill finish. This includes access to the latest equipment, controlled nucleation technologies, and automated systems, as well as scalable solutions that enable the transition from small-scale development batches to large-scale commercial production by platform approaches. CDMOs that offer end to end development and manufacturing services are able to integrate lyophilization activities and provide a seamless transition from drug development to commercial-scale production, ensuring consistency and quality at every stage.

Additionally, a seasoned CDMO can provide invaluable assistance in ensuring compliance with FDA, EMA, and other regulatory bodies' standards, reducing the risk of compliance-related delays or issues. Their expertise in risk management, process validation, and quality control minimizes potential issues during production and during dossier submission, which is also crucial for meeting market demands and timelines.

By outsourcing lyophilization to a reliable and experienced CDMO partner, pharmaceutical companies can focus more on their core competencies, such as drug discovery and marketing, while leaving the complexities of drug manufacturing to the CDMO.

To learn more about the intricacies of lyophilization and the role of strategic CDMO partnerships in optimizing the potential of this critical process, watch our on-demand webinar, Lyophilization excellence: Partnering for sterile fill finish success.