How Lyophilization Speeds Development of APIs and Polymers

Many drug substances, particularly biologics, commonly undergo lyophilization ahead of being packaged as a dry powder that will later be reconstituted and injected into patients. At times this freeze-drying method is requested for the final API. Other times it is required as an intermediate R&D step. We have found that our use of this process has been steadily increasing in the preparation of polymers and complicated molecules, along with other tools such as biotage and cryogenic chemistry.

Why? In drug development, time is always of the essence. A major reason is that the patent life of newly discovered drugs grows ever shorter, forcing drug developers to minimize drug development time. To achieve the goal of a shorter time to market, existing processes need to be upgraded with new methodologies for greater throughput. Consequently, we, as their CDMO, are constantly seek greater efficiencies. As better tools become available that can help optimize and speed processes, we evaluate them and incorporate them into our labs and GMP suites.

So it is with lyophilization. This article provides some background on freeze drying in drug manufacturing.

In the old days, if freeze drying was an intermediate step for the API in development, we would take the material and place it in glass flask in the lab. We would then chill the flask using acetone and dry ice to remove water molecules from the material under vacuum. That’s an inefficient method. It is not automated. It is not scalable. And It is not the way we do it today.

Today’s equipment makes lyophilization process far more efficient. That process entails:

• Pretreatment
• Loading
• Freezing at atmospheric pressure
• Primary drying (sublimation) under vacuum
• Secondary drying (desorption) under vacuum
• Removal of dried product from freeze dryer

As in all aspects of drug development, even when using equipment to perform processes nothing is easy or routine. In lyophilization, each API, depending on its physical characteristics and desired result, requires a different temperature, pressure and time setting. It’s like baking at home. Making popovers requires that the oven be set at a hot 450 degrees to achieve the characteristic hollow center, while other types of dinner rolls that have a more uniform consistency are prepared differently and are baked at a lower temperature. Needless to say, developing new chemistry is far more complicated than following a recipe from a cookbook. Each of the settings needs to be adjusted individually for every product. The more knowledge and experience the CDMO’s R&D and manufacturing teams have with similar compounds, the more quickly the lyophilization step evolves.

Reason to use lyophilization equipment

Repeatability is an important consideration when documenting every step of drug development in accordance with regulatory agency requirements. Equipment that automates the process

renders it repeatable, so that parameters such as temperature and pressure are well defined.

Lyophilization extends shelf life

Freeze-drying of active ingredients extends their shelf life. Back in the 1950s, lyophilization played a critical role in vaccination programs for lethal viral diseases such as smallpox. Using the freeze-dried therapeutic even in tropical climates maintained the smallpox vaccine’s potency for several weeks at room temperature. This essentially enabled the World Health Organization (WHO) to eradicate the disease.

The freeze-dried drug product is quickly reconstituted at the point of service or when preparing pre-filled delivery devices.

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Lyophilization in polymerization

While lyophilization plays a role as a step in development of some APIs, we find we are also using it in the many GMP polymers and monomers we produce.

Lyophilization is a sublimation process – the liquids in the product go from a frozen state to a gaseous state without going through a liquid phase. It leaves behind dry solids, and this process lends itself to development of numerous polymeric applications.

What is driving the GMP polymer market is the increase in chronic diseases combined with a better understanding of drug metabolism in patients.

The polymers we produce are used in a broad range of products. These include implantable devices that administer medications consistently to the patients who need them.

In cardiac patients, for example, our GMP polymers are used as free-radical scavengers while in cancer therapy, they are used as a drug delivery vector. They are also used in imaging applications, formulation of coatings, and in RNA/DNA drug synthesis.

These advanced polymer manufacturing capabilities enable our cGMP Advanced Polymer Manufacturing and Development Group to provide the expertise and sophisticated analytical techniques required for such projects.

GMP polymer synthesis is a unique capability that will continue to grow in demand as the pharmaceutical and medical device industries turn to polymers for controlled release drug delivery, surgical applications, wound management, delivery devices and other applications.

Assuring the highest level of GMP quality and expertise in this unique specialty is essential to the safety of polymer-based therapeutics.

Whether freeze drying or working at low temperatures like cryogenics, we’re seeing an increase in the demand for processes that require extreme cold. To learn more about our cryogenics, check out “How Cryogenic Capabilities Aid API Development.” If you have any questions, please call us at (978) 462-5555.