Of the top 100 drugs, 16% are lyophilized. The percentage of lyophilized biological drugs is even greater – 35%. Although lyophilization (freeze drying) has been used for more than half a century in drug product manufacturing for its ability to stabilize and extend the duration of pharmaceutical products, interest continues to grow, due mainly to the large and growing number of biologic drugs in development.
If the increasing requests for lyophilized products at our Seqens North America facility is any indication, the demand for lyophilization services is growing across the board. There are several reasons for this. We are seeing more and more material being produced in an aqueous medium, even when developing small molecule drugs. In drug synthesis we often use organic solvents that are easier to remove than water. However, there are chemicals for which water is a better solvent despite the fact that it is much more difficult to separate and remove.
This article provides information on why freeze drying has become necessary in drug and polymer manufacturing, and answers some of the questions we have been asked.
Biologics, GMP polymers require lyophilization
Although biologics are complex molecular entities that are often unstable in solution,
many biopharmaceutical materials are produced in an aqueous medium by necessity. The material is live – it’s a biologic. If we were to place a protein, peptide, or fermented product into a chemical medium it would be killed. Instead, it is grown in an aqueous medium where it is present in low concentrations. Removing the water with lyophilization is time consuming but remains the most efficient method of producing an active ingredient that will be packaged as a dry powder and later reconstituted just before being injected into patients.
In addition to lyophilizing more and more drug candidates we are also increasing the use of lyophilization in our GMP polymer production that is a growing part of our business as more combination products come to market.
Where just a few years ago we outsourced lyophilization to others, its increasing use, particularly in developing GMP polymers, led us to take all such projects in-house for greater efficiency. Whether required as an intermediate R&D step, developing new polymeric materials or in development of complicated molecules, freeze drying has become a critical CDMO tool for us.
Why is lyophilization one of the most expensive and time-consuming processes?
Lyophilization is time consuming to be sure. And of course the more time a project takes, the more expensive it is.
There are essentially three factors that contribute to the long time it takes to lyophilize:
- Generally, a tremendous amount of material is required for a small amount of output—50 gallons of solution might yield only 100 gm of powder. The process may need to be repeated until we have sufficient product for the use intended. And nothing is routine. Each API, depending on its physical characteristics and desired result, requires a different temperature, pressure and time setting.
- The lyophilization process requires placing material in reusable containers, which require rigorous cleaning before the next batch is added.
- The extensive QA oversight needed to assure that cleanliness has been maintained, and the paperwork involved in each of the steps involved–pretreatment, loading, freezing at atmospheric pressure, primary and secondary drying under vacuum, and removal of dried product from the equipment–all play a role in increasing the time it takes to produce lyophilized material.
In the old days, when freeze drying was an intermediate step in API development, we would take the material and place it in glass flasks in the lab. We would then chill the flask using acetone and dry ice to remove water molecules from the material under vacuum. That inefficient process has been replaced by an automated, scalable but still lengthy one.
What advances have occurred in lyophilization equipment and knowledge?
Despite automation and improvements in equipment and instrumentation—such as condensers that can handle higher vapor loads—lyophilization remains time-consuming and as such, costly.
However, the more knowledge and experience the CDMO’s R&D and manufacturing teams have with similar compounds, the more quickly the lyophilization step evolves without impacting product quality.
As we lyophilize more and more in drug product and polymer development, our understanding of the following critical factors has evolved for greater efficiency:
- Product critical temperature
- Optimization of shelf temperature
- Maintenance of chamber pressure
- Maximizing sublimation rate
- Freezing methods and their impact on crystal structure
Lyophilization in polymerization
The growing GMP polymer market is driven by the increase in chronic diseases combined with a better understanding of drug metabolism in patients. Lyophilization plays a key role in the many GMP polymers and monomers we produce.
That 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, leaving behind dry solids—is why the process lends itself to development of numerous polymeric applications.
The polymers we produce are used in a broad range of products these include, implantable devices that administer medications consistently to patients. Our polymers are also used to deliver cancer therapy, in imaging applications, formulation of coatings and in RNA/DNA drug synthesis.
These projects and others continue to enhance our cGMP Advanced Polymer Manufacturing and Development Group’s expertise and sophistication.
Is lyophilization worth the time and cost involved? Absolutely. It is one of the tools we need to use. And because many biologic drugs are unstable in solution, the expense of lyophilization is minor when considering the total cost of manufacturing these and other complex molecules. Besides, there is no good alternative.
For other articles about lyophilization and cryogenics (a process that uses super-freezing temperatures), check out “How Lyophilization Speeds Development of APIs and Polymers,” “The Economics of Cryogenic Chemistry in API Development
How Expanded Cryogenics Capabilities Benefit Sponsors,” and “Cryogenics: How Cryogenic Capabilities Aid API Development.” Or call us at (978) 462-5555.