[an error occurred while processing this directive]

Quality by Design

Particle Sciences - Technical Brief: 2012: Volume
PDF Version


In the past few years much has been said and written about Quality by Design (QbD)1,2. It has been discussed in many forums by the FDA and industry consultants as well. The FDA launched a pilot program in 2005 to allow firms an opportunity to submit chemistry, manufacturing, and controls (CMC) information obtained through the application of QbD3,4. To date only a handful of companies have submitted CMC information using the QbD model and it is still not well understood by industry or FDA regulators. For the companies that chose to follow this path, there is an opportunity for a shortened review period.

Current Status

International Conference on Harmonization’s Pharmaceutical Development Guidelines, ICH Q8, objective is to consistently deliver a high quality product by building proper controls and understanding of your process and monitor the right parameters and attributes1,2. It is a scientific, risk-based, holistic and proactive approach to pharmaceutical development, a deliberate design effort from product conception through commercialization with full understanding of how product attributes and processes relate to product performance. Quality is not necessarily to be tested into the finished product, in fact the finished product may not be tested at all. Under QbD principles, regulators will allow companies to rely on in-process and Process Analytical Technology (PAT) data to assure the manufactured product meets the established pre-determined quality attributes. Regulators’ expectations are that the information and conclusions related to the product should be shared with them as well as the control strategy to assure the product quality attributes are maintained.

The FDA's Center for Drug Evaluation and Research has expressed their expectation regarding QbD as, "QbD is a systematic approach to product and process design and development"3,4. QbD involves the following key elements:

  1. Target the product profile
  2. Determine critical quality attributes (CQAs)
  3. Link raw material attributes and process parameters to CQAs and perform risk assessment
  4. Develop a design space
  5. Design and implement a control strategy
  6. Manage product life cycle, including continual improvement

Both industry and FDA are on a learning curve as it relates to the acceptance criteria for real-time release. However, real-time release provides manufacturing flexibility and increased quality assurance and is a more modern approach to manufacturing and controls.

Design Space

A systematic evaluation of the risks associated with manufacturing a pharmaceutical product is required for implementation of QbD. Expectations are that all raw materials and product variables with a potential impact on product quality are evaluated and assessed using adequate assessment tools like fishbone diagrams, Failure Mode Effects Analysis (FMEA), and Pareto analysis. Even though risk assessment is based on experience and process knowledge, when stating prior experience as a consideration in assigning or evaluating risks and interdependency among product manufacturing variables, adequate explanation should be provided as to how this prior experience is applicable to the product process control strategy.3,4

The process parameters with the highest impact on the CQAs should be further studied to better understand their impact on product quality. The control strategy that is implemented for risk reduction and control needs to consider these parameters and their impact on product quality for changes both within and outside the design space.

Variation in process parameters is always a possibility and needs to be controlled. An understanding of the impact of process parameters in the final product is imperative in designing the proper process controls. Process parameters and their intersection in a "design space" concept need to be understood (Figure 1)5. The probability of falling outside of the design space per unit time needs to be evaluated so risk analysts can estimate probabilities of being outside (or inside!) of design limits, given various scenarios.

Risk assessment of process parameters helps increase assurance of product quality as process variability is identified and its impact to product CQAs is understood so it may be controlled to reduce variability and quality product produced when variability of process parameters are maintained within the design space.

The FDA has indicated a risk assessment is also important for effective communication between FDA and industry and for intra-company communication (such as between research/development and manufacturing and among multiple manufacturing sites)3,4.

The design space should be determined for raw materials as well as for the finish product so interactions are well understood and variability controlled so CQAs are not adversely affected and expected drug product quality is reproducible.

What does all that information provide?

  1. It demonstrates knowledge of the product
  2. It identifies possible sources of variability and how associated risks can be mitigated
  3. It allows for the assessment of the product quality attributes when one or more of the variables fall outside of the design space
  4. It forms the basis for continuous improvement

Control Strategy

Control strategy is also a critical element of QbD, and should include starting materials, intermediates and finished products. The strategy should include every aspect known that could impact the product. The following are suggested considerations for a control strategy:

Update manufacturing instructions:

  1. Set the most appropriate parameters
    1. Multivariate interactions need to be evaluated
  2. Correct ranges of operation
  3. Determine the proper data for trending and analysis

Create a control strategy:

  1. Control the quality of product & components
  2. Scale up and equipment impact
  3. Technology transfer considerations
  4. Validate the process
  5. Control critical processing parameters
  6. Implement PAT strategies, as possible
  7. Trend and analyze the right data
  8. Implement adequate supply chain practices

The collection of this data helps in controlling variability and risk as well as providing a Continuous Quality Overall Summary (CQOS) which will serve as the basis for continuous improvement during the product lifecycle.

Drug developers will need to pay attention and consider these requirements during development. This will include more stringent application of design of experiments (DOE), focusing on systematic thinking, and organizing data in meaningful categories. All of this leads to positioning the decision-making process based on the data and knowledge obtained from all stages of development.

Product Lifecycle

During the product lifecycle strong quality systems as mentioned below are certainly critical in maintaining adequate controls and feedback to assure control of product quality.

Quality systems:

  1. Change control
  2. Validation
  3. Trending and analysis
  4. Management review
  5. Quality risk management
  6. Operator training
  7. Product improvement program
    1. Six Sigma Lean Manufacturing

The implementation of Quality Systems in the manufacture of drug products helps the pharmaceutical companies:

  1. Improve quality of pharmaceutical products
  2. Improve cGMP compliance
  3. Facilitate continuos improvement
  4. Necessary for implementation & effective utilization of:
    1. Quality By Design (Q8 Pharmaceutical Development)2
    2. Risk Management (Q9 Pharmaceutical Risk Management)6
  5. Effective knowledge transfer
    1. CAPA
    2. Change control
    3. Trending and analysis
  6. Demonstrate a state of control
  7. Manage process parameters movement within the design space
  8. Identify adverse trends and implement adequate corrective actions

The information accumulated in the quest of fully understanding your product and manufacturing process will allow you to predict impact of variations in your supply chain during routine commercial manufacturing, and possibly of "improved" materials and components on the CQAs of your product. This information may allow you to design better and more meaningful experiments when studying the impact of new materials and control systems for the manufacturing process.

ICH Q9 Quality risk management (QRM)6 is requiring that risk to product quality be evaluated using gained scientific knowledge of the system that produces the product. The method of evaluation, formality and risk should be appropriate for the level of risk, the severity of the event, probability for occurrence of the event and the detection systems in place. QRM will help improve product quality, GMP compliance, and facilitate continuous product improvement.


  1. ICH Q8(R1) Pharmaceutical Development, June 2009
  2. ICH Q8(R2) Pharmaceutical Development, November 2009
  3. Chi-wan Chen, "Implementation of Quality-by-Design Principles in CMC Review: Office of New Chemistry Approach", Advisory Committee for Pharmaceutical Sciences, Oct 26, 2005
  4. Patricia Van Arnum, "A FDA Perspective on Quality by Design", Pharmaceutical Technology Sourcing and Management, 3(12), Dec 5, 2007
  5. H. Gregg Claycamp, "ICH Q9: Quality Risk Management", CDER Advisory Committee for Pharmaceutical Sciences, Oct 5-6, 2006
  6. ICH Q9 Quality Risk Management, Jun 2006

Particle Sciences is a leading integrated provider of formulation services and analytic services and both standard and nanotechnology approaches to drug development and delivery.

3894 Courtney Street, Suite 180
Bethlehem, PA 18017