Implementation of Quality by Design (QbD) Principles in Regulatory Dossiers of Medicinal Products in the European Union (EU) Between 2014 and 2019

Abstract

Background: Quality by Design (QbD) is a systematic risk-based approach to development, with predefined characteristics and quality risk management throughout the life cycle of a product. International Conference on Harmonization (ICH) guidelines Q8-Q11 give guidance on QbD applications with ICH Q8 (R2)-approved in 2009-describing the principles of QbD in detail. Since its adoption over 10 years ago, more information about QbD usage for the development of medicinal products is expected to be written in regulatory dossiers by companies.

Methods: The present study set out to evaluate the implementation of QbD principles and elements in all EU approved marketing applications (MA) (n = 494), based on information available in the European Public Assessment Reports (EPARs), for a period of six years (2014-2019), starting 5 years after QbD adoption.

Results: Of the 494 MAs, 271 were submitted with a full dossier (article 8(3)). According to EMA (38%), out of the 271 full dossier submissions, only 104 were developed using full QbD. This figure did not increase during this period. Interestingly, between 2014 and 2019, several MAs were not developed via full QbD implementation but used one or more QbD elements during development, including design space. In addition, a higher percentage of small molecule products were developed with QbD as opposed to biotechnology-derived products (78% vs. 22%, respectively).

Conclusion: Overall, QbD during development of medicinal products is still not commonly described in dossiers. However, more companies started mentioning QbD elements, thus making it a promising step toward QbD as the standard for development in the future.

Keywords: Design space; Drug development; EMA; EPAR; QbD; Quality by Design.

Fig. 1

QbD scheme with QbD elements

Fig. 2

QbD elements. a Percentage of QbD elements used in medicinal products developed with full QbD for the period 2014–2019 (n = 104). Light gray bars represent QbD elements used during the development of the active substance (AS); dark gray bars represent QbD elements used during the development of the finished product (FP). b Percentage of products which are not developed with QbD according to EMA but using one or more QbD elements (n = 167). c Percentage of products developed with QbD claiming a design space. AS active substance, CPP critical process parameter, CQA critical quality attribute, DoE design of experiments, FP finished product, PAR proven acceptable range, QTPP quality target product profile

Fig. 3

QbD in small molecule vs. biotech medicinal products. a Percentage of small molecule vs. biotech medicinal products developed with QbD for the period 2014–2019. b Percentage QbD usage of small molecules and biotech products submitted via full application. c Percentage of QbD during the different developmental phase of active substance and finished product for small molecules and biotech products. AS active substance, FP finished product

Fig. 4

QbD usage in SMEs vs. large pharmaceutical companies. a Total EPARs analyzed over the period 2014–2019. Black line represents the total EPARs (n = 494), dark gray line represents total products developed with QbD (n = 151), light gray line shows the total products developed with QbD submitted via a full application (n = 104). b Total products submitted by a SME. Black line shows the total products (n = 31), dark gray line represents the total products developed with QbD by a SME (n = 4), light gray line shows the total products developed with QbD by a SME and submitted via a full application (n = 1). SME small and medium enterprises