One example of a case in which skip testing is routinely used is for the monitoring of microbial attributes for certain low-risk
solid oral-dosage forms. Generally, this practice is widely accepted in many European Union countries. Other examples of tests
that the industry considers candidates for skip testing are provided in the sidebar "Tests to consider for potential skip
testing."
The industry strongly supports the application of skip testing when appropriate. Because only limited data are usually available
at the time of filing, skip testing typically would be implemented as a postapproval change, requiring justification and preapproval
by a regulatory agency before use. Nonetheless, conditions and criteria for the introduction of skip testing can be specified
in the original registration applications.
Sunset specifications
The concept of sunset testing involves establishing a predetermined time interval or number of batches as a postmarketing
commitment after which testing of certain attributes would be discontinued if specific criteria were met. It differs from
skip testing insofar as after the commitment is met, the test would no longer be part of the product specifications. This
strategy is particularly useful when only limited data are available at the time of submission and there is low risk to the
patient. In some cases, a sunset-testing approach could be used in conjunction with skip testing (i.e., skip-testing intervals are gradually increased until finally the test is retired from routine testing). Many of the same
considerations discussed for skip testing apply to sunset testing. Examples of tests the industry considers candidates for
sunset testing are listed in the sidebar "Tests to consider for potential sunset testing."
Parametric release
The concept of parametric release involves making release decisions by measuring critical operational parameters for a given
process in lieu of direct measurement of the quality attribute itself (1, 6). A typical example of a parametric release is
sterility testing for terminally sterilized products. In this case, the release of each batch is based on satisfactory results
from monitoring specific parameters such as temperature, pressure, and time during the sterilization process instead of conducting
actual sterility testing. Parametric release is also commonly used to release in-process materials. For example, solids mixed
in a V-blender are essentially released for further processing by the measurement of operational parameters, including the
mixing time and the rotation speed of the blender, provided that the parametric endpoints have been validated to ensure adequate
mixing. In some cases, blend uniformity is verified by off-line chemical testing of the powder blend or stratified testing
of the finished product (7). In principal, the concept can be extended to other types of testing.
Building on parametric release, the FDA has proposed a concept of real-time release (8) in which quality attributes are measured
either directly or indirectly in real time during processing using techniques of PAT. Thus, in the blending example given
above, parametric confirmation of the blending operation would be replaced with data from real-time sensors that would establish
when satisfactory blending had been achieved.
Through the use of in-process testing and process analytical technology (PAT) controls, there is a potential to substantially
decrease or eliminate end-product testing while improving compliance and reducing rework or rejection. The implementation
of PAT would either eliminate the need for conducting finished-product testing of particular attributes or would support skip-testing
or sunset-testing protocols by greatly reducing the risk of failure and risk to the patient. Using a "science and risk-based
approach to good manufacturing practices" in conjunction with strategies to reduce testing costs will provide benefits to
both the industry and the patient (9).
Conclusion
Fundamental questions about setting specifications for pharmaceutical products are currently receiving much attention for
both traditional therapeutic agents and biopharmaceuticals. Through its initiatives on PAT and CGMPs for the 21st Century,
the US Food and Drug Administration has provided the pharmaceutical industry with a clear mandate to take a new look at the
way product quality is defined and controlled (8, 9). These initiatives are stimulating considerable discussion with regard
to better ways to set standards that ensure the safety and efficacy of pharmaceutical products. The process of establishing
and maintaining meaningful product specifications throughout the product life cycle is an important part of that process.
Moreover, traditional concepts of demonstrating that processes are robust and operated in a state of control using process
validation and end-product testing are being challenged by the concept of real-time process monitoring, which will potentially
lead to increased process robustness, enhanced in-process controls, and presumably less of a need for verification through
end-product testing.
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