Author: John O'Reilly, managing director, BioPharma Engineering Ltd  BioPharma Engineering delivered its first continuous wet granulation processing suite for Pfizer in 2008. The suite was designed to produce up to 400kg of product per hour and operate continuously for up to 28 days between campaigns. It was used to continuously formulate up to four excipients and one active pharmaceutical ingredient through milling, blending, continuous wet granulation, continuous fluid bed drying feeding into 3000-litre intermediate bulk containers for downstream tableting and coating. Biopharma is currently working on the basis-of-design phase for a new continuous processing facility, which will leverage our previous experience in the delivery of continuous wet granulation with the  delivery of two large-scale wet granulation trains at 400kg/hr and 1000kg/hr, along with a continuous dry granulation process using roller compaction, which will operate at up to 300kg/hr. The customised equipment trains detailed above will also be complemented with a number of off-the-shelf fully continuous granulation, tableting and coating units operating at 100kg/hr, 150kg/hr and 200kg/hr ranges. [caption id="attachment_12875" align="alignright" width="4000"] Wet train[/caption] At BioPharma Engineering, we have extensive practical experience in design, delivery and qualification of continuous manufacturing for oral solid dosage production.  With the right design, continuous manufacturing will let an organisation stay ahead of the curve, reduce costs and increase throughput. We have set out a number of challenges and benefits in moving from batch to  continuous processing which we discuss here in further detail: 1. Equipment selection Equipment selection is critical to the successful introduction of a continuous granulation process. The selection of the equipment is decided by several factors. These include: campaign duration, product throughput, product formulation, solubility and cleaning frequency. The availability of raw materials and the delivery of the materials to the continuous suite is another factor to be taken into account in deciding an approach to continuous manufacturing. The utilisation of 'big bag' automated dispensing can dramatically reduce the amount of manual handling associated with traditional batch dispensing. It can also lead to reduced manual handling and labour costs. Availability of raw material in flexible intermediate bulk containers be a challenge in the current supply chain particularly from active pharmaceutical ingredient suppliers and is an area to be considered early in the move to a continuous train. In addition, a fit with product development/research and development equipment selection may be an important driver for manufacturing equipment selection. This needs to be considered in the longer term for new product introductions. It is crucial in the long term to keep a link between product development and a company's manufacturing system if it is to attract new products to its site. 2. Decreased production time & costs Removal of the manual interventions associated with batch production will lead to improved product quality, due to the removal of batch-to-batch variation. It will also allow for reduced costs due to increased batch size, less head count to staff the equipment and reduced costs of raw material due to savings incurred in packaging. A reduction in plant service costs - i.e. steam, compressed air, electrical services and cleaning materials - in relation to running one processing train versus multiple batch-processing trains can also add considerable cost savings to an existing facility. Improved efficiencies in compression will result, due to increased batch size - intermediate bulk container capacity can be increased as the granulate is continuously blended and also variability is reduced in the granulate, thus making the follow-on step/start up easier. 3. Facility & capital costs Capital costs to construct new solid dosage facilities that incorporate continuous manufacturing systems will be significantly reduced, allowing for more effluent of pharmaceutical revenue to be dedicated to shareholder value. With smaller and more energy-efficient buildings requiring less footprint, new facilities will be the less challenging parts of an overall capital expenditure programme. New facilities will undoubtedly be leaner and greener when using continuous processing as its manufacturing system. Current estimates of between 20-35% savings on facility build-costs are achievable where a reduced facility footprint is driven by use of relatively small continuous equipment instead of the batch equivalents. In continuous processing, multiple unit operations are directly coupled together. This means that the process has inherent containment attributes, thereby reducing manual material movements and work-in-progress storage requirements. 4. Benefits of continuous processing The decision to adopt continuous processing should ideally be based on process understanding and business requirement. Continuous wet and dry granulation processing may not be a suitable technology when a process relies on back mixing as a control mechanism, or is an inherently slow process. Several studies have demonstrated the benefits for this type of processing as follows:

• Unattended and lightly attended operations;
• Increased process efficiency with regard to output and yield;
• Reduced manufacturing cost due to low manpower and energy requirements;
• Reduced cycle time due to the inherent inefficiencies of batch processing;
• Reduced space and capital requirements due to the generally small size of continuous process equipment;
• Extension of working hours from eight-hour day to a 24/7 operation;
• Better quality attributes due to improved potential for process control.