Rottendorf Pharma is 100% dedicated to the manufacturing, packaging and formulation development of solid dosage forms. Thanks to performing a lot of pioneering work and to constantly solving complex and difficult tasks with our clients, Rottendorf has become a partner at eye level for our customers.
Clients profit from Rottendorf’s Total Technological Mastering (TTM) approach which eliminates the customer’s needs to provide expertise on product technology and technical operations. Rottendorf’s team consists of extremely well-trained employees who accompany the product, for instance, from the up-scaling stage to the creation and definition of the production process, and right up to the machine level. Thus we have the expertise from development right up to production.
Total Technological Mastering means for Rottendorf:
to fully understand the galenical design of the product and it's critical parameters during transfer
We eliminate the customer's need to provide expertise on product technology and technical operations
Recently, we were approached by a mid-size pharmaceutical company who had an active pharmaceutical ingredient (API) they wanted to begin testing in clinical trials.
The challenge was looking for a contract provider equipped to scale their formula for 5 kg development batches into 80 kg trial batches. For this pharma client, the deciding factor in selecting Rottendorf was our ability to adapt from lab-scale equipment to larger batch sizes and optimize the process for clinical trial batches with the ultimate goal of commercial distribution. We always optimize for the end-goal of commercial production. For the client, our ability to support their present needs as well as their future needs and following product approval, was critically important.
From Technical to Clinical Batches in a Compressed Time-frame
We immediately got to work on a technical trial batch and then adapted the manufacturing process to our equipment and larger batch sizes. To work efficiently under the constraint of a limited time-frame, we saved time by manufacturing both the technical batch and GMP clinical batches on the same equipment.
formula for 5 kg development batches into 80 kg trial batches
To accomplish the scale-up from 5 kg to 80 kg, we narrowed our focus to those aspects of the process where potential scale-up issues were identified. Specifically, the development team at Rottendorf determined ways to address issues that arose during the process:
In hot melt extrusion a new material, the extrudate, is formed when forced through an orifice or die under controlled conditions like temperature, mixing, feed-rate and pressure. Unlike simple extrusion, in hot melt extrusion polymer, drug and excipient blends are completely mixed in the molten state with the molten polymer acting as the thermal binder. When dealing with hot melt extrusion, the temperature must be higher than the melting point, and the drug or polymer must be kept stable throughout the thermal process.
In this case, the client's polymer API mixture was melting in the feeding zone and blocking it. This blockage was forcing production to stop every 30 minutes to clear the feeding zone.
We resolved the blockage issue by lowering the temperature in the feed zone. We also installed more vents to allow water in the API mixture to evaporate. From that point forward the extrusion went smoothly without any additional issues leading to an increased extrusion rate.
The goal was to produce a uniform mixture. The client had specified that the extrudate should be milled in a single pass to improve the uniformity. Typically, the more uniform the mixture, the higher the quality, and the higher the bioavailability and solubility in humans.
We found that when the extrudate was milled one time per the client’s specifications, it resulted in inconsistent particle size and distribution. Milling had to be repeated to obtain a homogeneous blend, which wasted valuable time in our tight time-frame.
We solved this problem by reducing the feed rate for the milling. This simple adjustment allowed us to produce a powder with the properties the client sought in a single milling step.
Finally, the last hurdle we overcame appeared during the compression phase. Common challenges with compression include poor powder properties, difficulty compressing the powder into a stable tablet, poor flow in the hopper, lack of lubrication, and cracking and sticking. For this trial batch, cracks on the tablets appeared after they were compressed.
Resolving this problem required two critical adjustments. First, we increased the dwell time during compression by slowing the compression speed. Second, we increased the pre-compression force to better remove dissolved gases from the tablets by reducing the main compression force. The result = no more cracked tablets.
We completed the initial process development in roughly four weeks. We followed the initial process development with GMP manufacturing of the trial batches. Production of trial batches were completed in less than six weeks.
This project with it's rapid turnarounds, sizable scale-up, and challenging production issues brought together expertise in a number of fields from technology transfer, regulatory and chemistry, to process design and engineering. We helped our client quickly manufacture trial batches in the necessary quantities, while taking future bulk production needs into account to ensure a smooth path towards commercialization.