The ideal quality system for final product is illustrated in Figure 5. The specification limits (LSL, USL) reflect restrictions
within which product is fit for use, and must conform throughout shelf life. The release limits (LRL, URL) ensure these limits
are met at release and throughout product shelf life, whereas the control or process capability limits (LCL, UCL) describe
process and assay variability. Under this paradigm, final product would be out of specifications (OOS) at release if it falls
outside the release limits. On the other hand, a lot would be out-of-trend (OOT) if it falls outside the control limits. An
OOT lot signals a possible problem with the process, which is subject to investigation. An OOT lot would nevertheless be fit
for use, and thereby could be safely released to the market.
Figure 5. The ideal quality system for final product, showing the relationship among specification, release and control limits.
The specification limits (LSL,USL) reflect restrictions within which product is fit for use,and must conform though tout shelf
life. The release limits (LRL,URL)ensure these limits are met at release and throughout product shelf life,whereas the control
or process capability limits (LCL,UCL) describe process and assay variability. Under this paradigm, final product would be
out of specifications (OOS)at release if it falls outside the release limits.
Process capability is reflected in the difference between control and release limits. Satisfactory process capability will
allow the process to vary over long-term manufacturing experience while remaining within specifications. Unsatisfactory process
capability, which will lead to frequent OOS results, will give the manufacturer an incentive to improve process consistency,
and thus process capability. In keeping with the regulatory relief expected from the implementation of Quality by Design (QbD),
the manufacturer is at liberty to update control limits without strict regulatory oversight, as long as these remain within
the release limits, and to improve process capability without regulatory consequence in the form of more restrictive release
2. When limits are to be supported by process consistency rather than fitness for use, set limits that appropriately reflect
the long-term process distribution, and provide incentives for continuous process monitoring and improvement.
Limits on attributes that are not linked to clinical safety or efficacy may be set based on process consistency and should
appropriately acknowledge the long-term process distribution.
Control limits that are based on process consistency are an integral part of a total quality system in which a robust process
is developed and then maintained. In such a system, control limits are used to monitor the process. QbD principles should
be acknowledged during development to ensure that manufacturing control limits are appropriate. Process understanding can
help ensure that limits accurately reflect product consistency. Under this paradigm, control limits should be set with adequate
full-scale manufacturing experience, where possible, changing the factors that impact consistency and define the design space
for the process.
Release limits that are set at the boundaries of process capability create the misconception that product that is atypical
or "statistically aberrant" is unfit for use. Lots manufactured using an adequately controlled process will appear unacceptable
as more information is gathered and the process matures. Process improvements will become difficult to implement, because
these are likely to result in a shift in the "quality" profile for the product. To avoid these problems, release limits should
be set beyond the limits of process capability to provide opportunity to monitor for shifts and trends and to implement process
improvements without affecting supply to the market.