An agile, mobile platform for continuous GMP manufacturing of liquid products, such as injectables and inhalable, capable of real time quality control is under development. The process module is designed to accomplish sterile compounding and fill-finish operations on a flexible platform. This platform integrates a cyber-physical system with sensor redundancy and high-fidelity digital twin models, enabling process analytical technology (PAT) to provide full physical real-time transparency of the system. A two-fold strategy is incorporated to accomplish this goal. The first step involves developing a drug product formulation that meets the target profile and the desired quality attributes of the final product. Once the formulation composition is optimized to hit the target product profile, we arrive at the second step that involves developing a manufacturing process using quality-by-design (QbD) principles. This process is scalable, flexible, robust, and can ensure quality control using real-time information. We aim then to make this process manufacturable in a GMP environment and at scale.
For this study, two model drug products from the FDA’s Drug Shortage List, namely albuterol sulphate (inhalable) and bupivacaine hydrochloride (injectable) are identified and used. These minimum viable products (MVPs) are developed and optimized for the process. Quality and analytical testing to assess the stability, sterility, tonicity, and pH are performed for the two formulations to ensure that they meet the desired specifications. Maintaining the critical quality attributes such as sterility, pH, conductivity/tonicity, and the API concentration in a formulation is important to ensure the patient’s comfort, safety, and compliance and the drug’s efficacy in the human body. On the other hand, stability testing ensures that the drug product will remain stable for the time and at the conditions that it will face during the formulation, filtration, and filling stages of the process as well as maintain its quality under long term storage conditions. The process is developed to mix the ingredients of the formulation recipe using a static mixer, which is filtered through a double-membrane ultrafiltration unit to get rid of particulates and pathogens, and is finally filled in a sterile, fill-finish system. This manufacturing process is equipped with highly accurate sensors and process analytical technology, that helps in collecting information such as critical process parameters (CPPs) and critical material attributes (CMAs) in real-time, thus enabling the system to maintain its quality by rejecting all out-of-specification (OOS) formulations and enabling the implementation of a feedback control strategy to ensure automation and control. Integrating a digital twin enhances predictive capabilities and system resilience, supporting proactive decision-making and agile process adaptation in a GMP environment.
Acknowledgement
This work is supported by the US federal government.