Hung out to dry?

Rebecca Vagenechten explains the importance of delivering a freeze drying step-change for the pharmaceutical industry.

Problem: "Siemens is at the forefront of accelerating process analytical technology (PAT) implementation in pharmaceutical manufacturing. Now Siemens is teaming up with the University of Ghent (UGent) to study how PAT can help pharmaceutical companies gain better efficiency and control when they freeze dry their products."

Freeze drying, or lyophilisation, is an important part of the manufacturing process of many pharmaceuticals, especially in the fast-growing area of biotech production.

By removing water, the product becomes more stable. But this end stability is dependent on the product remaining stable during the drying process itself. Freeze drying is a complex, time-consuming and, thus for the pharma industry, expensive, multiple-step process during which the starting material, in solution form, undergoes several transformations leading to the end dry product.

In most manufacturing environments we see that the only information that is being monitored during lyophilisation is process data on the parameters of the freeze drier and not what is actually happening with the product itself. The result is that any degeneration of the product during the process can only be identified and rectified by in-process sampling - which is difficult given the vacuum conditions. Instead, end quality testing is mostly used today, whereby those vials that are of an unsatisfactory quality are eliminated. Throwing away the bad vials costs money.

Understanding and continuously monitoring what is taking place within the product  during the actual freeze drying process not only can ensure product quality is maintained but can also provide a much more optimal management of the process itself. During lyophilisation, it is crucial to ensure that the endpoint of all intermediate process steps is reached before the next process step is initiated and to monitor the solid state of the freeze dried product.

Drawbacks of current practice

Until now, several process analysers have been developed and used in industry allowing the in-line and real-time determination of the freeze drying step-end points. These include thermocouples, manometric temperature measurements and use of vapour pressure methods. However, these systems are mainly based on the continuous monitoring of the product temperature, the water vapour content, or pressure changes inside the freeze-dryer chamber.

These existing techniques are also mostly indirect and often disturb the normal freeze drying procedure. They do not allow monitoring of all critical process aspects, do not improve understanding of the product behaviour during the process and/or cannot characterize the intermediate and end product quality parameters, which are essential for real-time product release.

SIPAT: making real-time release possible

Siemens is building on the study to deliver this goal of making real-time monitoring and real-time product release possible for manufacturers. We are combining the UGent approach, which is not done in real time as the data is collected after the process has finished, with our SIPAT software which links analyzers and PAT tools into one single system architecture.

SIPAT makes it possible to collect analytical data in real time and use it with additional process data in a model that gives continuous predictions on the quality of the batch. Most important, it enables companies to have a control strategy in order to deliver advanced process control and achieve robust, right first time manufacturing. With SIPAT it is possible to act during the run of the process to correct a batch if any parameters are going wrong. Instead of having end-testing, in which some product is lost or even a whole batch if quality turns out not to be correct, manufactures can be confident that the integrity of the product has been maintained throughout the freeze drying.

Next steps

Siemens and UGent are working collaboratively with manufacturers who are taking a keen interest in deploying this technology and combining it with SIPAT to achieve real-time release in their own freeze drying processes. The potential is there for a step change in this crucial and, increasingly important, stage in pharma and biotech production.

Rebecca Vangenechten is a Life Sciences Industry Consultant with Siemens. She is responsible for business development life sciences US and focuses on innovative technologies, including Process Analytic Technology (PAT).