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The big freeze: Obtaining the best results from lyophilisation

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In this article, Karen Bossert, vice president of operations at CDMO Particle Sciences, reviews the use of lyophilisation in pharma and the growing market need for this technology, as well as how practical expertise and operational experience help obtain the best results for pharma’s most advanced drug developers.

Managing shelf life and other critical delivery targets

Lyophilisation is a practical, commercially validated method to stabilise formulations and therapeutic molecules. The process relies on the control of pressure and temperature within the lyophiliser 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 lyophilisation, 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 lyophilisation 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 lyophilisation 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.

Lyophilisation is a mature commercial process, and multiple blockbuster drugs (including biologics such as Enbrel, Herceptin, and Rituxan) were made possible due to sterile lyophilisation. Currently, around 16% of the top 100 pharmaceuticals are lyophilised, 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 lyophilisation[1].

A better stabilisation strategy

Lyophilisation 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, lyophilisation can also be used to generate stable intermediates during drug product development and manufacturing. A lyophilised 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. Lyophilisation can generate a powder with flowability for milling or powder fills, or it can simply be used to remove residual solvent from a material.

Inherent complexities require comprehensive approach

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

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

Recognising high performance lyophilisation service providers

Although there is a clear and growing demand for lyophilisation in the market, providing expert lyophilisation 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 lyophilisation.

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 lyophilisation to be commercially viable. Without a formulation team skilled in excipient selection and an analytical group who can consistently characterise product performance, a CDMO cannot formulate the initial solution/suspension, design the lyophilisation process, and ensure that the final drug product is truly ready for market.

The future, based on a dry conclusion

Lyophilisation 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 commercialisation perspective, any drug developer considering lyophilisation 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 lyophilisation cycles to ensure a project has a chance of success.

[1] Lyophilization Equipment Market, Markets and Markets

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