Imagine mixing the ingredients to make a batch of cookies. First, mix the dry ingredients: flour, baking soda and salt. Second, mix the wet ingredients: butter, sugar, vanilla and eggs. Finally, mix the two batches together and then scoop out individual portions to bake. After the timer rings, the cookies are pulled from the oven and begin to cool; they look perfect and delicious. But as soon as you take the first bite, that smile turns into a frown. It’s a “bad cookie” and it tastes like a salt lick. The entire batch is ruined. Just think, if one had the ability to make each cookie individually, then the “bad cookie” might have been detected earlier and the “baker” could have fixed the recipe, so the entire batch would not be ruined. Sound familiar? It should, because this is the approach that universities and the pharmaceutical industry are validating for tablet production. Instead of making gigantic batches of medication that require months to process and release, pharmaceutical manufacturers are taking their cues from the food and fine chemical industries, making tablets from a linear process continuum that supports real time release, reducing the production time by more than 90 percent. Known as “Continuous Manufacturing” the method is being recognized for its efficiency and cost and quality control attributes.
INDUSTRY/ACADEMIC PARTNERSHIP
At the forefront of the continuous manufacturing research and development is Rutgers University. Early on, Siemens formed a relationship with Rutgers to help the pharmaceutical industry move forward, to push the envelope and modernize pharmaceutical manufacturing and dosage forms for a more efficient future. The foundation of this relationship is built on Siemens membership in the Center for Structured Organic Particulate Systems (C-SOPS).
Rutgers is C-SOPS’ academic leader and is joined by other university participants including Purdue, New Jersey Institute of Technology, and the University of Puerto Rico. Additionally, more than 40 companies are involved in supplying technology, training, mentorship, and product testing. The mission for C-SOPS is to develop a structured design, engineering, scaling, optimizing, and control process to manufacture tablets and effectively educate companies on how to adopt and test these efforts.
The ascertainable impact of this effort is to provide a science based and neutral ground to deliver a proof of concept that will enable and promote the transition from batch processing to continuous manufacturing in the pharmaceutical industry. This test ground is designed to help pharmaceutical companies show proof of concept for continuous manufacturing to the FDA, in order to aid them in acquiring FDA regulation approvals. In February 2013, Rutgers opened a full-scale continuous manufacturing production line on its campus. The research facility allows pharmaceutical producers to conduct performance and feasibility testing for the multiple production paths in continuous manufacturing. At the time of this article, the production line had been running only nine months; nevertheless, a great deal of research and development progress has already been made thanks to advanced process control and automating processes that improve efficiencies.
SIEMENS TECHNOLOGY CONTRIBUTION
Siemens donated its SIPAT data management system, a platform that manages enormous amounts of data, and PCS 7, a distributed control system (DCS) that controls the production line with integrated libraries, preconfigured standard blocks and faceplates. In addition to control, the DCS provides transparency to the process and enables optimization of the manufacturing line’s performance to Rutgers University. Additionally, Siemens provided on-site training to get the research team up to speed on how to use the technologies and the research team has access to a full-service support line for ongoing questions. The Associate Director for Industry Relations for C-SOPS at Rutgers, Doug Hausner, shared with Siemens that the benefit of using both of these technologies concurrently is that they “work seamlessly together.”
During the continuous manufacturing process, a large amount of data is collected, adding up to 4,000 data points every 1.5 seconds. SIPAT not only gathers this data accurately, it normalizes the data into a common timeline so technicians can make sense of the bombardment of information in order to execute decisions in real time. For example, when testing powder blends, which are eventually molded into tablets, the data management technology understands precisely when a blend is fully mixed, to ensure the medication is made to spec. If an error does occur in the mixing process, the SIPAT technology alerts the technician and the technology will automatically discard the ruined tablets, without wasting an entire batch. Additionally, if a variable needs to be adjusted to maintain product quality, such as changing the percentage of ingredients to the mix, advanced feedback control is utilized.
Compare it to the task of baking a cake. SIPAT technology ensures that all the sugar doesn’t end up in just one piece of the cake and that it’s distributed evenly throughout the entire cake. If for some reason a couple of slices were produced without any sugar, the system would place them in the waste basket automatically, in real time.
Ph.D. student, Abhishek Sahay, who interfaces directly with the SIPAT technology, pointed out a number of advantages that the Siemens technology provides him and his team in their continuous manufacturing research. First off, SIPAT enables them flexibility to make agile changes at different stages of the manufacturing process, enabling them to get the system up and running quicker because of the ability to adjust parameters along the line faster. Additionally, without SIPAT, technicians would have to interface with multiple separately operated interfaces which take time and specific training. SIPAT eliminates the time it takes to manage individual interfaces because the technician only has to use one, and that’s SIPAT.
Abhishek pointed out that “control is a critical element” and the PCS 7 provides transparency into the operation in order to supervise product quality and monitor performance indicators in order to efficiently optimize the production line with increased production flexibility.
SIPAT and PCS 7 also aid in proving regulatory compliance. The data that the technologies collect support proof of concept for continuous manufacturing in the pharmaceutical industry, which is required for getting FDA regulation approvals.
Siemens is helping to move the pharmaceutical manufacturing industry forward to improve efficiency and quality-control efforts via continuous manufacturing, by donating its leading-edge SIPAT and PCS 7 technologies to Rutgers University, training the staff to use the technologies, and providing support throughout the use of the products. The technologies deliver an easy-to-use interface that save a tremendous amount of time and provide transparency into the manufacturing optimization process.
MAJOR RESEARCH FINDINGSRutgers is already identifying major performance improvement metrics in its continuous manufacturing test environment. See Table 1 to compare key performance improvements between continuous manufacturing and batch processing. The operation improvements are impressive.In regards to testing the product, three fewer analysts are needed in continuous manufacturing. Additionally, less space is required in continuous manufacturing. The production line is built from the floor up; it’s a vertical construction that is about as big as a tractor trailer bed. In comparison, batch processing requires 6 rooms for processing. With a reduction in required space comes a reduction in financial investment. Upfront capital investment reduces dramatically from $24 million to $12 million, major savings right off the bat. One of the most impressive savings relates to the reduction in manufacturing cycle time. Instead of waiting 10-13 days to cycle through batch processing, it takes less than 1 day to go through the same process in continuous manufacturing. Furthermore, in conjunction with less cycle time, there is a much shorter release time to turn out pharmaceutical tablets, getting them to market quicker. Instead of 30 plus days, the release time is only five days, less than a week. At the same time, with continuous manufacturing, there is no longer a need to scale production in accordance to forecasted demand because companies will be able to produce what is demanded and deliver it to market in a shorter amount of time. All of these findings are contributing to demonstrating the impact of continuous manufacturing in the pharmaceutical industry from a science-based approach. These insights will enable and promote the transition to continuous manufacturing on a neutral ground for development and regulatory consensus.
RESEARCH TODAY AND IN THE FUTURE
As of August 2013, there were six fillings for continuous manufacturing with the FDA. Hausner is anticipating a quicker adoption rate for continuous manufacturing in the pharmaceutical industry in the future as more compelling proofs of concepts arise out of the C-SOPS research across the involved universities. Additionally, the FDA is actively promoting continuous manufacturing and supports the research effort.
Interest in continuous manufacturing is prevalent in numerous areas around the pharmaceutical industry. Major pharmaceutical companies are involved in testing concepts in continuous manufacturing, including Johnson and Johnson, Pfizer, GlaxoSmithKline, Novartis, Merck, Bristol-Myers Squibb, and Eli Lilly. Furthermore, a generic pharmaceutical company is also involved in testing continuous manufacturing, TevaPharmaceutical Industries. The interest in continuous manufacturing expands globally as China is investigating implementation plans as well. Equipment companies are innovating to stay in the game and are improving product designs to work in conjunction with continuous manufacturing processes and technologies.
The growing interest in continuous manufacturing for the pharmaceutical industry is also creating niche opportunities for students at the university level. The research is a launch pad for nation-wide curriculum in Pharmaceutical Engineering and Science because it is drawing attention to the pharmaceutical engineering field and is providing relevant experience for chemical engineers, to better aid them in securing a job after they graduate. The research also opens doors for classes specific to pharmaceutical engineering, so students are not limited to general chemical engineering courses and can gain knowledge specific to their field of interest. This growing advancement will positively impact the pharmaceutical industry going forward as higher skilled and experienced students enter the workforce.
Siemens is invested in helping to modernize the pharmaceutical industry, which will result in major economic and quality-control benefits for companies and ultimately end-users. We are aiding in the effort by donating leading-edge technologies (SIPAT and PCS 7) that facilitate a faster, flexible, and controlled research process, providing training and continuous support on how to use the technologies, and donating funds through our C-SOPS membership, an investment for a better future.
