(424c) Showcasing the Rapid and Flexible Path to Clinical Manufacture: A Case Study on the Development of a Novel Oral Suspension Drug Product in an Oral Solid Dosage GMP Facility

The Formulation, Laboratory, and Experimentation (FLEx) Center is a new multi-modality (small molecule, biologics, vaccine) Drug Product development and Good Manufacturing Practice (GMP) clinical manufacturing plant at Merck & Co., Inc., in Rahway, NJ, USA. The Oral Solid Dosage (OSD) suite within the FLEx facility is capable of producing oral solid drug products and drug product intermediates to meet the demands of early-phase clinical trials. Process engineers and formulators, in addition to other partner groups, work together to meet continuously changing clinical timelines requiring the need to remain flexible throughout the lifecycle of a clinical campaign.

Recently, a new process train requiring the implementation of new technology to the FLEx Center was completed in the OSD suite, the manufacture of an oral liquid suspension drug product. Numerous pilot scale batches were performed prior to clinical manufacture in order to develop the process train and determine the range of setpoints for several process variables. The process train consists of dispersing the active pharmaceutical ingredient (API) in a suspending vehicle and mixing for a set period in a stainless-steel pot with an overhead stirrer. Upon completion of mixing, the suspension is then dispensed into smaller bottles. Subsequent analytical testing revealed that the homogeneity of the liquid suspension was within specification while mixed continuously to ensure no settling of the API. As a result, this required the suspension to be mixed continuously up until the transfer into smaller bottles.

Scale-up to meet the demands of the clinical campaign required significant collaboration with partner groups (e.g., formulation science, pharmaceutical engineering, FLEx area management) and careful consideration to develop a robust manufacturing process. As such, newly implemented technologies and processes were required to be tested and approved to meet this demand in a GMP facility. First, a 50-liter suspension tank with built-in agitator was utilized, scaling up from a two-liter pot and overhead mixer. Before adding the API to the suspension tank, a “pre-suspension” of API and suspending vehicle was made in a smaller stainless-steel pot in order to ensure the breakdown of API clumps by increasing the mixing energy per unit volume. Next, as an added safeguard to ensure homogeneity of the suspension, material was recycled through silicon tubing from the bottom outlet of the tank back to the top inlet of the tank via peristaltic pump running in continuous flow mode. In order to perform the bottle filling operation, a tee fitting was placed downstream of the tank outlet and fitted with two manual valves on either side, one feeding material to the recycle loop and the other feeding material for bottle filling. Bottle filling was completed by utilizing an analytical balance and peristaltic pump operating in volumetric fill mode. Upon calibration of the pump, a fixed volume of suspension was dispensed from the tank to a glass bottle. Because the weight of the suspension in the bottle was defined as the critical quality parameter, the fill weight was easily verified by placing the tared bottle on the analytical balance. Finally, each bottle cap was manually torqued using a bottle torquing device.

Beyond scale-up and new design changes, the introduction of a new process in a GMP facility required significant new documentation and training to be completed. In addition to a series of new standard operating procedures (SOPs) and batch records to be written and approved, each new piece of equipment (e.g., torque tester) and product contact part was required to calibrated prior to batch execution. Furthermore, significant training of personnel was required including hands-on-trainings and acknowledgement of SOPs.

Despite the success of the clinical batch, several process improvements could be made to further optimize resources. For example, a specific hold time of the suspension was not established requiring the mixing of suspension and API to be completed on the same day as the bottle filling operation. Therefore, the establishment of such hold time could potentially spread the manufacturing process over a few days thereby reducing the burden to complete the batch in one day. In addition, for future clinical batches requiring significantly more supplies, the introduction of an automated bottle filling line would be desired to avoid the manual filling of hundreds or thousands of bottles. Finally, further efficiencies could be made through the development of guidance documents to understand the procedure for developing subsequent new processes in the facility.