(560c) Developing an Agile System for Continuous GMP Manufacturing of Liquid (Injectable and Inhalable) Products

The COVID-19 pandemic exposed the lack of manufacturing capacity of pharmaceutical products and supply chain vulnerability in the United States. Many common products, especially injectable drug products, that were needed to treat patients in respirators, were and continue to be in shortage. In addition to this, there is also a great need for flexible manufacturing that allows for rapid product switches with minimum downtime to ensure a steady supply of essential medications and mitigate over-reliance on concentrated sources for manufacturing. Versatile and continuous manufacturing (CM) systems that can produce multiple dosage forms in the same platform, with real time quality control (RTQC), are promising solutions to address these flexibility and drug shortage issues. Advanced manufacturing technologies (AMTs) improve the consistency and quality of products due to the presence of better manufacturing controls and minimum human intervention. These technologies also have the potential of increasing the flexibility of the production processes, thus helping improve the supply chain resilience and the ability to respond faster to public health emergencies. In terms of marketing, injectables are the second fastest growing segment in drug delivery technology and, while the number of inhalable drug delivery systems in the market is relatively low at present, the inhalable market has been predicted to reach 41.5 billion dollars by 2026. As a delivery system, inhalable drugs offer numerous advantages, such as rapid onset of action, high bioavailability, and non-invasiveness. This has led to an increased interest in the development of advanced manufacturing processes, especially for injectable and inhalable drug products. These products also have unique manufacturing challenges and quality control requirements, making them ideal candidates for the demonstration of the development of new advanced manufacturing technologies.

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.