5 Key Elements of Quality by Design in Pharma

Intentionally integrating quality directly into every manufacturing process beginning with research and development is desirable and possible. The outcomes are clearly superior to an after-the-fact testing and control process that “only detects and removes substandard products,” but “doesn't prevent them from being created in the first place.”¹ The benefits of embedding quality into every design and manufacturing phase include:²

• Right-first-time batches.
• Safer, higher quality, optimized products.
• Built-in change controls and quality assurance.
• Consistent compliance.
• Decreased oversight and increased flexibility within a proven design space.
• Shorter lead times and getting to market faster.

A Regulatory Perspective and Preference for Quality by Design

Quality flexibility opens the door to many ways of accomplishing this, however, it's not a slam dunk. It requires careful analysis and planning at the beginning with the end in mind. The U.S. Food and Drug Administration (FDA) and The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) emphasize a more systematic approach known as Quality by Design (QbD).³

Theoretical Foundations of QbD in Pharmaceuticals

QbD is a precise set of protocols that offers a preemptive and integrative approach to quality manufacturing built on scientific and mathematical foundations. QbD in pharmaceuticals stems from the FDA's recognition that increased testing does not increase product quality, and that quality needs to be built into a product.⁴ Additional data from experiments and statistical analysis required by QbD upstream is used to establish controlled parameters that can tolerate natural variance downstream without disruption and slowdowns.

In terms of yielding a quality product, having deep knowledge about the product and processes from the developmental phase results in better performance than traditional end-of-the-line testing. It also reduces the need for post-production interventions, which are riskier, more costly, and labor-intensive. The underpinnings of this methodology are listed below:⁵

• Thoroughly define product and process parameters, materials, and quality attributes.
• Complete sufficient empirical testing and multivariate statistical analysis upfront to understand material and process interdependencies.
• Optimize production to tolerate natural variance and mitigate anticipated risks.
• Engage in ongoing post-approval improvement of products and processes.

5 Practical Elements of QbD in Pharmaceuticals

To qualify for QbD approvals and permissions from regulatory bodies, a pharmaceutical manufacturer must clearly establish these key elements as part of their QbD approach:⁶

1. Quality (QTPP + CQA). The Quality Target Product Profile (QTPP) is a summary of the desired quality of the end product, taking into account safety and efficacy. It includes a list of critical quality attributes (CQAs) of any output material, such as uniformity, degradation, size, shape, and color, within an appropriate limit, range, or distribution.
2. Product (CMA). Deep product understanding is necessary to determine whether the product can meet patients' needs and maintain performance throughout its shelf life. Thorough product understanding must include all critical material attributes (CMAs) of any input material within an acceptable limit, range, or distribution to ensure the desired QTPP.
3. Process (CPP). Deep process understanding must include the identification of critical process parameters (CPPs), which by definition have a significant influence on the final product; links between CMAs, CPPs and CQAs; and a thorough understanding of scale-up principles. CPPs should be monitored and controlled during production to ensure the process yields the desired QTPP.
4. Control Strategy. In-process controls are preferred over traditional end-product testing. A production environment that operates within statistical control and within material and process ranges governed by the design space (DS) reduces the need for regulatory oversight. A quality management solution can be used to effectively implement the control strategy.
5. Continuous Improvement. Integrating quality throughout design and production allows manufacturers to make adjustments to processes and materials within the DS, even post-approval. Using an effective quality control solution makes it easier for companies to refine and redirect in real time and achieve the targeted results outlined in the QTPP.

How a Quality Management System (QMS) Supports Quality by Design

The objective of QbD is robust production, which implies predictable, consistent, and optimized outcomes that are risk resilient even with a known degree of process and material variability. The successful implementation of QbD in pharmaceuticals ensures controlled manufacturing operations and predictable product outcomes that pharmaceutical manufacturers are seeking. Although this level of quality integration can initially seem daunting, a purpose-built pharmaceutical quality management system (QMS) can help manufacturers overcome these hurdles.

According to Michael Lowenborg of DPT Laboratories, “QbD can be especially difficult to implement across the board when operations are fragmented, either geographically or functionally. Even when a QbD system is in place, technology and knowledge transfers can be problematic when new personnel are being introduced without any prior guidance, for example, when a product is making the transition from development to manufacturing.”⁷

This takes us full circle … back to the beginning with the end in mind. A pharmaceutical QMS that offers electronic document management, ensures training requirements are met, automates configurable workflows, and is cloud-based can meet these challenges head-on, especially when it is linked to automated manufacturing software. Such an enterprise solution can connect processes with products and offer deep data insights. An integrated solution provides the foundation necessary for more rigorous empirical study and statistical analysis that QbD demands, while also facilitating continuous improvement.

References:

1. QbD: Improving Pharmaceutical Development and Manufacturing Workflows to Deliver Better Patient Outcomes, Martin Koeberle, Wolfgang Schiemenz, Pharmaceutical Technology, August 31, 2017.
2. The Advantages of a 'Quality by Design' Approach in Pharma Drug Development, Matteo Zacché, Mattias Andersson, Phaarma Manufacturing, Jan 06, 2020.
3. Understanding Pharmaceutical Quality by Design, Lawrence X. Yu, et al., American Association of Pharmaceutical Scientists (AAPS), July 2014.
4. Supra note 3.
5. Supra note 3.
6. Supra note 3.
7. Quality-by-Design: The Good, The Bad, The Inevitable, Michael Lowenborg, Drug Development & Delivery, Oct. 2014.