What is quality by design?
Quality by design (QbD) builds quality into a product through understanding rather than testing it in at the end. It is the approach described in ICH Q8(R2) and used across pharmaceutical and biotech development, and the same logic applies to medical devices and other regulated products: define what the patient needs, find which product attributes deliver it, learn which process parameters and materials affect those attributes, and control them.
The QbD steps
- QTPP: a summary of the quality the product must have, from the patient's point of view.
- CQAs: the physical, chemical, biological or microbiological properties that must be within limits.
- Risk assessment: which material attributes and process parameters can affect each CQA (this tool's matrix; FMEA is used for detail).
- Process understanding: designed experiments establish proven ranges or a design space for the critical parameters.
- Control strategy: how each critical parameter and attribute is controlled, from supplier specifications to in-process tests.
- Lifecycle: monitor and improve, and manage changes within the established ranges.
Quality by design example
A team develops a 10 mg immediate-release tablet made by wet granulation. The QTPP calls for Q = 80% dissolution in 30 minutes and a 24-month shelf life. Of six quality attributes, five are CQAs; appearance has low impact and is not critical. The risk assessment of eight parameters finds four critical ones: API particle size (a CMA, high risk to content uniformity and dissolution), granulation water, the drying end point (water content) and compression force (dissolution). Wet massing time, blending time, press speed and lubrication time are key parameters to monitor.
The design space column shows each parameter's proven and normal operating ranges. The tool flags press speed: its normal operating range (60–110 thousand tablets per hour) goes beyond the proven acceptable range (40–100), so either more data is needed to extend the PAR or the NOR must be narrowed.
Tips
- Base criticality on patient harm, not on how hard an attribute is to control.
- Use prior knowledge first for the initial risk assessment, then confirm high-risk parameters with designed experiments.
- Revisit the risk assessment after development data comes in; risks should go down as understanding goes up.
- Go into detail on the high-risk parameters with an FMEA.
How to use this Quality by Design tool
- Write the QTPP. List the target product profile: dosage form, strength, release, purity, shelf life and packaging.
- List the quality attributes. Add each attribute with its acceptance criterion and its impact on safety or efficacy; medium or high impact makes it a CQA.
- Add parameters. Add process parameters and material attributes, with units.
- Assess the risks. Click each cell of the matrix to rate the risk that the parameter affects the CQA: H, M or L.
- Set ranges and controls. Enter the proven acceptable range, normal operating range, set point and control strategy for each parameter.
- Review and export. Check the critical parameters, range problems and missing controls, then export to PDF or Excel.
Frequently asked questions
What is quality by design (QbD)?
Quality by design 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 (ICH Q8(R2)). Instead of testing quality into the product at the end, QbD designs the product and process so that quality is built in.
What are the steps of QbD?
Define the quality target product profile (QTPP); identify the critical quality attributes (CQAs); assess the risk that material attributes and process parameters affect the CQAs; build process understanding (for example with DoE) to define proven acceptable ranges or a design space; set a control strategy; and manage the product through its lifecycle with continual improvement.
What is the difference between a CQA, a CPP and a CMA?
A critical quality attribute (CQA) is a property of the product that must be within a limit to ensure quality, such as assay or dissolution. A critical process parameter (CPP) is a process setting whose variability affects a CQA, such as compression force. A critical material attribute (CMA) is a property of an input material that affects a CQA, such as API particle size.
What are the PAR, NOR and design space?
The proven acceptable range (PAR) is the range of a parameter shown to give acceptable quality when other parameters stay constant. The normal operating range (NOR) is the narrower range used in routine production, inside the PAR. A design space is the multidimensional combination of parameters shown to assure quality, usually established with designed experiments.
How is criticality decided?
The criticality of a quality attribute depends mainly on the severity of harm to the patient if it is out of limits. In this tool, attributes with medium or high impact on safety or efficacy are CQAs. A parameter becomes critical when the risk assessment shows a high risk that it pushes a CQA out of its limits; medium-risk parameters are kept as key parameters to monitor.
Which guidelines cover QbD?
ICH Q8(R2) Pharmaceutical Development, ICH Q9(R1) Quality Risk Management, ICH Q10 Pharmaceutical Quality System and ICH Q11 for drug substances, with ICH Q12 on lifecycle management. The FDA has promoted QbD since its 2004 initiative on pharmaceutical quality for the 21st century.