The Quality Strength
"Quality cannot be tested into products; it has to be built in by design"
- Joseph M. Juran
QbD Definition:
Pharmaceutical QbD is a systematic, scientific, risk-based, holistic and proactive approach to pharmaceutical development that begins with predefined objectives and emphasizes product and processes understanding and process control.
ICH Q8(R2) Definition:
The International Conference on Harmonization (ICH) has defined QbD in ICH Q8R as "a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management."
QbD Fundamentals
QbD identifies characteristics that are critical to quality from the perspective of patients, translates them into the attributes that the drug product should possess, and establishes how the critical process parameters can be varied to consistently produce a drug product with the desired characteristics.
Core QbD Process:
- Establish relationships between formulation and manufacturing process variables (including drug substance and excipient attributes and process parameters) and product characteristics
- Identify sources of variability
- Use this knowledge to implement a flexible and robust manufacturing process that can adapt and produce a consistent product over time
Historical Context:
QbD was introduced by FDA in 2002. Merck & Co's Januvia (2006) was the first FDA approved product using QbD principles.
ICH Framework for QbD:
Pharmaceutical Development
Quality Risk Management
Quality Management
Quality by Design – GMP for the 21st Century
Key Elements of QbD
QbD involves the following key elements during pharmaceutical development:
1. Define Quality Target Product Profile (QTPP)
A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy.
2. Design and Develop Product and Manufacturing Processes
Systematic design of both the product and its manufacturing process based on scientific principles and risk assessment.
3. Identify Critical Attributes, Parameters, and Variability
Determine Critical Quality Attributes (CQAs), Critical Process Parameters (CPPs), and sources of variability.
4. Control Manufacturing Processes
Implement control strategies to produce consistent quality over time through process understanding and monitoring.
1. Quality Target Product Profile (QTPP)
QTPP Definition:
Quality Target Product Profile (QTPP) is a prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and hence the safety and efficacy, of a drug product is realized.
The QTPP forms the basis of design of the product. The QTPP guides formulation scientists to establish formulation strategies and keep the formulation effort focused and efficient.
Example: QTPP for Immediate Release Solid Oral Dosage Form
| Tablet Characteristic | Description |
|---|---|
| Identity | Correct drug substance and formulation |
| Assay and Uniformity | Accurate drug content and uniform distribution |
| Purity/Impurity | Acceptable levels of impurities and degradation products |
| Stability | Chemical, physical, and microbiological stability over shelf life |
| Dissolution | Appropriate release profile for therapeutic effectiveness |
Importance of QTPP:
The TPP (Target Product Profile) can play a central role in the entire drug discovery and development process, providing a clear target for all development activities.
2. Design Product and Manufacturing Process
A. Product Design and Development
In order to design and develop a robust generic product that has the desirable QTPP, a product development scientist must give serious consideration to the biopharmaceutical properties of the drug substance.
Biopharmaceutical Properties to Consider:
Physical Properties:
- Physical description (particle size, shape, and distribution)
- Polymorphism
- Aqueous solubility as function of pH
- Hygroscopicity
- Melting points
Chemical Properties:
- pKa
- Chemical stability in solid state and in solution
- Photolytic and oxidative stability
Biological Properties:
- Partition coefficient
- Membrane permeability
- Oral bioavailability
Comprehensive Assessment Required:
Biopharmaceutical properties should be assessed for every form for which there is an interest in development and every form that can potentially be created during processing (e.g., hydrates, anhydrates) or in vivo (e.g., less soluble salts, polymorphic forms, hydrates).
Mechanical Properties Understanding:
A sound understanding of mechanical properties of the drug and excipients can be useful in:
- Developing a processing method such as granulation or direct compression
- Rationally selecting excipients whose properties can compensate for the properties of the drug substance
- Helping assess critical material attributes and root cause analysis during process scale-up or failure
B. Process Design and Development
Process design is the initial stage of process development where an outline of the commercial manufacturing processes is identified on paper, including the intended scales of manufacturing.
This should include all the factors that need to be considered for the design of the process, including facility, equipment, material transfer, and manufacturing variables. Other factors to consider for process design are the target product quality profiles.
Feasibility Studies:
Depending upon the product being developed, type of process, and process knowledge the development scientists have, it may be necessary to conduct preliminary feasibility studies before completing the process design and development.
Tablet Manufacturing Process Selection:
The selection of type of process depends upon the product design and the properties of the materials. For example, tablet manufacturing typically involves one of two methods:
Direct Compression
- Most straightforward, easiest to control, and least expensive
- Uses two primary unit operations: mixing and compression
- Used when ingredients can be blended and compressed without modification
Granulation
- Used when powders are very fine, fluffy, will not stay blended, or will not compress
- Process of collecting particles together by creating bonds between them
- Includes wet granulation (adding liquid solution) and dry granulation (compaction without liquid)
Granulation Details:
Dry granulation can be conducted on a tablet press using slugging tooling, or more typically on a roller compactor. This process is used to form granules without using a liquid solution by compacting and densifying the powders.
3. Identify Critical Attributes, Parameters and Sources of Variability
Unit Operations in Pharmaceutical Manufacturing:
A pharmaceutical manufacturing process is usually comprised of a series of unit operations to produce the desired product. A unit operation is a discrete activity that involves physical changes, such as mixing, milling, granulation, drying, compaction, and coating.
Key Definitions:
Attribute:
A physical, chemical or microbiological property or characteristic of an input or output material.
Process Parameters:
Include the type of equipment and equipment settings, batch size, operating conditions (e.g., time, temperature, pressure, pH, and speed), and environmental conditions such as moisture. The quality and quantity of drug substance and excipients are considered as attributes of raw materials.
Critical Elements Identification:
During process development, raw materials, process parameters and quality attributes are investigated. The purpose of these studies is to determine:
Critical Raw Material Attributes (CMA)
Material characteristics that must be controlled to ensure product quality
Critical Process Parameters (CPP)
Process inputs that have a direct and significant influence on critical quality attributes when varied within regular operation range
Critical Quality Attributes (CQA)
Physical, chemical, biological, or microbiological property or characteristic that must be controlled directly or indirectly to ensure the quality of the product
Relationship Establishment:
The studies aim to establish any possible relationships among CMAs, CPPs, and CQAs, and to determine which attributes and parameters are critical to product quality.
4. Control Manufacturing Processes
Control Strategy (ICH Q10 Definition):
Control strategy is "a planned set of controls derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications and the associated methods and frequency of monitoring and control."
Historical Context:
Control Strategy is not a new concept - products have always had a more or less explicit control strategy - but in ICH Q8(R) (Step 2) document a 'Minimal Approach' to Control Strategy is contrasted with the 'Enhanced, Quality by Design Approach'.
Enhanced QbD Approach to Control Strategy:
In the enhanced approach, the control strategy is closely linked to both criticality and the Design Space. The results of the risk assessment identify those CQAs and CPPs that are included in the Design Space and subsequently must be included in the Control Strategy.
Components of Control Strategy:
The Control Strategy may include, for example:
- Raw material purchase specifications
- API characteristics
- Operating ranges for process parameters
- In-process controls and their corresponding acceptance criteria
- Release testing
- API or drug product specifications and their acceptance criteria
Control Strategy Development:
The control strategy should describe and justify how in-process controls and the controls of input materials (drug substance and excipients), container closure system, intermediates and the controls of end products contribute to the final product quality.
Elements of a Control Strategy:
Elements of a control strategy can include, but are not limited to, the following:
- Control of input material attributes based on an understanding of their impact on processability or product quality
- Product specification(s)
- Controls for unit operations that have an impact on downstream processing or end-product quality
- In-process or real-time release in lieu of end-product testing
Knowledge Space and Control Space:
Knowledge Space
↓
Control Space
↓
CONTROL STRATEGY
Key Principle:
The control strategy evolves throughout the product lifecycle as process understanding increases, allowing for continuous improvement and optimization of the manufacturing process while maintaining product quality.
QbD Implementation Benefits
Enhanced Product Quality
Quality is built into the product from the beginning rather than tested at the end, leading to more robust and consistent products.
Improved Process Understanding
Deep understanding of how process parameters affect product quality enables better control and optimization.
Reduced Variability
Identification and control of sources of variability leads to more consistent manufacturing outcomes.
Regulatory Flexibility
Regulatory agencies may provide more flexibility for process changes within the defined design space.
Efficient Manufacturing
Reduced batch failures, less rework, and more efficient use of resources through proactive quality management.
Patient Focus
Focus on quality attributes important to patients ensures products meet real therapeutic needs.
The QbD Paradigm Shift
QbD represents a fundamental shift from a quality-by-testing approach to a quality-by-design approach, where quality is proactively designed into products and processes rather than being solely assured through end-product testing.
