So the Food and Drug Administration has just completed a friendly visit to your facility, and the inspector has decided that your organization has deviated in regards to compliance with 21 CFR, Part 820, the Quality System Regulation (QSR) or another Part of the Code, e.g. 801, 803, etc. Now what?

For starters, management can commence with the public flogging of all of individuals responsible for the functional areas failing to pass muster during the inspection. Prior to signing the Form 483, the management representative can argue vehemently with the inspector, stating that his observations are inaccurate, and thus alienating the Agency. Another approach might be to climb onto the top of the table in the conference room and throw a tantrum, not unlike a spoiled two-year old. Even better, fake an immediate illness, let out a plangent scream of pain, run for the door, and never return.

Dr. D. would like to recommend reading earlier columns in the Medical Device Summit focusing on Devine Guidance (DG) and compliance with the QSR. Besides, if the organization was laced with rabid readers of Dr. D’s chrestomathies (look-it up), just maybe signing the old Form 483 might not have been necessary. Regardless, in this edition of DG, the doctor will focus on responding to Form 483 observations.

Sign the blasted Form 483
During the final debrief by the inspector, when the observations are presented, ensure the organization fully understands the nature of each observation. If the observation is inaccurate and documented evidence exists, now would be a good time to ensure clarification of the issue, with the investigator, occurs. I recommend locking the door, and not letting FDA depart the premises, until the observation is fully understood. Just do not attempt a kidnapping – just kidding.

Dr. D has seen instances were an observation has been rescinded during the final debrief, when the correct or additional evidence or clarification is presented. If the observation has already been corrected, please provide the necessary evidence to the inspector. What one should never do is enter a protracted argument over observations. Once points have been made, and the basis of the observations understood, the Form 483 should be signed. Ensure the inspector fully understands that your organization is committed to correcting the deficiencies.

What is a Form 483 (Notice of Inspectional Observations)?
Section 704 of the Federal Food, Drug, and Cosmetic Act establishes FDA’s authority to inspect facilities that fall under the governance of the Act. Additionally, Section 704 requires FDA to provide facilities inspected with a report that delineates all deviations noted during the inspection. From a historical perspective, the official birth year of the Form 483 was 1953, with the addition of Section 704(b) of the Act.

The good news is that a formal response to the Agency is not mandated by law. The bad news is that failure to respond to a Form 483 will in all likelihood result in FDA’s issuance of a warning letter against the organization failing to respond. Furthermore, there is a stated requirement that the initial response to the Agency be made with in 15 working days. That said, Dr. D “STRONGLY RECOMMENDS” all device manufacturers respond to each Form 483 observation within 15 days, even if you do not agree with the observation.

In fact, now would be the time to formulate and finalize a salient position as to why your organization disagrees with an observation. At the end of the day, if the observation is minor, Dr. D always recommends just fixing the issue instead of arguing the relevancy with the Agency. Why? Because losing sleep worrying about insignificant issues is just not worth the trouble.

Crafting a response to the Form 483
First, begin by understanding why your organization received the Form 483. In the eyes of the Agency, they issue Form 483s when an inspector determines an organization has failed to comply with a specific part of the code delineated under the Act. FDA employs the Form 483 as a vehicle to ensure organizations quickly and properly correct all noted observations. Remember, a response is not mandated by law; however, the Agency has the ability to unleash a whole lot of pain for organizations that chose not to comply with the request for correction. Trust Dr. D when I emphatically state, “If the Agency is not happy with your organization’s approach to responding to a Form 483, your organization is not going to be happy when they receive the warning letter.” Simply stated, “Warning letters equate to pain!”

The next step is to ensure a response is drafted and returned to the Agency within 15 working days. From FDA’s perspective, a prompt and well-positioned response equates to an organization taking the Form 483 seriously. Dr. D recommends always placing each observation into the Corrective and Preventive Action (CAPA) system, regardless of how innocuous it might be. This way progress for each of the observations can be tracked individually. Additionally, it makes the review of actions pursued easier to review by the Agency.

Furthermore, the response to the Form 483 should contain sufficient granularity so the Agency understands the steps being pursued to correct the non-compliances. For example, in responding to the Form 483, the doctor recommends the following information should be considered in the response:

1. A restatement of the Form 483 Observation;
2. The proposed corrective action or plan (ensure past, current, and future states influenced by the observation are assessed);
3. Reference to the specific CAPA number;
4. Ensure root cause is determined and addressed;
5. Potential impact to product;
6. Potential impact to the quality system; and
7. The targeted date for completion.

Finally, do not forget to add a cover letter to the response. Remember, a thorough and well-thought response to a Form 483 is an organization’s best preemptive defense in preventing the issuance of a warning letter. One final thought, make sure all of the corrections are implemented and effective. Why? Because during the Agency’s next friendly visit to your facility, they will revisit previous observations and verify they are closed.

Disagreeing with an Observation
It is okay to disagree with a Form 483 observation; however, it is up to the offending organization to draft a salient response that delineates the points of disagreement. If an organization disagrees, it is incumbent upon the organization to provide supporting evidence as to why they believe the observation has been incorrectly made. The Agency’s expectation is that these types of disputes can be resolved as part of the inspection debrief; however, that is not always the case.

One final thought: never ever, ever, ever, ever inform the Agency that the reason your organization cannot achieve compliance is because of resources constraints. As Dr. D has stated on multiple occasions, “Compliance to regulations is just part of the price of admission to play in the medical device industry.” If an organization does not have or will not invest in adequate resources, they are playing in the wrong sandbox.

Takeaways
At the end of the day, there are two options in regards to Form 483s. For option one, an organization can be proactive, accept the Form 483, and treat is as an opportunity for pursuing continuous improvement, while driving compliance to the QSR. For option two, an organization can ignore the Form 483. In doing so, said organization should be prepared to deal with the proverbial opening of a can of “FDA worms” and the subsequent warning letter that will be issued.

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG, when Dr. D will provide some guidance for dealing with the trials and tribulations associated with the receipt of a warning letter – cheers from Dr. D. and best wishes for continued professional success.

References:

1. Appel, C. (2010). How to respond to and avoid FDA form 483s. Retrieved November 27, 2010, from http://www.veriteq.com
2. Code of Federal Regulation. (2010, April). Title 21 Part 820: Quality system regulation.  Washington, D.C.: U. S. Government Printing Office.
3. Cooper, R. & Fleder, J. (2005). Responding to a form 483 or warning letter: A practical guide. Food and Drug Law Journal, 60(4).
4. Davis, A. (2010, November). How to respond to FDA 483. Retrieved November 27, 2010, from http://www.ehow.com
5. Devine. C. (2009, July). Exploring the effectiveness of defensive-receiving inspection for medical device manufacturers: a mixed method study. Published doctoral dissertation. Northcentral University. Prescott Valley, AZ. 
6. Godshalk, J. (2009). Best practices: Responding to FDA form 483. Retrieved November, 27, 2010, from http://fdanews.com/ext/conference
7. Lookabaugh, M. (2006, May). Responding to FDA 483s and warning letters – presentation to Parenteral Drug Association. Parexel Consulting. Lowell, MA.
8. Nelson, C. (2010, May). The definition of FDA 483. Retrieved November 27, 2010, from http://www.ehow.com
9. Taylor, N. (2009, February). Ignore a form 483? Not wise say FDA. Retrieved November 27, 2010, from http://www.in-pharmatechnologist.com