483s and Warnings

How to Respond

Warning Letter Language• “We reviewed your firm’s response and conclude that it is not

adequate.”– “Your firm provided neither a correction that addresses the release of non-

conforming product…nor a discussion of how your firm intends to ensure that all …product and services conform to specified requirements.”

– “Your firm did not provide evidence that its correction and corrective actions have been implemented.”

– “…your firm stated that it conducted a two year retrospective review…Your firm did not provide any results of or evidence that this review was conducted.”

– “The new procedure contains requirements for notification of the persons responsible for a nonconformance, but your firm has not provided any documentation of evaluation of past nonconformance to determine if there are any instances in which the person responsible needs to be notified.”

• “Your firm’s response to this observation appears to be adequate.”

Primary Objectives

• Instill confidence that your company:– Is committed to compliance at all levels of

Management– Has a quality system that is capable of correcting

the issues• Legitimately improve your Quality System and

add value to your business• Attain “closed” status with the Agency

483 Response Process

• Closing Meeting

• Internal Debrief

• Response Planning

• Response Writing

• Follow up

EIR “closed” under 21 C.F.R. 20.64(d)(3)

Closing MeetingGoals & Objectives

• Gain as clear an understanding as possible of what the concerns are, and why they are concerns.

• Leave the inspector(s) with the sense that (s)he has been heard by upper management.

Closing MeetingDos and Don’ts

Do Don’tHave Management present and engaged

Become defensive or argumentative

Seek clarification Appear dismissive

Correct factual discrepancies Tune out Discussions with Management

Take notes

Consider annotations

Internal DebriefGoals & Objectives

• Capture the “back story” for each observation.– When did it come up during the inspection?– Who was there? What was being said? – What documents were being looked at?

• Establish the context for each observation.– What Quality System element(s) are involved?– What interactions between QS elements are at

play?

Internal DebriefDos and Don’ts

Do Don’tBring in the people who were present Put this step off.

Put yourself in the inspector’s shoes Waste time in denial.

Have open and honest discussion Problem solve.

Document your output

Response PlanningGoals & Objectives

• Develop the 15 day plan for responding– Establish roles, responsibilities, and structure

around preparing the response.– Establish work teams who can work in parallel.– Establish a timeline for preparing the response

• Develop the response plan– Identify the actions necessary to address the

observation.– Establish key deliverables and dates

Response PlanningTypical Work Stream Approach

Steering Committee

Obs. 1 Obs. 2

(a) (b)

Obs. 3 (a-c) Obs. 3 (d) Obs. 4 …

Response PlanningDos and Don’ts

Do Don’tDefine appropriate scope. Think broader than the observation as written.

Just tweak. Consider meaningful changes that will reduce complexity.

Establish aggressive but achievable timelines Overcommit.

Consider the need for retrospective analysis and/or remediation

Stop at “retraining”

Consider whether you will respond to Discussions with Management

Succumb to “analysis paralysis”.

Ensure causes are understood and actions address causes.

Underestimate the time it takes to write, review, and approve the final response.

Ensure your action plans add value to your businessAssign CAPAs

Have regular status meetings

Get as much done, with objective evidence, before the initial response goes in.

Response WritingGoals & Objectives

• Provide the Agency with enough information for them to determine the actions you are taking are adequate.

• Make the Agency confident that you understand the issues, take them seriously, and that your Quality System is robust enough to address them.

• Set out a clear time line of when the issues will be addressed.

Response WritingDos and Don’ts

Do Don’tAddress observations in order, but broken into logical pieces.

Downplay the significance of the finding.

Be consistent in style and format (e.g., date formats, procedure naming, use of acronyms, etc.)

Be overly technical.

Write clearly, using complete sentences and layman’s terms. Use bullets where appropriate.

Get too granular. E.g., “Revise procedure” is one task that includes revising, approving, and training. Provide evidence!

Get independent review by someone who isn’t a subject matter expert.Provide objective evidence. Organize exhibits so they are easy to find.Proofread. It shows you care.

ABC

J. Doe

Cover Letter

Response

Action Tracker

Exhibits

Response WritingAnatomy of a Response

ABC

J. Doe

Cover Letter

Sender’s Address

Inside Address• Full name, title, &

address

Date• Spell month completely

Reference• FEI number from 482

Salutation• Formal (Dear Mr., Ms.)• End with colon, not comma

Body• Purpose• Type of inspection, dates,

inspector(s) names.• Statement of commitment to

compliance• Explanation of the format• Invitation for further contact,

contact name & details

Closing• Warm but formal (e.g.,

“Sincerely”, “Yours Kindly”)

:

Response

Restate the Observation• Verbatim. Proof read!• Use Bold, Italic, and/or Box to

separate from response.• Restate only the portion

addressed by the subsequent response.

Background• Provide appropriate context• Establish what was and was not

in place• Provide additional facts not

known to/stated by the inspector

• Explain the results of your investigation

Actions• Explain not only What you are

doing, but Why.• Provide completion dates.• Provide objective evidence of

what has already been completed. Label as Exhibits.

• Don’t forget actions to assess the impact of the finding on existing products, records, etc.

• May be broken into Remedial, Corrective, & Preventive actions.

Action Tracker

Observation• Broken out into sections that

match the response format.

Actions• Paraphrased from response, but

easily tied to the response.• Everything in the response with

an expected completion date should have a corresponding action in the tracker.

Expected Completion Date• Must match response.

Status• Started, Not Started, On Track,

etc.• When “Completed”, provide

date completed.

Reference Number Title Date

Exhibits

• Separate Exhibits with Tabs• Clearly Label all Exhibits• If necessary, provide Table of Contents.

Example:Exhibit A – Revised Procedure SOP-

XYZ• SOP-XYZ Rev. B • Document Approvals• Training Records

• List Exhibits in order they appear in response.

Hint:When drafting the response, call all exhibits “Exhibit X” until the draft is final, then number/alphabetize them. Highlight the X’s so they are easy to spot. Example: “…report of retrospective review was completed on 23 May, 2015 [Exhibit X].”

Follow upGoals & Objectives

• Demonstrate a steady cadence of completing actions on or ahead of schedule.

• Follow through until all actions are complete.• Receive a close out letter.

Follow upDos and Don’ts

Do Don’tEstablish an appropriate frequency based on action plans.

EVER miss a date. If it can’t be helped, provide an explanation and revise the expected date in the Action Tracker.

Treat the timeliness of follow up reports with the same urgency as the initial response.

Keep adding to the actions.

Try to require as few follow up reports as possible. Get in and get out.Provide an updated Action Tracker with each follow up report.Be clear in your last report that all actions have been completed and there will be no additional follow up reports.