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FDA and bio/pharma companies get serious about continuous manufacturing to ensure product quality.
The need for more efficient methods to produce breakthrough therapies and biosimilars, along with strategies to manufacture conventional drugs more economically and reliably, is sparking industry investment in more sophisticated and innovative systems for making drugs and biologics. The shift to personalized or precision medicine and cellular and gene therapies puts a premium on fast production of small batches of cutting-edge medicines. At the same time, pressure to reduce manufacturing costs and to avoid shortages and recalls demands more reliable methods for ensuring the quality of large batches of conventional drugs.
At a Congressional briefing on breakthrough therapies in April 2016 (1), Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), noted that the need to achieve more streamlined product development for breakthroughs and other complex biopharmaceuticals is prompting a shift away from batch processing to continuous manufacturing (CM) systems. Accelerated product development means that manufacturers have less time to refine processes, putting a premium on flexible systems able to produce small batches quickly and efficiently. More flexibility in stability testing also has become accepted for breakthrough products that have small lots sizes and are consumed quickly and thus have less need for two-year stability profiles upfront.
FDA encourages investment
Regulatory decisions are encouraging industry adoption of new manufacturing technologies after years of reluctance. In August 2015, FDA approved for the first time a 3D printed pill, a form of the epilepsy drug Spirtam (levetiracetam) produced by Aprecia Pharmaceuticals of New Jersey; it disintegrates more rapidly in the patient’s mouth to aid those who have difficulty swallowing (2).
In a landmark decision on a manufacturing change, FDA authorized a switch from batch production to a continuous manufacturing process at Johnson & Johnson’s Janssen plant in Guarbo, Puerto Rico (3). J&J expects its new CM line for producing the HIV drug Prezista (darunavir) will reduce manufacturing and testing cycle time by 80% and cut waste by a third. Entire batches will not have to be discarded if a problem appears, and the process requires only two rooms instead of seven. J&J expects to make three-fourths of its high-volume products through continuous manufacturing within a decade.
Vertex has drawn attention to its CM process for producing its cystic fibrosis drug Orkambi (lumacaftor/vacaftor), approved by FDA in 2015. The firm announced an agreement with contract manufacturer Hovione to establish a CM plant in New Jersey that will expand production for Vertex and give Hovione the capability of offering similar services to other clients (4).
According to press reports, GlaxoSmithKline is building a CM facility in Singapore, and Eli Lilly is investing in a CM operation in Cork, Ireland. Amgen has been shifting to more flexible production operations for its protein-based drugs for several years, most notably at a $200-million plant in Singapore that features modular designs and continuous processing. Amgen also is working with contract manufacturer Patheon to develop additional capacity for innovative production of new therapies in additional global markets.
Industry experts are encouraging such moves, as seen in a May 2015 report from Deloitte on “Advanced Biopharmaceutical Manufacturing” (5). The study summarizes how continuous manufacturing, single-use systems, and other technological innovations are transforming drug production, noting that the need to devise more effective drug-delivery systems and combination products makes manufacturing “more central to the effectiveness of medicine.” Pharma companies thus are collaborating more with component manufacturers and technology developers to devise portable manufacturing components that can be deployed quickly to critical locations.
Such industry investment decisions are gratifying to Woodcock and other FDA officials, who have been urging pharma adoption of modern manufacturing for years, most visibly as part of the agency’s 2002 Pharmaceutical cGMPs for the 21st Century initiative. A 2004 guidance urged adoption of a process analytical technology (PAT) framework for innovative pharmaceutical development that builds quality testing into pharmaceutical manufacturing processes (6).
Manufacturers, however, were reluctant to invest millions of dollars in such systems without assurance that innovation won’t slow product approval or draw objections from plant inspectors. CDER’s Office of Pharmaceutical Quality (OPQ) has renewed the quality manufacturing campaign by offering early advice on innovative systems and coordinating review and inspection to avoid delays. CDER published guidance in December 2015 outlining how its Emerging Technology Team (ETT) will coordinate assessment of new manufacturing technologies to facilitate approval of such systems and processes (7).
So far the ETT has participated in more than 25 meetings with sponsors to discuss manufacturing design and development issues and to offer recommendations for submission content for innovative technologies. The aim, says OPQ director Michael Kopcha, is to identify and address “potential roadblocks” and prevent delays related to adopting promising new technologies.
The Obama administration also is encouraging investment in advanced manufacturing technologies to facilitate efficient and reliable production of both conventional drugs and innovative cellular products and regenerative medicines. A report issued in April 2016 by the White House National Science and Technology Council identifies these topics as areas of “emerging priority” that warrant further federal government investment and public-private collaboration to move forward (8). Cutting-edge biologics require process control methods able to overcome technical challenges in developing new enzymes and proteins that can lead to regenerative therapies able to repair or replace non-functioning tissues and organs. And continuous manufacturing, which is widely used in the food, chemical, and petroleum industries, has the potential to provide multiple benefits for pharmaceutical and biotech manufacturers, including smaller size plants, less raw materials, streamlined storage and testing requirements, reduced product waste, and shorter manufacturing cycles.
The White House panel notes that such systems may be particularly important in producing medical countermeasures and treatments for infectious diseases, which often demand rapid responses to emerging threats. Modular and plug-and-play equipment with reusable, flexible, or interchangeable parts are especially important for producing specialty orphan or breakthrough drugs and emergency treatments. Support for advancing bio/pharma manufacturing methods already is coming from the National Institutes of Health, the Department of Defense, the National Institute of Standards and Technology, and the Biomedical Advanced Research and Development Authority (BARDA) in the Department of Health and Human Services. And FDA is working with BARDA to support enabling technologies that encourage commercial adoption of continuous manufacturing.
Many of these issues were discussed in April at a conference on continuous manufacturing in Baltimore, MD, sponsored by the International Society for Pharmaceutical Engineering (ISPE). Panels addressed whether CM creates unique considerations for process validation, managing deviations in real time, and use of sensors and monitoring systems. Key issues for CM implementation include batch definition, materials traceability, and control strategy support for integrated drug specifications. CM for bioprocessing, moreover, involves new approaches for dealing with deviations, ensuring microbial control, and using inline measurements to confirm proper process performance.
A related challenge is that all these innovations require manufacturers to identify and train specialized workers to have the expertise and experience needed to operate and manage modern production systems.
1. J. Wechsler, “Modern Manufacturing Required for Breakthrough Drugs,” PharmTech.com, April 15, 2016.
2. Aprecia Pharmaceuticals, “FDA Approves the First 3D Printed Drug Product,” Press Release, Aug. 3.
3. L. Yu, “Continuous Manufacturing Has a Strong Impact on Drug Quality,” FDAVoice blog, April 12, 2016.
4. Hovione, “Hovione and Vertex Partner in Continuous Manufacturing,” Press Release, March 10, 2016.
5. Deloitte, “Advanced Biopharmaceutical Manufacturing: An Evolution Underway,” White Paper.
6. FDA, Guidance for Industry PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (CDER, CVM, ORA, September 2004).
7. FDA, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base, Draft Guidance (CDER, December 2015).
8. Subcommittee for Advanced Manufacturing, “Advanced Manufacturing: A Snapshot of Priority Technical Areas Across the Federal Government,” Executive Office of the President, National Science and Technology Council, April 2016.
Article DetailsBioPharm International
Vol. 29, No. 6
When referring to this article, please cite it as J. Wechsler, "Modern Manufacturing Comes of Age," BioPharm International 29 (6) 2016.