Continuous Manufacturing Current Status
Change in the pharmaceutical industry is notoriously slow, so it wasn't surprising that many doubted continuous manufacturing (CM) would ever be adopted. But despite the skeptics, the technology is gaining substantial ground. Since 2015, four solid oral drugs produced by continuous processes have been approved by the US Food and Drug Administration (FDA) (Table A).
Of these four approved CM products, three were new molecular entities, indicating that companies have enough confidence in this emerging technology to use it for their high-value products. Production of Janssen’s Prezista, on the other hand, switched from batch to CM processing; the change was approved by the US FDA in April 2016.1
Europe is close behind the US, with two CM drug approvals2 , 13 and more anticipated soon, including Symdeko,3 which is expected to be approved in the European Union before the end of the year. Health authorities in Canada, Switzerland, Australia, and New Zealand have also approved applications for CM-produced solid oral dosage forms.4
While recent CM approvals have focused on solid dose tablet manufacturing, momentum is growing for both active pharmaceutical ingredients (APIs) and biologics. In a sense, CM in these areas is not new: single-unit operations such as flow reactors for API and perfusion bioreactors for biologics have been used for decades. Manufacturers now find it advantageous, however, to link these single-unit operations for full end-to-end production, or even integrate drug substance and drug product manufacturing (see article "The Advent of Continuous Manufacturing").
API manufacturing processes typically have more steps—and therefore more complexity—compared to solid dosage manufacturing. But with CM’s production efficiencies, interest in and adoption of continuous API manufacturing should increase once the first approval comes through. One Lilly continuous API good manufacturing practice facility can produce 3 kilograms a day of prexasertib monolactate monohydrate, a chemotherapy candidate for clinical trials.5 The process links each stage in the process to quality-control systems, combining synthesis with purification and crystallization. It also enables chemistries that would be impossible or too dangerous using traditional methods.
CM upstream perfusion for biologics is already well established and used to manufacture over 20 FDA-approved products.6 Perfusion alone is not a fair comparison, however, because it is a single-unit operation. There is significant interest in integrated multiunit continuous operation with downstream purification, and Genzyme, Merck, Bayer, and Sanofi are thought to be interested in this area.7
Government support for CM technology, already high, seems to be increasing, with support from the United Kingdom and European countries such as Belgium and Austria. The United States passed the 21st Century Cures Act on 31 December 2016, which promoted advanced pharmaceutical manufacturing.8 FDA leadership, which has led much of the drive for CM, also awarded $4.9 million in grant funding to support the introduction of CM techniques for pharmaceuticals.9 To accelerate the transition to industry, FDA Commissioner Scott Gottlieb called for funding to promote innovation on 13 February 2018.10
While the adoption rate for CM forms an impressive trajectory, the process of bringing the technology on board is not trivial. It requires new and different operator skills, vendors, and training to implement the technology successfully. Different flow and mixing patterns may also require different approaches to characterize and understand the process. Early adopters spent considerable time and resources to develop these capabilities before they brought products to markets. Despite these challenges, several companies now have plans for future installations, and multiple CM products are in the pipeline.
To encourage this new technology and alleviate industry concerns, several health authorities have established special working groups to shepherd development and provide advice:
- The FDA established the Emerging Technology Team in 2015 to “[support] industry’s development of innovative approaches in pharmaceutical design and manufacturing. The program provides an opportunity for early dialogue during technology development and prior to the submission of a drug application. This enables [the agency] to identify and resolve potential roadblocks early in the process.”11
- The European Medicines Agency expanded its existing Process Analytical Technology Team to include CM.
- Japan formed the Innovative Manufacturing Technology Working Group, which interfaces with industry to “discuss regulatory issues related to quality assessment and good manufacturing practice inspection to facilitate the introduction of innovative manufacturing technologies while ensuring appropriate quality. Continuous manufacturing is our primary target.”12
Each of these groups provides an avenue for early communication and enhanced dialogue. This is important for innovative pharmaceutical companies that are introducing continuous processing to the market, since many health authorities currently have little familiarity with the technology. The enhanced communication helps inform the health authorities of new approaches and provides direction and decreases regulatory uncertainty for companies.
|Eli Lilly and Company
|Advanced breast cancer
New technology is both a challenge and an opportunity for the pharmaceutical industry. CM, whatever its form, increases automation, process analytical technology, and the need for high-level process understanding and control. As it takes hold within the industry, it is imperative that we find some degree of alignment, if not standardization or harmonization, among our approaches. If we do not, adoption will remain slow as regulators seek to understand the new manufacturing technologies they encounter. In this arena, convening organizations such as ISPE can play a key role in bringing the community together to share knowledge and best practices, and disseminate the information globally.
Overall, 2018 is likely to be an interesting year for CM. Further continuous solid dose filings as well as the first API will likely see approval this year. Over time, we expect to go from an average approval rate of one per year to perhaps half a dozen in the same time frame. For those who have been working in this area, this will be truly rewarding. For everyone else, it should serve as a call to hop on the bandwagon of CM, a technology that is here to stay.
- 1Brennan, Zachary. Regulatory Affairs Professionals Society. “FDA Allows First Switch from Batch to Continuous Manufacturing for HIV Drug.” Regulatory Focus, 12 April 2016. https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2016/4/fda-allows-first-switch-from-batch-to-continuous-manufacturing-for-hiv-drug
- 2Mariott, Niamh. ”EMA Approves Janssen’s Prezista Continuous Manufacturing Line.” European Pharmaceutical Review, 27 June 2017. https://www.europeanpharmaceuticalreview.com/news/62587/ema-continuous-manufacturing/
- 13Vertex Pharmaceuticals. “Vertex Receives EU Approval for ORKAMBI® (lumacaftor/ivacaftor) in Children with Cystic Fibrosis Ages 6-11 with Two Copies of the F508del Mutation.” Press release. New York Times, 14 March 2018. http://markets.on.nytimes.com/research/stocks/news/press_release.asp?docTag=201801100400BIZWIRE_USPRX____BW5259&feedID=600&press_symbol=282560
- 3Pharmaceutical Technology Editors. “Vertex Receives FDA Approval for Continuously Manufactured Drug Product.” PharmTech.com. 15 February 2018. http://www.pharmtech.com/vertex-receives-fda-approval-continuously-manufactured-drug-product
- 4De Belder, Lawrence. “Impact of Learnings on Tech Transfer Strategy and Future Vision for Janssen.” IFPAC 2018 Annual Meeting, North Bethesda, MD, 11–14 February 2018.
- 5Yirka, Bob. “Eli Lilly Develops Continuous Manufacturing Process for Chemotherapy Drug.” MedicalXpress, 16 June 2017. https://medicalxpress.com/news/2017-06-eli-lilly-chemotherapy-drug.html
- 6Hernandez, Randi. “Unifying Continuous Biomanufacturing Operations.” BioPharm International. Process Development Forum, 14 June 2017. http://www.processdevelopmentforum.com/articles/unifying-continuous-biomanufacturing-operations
- 7Penn State. College of Engineering. “Supplement: Integrated Continuous Manufacturing of Biologics.” 18 September 2017.http://www.che.psu.edu/news/2017/zydney-supplement-integrated-continuous-manufacturing-biologics%20.aspx
- 8United States Congress. “21st Century Cures Act.” HR34. Public Law No: 114-255. 13 December 2016. https://www.congress.gov/bill/114th-congress/house-bill/34/
- 9Rutgers University. Office of Research and Economic Development. “FDA Awards $4.9 Million to Rutgers-Led Research Consortium to Expand Development of Continuous Manufacturing in the Pharmaceutical Industry” 15 October 2015. http://www.newswise.com/articles/fda-awards-4-9-million-to-rutgers-led-research-consortium-to-expand-development-of-continuous-manufacturing-in-the-pharmaceutical-industry
- 10US Food and Drug Administration. “Statement from FDA Commissioner Scott Gottlieb, MD, on Administration’s Request for New FDA Funding to Promote Innovation and Broaden Patient Access through Competition.” FDA Statement. 13 February 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm596554.htm?utm_campaign=02132018_Statement_FY19%20Budget&utm_medium=email&utm_source=Eloqua
- 11———. “Transcript: Emerging Technology Program.” https://www.fda.gov/AboutFDA/Center-sO ces/OceofMedicalProductsandTobacco/CDER/ucm576840.htm
- 12Pharmaceuticals and Medical Devices Agency. “Innovative Manufacturing Technology WG (IMT-WG).”https://www.pmda.go.jp/english/rs-sb-std/standards-development/cross-sectional-project/0012.html