Recent initiatives by industry and regulators around Quality by Design (QbD) included the integration of analytical methods
into the overall QbD program. The benefits of QbD such as regulatory relief, increased operational flexibility, better product
quality, and lower overall manufacturing costs, are well recognized. Many small companies find the implementation of QbD to
be a challenge. A two-step process can facilitate the implementation of QbD. The gradual process to QbD may be more manageable
for firms and regulators.
Stephan O. Krause, PhD
STEP 1: Method Performance Space Through Validation
The first step will expand the use of validation results to define a method performance space. Changes in this space can be
implemented without regulatory filing just like QbD intends to do.
A more effective use of development, validation, and post-validation data must be achieved to obtain immediate regulatory
relief and increased operational flexibility. The intent of this is to set a method performance space, similar to the current
vision for the design space. The required method development and validation elements—robustness and intermediate precision—can
be used to generate this data. Potential method changes should be simulated during the development and validation studies.
If these changes do not cause significant shifts in the overall test results, they are within the method performance space
and should not require regulatory notification. Two out of the four aforementioned benefits of QbD can be immediately obtained.
This step will get us ready for a method design space.
STEP 2: Method Design Space Through QbD
Executing QbD for methods to the fullest extent should grant many benefits. The advantage of generating a method design space
before validation is that it allows for consideration of risks early in the development process. Because the intent is to
push the method performance into a fixed set of design space limits during the product development phases well before validation,
QbD will demand rigorous selection, development, and optimization. This will improve actual method performance. As a contributor
to overall process variation, it will result in overall improved product quality.
Even with the use of the two-step process to QbD, small companies may still be faced with other challenges. The validation
of the design space for methods through validation protocol limits can be challenging. Critical method performance characteristics
may be difficult to capture at the time when the design space limits are set. The design space limits need to be exact.
QbD limits should take into account process variability. Typically, only method variation and process variation are considered.
Actual imperfections in sample or sampling consistency, for example, may require tighter QbD limits for the process or method
to comply with the overall QbD limits. Specific to QbD for methods, analytical equipment and reference standard qualification
should be included.
In addition to designing the space, risk-based recovery options for failed design space limits should exist that are similar
to investigation instructions for out-of-specification results for production. Further, method control charts should be connected
to process control charts to allow for adjustments in design space limits when needed.
Undoubtedly, optimized QbD for methods and processes and products will bring substantial benefits, at minimum the reduction
of regulatory burden for low-risk CMC changes.
Stephan O. Krause, PhD, is the director of quality at Mpex Pharmaceuticals, Inc., San Diego, CA, 858.875.6664, email@example.com
He is also a member of BioPharm International's editorial advisory board.