Continuous production processes are shaping the future of pharmaceutical solid dosage production. The advantages of this kind of processing are obvious, both from the economic and the product quality point of view, which overlap in some parts. By applying continuous manufacturing, a distinct reduction in machine footprint is possible. The required machines can be designed smaller, as they can produce the equal volume of materials as large batch processes solely by increasing the production time. Furthermore, unit operations can be combined in a single step. This leads to smaller designated areas that have to be installed under GMP (good manufacturing practice) conditions, which is a great potential to save expenses. Storage and transport of intermediates from different production sites, likely in different countries, do not occur, as the different unit operations are connected to each other. The amount of material produced only depends on the throughput and the production time of the machines and is thereby variable. This means that to scale up from smaller to bigger machines is not an issue and the production of material can easily be adapted to market demands. Additionally, this implicates the possibility of shorter times-to-market, as the market production of a product can be conducted on a pilot scale line.
Regarding quality, the need to completely monitor a process, has the most significant implications. Applying PAT alongside the process, the quality of the product is consistently monitored and deviations from preset ranges of the CQAs can be detected and eliminated by interventions of the control system. Thereby, the disposal of complete failure batches is omitted and fewer materials, which are out of specification (OOS), have to be rejected and the variability of a product decreases. The so-called real-time analysis of process and product furthermore implies the chance to establish a real-time release of medicinal products with the advantage of a possible 100 % and non-destructive control of all produced product. L.B. Bohle developed the production unit as a modular solution, to achieve the highest flexibility and efficiency for the customers.
L.B. Bohle offers the continuous processing line as a modular solution. As a result, we provide a worldwide unique system to produce coated tablets out of raw powders within a single production stream. With our strong partners Korsch (tablet presses) and Gericke (continuous feeding and blending) a fully integrated solution is presented. In contrast to existing systems, the modular system allows the flexible arrangement of different unit operations, opening the path for a specialized solution depending on the requirements of the customer. Several routes of manufacturing tablets from powders are feasible in our setup. Continuous direct compression for suitable powder mixtures or continuous wet granulation to improve the bulk properties of the powder before tableting can be conducted. Unique in our line is the inclusion of roll-compaction / dry granulation in a continuously working process, which is much more economic and less energy intensive in contrast to a wet granulation process.
Beside the fact that the continuous production unit saves production space it is a further main advantage that the unit can be quickly dis- and reassembled to produce different products on one line.
Further advantages are the reduction of time and budget for time consuming quality control of intermediate products, which also shortens the interim storage time.
The prior mentioned reduction in footprint saves plenty of energy due to the necessity to maintain smaller designated GMP-areas. Thereby, and by the reduced storage and transportation issues, the CO2-emission will decrease significantely and the location of all processing equipment in one room is feasible, with associated savings of up to 66% in heating, ventilation and air conditioning. This estimate agrees with figures published by Janssen for the continuous manufacturing of Prezista, where a reduction in the number of production clean rooms from seven to two was realised.
Due to the smaller sized equipment in use and little hold-up volumina of the continuously running processes, the necessary amount of cleaning agents decreases significantely, resulting in less waste water, compared to batch processes of equivalent size. Also material savings due to faster process development phases help to save energy and to reduce waste material.
Significant reduction of storage costs
Compared to a traditional batch manufacturing process, in a continuously running process, all unit operations are connected to each other and a seamless transition of intermediate products to subsequent unit operations is ensured. Merely the total flow rate of the system (kg/h) determines the tempo of this passage. Consequently, no storage of intermediate products, such as dry granules before tableting or tablet cores before coating is necessary ans storage containers or huge and clima-controlled storage rooms become needless. Moreover, this storage is not any longer required, as quality control of intermediates is omitted for the benefit of in-line controls by PAT, which facilitate real-time statements regarding the quality of the measured material.
Less production times
A consequence of the flow characteristic of continuous processes and the connection of several uinit operations to one huge process stream is the possibility to increase the lead time of material to be produced. An example is given by the company Janssen, which has been approved by the FDA in April 2016 to produce their product Prezista continuously via direct compression and continuous coating (the KOCO of L.B. Bohle is part of the Inspire-Line, which produces this product). These tablets, containing the anti HIV-drug darunavir, are now produced in only one day, compared to the prior applied batch process, which needed two weeks to produce the same amount of material.
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