Where now with quality by design?

Quality by Design (QbD) was introduced into the regulatory lexicon during 2005 (ICH Q8(R2))¹ in order to provide guidance for drug product development. It was later extended to cover drug substance development (ICH Q11)² and analytical method development, ie, AQbD (ICH Q14).³

A quality target product profile (QTPP) links the clinical requirements defined in the target product profile (TPP) with the quality requirements; ie, type of product, pack and likely shelf life. In addition, connectivity between product quality and various material, processing and quality attributes was envisioned.

Thus, the extensive knowledge base of input materials, formulation and process facilitated the definition of critical material attributes (CMAs) and critical process parameters (CPPs), resulting in a series of critical quality attributes (CQAs) that would form part of the overall control strategy – including specifications.

It was envisaged that QbD would be underpinned by design of experiments (DoE), quality risk management (ICH Q9)⁴ and a robust quality management system (ICH Q10).⁵ Thus, the pantheon of regulatory guidance covering development (ICH Q8, Q11 and Q14), risk management (ICH Q9) and quality management (ICH Q10) would work synergistically to deliver QbD.

The most revolutionary concept within QbD was the design space. This was defined as, “The multidimensional combination and interaction of input variables (eg, material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post- approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval”.¹

QbD was initially warmly welcomed by industry, as there were already significant concerns of the impact of non-robust products and processes on production. Firefighting was consuming extensive resource within R&D, production and the quality functions. Additionally, the cost and disruption caused by post-approval change submissions was not tenable long term. However, by the early part of the last decade doubts were beginning to surface within industry – particularly centred on regulatory relief, or the lack thereof. Many of the benefits were clear, ie, “enhanced product and process understanding, improved internal processes and leaner manufacturing”;⁶ but there were also major concerns regarding the “regulatory submission process, brought about by lack of harmonisation and clarity of expectations”.⁶ Other surveys highlighted the significant upfront costs of QbD and low return on investment (RoI).⁷ Regulatory agencies felt that QbD submissions improved the efficiency of the review process; however, only 50 percent of industry responders were in agreement with this viewpoint.⁸

The most contentious issue was the design space and notion that “working within the design space is not considered as a change”. However, the complexity of this new paradigm led to much confusion; how could a “multidimensional combination and interaction of input variables” be easily explained to regulatory agencies, particularly when the reviewers may not be specialist chemometricians, but broad-based CMC specialists?⁹ Additionally, would this result in common understanding within that agency and between different agencies? Or would different agencies demand different outcomes? This is a significant issue because a major promise of QbD was the assurance of global regulatory harmonisation for new drug applications and post-approval changes. This lack of a common regulatory understanding

has led to increased supply chain complexity and regulatory burden and hinders continual improvement and enhanced innovation.¹⁰ These authors¹⁰ suggested that control strategy is the more useful QbD concept for assurance of product quality, not design space.¹⁰ So, it would appear that QbD still has some way to go to ensure ‘common global understanding’.

References

1. ICH Q8(R2). Pharmaceutical Development. Current Step 4 version, dated August 2009.
2. ICH Q11. Development and manufacture of drug substances (chemical entities and biotechnological/biological entities). Current Step 4 version dated 1 May 2012.

3. ICH Q14. Analytical Procedure Development and revision of Q2(R1) analytical validation. Final concept paper dated 14 November 2018.
4. ICH Q9. Quality Risk Management. Current Step 4 version dated 9 November 2005.
5. ICH Q10. Pharmaceutical Quality System. Current Step 4 version dated 4 June 2008.
6. Kourti T, Davis B. The Business Benefit of Quality by Design (QbD). Pharm Eng Off Magazine of ISPE. 2012; 32(4): 1–10.
7. Johnston R, Lambert J, Stump E. An Industry Perspective on Quality By Design. BioProcess Int. 2012; 10(3): 26–35.
8. Cook J, Cruanes MT, Gupta M, Riley S, Crison J. Quality by design: Are we there yet? AAPS PharmSciTech. 2014; 15(1): 140–148.
9. García-Muñoz S, Luciani CV, Vaidyaraman S, Seibert KD. Definition of Design Spaces Using Mechanistic Models and Geometric Projections of Probability Maps. Org. Process Res. Dev. 2015; 19(8): 1012–1023.
10. Watson TJN, Nosal R, Lepore J, Montgomery F. Misunderstanding Design Space: a Robust Drug Product Control Strategy Is the Key to Quality Assurance. J Pharm Innov. 2018; 13: 283–285.