Establishing a Design Space for an Existing Generic Tablet Dosage Form for Efficient Manufacturing and Quality Assurance at Jepharm in Palestine رسالة ماجستير

Abstract

Quality has become a critical factor in the success of an organization. Quality management and planning through the implementation of Quality by Design (QbD) to establish a Design Space(s) and utilize Quality Improvement methods used in this research study have been proven to maximize efficacy, safety and increase manufacturing productivity while reducing the manufacturing cycle time. This research study is to utilize QbD to establish a Design Space(s) for efficient manufacturing and quality assurance at Jepharm in Palestine. More specifically, this study helps to reduce the manufacturing cycle time of an existing JR tablet pharmaceutical product with the ultimate focus on the patient. Qualitative data were collected to define the Critical to Quality (CTQs) characteristics while Palestinian Ministry of Health was contacted to understand the guidelines of QbD implementation in Palestine. Quantitative empirical 2018 and 2019 overall cycle time retrospective data for all products at Jepharm were collected and JR tablet was identified with the worst overall cycle time. Also, 2017 to 2019 retrospective data for the manufacturing of JR tablet were collected. The relationship between Critical Material Attributes, Critical Process Parameters and Critical Quality Attributes was identified for JR tablet. Design Expert 13 software was used to build the Design Space models. Four Design Spaces were established; the first one is for the response dissolution, the second one is for the response friability, the third and fourth ones are for the response API 2 Assay after compression and after coating. In August 2020, thirteen batches were executed, new processing data collected and the design spaces were finalized utilizing Design Expert 13 and Quality Risk Management. It was found that the manufacturing cycle time is the main and most critical process factor V affecting the overall cycle time of JR tablet. Final mixing and coating stages are the most critical unit operations affecting the manufacturing cycle time. Oscillating and sieving unit operations were modified to remove none value added activities while improving the compression operation due to better powder-mixture’s flow-ability, hence, eliminating capping and chipping of tablets. API 2 assay was found to be the most Critical Quality Attribute of JR tablet manufacturing process. In order to help better distribute API 2 in the final mixture and eliminate degradation of API 2, granulated material was dried to LOD <1.5% and geometric mixing was introduced before the final mixing stage. Mixing time was increased from 15 minutes to 30 minutes giving more time for homogenous mixing of API 2 since its concentration in the batch is about 0.3% and no baffles are present in the Bin Mixer. In addition, API 2 was found to be affected by temperature in the coating stage’s warming step with the inlet air temperature reaching a maximum of 63oC leading to an out-of-specification of API 2 assay with 15% reduction. The inlet air temperature to the coating machine was reduced to <32oC eliminating product degradation. These results are very important because the improvements made reduced the manufacturing cycle time by 45% and ensured that API 2 assay stays within (95% - 110%) limit which frequently failed this limit leading to reprocessing of batches. The control strategy was developed and training was completed accordingly. In July 2021, all of the uncovered improvements were validated by executing four actual production batches with excellent results.