Quality by Design (QbD) is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. QbD principles are heavily integrated throughout the ICH Quality Guidances, starting with ICH Q8 on Pharmaceutical Development.
Sponsors of investigational new drugs are encouraged to adopt the following basic approach:
Define what quality looks like and establish a Quality Target Product Profile (QTTP)
Define what product attributes ensure product quality and establish Critical Quality Attributes (CQAs)
Define how you'll measure those quality attributes and establish an Analytical Target Profile (ATP)
Define how you'll manufacture to consistently achieve your quality attributes and establish a Design Space
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval (ICH Q8).
Developers of cell & gene therapies essentially have two choices when it comes to platforms for drug product manufacturing: G-Rex® or Mechanized Bioreactors.
A comparison table below shows that virtually identical design spaces, with the exception that Mechanized Bioreactors require strict control over variables that are related to the movement of fluid.
Number & nature of cells seeded for culture
Reagent concentration, volumes, & temperature
Cell culture media formulation
Length & cycle time of unit operation(s)
Hold time between unit operation(s)
Cell culture environment(temperature, % CO2 & O2, Humidity, etc.)
Media flow rate
Cell culture vessel agitation rate
Sheer force
Instruments used(IQ/OQ/PQ and calibration procedures)
Formulation conditions
It is not hyperbole that the implications of choosing a platform that must or must not strictly control variables related to the movement of fluid is the difference between choosing scalability, flexibility, commercial viability, and company vitality.
Can develop design space at small or pilot scale?
Can time/cost efficiently set up multivariate experiments to understand CQAs & CPPs?
Can time/cost efficiently determine Proven Acceptable Ranges (PARs)
Can time/cost efficiently perform comparability studies & drive continuous improvement
Can time/cost efficiently validate commercial processes
Can time/cost efficiently drive post-approval product lifecycle management
G-Rex®’s simplified design space…
Mechanized Bioreactor’s design space…
The G-Rex® is the most scalable, flexible, adaptable, versatile, and commercially viable platform for developers of cell & gene therapies. Your success or failure begins with choices you make early. Choose wisely.
(Good Design Space)
(Poor Design Space)
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