FDA Inspection and Possible Outcomes
FDA inspections and subsequent regulatory and administrative follow-ups are conducted in accordance with FDA’s Compliance Program Guidance Manual, Program 7382.845, Inspection of Medical Device Manufacturers (2015). Part II of the guidance require each inspection to assess if the firm’s quality management system is effectively established and maintained by assessing post-market information, including Recalls, MDRs, Corrections and Removals, significant changes in device specifications or in the manufacturing specifications, and a follow up on previous FDA FORM 483 observations. The levels of inspections and detailed requirements are shown in Table 1. Approaches to inspections is based on FDA’s Quality System Inspection Technique (QSIT) (1999).
Levels of FDA Inspections
Compliance Follow-up, For Cause, and Risk Based Work Plan inspections are dictated by the previous FDA FORM 483 findings and other regulatory information and may differ from the typical QSIT approach. The inspectional guidance provided by the assignment, the district compliance branch, and/or CDRH will guide the direction of these inspections. However, elements of the QSIT Guide may also be utilized.
A Level 1 inspection may intensify to a Level 2, or above, as findings are discovered. A Level 1 inspection is an Abbreviated Inspection and may be used for routine surveillance. Level 1 inspections cover the CAPA subsystem, then either the Production & Process Control (P&PC) or the Design Control subsystem. For a Class I manufacturer, P&PC would normally be chosen. The following are considered in determining whether to select P&PC or Design Controls:
- CAPA findings during the inspection.
- The selection of the P&PC or Design Controls subsystem should be alternated over time.
- Significant changes since the previous inspection, such as product changes which required a new submission or application, or if there were any major process changes.
- Post market information indicating potential design problems.
Class I, II and III products are subject to both a Design Control inspection and a P&PC inspection, including engineering changes, DHRs, DMRs, validation of software used for production or quality systems, document control, and quality procedures. Class I products that are not automated with computer software are exempt from Design Control.
FDA’s guidance manual for medical device inspections has identified two outcomes for the inspector to consider: Situation I and Situation II. Situation I indicates there are one or more major deficiencies with the Quality System regulation, and the inspection will be classified as Official Action Indicated. Situation II is when inspections conclude there is minimal probability that the company would produce nonconforming and/or defective finished devices. Examples of Situation I major deficiencies include:
- No procedure(s) which address corrective and preventive actions.
- No procedure(s) on how the quality data will be analyzed and utilized.
- Where design controls are required, no design control procedure(s) for a particular device or family of devices, i.e., only high level design control procedures.
- Where design controls are required, no design change control procedure(s).
- No documented process validation for process(es) for which the results cannot be fully verified.
- A deficiency in one or more element(s) of the subsystems. The QSIT Guide focuses on the most important aspects within each subsystem and can be utilized to determine what the Agency believes is critical and therefore would constitute “major” problems if not adequately addressed. Particular attention should be paid to the relationships of requirements. For example, deficiencies in both purchasing controls and acceptance activities can indicate a major deficiency because control of components and suppliers depends on a mix of both activities, and if there are problems with one or both, assurances are greatly diminished.
- The existence of products which clearly do not comply with the manufacturer’s specifications and/or the Quality System regulation and which were not adequately addressed by the Corrective and Preventive Actions Subsystem (CAPA) program.
- Non-correction or inadequate correction of major deficiencies from previous inspection(s). Repeat deficiencies of same or similar deficiencies from previous inspection(s).
Ramifications of an OAI classification
Based on the significance (risk) of the device and the findings, the FDA district office (in conjunction with CDRH in DC) will consider which administrative and/or regulatory action to initiate. Possible actions include a Warning Letter, an injunction, detention, seizure, civil penalty, and/or prosecution. We have seen several outcomes where close supervision of the firm by the Center for Disease and Radiological Health (CDRH) based in Washington DC, followed by a Level 2 inspection, is the course of action chosen by the FDA.
Vision28 Checklist for FDA FORM 483 responses
What to do after an inspection
The inspection is over, and the FDA Inspector is presenting you with their findings. Your next steps are critical to your business: manufacturers who are not prepared to respond to observations of nonconformances cited on FDA’s Form 483 quickly and thoroughly may receive a Warning Letter. The following check list for dealing with FDA FORM 483s is designed to help you avoid a Warning Letter.
FDA Inspection Close-out Meeting
- FDA Inspector will issue you a Form 483 listing what the inspector believes are serious, objectionable conditions found during the inspection.
- Ask questions until you understand all of the FDA inspector’s 483 observations.
- No not argue with the inspector, be courteous and professional.
- No need to annotate the FDA Form 483 with “promise to correct”.
- Do not promise actions, you need to think through the ramifications of all your choices.
Planning your FDA FORM 483 responses
- Start working on your 483 responses right away, you only have 15 business days to respond.
- For contingency scheduling, its best to be prepared to respond in 15 calendar days.
- Do not over promise.
- Do limit the response only to what was specifically cited and systemic corrections that would be expected by FDA to prevent future problems in this area.
- Ensure your responses are limited to actions required to fulfil the regulations; no “nice to have” responses.
Writing the FDA FORM 483 responses
- Make clear you are taking the observations of nonconformances seriously.
- Address all the observed nonconformances using the Corrective and Preventive Actions (CAPA) quality system.
- Make corrections immediately, if possible, and include in your response:
- a description of your corrections in your 483 responses,
- the evidence that demonstrates you corrected the nonconformance,
- and the evidence you have verified that the correction to the nonconformance is effective, and that the correction does not introduce any new adverse effects.
- Give detail descriptions of the corrections you will be making, and a realistic schedule of completion.
- FDA will require monthly updates of your scheduled corrections.
- FDA will follow up each response in their next inspection, so always do exactly what you said you would do. They will check to make sure you did not revert to practices that caused the original observation.
- FDA will find any inconsistency or misleading statements in your response and will “pull the thread” until everything unravels.
Escalation of FDA Responses
If you do not respond to the FDA FORM 483, or your response shows you do not take FDA seriously, or if you respond inadequately, the next step is a Warning Letter. Warning Letters are public information available to your customers and your competitors.
If your response to the Warning Letter is inadequate, the next step is a consent decree. This is a legal agreement between you and FDA overseen by a federal judge. Companies agree to consent decrees to avoid litigation.
Needless to say, you want to avoid a Warning Letter!
Vision28 can help you chart a course for a successful FDA FORM 483 response
It does not matter how you got here, what matters is how you manage the situation. Impulsive responses lead to bad judgments and mistakes. To effectively manage the situation, you need to plan for success. We suggest you contact us immediately so that we can help you manage the situation and chart a course for success. We will work with you to write an appropriate response, structure it in a format FDA expects, and submit it before the deadline.
Preventing an FDA Warning Letter
To ensure FDA is satisfied with your FDA FORM 483 nonconformance responses, we also recommend that you have Vision28 conduct an FDA mock inspection after you have remediated the observations as described in your FDA FORM 483. We will examine each response and verify you have done exactly what you said you would do and that your corrective actions are effective and do not introduce new adverse effects. We will then communicate the results of this inspection to the FDA as part of your close-out letter, which demonstrates that you have taken the 483 seriously and you have had a third party help your remediation efforts.
An FDA FORM 483 does not have to lead to serious business interruptions. You just need to have the right partner to work through what needs to be done.