Review Experiences and Regulatory Challenges for Pharmaceutical Development in Japan Using a Quality-by-Design Approach.

Abstract

A significant number of inquiries are issued during the review of pharmaceutical products developed using the quality-by-design (QbD) approach in Japan. The purpose of this article was to identify key elements specific to QbD development that should be described in the Quality Overall Summary (QOS) dossier. The review reports of the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) were investigated to identify review points for QbD products. Based on the results, key considerations for preparing the QOS of QbD products were determined. The primary review points for QbD products were control strategy (∼30%), design space (∼15%), and real-time release (∼15%). Additionally, the market authorization application form (AF) was discussed more frequently for QbD products than for products developed using a traditional approach. Based on the results, a "QOS checklist for QbD products" was developed to highlight key elements of QbD products that should be included in the QOS. It is important to explain the scientific rationale for the control strategy, design space, and real-time release in the QOS and how "regulatory flexibility" is expressed in the AF. The QOS checklist enables applicants to prepare an appropriately detailed QOS that should satisfy the PMDA's critical review points. The following are recommended for further discussion topics to enable efficient and consistent review by the PMDA for QbD products: (1) Clear guidance on how to express "regulatory flexibility" in the AF and (2) a "QOS checklist for QbD products" that is agreed upon by both regulatory agencies and pharmaceutical companies.