Executive Summary

Rutgers University professor testifies in support of bill directing the FDA to designate National Centers of Excellence in Continuous Manufacturing; other bills target generic labeling, orphan exclusivity and counterfeit devices.

While brand name companies are adopting continuous manufacturing, others are struggling with the cost and knowledge required for implementation, Rutgers University professor Fernando Muzzio testified at a congressional hearing.

Speaking before the House Energy & Commerce Health Subcommittee on 24 January, Muzzio voiced support for H.R. 4866, the National Centers of Excellence in Continuous Pharmaceutical Manufacturing Act. Introduced in October by E&C Committee Chairman Frank Pallone Jr., D-NJ, and Rep. Brett Guthrie, R-KY,  the measure would amend the 21st Century Cures Act to direct the US Food and Drug Administration to designate national centers to work with the FDA and industry to craft a national framework to implement continuous manufacturing. The centers would also support research and development, workforce development and standardization,  and collaborate with manufacturers to support adoption of the technology.

Muzzio said that 10 to 15 brand-based companies have implemented continuous manufacturing for finished solid dose products. He noted that the FDA has approved six finished dosage products using continuous manufacturing processes manufactured by four companies – Pfizer Inc., Eli Lilly & Co., Vertex Pharmaceuticals Inc. and Johnson & Johnson. He said every brand-based pharmaceutical company is working on this technology and preparing submissions.

“If we want to extend it and really have a major impact, the key issue is to make sure that the know-how required to implement this technology becomes available to other sectors of the industry, the generics, the over-the-counter manufacturers,” he said. “We should create places where companies can come and get the help they need in demonstrating the technology for their products and in facilitating the manufacture of clinical supplies without having to spend $15m or $20m to get a system implemented.”

Muzzio is also director of the Rutgers-led Center for Structured Organic Particulate Systems (C-SOPS), an engineering research center dedicated to the design of pharmaceutical products and their manufacturing processes. In his written testimony, Muzzio noted that the center was funded by the National Science Foundation in 2006 and in 2016 the FDA became its main federal sponsor, providing support for research and educational activities. The center partnered with J&J in 2010 and implemented the first FDA-approved conversion from batch to continuous manufacturing for the HIV drug Prezista (darunavir).

Hurdles For Generic Manufacturers

Subcommittee chair Anna Eshoo, D-CA, asked Muzzio if generic manufacturers are using continuous manufacturing. He replied that some of the largest generic companies have attempted to implement it.

“We know that in a couple of cases they bought equipment, they installed it, they tried to make it work,” he said. “But there is a large amount of know-how that is required that brand companies created over a decade.”

Muzzio said an environment to help the rest of industry access this know-how could be created in just a few months.

Generic manufacturers have expressed concern that brand companies might use continuous manufacturing to make it difficult for them to match drug quality using conventional batch methods. (Also see “Will Continuous Manufacturing Mean Continuous Generic Delay? FDA Hears AAM’s Warning” – Pink Sheet, 4 Dec, 2017.)

In a memo prepared for the hearing, subcommittee members noted that Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, testified at a hearing last year about the value of advanced manufacturing to reduce the nation’s dependence on foreign sources of active pharmaceutical ingredients and reduce quality issues that trigger drug shortages or recalls. (Also see “Real-Time Manufacturing Volume Reporting Could Help Prevent Drug Shortages, Woodcock Tells Congress” – Pink Sheet, 31 Oct, 2019.)

The agency issued draft guidance on continuous manufacturing in February 2019 to encourage pharmaceutical companies to adopt the technology. (Also see “FDA Drafts Guidance To Spur Uptake In Continuous Manufacturing” – Pink Sheet, 1 Mar, 2019.)

Rep. Morgan Griffith, R-VA, asked how continuous manufacturing could be beneficial in responding to an outbreak like the coronavirus.

Muzzio replied that if the technology were in place so rapid development methods could be implemented for a wide variety of products, a manufacturer could be assigned the task of creating multiple versions of a potential product. “That manufacturer could come back with suitable versions of a possible product in days or weeks, which is much faster than we can do today,” he said.

Orphan Exclusivity Loophole

The hearing included testimony on three other bills that would grant the FDA new authority regarding drug safety and transparency.

H.R. 4712, the Fairness in Orphan Drug Exclusivity Act, would update the Orphan Drug Act to require drug manufacturers seeking orphan drug designations to demonstrate that there was no reasonable expectation at the time of approval that they could recover the cost of developing and making the drug. Manufacturers would have to demonstrate this annually for the seven-year period of orphan exclusivity.

Kao-Ping Chau, University of Michigan Medical School, testified that since 1983, only three drugs have received orphan status under the cost recovery prong of the Orphan Drug Act, one of which was Indivior PLC’s Sublocade (buprenorphine extended-release). FDA revoked Sublocade’s orphan designation in November. (Also see “US FDA Revokes Orphan Drug Designation For Indivior’s Sublocade” – Pink Sheet, 11 Nov, 2019.)

Chau said H.R. 4712, introduced in October by Rep. Madeleine Dean, D-PA, would close the loophole that allowed Sublocade to get orphan status and would assure that generic versions of Sublocade could come on the market by December 2024 even if Indivior were to successfully challenge the FDA’s revocation.

Generic Labeling

H.R. 5668, the Modern Labeling Act of 2020, introduced by Rep. Doris Matsui, D-CA, and Guthrie in January, gives the FDA the authority to require modifications of outdated labeling for generic drugs. Under the Hatch-Waxman Act amendments to the Food, Drug and Cosmetic Act, generic products must have the same labeling as the brand name product.

Jeff Allen, president and CEO of Friends of Cancer Research, testified that this is a problem in cases where the brand name reference-listed drug has been withdrawn from the market and the labeling “becomes frozen in time.”

The FDA has sought to address this issue. In 2013, it proposed a rule that would have allowed generic sponsors to update their product labeling on their own. But the agency withdrew it five years later. (Also see “US FDA May Ask Congress For More Resources After Withdrawing Generic Label Reg” – Pink Sheet, 13 Dec, 2018.)

In 2018, the FDA launched the initiative Project Renewal to modernize the labeling of approximately 40 older generic chemotherapeutics to assure the labeling reflects how the drugs are being used in clinical practice. (Also see “Project Renewal: US FDA’s Plan To Update Generic Cancer Drug Labels Depends On NDA Holders” – Pink Sheet, 28 Nov, 2018.)

Counterfeit Devices

Another bill, H.R. 5663, the Safeguarding Therapeutics Act, would give the FDA the authority to destroy counterfeit medical devices and combination products valued at $2,500 or less at the point of entry. The agency has this authority for drugs that have been denied entry into the US. Counterfeit devices are now typically returned to the sender.

Ranking member Michael Burgess, R-TX, and other committee members recalled a visit they made to the mail facility at John F. Kennedy International Airport with then-FDA Commissioner Scott Gottlieb. Burgess said they were told some suspect products returned to the sender could recirculate through the facility with FDA markings on the packaging.

J&J’s VP Global Brand Protection Richard Kaeser spoke in support of the legislation, which was introduced on 21 January by Rep. Guthrie and Eliot Engel, D-NY. He noted that the market for counterfeit drugs is estimated at $200bn per year and that Interpol (the International Criminal Police Organization) estimates that one million people die each year from taking counterfeit medicines globally.

https://pink.pharmaintelligence.informa.com/PS141626/Continuous-Manufac…