Making the Difficult Look Easy: PAT at Talecris

Editor's Note: Fragile proteins are at the heart of some of the most important life-saving therapies available today. However, manufacturing these proteins can be far more challenging than making traditional pharmaceuticals. One of the greatest challenges is simplifying and controlling the manufacturing process, a process that is itself changing as micro-organisms adapt to their environments.At a time when controversy still surrounds the application of process analytical technologies and advanced control to biopharmaceutical manufacturing, the therapeutic protein manufacturer Talecris Biotherapeutics is making great strides in improving the analysis and control of its processes. In this article, Talecris’ PAT team summarizes best practices and recent examples of success.

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By Gerrit Vogel, Joydeep Ganguly, Dr. Anne Bertelsmann, Dr. Douglas Burns, Dr. Gerold Mohn, Dr. Prasanna Deshpande, and Dr. Pete Vandeberg, Talecris Biotherapeutics *

Nearly 10 years ago, we sought a structured process for analysis technology, in order to better monitor and control the manufacture of our fragile protein therapies. Looking back, we now realize that we were striving toward the goals of Process Analytical Technologies (PAT). Since then, our use of PAT has evolved to keep up with new manufacturing processes and technologies, and most recently with FDA’s PAT guidance [1], released in September 2004.

* Talecris is based in Research Triangle Park, N.C., with facilities in Clayton and Raleigh, N.C., and Melville, N.Y. It was formed in 2005, when the assets of Bayer HealthCare’s Biological Products Division’s plasma business were purchased by private investors.

In order for PAT to truly be effective and useful during the entire manufacturing cycle, it must reflect all aspects of the manufacturing process and encompass all business segments that stand to benefit from FDA’s guidelines. It was important to establish an organizational framework to support PAT.

We began by forming a multidisciplinary Core Team whose mission is to promote initiatives and review opportunities for PAT application. This team’s direction is then executed by a PAT Implementation and Coordination Group, which was formed to prepare proposed PAT solutions for evaluation and, once approved, to coordinate and facilitate the execution of a PAT effort.

The next step was to develop a "PAT Master Plan" to define our company’s interpretation of the FDA guidelines. The Master Plan serves as a road map for all PAT implementations — from initiation to execution — and ensures consistency across all company efforts. Within the Master Plan, the Core Team outlined five implementation steps to achieve process understanding for any PAT effort:

1. Identify an opportunity that would benefit from a PAT approach. For each opportunity, this required also identifying the critical quality attributes that must be monitored and controlled during the process.



2. Monitor the process through the use of online instruments.



3. Statistically analyze the process to determine how the critical quality attributes relate to the efficacy of the overall process. This includes the development, verification and validation of any statistical models that could define the process.



4. Ensure control of critical quality attributes at all times and within specified limits.



5. Report findings to ensure that the process is in control throughout the processing period.

How do these steps come together day to day? Typically, PAT projects originate from a particular business unit’s “need,” when someone from that unit contacts a member of the Implementation Team to formally request PAT support.

That Implementation Team member then develops a detailed scope, benefit and timeline and puts the potential project on the PAT project list, which the Core Team then evaluates, using the Master Plan to determine whether or not to pursue the project and how to rank its importance among other PAT initiatives. Once any project is approved, the Implementation Team develops a business case for the project and presents it to management for funding. The Implementation Team then works with the project management organization to bring the project to fruition and monitor its results following implementation.

This multidisciplinary approach, and the full support of corporate management, have allowed Talecris to complete numerous successful PAT initiatives in relatively little time. Nearly 20 PAT projects are now in process at the company, which together promise to have extensive and broad-reaching benefits.

The following are three related examples that have already delivered encouraging results and benefits, and demonstrate the value of a multidiscliplinary approach to PAT.

Replacing manual spark testing

Utilizing PAT principles, Talecris’ packaging department was able to develop a way to monitor seal integrity in lyophilized products, moving from a manual, subjective testing method to a more robust system, resulting in faster, more accurate and more reliable readings.

Talecris, like many other biological manufacturers, uses lyophilization, or freeze-drying, to prolong the shelf life of proteins. Lyophilized products are sealed under vacuum at our manufacturing facility. The end user then reconstitutes the lyophilized product with a diluent supplied in separate vials. Transferring the diluent into the product depends upon the vacuum in the product vial. Thus, the vacuum is not only an indication of the integrity of the container’s seal, but is also necessary for the end user to reconstitute the product.