In 2004, FDA published a final guidance for industry introducing the concept of process analytical technology (PAT) and redefining
pharmaceutical manufacturing and quality assurance for the future. That guidance also addressed a concept known as "real time
release," defined as "the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on
process data" (1). The PAT component includes, according to the guidance, "a valid combination of assessed material attributes
and process controls," and builds upon the 1985 guidance on parametric release, which is used primarily in heat-based sterilization
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A few years later, in August 2009, the parties to the International Conference on Harmonization (ICH) adopted ICH Q8(R2) Pharmaceutical Development, which used the term "real time release testing" (RTRT). The definition of this term in ICH Q8(R2) shifted the emphasis from
the decision to release a batch to the measurements themselves, as follows: "the ability to evaluate and ensure the quality
of in-process and/or final product based on process data, which typically include a valid combination of measured material
attributes and process controls."
There are many benefits to be gained from RTRT applications. "From an industry standpoint, RTRT approaches seem to have economic
benefits from manufacturing efficiency, such as reduced inventory and lower laboratory costs," says Christine Moore, PhD,
deputy director for science and policy at the FDA Office of New Drug Quality Assessment (ONDQA), which falls under the Center
for Drug Evaluation and Research (CDER). "Quality can also benefit resulting in higher yields or lower rework or rejection
rates. From a regulator's and a consumer's standpoint, the integrated real-time analysis and control feasible with RTRT have
the potential to provide an increased assurance of product quality."
Adds Grace McNally, senior policy advisor within FDA's Division of Manufacturing and Product Quality, Office of Compliance,
which also falls under CDER, "One of the benefits of on-line or at-line testing is the ability to perform rapid analysis in
real-time. PAT tools typically enable nondestructive testing and provide the opportunity for enhanced monitoring during the
manufacturing process, and greater product and process understanding."
Despite the potential gains that can be realized from RTRT, industry still is trying to work out the practicalities of implementing
the approach, and therefore, is not yet fully benefitting from its promises. Many questions remain regarding the instrumentation
to use, when and where on the manufacturing line to conduct tests, how to evaluate on- or in-line analyzers during manufacture,
and what regulatory authorities expect.
Industry's hesitation toward applying RTRT was abundantly clear during the October 2010 ICH Quality Implementation Working
Group (IWG) workshop, held in North Bethesda, Maryland. A breakout session on control strategy addressed RTRT controls and
brought up even more questions about its application, such as what to do in case of instrumentation failure, how to differentiate
between RTRT and in-process tests, how to describe RTRT in specification, and where to record RTRT information in regulatory
submissions, such as the common technical document.
The issue stretches across the Atlantic. The European Medicines Agency (EMA) published a new draft guideline on RTRT just
last year to replace its former guideline on parametric release (2). The new document is meant to align better with the ICH
terminology and to allow for real time release tests beyond that of sterility testing, which is the most common real time
During the past nearly two years, the ICH Quality IWG has constructed and posted on its website a list of common questions
and answers about the organization's quality guidelines (Q8, Q9, and Q10). The current version includes 11 Q&As devoted solely
to RTRT (3). As industry moves more toward a quality-based approach, some RTRT questions may fall into place. In the meantime,
Pharmaceutical Technology gathered input from industry and regulatory experts already making headway in this area.