Market trends and FDA encouragement push companies to explore new processes

Fewer than four years ago, there was only one U.S. Food and Drug Administration (FDA)-approved product manufactured through a continuous manufacturing (CM) process. Today, four companies are manufacturing five approved products using CM. Twenty additional companies, both brand-name and generic, have approached the FDA with efforts to develop and implement CM processes. Studies forecast that the global pharmaceutical continuous manufacturing technology market, worth $1.74 billion in 2016, will expand to $3.69 billion by 2025.1

The pharmaceutical industry is moving away from multi-thousand-ton blockbuster drugs and toward drugs developed on the single-digit-ton scale. This shift in volume propels a corresponding fast-paced and flexible approach to manufacturing, which is driving the development of new process flow technologies. In Feb. 2019, the FDA released a statement in support of CM processes, attesting that they allow manufacturers to more easily scale operations to meet demand and reduce drug shortages. The statement also said that continuous manufacturing could provide a more robust, lower cost and diverse supply of drug products.2

While CM approvals to date are for small molecule solid dosage forms, the trend toward CM also compliments the increasingly popular use of single-use process equipment, particularly in biotherapy production, as manufacturers attempt to integrate single-use systems into continuous production platforms. The pharmaceutical industry will likely see a convergence of these two technologies particularly in filling operations for biotech and small molecule injectables and other liquid formulations, where single-use systems can be used for continuous production campaigns and then replaced with new, pre-sterilized assemblies to eliminate on-site sterilization, cleaning, and risk of cross-contamination.

Drivers For Adoption

Manufacturers can configure existing filling operations for liquid dosage forms to single-use systems that fit within CM models with relative ease. They formulate drugs in a single-use mixer, then apply them to a single-use filter capsule and utilize a pre-sterilized, single-use tubing manifold and filling needles for final dosage filling. This process eliminates downtime for cleaning and sterilization and allows manufacturers to build capacity in less time and at a lower cost. Single-use CM systems also offer greater flexibility during process design. They make it easier, faster and less expensive to change system configurations, especially beneficial for clinical batches and multi-product facilities.

Although the development of new biologics receives much of the attention, small molecule active pharmaceutical ingredients (APIs) and solid oral dosage forms still represent more than 90 percent of drugs on the market, as well as those in late-phase development, according to Fraser Institute. CM brings several advantages to small molecule production, as it offers the ability to increase the yield and purity of APIs, while also improving efficiency and operating costs. Therefore, small molecule processing is one of the areas most likely to see widespread adoption of CM systems.

Considerations For Manufacturers

Developing a CM process for a new drug or implementing CM for an existing batch process does demand significant time, effort, and money. Adapting any manufacturing process to CM requires in-depth chemical and mechanical engineering understanding as well as the right technologies. All good manufacturing practices (GMPs) have been written for traditional batch processes and shifting to new methods carries complications and costs. The FDA has shown some leniency in how companies may define their processes and released guidelines to support flexible approaches in the manufacturing of pharmaceutical products in 2017.3

For manufacturers of some products with low-margin profits — like generics — the costs of shifting to CM methods may not justify the long-term improvement efficiencies. The FDA recognizes that there are significant financial barriers to adoption in their Feb. 2019 statement. The agency has charged its Emerging Technology Team with the task of helping early adopters of CM identify and solve implementation challenges and navigate the application review process for products made using CM.

The FDA encourages manufacturers to adopt continuous practices because of the qualitative improvements they offer over traditional batch processes. The agency sees continuous manufacturing as a means of improving safety margins and drug quality assurance by keeping production within compliance. It reduces variability between individual batches and, by extension, the risk of adverse events with patients. Small molecule therapies manufactured by new technologies offer an accelerated route for drugs to enter clinical trials or the market, positively impacting patient care.

Before implementing a CM process, it is important to consider multiple factors. Implementing CM for a new product eliminates the sometimes challenging regulatory requirement to prove equivalence to an existing batch process, but the learning process for CM with a new drug can still burden a tight launch deadline. Feasibility assessments can aid in that decision. Small molecule batch processes simply requiring elimination of intermediate storage steps are a good place to start. Protein bio-therapeutics, due to their complexity and process-dependency are more likely better to start at clinical stages, rather than changing an approved batch process.

The International Society for Pharmaceutical Engineering (ISPE) suggests some key considerations to be (1) whether equipment must be dedicated to a single drug, or applicable to multiple drug products, (2) whether there is a preference for lean manufacturing with fast changeout time, or flexibility for future modifications, and (3) how much control is desired, extent of implementation of PAT, automation, etc.4

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Conclusion

Although CM is still in its infancy within the pharmaceutical industry, it stands to improve the overall quality of both small molecule drugs and biotherapies, reduce costs and lower time to market. Manufacturers of APIs, bulk formulations, and dry powders used in solid dosage pharmaceuticals are likely to be early CM adopters because conversion is relatively easy in these areas. With the FDA’s continued encouragement, CM is expected to grow rapidly within the pharmaceutical industry in the coming years.

As the practical implementation of CM is still an emerging field, it is important to gain knowledge from those in industry, regulatory agencies and academics who have prior first-hand experience and strategies, and are seeking to share and influence the progress of CM, as well as achieve regulatory acceptance. This can best be done by attending focused conferences, participating in equipment supplier webinars and trainings, and networking with similarly interested players in scientific society workgroups.

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About The Author:

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 SVP, 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.

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