Implementation of the Quality by Design approach for developing the composition and the manufacturing technology of an injectable drug for intra-articular introduction

Abstract

Aim. To implement the Quality by Design (QbD) approach in order to develop the composition and the manufacturing technology of injectable hyaluronate sodium (HS) in combination with chondroitin sulfate (CS) for intra-articularintroduction. Materials and methods. The composition of the solution for injection was developed using samples of the active pharmaceutical ingredient (API) of HS and CS. The approaches of the ICH international guidelines were used to create the QbD protocol. The quality target product profile (QTPP) was developed based on the literature review, analysis of similar drugs and the previous in-house experimental studies. Determination of critical quality assessment (CQA) product indicators was performed by risk analysis for all quality indicators listed in QTPP. The risk assessment of quality indicators was performed by assessing them according to the Risk Priority Number system (hereinafter – RPN) by a 9-point scale. When studying the composition and the manufacturing technology of the injectable solution the quality risk management (QRM) was developed according to the Ishikawa diagram. Results and discussion. It has been found that the QbD concept is a systematic approach to the drug development. At the first stage QTPP was developed. Based on the QTPP data the CQA indicators were determined, and quality risks were assessed. The critical process parameters (CPP) of the solution for injection based on HS and CS, their control methods, as well as the critical material attributes (CMA) were determined. Based on the data obtained the drug control strategy was proposed taking into account the need to minimize the repetition of control experiments. Using the Isikawa diagram the variability of the material and the process with the environmental factors affecting the qualityof the solution for injection with HS and CS was shown.Conclusions. Using the basic QbD approaches when developing the composition and the manufacturing technology of an injectable drug for intra-articular introduction it has been found that the route of administration, dose, potency, and consumer properties of the product are important aspects of QTPP. It has been proven that the quality indicators, such as transparency, viscosity, sterility and the quantitative content of API are determined as CQA to achieve the objectives defined in QTPP. The study shows that almost all stages of production are critical, therefore, they need to be constantly monitored and checked to obtain a quality product. In further experimental studies to confirm the composition developed and the manufacturing technology according to QRM it is necessary to focus on such indicators as the solution temperature, stabilization time, degassing mode and filtration conditions.