FDA’s Office of Regulatory Affairs (ORA) is the lead office for all field activities, including inspections and enforcement. During an inspection, ORA investigators may observe conditions they deem to be objectionable. These observations are listed on a Form FDA 483 when, in an investigator’s judgment, the observed conditions or practices indicate that an FDA-regulated product may be in violation of FDA’s regulations.
In FDA’s fiscal year 2023 (10/1/2022 to 9/30/2023) the Agency issued 720 Form FDA 483s (“483”) to medical device establishments (a 34% increase from FY 2022). The top five citations were, in order, lack of or inadequate corrective and preventative action (CAPA) procedures, lack of or inadequate complaint procedures, lack of or inadequate non-conforming product procedures, lack of or inadequate procedures for purchasing controls, and finally, inadequate CAPA documentation.
While it is not a requirement to provide a written response to a 483, it is a firm’s best opportunity to demonstrate its understanding of the seriousness of the issue(s) observed (and not observed), its plan to further investigate and review the issue(s), and its commitment to addressing the issue(s) in a timely manner, in order to reduce the likelihood of receiving a Warning Letter or further enforcement action. OnemataDC not only recommends responding to a 483, but there are specific strategies we recommend firms employ in their written response to best avoid a Warning Letter. Below we outline some key tips and tricks, based on our firsthand experience and publicly available data, to help a medical device firm respond to a 483:
Many firms open a CAPA to address an observation, or grouping of similar observations, and inform FDA that a CAPA has been opened in its 483 response. However, simply opening a CAPA is not sufficient. To best avoid the observation(s) from making their way to a Warning Letter, a firm should progress through as much of the CAPA process as possible and include records of the progress in its initial response to the 483. Subsequent response(s) to the 483 should continue to show progress of the CAPA via production of records, and ensure any changes which are implemented are evaluated as part of the CAPA and verified for effectiveness prior to closure of the CAPA. For example, in this Warning Letter, the Agency referenced that the CAPA(s) were not through verification of effectiveness (VOE).
Similar to the above, many firms either author/release a new procedure, or modify an existing procedure, to address an observation or similar observations. Again, this will not be sufficient to reduce the likelihood of a Warning Letter. A firm must demonstrate via production of records that the new or modified procedure has been implemented (e.g. Change Order releasing procedure, training records of impacted personnel on the newly released procedure, Verification and/or Validation of new process, etc.). This is an example of a Warning Letter which references that procedures were not implemented.
There are situations where the investigator could find that documentation is not adequate, and cite this inadequate documentation as an observation. It will not be sufficient to simply correct the cited documentation to avoid a Warning Letter. FDA will expect a documented review on a scale and scope commensurate with the risk of the issue(s) associated with the record(s). The review is to establish the firm has sufficiently reviewed the available information to demonstrate the issue(s) is understood, and is under a state of control, through the identification of inadequate record(s) and the plan for the correction of the inadequate record(s) (whether that is immediate, or with estimated dates of completion provided, etc.). An example of a Warning Letter referencing the absence of a retrospective review can be found here.
The issuance of a 483 indicates that the manufactured product(s) may be in violation of FDA regulations. As such, the Agency will expect a firm to justify why manufacturing and distribution of the product(s) is/are able to continue, and if unable to provide a reasonable justification, to cease manufacturing and commercial distribution until the quality management system (QMS) is brought back into compliance. Justifications can include elements such as, but not limited to; discussion on the impact of the observation(s) to product in all material stages, discussion of any changes, and/or Verification/Validation, which have been completed to address the issue(s) on an interim and/or permanent basis, discussion of other elements which demonstrate a state of control has been established for the issue(s), etc. Here is an example of a Warning Letter issued an HCT/P firm which references the absence of a justification for continued distribution.
Similar to above, the Agency will expect a firm to justify why non-conforming product (manufactured under a violative QMS) may remain in the field, or, recall the non-conforming product in accordance with a justifiable recall scope. An example can be found here of a Warning Letter issued to an HCT/P firm referencing the absence of a justification for keeping violative product in the field.
Note that this is not an exhaustive list, and there are many more strategies we could recommend based on a particular firm’s situation. If you would like to learn more, or if you need expert help planning and executing compliance projects, please reach out to us.