High equipment costs and restrictions on capital spending are currently barriers to implementing PAT and continuous processing
technologies. In addition, revised European regulatory guidance requires refiling of NIR instruments after calibration updates
(3). “This new guidance on NIR is very restrictive. It does not allow for changes in raw materials, instrument maintenance,
and all the routine occurrences that require calibration maintenance,” notes Hammond.
Although real-time release (RTR) is a goal for industry and for regulators, only a few companies have achieved it as a commercial
reality. In RTR, product quality assurance is based on online analysis, and the product is released as it is produced rather
than a batch being held while waiting for quality-control testing. RTR could be implemented for batch processing, in that
a batch could be released if there were no deviations throughout the batch. In continuous processing, product could be released
continually given no deviations. Theoretically, online measurement would identify out-of-specification product and allow it
to be segregated or even identify a change in CQAs before the product goes out of specification (4).
A new program, Accelerating Innovative Research (AIR), builds on the C-SOPS infrastructure at Rutgers and is focused on working
with existing PAT as well as partnering with companies to move RTR testing technology forward. The program will involve working
with large pharmaceutical companies to run specific formulations as case studies in an effort to build up a toolbox of knowledge
on how spectroscopic data can be used for RTR testing.
Implementing closed-loop control is a step towards RTR. “Intelligent processes that are proactively controlled to ensure the
expected outcome are inherently capable of supporting a RTR strategy. Regulators have always stated that tight control of
the unit operations leading up to final product is the best way to ensure quality of the product and enable a RTR filing,”
says Hammond, who notes that Pfizer’s Chantix RTR application is now filed in all major markets and most of the rest of world.
“The value of RTR has been reduction in laboratory testing. The focus in the future will be on enabling a modern supply chain,
with flexible response to a pull from the market, and maintaining lower inventory.”
Many in industry and academia say that continuous manufacturing using online PAT with closed-loop process control and real-time
release represent the future of solid-dosage manufacturing. These concepts are part of a “seismic shift in culture change
within the pharmaceutical industry, which continues to put the spotlight on manufacturing in a way that has been absent in
the past,” concludes Freeman.
1. FDA, Pharmaceutical cGMPs for the 21st Century—Risk-Based Approach: Final Report (Rockville, MD, 2004).
2. FDA, Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (Rockville, MD, 2004).
3. EMA, EMEA/CHMP/CVMP/QWP/17760/2009 Rev2, “Guideline on the use of Near Infrared Spectroscopy (NIRS) by the pharmaceutical
industry and the data requirements for new submissions and variations, draft” (London, 2012), www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/02/WC500122769.pdf,
accessed March 4, 2013.
4. K. Schoeters, Pharm.Tech. Eur. 23 (2) 20-21 (2011).
FIGURES ARE COURTESY OF GEA PHARMA SYSTEMS