By Jerry Martin
Change comes slowly to a risk-averse industry
New manufacturing methods that cut processing steps, speed production, improve efficiency and increase quality and safety all sound like great ideas. That’s the promise continuous manufacturing offers the pharmaceutical industry as an improvement over the traditional batch processing methods that have been practiced for decades.
Continuous manufacturing is inherently more efficient than batch operations because it integrates processing with fewer steps, and it is safer because it requires little or no manual handling. This method applies to on-line monitoring and quality testing in real-time and results in more consistent quality compared to producing individual batches. It also has the potential to make operations more flexible, with smaller equipment and facilities and lower capital costs. More consistent pharmaceutical quality may also increase patient safety and reduce adverse events.
For the latter reason, especially, the U.S. Food and Drug Administration (FDA) has been a strong advocate of continuous manufacturing of pharmaceuticals, and the agency has not been shy about urging drug manufacturers to adopt these new methods. Industries such as automotive, semi-conductor, food production and many other sectors have all moved to continuous manufacturing because of the economic and quality advantages it offers.
So, why is a large segment of the drug industry so hesitant to take the plunge? What’s keeping these manufacturers tied to old methods that are slower, less reliable and more prone to human error?
Two words: cost and uncertainty.
First, let’s address the issue of cost. Some products—like generics—already face tight profit margins. While it may be true from a long-term perspective that continuous manufacturing reduces costs, there is little incentive for some companies to invest in new capital equipment, change and validate new procedures and then endure the scrutiny of new regulatory filings, even with the promise of enhancing manufacturing quality.
Unfortunately, we are seeing drug shortages not only of basic products like saline solution, but also of critical acute-care medications. While the causes of current drug shortages are many and complicated, there’s no question that some manufacturers are turning away from producing drugs with low profit margins rather than investing in modern production methods. In such an environment, adopting new technologies is a hard sell. While the FDA stresses the importance of quality improvements in manufacturing, some companies question whether the returns are worth the effort.
Now, let’s address the challenges posed by uncertainty. Despite the public advocacy of continuous manufacturing, there are perceptions that the FDA does not always speak with a unified voice. On the one hand Dr. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) has advocated continuous manufacturing, calling it “cleaner, flexible, more efficient”. But FDA reviewers and inspectors—those in the trenches—are often hesitant to accept change procedures without extensive validation documentation and demonstration of improved quality. Many of FDA’s own regulations are written for batch processes, and some feel the agency should provide more guidance on how companies can actually develop a continuous process. The mechanism to adopt continuous manufacturing is vague, and for a notoriously risk-averse industry, this often creates an insurmountable barrier to entry.
From the industry perspective, there appears to be a lot of risk with no assurance that a continuously manufactured drug product will be approved. So, we have a dilemma. The FDA is urging adoption, but absent clear guidance and reassurance of success, many in the industry are hesitant to move forward.
Despite this seeming impasse, we are heading down the road of adoption, but it’s a long road. Last April FDA approved, for the first time, a change in a manufacturer’s production from batch to continuous manufacturing. This was for Janssen Therapeutics’ HIV medication Prezista (darunavir). The approval represents an important milestone in industry adoption and should lead to more applications and approvals.
Some other companies have broken the mold and ventured directly into the world of continuous manufacturing. An example is Vertex, which manufacturers the cystic fibrosis drug Orkambi (lumacaftor/ivacaftor). Vertex has used continuous manufacturing for its drug since its approval last July.
Looking at the manufacturing landscape, some aspects of pharmaceutical production lend themselves to continuous manufacturing and they will likely become the focus of early adopters for the industry. Examples include Active Pharmaceutical Ingredients (APIs), bulk formulations and dry powders used in solid dosage manufacturing—traditional batch processes that can be converted to continuous manufacturing relatively easily. This, however, raises a question about process validation because FDA’s current regulations are written for batch formulations. One possibility: if a continuous process is validated, it may eliminate the need to test each batch. Whether continuous manufacturing and its regulatory overseers will actually enable the pharmaceutical industry to eliminate batch designation and release testing is still an open question, however.
Other aspects of drug production will take even longer to change. For biopharmaceutical processing of monoclonal antibody and recombinant protein drugs, batch methods are entrenched and the technology for continuous manufacturing is still evolving. Some cell culture production takes place in a semi-continuous fashion, but chromatography and other purification steps are still done in batches, along with final formulation and filling.
Despite the challenges ahead, continuous improvement is desirable. There is no question that the FDA will continue to drive the industry toward continuous manufacturing as part of Good Manufacturing Practices (GMP). What manufacturers and processors can do now is share best practices and prepare for the transition. Companies that start offering solutions may find FDA a key partner.
Part of information-sharing and preparing for change involves participation in key industry events. This year’s Pharma EXPO (McCormick Place, Chicago; Nov. 6 – 9, 2016) will provide an opportunity to see the latest advances in automation and continuous manufacturing technologies. The event is co-produced by PMMI, The Association for Packaging and Processing Technologies, and the International Society for Pharmaceutical Engineering (ISPE). Pharma EXPO will be co-located with PACK EXPO International 2016. Together, the shows will feature more than 2,500 exhibitors and draw 50,000 attendees.
To register for Pharma EXPO, visit www.pharmaexpo.com. Registration grants attendees access to both Pharma EXPO and PACK EXPO International 2016.
PMMI, The Association for Packaging and Processing Technologies, represents the voice of more than 700 North American manufacturers of equipment, components and materials for processing and packaging. We work to advance a variety of industries by connecting consumer goods companies with manufacturing solutions through the world class PACK EXPO portfolio of trade shows, leading trade media and a wide range of resources to empower our members. The PACK EXPO trade shows unite the world of processing and packaging to advance the industries they serve: PACK EXPO International, PACK EXPO Las Vegas, Pharma EXPO, PACK EXPO East, EXPO PACK México, EXPO PACK Guadalajara and ProFood Tech, launching in April 2017. PMMI Media Group connects manufacturers to the latest solutions, trends and innovations in processing and packaging year-round through brands including Packaging World, Automation World, Healthcare Packaging, Contract Packaging and Packaging + Processing OEM. PMMI Business Drivers assist members in pursuing operational excellence through workforce development initiatives, deliver actionable business intelligence on economic, market and industry trends to support members’ growth strategies, and actively connect the supply chain throughout the year. Learn more at PACKEXPO.com, PMMIMediaGroup.com and PMMI.org.
About Jerry Martin
Jerry Martin is an independent consultant to pharmaceutical manufacturers and equipment suppliers for filtration, single use manufacturing, marketing, business development and regulatory compliance. He was previously Sr. Vice President, Marketing and Global Scientific Affairs for Pall Life Sciences where he served the pharmaceutical, biotech, medical device and vaccine industries for over 37 years. He is currently chairman emeritus of the Bio-Process Systems Alliance, the single-use manufacturing trade association and a member of the USP Expert Panel on Plastic Systems Used for Manufacturing Pharmaceutical Products. He holds an M.Sc. in Microbiology from the University of Toronto.
 Source: "Critical drugs for hospital ERs remain in short supply," National Public Radio, May 2, 2016. http://www.npr.org/sections/health-shots/2016/05/02/476486009/critical-drugs-for-hospital-ers-remain-in-short-supply
 FDA Perspective on Continuous Manufacturing (powerpoint presentation), IFPAC Annual Meeting (Jan. 2012), slide 2. http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM341197.pdf
 Source: Yu, L., "Continuous manufacturing has a strong impact on drug quality," FDA Voice, U.S. Food and Drug Administration (blog), April 12, 2016.