The Facility of the Future has to be more agile, flexible and efficient than it is today. How to get there? By innovating — introducing new processing concepts, analytics and control — and pulling it together with attention to flow and ergonomics.
With some 60 percent of pharmaceutical therapeutics on the market delivered in oral solid dose (OSD) form, the category remains a pharmaceutical stalwart and its historical dominance is likely to continue for decades.1 The pace of solid dose pharmaceutical development and market growth is robust. Since 2013, roughly half of all new molecular entities approved each year by the FDA have been solid dose forms, and drug innovators are investing R&D dollars toward more effective, patient friendly and therapeutically effective adherence-promoting solid forms.2 There are few sectors in pharma that do not have some stake in OSD innovation and development. From the world’s branded, generic and OTC producers to the supply chain’s contract service and equipment providers, few are expecting anything less than continued growth and investment in this category. It is clear that oral delivery of solid dosage forms will remain the preferred route, but only if they can be formulated and manufactured in appropriate doses and at quality levels. Experts and other industry watchers understand that OSD manufacturing, new drug candidates, reformulations, combination drugs, bioavailability technologies and complex controlled-release formulations — not to mention emerging life-cycle–management strategies — will continue to fuel the sector’s growth and uptake of manufacturing innovation.
NEW STRATEGIES FOR CAPACITY AND QUALITY
From answering regulators to competing in global markets, pharmaceutical developers are pursuing distinct strategies to remain compliant, competitive, relevant and successful. Much of this hinges on the ability to manufacture defect-free products at volume. With innovation dollars shifting from blockbusters to value leaders and with cost and price pressures mounting, the ability to manufacture OSD medicines at the lowest cost possible is a leading driver of recent pharmaceutical economics. To get there, pharma has been aligning production and processing assets in a coherent operations-focused manner, innovating to sustain progress quality and profitability in the post-blockbuster, Pharma 3.0 era.3
Trends in pharma OSD processing capacity reveal drug innovators and drug manufacturers slowly shedding dated, dedicated fixed-scale manufacturing and processing facilities, especially those challenged to sustain compliance cost effectively. The pharmaceutical manufacturing landscape is shifting, moving to replace and transition to more flexible cost-effective and efficient capacity. Discrete batch processing, which has characterized 99 percent of OSD manufacturing process since the first mass-produced tablet was pressed, has reached its technical and efficiency limits. Although there will always be applications that should and will remain batch-oriented, hybrid and continuous methods are ready for mainstream application in pharma.
Much of this legacy capacity is being supplanted by contract manufacturing and services providers. The world’s generic producers are also being caught up in the movement to refine their quality profile as regulators push these high-volume manufacturers further. It is widely acknowledged that the CDMO sector is driving capital spending, but the industry’s demand for access to best-cost operationally excellent capacity is spurring spending and organizational changes in most sectors, and that, in turn, is driving OSD manufacturing innovation.
ACCELERATING OPERATIONAL EXCELLENCE
While the pace of change and the adoption of advanced manufacturing and processing solutions may not be occurring as fast as some feel is possible or necessary, pharma’s leaders are exploring next-generation manufacturing strategies in measured and deliberate ways. But change and advancement must come if the industry is to remain successful in meeting the expectations of regulators, healthcare providers, payers, and above all else, the patient. As pharma’s process and production ecosystem evolved, process cost and efficiency has only become a serious consideration when drugs come off of patent.
Pricing followed more cost-plus models, with the industry charging what the market can bear. Once a drug comes off of patent, the commoditization of that drug begins. Companies are now being prompted to implement and institutionalize process technologies effective at maximizing quality at an effective volume cost, even when a drug first comes to market. There is incredible competition to be the leading prescribed medication.
For nearly two decades now, regulators have focused much of their oversight on the processes and technical means that companies employ to manufacture drugs. Central to its drug-quality, consumer-safety mission, the FDA in particular recognized that manufacturing quality and efficiency was key to advancing drug safety and effectiveness while helping to push the drug-cost curve down. However, with the industry beholden to batch process and a regulatory basis that was serving to further entrench the status quo, the FDA recognized it was going to need to reform its policies and create economical and practical pathways to the higher-order, higher-quality and lower cost pharmaceutical processing the agency was promoting as the key to drug safety.
INDUSTRY RESPONSE
Alongside academia, Pharma’s engineering community responded to the call, and industry groups, including the International Society of Pharmaceutical Engineers, began collaborating with the FDA to explore and recommend the best processing and technical strategies for manufacturing drug products, especially OSDs (those in highest demand and in production around the world). This dialogue has produced a number of tactical and technical recommendations that have real potential to drive quality up and costs down, including better, more pervasive application of process analytical technologies (PAT) in batch processing and continued emphasis on continuous manufacturing (CM) processing, and the quality by design methodology it supports.
Beyond the headlines, pharma process engineers have reached a particular crossroads in their pursuit of operational excellence and efficient, cost-contained high quality processing. Again, drug makers' manufacturing strategies are revealing how they think they can best manage risk and sustain business and revenues. Some projects support adopting more sweeping processing advancements like CM, justified by market potential, while others serve to manage risk (i.e., financial) and exposure through an incremental but methodical optimization of batch based processing.
Because batch processing in pharma is so well established, with plenty of capacity delivering value and revenue, there continues to be a great deal of investment in optimizing batch operations and quality-enhancing analytical equipment and controls.
Drug manufacturers’ uptake of analytical technologies is supported by more affordable access to reliable instrumentation and controls. In the last few years, PAT technologies that measure and help control granule size have introduced a new level of transparency as well as the ability to control process variation within batch-processing operations. Coupled with data and information technologies, this further supports better quality and efficiency.
For many in OSD manufacturing, the viable strategy is to optimize batch process segments and align production and associated manufacturing steps to speed the flow of process and materials through the production train and manage any risk to product quality from either a process or operations standpoint. This is a strategy that AstraZeneca (AZ), for example, is pursuing vigorously. Over the past four years, AZ transformed its aging OSD facility in Delaware, completely transforming the facility in pursuit of high-level quality and cost control — as well as future-proof flexibility — as part of their international supply chain.
CRB was a key contributor to the success of this project, which through careful planning and execution transformed the facility without interrupting operations. OSD manufacturers like AZ are reframing what it means to reform their operations and achieve, by their own measure, operational excellence. It also shows that operations executives who take the time to do the studies can find a measured and risk managing path to better product quality and sustainable cost-containment.
NEXT-GEN MANUFACTURING CONTINUES
Vertex, Hovione and Janssen have also successfully demonstrated their commercial commitment to CM; from this point going forward, no conversation or planning regarding next-generation OSD processing can exclude continuous manufacturing from the dialogue.4 With so much experience with the methods and application of CM in other process industries, the movement to introduce its quality and efficiency drivers to pharma is gaining momentum. Regulators, especially the FDA, are advocating this solution, attributing the recent successful development and approval of CM facilities to the collaboration it has fostered with the industry and engineering community to promote more widespread adoption of the methodology. In CRB’s experience, everything is in place for OSD manufacturers to seriously consider more 'all-in' manufacturing strategies based on CM because of its risk-based, science based approaches and the inherent flexibility of continuous processes.
Whether addressing new product manufacturing, managing an aging processing infrastructure, or developing new capacity to meet decade-spanning business plans, capital will only be spent once the investment’s potential is thoroughly vetted. Project success is also increasingly predicated on efficient execution. It is here that CRB, for example, deploys its knowledge, experience and engineering wisdom within a highly developed methodology, providing a clear, defined project management process that promotes speed and cost-effective execution to deliver on project time lines, process innovation, and development and compliance objectives.
As drug innovators and manufacturers navigate the Pharma 3.0 landscape, they are increasingly being tasked by society to lower costs — that is, lower drug prices through lower manufacturing costs. With that goal in mind, the OSD “Facility of the Future” has to move beyond the lab-batch and compound pharmacy roots. Pharma’s uptake of state-of-the-art processing and facility designs and technology is accelerating, and that progress is already making an impact on pharma’s ability to fulfill its promises and potential to society in general, as well as its specific obligation to patients worldwide.
REFERENCES
- Wright, Tim. “Solid Dosage Manufacturing Trends.” Contract Pharma. 6 Mar. 2015. Web.
- Langhauser, Karen. “On Solid Ground: Pharma’s Most Mature Dosage Form Endures.” Pharmaceutical Manufacturing. 12 Apr. 2016. Web.
- Kuehn, Steve. “Future Pharma Partner Models: Pharma 3.0.” Pharma’s Almanac. 1 Aug. 2016. Web.
- Yu, Lawrence. “Continuous Manufacturing Has a Strong Impact on Drug Quality.” FDA Voice. U.S. Food & Drug Administration. 12 Apr. 2016. Web.
ABOUT THE AUTHORS
Christa Myers
Senior Pharmaceutical Engineering Specialist, CRB
Christa Myers has more than 20 years of experience providing clients with insight as to how innovative technologies apply to process and facility designs. Building on her years as an operator, Christa has used her firsthand approach and understanding to assist her clients in designing facilities and equipment – each facility is unique, with different drivers, different products and different dosing mechanisms.
LinkedIn www.linkedin.com/in/christa-myers-b250a55
Email [email protected]
Todd Vaughn
Senior Process Specialist & OSD Expert, CRB
Todd Vaughn is a process specialist with 18 years of experience in process design within the pharmaceutical industry. His knowledge and application of industry regulations and cGMPs has made him valuable to his clients in design, commissioning and qualification of pharmaceutical processes. Todd specializes in the design of oral solid dosage, potent compound processing, and bulk pharmaceutical chemical process facilities.
LinkedIn www.linkedin.com/in/todd-vaughn-3b50305
Email [email protected]