On January 22, 2021, FDA issued a Warning Letter to Yuyao YiJia Daily Chemical Co., Ltd., an over-the-counter drug manufacturer located in Ningbo, China. The Warning Letter was issued based on FDA’s review of “the records [Yuyao] submitted in response to [FDA’s] March 31, 2020 request for records and other information pursuant to section 704(a)(4)” of the Federal Food, Drug, and Cosmetic Act (21 USC 374(a)(4)). This appears to be the first FDA Warning Letter issued to a drug manufacturer based entirely on a remote records review, and has significant implications for drug manufacturers, including Chinese drug manufacturers.
We discuss FDA's records request authority, the significance of this Warning Letter, and our recommendations for Chinese drug manufacturers below.
Background on FDA's Records Request Authority
Enacted in 2012, the Food and Drug Administration Safety and Information Act (FDASIA) gave “FDA new authorities to help ensure the safety, effectiveness, and quality of drugs in the United States.” Specifically, section 706 of FDASIA amended 21 USC 374(a) of the Federal Food, Drug, and Cosmetic Act to permit FDA to “obtain certain records and other information from a drug manufacturer in lieu of or in advance of an inspection.” Amended 21 USC 374(a) states:
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.
The authority to request records in lieu of an on-site inspection was intended to provide FDA with greater flexibility with respect to foreign inspections. In the Senate’s hearing to approve FDASIA, U.S. Senator Harkin noted that the provisions in FDASIA were enacted to “ensure that the FDA can swiftly approve drugs and medical devices [and] protect patient access to new therapies . . . It will keep patients safer by modernizing the FDA’s inspection process for foreign manufacturing facilities, while also improving access to new and innovative medicines and devices.”
Notably, although FDA has stated that a company’s failure “produce . . . records in a timely manner, without reasonable explanation” in response to an FDA records request pursuant to 21 USC 374(a)(4) constitutes a refusal or a denial of an “inspection” under 21 USC 351(j), the agency has also stated that it does not consider a remote records review to be an “inspection.” This distinction is an important one, especially for sites that are currently classified “official action indicated” or “OAI” and sites listed in pending applications (NDAs, BLAs, ANDAs, and supplements) and identified by FDA as requiring an on-site inspection to verify readiness for commercial manufacturing. In such cases, FDA has stated that “inspection” means on-site inspection, and that a records review does not replace an on-site inspection.
FDA's Use of Its Records Request Authority During the COVID-19 Pandemic
Consistent with this legislative intent, shortly after the start of the COVID-19 pandemic, FDA announced it would begin using this authority to evaluate manufacturers’ compliance with “applicable FDA requirements,” including drug current good manufacturing practice (cGMP). Specifically, the press release states, “When we are temporarily not able to physically inspect foreign produced FDA-regulated products or manufacturers, as an interim measure we employ additional tools to ensure the safety of products imported to the U.S., which have proved effective in the past. These include . . . requesting records ‘in advance of or in lieu of’ on-site drug inspections.”
FDA also announced that the agency had already begun using its records request authority to perform record/desk reviews in lieu of on-site inspections in China: “we began exercising this authority when we postponed on-the-ground inspections of manufacturers of FDA-regulated products in China earlier in the outbreak.”
Yuyao Warning Letter and Takeaways for Chinese Manufacturers
On January 22, 2021, FDA issued Warning Letter 320-21-16 to Yuyao YiJia Daily Chemical Co., Ltd. (Yuyao). The Warning Letter was issued based on FDA’s review of “the records [Yuyao] submitted in response to [FDA’s] March 31, 2020 request for records and other information pursuant to section 704(a)(4) [21 USC 374(a)(4)].” According to FDA, these records demonstrate that Yuyao’s “methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP” and therefore the company’s drugs are adulterated.
This is the first Warning Letter issued to a foreign drug manufacturer under FDA’s records request authority since the start of the COVID-19 pandemic, and it raises several important issues for Chinese drug manufacturers. These issues, and our recommendations on how to avoid a similar Warning Letter, are discussed below.
FDA can keep records requests open with extended periods of time. When FDA issues a request for records in lieu of an inspection, FDA does not issue a Form FDA 483 to close out the records request. In fact, there is no formal “close-out” at all; rather, FDA can (and does) keep records requests open for weeks or months and will often request additional information from the company. This appears to be the case with Yuyao, as the Warning Letter notes that FDA sent Yuyao a “follow-up communication on May 8, 2020.” This illustrates the importance of fully and quickly responding to an FDA records request, as doing so will reduce the risk of receiving follow-up requests from FDA.
Companies have extremely limited opportunities to respond to any issues or concerns. Because FDA does not issue a FDA 483 or otherwise “close-out” a records request, companies are generally not presented with any formal findings or observations or provided an opportunity to respond until it’s too late. Indeed, FDA’s records review observations are for the most part documented internal memoranda that can only be obtained through a Freedom of Information Act (FOIA) request, which is a time-consuming and lengthy process that is impractical for many drug manufacturers.
In the case of the Yuyao Warning Letter, the Warning Letter itself states that “[t]his letter notifies you of our findings and provides you an opportunity to address the above deficiencies”, suggesting that, in FDA’s view, the Warning Letter served as notice of FDA’s observations.
In recognition of this lack of transparency, on February 1, 2021, FDA announced that it would be “implementing an interim process to communicate issues identified following a review of records” for pre-approval inspections (PAIs) and pre-license inspections (PLIs) for CDER-regulated products. According to the announcement, “FDA intends to communicate issues to facility representatives following the completion of its review of records” and will “consider any formal responses regarding these issues, including documentation of corrective action, prior to taking an action on a pending application impacted by these issues.” This gives manufacturers the opportunity to submit 483 response-like documents for records requests relating to pending applications. Manufacturers should take this opportunity to respond in full to any findings noted by FDA following a records review, just as would be the case with a FDA 483 following an on-site inspection.
OTC drug manufacturers continue to be under increased FDA oversight. Historically, OTC drug manufacturers have received less scrutiny from FDA than prescription drug manufacturers. But FDA has stepped up oversight of OTC drug manufacturers in the last several years, especially foreign OTC drug manufacturers. As a result of the COVD-19 pandemic, manufacturers of hand sanitizers have come under increased oversight. In fact, FDA recently placed all hand sanitizers manufactured in Mexico on Import Alert, the first country-wide import alert in FDA’s history.
Every interaction with FDA is important. This Warning Letter highlights the importance of prioritizing all interactions with FDA. While companies take an “all hands on deck” approach to on-site FDA inspections, other interactions with FDA often receive less attention. This includes responding to records requests. Companies should commit the resources needed to closely review FDA’s requests, carefully review all records before providing them to FDA, and prepare a clear and comprehensive response to any observations raised by FDA. This Warning Letter shows that companies must put their best foot forward with every interaction with FDA.
Although this is the first Warning Letter issued to a Chinese drug manufacturer based on a records request, it is unlikely to be the last. Further, the COVID-19 pandemic continues to impact FDA’s ability to perform on-site inspections, and FDA is likely to continue to use its records request authority to assess manufacturers’ cGMP compliance. Chinese manufacturers should take such requests seriously; doing so will help prevent FDA compliance actions, including Warning Letters and Import Alerts, and prevent delays in application approvals.
