Eight Opportunities for QbD

Mitigating risk within the product lifecycle begins with an open mind

By Heath Rushing, Principal, Adsurgo LLC

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In her talk to ISPE conference attendees in November 2013, Food and Drug Administration’s CDER Director Dr. Janet Woodcock presented on the current state of Quality by Design . She suggested that drug manufacturers need to focus not on “doing” QbD but on having a culture of quality and continuous improvement.

As first presented in Guidance for Industry – Q8 Pharmaceutical Development, pharmaceutical development studies should include a systematic understanding of the process to establish a control plan. This control plan is part of a comprehensive quality risk management strategy. Although QbD was originally presented in the context of pharmaceutical development, in order to achieve the objectives of a more complete model for pharmaceutical quality system, the QbD mindset should be built into the entire product lifecycle.

In 1992, Joseph M. Juran presented a framework consisting of three distinct phases to achieve quality by customers; it is known as the Juran Trilogy:

1. Quality planning: Quality should be designed into the process to ensure delivery of a product that consistently meets the needs of your customer.
2. Quality control: A system needs to be implemented and maintained to ensure the process used to make the product remains in a state of statistical control.
3. Quality improvement: A culture should be established that rewards the continual improvement of the process/product.

Juran emphasized the adoption of this methodology is not specific to any particular department; this needs to be adopted company-wide, in every phase of the product lifecycle. He detailed his methodology in a book titled Quality by Design.

In April of 2009, the FDA presented a comprehensive model that drug manufacturers should follow for their pharmaceutical quality systems. Three main objectives are achieved by implementing the proposed model:

• Achieve product realization: The establishment, implementation, and maintenance of a system that allows the delivery of products with the quality attributes appropriate to meet the needs of patients, health care professionals, regulatory authorities and other internal and external customers.
• Establishing and maintaining a state of control: The development and effective use of monitoring and control systems for process performance and product quality, thereby providing assurance of continued suitability and capability of processes.
• Facilitating continual improvement: The identification and implementation of appropriate product quality improvements, process improvements, variability reduction, innovations, and pharmaceutical quality system enhancements, thereby increasing the ability to fulfill a pharmaceutical manufacturer’s own quality needs consistently.

The FDA detailed this methodology in Guidance for Industry - Q10 Pharmaceutical Quality System. Does this sound familiar? The objectives achieved by implementing the proposed model for your pharmaceutical quality systems are directly aligned with the QbD methodology presented by Juranin 1992.

It is understandable that the principles proposed by regulatory agencies should align with well-established methodologies from the quality literature. However, there is the question of when and where (in a company) this methodology should be implemented. As stated earlier, Juran would contend it should be adopted company-wide, in every phase of the product lifecycle. I believe Dr. Woodcock would agree.

What follows is a basic model for building quality into the product lifecycle, with emphasis on how it relates to QbD:

• Set Specifications
• Measurement System
• Critical Quality Attributes (CQAs) and Input Parameters
• Process Development
• Control or Risk Management Plan
• Validate the Process
• Commercial Manufacturing
• Product Discontinuation

This basic framework for integrating a quality system into the product lifecycle is similar to the framework prescribed by regulatory agency guidance documents; the terms used may be different but the concepts are the same. In fact, the majority of the steps are in what Juran called the quality planning phase of the product lifecycle.

Set Specifications: Although the regulation says specifications must be consistent with the process average and variance [21 CFR 211.110 (b)], it does not preclude drug manufactures from using other information to set specifications. They should also be based on the needs of the customers: patients, health care professionals, regulatory authorities, as well as both internal and external customers.

These meaningful specifications can then be used as criteria for analytical method and process validation, as well as establishing a design space for product development and process capability for commercial manufacturing.

Measurement system: In pharmaceuticals, this is known as analytical method (assay) development, qualification, validation, and transfer. Guidance documents do not require validated analytical methods for QbD studies, but do require a justification of the reliability of measures (accurate and reliable) used in pharmaceutical studies.

Critical Quality Attributes (CQAs) and Input Parameters: CQAs should be established and risk assessment tools should be used to identify and prioritize process parameters that will be evaluated in QbD studies.

Process Development: A QbD approach for pharmaceutical development studies should include both a systematic understanding of the process and the use of this understanding to establish a control strategy as part of a comprehensive quality risk management program. The systematic understanding should include both an identification of process parameters that impact the CQAs and determination of a functional relationship (mathematical model) linking those process parameters to the CQAs.

Control or Risk Management Plan: As outlined by Guidance for Industry Q9 Quality Risk Management, a typical quality risk management process has five key elements; the proposed model suggests risk management tools should be used throughout each of these elements.

Validate the Process: As outlined by Guidance for Industry Process Validation, the goal of the process design stage is to capture process knowledge and understanding from the process design (pharmaceutical development) stage. It is essential to use this knowledge to establish a strategy for process control (from the risk management stage).

Commercial Manufacturing: Guidance for Industry Q11 – Development and Manufacture of Drug Substance presents two different approaches for developing a drug substance, the traditional and enhanced approaches. “In an enhanced approach, risk management and scientific knowledge are used more extensively to identify and understand process parameters and unit operations that have an impact on critical quality attributes (CQAs) and develop appropriate control strategies applicable over the lifecycle of the drug substance….” Although the guidance does not advocate one approach over the other (“A company can use either a traditional approach or an enhanced approach to drug substance development, or a combination of both.”), it is obvious the enhanced approach more closely aligns with the current thinking on incorporating QbD methodology into the product lifecycle.

Product Discontinuation: The importance of each of these quality planning steps are realized in the objectives for integrating a pharmaceutical quality system across the product lifecycle, up through product discontinuation.

Guidance for Industry Q10 Pharmaceutical Quality System suggests that three main objectives are achieved by implementing the proposed model:

1. Achieve product realization.
2. Establishing and maintaining a state of control.
3. Facilitating continual improvement.

It is easy to recognize that each step in this model either provides required inputs to pharmaceutical development studies using QbD, represents the actual studies,or provides the information required for preceding steps in the product lifecycle (risk management, process validation, commercial manufacturing). Each step of the quality planning model is imperative for achieving the objectives outlined in Guidance for Industry Q10 Pharmaceutical Quality System.

Juran contended QbD methodology should be adopted company-wide, in every phase of the product lifecycle.

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