Response Not Adequate, Ouch!
For this week’s guidance, Dr. D struggled over making the decision to write about the need to establish procedures, the importance of acceptance activities, or the joys associated with responding to Form 483 observations. The doctor was able to waltz through the FDA’s Warning Letter Database and find a warning letter that provided great examples of all three topics. However, for this week’s Devine Guidance (DG), the doctor decided to focus on responding to Form 483 observations. Over the years, Dr. D has pontificated, on multiple occasions, the importance of formulating an acceptable response to a Form 483 observation. Many of you readers have already had the pleasure of responding to inspectional observations. Some have had more than one opportunity to experience the joys of responding to Form 483 observations. A few of the readers have had the pleasure of being on the receiving end of a warning letter. Astute Chief Jailable Officers (CJOs) recognize the importance of providing the FDA with a complete response, including documented evidence of correction. Even better, most CJOs will do everything in their power to ensure their establishments remain in compliance with all applicable quality, regulatory and statutory requirements. Remember, the word compliance is not some neologism (look-it-up). Additionally, compliance is not just another buzzword to be taken lightly. Furthermore, and contrary to the popular beliefs of many, “There is no such thing as minimum compliance or maximum compliance, there is only compliance.” Enjoy!
Warning Letter – August 3, 2016
Folks: Receiving 11 Form 483 observations during an agency inspection is almost always going to end badly for the offending establishment. Sprinkle in eight responses coming from FDA beginning with: “We reviewed your firm’s response and conclude that it is not adequate”, and the awarding of a not-so-prestigious FDA Warning Letter will be in the offending establishment’s future. A CJO does not need to be clairvoyant to see this outcome. The following warning letter excerpt, extracted from a 2016 warning letter, is not necessarily unique to the establishment on the receiving end of the warning letter referenced in this week’s guidance. In fact, during the course of a year, this same type of agency response can be seen in many of the warning letters issued each year by FDA. On a positive note, this type of agency response can be prevented with a clear and concise response to each Form 483 observation received when our friends from the agency appear in an establishment’s lobby for a friendly cup of java and an inspection.
Warning Letter Excerpt
Observation Five (5) – Failure to establish and maintain procedures for acceptance activities, as required by 21 0CFR 820.80(a). For example, your firm does not have written procedures for receiving, in-process, and final acceptance activities. Additionally, your firm conducts pressure testing on compression socks as part of final acceptance. Pressure testing is conducted using different calf and thigh former girths than specified in the equipment manufacturer’s instructions. However, no justification is documented for this change to the test process.
We reviewed your firm’s response and conclude that it is not adequate. Your firm indicated it will create procedures and contact the equipment manufacturer (b)(4) in a manner not specified in the instructions. However, there is no indication your firm plans to evaluate the potential impact of inadequately documented acceptance activities for previously distributed devices.
21 CFR, Part 820.80(a) – Receiving, In-process, and Finished Device Acceptance
(a) General. Each manufacturer shall establish and maintain procedures for acceptance activities. Acceptance activities include inspections, tests, or other verification activities.
Compliance for Dummies
Dr. D has always taken a before-state (historic), current-state, and future-state (post-correction) approach when responding to a Form 483 observation. What in the heck does that mean? For example (reference this week’s warning letter excerpt), if an establishment does not have procedures for acceptance activities, once the procedures have been established (defined, documented and implemented), a decision must be made on what to do with previously accepted product. Most establishments will bite the proverbial bullet and absorb the unanticipated costs associated with the re-inspection and/or re-test of previously accepted product. In the establishment’s response to FDA, the response should contain wording that clearly defines the activities being pursued to mitigate the inspectional observation such as:
- Scripting a procedure
- Performing re-inspection and/or re-test of previously accepted product
- Steps to be taken if previously accepted product is found to not be in compliance with its product specification, such as rework or a potential market withdraw (Recall, that nasty six-letter word)
- A thorough review of the Quality Management System (QMS) to verify if additional procedures need to be written
- Steps to be taken to preclude any recurrence of the same observation(s) in the future
Additionally, the agency loves to see documented evidence of compliance. In God We Trust, but all others bring data (thank you Dr. Deming). If a new procedure has been established in support of correcting a compliance deficiency, provide a released copy of the document to FDA. Trust the doctor when I say, the FDA loves to read procedures, you write it and the agency will read it.
Furthermore, if inspection and test activities are being pursued, provide the results of this additional testing as part of the response. Now granted, the FDA will probably not ask for all previously accepted products to be 100% tested, retested, inspected or re-inspected; however, the agency will expect some level of due diligence pursued. If a sampling approach is pursued, the FDA will expect to see a valid and cohesive sample-size rationale for the sample size selected. If the sample size is n=1, the CJO will definitely have some serious explaining to do.
Finally, responding to Form 483 observations is really somewhat of a unique art form. For example, the following elements should be included in the response:
- A regurgitation of the initial observation
- Containment activities pursued
- Impact to finished medical devices previously entered into commerce
- Impact to the QMS
- Steps taken to correct the compliance issue
- Verification of Effectiveness (VOE) of mitigation activities implemented
- Steps take to preclude a recurrence of the compliance issue
- Documented evidence for the previously mentioned bulleted points being executed
Now this may seem like a whole bunch of work for responding to a Form 483 observation, but trust Dr. D when I say that this truly is a pay-me-now versus pay-me-later scenario. The doctor has experienced, firsthand, the regulatory and ultimately fiscal pain associated with mitigating a prized agency warning letter. Believe it or not, it is so much easier to remain in compliance and the good graces of FDA versus having to navigate the tumultuous regulatory waters of a warning letter. Before the doctor forgets, make sure the response to any and all Form 483 observations finds its way into the hands of FDA within 15 days. Why? Can you say warning letter?
Takeaways
For this week’s guidance, the doctor will leave the readers with four takeaways. One: Each time you come across the term establish in the Quality System Regulation (21 CFR, Part 820), that is code for writing a procedure. There is no time like the present to start writing. Two: When responding to a Form 483 observation, always, let the good doctor repeat always, provide documented evidence of correction. Three: Ensure that previous, current and future-state scenarios are addressed. Unfortunately, sometimes a market withdraw may be the flavor of the day if the results of product re-testing and re-inspection proves to be problematic. Four: Make sure the FDA has the response within 15 days. If not, the failure to respond to Form 483 observations will quickly escalate to a warning letter. In closing, thank you again for joining Dr. D, and I hope you found value in the guidance provided. Until the next installment of DG, cheers from Dr. D., and best wishes for continued professional success.
References
- Code of Federal Regulation. (April 2016). Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
- Code of Federal Regulation. (April 2016). Title 21 Part 803: Medical device reporting. Washington, D.C.: U.S. Government Printing Office.
- Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation –21 CFR, Part 820. Charleston, SC: Amazon.
- Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
- FDA. (August 2016). Inspections, Compliance, Enforcement, and Criminal Investigations. A.R.C.O.S., Srl. Accessed January 22, 2017. Retrieved from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm515195.htm
Related Articles
-
The new guidance is intended to establish confidence in automation used for production or quality assurance systems and describe various methods and testing activities that may be applied to establish computer software assurance and meet regulatory software validation requirements.
-
The updated guidance document clarifies what constitutes a statement of the basis for the deficiency and includes examples of well-constructed deficiencies and industry responses to facilitate a more efficient review process.
-
The revised cybersecurity draft publication is not intended to be a checklist for healthcare organizations to follow, but rather a guide to help them comply with the HIPAA Security Rule.
-
The draft guidance proposes updates to clarify how the Breakthrough Devices Program may be applicable to certain medical devices that promote health equity, as well as considerations in designating eligible devices that may benefit populations impacted by disparities in health…
