Presentation reviewing key issues and tactics associated with dealing with a company's reply to an FDA inspection and related warning letters. Includes lessons from actual responses.

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Successfully Responding to FDA
Inspections (483s) & Warning Letters
A Compliance2goSeminar
February 7, 2013
MichaelA. Swit, Esq.

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Standard Disclaimers
• Views expressed here are solely mine and do not
reflect those of my firm or any of its clients.
• This presentation supports an oral briefing and
should not be relied upon solely on its own to
support any conclusion of law or fact.
• These slides are intended to provide general
educational information and are not intended to
convey legal advice.
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What I Will Cover
• FDA’s Expectations on Replying to Inspections &
Warning Letters – the August 2009 Hamburg Speech
• How to Handle The Actual Inspection
• How to Respond to 483s & Warning Letters
• Lessons from Actual Responses
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How to Avoid Adverse Inspections &
Warning Letters
… in a Single Slide

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The Answer Is Simple – Comply!
• But, how? –
• Please Teach Vigorous Risk Avoidance
Comprehensively & Corporately
– Thus, to ensure you comply, you must have:
 P = Procedures
 T = Training
 V = Validation
 R = Records
 A = Audits
 C = Communications – open channels
 C = Compliance Culture from the Top
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FDA’s New Enforcement Culture under
Commissioner Hamburg
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All Inspections – 2004 to 2010*
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15,170
2009
17,635
2010
*2011 Data not available yet

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Warning Letters – 2004 to 2011
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Commissioner Hamburg Revives FDA’s
Compliance Culture –
The August 6, 2009 Speech
and its Impact
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Hamburg: Why We Need
Effective FDA Enforcement
• Conceded FDA enforcement efforts have been
deficient
• Five key benefits of effective enforcement:
– Protect public health by promptly intercepting unsafe or
fraudulent products – prevents additional harm
– Deter others who might violate law
– Informs public of potential harm
– Creates level playing field for industry
– Instill public confidence in FDA
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Hamburg: Four Essential Elements for
Effective FDA Enforcement
• Vigilance – both FDA and Industry
– FDA – Regular inspections and follow-ups
– Companies
 Must work quickly and thoroughly to correct problems
 Must understand
 if you cross the line, “you will be caught”
 If you fail to act, FDA will
• Strategic enforcement –
– Greater focus on significant risks and violations
– More meaningful penalties to “send a strong message to
discourage future offenses”
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Four Essential Elements for
Effective Enforcement …
• Quick action – FDA must respond rapidly,
especially to:
– Egregious violations
– Violations that threaten the public health
• Visible efforts – FDA must show all stakeholders it
is on the job
– Will publicize enforcement actions widely – including
rationales for action
– Goal:
 Increase confidence in FDA
 Deter non-compliance
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Six New FDA Enforcement Mandates …
• Impose clear post-inspection deadlines
– Generally –15 business days to respond to 483
– After that, agency can issue warning letter or take other
enforcement action
• Speed the warning letter process – by limiting
review by FDA Office of Chief Counsel to warning
letters that present significant legal issues
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Six New FDA Enforcement Mandates …
• Work more closely with FDA’s regulatory partners
– Example: in some cases, such as food safety, state, local, and
international officials can act more quickly than FDA
– When public health is at risk, the agency will coordinate with
its regulatory partners to take rapid action
• Prioritize follow-up on all warning letters and other
enforcement actions
– FDA will work quickly to assess the corrective action taken by
industry after a warning letter, a major product recall, or other
enforcement action
– Via new inspection or other form of investigation
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Six New Enforcement Mandates …
• FDA will be prepared to take immediate action to
respond to public health risks
– Actions may occur before a formal warning letter is issued – at
any time
– Days of multiple responses to inspections – over
• Develop and implement a formal warning letter
“close-out” process
– If FDA determines a firm fully corrected violations in a
warning letter, agency will issue an official “close-out” notice
and post on FDA Web site
– Seen as an “important motivator” for corrective action
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Enhanced Enforcement In Action –
Timely 483 Responses Policy
• Aug. 11 Federal Register notice – Post-inspection
483 responses timing policy published – 15 business
days
• Timely Responses
– FDA will conduct “detailed review” in deciding any
enforcement action
– If FDA issues a warning letter, letter will address sufficiency
of response
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Enhanced Enforcement In Action –
Timely 483 Responses Policy …
• Late responses
– Response will not be considered by FDA in deciding to take
enforcement action such as a warning letter
– If warning letter issues after a late 483 response, FDA will
consider the 483 response in assessing firm’s later reply to
warning letter
• Purpose of Warning Letter:
– “ensure … seriousness and scope of the violations are
understood by top management … and that the
appropriate resources are allocated to fully correct the
violations and prevent their recurrence”
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How to Handle The Actual Inspection
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How to Prepare for an Inspection
• Know the training and tactics of FDA Investigators
– Investigations Operations Manual (IOM)
http://www.fda.gov/ICECI/Inspections/IOM/default.htm
 See how FDA approaches inspections
– Compliance Program Guidance Manuals
http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProg
ramManual/ucm2005382.htm
– Other Guidance Documents
• Review other Companies’ 483s and Warning Letters
– know what the current “hot buttons” are
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Preparing for an Inspection
• Have a written corporate policy for FDA inspections
• Establish attitude of the company – must come from the
top
• Conduct independent external audits and internal
audits – find the problems before FDA does
– FDA policy – written audits done under a regular audit
procedure are normally not subject to inspection [see
Compliance Policy Guide #130.300); exceptions:
 “Directed" or"for-cause" inspection and investigations ofa sponsoror monitorof a clinical
investigation;
 In litigation
 Inspection warrant where access to records is authorized by statute;and
 Judicial search warrant.
http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm07
3841.htm21

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Train Personnel for Inspections
• Every employee must know his/her job function
and regulatory obligations
• Designate an inspection coordinator
• Document employee credentials, training and
knowledge
– QA/QC, GCP documentation
– Study, manufacturing and other protocols
– FDA program and inspection guidance documents
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Corporate Inspection Policy & Procedures
• Address GCP, GMP, GLP and other types of
inspections/inquiries
• Designate Who will interact with FDA Investigator
– Inspection Coordinator and Inspection Group
– Clinical Director Study Coordinator/Principal Investigator
– Production Employees
– Receptionist/Secretary
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Inspections of Records
• What records will be made available – know what you
must disclose under Section 704
• Have specific policies on:
– photographs
– tape recorders
– copying records (shipping, financial and business records)
• Questioning of personnel
– no duty to answer verbal questions, but the reality is you should
– don’t speculate; if don’t know; say you will find out
• Sampling –
– if FDA samples, you sample
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Personnel Interacting With Inspector(s)
• Receptionist/Secretary -- confirm FDA is at correct
name and institution (e.g., Par v. Parmed; Par v.
Barr); record inspector’s badge number
• Never leave investigator unattended
• Receptionist should have list of inspection
coordinator and alternate persons:
– Clinical Director / Study Coordinator / Principal Investigator
– Production V.P. / Quality Control Manager
– Executive V.P. / President
– Legal Counsel
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Duties of Inspection Coordinator
• Examine Credentials and 482 Forms
• Ask What Type of Inspection
• Write down all pertinent information
– contact core group
 internal
 external – you should have key experts identified in advance
 e.g., “micro” expert
 FDA attorney
– work out inspection agenda
– inform investigator of corporate policies – e.g. photographs
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General Tactics During Inspection
• Designate a Conference Room
• Don’t Allow Access to Areas Beyond Scope of
Inspection under § 704
– You get the items if needed
• Never Mislead the Investigator
• Don’t Panic (e.g., over missing documents, or
questions you don’t know answers for immediately)
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Defensive Strategies During/After
Inspection to Avoid Enforcement
• Draw the investigator into a conversation when a
problem is identified:
– more details (so that I may investigate);
– how/why is what we are doing (apparently) inadequate (so I
may explain to management)
• Daily Debriefs
– internally after each day of inspection
– try to get FDA inspector to do a daily debrief
 what is planned for next day
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FDA Investigative Techniques for
Gathering Evidence During Inspections
• Questioning employees at home at night or on the
weekend
– Permitted under FDCA Sec. 704
• Can go through trash, obtain grand jury subpoenas
and search warrants for telephone and business
records
• Collaboration with FBI and FDA’s OCI
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Home Interviews …
• Prepare employees to contact company legal
counsel before speaking with an investigator (this
assures no waiver or corporate privilege or
disclosure of confidential information)
• Company SOP should reflect desire to cooperate
with FDA to the extent that company understands
the purpose of the investigation and will not waive
or jeopardize its or its employees legal rights
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Inspection Exit Interview
• 483 Observations
• Ask For:
– Explanation and Details
– Examples
• Write Down Exactly What Investigator Says
– some firms are videotaping (OK by FDA per IOM)
• If observation has been corrected, ask that to be
noted on the 483
• If observation is wrong, politely engage in
dialogue. If you can show, inspector may delete
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Disagreements with 483 Observations
• Make notes of your requested comments and
include them in your 483 response
• Never “argue” with inspector
• Never make verbal promises, only written
responses – be careful with correction timelines
• Affidavits
– Never sign them and don’t even listen to a reading
– If they push, ask them to send to your attorney for review
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The Written Response to
483s & Warning Letters

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The Response – Assessing Allegations
• Assess each allegation/observation
– Focus on specifics
– Focus on system-wide implications
– Focus on global implications
– Consider affected products
– Consider root-cause analysis
• Focus on the regulatory requirement(s) associated
with each allegation/observation
• Develop corrective action plan to achieve
immediate, short-term, and long-term correction
and to prevent recurrence
– Know when to seek outside assistance
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The Written Response
• Provide specific evidence to minimize public health
risk
– number/scope of product’s distribution
– ability to do stock withdrawal or recall
– technical assessment
• If inspection follows product recall,
– Note company was “on the ball” and caught the problem, as it
was supposed to; foreclosing greater risk
– If did not catch, say what changes are being made to catch
sentinel events/data in the future
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Written Response to the 483
• Address each observation separately
• Never agree that an observation is valid:
– instead, state changes you intend to make
• Disagreements:
 Present your argument – remember – Science wins!!
 Be responsive, not argumentative
• Attach copies of changed documents
• Time lines –
– be specific, but be sure
– deliver what you promised when you promised it
 Send in follow-ups when due on timelines
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Keys to The Written Response
• Show the likelihood of recurrence of the
problem/violation is low
• Show the company is doing all it can reasonably to
remedy the situation: specific steps, timetable,
monitoring
• Problems attributable to a specific cause have/will
be fixed with permanent remedies
• Show that senior management understands
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FDA Expectation on Your Response
• Wants to Hear Your D.R.U.M. – expects your
response to have these qualities:
– Direct – i.e., address the items directly raised in the 483 or
warning letter
– Related – go beyond those to potentially related problems
– Universal – expand to review those issues company-wide
– Monitoring and Management –
 show that you will stay on top of the issues
 show that senior management is involved
Source: “Compliance and Enforcement.” Presentation by David K. Elder, Director, FDA Office of
Enforcement, at the Orange County Regulatory Affairs (OCRA)/FDA Joint Educational
Conference. June 15, 2005. Irvine, California.
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483/EIR: Inspection Results
• NAI – “No action indicated” -- no objectionable
conditions or practices were found during the inspection
(or the objectionable conditions found do not justify
further regulatory action)
• VAI - “Voluntary action indicated” -- objectionable
conditions or practices were found, but the District is
not prepared to take or recommend any administrative
or regulatory action
• OAI – “Official action indicated” -- regulatory and/or
administrative actions will be recommended
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FDA Enforcement Discretion
• Prior History of Company’s Compliance
– 483’s, warning letters, recalls, etc. -- and company’s
response(s)
• Health risks
• Likelihood of recurrence
• Discretion in action –
– K-V vs. FDA – Makena® pharmacy compounding; just
filed in federal court in D.C. on July 5
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Lessons from Actual Responses
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Failure to Implement Corrections
• 7) Failure to adequately establish procedures for corrective and preventive action;
as required by 21 CFR 820.100(a). For example, your firm's CAPA procedures, QOP-
85-04, Corrective and Preventive Action do not require written documentation when
proposing a Corrective Action Request, therefore limiting the ability to determine
recurrence of nonconforming product or quality problems. Your firm has not defined
what constitutes a sufficiently serious or recurring nonconformity'' in either your
Corrective and Preventive Action procedures or your Supplier Evaluation and
Monitoring procedure, (QOP 74-01) to define the criteria to initiate a Corrective Action
Request. Additionally, your Control of Non-Conforming Product procedures (QOP-83-
01) allow your form to close out non-conforming product reports if a disposition
decision is made to "scrap" or accept product "as is" without further evaluation to
determine if a corrective or preventive action is appropriate. Your responses, dated
March 7, 2012 and May 29, 2012 were inadequate. Your promised Corrective
actions have not yet been implemented.
• American OptiSurgical --
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm309410.htm
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Inadequate Corrections
• Failure to develop, maintain, and implementwritten MedicalDevice
Reporting (MDR) procedures, as required by 21 CFR Part 803.17.
• For example: Your firm’s procedure does not include the requirements for submission
of MDRs to FDA. Your firm’s procedure, (b)(4) as written, does not establish internal
systems that provide for timely and effective identification, communication, and
evaluation of events that may be subject to MDR requirements, a standardized review
process or procedure for determining when an event meets the criteria for reporting,
timely transmission of complete medical device reports, and documentation and
recordkeeping requirements, as required by 21 CFR Part 803.17.
• We reviewed your firm’s response dated June 1, 2011,and conclude that it
is not adequate.Although you provided an English translation of your
firm’s procedure,(b)(4) it does not meet the requirementsof 21 CFR Part
803.17 as stated above.
• Aesculap AG
• http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011
/ucm273502.htm43

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Repeat Violations
• The first postmarketing adverse drug experience (ADE) reporting
complianceinspectionof Acorda Therapeuticswas conducted in 2006.
Observations from the 2006 inspection included late submission of 15-day
Alert reports, failure to develop written procedures,and failure to submit
follow-up reports. A second postmarketing ADE reporting compliance
inspection of Acorda Therapeuticswas conducted in 2009. Observations
from the 2009 inspection included late submission of Field Alert Reports
and the repeat findingsof late submission of 15-day Alert reports and
failure to develop written procedures. Additionally,during the 2009
inspection, the FDA Investigator noted that your firm did not complete
corrective actions until 2007, even though your response to FDA, dated
January 19, 2006, stated that all corrections had been made.
• Acorda Therapeutics
• http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012
/ucm303979.htm
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Not Including Revised/New Procedure
• Failure to establish and maintain procedures for receiving,reviewing and
evaluating complaintsto determine whether the complaintrepresents an
event which is required to be reported to FDA under 21 CFR Part 803,
MedicalDevice Reporting,as required by 21 C.F.R. § 820.198(a)(3).From
December 2011 - January 2012, your firm received at least 11 complaints of
artifacts associated with the use of the Bella blanket during mammography
procedures. Review of these complaints revealed that you determined an
adverse event was not required, however, your firm did not obtain the
information necessary to make this determination. For example, you did not
assess whether a mammogram needed to be repeated or if the artifacts had the
potential for misdiagnosis for each complaint. Your response did not include
a revised complaintprocedure.
• Beekley Corporation
• http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012
/ucm309890.htm
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Failure to Address Allegation
• 3. Failure to document the results of finished
acceptance activities as required by 21 CFR
820.80(e)(3). We acknowledge that you have
implemented a specification that your Bella blankets to
now include a “point” pattern, however you are not
recording the results of your inspections on your weekly
“Production Report Release approval “ forms. Your
response does not address this violation.
• Beekley Corporation
• http://www.fda.gov/ICECI/EnforcementActions/Warning
Letters/2012/ucm309890.htm
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Not Addressing Cause of an Observation
• 5. Design validation did not include adequate risk analysis, as required by
21 CFR 820.30(g). For example, the risk analysis for the Adjustable Laser
Probe was incomplete, in that the Failure Mode and Effect Analysis (FMEA)
was not assessed for new risk determinations or for the revision of risk priority
numbers following a report of a device malfunction on June 21, 2010.
We have reviewed your response and have concluded that it is not adequate.
Your response to the observation was to cease distribution of the Adjustable
Laser Probe and to voluntarily recall the product. This response does not
address the corrective action necessary to address the cause of the
observation to prevent its recurrence. The observation merely used this
device as an example of a deviation. You must assure that design control
procedures are adequately established for all of its applicable devices.
• Peregrine Surgical--
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010
/ucm238045.htm
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Inspection Observations Clash with Reply
• 1. Failure of managementwith executive responsibility to establish its
policy and objectives for, and commitmentto, quality. Failure of
managementwith executive responsibility to ensure that the quality
policy is understood, implemented,and maintained at all levels of the
organization, as required by 21 C.F.R 820.20 (a).
We have reviewed your responses and have concluded that they are inadequate.
Your response of April 15 states that quality procedures have been improved
over the past 11 months and that meetings are held frequently to ensure full
Quality System regulation compliance. However, evidence obtained during
this inspection does not support this assertion. You do not appear to be
following your Quality Manual, for example failing to maintain complete
design controls records, and to documentverification and validation
activities.
• Allez Spine
• http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2008
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Failure to Do Root Cause Analysis
• d. Your firm has failed to thoroughly investigate several
customer complaints. For example, you received complaint
#(b)(4) on March 1, 2010, citing dark particulate matter in a vial of
Heparin. You investigated and determined that the particle was
most likely due to a vendor issue; however, you did not perform an
assessment of the vial supplier.
• In your response, you state that you have not identified any other
defects of this nature. Your response is inadequate since you
have not addressed the potential root cause of a vial defect as
identified in your investigation.
• APP Pharmaceuticals
• http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012
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Final Sermon: Comply!
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Please Teach Vigorous Risk Avoidance
Comprehensively & Corporately
• Thus, to ensure you comply, you must have:
– P = Procedures
– T = Training
– V = Validation
– R = Records
– A = Audits
– C = Communications – open channels
– C = Compliance Culture from the Top
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Questions?
• Call, e-mail or fax:
Michael A. Swit, Esq.
Special Counsel, FDA Law Practice
Duane Morris LLP
San Diego, California
direct: 619-744-2215
fax: 619-923-6248
maswit@duanemorris.com
• Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel
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About Your Speaker
Michael A. Swit, Esq., is a Special Counsel in the San Diego office of the international law firm,
Duane Morris, LLP, where he focuses his practice on solving FDA legal challenges faced by
highly-regulated pharmaceutical and medical device companies. Before joining Duane Morris in
March 2012, Swit served for seven years as a vice president at The Weinberg Group Inc., a
preeminent scientific and regulatory consulting firm in the Life Sciences. His expertise includes
product development, compliance and enforcement, recalls and crisis management, submissions
and related traditional FDA regulatory activities, labeling and advertising, and clinical research
efforts for all types of life sciences companies, with a particular emphasis on drugs, biologics and
therapeutic biotech products. Mr. Swit has been addressing vital FDA legal and regulatory issues
since 1984, both in private practice with McKenna & Cuneo and Heller Ehrman, and as vice
president, general counsel and secretary of Par Pharmaceutical, a top public generic and specialty
drug firm. He also was, from 1994 to 1998, CEO of FDANews.com, a premier publisher of
regulatory newsletters and other specialty information products for FDA-regulated firms. He has
taught and written on many topics relating to FDA regulation and associated commercial
activities and is a past member of the Food & Drug Law Journal Editorial Board. He earned his
A.B., magna cum laude, with high honors in history, at Bowdoin College, and his law degree at
Emory University.
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