(624a) “Continuous Manufacturing Development of an Ultra-Low Drug Load Fixed Dose Combination Product – Challenges and Successes”

Continuous manufacturing (CM) is an advanced manufacturing technology increasingly used in the pharmaceutical industry to develop and commercialize solid oral dosage (OSD) products. CM technologies offer benefits around development, operations, supply chain, and process intensification in pharmaceutical manufacturing. Some of the major benefits around process development include lower time and material requirements during process development, scale up, validation, and qualification. Operational and supply chain benefits include improved capacity utilization, facile implementation of process analytical tools, reduced footprint, flexible batch sizes, and improved inventory control. These benefits have pushed multiple innovators, generics, and contract manufacturing organizations to adopt CM technologies and develop internal capabilities. However, challenges remain around CM technologies, particularly around their implementation at early stages of development, broad industry adoption, and the reliability of supply chains built around the technology. Early product development strategies often involve use of batch processes and/or parallel product development workstreams using both batch and CM processes. These strategies can lead to major challenges for both product and process definition using CM processes once products reach later stages of the development lifecycle, given that optimal formulation composition may be different for batch and CM processes.

Herein we discuss the successes and challenges of the CM development efforts for a fixed-dosed combination (FDC) product at Merck. The FDC was composed of 2 active ingredients with an ultra-low (<1% wt/wt) and high (>60% wt/wt) drug load. The FDC was developed with both batch and CM parallel workstreams as a pilot program to evaluate the benefits and challenges around the the implementation of CM processes and benchmark with more conventional technologies. Throughout the development effort, both process and operational benefits around product manufacturing were realized using CM technologies. Intensified process development was realized through the implementation of consolidated manufacturing campaigns that showed good process performance at commercially relevant scales using a fraction of material required for a parallel batch workstream. However, this product was ultimately developed using batch technologies because of technical, regulatory, and business elements surrounding the product strategy. The major hurdles for the CM processing workstream related to: (1) processability of the ultra-low drug load component, (2) translation of batch-developed formulation, process, and product definition elements to CM, (3) limited available infrastructure for commercial manufacture at the time of development, and (4) strategic risks from potential formulation and process changes at late-clinical stage. These challenges along with the with uncharted regulatory framework of the technology led the program to not consider moving forward with CM. In this presentation, we discuss in further detail these challenges and the strategies developed to mitigate these challenges for subsequent products in development.