Major shifts are approaching or are already underway across pharmaceutical manufacturing strategies, reflecting a range of driving forces. Emerging technologies are ushering in a future where the old model of the blockbuster drug is outdated, replaced instead with a panoply of customized, small-volume drugs specifically targeted to a small patient population (or even an individual patient) on the basis of narrowly defined disease subcategories and other genetic factors. The recent explosion of drug candidates granted accelerated development designations, like fast track, breakthrough therapy, and orphan drugs, has increased pressure on manufacturers to increase productivity to reduce development costs and reduce the time needed to get new therapies to the market. A clear path to reducing costs and reducing time to market for these new drugs is a transition from batch processing to continuous processing in drug substance and drug product manufacturing.
Slow Progress Toward Adoption of Continuous Processing
While many other materials processing industries, including the chemicals, polymers, and food industries, have widely adopted continuous processing approaches to reduce costs and optimize quality, the pharmaceutical industry has been slower to embrace them. This largely reflects the more conservative and risk-averse nature of the industry. Batch processing has long been the gold standard, embraced by both manufacturers and regulatory bodies, for whom batches have been useful to identify and track unit dosage forms.
However, batch processing significantly lacks flexibility in scaling capacity, and batch operations typically require larger manufacturing footprints and less efficient use of space than continuous processing operations. In contrast, scaling up production with continuous processing equipment requires a far smaller increase in the magnitude of the physical equipment needed. Equipment designed for continuous operation is typically two or more orders of magnitude smaller than the equipment required to process an equivalent amount of product via batch production.1 Beyond the impact on the manufacturing footprint, the reduced equipment scaling required with continuous processing equipment sidesteps complications resulting from changes in equipment surface area to volume ratios typically experienced when scaling up batch production. Additionally, continuous processing equipment operates primarily at a steady state, making it an ideal fit for automation and process monitoring via process analytical technology (PAT).
One major obstacle preventing companies from more fully embracing continuous processing is the fact that the manufacturing processes for a given drug are typically locked in and unchangeable following patent approval. Past that stage, it is less likely that cost reductions associated with a more efficient continuous process will offset the cost of developing and validating a new process and obtaining regulatory approval. Companies with larger investments in batch processing will likely be resistant to the change, as well as companies that work in niche markets where API is limiting. Pharmaceutical companies that already outsource a large fraction of their manufacturing appear freer to explore the advantages of continuous processing with their outsourcing partners.
Benefits are Clear
Despite the legitimate concerns about the regulatory challenges inherent in transforming manufacturing processes from batch to continuous models for patented drugs, one of the primary proponents of the adoption of continuous processing is the U.S. Food and Drug Administration itself, which has been championing its potential for both drug substances and drug products since 2004 and has been more vocal in its advocacy recently.2,3 The 21st Century Cures Act, enacted by the U.S. Congress in December 2016, called on the FDA to support the development of continuous manufacturing to accelerate drug development and commercialization.
As more pharmaceutical companies and CDMOs perceive the value of continuous manufacturing as demonstrated by earlier adopters, and more clarity is achieved regarding quality assurance and regulatory requirements, it is likely that the same cost and quality concerns that have driven other industries to embrace continuous processing will lead to wider adoption in pharmaceutical manufacturing. Many manufacturers are already converting selected unit operations and processes from batch to continuous processing models, supplemented with real-time monitoring using cutting-edge PAT, particularly those companies producing new, small-volume drug products.
Adoption of continuous processing
Continuous processing equipment is already in wide use for other unit operations, such as tableting and milling, although many manufacturers combine aspects of continuous and batch approaches at these steps. Continuous processes have also been employed for crystallization and drying.
Innovative continuous processing equipment can increase the efficiency of the manufacturing process while maintaining high product quality and performance, and also allow for quality assurance via PAT systems that monitor processing in real time and control the continuous operations. PAT systems are truly indispensable for sustaining optimal continuous processing conditions, and recent innovations have generated many tools for monitoring the continuous processing of drug substances and drug products.
Many large pharmaceutical companies, including Novartis, Merck, Bayer and AstraZeneca, have invested in continuous manufacturing systems for both small molecule APIs and biologics, and those that have not yet are likely evaluating options. While CDMOs are typically quicker to adopt new technologies, this has not been the case in general with continuous processing. This likely reflects a lack of the resources needed to invest significantly in the manufacturing process, combined with the inertia that results from current success with batch production and a shortage of necessary expertise.
Expertise Required for the Transition
Preparing to make a transition from batch to continuous processing operations requires more than just new equipment: it demands a transformation of the entire manufacturing operation and the mindset of the staff. To take full advantage of continuous processing, manufacturers must embrace Quality by Design approaches with testing during the process instead of at the end, which will require more analytical chemists and more process controls. Operators accustomed to batch processes will need to be retrained, not only on individual pieces of equipment but also on the new, broader manufacturing strategy.
Pharmaceutical companies and CDMOs embarking on continuous processing approaches find themselves in the position of needing to procure a variety of new kinds of equipment with which they are largely unfamiliar. As such, it is critical that they partner with an equipment provider who possesses the necessary expertise and experience to support the critical decisions in this transition.
Additionally, converting an operation from batch to continuous processing means that a company will need to divest equipment assets that are not appropriate to continuous production, ideally in a timely manner to avoid delays and storage costs. A strategic partnership with a used equipment reseller like Federal Equipment Company can help a company acquire new needed equipment and sell off outdated equipment to streamline the conversion.
An additional concern during a significant update of a manufacturing facility is ensuring that the facility and other assets are protected during equipment removal and installation. Federal Equipment Company is a trusted partner that guarantees that equipment will be removed efficiently, effectively, and safely from any facility.
References
- Mollan Jr., Matthew J., Mayur Lodaya. “Continuous Processing in Pharmaceutical Manufacturing.” Pharma Manufacturing. 2004. n.d. Web.
- Rockoff J.D., “Drug Making Breaks Away From Its Old Ways,” The Wall Street Journal, 8 Feb. 2015. Web.
- Wechsler, Jill. “Congress Encourages Modern Drug Manufacturing.” Pharmaceutical Technology. 1 May 2015. Web.
