Putting the “c” in cGMP: How to Remain Current
“What Attorneys Need to Know”
July 10, 2013
Washington D.C.
Roy Sturgeon, Ph.D.
Lachman Consultant Services Inc.
[email protected]
 How to Get and Stay Current
 What’s the Industry Perspective?
 Aggressive GxP Enforcement Environment
 Increased Data Integrity Focus
 During PAIs and Other Inspections
 Accountability and Prosecution
Industry Priorities/Strategies
 Uninterrupted Supply of High Quality Approved
Products on Time at a Reasonable cost
 Quality Culture
 Compliance with Rules and Regulations
 Janet Woodcock, MD, USFDA Mission:
 To have a maximally efficient, agile, flexible
pharmaceutical manufacturing sector that reliably
produces high quality drug products without extensive
regulatory oversight.
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Global Market Swamped in Product Recalls,
Enforcement and Shortages
 Regulatory Agencies assertive with companies about recalls.
Global Regulatory Agencies (Except FDA) have mandatory recall
 Overall enforcement environment , focus on corporate and
individuals, poster child criminal and civil actions - resulting in
aggressive company decisions to recall
 Many recalls based on GMP “lack of assurance” of quality versus
actual/probable defects.
 More aggressive recall classifications (I, II, III) and associated
product removal strategies
When Do Attorneys Get
 Usually Late – “When the Sheriff is at the Door”
 After 483s, WLs, Recalls, Seizures, Data Integrity, Problem
 Ideal - In Strategy Development/Reviews at Senior
Executive/Board Levels, Compliance Planning
 In Deploying Appropriate Controls
Advising on Corporate & Individual Liability
and Responsibility for GMPs
 FDA deputy chief counsel for litigation Eric Blumberg calls
for greater use of the Park Doctrine and jail terms in
healthcare fraud prosecutions, holding executives personally
responsible (strict liability) for regulatory infractions, even
without personal knowledge or intent to defraud.
 Glaxo Settlement Adds New ‘Financial Recoupment
Program’ (8-17-12) - This “puts at risk of forfeiture and
recoupment an amount equivalent to up to three years of
annual performance pay (i.e., annual bonus, plus long term
incentives) for an executive who is discovered to have been
involved in any significant misconduct”.
July 30, 2012
 Court allows HHS to ban executives from industry
 GSK ex-Officials targeted?
 Appeals Court upheld a 12-year ban from government
programs for former CEO Michael Friedman, general counsel
Howard Udell and former CSO Paul D. Goldenheim in the
government's case that was settled in 2007 for $634.5 million
over marketing of OxyContin.
FDA - Focus on Risk
 GMP & Product Quality
Risk Factors
 Contamination Prevention
Sterility Assurance
Microbiological Quality
Cross Contamination
Intentional (melamine; OSCS)
 Data Integrity
GxP Data and Records
 Global Sources
 Drug Safety
 Bioresearch Monitoring
GCP (Sponsors; Monitors; IRBs;
GLP Studies
BA/BE Studies
 Unapproved New Drugs
“Grandfathered” NEW Drugs
 Improper Sales/Marketing
Control/Practice of Sales Team
Web Sites
Gray Market and Stolen Drugs
Enforcement Priorities
Contamination Prevention –
micro, chemical, intrinsic,
extrinsic, particulates
High Risk Compounded
Internet Health Fraud
Unapproved Drugs
Data Integrity
Response to Contamination
Adverse Event reporting
Investigations Program
Supply Chain
CAPA Programs
Quality Systems/Quality
OTC Drug Quality
CMOs and Material Vendor
Field Alert Reporting
Prevention or Prompt
Mitigation of Drug
Getting Ready for PAI
What You Need to Know
 Knowledge of Laws,
Regulations, Guidances,
 Training (GMPs, Ethics, etc.)
 Good Documentation
 Data/ Record Keeping
 Knowledge of FDA Processes
 Capacity
 Organized to Execute?
 Infrastructure
 Standards, SOPs and
 Metrics
Enabling Documentation
 Right People in Right
 Clear Roles, Responsibilities
 Evidence (raw data and
 Follow Up
and Accountabilities
Assessments for PAI
 Readiness for Commercial Manufacturing
Materials Handling
Process Feasibility
 Conformance to Application
 Data Integrity
FDA Has Not Forgotten
the Generic Drugs Scandal
What is a GMP Violation?
 What deems a drug adulterated?
• Distinguish from the facts of a drug
• “Most prosecuted cases turn on proof of failure to follow GMP
practices – NOT the final quality of the drug”
Major Reasons for Failing PAIs
 Not ready for inspection or lacks operational capability for
responsibilities described in CMC
 General GMP Status is Unacceptable (i.e., “OAI”)
 GMP Deficiencies for Pivotal Clinical, Scale-Up, Stability
and/or BE Batches
 Data inconsistencies
 Insufficient batch record detail to drive and document execution
 Justification for critical process parameters and critical
ingredient and product quality attributes
Top 10 FDA Domestic Inspection Citations October
2010 - October 2012
Testing and release for distribution
Cleaning /sanitizing /maintenance
SOPs not followed/documented
Training - operations, GMPs, written…
Written procdures not…
Control proceudres to monitor and…
Investigations of discrepancies/failures
Scientifically sound laboratory controls
Absence of written procedures
Procedures not in writng/fully followed
50 100 150 200 250 300 350 400
 DOJ makes GMP Regulations “Top Area of Focus” for
 95% of Park Doctrine Prosecutions have been in last 6
Years – Targets Board Members and Senior Executives
What is a GMP Violation?
 What deems a drug adulterated?
• Distinguish from the facts of a drug
• “Most prosecuted cases turn on proof of failure to follow GMP
practices – NOT the final quality of the drug”
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Major FDC Act Violations Unchanged
 Submitting false and/or misleading
information to the agency
 Falsification of GXP records,
regardless of whether submitted to
 Distributing a drug product in
violation of investigational or
approved requirements
 False/misleading use, promotion or
 Drug safety monitoring and
reporting violations
 Adulteration of drug substance
or finished drug product
 Commercial or clinical use
 Not meeting appropriate,
established specifications
 Contamination
 Manufactured in violation of
GMP requirements,
regardless of whether
analytical specs met
 Unlawful distribution of
clinical materials or physician
Significant Post-Approval Findings
Post approval inspections often triggered when PAIs are waived and when
there are > average # of FARs and Recalls. Significant findings:
 Lack of justification for critical process parameters, operating ranges
and control strategies.
 Scale-up to commercial process not adequately validated prior to
 Stability testing commitments not met; unreported stability test failures;
expiry dates unsupported
 Unreported/unapproved changes to material/component suppliers,
contractors, specifications, facilities, equipment, process, test methods,
 Discrepancies suggesting fraud or deception
 Unfulfilled application commitments
 Inadequate Pharmacovigilance programs
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How to Fix Significant GMP Deficiencies
Data Integrity Issues - How They Happen
 Non-Deliberate
› Raw data misplaced – lack of clarity/training in procedures to
require retention of all data
› Data misfiled, can’t be located
› Errors in transcription
› Lack of adequate review of final records
› Rushing to meet deadlines causes errors to be overlooked
 Deliberate
› Fear of discovery of failure or error by management or regulators –
desire to “avoid pain”
› Desire to achieve objectives resulting in covering up errors
› Rare if a systemic effort to falsify records by management
Fraudulent Practices
 Creating passing test results without performing the test
 Substituting test results from one sample/batch to another
 Backdating records/reports
 Falsifying GxP documents – submitted or not
 Reporting only acceptable results (running “practice injections”
and deleting any unacceptable results)
 Reporting unrealistic results
 Data that looks “too perfect” or same
 Forging signatures, sharing passwords, software that allows for
deletion of results/data by all analysts/employees
What to Do
 For alleged or suspected wrong doing, obtain assistance from
qualified/experienced third party expert:
 Consultant(s) with experience in fraud Investigations
 Attorney/Law Firm - internal and/or external
 Establish the scope and breadth of the problem
 Bracket dates when alleged wrong doing occurred
 Determine if product(s), applications effected
 Develop internal investigation plan
Identify / isolate suspect documents
Locate raw data
Compare raw data to summaries
Tabulate data and sort by each variable
Identify / resolve inconsistencies
What to Do
 Examine firm’s organization
 Examine roles, responsibilities and accountabilities
 Identify personnel alleged/suspected of involvement
 Determine scope of involvement of each employee
 Consider higher ups - managers, directors, etc.
 Conduct Interviews (by third party and attorney (s))
 Investigate all work of suspected personnel
 Determine root cause of problem:
 Poorly defined procedures, roles, responsibilities, training gaps,
incompetence, deliberate wrongful acts, financial gain/incentives, others
 Involve legal counsel in all decisions
 Consult FDA’s “Points to Consider for Internal Reviews and Corrective
Action Operating Plans”
 Take personnel action where justified by facts
Lachman Consultant Services Inc.
Ethics and GMP Training
 Importance of preserving raw data and reporting all data
including failing data in addition to passing data
 Creating accurate data summaries and verifying raw data to
support the summaries (electronic and paper records)
 Business ethics – adopt the elements of the HHS OIG seven
point compliance program for pharmaceutical companies
 Include whistleblower protection and a telephone/email
“hot line” for reporting alleged wrongdoings
Fix the Problem
 NEVER alter / destroy original data, documents
Enter correct data or prepare addendum
Justify / explain errors
Preserve as part of formal record
Determine root cause
Correct and prevent root cause of errors
 Re-audit following corrections (by independent third party
and internal auditors)
 Assess the specific and system matters
 Document and resolve any additional findings
 Firms must have strong quality and ethics programs and maintain
management oversight procedures and clear personnel policies
that prevent data integrity matters, be able to detect them if they do
occur, and deal with them effectively
 Data integrity - focus and concern during any FDA inspection
 Not all data integrity matters are “fraud”, isolated instances of data
integrity matter where not deliberate are easily remediated
 A pattern or practice of data integrity matters, or the commission of
deliberate wrongful acts, are extremely serious and must be dealt
with timely and adequately
 FDA has administrative and legal remedies it can apply when
companies fail to have the above in place and adequately in use
Advice to Attorneys
from Dr. Mom
 “It’s easier to keep firms out of
trouble than to get them out of
 AND a lot less expensive
Thank You!
Roy Sturgeon, PhD
Lachman Consultants
Westbury, NY 11590
Email: [email protected]
Lachman Consultant Services Inc.
2011 Enforcement
 Seizures – 8
 Injunctions – 18
 Convictions – 375
 Warning Letters - >1700 (1200 Tobacco, 159 – Drugs &
Devices for 6 months)
 Recalls – Drugs – 1616
 Import Refusals - >27,000
 Fines - > $4.5 Billion
Corrective Actions by Company
 Will depend on facts from investigation
 Actions should include:
 Communicate effectively with FDA and other law
enforcement agencies
 Take actions and/or remove all personnel
(employees, contractors and others) who were or
may have been involved in wrongful acts
 A credible investigation using a competent third
parties (consultants/attorneys)

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