By Mark I. Schwartz –
FDA’s Field Alert Report (or FARs) reporting requirements are authorized under 505(k) of the Federal Food, Drug, and Cosmetic Act. The requirements have been in effect since the agency promulgated the regulatory provision at 21 CFR 314.81(b)(i) in 1985. The regulatory provision states, in part, that:
The applicant shall submit information of the following kinds about distributed drug products and articles to the FDA district office that is responsible for the facility involved within 3 working days of receipt by the applicant. The information may be provided by telephone or other rapid communication means, with prompt written followup. The report and its mailing cover should be plainly marked: "NDA – Field Alert Report."
(i) Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article.
(ii) Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed product, or any failure of one or more distributed batches of the drug product to meet specifications established for it in the application.
The purpose of the FAR is to quickly identify drug products in the field that pose a potential health hazard to the public. All drug manufacturers with approved NDAs and ANDAs are required to submit a FAR to the FDA if they find any significant problems with an approved drug. In the preamble to the final rule in 1985, the agency stated that “…because these reports can lead to preventing potential safety hazards from products already in distribution, the agency emphasizes that the reports are required for both confirmed and unconfirmed problems.”
Manufacturers are to submit their FARs via Form 3331. Also, in contrast to postmarket adverse drug experience reporting under 21 CFR 314.80, FARs potentially involve one of a variety of drug quality issues that could be of interest or concern to both the field office and CDER.
According to the Compliance Program Guidance Manual 7356.021 (CPG), which was updated within the past year and upon which much of the information below is based, the three working days begins when the applicant becomes aware of a problem either through a complaint or internal testing, such as during stability testing or testing of reserve samples. It does not begin the day that the applicant confirms or invalidates a problem. The CPG further states that dissolution failures, impurity level problems, mislabeling issues (including possibly obscured labels, missing labels and incorrect labels) and sub-potency and super-potency issues concerning distributed products all fall within the ambit of 314.80(b)(ii).
FDA has previously stated that the following situations also meet the reporting threshold under 314.80(b)(ii): problems with appearance or particulates, dissolution failures, broken, or split tablets, unknown spots on tablets, as well as lyophilization problems such as finding moisture in the vialed product. Even if the product is at its expiration date, FDA still expects the firm to report these problems.
However, if the manufacturer can invalidate the problem (such as a problem that ends up being due to a lab error) within the three working days allotted under the regulation, then a FAR is not required. If further investigation is required and goes beyond the three working days, then a FAR must be submitted to FDA. FDA recommends reviewing the Guidance on Investigating Out-of-Specification Test Results for Pharmaceutical Production for assistance with investigating out-of-specification (OOS) test results.
Not surprisingly, foreign holders of NDAs or ANDAs must follow these FARs requirements as well, however, the foreign application holders’ U.S. agents are responsible for reporting the FARs to FDA, and the foreign agent is required to submit the FARs to the district office where they are located. What is interesting, and indeed somewhat suspect, is the statement in the CPG that drugs “distributed in foreign markets” must also follow these requirements. It is unclear what statutory authority FDA would cite for requiring firms with drugs distributed in foreign markets to file field alerts, since these products, by definition, are not under an NDA/ANDA.
For FARs that affect more than one product, firms should submit one FAR per NDA/ANDA of distributed product. Multiple lots of the same product may be submitted in one form.
Most district offices have a Drug Quality Reporting System/FARs email box dedicated to receiving FARs from the firms in their districts. Firms are generally instructed to send all FARs to this one mailbox. Usually the district coordinator serves as the district’s contact point to facilitate communication with the drug manufacturer on matters pertaining to the status of a FAR.
The district office performs assessments on all FARs (whether initial, follow-up or final) and provides them to CDER. It is the district office’s responsibility to determine whether the firm’s root cause analysis and CAPAs are adequate to mitigate the risk and to comply with FDA regulations, as well as to request a timeline for the firm’s completion of their investigation.
The district office that is the recipient of a FAR is supposed to send its report on the FAR (this includes the initial, follow-up and final FAR) to CDER’s Drug Quality Reporting System (DQRS) within five working days after receipt from the firm.
As part of the district’s preparation for inspections, they are expected to review any FAR to be covered while on inspection. The district is expected to request from CDER DQRS the FAR history associated for a specified firm and drug product. So, whatever the firm has done internally to close out the issues related to their FARs since the last inspection, these are likely to be reviewed on a subsequent FDA inspection.
Indeed, when reviewing firm SOPs during an inspection, the investigators are to note the firm’s handling and reporting of NDA FARs to ensure their compliance with FDA regulations. The failure of a firm to submit a FAR for a distributed and violative product is reportable as an FDA-483 observation.
The CPG further recommends that significant violations related to a FAR, as well as under-reporting or lack of FAR reporting, should be included in recommendations for advisory actions (i.e., the issuance of an untitled or warning letter, among other possibilities).
Therefore, this serves as a reminder to firms that even when you have closed out your FARs with the district, and even if you have not received any comments or concerns regarding your filing, FDA investigators will be reviewing the firms’ internal documents to all FARs on the subsequent inspection. Forewarned is forearmed, as the proverb goes.