Prior to the Warning Letter—Best Practices in Responding to FDA's Form 483 Observations

09.06.11 | Permalink

Prior to receiving a Warning Letter most companies will receive a Form 483 Report. At that point, the FDA is signaling that the company is not in compliance in one or more areas that are regulated by the FDA. Because the objective of a Form 483 is to fix problem areas and to have a company bring itself into compliance, it clearly demonstrates that the FDA has compiled a serious list of observations and wants the company to voluntarily improve compliance. Another use for the 483 is that it can start to create a legal record for further compliance actions.

 While no law requires a response to the 483, a company is encouraged to respond in order to appease the FDA and avoid a Warning Letter. The FDA, under its new rules, will only consider a response that is submitted within 15 business days after the close of the inspection to the FDA.

The response to the 483 does not have to be demonstrative on the issue of remediation or commit to having fixed all the observations in the 483. In fact, just the opposite, the FDA would be suspicious if a company claimed to have remediated all of the observations that were present in the Form 483 within 15 days.

The Form 483 response is most important to acknowledge that the company and its management understand what the FDA believes is lacking in the company’s compliance. It is the chance to acknowledge that these issues exist and they are currently being corrected. While the company may indicate that it does not agree with all of the FDA’s observations, the company should still pledge to fix these observations and begin the remediation process. A well documented and detailed plan, with a reasonable timeline that addresses the observations in the 483 and gives firm target dates for bringing these areas into compliance with the FDA rules and regulations is the most important step to creating a good 483 response.

The key to an effective response to 483 observations allows the FDA to know that the company understands the expectations, takes the 483 seriously, and has implemented a concrete plan to make the changes necessary. Every basic response should contain a reiteration of the observation, the citation, the corrective action plan, and the target due date for accomplishing the corrective action. In going one step further, a preventive action should be addressed. While the corrective action describes the action that corrects a specific observation, a preventive action broadens the answer, and allows the company to express that it will address any systemic concerns which may be a part of an observation. The FDA’s observations through their inspectors only represent a “sampling” of greater concerns. For example, if one manufactures a half a dozen products, but the FDA only observes two products being manufactured, the Agency’s comments will be limited to the problems associated with only those two products. If one uses the same processes that the FDA cited as problematic with the other four products, the implied expectation of the Agency is that the manufacturer will fix the cited problems in every one of its products. Hence, the preventive action is a necessity.

A mistaken notion would be that all is well by “fixing what was pointed out” or arguing with the Agency that the manufacturer is more right than the Agency. This would be futile at best, and sure to invite further inspections and enforcement actions and result in a Warning Letter.

Remember, in responding to the 483 begin with a compliance statement, or in other words, what action will be taken to bring the issue into compliance with the regulations? It is important to indicate the commitment of senior management and the company to comply with all application laws and FDA regulations. If the product was impacted in any manner, indicate the impact to the product. In many cases the FDA will observe Current Good Manufacturing Practice violations that have no impact on the product, yet, could possibly mean the product was adulterated in the FDA’s view. However, the consequences for having observations that impact the product’s quality are much greater than observations that have had no impact on the product’s quality. It is best if the manufacturer can test at an independent lab all of its products to make sure they are within specification deemed appropriate for the product, either by its NDA, ANDA, PMA or 510k. Having observations that do not impact the product will substantially bode in favor of the manufacturer.

The Warning Letter as Opposed to the Form 483 Observations

The Form 483 is issued by the inspectors as their observations is based and only on their observations. The Warning Letter is sent from a higher level of FDA officers or officials. The Warning Letter indicates that upon review of the inspector’s 483 forms, serious violations may exist that may prompt further FDA enforcement. Always remember that the FDA believes that Warning Letters are issued for what they consider matters of regulatory significance.

What Issues on the 483 Form Observations Are Most Likely to Prompt a Warning Letter?

 In summary, most Warning Letters are issued for violations that involve the following areas:

  • Inadequate procedures in a regulated area causing that area not to conform to FDA regulations;
  • Procedures that conform to FDA regulations, but the inspectors observe that they are not being followed; and
  • Procedures that conform to FDA regulations and are observed as being followed, but do not have adequate documentation to show that they are being followed (one of the most common reasons for citation).

The most common reasons for receiving a Warning Letter:
 

  1. An inadequate or non-existent Quality Assurance Unit. 
  2. Having corrective and preventative action procedures that are not adequate. 
  3. Having procedures that are adequate but inadequately documented.
  4. Process validation procedures that are not adequate.
  5. Quality audits by the Quality team were not adequately conducted and problems found were not adequately investigated.
  6. Executive management failed to ensure quality at all organizational levels.
  7. Procedures controlling Quality are inadequate.
  8. Systems designed to control the processes are inadequate.
  9. Deviations remain undocumented and not investigated.

The Role of Experienced Food, Drug, Medical Device and Cosmetic Regulatory Attorneys

 

Having had numerous clients in enforcement situations, and having averted numerous enforcement actions by properly responding to many Warning Letters or Form 483 observations, we have a unique perspective on the Agency as it operates currently. In 2011, the FDA Center for Devices and Radiological Health (“CDRH”) issued over 204 Warning Letters. During the same time period for 2010, the FDA’s Center for Drug Evaluation and Research issued 171 Warning Letters for violations as well.[1]    So far in 2011, 59% of the Warning Letters have been issued for problems in Corrective and Preventative Action (or “CAPA”) deficiencies. Another 51% for design controls, 32% for production and process controls, and 25% for lack of management responsibility.[2]

So what are the immediate impacts of having a Warning Letter issued? First of all, Warning Letters are publicly posted, and oftentimes played up by your competition. In addition, patients and plaintiffs’ attorneys are quick to embrace compliance actions as a basis or support for suits against the manufacturers. As for the FDA, the issuance of a Warning Letter will have a direct impact on whether the Agency proceeds with any pending applications for product approvals, or raises the scrutiny level that it provides to a particular company, or initiates a request for a recall.

The manufacturer’s first step in responding to a Warning Letter is to hire an experienced attorney who knows the FDA as audience. Don’t forget the response is the company’s first impression to show the FDA that it understands the observations and violations, and can establish a comprehensive corrective action plan to address the observations and violations mentioned in the Warning Letter. While you want to address the specific observation and identify its root cause, you must also identify the solutions to the root cause identified. A retrospective review is often helpful, and a knowledgeable regulatory attorney can guide you in this response. The attorney can help you establish reasonable and practical timeframes and attach objective evidence of your accomplishments, and the results of any reviews you care to share with the Agency to add credibility to your response. The response should show that you understand the Agency’s observations and have the ability, either with your internal staff, or through third party independent consultants, to bring your organization into compliance. It is important that the FDA understands your organization realizes the observations made in the Warning Letter are not all encompassing in themselves, but rather an indication of problems that exist in various systems throughout your organization.

 An experienced attorney can accomplish this in his response to the FDA’s Warning Letter without admitting to serious deviations or violations. The attorney can also guide you in addressing items that are discussed on the FDA Form 483, but do not appear in the Warning Letter. An experienced attorney can direct you to a third party consulting review team that will be able to help you with the technical and scientific aspects of conforming to FDA regulations.

 We would add most importantly that you need to keep the FDA apprised of your progress. At first, we recommend using 30 to 60 day updates to describe to the FDA the progress you have made, and to compare that progress to the timeline and dates you have given to the FDA to complete the corrective action. Showing that you are “on track” to meet your obligations in a timely manner will go a long way to appeasing the FDA. Unfortunately, if you fix many violations that were cited in the letter, but never report these to the FDA in a monthly or bi-monthly update, the FDA may still believe that you are in violation and take further action. Also, after the initial time period when the most critical progress has been reported to the FDA, we still strongly recommend that you send a quarterly update to the FDA indicating your progress until the FDA closes out the Warning Letter usually by an additional inspection. I recommend sending the response within 15 business days.

Conclusion

 The properly experienced Food, Drug, Medical Device and Cosmetic attorney can be a tremendous asset to a company in responding to both Form 483’s and Warning Letters. Involving an experienced FDCA attorney early in the process can reduce your chance of going into further enforcement, incurring much expense for correcting further inspections and legal actions. It is important to remember that the response to the Warning Letter is the impression that the FDA gains of the company. In our considered opinion, we have noted that with many of our clients the FDA understands from the response of the Warning Letter that the client understands the FDA’s positions and observations, will correct those positions and observations into compliance, and establish preventative actions to prevent issues from occurring in the future. By bringing in experienced regulatory attorneys early in the process, companies can avoid much expense, unnecessary aggravation, and heightened scrutiny by the FDA.



[1] FDA enforcement statistics summary for year 2010.

[2] The percentage adds up to more than 100 because letters cite more than one area in the same letter.


 

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