Continuous manufacturing has been common practice in many industries for decades, but it is just now entering the early phases of adoption in the pharmaceutical industry. With effective online analytical capabilities available, equipment suppliers have been able to develop systems for various aspects of the tableting process, and drug manufacturers are beginning to realize the many benefits of continuous processes. Although challenges remain, expectations are high for the eventual fuller use of integrated continuous processes for solid-dosage manufacturing.
Benefits of continuous processing
There are several benefits associated with effective continuous production systems. Increased safety and lower costs are on top of the list. “Continuous processes are more integrated with fewer steps, which leads to less manual handling and increased safety,” says Kris Schoeters, product manager continuous processing for GEA Pharma Systems. “In addition, the equipment and facilities are much smaller, allowing flexible operation at lower capital costs, with less work-in-progress materials.” Along with the monitoring and tracking, which are a fundamental aspect of continuous manufacturing, there also is better control of the process than is possible with batch processes, so both the consistency and quality of tablets are improved, according to Stephen Boswell, director of S3 Process, a provider of process equipment.
Additionally, the development time and costs for continuous processes are often less than those for conventional batch-manufacturing operations. “Inherent R&D advantages include quicker capabilities to test a variety of process conditions and the use of smaller quantities of expensive API,” notes Sharon Nowak, global business development manager for food and pharmaceuticals with K-Tron Pitman. Adds Ivo Backx, manager of business and project development for the pharmaceutical industry with Siemens: “The time is shrunk at the development stage and during the move from development to production, in part, because process analytical technology (PAT) tools are an integral part of the development process and also because there is no need for scale-up to different equipment. Commercial-scale quantities can be produced on the same continuous tableting equipment used during the development stage.”
Benefits continue to accrue after product launch as well. Capacity can be dynamically adjusted to meet market requirements by running a process for longer or shorter periods, according to Backx. Boswell adds that with smaller equipment and less capital investment, it is also possible to locate continuous tableting lines in a greater number of geographic locations so that transportation costs are lower and drugs can be formulated for the local market. “Such advantages are particularly critical for US and European manufacturers to remain competitive,” he notes.
Overall, companies that implement continuous manufacturing processes expect a fast return on investment and cost savings from 10-20% compared to batch operations, according to Backx. Furthermore, with the reduced waste generation, greater product recovery, lower energy consumption, and overall improved operation efficiency, continuous processes enable “greener” manufacturing.
Adoption in the pharmaceutical industry
Even with these benefits, pharmaceutical companies have been unwilling until recently to make a move toward continuous tableting. “There has been a hesitancy to make investments in continuous manufacturing. It is quite a big step for drug manufacturers to take,” says Boswell. Some of that hesitancy, according to Schoeters, has been related to the need to establish that each batch of product, ultimately released following sampling and testing of finished product, is homogeneous. “Traditionally, this characteristic is established by blending the batch immediately prior to compression, but in a continuous process, the batch is never assembled in one place. Previously, the available on-line monitoring tools were not efficient enough.”
Recent developments in the use of PAT for on-line and at-line monitoring to prove the quality of product and process continuously as well as the design and engineering of continuous process components in pharmaceutical execution, have helped pave the way for continuous processing consideration, according to Nowak.
The introduction of equipment for flexible, compact, quasi-gram-scale continuous manufacturing has also been critical, according to Schoeters. GEA focused on integrating the entire process cycle from weighing, blending, granulation, and drying up to tablet compression in its systems. “Also important is a steady-state controllable flow of ingredients into the granulator, even in the face of often-challenging powder flow properties, and to ensure plug flow so that tracing of ingredients for specific ‘batches’ can be established.” Adds Boswell: “A substantial derisking of R&D scale-up is possible with certain continuous technologies, such as that from Gerteis, where process parameters are the same between clinical-trial to large-scale manufacturing, [thereby], saving substantial scale-up cost and risk.”
K-Tron also has addressed the need for equipment that can process smaller quantities of material for both development and pilot-plant continuous processes and for poorly flowing APIs and excipients. It has systems designed to deliver as little as 20 grams per hour with high accuracy, according to Nowak, and its latest feeder, which will be introduced at Interphex in April, functions effectively with difficult cohesive powders.
FDA’s support of continuous processing is also causing many pharmaceutical companies to seriously pursue this option in development and manufacture. Still, Backx warns that companies need to have a clear understanding of their business goals when implementing continuous tableting or any other continuing manufacturing operation. “For some companies, continuous manufacturing might provide a new approach to improving a problematic process through increased process understanding and control while others may be looking to first implement continuous manufacturing for drug-development efforts rather than changing existing processes.”
Dealing with integration issues
Of course, there are challenges still to be faced before continuous tableting will be widely adopted in the pharmaceutical industry. Nowak points to two major issues that are currently being addressed: the integration of the complete continuous process and defining both the actual lot size being produced and the size and frequency of sampling measurements.
Schoeters agrees that full integration of all of the different PAT measurements is critical, as is intelligent feed-forward and feed-back loops and control systems to ensure the most efficient performance.
K-Tron, which has experience with these types of online feed-loop controls in equipment for the plastics and food industries, expects that they can easily be modified for utilization in a continuous blending or granulation process to assist in the overall quality of the product and process, according to Nowak. “The ability to monitor material feed properties and integrate this data into a sophisticated overall data management tool will not only provide for enhanced process understanding, but also enable end-users to specifically understand the process impacts of different lots of raw materials.”
There are also implications for facility design that must be considered. “The workflow within facilities must change with the adoption of complete continuous tableting processes,” says Boswell. “Those changes won’t happen overnight, but they will happen over time.”
Regulatory-related issues are causing some companies to remain cautious. The uncertainty regarding how regulators will formalize the approval of continuous manufacturing and real-time release strategies is a concern, notes Backx. He points out, though, that the uncertainty is largely due to the lack of experience rather than any actual regulatory impediments. Some are also worried about continued emphasis on the term “batch” in regulations. “This concern is unfounded, however; regulatory definitions for the term ‘batch’ already include those batches produced through continuous methods—the mode of manufacturing is not mentioned. Companies establish the ‘specific quantity’ of output that will count as one batch for tracking and tracing and potential recall purposes,” Backx explains.
Cooperation will ensure advances
As pharmaceutical companies begin to realize the significant potential for cost savings and quality improvements, many of these issues and concerns will be addressed. Companies, such as Siemens, GEA Pharma Systems, K-Tron, and S3 Process, are working closely with customers in the pharmaceutical industry, software platform manufacturers, and universities to gain greater process understanding and develop fully integrated continuous tableting systems that will ultimately include data-driven quality verification for in-line assurance and real-time product release.