US FDA Assesses Over 500 Biopharma Plants Remotely Via Records Review; Refines Process
Executive Summary
Agency may share outcomes of remote record reviews in lieu of inspections at US and foreign facilities.
Despite the coronavirus pandemic’s inspection hiatus, the US Food and Drug Administration’s field organization, the Office of Regulatory Affairs, has been able to make judgments on the quality of hundreds of drug manufacturing facilities without visiting them.
That finding, delivered by FDA assistant commissioner Elizabeth Miller at this year’s virtual Parenteral Drug Association/FDA conference, provides some degree of assurance to pharmaceutical companies that many expected approvals will not encounter inspection-related delays while the COVID-19 virus circulates widely.
Although by all accounts the FDA remains cautious about relying on video technology for virtual plant walk-throughs, the agency appears to be accomplishing a lot simply by reviewing documents remotely.
Inspectors are basing many of their site assessments on records they requested under authority of Section 704(a)(4) of the Food, Drug and Cosmetic Act, added by the July 2012 FDA Safety and Innovation Act to enable greater oversight of foreign facilities.
The agency suspended all but mission-critical inspections abroad on 10 March and domestically on 18 March. Domestic surveillance inspections resumed in July, but on a limited basis.
Miller, who is the assistant commissioner for medical products and tobacco operations, said the agency will make it a priority to conduct inspections with pending user goal dates “using a benefit versus risk calculation that will factor public health and access to critical therapies.”
Records Serve As Basis For Recommendations
Many in industry have clamored for the FDA to fill the gap with virtual walkthrough inspections using video technology, but the agency has been slow to adopt that approach.
However, the agency’s embrace of the 704(a)(4) authority to request records in lieu of, or in advance of inspections was evident from the numbers Miller shared in her PDA/FDA remarks.
By 31 August, the agency had issued 424 records requests to pharmaceutical manufacturing facilities, 229 of them to foreign establishments and 195 to domestic facilities.
Miller said 111 of the 424 drug establishment records requests were made in support of application reviews. “To date, these requests have yielded 77 approval recommendations and 15 withhold recommendations.”
She noted that during the same period, the agency issued 123 records requests to biologics facilities, 15 of them foreign and the other 108 domestic.
A Carrot And A Stick
Miller said the industry has generally complied with the agency’s records request in a timely fashion, with a response rate of 95%.
“Industry has been very responsive and has been generally meeting the requested response time frames,” she said. “In some cases, we have been granting extensions where requests are reasonable.”
One reason for the strong response may be the advantages that come with passing inspections, which can include greenlighting of applications to market drugs and biologics, as well as to proceed with changes in manufacturing processes and analytical technologies.
Another reason may be the risk that comes with any failure or delay in responding, as outlined in Section 501(j) of the FD&C Act, also added by FDASIA. This provision allows the agency to deem a drug adulterated if it is manufactured at a facility that has delayed, denied or limited inspection, as defined in guidance. (Also see "How FDA Will Use Its New Authority against Denying, Limiting or Refusing Inspections – And Why Industry is Still Worried" - Pink Sheet, 21 Nov, 2013.)
“When a firm refuses to respond to a records request, the FDA may initiate an inspection or pursue other action under our authority,” Miller said. “The FDA may detain a foreign firm’s products upon entry without physical examination when they are offered for import review.”
She said that inadequate responses to remote records requests have led the agency so far to place two sites on Import Alert 99-32, which it uses to detain product presented for import from facilities that refused FDA foreign establishment inspections, per the Section 501(j) authority granted under FDASIA.
The agency has added 15 sites to that import alert in 2020, the other 13 presumably due to onsite inspection refusals. The most recent additions, on 26 August, were two companies in China’s Guangdong Province – Anfei Technology Co. Ltd. in Shenzhen and Dongguan Chunzhen Biological Technology Co. Ltd. in Dongguan.
Records Request Outcomes
As the agency relies more heavily on records requests in lieu of inspections, one aspect of the process has drawn complaints from industry – the lack of closure. But that may change.
A site inspection ends with a “no action indicated” finding or a list of inspectional observations on a Form 483. There is nothing comparable for records reviews.
The FDA requests records by email using Form 4003. After receiving records, the agency replies using Form 4003a to acknowledge receipt in a process spelled out in Staff Manual Guide 9004.1, Policy and Procedures for Requesting Records in Advance of or In Lieu of a Drug Inspection.
The Form 4003a acknowledgement “provides a complete list of all records requested and received, and includes language stating that we have reviewed the records provided, we have no further requests at this time,” Miller noted.
“We are aware of the requests for a more formalized process that we further elaborate on outcomes, and this is being considered within the agency,” she said.
Program Refinement And Expansion
Miller said the agency has launched an initiative to use remote regulatory assessments for programs to which the 704(a)(4) authority “does not explicitly apply.”
This effort focuses on records that companies are required to maintain at their sites for the FDA’s review.
“In certain circumstances when conditions are observed that may present an imminent health hazard, the agency will pursue an onsite inspection,” she said. “If an onsite inspection cannot be conducted immediately, FDA may take other actions to protect the public.”
For example, she said, “In the pre-approval context, a remote regulatory assessment may result in a non-approval, a delay or a request for additional information.”
She noted that the agency is relying on information from remote assessments to set priorities for site inspections and help focus them.
Updated Process Expected In October
Miller said ORA has developed templates and procedures across its biologics, pharmaceuticals and bioresearch programs to ensure consistent implementation.
But as the pandemic lingers, the office is doing more to improve the remote assessment process.
“Rest assured, we continue to refine this new operation and work groups within the agency continue to work upon expanding the assessments and our work plan for the next fiscal year. We will use this operation starting in the beginning of October.”