The attainable regions for Critical Quality Attributes (CQA) in the manufacture, such as Particle Size Distribution (PSD), and performance, such as fraction absorbed, of Solid Oral Dosage Forms (SODF) can be highly dependent upon the types and operation of the end-to-end production steps. This is particularly the case for low-dose drug products, where other factors, such as Content Uniformity (CU) of SODF can also be of a major concern. The CU of SODF is known to be highly dependent upon the particle size distribution of the Active Pharmaceutical Ingredient (API), with control of API particle size being a common approach to ensuring the content uniformity of drug products. In this work, we examine a continuous cascade cooling crystallization process and explore the impact of varying process configurations, both drug substance and drug product, on the attainable processing regions, subject to various processing and performance constraints. The continuous cooling crystallization of paracetamol and ethanol solutions was employed as an example case. Additional drug substance and drug product manufacturing steps were also considered in a modular fashion, in order to investigate their impact on the attainable regions, including filtration, wet and dry milling. The final performance of the drug product was determined via a segmented model of the Gastro-Intestinal (GI) tract. This model describes the dissolution and permeation of the API in the GI tract, yielding the fraction of the API absorbed in the patient as function of time and hence the bioavailability of the drug
in-vivo.
A number of optimization objectives were posed, which included increasing throughput of the API and the number of crystallizer stages, whilst maintaining a target CU of the final product, sufficient bioavailability and other processing constraints, in order to evaluate these attainable regions. Once the attainable region of a given CQA versus total production time was determined, the robustness within the attainable region was evaluated and explored via Global Sensitivity Analysis (GSA). This holistic approach to the modelling of API manufacture and end performance, allows the interdependent processing steps of drug substance and drug product manufacture and their impact upon in-vivo drug performance to be considered in a more cohesive way.
