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Law360 (February 19, 2021, 5:51 PM EST) --
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| Peter Lindsay |
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| Nathan Sheers |
1. Inspection Delays Present Challenges and Opportunities for Maintaining Inspection Readiness
2020 saw a significant downturn in drug inspections by the FDA. The agency typically conducts more than 1,600 inspections of foreign and domestic drug manufacturing establishments each year.
And since 2015, the majority of drug inspections have been at foreign sites. The release of a recent U.S. Government Accountability Office report revealed that from the FDA's postponement of inspections in March until Oct. 1, 2020, the FDA's inspection numbers plummeted to only three foreign mission-critical inspections and 52 in the U.S.[1]
COVID-19 will likely continue to hinder the FDA's ability to conduct in-person visits at foreign facilities in 2021. An FDA official recently announced via Twitter that the agency had begun conducting prioritized inspections in China and is planning to initiate prioritized inspections in India shortly.[2] But the FDA has acknowledged it will need to monitor the global situation and assess the feasibility of returning to in-person foreign surveillance inspections as conditions begin to improve.[3]
Given the significant logistical challenges in manufacturing and distributing COVID-19 vaccines, it is likely that general inspection efforts may very well be impeded in many foreign countries through at least 2021.
The FDA also faces continuing challenges to ramping up inspections within the U.S. The FDA uses its own rating criteria to determine when it is safe for agency personnel to conduct routine surveillance inspections domestically.
The FDA reported to the GAO that in early December, conditions were appropriate for conducting such surveillance inspections in only 49 U.S. counties, leaving more than 3,000 remaining counties with conditions that only permitted mission-critical inspections.[4]
COVID-19 positivity rates appear to be improving currently in many areas of the country but are still at elevated levels, and may increase again as new COVID-19 variants gain ground and vaccination rates lag. COVID-19 will likely continue to negatively impact in-person domestic inspections in 2021.
While in some cases, the delay in inspections may provide some breathing room for drug GMP manufacturing sites, it is important that companies continue to take steps to drive or maintain compliance sustainability.
COVID-19 limitations have likely challenged certain normal oversight, including the ability to perform corporate or third-party reviews. The recent change in the administration is also important. Past Democratic administrations have resulted in more warning letters and enforcement actions.
As a result, it is more important than ever to confirm good manufacturing practice, or GMP, compliance as the FDA's attention shifts from COVID-19 fraud to refocusing on the agency's key manufacturing and quality concerns. Third-party reviews, even if virtual, may be helpful in assessing key risk areas based on a manufacturing site's product mix, past history and likely agency focus areas, including any customer complaints.
2. Preparations for Remote Evaluations and Other Alternative Surveillance Tools
Given COVID-19 travel limitations, the FDA expanded the use of other surveillance tools to evaluate the quality of drug products imported into the U.S. The alternative tools routinely implemented by the FDA included:
- Sampling and testing of products arriving at the U.S. border;
- Using information shared by certain foreign regulatory authorities through mutual recognition agreements and other confidentiality agreements; and
- Requesting records directly from facilities in advance of or in lieu of certain drug inspections.[5]
It is important for companies to note that the FDA's routine use of these tools has resulted in further action by the agency. For example, surveillance testing of alcohol-based hand sanitizers at the border resulted in multiple firms receiving warning letters and ultimately an umbrella import alert against all firms manufacturing such sanitizers in Mexico, unless they are on a preidentified list of acceptable firms.[6]
In addition, the FDA recently issued a warning letter to a Chinese over-the-counter drug manufacturer, including hand sanitizers, who had not provided an adequate response to a record request.[7] And the FDA's review of manufacturing records submitted pursuant to a record request associated with a pending application resulted in a complete response letter from the agency.
It is therefore critical that companies adjust their processes to ensure good communication with the FDA and to minimize the possibility of negative outcomes from the FDA's use of these tools.
For example, the FDA representatives have reported that the agency issued 578 record requests to pharmaceutical and biological product manufacturing facilities as of Sept. 30, 2020.[8] In some instances, companies have experienced frustration with the FDA's record request process and the lack of formal opportunity to address potential concerns.
The FDA recently updated its guidance to note that both the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research have implemented interim processes to communicate with manufacturing facilities regarding issues identified following a review of records requested in advance of or in lieu of a preapproval or prelicense inspection.[9]
Even with these new processes in place, companies will need to be very attentive to ensure that the FDA receives and understands the information provided.
Another complicating factor for companies is the current uncertainty about how the FDA will use the information it collects through alternative tools within its traditional inspection program or what opportunities the industry may have to address any concerns the FDA may have.
The agency has taken the position that establishment records alone cannot substitute for an FDA surveillance inspection.[10] The FDA has noted in the past that only FDA in-person inspections and European regulator reports through the mutual recognition process can satisfy U.S. statutory requirements for surveillance inspections.[11]
This hesitancy is perhaps based on the agency's current review of potential legal issues related to how it may use information gathered through alternative tools, which likely includes whether these tools technically fit within the inspection authority described in the Federal Food, Drug and Cosmetic Act.
While the ambiguity around records requests remains, at this stage the FDA appears willing to move forward with remote evaluations. The FDA has announced that it is conducting a pilot program and developing COVID-19 guidance related to remote evaluations using interactive video or other types of interactive tools.
The FDA has been slower to explore and adopt remote evaluations as some European regulatory authorities and others have already conducted inspections and audits using remote technologies. The recent GAO report also encouraged the FDA to consider remote oversight.
In light of the FDA's apparent move toward remote evaluations, companies need to reassess their inspection readiness processes to account for remote technologies and records requests.
Technological preparation will be key, of course. But additional preparation will likely be necessary to ensure effective communication. Inspection processes typically rely on both formal and informal feedback during in-person conversations and wrap-ups. Remote evaluations may not offer the same opportunities to identify areas of concern, confusion or miscommunication as in-person review.
As a result, more proactive discussion or provision of context may be necessary to present an accurate picture of the site's status. Companies need to begin to think through how their normal inspection cadence will be altered through the use of remote evaluations and alternative tools.
3. Need to Consider Ongoing COVID-19 Impact
The current pandemic has introduced new pressures for many companies grappling with at least partially remote workforces and supply chain constraints.
Recognizing this, the FDA developed guidance documents that provided additional flexibility in a number of areas during the COVID-19 public health emergency. Companies utilizing this flexibility need to ensure that any deviations from routine processes were appropriately justified and documented consistent with their quality systems.
Companies also need to consider the impact to facilities that anticipate a preapproval inspection or prelicense inspection in 2021 or facilities that may be classified as "official action indicated."
Thus far, the FDA's inspection challenges have not significantly impacted the overall numbers of FDA drug approvals.
As of November 2020, the FDA reported to the GAO that it was operating above its 90% on-time action performance goal for approval decisions.[12] But the inability to conduct preapproval inspection has led to approval delays and will likely lead to even more delays going forward as regulatory deadlines for applications submitted during the COVID-19 pandemic come up, particularly if the FDA cannot increase substantially its inspection reach.
Similarly, firms seeking reinspection for facilities with "official action indicated" status from a previous inspection will need to wait for an in-person reinspection under the FDA's current approach. To date, the FDA representatives have been cautious about using alternative tools to change "official action indicated" status given its past experience where such facilities often did not successfully pass an in-person reinspection.
Facilities will need to maintain a high degree of compliance awareness so that they can successfully pass a remote inspection and avoid the even more consequential and enduring downside of an "official action indicated" inspection result.
Peter Lindsay and Nathan Sheers are partners at Paul Hastings LLP.
The opinions expressed are those of the author(s) and do not necessarily reflect the views of the firm, its clients or Portfolio Media Inc., or any of its or their respective affiliates. This article is for general information purposes and is not intended to be and should not be taken as legal advice.
[1] United States Government Accountability Office, Report to Congressional Committees, COVID-19: Critical Vaccine Distribution, Supply Chain, Program Integrity, and Other Challenges Require Focused Federal Attention, GAO-21-265 (January 2021), at 150-51 (hereinafter "GAO COVID-19 Report").
[2] Twitter post by Dr. Patrizia Cavazzoni, FDA (Jan. 26, 2021).
[3] GAO COVID-19 Report at 150.
[4] GAO COVID-19 Report at 151.
[5] FDA, Guidance for Industry: Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers (Updated Jan. 29, 2021), at 4.
[6] Import Alert 62-08.
[7] FDA Warning Letter to Yuyao YiJia Daily Chemical Co., Ltd. (Jan. 22, 2021).
[8] Bowman Cox, Preparing for the Return of US FDA Inspections, The Pink Sheet (Feb 05, 2021).
[9] FDA Guidance for Industry: Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers (Updated on January 29, 2021), at 5.
[10] GAO COVID-19 Report at 154.
[11] GAO COVID-19 Report at 153. Interestingly, under an interim policy, FDA has allowed the combination of these two tools (non-European inspection report and record request) to support its risk-based surveillance of establishments already manufacturing drugs marketed in the U.S. Id. at 154.
[12] GAO COVID-19 Report at 155.
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