You receive a Warning Letter-- you have 15 days to submit a response. If FDA finds your response inadequate, you may receive a Consent Decree, which will cost millions to remediate. You need a process in place to react to a Warning Letter before it is delivered. These experts will discuss planning, procedures, training and ways to keep from getting a warning letter in the first place.

1. Responding Effectively to FDA 483
Observations & Warning Letters
Presented by:
Pamela Forrest, Esq.
Partner – King & Spalding
Norman Rabin
Quality Director, Solutions Delivery – Maetrics, LLC

2. 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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3. Why Responding Effectively Matters
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4. 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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5. 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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6. 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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7. Potential Consequences of an Inadequate
483 Response
• Warning Letter
• Untitled Letter
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8. 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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9. 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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10. 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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11. How to Prepare an Effective Response
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12. 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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13. Sample 483 Observation
OBSERVATION X
The 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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14. 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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15. 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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16. 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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17. 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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18. 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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19. 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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20. 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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21. 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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22. 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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23. 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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24. 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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25. How to Avoid Common Pitfalls
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26. 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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27. Failing to Address Systemic Issues
• As discussed earlier, simply correcting the
specific examples that FDA listed is not
sufficient.
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28. 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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29. 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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30. 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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31. 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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32. 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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33. 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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34. 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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35. Thank you!
Questions?
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36. Preparation is a Good Foundation
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37. Pre-Inspection Activities
Being 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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38. 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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39. 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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40. 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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41. 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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42. 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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43. Defining Inspection Management
Response 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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44. 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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45. 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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46. 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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47. 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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48. 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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49. 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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50. Thank you!
Questions?
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