Successfully Responding to FDA Inspections (483s) & Warning Letters

Solving FDA Legal Challenges for the Life of a Life Sciences Company -1- www.fdacounsel.com
LAW OFFICES OF MICHAEL A. SWIT
Successfully Responding to FDA
Inspections (483s) & Warning Letters
A Compliance2go Webinar
November 10, 2015
Michael A. Swit, Esq.

Standard Disclaimers
➢ Views expressed here are solely mine and do not
reflect those of my law 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.

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

How to Avoid Adverse Inspections & Warning
Letters
… in a Single Slide

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

FDA’s Enforcement Culture under and after
Commissioner Hamburg
6

Commissioner Hamburg Revives FDA’s
Compliance Culture –
The August 6, 2009 Speech
and its Impact
7

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
8

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”

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

Six 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

Six 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
12

Six 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
13

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
14

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”

2014 and 2013 Inspections Statistics
2014 2013

How to Handle The Actual Inspection

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/ComplianceProgramMan
ual/ucm2005382.htm
– Other Guidance Documents
➢ Review other Companies’ 483s and Warning Letters –
know what the current “hot buttons” are

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 of a sponsor or monitor of 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/ucm073841.
htm

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

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

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

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

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

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)

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

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

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

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

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

The Written Response to
483s & Warning Letters

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
34

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

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

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

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.

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

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

Lessons from Actual Responses

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

Inadequate Corrections
➢ Failure to develop, maintain, and implement written Medical Device
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 requirements of 21 CFR Part 803.17 as
stated above.
➢ Aesculap AG
➢ http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm
273502.htm

Repeat Violations
➢ The first postmarketing adverse drug experience (ADE) reporting
compliance inspection of Acorda Therapeutics was 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 Therapeutics was conducted in 2009. Observations
from the 2009 inspection included late submission of Field Alert Reports
and the repeat findings of 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/u
cm303979.htm

Not Including Revised/New Procedure
➢ Failure to establish and maintain procedures for receiving, reviewing and
evaluating complaints to determine whether the complaint represents an
event which is required to be reported to FDA under 21 CFR Part 803,
Medical Device 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
complaint procedure.
➢ Beekley Corporation
cm309890.htm

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/WarningL
etters/2012/ucm309890.htm

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

Inspection Observations Clash with Reply
➢ 1. Failure of management with executive responsibility to establish its policy
and objectives for, and commitment to, quality. Failure of management with
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 document verification and validation activities.
➢ Allez Spine
➢ http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2008/ucm
1048186.htm

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
cm293068.htm

Final Sermon: Comply!

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

Questions?
➢ Call, e-mail or write:
Michael A. Swit, Esq.
San Diego, California 92130
m: 760-815-4762
e: mswit@fdacounsel.com
web: www.fdacounsel.com
➢ Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel

About Your Speaker
Michael A. Swit, Esq., has been addressing critical FDA legal and regulatory issues for over 30
years. Before returning to his private law practice in late 2017, he served for 3 years as the chief
regulatory counsel at a leading developer of diagnostics and research tools. Prior to that, Swit was a
special counsel in the FDA Law Practice at the global law firm of Duane Morris LLP, in its San
Diego office. 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, therapeutic biotech products, medical devices, and IVDs.
His FDA legal and regulatory work also has included tenures 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, where he helped spearhead the
company’s emergence from the Generic Drug Scandal. 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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