Dealing with equipment failures
Of great concern among industry is what to do in the event of an equipment or instrumentation failure while an RTRT process
or analysis is being run. "Generally, it is not acceptable to discount PAT measurements and return to a conventional approach
simply because the PAT fails a batch," says Pfizer's Hammond. "It must be proven that the equipment has malfunctioned in some
way. As most PAT instruments now have very sophisticated self-diagnostic procedures, it is better to have the PAT device automatically
cease to function if any of the internal diagnostics fail. Thus, suspect results are not generated."
Furthermore, a manufacturer applying an RTRT test that fails might also use a risk-assessment process to decide how to proceed.
"The possibility of using the traditional analytical procedures that are registered for the product is something the industry
needs to make PAT a viable proposition. All mechanical electrical systems can malfunction, and pharmaceutical manufacturing
needs a way to ensure business continuity if a PAT system does break down," says Hammond.
According to FDA's McNally, "In the event of on-line or in-line equipment breakdown, the control strategy provided in the
application can include the use of alternative tests or monitoring in case of equipment failure. The alternative approach
could involve use of in-process and end product testing or other options, while maintaining an acceptable level of quality."
Of note, EMA's new draft guideline on RTRT includes very similar language with regard to dealing with equipment failure (2).
Overall, both regulatory authorities seem to agree that testing or monitoring equipment breakdown needs to "be managed in
the context of a deviation under the quality management system and can be covered by GMP" (2).
This may be particularly important for those PAT systems that can produce false negatives, such as those using spectroscopy
and chemometric methods, adds McNally. "The manufacturer should ensure an effective calibration program is in place. This
includes procedures to follow in the case of an out-of-specification (OOS) result from a PAT tool and steps to be taken to
maintain and recalibrate the calibration model."
Some of the ICH questions and answers on real time release address this issue in more detail (3).
To date, the pharmaceutical sector seems to be moving forward with RTRT but at a slow pace. The concept "is no longer treated
as an unobtainable goal," says Malvern's Vaisman. "Many companies in industry and in academic research centers are making
significant inroads in implementing continuous manufacturing trains and RTRT. That said, RTRT is not yet the norm," he adds.
Cost may be a factor in the rate of implementation, point out GE Analytical Instrumentation's Richard Godec and Jonathan Yourkin,
new product development manager, and global pharmaceutical product manager, respectively. Because analytical tools are still
being developed and many companies' senior management and quality teams are not yet on board, RTRT is a bit of a double-edged
sword. "The main advantage of RTRT is the cost-effective control of the manufacturing process to meet all quality and product
specifications. The main disadvantage, however, is that there is an initial investment required to achieve RTRT of finished
drug products," they say.
On the regulatory side, FDA "has reviewed and approved several applications using RTRT approaches, but the numbers are still
small," says Moore. "The applications containing RTRT approaches have been challenging to review; they not only include new
science but also have new approaches to fulfilling regulatory requirements. We (the FDA) are still learning, and every application
has different nuances. We strongly recommend that companies looking to implement RTRT request a meeting with the FDA to discuss
their proposal prior to submission."
Be sure to check out the online only features related to this article on powder processing and on analytics
1. FDA, Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, September 2004).
2. EMA, Guideline on Real Time Release Testing (formerly Guideline on Parametric Release), draft, February 2010.
3. ICH, Quality Implementation Working Group on Q8, Q9, and Q10 Questions and Answers (Nov. 11, 2010),
4. FDA, Draft Guidance for Industry, Process Validation: General Principles and Practices (Rockville, MD, November 2008).