Quality by design

Integrated planning requires a team with a leader whose sole accountability is for the total success of the new product from defining the opportunity through customer purchase, use, service, and recommendation to others. This team leader reports directly to a senior executive, or the team leader can be a senior executive. Each team member's job is to ensure the success of the new product.[9] In addition to organizational integration, a successful team must begin with clearly articulated common goals for the product that are measurable and authorized by the enterprise. These goals must, at a minimum, cover such elements as:

• The customers or customer segments to be served by the new product
• The relative and absolute quality goals
• The volume of sales or revenue to be generated in an initial time period and for the long run
• Market share, penetration, or sales relative to key competitors
• The release date

The team will follow a structured process. The structure is the common framework for all participants in launching the new product and helps ensure success.[9]

Quality by design starts and ends with the customer.[1] Every new product introduction has some amount of trade-off involved. If there are multiple customers, they may have conflicting needs. Even the same customer may have needs that compete with each other. Capacity and speed compete with cost of operation. Capacity can compete with speed. Flexibility and feature-rich offerings may have reduced ease of use, and so on.[7]

Quality by design offers a range of tools and methods intended to make these tradeoffs explicit and optimal for the customer. Some tools are highly mathematical, and others relate more to customer behavior. Quality by design sets strong expectations for creative approaches to functional design, product features and goals, and production design.[10]

Quality by design incorporates modern tools to preemptively control variation. These tools and methods begin by measuring and understanding the variation that exists by using historical data, testing, and modeling to help forecast, analyze, and eliminate the deleterious effects of variation using standard statistical techniques.[10] Process control consists of three basic activities:

1. Evaluate the actual performance of the process
2. Compare actual performance with goals
3. Take action on the difference [7]

The final activity of the quality by design process is to implement the plan and validate that the transfer has occurred.[7]

The following activities are guiding the implementation of QbD:

• In FDA's Office of New Drug Quality Assessment (ONDQA), a new risk-based pharmaceutical quality assessment system (PQAS) was established based on the application of product and process understanding.
• Implementation of a pilot program to allow manufacturers in the pharmaceutical industry to submit information for a new drug application demonstrating use of QbD principles, product knowledge, and process understanding. In 2006, Merck & Co.'s Januvia became the first product approved based upon such an application.[13]
• Implementation of a Question-based Review (QbR) Process has occurred in CDER's Office of Generic Drugs.
• CDER's Office of Compliance has played a role in complementing the QbD initiative by optimizing pre-approval inspection processes to evaluate commercial process feasibility and determining if a state of process control is maintained throughout the lifecycle, in accord with the ICH Q10 lifecycle Quality System.
• First QbD Approval - including design space - for Biologic License Application (BLA) is Gazyva (Roche) [14]

While QbD will provide better design predictions, there is also a recognition that industrial scale-up and commercial manufacturing experience provides knowledge about the process and the raw materials used therein. FDA's release of the Process Validation[12] guidance in January 2011 notes the need for companies to continue benefiting from knowledge gained, and continually improve throughout the process lifecycle by making adaptations to assure root causes of manufacturing problems are corrected.

Working with regulators in the European Union (the European Medicines Agency) and Japan, the FDA has furthered quality by design objectives through the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The ICH Guidelines Q8 through Q11 encapsulate these unified recommendations and provide some assistance for manufacturers to implement quality by design into their own operations. ICH Guideline Q8 describes QbD-based drug formulation development and was first published in 2004, being subsequently revised in 2008 (Q8(R2)).[15] The ICH Guideline Q9 describes Quality Risk Management plans,[16] Q10 explains Pharmaceutical Quality Systems,[17] and Q11 refer to the development of active pharmacological substances including biologicals.[18]

In November 2017, the ICH issued Guideline Q12 for public consultation to extend the recommendations for the Product Lifecycle Management Plan that were initially defined in the Guideline Q10.[19] According to the ICH, Guideline Q13 will extend the previous guidelines to accommodate continuous pharmaceutical manufacturing[20] and Q2 (Analytical Validation) will be revised and extended into the guideline Q2(R2)/Q14 to include Analytical quality by design or AQbD.[21]

The ICH Steering Committee meets twice a year to discuss the progress of its efforts. This practical input should help ensure that quality risk management and knowledge management are used to make lifecycle adaptations that maintain process control and product quality.