Pandemic Will Continue Limiting US FDA Inspections In Driving FY 2021 Drug GMP Warnings
Source : 'HBW Insight'
Many if not most of the drug adulteration regulatory actions by the US Food and Drug Administration in fiscal year 2021 will be based on alternatives to agency inspections that are precluded by coronavirus-related travel restrictions, according to Donald Ashley, director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research.
“I anticipate that for the remainder of this fiscal year that a large percentage, and, who knows, perhaps the majority of our adulteration regulatory actions will continue to be based upon these alternative tools rather than FDA inspections,” said Ashley on 15 December during the Food and Drug Law Institute’s enforcement, litigation and compliance conference conducted online.
The agency historically has based 100% of its drug adulteration warning letters on inspections. COVID-19-related travel restrictions changed that slightly in FY 2020, when 2% of drug good manufacturing practices warning letters were based on testing of samples presented for import, but the change became even more pronounced in the first two months of FY 2021, with 59% of the actions related to sample testing and 41% to inspections.
For import alerts, the shift is even more extreme. In recent years, all but 1% to 4% of import alerts were based on FDA inspection findings. The exceptions were based on sample testing, and in FY 2019 also on records requests in lieu of or in advance of inspections of drug manufacturing facilities, as allowed in Section 704(a)(4) of the Food, Drug and Cosmetic Act.
The sample-related share increased to 38% in FY 2020 and 56% in the first two months of FY 2021. The records-request share accounted for 5% in FY 2020 and 44% so far in FY 2021, with none based on inspections so far.
Although the FDA increasingly has relied on the US/European Union mutual recognition agreement for inspection coverage in the EU, it relied on the agreement for one drug adulteration regulatory action in FY 2020, accounting for 1% of import alerts.
Ashley noted the agency has continued to conduct mission-critical pre-approval and for-cause inspections during the pandemic, to the extent possible, and has resumed domestic surveillance inspections in areas where COVID-19 transmission is low and declining.
He spoke about remote regulatory assessments, which are based on records requests, but didn't discuss prospects for virtual FDA inspections involving video plant walk-throughs, something industry has been requesting. The agency had conducted more than 500 remote assessments by mid-September. ()
CDER Compliance office Director Donald Ashley: "perhaps the majority of our [FY2021] adulteration regulatory actions will continue to be based upon these alternative tools rather than FDA inspections."
Ashley showed little sympathy for companies that flunked their most recent inspection and are anxious to get “official action indicated” findings removed from form 483 reports inspectors submitted. Such facilities remain in limbo, unable to proceed with product launches and manufacturing changes until the FDA can send inspectors to clear them, and unable to convince the FDA to rely on inspection alternatives.
Historically, “even though the firm has told us that they’ve done all the remediation, they’ve sent in the SOPs, they’ve sent in the documents, maybe they’ve sent in some consultant reports, half the time upon reinspection, they're still official action indicated,” Ashley said.
Given that roughly half of OAI sites would fail re-inspection, the agency is not anxious to risk remote alternatives that could miss problems, he said. “That really gives us reasons for pause the relying really closely on remote regulatory assessments in instances where we know there's a problem in advance. We’re obviously looking at it closely, but that’s what we’re wrestling with.”
FDA officials have in recent months expressed a willingness to consider proposals for inspection alternatives from such companies. ()
Extended regulatory limbo for such facilities could be anticipated as travel restrictions continue, given the increased dependence on inspection alternatives expected in FY 2021 and the reluctance to use such alternatives for OAI re-inspections.
Meanwhile, manufacturers of drugs, biologics and devices that received FDA emergency use authorization must prepare for the day the emergency is declared over, Ashley and others speaking during the FDLI session said.
Erin Keith, associate director for compliance and quality in the FDA’s Center for Devices and Radiological Health, said her office has “spent a great deal of time thinking about that.”
Daniel Kracov, an Arnold & Porter partner who moderated the session, said he has found many companies with products for COVID-19 “haven’t really thought ahead in terms of what’s going to happen when the emergency ends.”
The emergency could end before EUA applications are filed or approved. In addition, enforcement discretion policies and regulatory waivers established for the emergency will have to end.
Ashley noted the CDER compliance office has issued more than 40 regulatory discretion decisions to ease pandemic-driven drug shortages by, for example, extending expiration dates, allowing the import of products approved for foreign markets and allowing the release of drug product stability batches.
Keith said CDRH is developing policies “that will help transition the products that are currently in the marketplace helping to support the public health emergency back to normal operating status. And we recognize that industry’s going to need a road map and a set of expectations and milestones to meet in order to become compliant with normal expectations.”
As for companies that may want their emergency products to remain on the market, she said, “we have already started to message to our industry that now would be the time to start having those conversations with the appropriate review divisions about what might be necessary to support that application and to begin that process so that when we do get to the point where the public health emergency is over and we’re implementing that transition plan, that they’ll be able to comply with the plan that we put out in the timeframe that we describe and set as expectations for compliance.”
Ashley noted that under the FDA’s 2017 EUA guidance, patients being treated under an EUA when it is withdrawn “can continue to receive that treatment.” He said the guidance also mentions the FDA’s investigational new drug regulations “as a possible avenue for use of a product,” presumably under their expanded access provisions.
This year’s surge in sampling-related enforcement actions stemmed from efforts to meet surging demand for hand sanitizers beginning in March as recognition grew that the pandemic had arrived in the US. ()
Thousands of products were introduced to the US market to meet that demand, including, as the FDA soon discovered, methanol-contaminated hand sanitizers from dozens of firms in Mexico that registered to manufacture drugs available in the US after the agency temporarily eased standards for making the products in response to soaring consumer demand, Ashley said.
Because hand sanitizers are regulated as OTC monograph drugs, manufacturers can ship them to the US without having their facilities and processes inspected.
Ashley noted CDER Director Janet Woodcock warned Congress about the difficulty of assuring the quality of OTC monograph drugs shipped from uninspected foreign facilities in December 2019 testimony, saying, “this increases the risk of exposing American patients to unsafe or ineffective drugs and requires resource-intensive efforts on FDA’s part to identify and respond to any problems that arise subsequently.”
Working with US Customs and Border Patrol, the agency flagged suspect shipments at the border and sent them to FDA laboratories for further testing, which showed that in many cases poisonous methanol accounted for 1% to 80% of the contents. Ethanol was often sub-potent, there was high variability within and between lots, and in a few cases, 1-propanol was found.
The agency so far has added 54 of these manufacturers to a new import alert 66-78 established in July for detention without physical examination of drugs based on analytical test results. ()
There have been warning letters, he noted, adding that there will be more in FY 2021. ()
This article previously was published by Informa Pharma's Pink Sheet newsletter.
By Bowman Cox