Quality by Design (QbD)

Quality by Design (QbD) is a strategic approach employed in various industries, including pharmaceuticals, manufacturing, and product development, to ensure the consistent delivery of high-quality products. It involves a systematic and proactive process of integrating quality considerations throughout the entire product lifecycle, from conception to production.

In the context of pharmaceuticals, Quality by Design focuses on optimizing the development, manufacturing, and control processes of drugs to enhance their safety, efficacy, and overall quality. It requires a deep understanding of the product's critical quality attributes (CQAs), which are the measurable characteristics that determine its performance, and the critical process parameters (CPPs), which are the variables affecting the manufacturing process.

The core principle of Quality by Design is to identify and understand the relationships between the product's CQAs and the CPPs that influence them. This knowledge is gained through a combination of scientific experimentation, risk assessment, and statistical analysis. By thoroughly studying these relationships, manufacturers can establish a design space within which the product can consistently meet the desired quality standards.

The design space defines the range of CPPs that ensure the product's CQAs are within acceptable limits. It provides flexibility for process optimization while maintaining the required quality attributes. Within this design space, manufacturers can establish appropriate process controls, monitoring techniques, and quality assurance systems to ensure consistency and predictability in product performance.

Implementing Quality by Design offers several advantages. It enables manufacturers to better understand their processes, reduce variability, and mitigate risks. By integrating quality into the product development and manufacturing phases, potential quality issues can be identified and addressed early on, reducing the likelihood of post-production problems. Additionally, QbD facilitates continuous improvement by providing a framework for ongoing process optimization and innovation.

The Quality by Design development process begins by carefully defining the requirements of the final product, including use targets, safety profiles and product efficacy goals. The steps in the process include:

• Definition of a product quality profile that represents in-vitro how the product will perform in-vivo. This profile is a quantitative representation of the clinical safety and efficacy targets for product developers.
• Summarizing and centralizing what is known about the Active Pharmaceutical Ingredient (API), excipients and process, and identifying knowledge gaps in order to prioritize study based on risk evaluation
• Design of the composition of the product and careful definition of the quality characteristics that need to be controlled in order to achieve the product quality profile
• Development of a flexible process for the product that has the defined quality characteristics
• Determination of key process specifications and starting material characteristics to be managed in order to achieve the desired end product characteristics. To have a flexible process requires that the acceptable performance envelope of the process is well defined and the boundaries of acceptability are well understood. A methodology, such as Design of Experiments (DoE), may be used to aid in process performance.
• Establishment of an overall control strategy for all aspects of the manufacturing process. Risk assessment for the various steps should be considered in the control process. PAT methodology may be employed as part of the overall control strategy.
• Constant auditing of the manufacturing process and revision, as necessary, to maintain final product quality

Historically, Quality by Testing (QbT) was utilized to develop processes. However, this approach has the following challenges:

Product quality and performance supported by end product testing leads to:

• Limited understanding of the process or key process parameters based on risk assessment
• Limited science-based understanding of the process, managing of key variables, and their effect on end-product quality.
• Limited understanding of process design space and relationship to product quality

In general, there is less time devoted to understanding why processes fail and more emphasis on testing and reworking out-of-spec products as necessary. Quality assured by testing and inspection also results in:

• Data-intensive submission, disjointed information without consideration of the entire process
• Specifications based on batch history
• A validated and approved process discourages changes
• Focus on reproducibility, often avoiding or ignoring variations 

Quality by Design encompasses all major aspects of pharmaceutical production. In drug development, a methodical, multivariate approach is used to construct an effective process design based on assessing the risk associated with various steps. In the manufacturing process, a QbD strategy permits process flexibility within the defined design space. Process control effectively uses process analytical technology to track process trends and quality assurance is a necessity of risk-based control processes, which ensures less likelihood of batch failure.

• Quality built into product and process by design, based on scientific understanding
• Knowledge-rich submission – showing product knowledge and process understanding
• Specifications based on product performance requirements
• Flexible process within design space – allowing continuous improvement
• Focus on robustness – understanding and controlling variations

Design, analyze and control manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials.

• Define design space via multivariate data analysis encompassing Critical Process Parameters (CPPs)
• Use inline or online Process Analytical Technology (PAT) to track CPPs (e.g. ReactIR, ReactRaman, EasySampler, ParticleTrack, EasyViewer, pH, calorimetry)
• Confirm that the process is operating within design space via process monitoring and trending
• Use knowledge derived from process performance monitoring to continually improve process within design space
• Enable real-time release of intermediates or an end product

1. In-Situ Raman Spectrometer — in-situ analysis of multiphasic reactions, polymorphs
2. In-Situ FTIR Spectrometer — in-situ reaction kinetics, mechanisms and pathways
3. PVM Particle Size Analyzer — inline imaging and analysis of particle formation and growth
4. FBRM Particle Size Analyzer — inline particle size analysis with FBRM® technology
5. Automated Chemical Synthesis Reactor — precise and automated execution and documentation of process conditions
6. Reaction Sampling System — automated, representative sampling
7. Process Development Software, Modeling, and Simulation — scale-up efficiently with software for data analysis and control, modeling and simulation

If you have questions or need help with your technical application, our team of Technical Application Consultants is ready to guide you in the right direction.