The Art and Science of Lyophilization in Biologic Drug Development

As the pharmaceutical industry advances complex, potentially life changing biologics, lyophilization, also known as freeze-drying, has emerged as a critical process 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.

Lyophilized products demonstrate and exhibit improved thermal stability, eliminating the need for costly frozen storage and reducing risks during transportation.  This advantage is particularly important for products shipped to regions with challenging environmental conditions, such as tropical climates, where cold-chain infrastructure may be limited.

Mastering the Lyophilization Cycle

Lyophilization involves a series of steps to achieve optimal product stability and quality. While there are individual intricacies within these steps, they 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 and subsequent thermodynamic arrangement of the product to ensure full nucleation of the solvent and generate a solid matrix. Thermal treatment is a simple yet crucial step to ensure full nucleation of the solvent and generate uniform frozen matrix to prepare the product for sublimation. Controlled freezing rates, along with annealing and process knowledge of supercooling effects, are often employed to achieve uniform ice crystal distribution.  

At the beginning of the lyophilization process, products must be formulated in such a way that they are suitable to undergo thermal treatment. Cryoprotectants such as saccharides and polyols, together with bulking agents may be added during formulation to protect the product from damage caused by freezing stresses. Advanced technologies including heat-flow analysis and crystal-sizing techniques can be utilized to hone in on the intricacies of the product during this phase.  Within the Process Development space, nucleation on-demand can help 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. Employing process analytical tools such as Pirani gauge analysis and thermal characterization techniques to monitor and adjust conditions, ensures optimal results during development and well into GMP manufacturing. Balancing drying time with product stability, minimizes processing costs while safeguarding product quality.
  • Secondary Drying. This step involves the removal of bound moisture from the product. Increasing the temperature under controlled conditions, ensures that any residual moisture is desorbed without damaging the drug’s active ingredients. This phase is particularly delicate, as any mishandling could lead to degradation or structural collapse of the lyophilized product.  Assessing the residual moisture by sampling product within the lyophilizer during development runs, provides an acceptable range of secondary drying times and drug product residual moisture and stability considerations in real time. 

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, investments in state-of-the-art equipment and rigorous process validation of equipment, with product-specific considerations in mind is key.

One of the critical aspects of successful lyophilization is ensuring that the product’s Critical Quality Attributes (CQAs) are maintained throughout the cycle. Experience in handling large-scale lyophilization projects builds knowledge and expertise to be able to anticipate and address potential issues early in the development process, and ensure they 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), cycle parameters to create a robust, scalable process can be fine-tune.

Lyophilization 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. When scientific team works closely to understand the specific requirements of the drug product, whether it be a monoclonal antibody, oligonucleotide, peptide, or other biologic, the lyophilization cycle is tailored to meet the exact needs of the product, optimizing its stability, efficacy, and reconstitution time.

As pharmaceutical companies continue to pioneer new molecules and treatments, it is clear that the stability of these molecules has increasingly become a detrimental factor upon every iteration, and that lyophilization is the pathway to a solution. 


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Our dedicated team of specialists will be happy to discuss any of your lyophilization needs. Contact us on +1 215-613-3600 (US) or +44 1495 711 222 (UK/EU) or email talkfuture@pci.com

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