The lack of a commercial laboratory, pilot and small manufacturing scale dead end continuous filtration and drying unit it is a significant gap in the development of continuous pharmaceutical manufacturing processes for new active pharmaceutical ingredients (APIs). To move small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd. The performance of the prototype was evaluated by comparison with manual best practice exemplified using a modified Biotage VacMaster unit to gather data and process understanding for API filtration and washing. The ultimate objective was to link the chemical and physical attributes of an API slurry with equipment and processing parameters to improve API isolation processes. Filtration performance was characterized by assessing filtrate flow rate by application of Darcy's law, the impact on product crystal size distribution and product purity were investigated using classical analytical methods. The overall performance of the 2 units was similar, showing that the prototype CFD20 can match best manual lab practice for filtration and washing while allowing continuous processing and real-time data logging. This result is encouraging and the data gathered provides further insight to inform the development of CFD20.

A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage requires a series of extra investigations to evaluate the effect of different equipment geometry or even the adaptation of the parameters selected to a different isolation mechanism (e.g., from dead end to cross flow filtration) with a consequent increase of R&D cost and time along with an increase in material consumption. The CFD25 is an isolation device used in the first instance to develop an isolation strategy in batch (optimization mode) using a screening DoE approach and to then verify the transferability of the strategy to a semicontinuous process (production mode). A d-optimal screening DoE was used to determine the effect of varying the input slurry. Properties such as solid loading, particle size distribution, and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. A series of crystallization (ethanol, isopropanol, and 3-methylbutan-1-ol) and wash solvents (n-heptane, isopropyl acetate and n-dodcane) were used for the process. To mimic a real isolation process, paracetamol-related impurities, acetanilide and metacetamol, were dissolved in the mother liquor. The selected batch isolation strategy was used for the semicontinuous isolation run. Throughput and filtration parameters, such as cake resistance and flow rate, cake residual liquid content and composition, cake purity, particle−particle aggregation, and extent and strength of agglomerates, were measured to evaluate the consistency of the isolated product produced during a continuous experiment and compared with the isolated product properties obtained during the batch process development. Overall, the CFD25 is a versatile tool which allows both new chemical entity process development in batch and the production of the active pharmaceutical ingredient in semicontinuous mode using the same process parameters without changing equipment. The isolated product properties gained during the semicontinuous run are overall comparable between samples. The residual solvent content and composition differs between some samples due to filter plate blockage. In general, the mean properties obtained during semicontinuous running are comparable with the product properties simulated using the DoE.

One of the key challenges that the pharmaceutical industry is trying to address is to maintain particle properties across the entire purification and isolation process. This research focuses on the effect of slurry properties, wash solvent, filtration and washing mechanisms on API agglomeration/granulation during the processes of downstream isolation and the impact on the physical properties of the product. In this investigation, each isolation step was analysed to identify factors that have the potential to affect the final product qualities using a multivariate statistical design of experiments approach.The factors which were most detrimental in increasing particle agglomeration, were found to be the particle size of the input material, the quantity and identity of wash solvent and the drying mode. Low boiling point aliphatic