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US: GAO, USP reports say regulatory enhancements needed to promote advanced manufacturing

2023/03/15  RAPS

The Government Accountability Office (GAO) and the United States Pharmacopeia (USP) asserted in two recent reports that the regulators need to address some of the ambiguities associated with advanced manufacturing to accelerate adoption in the pharmaceutical industry. The GAO further recommended that the US Food and Drug Administration (FDA) should set benchmarks to better measure uptake to this mode of manufacturing.

A USP official discussed both reports, as well as his perspectives on the industry’s adoption of advanced manufacturing methods, in an interview with Focus.

According to GAO, the COVID-19 pandemic revealed vulnerabilities in the medical supply chain that led to drug shortages while FDA has highlighted advanced manufacturing to boost supply chain resiliency. Yet, said GAO, “at the time of this report, few drugs had been made using advanced manufacturing.”

GAO noted that that between 2015 and last October, the agency had approved 16 applications or supplements that used advanced manufacturing technology. Yet during this same period, CDER had accepted 112 proposals for participation in its Emerging Technologies Program (ETP).

Advanced manufacturing can include novel manufacturing methods to improve process robustness, novel dosage forms, continuous manufacturing, new modeling tools for analytical testing and novel container closure systems.

Regulatory barriers and performance benchmarks
The GAO report, which was released on 10 March, said multiple regulatory challenge are impeding the uptake of advanced manufacturing. The report was required under the Coronavirus Aid, Relief, and Economic Security (CARES) Act, which called on GAO to publish a report on the federal response to the COVID-19 pandemic.

GAO interviewed 15 industry stakeholders for the report. Respondents said they were reluctant to use advanced manufacturing because regulatory challenges “contributed to uncertainty about when and whether a drug manufactured using advanced manufacturing will be approved. This uncertainty weakens the business case for, and contributes to slow adoption of, advanced manufacturing.”

Regulatory definitions were cited as a challenge to 11 stakeholders, and one stakeholder said FDA’s manufacturing quality regulations “are not designed for some types of advanced manufacturing, such as distributed manufacturing where manufacturing units deployed to multiple locations may not fit the regulatory definition of a manufacturing establishment.”

Global harmonization was also cited as another challenge by 14 stakeholders. One stakeholder said that it interacts with 15 major and 50 minor regulatory authorities globally and that using a new manufacturing platform could create delays when seeking approvals from these global authorities.

Increased application review times and uncertainty about product approval was cited as a concern by 13 stakeholders. FDA does not approve manufacturing technology independent of a product application but reviews the manufacturing technology in the context of the product it is being used to produce. “Even if a technology has been used before, it is unclear whether FDA will approve an application that uses the technology for a different product,” the report states.

FDA has not fully assessed advanced manufacturing programs
While FDA initiatives support the adoption of advanced manufacturing through its ETP and Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) programs, GAO said the agency has not used performance goals to assess how well these initiatives are working.

The agency “has not formalized performance goals that define the specific results it expects its efforts to achieve in the near term.” For example, FDA has not formally documented performance information for ETP.

In response to the report FDA said, “An individual drug company’s decision to adopt advanced manufacturing is based on multiple factors, most of which are outside the scope and control of FDA.”

USP report notes regulatory challenges
Similar to GAO’s findings, USP also found that regulatory barriers are impeding the industry’s adoption of advanced manufacturing. The report was a summary of its 2022 Convention Exchange Series and included the observations of convention members, subject matter experts and USP staff at a series of meetings last year to address barriers and potential solutions to global pharmaceutical supply chain vulnerabilities.

One of the workstreams addressed reducing barriers to advanced manufacturing technologies and concluded that “the challenges to AMT adoption for generic pharmaceutical manufacturers include the lack of regulatory guidance regarding new product development and approval or when converting from batch to a continuous process.”

Other challenges include how to navigate the product lifecycle, and the lack of clarity around patents and exclusivity parameters.

Parallels between USP summary report and GAO recommendations
Dennis Hall, USP’s vice-president for advanced manufacturing technologies, said the GAO report offers a more comprehensive look at advanced manufacturing while the USP’s report is more of a survey of its membership in different areas. USP’s report also explores supply chain preparedness and ensuring a quality supply of antimicrobials for combatting antimicrobial resistance.

Yet both reports cite regulatory challenges as obstacles for companies to invest in advanced manufacturing.

“It doesn’t surprise me at all that there are parallels between what GAO was seeing in their interviewing of pharmaceutical companies,” said Hall. “There is a high likelihood that the responses of those companies reflect part of our convention in some capacity.”

“What you are seeing in this report and what we heard at our convention exchange series is that the [advanced manufacturing] model is not necessarily scalable to every single company that might want to implement advanced manufacturing technologies and they would like to see FDA provide more detailed and prescriptive guidance as opposed to the more general guidelines they have,” Hall added.

Even companies that have the capital to invest in advanced manufacturing may be reluctant to do so due to risk and the regulatory uncertainty as to whether the applications will be accepted by FDA.

Focus on hybrid methods
Hall said he would like to see the narrative of advanced manufacturing shift a bit to recognize companies that are using hybrid models that incorporate both advanced manufacturing and traditional batch manufacturing. He said that incorporating end-to-end continuous manufacturing is not a practical reality for many companies.

Such end-to-end continuous manufacturing “is great but that will not happen with many products because they are not set up for that and it takes a lot of energy to do those kinds of innovations, but this can be very well applied within the manufacturing process. And the hybrid system is probably a better next step than just trying to go completely to continuous manufacturing end-to-end.”

He said that some products are being approved on a hybrid line combining both. For example, the active pharmaceutical ingredient (API) is made on a flow chemistry model using continuous processes, while the finished product is made on a batch production line.

For flow chemistry “you don’t have to do end to end manufacturing to use it. You can use hybrid systems where you are using advanced manufacturing on part of it but not the whole thing. FDA looks at it and says it’s a batch because the end product uses batch release traditional methods, when in reality part of that manufacturing was using an advanced manufacturing technology. I think the industry doesn’t have a good handle on how much that is happening in API production and for finished products.”

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