Quality by design (QbD) is a scientific and risk-based approach to pharmaceutical product development that begins with predefined objectives. Instead of relying on finished product testing alone, QbD ensure the product quality throughout the development process.
Objective of QbD Approach
- Patient safety and product efficacy
- Scientific understanding of pharmaceutical process and methods
- Science based risk assessment
- Understanding of critical quality attributes
- Robust method and process.
Elements of QbD
QbD comprises different elements of pharmaceutical development mentioned in the ICH guideline Q8. Which include,
- Defining an objective (QTTP),
- Determination of critical quality attributes (CQA),
- Risk assessment,
- Development of experimental design,
- Designing and implementing control strategy,
- Continuous improvement.
Quality Target Product Profile (QTPP)
Quality target product profile (QTPP) forms the basis of QbD, which is in relation to the predefined objective criteria mentioned in the definition of QbD.
- Quality characteristics: sterility, purity etc. (including specific safety-related impurities where necessary)
- Pharmacokinetic characteristics: dissolution etc.
- Therapeutic effect
- Target patient population: neonate, adult etc., clinical diagnosis.
- Shelf life: temperature, light conditions etc.
- Dosage form: liquid for injection, solid tablet etc.
- Route of administration: oral, IV, IM, SC
- Clinical setting: self or clinic administration
- Primary/secondary packaging: glass or plastic vial/syringe; blister packaging etc.
Critical Quality Attributes (CQA)
According to ICH Q8 (R2) ‘‘A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality’’.
- Potential CQAs are derived from the QTPP and guide product and process development.
- CQAs are identified by quality risk management and experimentation to determine the effect of variation on product quality.
- The CQA list can be dynamic and may be updated based on product and process knowledge.
It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. Risk assessment helps to increase quality of method or process. Also it is determinant for effect of input variable on method or processes. Some methods of risk assessment are mentioned in ICH guideline Q9 as follows:
- Failure Mode Effects Analysis (FMEA);
- Failure Mode, Effects and Criticality Analysis (FMECA);
- Fault Tree Analysis (FTA);
- Hazard Analysis and Critical Control Points (HACCP);
- Hazard Operability Analysis (HAZOP) etc.
Where Does Risk Assessment Belong?
- Process Development
- Control Strategy
- Tech Transfer and/or
- Validation/CPV (Continued Process Verification)
Design of Experiment (DoE)
Experimental design is the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Design space is proposed by the applicant and is subject to regulatory assessment and approval of ICH Q8 (R2). Pharmaceutical development scientists have begun making use of computer-aided process design and process simulation to support process development and optimization of manufacturing.
Control Strategy (CS)
Control strategy is required to ensure that material and process are within the expected lower and upper limits. Parameter and material are routinely controlled during production in order to assure reproducibility.
- Many CS elements are developed via risk assessments: CQA/CPP, Raw Material, Components, and Specifications.
- A CS is the final outcome of process development/design.
- A CS is constituted of many parts, many of which are developed/written at different points in time throughout process development.
Continuous Improvement is the last component of the QbD Process. Where product quality can be improved throughout the product lifecycle; companies have opportunities to opt inventive approaches to improve quality. Process monitoring and evaluation can be performed by:
- Short Term- IPCs, release criteria.
- Long Term- CPV
Other components of Continuous Improvement include good integration of process knowledge into change control, deviation management, etc.
QbD and New Process Development
- The goal of process development is creation of a process control strategy.
- QTPP, and provisional CQAs and CPPs, is essential to guide for new process development.
- FMEA and similar tools are very useful for initial CQA and CPP assessments.
Applying QbD to Legacy Products
- The minimal requirement for legacy include an established control strategy and process validation which are necessary to create a CPV program.
- Risk assessment is used in developing the CPV program