It has been over three months since FDA issued its press releases stating that it was postponing most foreign and domestic facility surveillance inspections (see here and here). Since then, apparently only “mission critical” surveillance inspections have taken place, leaving the bulk of registered facilities on FDA’s inspection list to await the agency’s eventual return. While this might be good news for some drug facilities, it is creating an enormous headache for many more, including those that are currently listed as Official Action Indicated (OAI), since it is difficult to get a New Drug Application (NDA), Abbreviated New Drug Application (ANDA) or Biologics License Application (BLA) approved when one of the manufacturing facilities in a drug application is listed as OAI on FDA’s inspection database.
And it is nearly impossible for the review process to reach a successful conclusion if FDA finds that a manufacturing facility is exhibiting major deviations from current Good Manufacturing Practice, which is associated with an “unacceptable” state of compliance. Worse yet, even if the OAI classification is associated with a manufacturer of an Active Pharmaceutical Ingredient, rather than that of a Finished Dosage Form, FDA may, and frequently does, block review of the NDA, ANDA and BLA for the finished drug product made with that API (or drug substance).
Without any public statements on this issue from FDA, it is difficult to understand why this bottleneck is occurring. After all, FDA has had the statutory authority to conduct so called “paper inspections” since the Food and Drug Administration Safety and Innovation Act (FDASIA) was signed into law on July 9, 2012. Section 706 of FDASIA (codified at 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA)) specifies FDA’s authority to demand production of drug records remotely by the addition of the following text to the FDCA:
(4)(A) Any records or other information that the Secretary may inspect under this section from a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug shall, upon the request of the Secretary, be provided to the Secretary by such person, in advance of or in lieu of an inspection, within a reasonable timeframe, within reasonable limits, and in a reasonable manner, and in either electronic or physical form, at the expense of such person. The Secretary’s request shall include a sufficient description of the records requested. [emphasis added]
In addition, FDA has section 505(j) FDCA, which states that a drug shall be deemed to be adulterated:
If it is a drug or device and it has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection. [emphasis added]
In guidance that FDA published in October 2014, entitled Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection, FDA has interpreted section 501(j) FDCA as including some circumstances where inspection records are not provided by an establishment pursuant to 704(a)(4) FDCA.
“…[T]he ability to access and copy records is a critical aspect of FDA inspections. Not allowing an authorized representative of the FDA access to or copying of records that FDA is entitled to inspect by law, including not providing records that FDA requests pursuant to section 704(a)(4) of the FD&C Act, may be considered limiting an inspection. Examples of records limitations include, but are not limited to…:
- A facility provides some, but not all of, the records requested by the FDA investigator that FDA has authority to inspect.
- A facility provides the FDA investigator the requested records that FDA has authority to inspect, but they are unreasonably redacted.
- A facility refuses to provide records that FDA requests pursuant to section 704(a)(4), or such records are unreasonably redacted.” [emphasis added]
In addition, on August 25, 2017, FDA published SMG 9004.1 “Policy and Procedures for Requesting Records in Advance of or in Lieu of a Drug Inspection” that outlines the relevant timeframes for receipt and review of establishment records, and the types of records that can be requested.
Hence, it is unclear why agency resources, which have not been used for on-site surveillance inspections for over 90 days, have not been quickly redirected, en masse, to “paper inspections” under section 704(a)(4) FDCA. Nor is this simply an issue of FDA falling behind on inspections.
In the era of Covid-19 and anecdotal evidence of people hoarding medicines, the possibility of growing drug shortages has become a public health issue, and hence there is no excuse for further delaying approval of NDAs, ANDAs and BLAs due to FDA investigators who cannot travel to an OAI facility to perform a follow-up inspection. To make matters worse, some of these facilities could be manufacturing the next drug or biologic that preliminary evidence shows is helpful in treating Covid-19 symptoms.*
*As a postscript, there are indeed avenues to seek marketing authorization if the drugs are on FDA’s Drug Shortage List, or are used to treat COVID-19. Hyman, Phelps has extensive experience assisting clients in seeking Emergency Use Authorizations for pharmaceuticals and medical devices, even if the products are not approved (or, in the case of medical devices, cleared). We also have advised clients who have sought permission to distribute drugs that are experiencing shortages, despite prior adverse findings by FDA.