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Responding to 483's

The FDA Form 483 and warning letters are the most feared pieces of paper a firm never wishes to get.
By: Madhu Raju Saghee, Corporate Quality Assurance, Gland Pharma 
Article Taken From Express Pharma, June Edition

In recent months, the volume of 483s and warning letters issued have increased dramatically and this trend may spiral up in future. A form 483 does not necessarily predict disaster, but if not responded to effectively, things can go downhill, allowing the issuance of a warning letter pretty quickly. What you say in your response, can mitigate the risk of a warning letter. A prompt response with proposed 'corrective actions' is essential to avoid further action by the FDA, and it lets FDA know that your company understands the expectation and takes the 483 seriously.

What is an FDA-483?

FDA issues a form FDA 483 (inspectional observations) upon completion of an inspection, to notify an inspected establishment's top management of objectionable conditions relating to products and/or processes, or other violations of the Federal Food, Drug, and Cosmetic Act and related acts that were observed during the inspection. It is issued in pursuant to by Section 704(b) of the FFDCA, or "to assist firms inspected in complying with the Acts and regulations enforced by the FDA."

There is no law or regulation which says that the firm has to respond to a 483. However, every prudent firm that receives a 483 does respond to it, both orally and in writing, which has become an expectation. Once a 483 is issued, virtually every firm rebuts in writing; failure to do so will be seen as anomalous on your firm's compliance and philosophy for attaining and maintaining compliance.

The FDA 483 form includes the following preface1:"This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations; and do not represent a final agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address [on the form]."

Anita Richardson, Associate Director for Policy Office of Compliance and Biologics Quality, says that there are four reasons for submitting a well-reasoned, complete, and timely 483 response-it could possibly

mitigate an FDA compliance decision for further action, (eg untitled letter, warning letter), it demonstrates to the FDA (and other stakeholders) an understanding and acknowledgement of the observations, it also demonstrates a commitment to correct, ie the intent to voluntarily comply, and it establishes credibility with FDA.

Original intentions of FDA form 483

In previous days many firms, mainly food establishments, complained that FDA enforcement actions took place without warning. For this reason FDA developed several tools to inform regulated industry that it had found deficiencies and might proceed with regulatory action. The tools included the 'NAF letter' or Notice of Adverse Findings, which no longer is used, and the 483 and warning letters. At present warning letters and the 483 have taken on a whole new meaning as for many firms they are the enforcement actions2.

The profound change to 483 is its inception of Turbo EIR, which is a computer programme that provides introductory wording for FDA-483 observations. It encompasses canned 483 citations which searches through the drug GMP citations for the appropriate citation for the observed violation. For example, as per deviations pertaining, the documented written procedures applicable were not be followed, specifically the quality assurance auditing staff failed to fully follow established standard operating procedure (SOP) with regard to the auditing of personnel working in the aseptic core. The audits performed have not identified deficiencies in the systems designed to prevent microbial contamination of drug products purported to be sterile.

So the observation has the regulatory citation and the supporting part of the observation. We must concentrate on the supporting part of the observation, not the boiler plate language2.

New FDA programme—the 15 day deadline

On August 11, 2009, FDA issued a Federal Register notice1 announcing a programme to support public health protection by facilitating the timely issuance of warning letters. Under this programme, it establishes a timeframe for the submission and agency review of responses to Form FDA-483s before the agency's issuance of warning letters. The stated goal of the programme is to facilitate the agency's timely issuance of warning letters. These procedures have been prompted by the efforts of Dr Margaret A Hamburg, the new FDA Commissioner, to intensify the agency's enforcement programme. The purpose of this new initiative is to optimise resource utilisation, issue warning letters promptly, and promote prompt voluntary compliance.

Previously, after issuance of a 483, the firms used to submit a formal written response to the observations listed in the form 483; however, such responses can sometimes take many months which delays the issuance of warning letters in a timely manner. So to facilitate the timely issuance of warning letters, from September 15, 2009, FDA allows only 15 business days to respond to a 483 from the date of issuance of the 483. As stated in the following notice1:

"FDA will generally allow firms 15 business days to provide a response to FDA 483 observations. If we receive a response to FDA 483 observations within 15 business days after the FDA 483 was issued, we plan to conduct a detailed review of the response before determining whether to issue a warning letter. If we issue a warning letter after reviewing a firm's timely response, the warning letter will recognise receipt of the response and reply as to the apparent adequacy of the firm's corrective actions set forth in the response".

In a nutshell, the response to FDA 483 Observations received within 15 business days will have a detailed review and any warning letter issued will acknowledge 483 response and comment on firm's corrective actions. If FDA receives a 483 response more than 15 days after the 483 was issued, the agency will not likely delay the issuance of a warning letter in order to review the 483 response. This initiative expedites the issuance of warning letters. Only significant legal issues will be reviewed by the Chief Counsel. It will prioritise enforcement follow up after warning letter or recall, such as re-inspection or investigation. FDA will no longer issue multiple warning letters before taking enforcement action. Immediate action will be considered for egregious violations. FDA will conduct an assessment of this programme after 18 months, and will then decide whether to implement it permanently.

Responding to form 483

If your firm has just been issued a 483, your response has to provide accurate information and be clear and concise. As stated by John Godshalk, Senior Consultant, Biologics Consulting Group4, to write an effective response, you need to understand each observation. At the inspection close-out, make sure you understand each observation, the thinking or rationale behind it and what the FDA inspector/investigator wants the firm to do. Some observations are poorly written; it is up to you to understand what the FDA inspector wants if the observation is unclear.

As noted in - IOM 5.2.3 "Industry may use this opportunity to ask questions about the observations, request clarification, and inform the inspection team what corrections have been or will be made…" You need to understand significance of observations relating to product quality before planning and proposing an effective corrective action.

The basic response to any inspectional observation should firstly be in bold letters so it is easy to read, and should contain the reiteration of the observation (the citation), and the corrective action or CAPA, what the firm will do about the observation to fix the problem or address it to correct the non-compliance, the due date, and when the correction will be in-place. In the first paragraph of the response letter, provide a statement that your establishment understands the need to comply with FDA regulations. If your intent is to follow the law and create a good working relationship with FDA, it is vital that the promised corrective and preventive action is performed in a timely manner3. So a commitment/statement from senior leadership must be included. The cover letter must be signed by a very senior manager or high level VP of quality with brief opening stating commitment to compliance and offering to meet or confer by phone if necessary to clarify response. Consider requesting disclosure of the response if the 483 is disclosed under FOIA.

Each observation should be addressed individually and separately, and the response should be well organised and factually correct. It must not contain speculation or unsupported assertions. The responses are backed up with feasible and reasonable documentation, but does not 'overkill' by supplying too much detail. All the corrective plans proposed should have target completion date in the response. Where necessary, include interim controls until full correction is achieved. The corrective response must be communicated to FDA in a prudent manner and must be specific (eg observation-by-observation). The scope of CAPA plan with the root cause must be defined and method of verification and/or monitoring for corrections is provided. Lastly the CAPA plan must be realistic and must be able to deliver what you promise. The list of affected products should also be addressed and an assessment of product impact must be included.

Pitfalls-things NOT to say

David L Chesney, Vice President, PAREXEL Consulting, says that a 483 response should never include statements like--"The investigator was out to get us", "We have been inspected many times and this never came up before" (FDA response--'Gee, too bad we missed it all those times…good thing we saw it this time), "Everyone in our industry does this in this way" (FDA response--'Thanks for alerting us that this is an industry wide problem! We will follow that up), "We are a small business trying to survive" (FDA response — 'So, because you are small, we should allow you to operate out of compliance? Is that your point?'), or "The investigator does not know our industry", and so on.

You need to ask yourself if the observations are factually accurate, and whether we agree that they represent objectionable conditions or practices. The investigator's background and knowledge do not matter if the answer to these questions is "yes"! Saying that you are taking this up with your elected representatives is your right, and it is up to you if you want to do that, but saying that in the letter will not make your response to the 483 more effective.

As said by Mark Lynch, Senior Compliance Consultant for KMI-Parexel, Rockville, it is common for drug, device and biologics manufacturers to get slapped with a warning letter for failing to adequately address the 483. As many as 75 percent of warning letters may have been triggered by the fact that companies drawing 483s after GMP inspections did not adequately respond to the FDA investigator's observations. Lastly, it's not just putting a bandage on a leaking tank, but to figure out why all the tanks leak and show FDA how you are going to prevent that from happening again.

1) Fed Register Vol. 74, No. 153, Aug. 11,2009, p. 40211, FDA-2009-N-0335
2) The FDA 483 by Carl Anderson, Immel Report™, Special Reprint, 2007
3) Response to the FDA 483 by Mary Ann Tourault, CITINGS®, April 2002
4) Presentation; Best Practices: Responding to FDA Form 483's, by John R Godshalk
5) Presentation; Writing An Effective 483 Response by Anita Richardson at 5th Annual FDA and the Changing Paradigm for HCT/P Regulation
University of Rhode Island and Pharma Conference Las Vegas, 2009.
6) Presentation; Responding to FDA-483 Observations by David L. Chesney, PAREXEL Consulting at AOAC Southern California Section Meeting, 2008

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