“We believe the world would be a healthier place if tomorrow's medicines were made available today.” Much more than a declaration of intent, this is the mission of Patheon, a provider of contract development and commercial manufacturing services. The CDMO offers an industry-leading range of services that spans across all phases and scales.
Patheon’s portfolio includes specialized capabilities for highly potent and controlled substances, aseptic filling and lyophilization, complex formulations, solubility enhancement and difficult-to-manufacture APIs.
The company’s site in Bourgoin, France, with accomplishments that date back to the 1960s, is authorized by the FDA to safely handle API processes with a minimum OEB 4/OELs > 10 ng/m³ (Category 3b). Patheon Bourgoin is focused on solid oral dosage manufacturing, utilizing compatible processes to allow smooth process scale-up from clinical batches and small commercial batches (1-150 kg) to larger commercial process scales (150-750 kg). Contained processing is utilized to minimize the need for personal protective equipment (PPE) for routine operations.
In 2012, IMA Group and Patheon began a partnership to test the performance of IMA coaters, as Patheon planned on using the Perfima 500 (650 L drum) production coater at their Bourgoin facility to coat a highly potent API. The preliminary tests for Perfima, a perforated coating pan for tablet film and sugar coating, took place at the IMA Active Process Laboratory in Bologna, Italy.
Trials were conducted on both pilot and production coaters, the Perfima Lab (30 L drum) and Perfima 200 (250 L drum), to test and scale up process conditions using a potent core and a similar coating agent. After initial trials were completed in the lab, the commissioning and installation phase for the larger Perfima 500 coater was performed in Bourgoin, using base parameters identified by Patheon during development on a Perfima Lab (70 L drum).
Challenges in implementation
Though the IMA and Patheon teams considered the target an easy challenge due to the optimal performance achieved on the pre-validation batches in the 70 L drum, they hit unexpected obstacles when the process parameters were transferred to the larger Perfima 500.
The behavior of the tablets changed significantly in the different pan size of the Perfima 500. Due mainly to the tablet core geometry, many of the preliminary batches did not comply with AQL standards due to edge chipping and coating erosion defects. Tablets were subject to erosion in two main areas of contact with the coater.
The main challenge in troubleshooting came from the fact that almost all process parameters were already fixed except for pan speed, atomization pressure and gun distance (thermodynamic parameters could not be changed), and the process had been transferred in containment mode, meaning operator contact with product was not possible.
Eliminating edge chipping and erosion
To overcome the challenge, it was necessary to come in direct contact with the process. The teams decided to bypass the containment safety system to solve the issues, using placebo tablets with characteristics that matched the API tablets.
An IMA process technologist, customer specialists and Colorcon technical staff combined their expertise. They adjusted the loading and unloading procedure, and identified pan speed and gun distance as crucial parameters to optimize:
The pan speed was decreased from 12 rpm to 5 rpm to reduce the stress on the tablets’ surface.
To coat and protect the tablets’ surface quickly and avoid core erosion, the gun distance, originally 21 cm, was set to 20 cm at the beginning of the process and 23 cm at the end. The optimal orientation of the guns was found to be a 90° angle between the gun to the core bed. This strategy led to vastly improved coating quality in a spray time of less than 90 minutes.
These adjustments enabled the teams to eliminate the edge chipping and core erosion encountered during pre-validation batches efficiently, as only two tests were necessary to achieve the AQL standards (4 defects on 1,250 tablets).
Though the main process parameters were already fixed, the critical cooperation between IMA, Colorcon and Patheon made it possible to quickly achieve AQL standards with the highly potent product.