Impacts of Process Analytical Technology

The process analytical technology (PAT) initiative has been percolating at the US Food and Drug Administration for a long time, explained FDA's John E. Simmons at the AAPS Annual Meeting and Exposition on Wednesday. "If you think of PAT as an isolated set of applications, I think you are missing the point," Simmons said. "The FDA would like PAT to become commonplace - not to be an initiative, but common practice."

FDA began researching process analytical technology in 1999, spurred by a debate concerning blending and uniformity. The initiative was created due to an increase in warning letters, regulatory uncertainty, and the numbers of complex drug products being developed. According to FDA, PAT is a framework approach not a regulatory approach or guideline.

The important thing to note, explained Ganapathy Mohan, PhD, of Sanofi-Aventis Pharmaceuticals, is that current good manufacturing practice (CGMP) guidelines came into existence 30 years ago. "It's now time for a change, and the CGMP for the 21st Century is this change."

In his presentation, "PAT from Conception to Release of Clinical Supplies," Mohan said that PAT initiatives are part of a regulatory progression. The goals of PAT include the ability to design and develop well-understood processes that will consistently ensure a predefined quality at the end of the manufacturing process. Information also must be synthesized down to useful information.

To get started, Mohan said a company must evaluate its current operations and assess all critical process parameters. "Is the existing technology adequate to achieve thorough understanding of the process? If the answer is yes, then do nothing."

If the answer is no, then a company needs to think about options.

A team with multidisciplinary expertise should identify products that could be piloted. Assess the value that could be achieved, obtain management buy-in, and finally, build the project step by step.

For Sanofi-Aventis, the solution was to build a system that could handle multiple components simultaneously and then train that system to create the same product every time.

"Pfizer uses PAT because we realized that we had variations in product five years ago," said Steve Hammond of Pfizer Global Manufacturing in his presentation, "Application of PAT in pharmaceutical manufacturing." The company uses an umbrella approach to solving a problem, including organization initiatives, new technology, and tools. "The role of PAT within Pfizer is to gain improved process knowledge to identify and remove sources of variability and achieve reliable product and quality - to basically get it right the first time," Hammond said.

Pfizer implemented various PATs to monitor variation throughout the manufacturing process, determined what is critical to quality (CTQ), and used PAT to remove and control unwanted variation in CTQ parameters.

Tools used by Pfizer as part of its PAT initiative include:

• a robust probe for real-time monitoring;

• a focused-beam reflectance to calculate crystallization and monitor the reaction as it takes place;

• an imaging system that can be mounted in a hatch cover of a mixer to monitor the product as it's made.

"PAT can be used as part of a tool box to optimize the way we manufacture," Simmons said." It can provide greater understanding of what to control, and it provides a means to control critical attributes in real time."

But what does a company do with all the data gathered from this new technology? Jean-Marie Geoffroy, PhD, of TAP Pharmaceutical Products explained how his company uses batch records for something other than a document to turn over to FDA when they request the information. Through digital warehousing, companies can use the information to capture trends and instantly spot troubles in production. Real-time monitoring can be used to instantly spot irregularities in different systems such as fluid-bed drying and tablet coating.

"Organizations that will be successful with PAT are those that will embrace cross-functional development and implementation," Geoffroy said. "Significant data management will be required to survive the deluge of information."

Said Simmons, "I think you are going to see a timeline, and those who aren't thinking about producing a product with minimal failure are going to be left in the dust and you are going to see more mergers and acquisitions."

Other speakers:

Quality by Design: Concepts and Execution in Development,Kenneth R. Morris, PhD, Purdue University