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Good 483 responses can squelch warning letters

By Hank Schultz , 24-Sep-2012
Last updated on 25-Sep-2012 at 17:52 GMT

Good responses to 483 can avoid a warning letter.  Including in those responses key elements of organization and documentation can improve the chances for success, an experts say.

Sessions at a recent industry event held in Boulder, Colo. by a consultancy called FDA Compliance Group focused on the intricacies of responding to a 483.  One important message needs to permeate the response.

“FDA wants to know that you are operating in a state of control,” said Shelly Maifarth, one of the principles of the consultancy.

Maifarth should know; she had a 22-year career at FDA, including as a compliance officer, the level at which decisions about the issuance of 483s and warning letters is taken. Maifarth laid out some key strategies that companies can use to craft the best responses.

A non-negotiable item at the outset: Responses to a 483 must be received within 15 business days.  Responses received after that date won’t be consider by the agency in making a decision about issuing a warning letter.

Commitment to change is key

The response should consist of a cover letter, a body covering the technical aspects and attached supporting documentation.

The cover letter is best addressed to the director of the appropriate FDA district, Maifarth said, with a copy going to the compliance officer in charge of the case. It needs to demonstrate a commitment to compliance at the highest levels of a company’s organization.

In the response body, Maifarth said, less is more.  Be concise and clear; excess verbiage in and of itself will not sway FDA in your favor, she said. She recommended copying in italics the verbatim observations from the 483.  Paraphrasing can unintentionally change the meaning.

In response to specific observations, Maifarth suggested using working such as, “we take this observation seriously” and “we commit to implementing … to address this oberservation.” There is no need to admit guilt or non-compliance on these issues, she said.

A 483 response should include both plans for both specific and systemic corrections, said Martina LaGrange, the other partner at FDA Compliance Group who also worked at FDA.  Specific problems are indicative of deficiencies in the systems used to create the records or manufacture the products being cited in a 483.

“An example of a specific fix would be: ‘We have created a batch record for our vitamin C (if the 483 said you did not have such a record).’ A systemic fix would be: ‘We have 16 other products and we are going to provide batch records for them.’ ”

“Provide hard copy documents of the fixes with your response. Highlight the changes in your SOPs in yellow.  Don’t make compliance officer dig through your multiple-page SOP to find the specific fix,” she said.

Give FDA a model for change

Such systemic corrections can be very difficult to implement properly within the 15-day window, Maifarth said. The best thing to do for problems that are too big to manage within that time frame is to provide in the response a well-documented plan for developing those fixes and incorporating them into your operation. FDA wants to see a plan for a cogent fix to the problem, not a Band-aid, she said.

“You need to send in a good model of what you are going to do. FDA knows that anything you try to do in 15 days, if it’s that much work, is probably going to be wrong,” she said.

These models should aim to fix problems within six months, she said, and the sooner the better.  And the new procedures need to have complete training documentation submitted with the response, or a plan to submit that documentation when the procedures are finalized.  Maifarth called lack of training records“low hanging fruit for an inspection.”

Maifarth also suggested using a tabbed binder divided by sections corresponding to each observation in a 483, and suggested using a simple, logical numbering system for key paragraphs.

The whole should convey an image that your company has thought the issues through carefully and is acting responsible, expeditiously and thoroughly to address the problems.

“You want to be able to take a complete story in the body of the document,” Maifarth said.