QRM Process

Quality by Design in the Design Space

Process Analytical Technology (PAT) facilitates the implementation of Quality by Design (QbD). It is a system approach that defines the desired product performance. According to Ms. Chi-wan Chen, Director of the Office of New Drug Quality Assessment, CDER/FDA, QbD is an opportunity to identify the product’s important attributes leading to a quality product.

“The concept of QbD is to determine the critical quality attributes of a product resulting in a target product profile,” said Chen, speaking at an IFPAC session on Monday. The idea is that process variability leads to product variability. Monitoring the parameters of drug attributes results to less process and ultimately, less product variability.

“The advantage of the design space is it provides a wider range within which material attributes can vary in the future without supplemental FDA approval,” said Chen.

QbD also helps make possible a real-time release (RTR) of a product. It gives the ability to evaluate and ensure acceptable quality of the product based on process data. According to Chen, this leads to manufacturing flexibility as well as manufacturing efficiency.

Of course, like any relatively new initiative there are challenges. For the FDA, it is defining and implementing this concept. This means review and inspection must be integrated. For industry, there is apprehension. Global acceptance of QbD still needs to be explored on an individual drug basis. In addition, the process goals must be communicated across all business units which requires cultural business changes.

Real World Examples

Michael Juhnke, Novartis (Basel, Switzerland) explained how his company is using QbD for a milling process. They set out by trying to define the critical process parameters of this application. By using failure mode and effects analysis and risk prioritization they established risk priority numbers.

“Part of the design space is risk management,” said Juhnke.

Novartis worked to develop their milling process understanding. Flowability, sphericity and morphology were identified as key attributes. This led to a screening design of experiment using 20 different parameters. Ultimately, the nozzle pressure, clarifier speed and feed rate were determined as the key process parameters. A knowledge baseline was established where all the risk priority numbers were under the recognized thresholds. In the end, no product testing for particle size was deemed necessary.

Merck has already realized the benefits of a QbD process. The FDA approved a QbD real-time release submission in 2006. The development cycle of this product started before an ICH QbD process was even established.

In his talk, Gert Thurau, Merck (West Point, Pa.) took a look back at the experiences gained during the review and approval of the filing with the FDA and regulatory agencies world-wide. “Our experiences and interaction with U.S. regulators on a QbD process has been very positive. You need to communicate your approach to regulators and convince them your processes are correct.”

The product, which was a new chemical entity, used a PAT NIR application with variables including potency, blending characteristics and tablet compression. “Once you really understand the inputs and process components to achieve the output, then the actual model may vary,” said Thurau. “However, the input will give the desired output by using design of experiments, correlations or specific modeling.
 
According to Thurau, understanding the contribution of every variable will lead to a predictable, controllable process. Continuous improvement will occur through proactive process monitoring.

Getting to these desired outcomes was not easy. It required a cultural change at the Merck plant. Quality systems, operations, IT systems and skill sets all had to be changed for the process to work. The plant’s first impression was they did not know if they could handle it.

The results proved otherwise. “The real-time release process is less labor intensive which led to job enhancements. The site now sees the process as a positive and the workers can’t wait to start a new project,” said Thurau.

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