Responding Effectively to FDA 483 Observations & Warning Letters

Presented by:

Pamela Forrest, Esq.Partner – King & Spalding

Norman RabinQuality Director, Solutions Delivery – Maetrics, LLC

Agenda

• Why Responding Effectively Matters

• How to Prepare an Effective Response

• How to Avoid Common Pitfalls

• Preparation to Avoid unnecessary citations

• Exercise: Write an appropriate response to…

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Why Responding Effectively Matters

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What is an FDA-483? Start of the Warning Letter!

• The form used by FDA investigators to officially record inspectional observations at the completion of an establishment inspection.– The issuance of written inspectional observations is required by FDCA

§ 704(b) [21 USC § 374(b)].• 483 observations are made when, in the investigator’s judgment, the

observed conditions/practices indicate that a drug may have been adulterated or is being processed, packed, or held under conditions that may cause a drug to become adulterated or not conform to specifications.– 483 observations are not violations.

• Presented to management on the last day of the inspection.• 15 working day deadline for submission of firm’s response.

– If received by FDA after 15 working days, the Agency will not review the response before issuing a Warning Letter.

• Source: FDA, Review of Post-Inspection Responses, 74 Fed. Reg. 40211 (Aug. 11, 2009), http://www.gpo.gov/fdsys/pkg/FR-2009-08-11/pdf/E9-19107.pdf

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What Is an FDA-483? (Cont’d)

• 483 contents:– Significant objectionable conditions or practices.

• Observations of questionable significance are not listed on the 483, but are discussed verbally with the firm’s management during the inspection and are reported in the Establishment Inspection Report (EIR).

– Non-GMP areas may be addressed, e.g., postmarketing adverse drug experience reporting issues.

– Listed in descending order of significance.– Recurring/repeat observations may be explicitly noted.

• 483s should not contain observations regarding:

– Content of labels and labeling. – Promotional materials.– Establishment registration.

• Source: FDA Investigations Operations Manual, subchapter 5.2.3, Inspection Procedures, Reports of Observations

• http://www.fda.gov/ICECI/Inspections/IOM/ucm122530.htm• Field Management Directive No. 120• http://www.fda.gov/iceci/inspections/fieldmanagementdirectives/ucm096015.htm

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Impact of a Significant 483

• Export: FDA has the authority to refuse to issue Certificates to Foreign Government (CFGs) for export of pharmaceutical products. – FDA policy states that CFGs will be denied if the manufacturing facility

for the products to be exported is not in compliance with current good manufacturing practices.• Exception: if the particular product is not affected by the cGMP deviations.

– Source: FDA, Guidance for Industry: FDA Export Certificates, July 2004, http://www.fda.gov/regulatoryinformation/guidances/ucm125789.htm

• Import: For foreign manufacturing establishments, FDA has the authority to issue import alerts. – FDA can authorize detention without physical examination for

products that appear to be adulterated, misbranded, or unapproved. Significant perceived GMP violations, indicated by serious 483 observations, can lead to a drug being deemed adulterated.

– Source: FDA, Regulatory Procedures Manual, Chapter 9: Import Operations and Actions, April 2013, http://www.fda.gov/downloads/ICECI/ComplianceManuals/RegulatoryProceduresManual/UCM074300.pdf

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Potential Consequences of an Inadequate 483 Response

• Warning Letter

• Untitled Letter

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What is a Warning Letter?

• According to FDA, “Warning Letters are issued to achieve voluntary compliance and to establish prior notice.”

• Used to ensure that a firm’s top management understands the seriousness and scope of the violations.

• Issued only for violations of regulatory significance:– Violations that may lead to enforcement action if not promptly

and adequately corrected.

• Are informal and advisory and do not commit FDA to taking any additional action.

• 15 working day deadline for submission of firm’s response.– Source: FDA, Regulatory Procedures Manual, Chapter 4-1: Warning Letters, July 2012,

www.fda.gov/ICECI/ComplianceManuals/RegulatoryProceduresManual/ucm176870.htm

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Impact of Warning Letters

• Boilerplate language summarizes the immediate consequences of a Warning Letter.– NDAs: “FDA may withhold approval …of new drug applications

listing your facilities, until the above violations are corrected.”– CFGs: “FDA may withhold approval of requests for export

certificates … until the above violations are corrected.”– Contracting: “Other federal agencies may take this Warning

Letter into account when considering the award of contracts.”

• If the inspected establishment is an OUS facility, FDA may issue an import alert, preventing product from that facility from being imported into the United States.

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Potential Consequences of an Inadequate Warning Letter Response

• Corporate Warning Letter• Regulatory Meeting

– When a company has corrected the majority of violative conditions noted in a Warning Letter, used to provide additional encouragement, direction, and assistance in achieving compliance.

– FDA may remind a firm or individual in a Regulatory Meeting that failure to make appropriate corrections in a timely manner may result in enforcement action.

• Source: FDA, Regulatory Procedures Manual, Chapter 10-3: Regulatory Meetings, http://www.fda.gov/ICECI/ComplianceManuals/RegulatoryProceduresManual/ucm179538.htm

• Seizure• Injunction/Consent Decree

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How to Prepare an Effective Response

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Step 1: Deconstruct Each Observation

• Before beginning to draft a response to a 483 or Warning Letter, it is critical to “deconstruct” the observations, so as to identify as precisely as possible FDA’s concerns.

• 483 Observations and Warning Letter items are not always clearly written.

– In order to comprehensively deconstruct an observation, it is often necessary to utilize information learned through discussions with the investigator during the course of the inspection and/or at the presentation of the 483.

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Sample 483 Observation

OBSERVATION XThe quality control unit lacks authority to fully investigate errors that have occurred. Specifically, the quality control unit does not investigate and evaluate the failure of filling operators to perform specified interventions during aseptic media fills. For example: a. For Media Fill Lot Number XXX, project number XXX filled on 1/8/2014,

the required interventions: XXX were not performed. b. For Media Fill Lot Number XXX, filled on 6/25/2014 and 6/26/2014, the

following required interventions were not performed: “Remove jammed vials on filling line,“ “Change mask change during fill" and “Stop filling line and clean spill.”

c. For Media Fill Lot Number XXX, project number XXX filled on 9/23/2014 the required intervention: XXXX was not performed.

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Deconstruct the Observation into its Elements

• The quality control unit lacks authority to fully investigate errors that have occurred. – The overall observation is pointing out a gap in the responsibilities of

the quality control unit (21 C.F.R 211.22(a)): “and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated.”

– It is not clear if the overall observation regarding “lack of authority” is factually correct. A “lack of authority” observation should be supported by a description of the procedure(s) or other document(s) that fail to provide the quality control unit with the authority to perform investigations, or a statement that such procedures do not exist.

– During the close-out meeting the observation that the authority is lacking should be discussed and clarified. Are there pertinent procedures that are unknown to the investigator?

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Deconstruct the Observation into its Elements (Cont’d)

• [T]he quality control unit does not investigate and evaluate the failure of filling operators to perform specified interventions during aseptic media fills.

– The specific issue is that errors are not investigated; note that this is not the same issue as a lack of authority to fully investigate errors.

– It is not clear if this specific issue “does not investigate” is intended to be the support for the “lacks authority” issue.

– This also should be clarified during the discussion.

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Deconstruct the Observation into its Elements (Cont’d)

a. For Media Fill Lot Number XXX, project number XXX filled on 1/8/2014, the required interventions: XXX were not performed.

b. For Media Fill Lot Number XXX, filled on 6/25/2014 and 6/26/2014, the following required interventions were not performed: “Remove jammed vials on filling line,“ “Change mask change during fill" and “Stop filling line and clean spill.”

c. For Media Fill Lot Number XXX, project number XXX filled on 9/23/2014 the required intervention: XXXX was not performed.

– Specific examples of failure to investigate errors are provided.

– The above observations, place product produced on these lines in jeopardy

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Step 2: Prepare the Response to Each Observation

• Recommended format (for each observation):– Section 1: Background (if needed)

• Provide important context, necessary clarifications, etc.

– Section 2: Completed Actions• Include actions completed to address both specific examples and systemic

issues.

• Reference and attach documents demonstrating that “completed actions” were actually completed; direct FDA to the specific portion of the document that is pertinent.

– For revised SOPs and related documents, reference and attach training records.

– Section 3: Planned Actions• Include actions planned to address both specific examples and systemic issues.

• Include projected completion dates for each planned action.

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Open a CAPA (Investigation) for Each Observation

• CAPA is the quality system for identifying and correcting quality problems and should be used for problems identified by FDA as well as by internal means.

• More than one observation may be addressed in a single CAPA if they are the same issue or have the same root cause.

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Include, as Appropriate, the Following Content for Each Observation

• The systemic actions to address the underlying problem(s) or root causes.

• The targeted actions to address the specific example(s).

• If there is impact on marketed product, the actions that were or will be taken concerning this product; if there is no impact, a description of how this was determined.

• Any interim controls put in place to assure compliance until permanent corrections can be effected.

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Ensure the Response Addresses Systemic Issues

• Identify the root cause(s) of the issues discussed in the observation and develop appropriate systemic corrective actions, for example:

– Revisions of existing SOPs and/or development of new SOPs.

– Additional training.

– Retrospective reviews to identify similar gaps.• These may entail reviews of the identical issue for a

longer timespan in the past or for other products, reviews of similar issues in other quality systems, etc.

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Address the Specific Examples

• Address and correct each separate issue and example identified in the deconstruction.

• If a specific example cannot be corrected, explain why (e.g., information not available and cannot be obtained for an older complaint).– Provide any actions that will lessen the impact in

those cases (e.g., similar examples will be identified and thoroughly investigated, including retrieval of products or information necessary for investigation).

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Address Potential Impact on Marketed Product

• If there is impact, describe the actions that will be taken (e.g., quality hold, field action).

• If there is no impact, describe how this was determined.

• Impacted product may include the product (lots) in the examples, other lots of the same product, other similar products, or products impacted by the same quality system gap.

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Consider Putting in Place Interim Controls

• If corrective actions to prevent recurrence will take significant time to address, include, where appropriate, immediate actions to ensure products being manufactured and shipped are adequate. For example:

– Additional inspections or testing.

– Additional manufacturing controls or process monitoring.

• Such interim controls may make it possible to continue manufacturing and distribution pending implementation of corrective actions.

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Step 3: Draft the Cover Letter

• Critical elements:– Commitment to provide periodic updates (FDA

typically expects monthly updates).

– Commitment to address not only specific examples in 483/Warning Letter, but also systemic issues.

• Other elements that may be needed:– Request for a meeting with FDA.

– Any background or context that is important for the response as a whole.

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How to Avoid Common Pitfalls

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Pitfall: Trying to “Get It in Early”

• In most cases, there is no benefit from submitting a 483 or Warning Letter response prior to the 15 working day deadline.

• Preparing an effective response takes time, and the full 15 working days should be used to draft the best possible response.

• But, don’t be late.

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Failing to Address Systemic Issues

• As discussed earlier, simply correcting the specific examples that FDA listed is not sufficient.

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Pitfall: Not Providing “Due Dates” for Actions, or Providing the “Wrong” Ones

• Anticipated completion dates for planned actions must be provided.

• However, overly aggressive deadlines are unlikely to be met, and can cause a firm to have to continually explain why its corrective actions are “late.”

• Realistic deadlines should be chosen.

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Pitfall: Referring FDA to Attachments Without an Explanation

• Simply referring FDA to an attached document is not an adequate response.

• The narrative should explain the completed action.– For example, if an SOP was revised, the narrative

should describe specifically what was revised.– The narrative also should cite the specific sections of

the attached document that support the completed action (e.g., the sections of the SOP that were revised).

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Pitfall: Failing to “Correct the Record”

• Sometimes 483s and Warning Letters contain inaccuracies.

• Firms should politely point out such error(s) in the “Background” section of the response.

• The observation may be poorly phrased or incorrect in some specific aspect, but there may be a valid point; “correct” the observation and address the actual issue.

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Pitfall: Excessive Self-Incrimination

• It is not necessary for the response to point out new issues that FDA did not include in the 483 or Warning Letter.

• It is also not necessary to repeat the observation itself.

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Pitfall: Failure to Carefully Review All Documents Prior to Submission

• If gaps or errors exist beyond those discussed in the 483 or Warning Letter, this may broaden the scope of FDA’s concern and lead to additional enforcement scrutiny.

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Pitfall: Defending Practices/Procedures that Are Clearly Non-Compliant

• If the 483 or Warning Letter describes noncompliances that exist as a result of a particular procedure or practice, then there is little to be gained from defending that procedure/practice.– For example, if the 483/Warning Letter states that the firm’s

complaint investigations are not thorough enough and provides examples where critical information needed to assess Adverse Event reportability was not obtained during the investigation, then defending the firm’s complaint investigation procedures/processes is unlikely to be prudent.

– Rather, the response should focus on the company’s efforts to identify the root cause(s) of the deficient investigations and to implement appropriate corrective actions.

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Pitfall: Failure to Draft the Response in a Clear and Understandable Manner

• The writing matters, and clarity is critical.

• Extraneous information is distracting and can prevent FDA from understanding that substantial improvements have been or will be made.

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Thank you!

Questions?

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Preparation is a Good Foundation

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Pre-Inspection ActivitiesBeing prepared can avoid unnecessary observations.

Every Firm Should Do This

• Create an Inspection Response Team• Team Representatives from

– The Quality Unit– Design Development– Manufacturing– Warehousing and Distribution; Purchasing– IT– Facilities and Engineering– Validation

• The Primary and Secondary Hosts (Part of the Response Team, Front Room Leads)• The Scribes (at least 4) (Part of the Response Team)• The Communications System• The Front and Back Rooms

– Set-up and Functions– The Back Room Lead– The Document Request Process

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Pre-Inspection Activities

Every Firm Should Do This Prior To An Inspection

• Review the past 483s and any regulatory letters for completion.• If you are expecting a pre-approval inspection, make sure you have a copy of the

filing and review it.• If there were any recalls since the last inspection review and assure close-out.• For OPEN complaints; are the time limit requirements being met?• Review all open CAPAs; are any lingering?• Review your Management Quality Review Meeting Action Assignments.• Review your internal Audit Plan and findings; schedule met, are ACTIONS

completed?• Review all Out of Specification Reports; are they all closed?• Review all Out of Calibration Reports; are they all closed?• Are there job descriptions for all GMP positions?• Review your training program compliance status—is everyone up to date?

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Defining Inspection Management

FDA Inspectors are In Your Lobby, Your Team Should Be Trained To Respond Correctly

• In many Firms the first point of contact is your Receptionist. Ask their names, make sure you have the spelling correct and their titles – this person is the face of the Firm– If they are in the wrong location, direct them to the correct location– Prepare ID Badges– Have them sign in and offer them a seat while they wait a short time– Call the Director of QA, the Plant Manager or The Manager of QA

• Director of QA to contact the Back Room Coordinator• Back Room Coordinator

– Contact the Inspection Response Team– Set Up the Back Room– Activate the Communication System– Prepare the Request System– Get all necessary Back Room supplies– Notify every onsite Department Manager– Notify Corporate, if applicable

• Inspection Response Team Mobilizes– Research Inspector(s)

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Defining Inspection Management

Opening Meeting, Establishing Professional Rapport

• Inspection Host (QA Director or Manager, typically)– Greet and meet, go to designated inspection room, exchange cards– Ask for the reason for the Inspection– Ask for the FDA Form 482, Notice of Inspection, and for investigator’s credentials*– Suggest to the Inspector that you would like to provide a 15 minute Site Presentation

• Site Presentation Reason and Content– Provides valuable overview of the site and surrounding area, Facilities, and Operations– History of Company– Products manufactured at site or site’s function (if not manufacturing)– Aerial shot of site and surrounding area or diagram of same**

• What businesses are adjacent to the site?• Where are the major functions located at the site?

– Organizational Diagram of Site Operations• Who is responsible for what?• Who is in charge? In case of violative actions, who is in charge at the site?

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While the Opening Meeting is Happening…

• Department Managers and Inspection Response Team– Do immediate tour of Facility

• Facility Order • Facility Cleanliness, inspect all plant areas including the break rooms, lunch areas, and the restrooms• Personnel Appearance and Readiness• Ensure all operations in process have up to date documentation

– Based on Inspection reason, additional preparation may be necessary at this point• For Cause: Gather information relating to the Cause - Complaints, CAPA, Recall Information• Pre-Approval: Gather the PMA/510(k), NDA, BLA filing, all Related Product and Process Validation

Packages• Bi-Annual Inspection: Review files of new products or major changes to Products, the Production

Schedule, all Major Change Controls since the last Inspection, review all open CAPAs, review open Complaints and Complaint Trends since last Inspection, and all MDR and AE since last Inspection. Look for patterns and trends

• Ensure all Training is up to date• Check status of Out of Specification Investigations, Out of Tolerance, and Out of Calibration

– Inform all employees to be cautious with hallway, restroom, and break room conversations– Be aware of possible Investigator’s presence in restaurants, etc., no business talk

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Defining Inspection Management

Front Room Conduct

• Two Scribes in the Front Room are suggested• The primary Scribe transcribes the proceedings

– What did the Investigator say or ask?– What is he/she reviewing?– What has a SME stated?– What has the Investigator stated they will look at next, etc.?

• The Host (QA Director) will enter each FDA request on a form, paper or electronically• Request goes to the Back Room for fulfillment• The Host will review every document or record that is brought back to the Front Room

– Quickly reviews any comments or notes for the Host from the Back Room– Ensure that this is the document or record requested before giving to the Investigator– Host should not provide the document to the investigator until the question is adequately answered if at all

possible

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Defining Inspection ManagementResponse time is an indicator of the QMS status

Back Room Conduct (cont’d)

• 10 Basic Steps to Request Handling– Request is initiated– Request is logged– Request is reviewed and clarified, if necessary– Request is assigned to the associated Department Manager– Requested document or record is retrieved– Document or record is photocopied x2 or x3– Each page of each copy is stamped COPY and CONFIDENTIAL, front page of

each copy has REQ Number – SME reviews the document or record for compliance– Document delivered to the Front Room– Request is CLOSED and log updated

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Communications

“When all other means of communication fail, try words.” ~ Anonymous

• Communicate in real time regarding the direction of the Inspection to:– All Department Managers– To the entire Response Team

• The Back Room Lead is to prepare and distribute a daily summary of major inspection points• The Daily Summary shall contain the following fields:

– Site and Auditing Body (e.g., FDA)– Day “#” Update (Day 1, Day 2, etc.)– Investigator(s) Name(s)– Reason for Inspection– Confirmed Observations (from today)– Potential Observations– Summary (List of topics/areas reviewed)– Topics/Areas for Review Tomorrow– Name of Audit Host Lead/Point of Contact

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The Daily Close-Out Meeting

“Our real problem, then, is not our strength today; it is rather the vital necessity of action today to ensure our strength tomorrow.” ~ Dwight D. Eisenhower ~

• Request that the Investigator hold a brief daily Close-out Meeting • Take accurate notes, use a scribe• Ask if there are any deficiencies, any major or minor observations• Ask if the Inspector is getting everything they require, • Is there is any need to clarify any controversial or obtuse observation with the

inspector—do it now!• Ask what time to expect them in the next day, if applicable• Thank the Inspector and escort them to the exit• All Department Managers, SMEs, Response Team Members, all QA/Compliance

staff remain• Start remediation now of any possible observations mentioned by the investigator

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Final Closing Meeting

Inspection Close and the FDA Form-483

• Attendees at the closing meeting should include:– Highest ranking individual at the site– The Response Team and Critical SMEs (by invitation)– Department Heads

• The FDA Investigation Team will review inspection results, may read the F-483• Clarify any items that have not been resolved with the Investigator• Ask if there will be a Closure Report (Establishment Inspection Report) and when you can expect a

copy• State that you want the opportunity to redact confidential/proprietary information from the report

(these reports become available to all via Freedom of Information Act)• Ask if the Investigator will recommend NAI (No Action Indicated), VAI (Voluntary Action Indicated),

or OAI (Official Action Indicated). OAI may lead to a Warning Letter, Injunction or Seizure.• Do not make any admissions of guilt to the Investigator of non-compliance; do not sign anytrhing• Once investigators have gone, initiate a plan to answer the F483, which the investigator will leave

upon their departure

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WRITE A RESPONSE TO…

• 1. Failure to establish and maintain procedures for validating device design. [21 CFR 820.30(g)]

• For example:– The 2012 Design Input Plan, Design Output Plan and

Design Review for the XYZ Calibrator were not documented until October 2014, more than 2 years after the design of the product.

– An Engineering Change Request was not written for the change from threaded to crimp cap for the XYZ Mid-Range Standard Kit (List #) until 10/30/14. The actual change was effective 1/17/11.

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WRITE A RESPONSE TO…

• INVESTIGATION OF FAILURES• “Your investigation into the deaths of two [redacted]

during safety and potency tests [redacted] and the associated lack of investigation regarding Adverse Events [redacted] and [redacted] are inadequate. The relationship between the [redacted] deaths and the Adverse Event reports, which all implicated [your product] bulk lot #06TMG0080, should have triggered a comprehensive, in-depth investigation into all areas of the production process including manufacturing records and any associated deviations that occurred.”

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WRITE A RESPONSE TO…

1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, (21 CFR 211.113(b)).a. Non-integral (b)(4) gloves were used in Suites (b)(4) and (b)(4) for conducting aseptic processing operations. certain records indicated that you were testing (b)(4) gloves for integrity, but the integrity data indicated testing for (b)(4) gloves. You did not follow your procedure PDN/039/R10, "Leak Testing of (b)(4) Glove” for testing glove integrity. You did not test each glove represented in your firm’s analytical data, as required by the SOP. Instead, you repeatedly used the results for your (b)(4) gloves to falsely represent the results of your (b)(4)gloves.

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Thank you!

Questions?

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