(603b) How Small Can We Go? Miniaturizing a Continuous Direct Compression (CDC) Line for Early Development of Oral Solid Dosages

Continuous manufacturing (CM) technologies are increasingly being used in the pharmaceutical industry to develop and commercialize oral solid dosage products. Although there are many advantages to continuous processing, several disadvantages exist at small scale. Compared to batch small scale development, CM requires relatively large amounts of material to reach and maintain steady state (i.e., hold up), leading to yield losses often unacceptable during early development. These challenges make it difficult to assess CM capability in early development, later making its implementation more difficult as batch development formulation and process decisions are more entrenched in the product development lifecycle. Development of small-scale CM technologies can realize the technology’s many development benefits and improve chances of implementing CM for products from early clinical through commercial manufacture.

Continuous direct compression (CDC) is one of the critical CM technologies in the oral solid dosage field. The process train is composed of 3 major unit operations: feeding, continuous blending, and compression. Multiple small-scale equipment exists for feeding and compression, however, options around small scale continuous blending equipment are limited. The team at Merck designed and printed a unique modular design to further extend the options for continuous blending. In this work, a small-scale CDC line was constructed using the Merck-designed 3D printed modular continuous mini-blender, a set of a K-Tron MT-12 and KT-20 loss in weight feeders, and a four-station Riva Piccola Touch tablet press. Three independent studies were conducted on the equipment: (1) an evaluation on low throughput processability, (2) an evaluation the residence time distribution of the CDC line, (3) a manufacturing evaluation of different formulations using co-processed excipients and challenging formulations. The use of co-processed excipients was evaluated to minimize the number feeders required in the CM line, which further enables the small scale of the equipment.

The miniature CDC line was evaluated at throughputs ranging between 1 to 3 kg/hr. Minimal material losses (~50-150g) were observed, leading to process yields over 80%. More than 10,000 tablets were manufactured using multiple test formulations. Evaluated formulations showed good processability through the mini-CM line at all processing ranges. Co-processed materials were shown to provide similar processability and product characteristics to physical mixtures of those excipients using 2 different active ingredients. The 3D printed modular blender was capable of handling and maximizing yields across the range of studied formulation compositions. RTDs were estimated using both impulse and cumulative disturbances. The RTDs were measured both by changes in concentration as well as changes in the tablet press parameters (e.g., ejection force). Overall, the small-scale CM capabilities demonstrated in this evaluation may enable future pipeline programs to assess CDC processing at an earlier stage and utilize material sparing techniques. Earlier implementation of CM technologies may streamline scale up and development process to reduce cost associated with technical transfer batches to clinical and commercial supply.