The Big Freeze: Obtaining the Best Results from Lyophilization

Dr. Karen Bossert, Vice President of Operations
June 2019, European Pharmaceutical Manufacturer

Managing shelf life and other critical delivery targets

Lyophilization is a practical, commercially validated method to stabilize formulations and therapeutic molecules. The process relies on the control of pressure and temperature within the lyophilizer to remove liquid from formulations containing thermally sensitive active pharmaceutical ingredients (APIs) or formulation components. The resulting solid exhibits greater stability than the aqueous solution and can be stored for longer periods at potentially higher temperatures compared to its liquid precursor and may include ambient conditions. This technology has been particularly useful for large molecule developers - a growing segment of the pharmaceutical industry. With lyophilization, fragile biologics no longer require expensive complex logistics such as rigorous cold-chain custody validation regimes and constant documentable refrigeration at the dispensary level.

The market’s growing need

As API and formulation stability challenges become more common, growing numbers of pharmaceutical and biotech manufacturers view lyophilization as an enabling technology for the next generation of therapeutics.

Over the past five years, there has been a marked increase in the use of lyophilization in pharmaceutical and biopharmaceutical manufacturing – around 13.5% growth each year. This growth is being driven by many factors, including the complexity and variety of drug formulations that are coming through the pipeline.

Lyophilization is a mature commercial process, and multiple blockbuster drugs (including biologics such as Enbrel, Herceptin, and Rituxan) were made possible due to sterile lyophilization. Currently, around 16% of the top 100 pharmaceuticals are lyophilized, including a third of all biologic drugs and half of all new injectable/infusible drug approvals. In the future, market analysts predict that a quarter of all biotechnology and pharmaceutical products will undergo lyophilization.

A better stabilization strategy

Lyophilization offers parenteral drug developers great utility because it results in a stable powder for injection that is easily packaged and transported as a finished product. However, lyophilization can also be used to generate stable intermediates during drug product development and manufacturing. A lyophilized stock of sensitive API has a longer shelf life, which is useful for APIs that lack the stability to be processed in an aqueous state. Lyophilization can generate a powder with flowability for milling or powder fills, or it can simply be used to remove residual solvent from a material.

While lyophilization offers clear advantages, the process itself still requires good science, best-practice operations, and optimized equipment to ensure lyophilization processes meet the molecule’s requirements without compromising its therapeutic goals. This demands significant investment in time, money, and staff resources:

  • Specialized knowledge required: Lyophilization cycle development and scale-up relies on a thorough understanding of the freezing and sublimation processes. This requires extensive characterisation of the drug product as well as studies to understand the effect of packaging and batch size on processing.
  • Additional contamination risk: Many lyophilized products are not amenable to terminal sterilisation and must be manufactured under aseptic conditions to maintain product sterility. This is a major challenge that requires extensive validation and monitoring of equipment and procedures to execute.
  • High capital investment: R&D development of a lyophilization cycle can take place with pilot scale equipment in small batches. However, large-scale lyophilizers and the associated cleanroom facilities to accommodate sterile fill-finish cost millions of dollars to install and maintain.

Developing, scaling, and validating a lyophilization cycle is challenging, and many small and large pharmaceutical companies choose to place their lyophilization processes in the hands of CDMOs for clinical and commercial manufacturing.

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Recognising high performance lyophilization service providers

Although there is a clear and growing demand for lyophilization in the market, providing expert lyophilization capabilities demands more than installing the newest state-of-the-art equipment and systems.

From analytical and quality support to validation and regulatory guidance, it is vital to ensure that contract development and service providers offer critical supporting services, including complex formulation expertise and experience with analytical method development and validation. These skills allow CDMOs to meet target product profiles and effectively verify product performance before and after lyophilization.

For example, a growing number of drug products rely on complex formulation approaches such as encapsulation in polymeric microparticles or liposomal platforms. These products often provide poor stability in their native states and rely on lyophilization to be commercially viable. Without a formulation team skilled in excipient selection and an analytical group who can consistently characterize product performance, a CDMO cannot formulate the initial solution/suspension, design the lyophilization process, and ensure that the final drug product is truly ready for market.

The future, based on a dry conclusion

Lyophilization is rapidly gaining ground as more and more drug products benefit from this manufacturing process. With the increase in complex molecules and unstable compounds in the drug development pipeline, it is likely that the demand for expert capabilities implementing this method will only increase.

From a commercialization perspective, any drug developer considering lyophilization must ensure that they have the necessary capacity and capabilities, whether in house or outsourced. Any CDMO partner brought in to assist in a project must possess more than just a “freeze dryer” to get the job done. They must have formulation and analytical expertise along with experience developing, scaling, and validating lyophilization cycles to ensure a project has a chance of success.

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