Laboratory diagnostic tests and affiliation with drug and device manufacturers have made labs a popular target for U.S. Food and Drug Administration (FDA) quality system inspection. Going through an FDA inspection can be an ordeal, especially if you are unprepared. And once the inspection ends, you may receive the dreaded Form 483 setting out the inspector’s "observations," i.e., alleged violations of the Food Drug and Cosmetic Act spotted during the inspection.
You then have 15 days to respond. And if the FDA is not satisfied with your response to the 483, it may escalate and issue you a Warning Letter. Here are 15 best practices for responding to 483s and avoiding Warning Letters.
1. Respond within 15 Days
The FDA expects labs to respond in writing within 15 working days of receiving the 483, either by specifically addressing the observations cited or requesting clarification. In the latter case, the 15-day clock starts ticking again when clarification is received.
2. Make Sure Your CEO Has Hand in Response
Failure of upper management to exercise appropriate oversight is among the most common of 483 observations. Accordingly, it is highly advisable to show the FDA that your CEO had a hand in preparing the response—either by having the CEO sign the response letter or having the lab compliance manager sign the letter and cc’ing the CEO.
3. Strike the Right Tone
The tone of the 483 response may be as important as its substance. Although you need not agree with all of the observations, be careful not to come off as resistant, uncooperative or defensive. Specifically say that you take the matter seriously and that your lab is fully committed to quality, safety and compliance. Sample language:
[Lab name] takes very seriously the matters raised in the observations as well as its responsibilities to provide a quality and safe product to the public in accordance with FDA regulatory requirements.
Some labs go a step further by expressing appreciation to the FDA for its constructive feedback and suggestions. Others include praise for the investigator and his/her team. Having established the appropriate tone and attitude, you can state your points of disagreement.
4. Describe Immediate Response
The expectation and unwritten rule is that once a lab receives a 483, it should immediately open a new corrective and preventive action (CAPA) investigation to:
- Address the concerns raised;
- Identify causes; and
- Determine the necessary corrective actions.
Do not respond to the FDA until you complete the initial investigation so you can refer to the investigation and its findings in the response letter.
5. Address Each CAPA Cited
Many 483 observations cite specific CAPAs in which implementation breakdowns occurred. The expectation is that you will address each and every one of the cited CAPAs—even the ones that you have closed—in your investigation and response letter.
6. List Root Cause of Each Cited Mistake
The initial investigation should identify the root cause of each cited incident in which a mistake occurred. List root causes for the different incidents in the response letter.
7. List Corrective and Preventive Actions for Each Root Cause
Describe the actions you have taken or propose to take to correct the problem identified in the root cause and prevent it from happening again. Do not simply tell the FDA that you are going to fix the problem; explain how. It may be appropriate to classify actions into two categories: i. immediate corrections; and ii. long-term solutions.
8. Describe Training and Other Implementation Actions
After you tell the FDA about your corrective and preventive actions, explain how you plan to implement them. Although details differ in each case, implementations typically include training personnel affected by changes made.
9. Specify Implementation Dates or Timetables
List the date of implementation for corrective and preventive actions you have completed and a rough deadline or timetable for actions still in the pipeline.
10. Describe Verification Efforts
The FDA requires you to verify the effectiveness of your corrective and preventive actions. Be sure to describe your verification efforts in the response letter.
11. Provide Documentation
Failure to provide adequate detail about corrective and preventive actions can lead to Warning Letters. So include copies of modified protocols, forms, procedures and policies with your response. It may also be advisable to include documentation of verification activities.
12. Provide Regular Implementation Updates
If your proposed corrective and preventive actions plan is expected to take two months or longer to implement, give the FDA regular monthly progress reports on the status of each measure until all actions are implemented.
Takeaway: To avoid escalation into Warning Letters, labs must respond to FDA Form 483s in writing within 15 days. The response must be appropriately toned, thorough, specific, supported by documentation and be signed by or cc’d to the lab CEO. It is equally important to follow up and implement the corrective actions your response letter describes and keep the FDA apprised of progress in implementation.