Now gaining momentum in the pharmaceutical industry, CM presents a new approach to oral solid dosage (OSD) form production and meets the industry’s demands for faster product development, reduced costs and increased manufacturing flexibility.
Providing higher yields, lower utility consumption and reduced waste, CM is enabling drug makers to move away from stepwise and time-consuming batch processing to a fully integrated and closely controlled process that gives excellent product consistency by intrinsic design.
The use of CM technologies and inline PAT monitoring is a key driver of building quality by design (QbD) into the complete product lifecycle, from R&D through to manufacturing, with the ultimate aim of getting safer medicines to market in a more efficient and cost-effective way. Using model-based supervisory advanced process control (APC) to capture unique equipment, material and PAT characteristics creates a system that increases precision and optimises the yield, capacity and OEE of CM equipment.
Environmentally friendly with a much smaller footprint, CM is helping the pharmaceutical industry to produce higher quality products, enhance drug safety and reduce its industrial footprint, which provides significant advantages to governments, companies and patients alike.
For decades, the batch production of blockbuster solid dosage forms dominated the industry. Profitability was such that companies were not incentivised to innovate or risk developing new manufacturing technology. In the post-blockbuster era, however, it is increasingly recognised that material costs during drug development are significant, new drug products are likely to be manufactured in much smaller quantities and that, for novel treatments, the development of a bespoke commercial manufacturing process is not guaranteed.
Such pressures have put the costs, risks and timelines associated with traditional batch-based development and manufacturing under scrutiny. Plus, regulators are increasingly supportive of CM and manufacturers are realising that current quality assurance costs are disproportionately large compared with other industries, wherein the production, detection and removal of out-of-specification product is vanishingly small.
Shifting the paradigm
Yet, despite agency support and the mounting body of evidence in favour of CM, doubts remain. Questions are frequently asked about CM’s ability to handle anything but large volumes of low-cost drugs, the finances involved in purchasing and installing appropriate equipment, whether regulators can keep up with the technical developments in continuous processing and, perhaps most poignantly, whether the conservative pharmaceutical manufacturing industry will grasp the nettle and appreciate the full benefits of “going conti.”
GEA believes that the “large-volume, low-cost” argument is somewhat dated. “What we’re seeing now is the exact opposite,” observes Richard Steiner, Business Development Manager, ConsiGma. “If you look at market approvals and new launches, for example, it’s quite clear that some of the larger ethical drug manufacturers are now the front runners: they’re testing and challenging the CM business case with their legacy products and subsequently using these CM platforms to develop pipeline products and file for new drug applications (NDAs).”
Regarding costs, the initial investment in any CM solution is going to be a financial challenge; but, as with the implementation of any disruptive technology, the early stages are time-, effort- and cost-intensive, including the associated organisational changes.
“When, and only when we establish economies of scale will the financial burden decline as CM equipment becomes a commodity … as opposed to a tailor-made and engineered-for-purpose solution,” adds Richard.
And, in terms of regulation, Lawrence Yu, FDA’s Deputy Director for the Office of Pharmaceutical Quality, noted: “If drug makers paid more attention to high quality manufacturing, it would prevent the regulatory problems that lead to plant closures and costly fixes. Continuous processing also allows manufacturers to respond much quicker to changes in demand, potentially contributing to the prevention of drug shortages.”
A key element of the US Food and Drug Administration’s Pharmaceutical Quality for the 21st Century: A Risk-Based Approach initiative, the agency understands that, although it’s not easy for drug manufacturers to transition from batch to continuous manufacturing, there are significant rewards.
Real-world proof
Additionally, as the continuous processing of pharmaceuticals has moved out of the laboratory and into production environments, questions regarding the capability of the equipment to reliably and compliantly produce high quality product for long periods of time have been raised.
Wishing to investigate, GEA, in collaboration with MSD, a tradename of Merck & Co., Inc. (Kenilworth, NJ, USA), recently conducted a successful robustness run on GEA’s ConsiGma CDC 50 Continuous Direct Compression system for a period of 120 hours. The trial run was monitored using a suite of tools, including the high-frequency measurement of more than 100 process and environmental parameters, such as spectroscopic analysis of the powder blend and physical testing of finished product; soft sensors were used to predict critical quality attributes (CQAs).
By the end of the 120-hour trial, more than 15 million tablets had been made using approximately 6200 kg of raw material in a single production area. Importantly, final analysis indicated that the campaign length could be increased even further and run for longer. Benchmarking against a typical batch process, producing the same quantity of tablets would have required 10 separate campaigns and taken a team of operators working in parallel in three production areas for 5–7 days.
Summary statistics revealed that greater than 99.5% of the production run met or exceeded CQA specifications and less than 0.5% of the tablets were out-of-specification, providing a solid body of proof that the technology is eminently suitable for the efficient completion of campaigns that formerly involved longer and more complex batch processes.
The reality of pharmaceutical CM
Richard appreciates that operational expenditure cost savings are not actually key focus points when it comes to CM benefits.
“There’s much more interest within the pharmaceutical sector in faster product development, expedited market launch and greater supply chain agility. What’s currently underestimated is the positive effect of CM on quality — in terms of both time and cost. It’s all about the OEE, which influences the ROI. It’s important at this stage to highlight certain country specific differences; the arguments in favour of CM in high-cost geographies may not be valid in pharmerging economies. Nonetheless, we are seeing a great deal of interest in every major pharma market, worldwide,” he says.
But, by continuing to publicise their success stories and launching more and more NDAs based on CM process technologies, he believes that “conti pioneers” can convince the industry that this is the future of drug production, as well as filing those products throughout global markets and supply chains, by building partnerships and developing standardised manufacturing platforms that deliver faster engagement and shorter project execution times.
To expedite this process and examine the fact and fiction of continuous manufacturing in the pharmaceutical industry, GEA, Siemens and Perceptive Engineering will jointly host an inaugural three-day conference comprising two days of presentations from early adopters, one of which will take place at the National Formulation Centre in Sedgefield, UK, courtesy of the Centre for Process Innovation (CPI), and a chance to visit the MSD Cramlington plant.
Taking place on 26–28 March 2019 in Durham, UK, and with an expected attendance of 80–120 delegates, the event will focus on the real-life experiences of existing CM technology users in the development and manufacture of oral solid dosage forms. Topics on the agenda will include the current status of “going conti” as well as future plans and expectations.
With 14 years of inspiration, GEA has firmly established its longevity in the continuous manufacturing market. And having completed more than 70 projects involving a variety of filed and authorised products, including the first ever FDA-approved breakthrough therapy developed and manufactured using the ConsiGma platform, no other company has as much experience and done more to pioneer continuous manufacturing for the pharmaceutical industry. “How do we do this?” concludes Richard: “By making science work.”
