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Data Integrity:
Compliance
Ajaz S. Hussain, Ph.D.
KEYNOTE OPENING SESSION
Critical Update — Navigate the
2016 FDA Data Int...
Since20o8FDAhasbeen
increasingthenumberof
inspections atforeign
facilities;parity(per
FDASIA)with frequencyof
domesticinsp...
Breach of data
integrity
 Breach: an act of breaking or failing to observe a law,
agreement, or code of conduct.
 Failur...
Breach of data
integrity
 Data: facts and statistics collected together for
reference or analysis.
 Evidence based decis...
CarmeloRosa:
Data Integrity,
EssentialPartof
aQualitySystem
DIA Multicenter International
Data IntegrityWorkshop. 13-14,
N...
"Dataintegrity[issues]reallysoundsoff
alarmbellsforus...ifyouseedata
integrity[issues]on thesurface,thereis
likelyalotgoin...
Data integrity related to
Quality,Safety &Efficacy?
“All 70batches were retested
andallwere foundto bein
specification. “
...
Themainreasondatais
deletedisbecause
the analyst (often) knows the
result is not correct for reasons
not related to qualit...
Quality = Meeting
Specifications
Central drug controller
unveils ‘world’s biggest’
quality check
This survey is likely to
...
Reactive System
Errors & failure are our
drivers; low tolerance
Few failures sufficient to
change laws seeking
change in o...
Importance ofCGMP
& Documentation
Past tragedies that
occurred with products
that “met specifications”
Limitations of
phar...
8/24/2016 Confidential. Designed for Ipca labs by Ajaz S. Hussain, Ph.D. 12
Are you
aware?
Six Blind Men &the
Elephant orElephant in
the Dark?
Pharmaceutical
‘market failure’,
‘information
asymmetry’ &
cognitive b...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 14
Attitude/drivers:
Output oriented
Non-compliance
Slow to fi...
Breach of data
integrity
 Integrity: the state of being whole and undivided; the quality of
being honest and having stron...
Streetlight effect
 A policeman sees a drunk man searching for
something under a streetlight and asks the drunk what
he’s...
Outline: Keynote
Effective
Remediation,
Proactive Compliance
Global Regulatory
Landscape
FDA Draft Guidance
2016
Top Chall...
Keynote Stance:
Attitude of a person
or organization
towards CGMP
Stance
Ex-
Regulator
Advisor
Patient
Questions
Why?
How?...
Questions
Ex-Regulator
Why an increase
in BDI?
How to ensure
effective CAPA?
What will
promote
confidence?
Advisor
Why con...
Stance:
Ex-Regulator
Effective Remediation
to Proactive
Compliance
Global Regulatory
Landscape
FDA Draft Guidance
2016
Top...
Outline (contd.)
WhyanincreaseinBDI?
Howto ensureeffective
CAPA?
Whatwillpromote
confidence?
 Evaluate the Global Regulat...
Stance:
Advisor (Industry)
Effective Remediation
to Proactive
Compliance
Global Regulatory
Landscape
FDA Draft Guidance
20...
Outline (contd.)
Whyconfidence is a
CQA?
How confidence is
achieved & sustained?
What confidence
contributes to top&
botto...
Stance:
Patient
 An implicit stance
 Health-care system- medical errors the third leading cause of death
 Evidence of t...
Evaluate theGlobal
Regulatory Landscape
Historical
perspective
Current context & trends
Global regulatory
expectations
Ass...
Definition Data integrity refers to the completeness,
consistency, and accuracy of data.
Complete, consistent, and accur...
Historical
perspective(personal
observations @FDA)
 When breaches in data integrity are reported by insiders and/or
obser...
Historical
perspective(US
Regulatory snap-shot)
 Application Integrity Policy
 Integrity of data and informationin appli...
Historical
Perspective:Role
of data integrity
inCGMP for
drugs (USA)
Implicit
(past)?
Requirements
(e.g., 21 CFR)
§ 211.68...
§ 211.68
“backup data are
exact and
complete,” and
“secure from
alteration,
inadvertent
erasures, or loss”
Irvine Stem Cel...
Review selectedWLs &
NOCs
US FDA, EU (MHRA/EMA) ,WHO
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 31
Prior ...
Ourinvestigator identified
significant violations ofcurrent
good manufacturing practice
(CGMP) regulations for finished
ph...
Theseviolationscause
yourdrugproductsto be
adulteratedwithinthe
meaningofSection
501(a)(2)(B)…..
 Your laboratory records...
Statement of Non-
compliance with
GMP
Exchangeofinformation
betweenregulators
8/24/2016 ©Ajaz S. Hussain | Insight,Advice ...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 35
Evidenceof data integrity issues withinGMP documentations,
...
Nature of non-
compliance
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 36
Major deficiencies
Data falsifica...
WHOPrequalification
Team-InspectionServices
Seriousconcernsregarding
the integrity,reliability
andaccuracyofthe data
gener...
Notice ofConcern
Steps taken by
inspectors
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 38
 The company fa...
Notice ofConcern
Inadequate
responses
 The corrective and preventive actions described in your response,
consisted of ins...
US FDA 8/1/2016 2015 2014 2013 2012
§ 211.68 0 7 0 5 7
§ 212.110(b) 0 0 0 0 0
§ 211.100 4 5 2 2 8
§ 211.160 3 1 1 6 5
§ 21...
EudraGMDP
(Public Site)
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 41
 GMP Non-
Compliance Search
Result...
Global regulatory
landscape (CGMP)
Likelihoodof protracted
remediation: High(USA)
Likelihoodof effective
CAPA:Low(USA)
 T...
Why an increase
in BDI?
How to ensure
effectiveCAPA?
What will
promote
confidence?
 Growing cluster of BDI due to improve...
Summary:Context
Breaches of data integrity (DI)
in CGMP a “hot topic”
DI implicit and integral to QMS
Violations being not...
Data Integrity &
Compliance withCGMP
April 2016 DraftGuidance
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC ...
Implicit to
Explicit:The
role of data
integrity
 CGMP for drugs, as required in 21 CFR parts 210, 211,
and 212
 Part 210...
Making it
explicit
 CGMP record :Any and all data to fulfill CGMP
requirements; cannot be excluded from decision-making
p...
Making it
explicit
 Audit trails : “secure, computer-generated, time-stamped electronic
record that allows for reconstruc...
US FDA:
Remediation
expectations
(Warning Letter)
 Third party auditor with experience in detecting data integrity
proble...
US FDA:
Remediation
expectations
(Warning Letter)
 Third party auditor with experience in detecting data integrity
proble...
US FDA:
Remediation
expectations
(Warning Letter)
 Third party auditor with experience in detecting data integrity
proble...
US FDA:
Remediation
expectations
(Warning Letter)
 Third party auditor with experience in detecting data integrity
proble...
US FDA:
Remediation
expectations
(Progress reports)
 Provide an update on the status of your on-going
review of data gene...
US FDA:
Remediation
expectations
(Progress reports –
extended to
applications)
 Provide details on the following items in...
US FDA:
Remediation
expectations
(Progress reports)
 Provide verification that metadata files not identified
by the algor...
US FDA:
Remediation
expectations
(Reminder)
 Note that the FDA will refuse to approve an abbreviated
application for a ne...
Outline (contd.)
WhyanincreaseinBDI?
Howto ensureeffective
CAPA?
Whatwillpromote
confidence?
 Evaluate the Global Regulat...
Outline (contd.)
Whyconfidence is a
CQA?
How confidence is
achieved & sustained?
What confidence
contributes to top&
botto...
Stance:
Advisor (Industry)
Effective Remediation
to Proactive
Compliance
Global Regulatory
Landscape
FDA Draft Guidance
20...
Quality = Meeting
Specifications
Central drug controller
unveils ‘world’s biggest’
quality check
This survey is likely to
...
Importance ofCGMP
& Documentation
 Past tragedies that occurred
with products that “met
specifications”
 Limitations of
...
India has the second-largest number
of manufacturing facilities outside of
theUS registered with theUS FDA
Key highlights:...
Indianpharmaceutical,
majorstridesto becoming
proactive
Over one-third of the total
data integrity reviews
conducted by EY...
Streetlight effect
 A policeman sees a drunk man searching for
something under a streetlight and asks the drunk what
he’s...
Humans are
predictably
irrational; some
are capableof
deliberately
poisoningothers
to make money
 Daniel Kahneman and Amo...
From “Art” to“Science”
ofpharmaceutical
product andprocess
development
21st Century Desired
State: Strengthen
scientific f...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 67
Attitude/drivers:
Output oriented
Non-compliance
Slow to fi...
Individual &
Organizational
Behavior
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 68
Attitude &
Rationaliza...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 69
Anatomy ofTesting intoCompliance (dissolution)
Attitude
tow...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 70
Pharma patterns suggestive of ‘intentional holes’“….records...
Predictably
irrational:
Cognitive
biases,…..
 The cGMP issues with BDI currently being noted “new”?
 Not likely – rigor ...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 72
Epistemic Trust
Toppled Knowledge Pyramid: Preventing a Com...
“a lot going on
underneath…”
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 73
 To understand FDA regulation...
Outline (contd.)
Whyconfidence is a
CQA?
How confidence is
achieved & sustained?
What confidence
contributes to top&
botto...
Frameworkdevelopedfor
Culture of Pharmaceutical
Quality
Bonus Material
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solut...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 76
Framework:
Culture of
Pharmaceutica
lQuality (CPQ)
Culture ...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 77
Attribute Rating
Good progress,
continue efforts
already in...
WhyCulture of
Pharmaceutica
lQuality
(CPQ)?
FDA inspections are
Periodic, of limited
duration, face
information asymmetry,...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 79
Building the
connect the
dots
framework
Pharmaceutical GXPs...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 80
Culture –
Pharma
Quality
Quality is
Normal
Quality is
Easy
...
Going beyond
rules pays..
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 81
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 82
Predictors of
Culture of
Quality
Only four
attributes
actua...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 83
Specific considerations for Pharmaceuticals:We make two int...
Important to
account for
pharmaceutical
‘market failure’,
‘information
asymmetry’ &
cognitive biases
(blind-spots)
8/24/20...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 85
Struggle for effective cGMP remediation
Company 1: Struggli...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 86
US FDA’s
emphasis on
management
responsibility
Richard L. F...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 87
US FDA’s evolving
thinking on
maturity ofQMS
Richard L. Fri...
Historically
resolution of
process problems
slow
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 88
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 89
Multiple
causes; getting
to “root” is
difficult
Specific
considerations for
‘Pharmaceuticals’
Sector-wide issues
 Market failure and information asymmetry
 Two products...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 91
Principles of “Out of theCrisis” byW. Edward Deming
MITPres...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 92
Pharmaceutical Quality for 21st Century had intended to lim...
A, B,C, D
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 93
• Appreciation for System
• Organization viewed a...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 94
CPQ: Need for Emphasizing SystemsThinking & Practices;QbD
i...
The Power of
Habit:WhyWe Do
WhatWe Do in
Life and Business.
CharlesDuhigg(2012)
• Scientific methodology
• Engineering Des...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 96
Maturity Level &Assurance ofQuality
Managed Characterized,
...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 97
X,Y &Z: Reduce Fear,Awareness & Mastery
Reduce
Fear of
Erro...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 98
Framework: Culture of Pharmaceutical Quality (CPQ)
Culture ...
CPQ: Founded
onQuality by
Design
 We do our best to develop medicines and the evidence needed to
satisfy the needs of pat...
From “Art” to“Science”
ofpharmaceutical
product andprocess
development
21st Century Desired
State: Strengthen
scientific f...
8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 101
Epistemic Trust
Toppled Knowledge Pyramid: Preventing a Co...
We will never solve the problems
tomorrow with the same order of
consciousness we are using to create
the problems of toda...
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Data Integrity Validation Keynote Address Boston August 2016

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Critical Update — Navigate the 2016 FDA Data Integrity Compliance Draft Guidance and Other Global Regulations
Evaluate the Global Regulatory Landscape
Expectations of the 2016 FDA Draft Guidance
Overcome Top Challenges
Proactive Approach to Assurance of Data Integrity
Bonus Material

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Data Integrity Validation Keynote Address Boston August 2016

  1. 1. Data Integrity: Compliance Ajaz S. Hussain, Ph.D. KEYNOTE OPENING SESSION Critical Update — Navigate the 2016 FDA Data Integrity Compliance Draft Guidance and Other Global Regulations Evaluate the Global Regulatory Landscape Expectations of the 2016 FDA Draft Guidance Overcome Top Challenges Proactive Approach to Assurance of Data Integrity Bonus Material 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 1
  2. 2. Since20o8FDAhasbeen increasingthenumberof inspections atforeign facilities;parity(per FDASIA)with frequencyof domesticinspectionsby 2017? Whatabout‘rigorof inspections’- unannounced inspections? 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 2 5 24 0 5 10 15 20 25 30 2010-2012 2013-2015 2016-2018 Breaches of DI Noted in FDA CGMP Warning Letters 500 1000 1500 2000 2500 3000 3500 2008 2010 2012 2014 2016 FDA CGMP Inspections Overseas Drug Facilities ?
  3. 3. Breach of data integrity  Breach: an act of breaking or failing to observe a law, agreement, or code of conduct.  Failure (or error)Vs Planned (or malicious)  Planned (or by design): Local vs System-wide  Cheating by Design 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 3
  4. 4. Breach of data integrity  Data: facts and statistics collected together for reference or analysis.  Evidence based decision-making  Assurance:Quality, Safety & Efficacy  Market access, cost of doing business, profitability 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 4
  5. 5. CarmeloRosa: Data Integrity, EssentialPartof aQualitySystem DIA Multicenter International Data IntegrityWorkshop. 13-14, Nov. 2014.Bangalore, India.  “Testing into compliance, data manipulation, data deletion/ record destruction, misreporting, disregarding failing and/or questionable results, all leading to possible breaches in the integrity of critical data, has become one of the most important and relevant topics currently discussed by industry and regulators from around the world.” 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 5
  6. 6. "Dataintegrity[issues]reallysoundsoff alarmbellsforus...ifyouseedata integrity[issues]on thesurface,thereis likelyalotgoingonunderneath.“ ThomasCosgrove, FDA on Observations related to Breaches of Data Integrity (BDI)I 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 6 The FDA issued warnings to 10 drug companies in 2015 for data integrity violations – the most in at least 10 years.
  7. 7. Data integrity related to Quality,Safety &Efficacy? “All 70batches were retested andallwere foundto bein specification. “ FDA is unnecessarily obsessed with data integrity issues? 8/24/2016 © Ajaz S. Hussain| Insight, Advice & Solutions LLC 7 http://www.pharmacompass.com/pharma-news/data-integrity-has-no-relationship-with-product-quality ALL OTHERS BRING DATAhttp://www.pharmacompass.com/pharma-news/18-reasons- spelt-out-by-peter-j-werth-to-delete-analytical-data
  8. 8. Themainreasondatais deletedisbecause the analyst (often) knows the result is not correct for reasons not related to quality (gross errors/laboratory gross errors). They do not want to conduct an expensive, time-consuming, and cumbersome OOS (out-of- specification) investigation. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 8 http://www.pharmacompass.com/pharma-news/18-reasons- spelt-out-by-peter-j-werth-to-delete-analytical-data Acceptable reasons for deleting?
  9. 9. Quality = Meeting Specifications Central drug controller unveils ‘world’s biggest’ quality check This survey is likely to make or break India’s reputation as one of the leading manufacturers of generic drugs in the world. 8/24/2016 © Ajaz S. Hussain| Insight, Advice & Solutions LLC 9 http://indianexpress.com/article/india/india-others/central-drug-controller-unveils-worlds-biggest-quality-check/
  10. 10. Reactive System Errors & failure are our drivers; low tolerance Few failures sufficient to change laws seeking change in our behavior Our success is not acknowledged by law makers (public) 8/24/2016 © Ajaz S. Hussain| Insight, Advice & Solutions LLC 10
  11. 11. Importance ofCGMP & Documentation Past tragedies that occurred with products that “met specifications” Limitations of pharmacovigilance Basic duty of care for patients we serve Not making false claims Epistemic trust Even playing field 8/24/2016 © Ajaz S. Hussain| Insight, Advice & Solutions LLC 11
  12. 12. 8/24/2016 Confidential. Designed for Ipca labs by Ajaz S. Hussain, Ph.D. 12 Are you aware?
  13. 13. Six Blind Men &the Elephant orElephant in the Dark? Pharmaceutical ‘market failure’, ‘information asymmetry’ & cognitive biases (blind-spots) 8/24/2016 © Ajaz S. Hussain| Insight, Advice & Solutions LLC 13
  14. 14. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 14 Attitude/drivers: Output oriented Non-compliance Slow to fill gaps in IT controls & other safeguards Poor staff training , inability to escalate issues Inadequate QA & supervisory oversight & planning Lack of Sr. Mgmt. involvement in quality; not asking the right questions Human factors that undermine a QMS Culture of Pharmaceutical Quality (latent factors) Production pressures; weak leadership skills; silos Overwork, fear of error, low empowerment Reliance on previous audits (reactive); not-broken – why fix it? Ineffective root-cause investigations & CAPA If “a lot going on underneath” – What is the root cause? Set ofWhys Set ofWhys Set of Whys Set of Whys
  15. 15. Breach of data integrity  Integrity: the state of being whole and undivided; the quality of being honest and having strong moral principles  Time to approval, manufacturing costs, and profitability are precisely and frequently measured  It is easier to improve what we measure;Attitude documentation is not critical to quality  Pharmacovigilance is a blunt (or highly variable) instrument; review & inspections can be heterogeneous  Can be a reason to rationalize deviant behavior; I am not causing any harm (rationalization)  The end justifies the means  increasingly dominant mindset; humans are predictably irrational (incentive & pressure) 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 15
  16. 16. Streetlight effect  A policeman sees a drunk man searching for something under a streetlight and asks the drunk what he’s lost.  The drunk says, “I lost my keys,” and they both look under the streetlight together.  After a few minutes, the policeman asks if he’s sure he lost them here.  The drunk replies, “No, I lost them in the park.”  The policeman asks, “Why are you searching here then?”  The drunk replies, “This is where the light is. 8/24/2016 © Ajaz S. Hussain| Insight, Advice & Solutions LLC 16 David H. Freedman (August 1, 2010)."The Streetlight Effect". Discover magazine Why Is The Placebo Effect Exploding In The U.S. But Nowhere Else? Forbes |Pharma & Healthcare OCT 7, 2015 We are finally beginning to understand that irrationality is the real invisible hand that drives human decision making. The End of Rational Economics. HBR July-August 2009
  17. 17. Outline: Keynote Effective Remediation, Proactive Compliance Global Regulatory Landscape FDA Draft Guidance 2016 Top Challenges Culture of Pharmaceutical Quality 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 17
  18. 18. Keynote Stance: Attitude of a person or organization towards CGMP Stance Ex- Regulator Advisor Patient Questions Why? How? What? 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 18
  19. 19. Questions Ex-Regulator Why an increase in BDI? How to ensure effective CAPA? What will promote confidence? Advisor Why confidence is a CQA? How confidence is achieved & sustained? What confidence contributes to top & bottom-line? Patient Why confidence in quality matters? How to communicate confidence? What metrics to track? 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 19
  20. 20. Stance: Ex-Regulator Effective Remediation to Proactive Compliance Global Regulatory Landscape FDA Draft Guidance 2016 Top Challenges Culture of Pharmaceutical Quality (Bonus) 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 20 Why an increase in BDI? How to ensure effective CAPA? What will promote confidence?
  21. 21. Outline (contd.) WhyanincreaseinBDI? Howto ensureeffective CAPA? Whatwillpromote confidence?  Evaluate the Global Regulatory Landscape  Historical perspective  Current context & trends (483’s &Warning Letters)  Global regulatory expectations  Assess EU statements of non-compliance with  GMP andWHO notices of concern  Understand FDA regulations and draft guidance  Expectations of the 2016 FDA Draft Guidance  What does the draft guidance really tell us?  What to expect for the full implementation of this guidance  How to implement meaningful and effective strategies that align with cGMP 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 21
  22. 22. Stance: Advisor (Industry) Effective Remediation to Proactive Compliance Global Regulatory Landscape FDA Draft Guidance 2016 Top Challenges Culture of Pharmaceutical Quality (Bonus) 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 22 Why confidence is a CQA? How confidence is achieved & sustained? What confidence (should) contribute to top & bottom-line?
  23. 23. Outline (contd.) Whyconfidence is a CQA? How confidence is achieved & sustained? What confidence contributes to top& bottom-line?  Overcome Top Challenges  Understand human factors — Cognitive biases and ‘blind spots’  How does these factors contribute to breaches in assurance of data integrity?  Implement appropriate (soft and hardware) controls to ensure an effective quality management system  Simplify the framework for the culture of pharmaceutical quality  Proactive Approach to Assurance of Data Integrity  Expected challenges in remediating breaches in data integrity  How to conduct effective investigations  How to make the necessary corrections  How to measure effectiveness and assess confidence to prevent reoccurrence  Effective communication — Credibility and rebuilding trust with FDA 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 23
  24. 24. Stance: Patient  An implicit stance  Health-care system- medical errors the third leading cause of death  Evidence of the increasing importance of placebo/nocebo effect  Our (pharmaco-) vigilance is blunt and highly variable  We measure top & bottom-line precisely and frequently  We are predictably irrational; sustained high level of fear/anxiety  We are all patients and we must all be regulators  Confidence (in medicine, regulators and companies) is a Critical Quality Attribute (CQA)  As a patient – have confidence that the medicine will do what it is supposed to do 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 24
  25. 25. Evaluate theGlobal Regulatory Landscape Historical perspective Current context & trends Global regulatory expectations Assess EU statements of non- compliance with GMP and WHO notices of concern Understand FDA regulations and draft guidance 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 25
  26. 26. Definition Data integrity refers to the completeness, consistency, and accuracy of data. Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA) FDA’s Draft Guidance for Industry: Data Integrity and ComplianceWith CGMP (April 2016 ) 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 26
  27. 27. Historical perspective(personal observations @FDA)  When breaches in data integrity are reported by insiders and/or observed by regulators  Problem are often way beyond individual errors  Root causes are systemic and system wide  Reasons for rationalization include regulatory approval/validation and “doing no harm”  Business reasons (pass a filing batch or study) for allowing breaches to occur ExpertWitness for the Prosecution Requests (e.g.,Center Director) to facilitate difficult to resolve CGMP issues; prevent drug shortages Warning Letter (re-design product/process) Lingering Consent Decrees (re- design product/process) 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 27
  28. 28. Historical perspective(US Regulatory snap-shot)  Application Integrity Policy  Integrity of data and informationin applications submitted for FDA review and approval.  AIP List (CDER): Hill Dermaceuticals, Inc., Ranbaxy Laboratories, Ltd., BiopharmaceuticsInc.*,Solopak Pharmaceuticals, Inc.,SuperpharmCorp* (* to the agency's knowledge,the firm is out of business)  Bioresearch Monitoring  FDA Debarment List (Drug ProductApplications)  Good Laboratory Practice (GLP),Amendment, Final Rule, 9/4/1987  ComputerizedSystems Used inClinical Investigations  Compliance PolicyGuides:  Fraud,Untrue Statements of Material Facts, Bribery, and IllegalGratuities (CPG 7150.09) (July, 1991)  International Memorandaof Understanding (June, 1995)  FDAAccess to Results ofQualityAssurance ProgramAudits and Inspections (CPG 7151.02) (January 1996)  Part 11, Electronic Records; Electronic Signatures — Scope and Application  March of 1997, FDA issued final part 11 regulations  CPG 7153.17: Enforcement Policy: 21 CFR Part 11  Several draft guidance documents  Federal Register of February 4, 2003 (68 FR 5645) – withdrawalof draft guidance,…… Prosecution recommendations, including referrals for criminal investigation Criminal Prosecution after Section 305 Notice & without Section 305 Notice Special Procedures and Considerations for Park Doctrine Prosecutions 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 28
  29. 29. Historical Perspective:Role of data integrity inCGMP for drugs (USA) Implicit (past)? Requirements (e.g., 21 CFR) § 211.68 § 211.180 § 211.160 § 211.188 § 211.194 Other (Part 11, etc.) Explicit (Draft Guidance 2016)? 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 29
  30. 30. § 211.68 “backup data are exact and complete,” and “secure from alteration, inadvertent erasures, or loss” Irvine Stem Cell Treatment Center 12/30/2015 CDER CGMP/Deviations/Biologics License Application (BLA) No Chan Yat Hing Medicine Factory 12/15/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No Sandoz Private Limited 10/22/2015 CDER CGMP/Active Pharmaceutical Ingredient (API)/Adulterated No Mylan Laboratories Limited 08/06/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No Hospira Spa 03/31/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No Apotex Research Private Limited 01/30/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No Micro Labs Limited 01/09/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No Allergy Laboratories, Inc. 10/04/2013 ORA CGMP Deviations No Agila Specialties Private Limited 09/09/2013 CDER CGMP/Finished Pharmaceuticals/Adulterated No Jabones Pardo S.A. 08/22/2013 CDER CGMP/Finished Pharmaceuticals/Adulterated/Misbranded No RPG Life SciencesLimited 05/28/2013 CDER CGMP/Finished Pharmaceuticals/Adulterated No Puget Sound Blood Center and Program 04/16/2013 Seattle CGMPs for Blood & Blood Products/Finished Pharmaceuticals/Adulterated No Performance Products Inc. 11/20/2012 Kansas CGMP/Finished Pharmaceuticals/Animal Drugs/Misbranded No 07/16/2013 Celltex Therapeutics Corporation 09/24/2012 CDER Human Cells, Tissues & Cellular Products Yes Infupharma, LLC 07/30/2012 Florida CGMP for Finished Pharmaceutical/Adulterated No 06/26/2013 Shamrock Medical SolutionsGroup LLC 06/15/2012 Cincinnati CGMP for Finished Pharmaceuticals/Adulterated/Misbranded No Compania Internacional de Comercio, S.A. de C.V. 06/13/2012 CDER CGMP/Finished Pharmaceuticals/Adulterated No Gulf Pharmaceutical Industries 02/23/2012 CDER CGMP/Finished Pharmaceuticals/Adulterated, No Biochem Laboratories Inc. 02/17/2012 New Jersey CGMP Regulationsfor Finished Pharmaceuticals/Adulterated No 11/18/2013 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 30 Company Date Issuer Subject RL Posted Closeout
  31. 31. Review selectedWLs & NOCs US FDA, EU (MHRA/EMA) ,WHO 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 31 Prior to issuance of DI guidance (drafts)
  32. 32. Ourinvestigator identified significant violations ofcurrent good manufacturing practice (CGMP) regulations for finished pharmaceuticals,Title 21,Code ofFederal Regulations, Parts 210 and211.  Your firm (a CMO) failed to  ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).  exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).  to follow written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and to document same at the time of performance (21 CFR 211.100(b)).  establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)). 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 32
  33. 33. Theseviolationscause yourdrugproductsto be adulteratedwithinthe meaningofSection 501(a)(2)(B)…..  Your laboratory records did not contain all raw data generated during each test for finished drug products manufactured at your firm.Your quality unit relied on incomplete records to make batch release decisions in support of regulatory submissions to the Agency.  A QC analyst deleted original test method validation data and admitted plans to fabricate sample preparation data.  The trial injection was stored in the “trails” [sic] folder located on a personal computer.The release chromatogram identified injection (b)(4)141119009 as the sample.The trial and release chromatograms for (b)(4)141119009 do not match, and they identify different peaks. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 33
  34. 34. Statement of Non- compliance with GMP Exchangeofinformation betweenregulators 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 34
  35. 35. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 35 Evidenceof data integrity issues withinGMP documentations, buildings were also falsified to mislead…… Directive 2003/94/EC GMPCWithdrawn!
  36. 36. Nature of non- compliance 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 36 Major deficiencies Data falsification in relation to training records Not routinely recording unplanned deviations Poor QA oversight
  37. 37. WHOPrequalification Team-InspectionServices Seriousconcernsregarding the integrity,reliability andaccuracyofthe data generatedandavailableat yourmanufacturingsite andonyourabilityto preventcontamination andcrosscontamination of yourproducts.  The company failed to  adequately perform dissolution tests and may have manipulated dissolution test results  ensure the integrity of data  adequately conduct stability tests in line with stability protocols and commitments:  maintain adequate records of equipment usage and failed to ensure data integrity in production  provide adequate controls of contamination and cross-contamination of the product  maintain adequate standards of housekeeping and hygiene  adequate and true records for in-process controls in production  package products under adequate conditions on blister packaging lines  ensure cleanliness of the air supply to manufacturing areas where the product may have been exposed  The company may have falsified analytical test data 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 37
  38. 38. Notice ofConcern Steps taken by inspectors 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 38  The company failed to adequately perform dissolution tests and may have manipulated dissolution test results  The laboratory was requested to perform, under observation, the dissolution tests for X  During the first test, one of the solution vials inside the auto-injector was switched, without notifying inspectors of what was being done  However, after injection, the refrigerated bracketing solution did not fall within system suitability acceptance criteria (x.xx % RSD) and the run was rejected by the company  Dissolution results were … did not comply …  The run was restarted overnight in absence of the inspectors and passing dissolution results …were obtained  The inspectors requested that the dissolution test be repeated, in front of them  Results of…..were obtained, which differed from the results obtained by the laboratory in the absence of inspectors
  39. 39. Notice ofConcern Inadequate responses  The corrective and preventive actions described in your response, consisted of installing and qualifying one new dissolution tester.  This response is inadequate because it does not address the inability of your current quality management system to detect and prevent intentional and biased influencing of dissolution testing results.  The issues of training and personnel qualification, for instance, are still not addressed. Moreover, you have yet to provide a suitable explanation as to why the xx passed  Your explanations that the dissolution test results may have been affected by calibration, ….. is not substantiated by adequate evidence either.  Your statement that the deviation between the results obtained in the absence of inspectors are within the normal acceptable range is debatable and was not supported by any statistical calculations or scientific evidence. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 39
  40. 40. US FDA 8/1/2016 2015 2014 2013 2012 § 211.68 0 7 0 5 7 § 212.110(b) 0 0 0 0 0 § 211.100 4 5 2 2 8 § 211.160 3 1 1 6 5 § 211.180 0 1 2 2 3 § 211.188 0 3 2 1 6 § 211.194 3 3 0 4 6 § 212.60(g) 0 0 0 0 0 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 40 “backup data are exact and complete,” and “secure from alteration, inadvertent erasures, or loss” “stored to prevent deterioration or loss” “documented at the time of performance” and that laboratory controls be “scientifically sound” “original records,” “true copies,” or other “accurate reproductions of the original records” “complete information,” “complete data derived from all tests,” “complete record of all data,” and “complete records of all tests performed”
  41. 41. EudraGMDP (Public Site) 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 41  GMP Non- Compliance Search Results  Total Records: 104, Wed Aug 03 01:51:46 BST 2016
  42. 42. Global regulatory landscape (CGMP) Likelihoodof protracted remediation: High(USA) Likelihoodof effective CAPA:Low(USA)  Tom is right! When issues related to DI are noted - it should sounds off alarm bells …there is likely a lot going on underneath!  Company responses illustrate the lack of appreciation for QMS and inability to undertake effective investigations and CAPA  IT controls necessary but not sufficient – human factors and management accountability specifically need to be addressed to improve QMS and to ensure effective CAPA  US regulations provide more precise context BDI as these relate to QMS deficiencies (some WHO NOC trending similar to US FDA approach)  Different emphasis and actions related to GLP and GMP (infrequent use of AIP by FDA); QC vs. Production records  Remediation expectations differ with respect to the need to account for past and current deviations, in outlining the role of 3rd party experts, and effectiveness of CAPA 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 42
  43. 43. Why an increase in BDI? How to ensure effectiveCAPA? What will promote confidence?  Growing cluster of BDI due to improved regulatory awareness of the issue (in part to whistleblowers), increased attention to DI during inspections, improved ability to rigorously audit IT systems and gather information from company staff, and increasing frequency and rigor ( e.g., unannounced visits) of inspections  Effective root-cause investigation; system wide. 5Whys across the system; including upstream to holes in validation, development, regulatory review and approval. Verification of CAPA effectiveness and sustainability based on objective metrics  Efficient effective remediation (WL close-out) and rapidly declining incidences ofWLs & Import Alerts in 2017 on-wards (proactive compliance). 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 43
  44. 44. Summary:Context Breaches of data integrity (DI) in CGMP a “hot topic” DI implicit and integral to QMS Violations being noted - a new trend or due to improved detectability? Individual and organizational behaviors; errors or malicious? What to do when the knowledge pyramid is toppled? 8/24/2016 © Ajaz S. Hussain| Insight, Advice & Solutions LLC 44
  45. 45. Data Integrity & Compliance withCGMP April 2016 DraftGuidance 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 45 To understand FDA regulations we must take a systems perspective when reviewing
  46. 46. Implicit to Explicit:The role of data integrity  CGMP for drugs, as required in 21 CFR parts 210, 211, and 212  Part 210 CGMP in Manufacturing, Processing, Packing, or Holding of Drugs; General;  Part 211 covers CGMP Finished 19 Pharmaceuticals; and  Part 212 covers CGMP for Positron 20 EmissionTomography Drugs.  Flexible and risk-based strategies to prevent and detect data integrity issues  Strategies to manage data integrity risks based upon their process understanding and knowledge management of technologies and business models.  Electronic signature and record-keeping requirements are laid out in 21 CFR part 11 and apply to certain records subject to records requirements set forth in Agency regulations, including parts 210, 211, and 212. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 46
  47. 47. Making it explicit  CGMP record :Any and all data to fulfill CGMP requirements; cannot be excluded from decision-making process without “valid, documented, scientific justification”  Metadata: “structured information that describes, explains, or otherwise makes it easier to retrieve, use or manage data.” All electronic CGMP records must include metadata  Workflow validation: “appropriate controls to manage risks associated with each element of a computer system”  Access control “restrict the ability to alter specifications, process parameters, or manufacturing or testing methods by technical means (for example, by limiting permissions to change settings or data.)” 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 47
  48. 48. Making it explicit  Audit trails : “secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the creation, modification or deletion of an electronic record.” Reviewed and approved by quality personnel  Trail Injections: Standard solution (not sample) for system suitability “requirements for precision are satisfied.” If a sample needs to be used “properly characterized (as) secondary standard”  Tips/escalation of issues: Train staff to detect and report. investigated under the documented CGMP quality system to “determine the effect of the event on patient safety, product quality, and data reliability; determine the root cause; and to ensure the necessary corrective actions are taken.”  Remediation expectations mirror those developed for the Application Integrity Policy; “hiring a third party auditor [to] determine the scope of the problem, implement a corrective action plan (globally), and remove at all levels individuals responsible for problems from CGMP positions.” 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 48
  49. 49. US FDA: Remediation expectations (Warning Letter)  Third party auditor with experience in detecting data integrity problems  Identify any historical period(s) during which inaccurate data reporting occurred at your facilities.  Identify and interview your current employees who were employed prior to, during, or immediately after the relevant period(s) to identify activities, systems, procedures, and management behaviors that may have resulted in or contributed to inaccurate data reporting.  Identify former employees who departed prior to, during, or after the relevant periods and make diligent efforts to interview them to determine whether they possess any relevant information regarding any inaccurate data reporting. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 49
  50. 50. US FDA: Remediation expectations (Warning Letter)  Third party auditor with experience in detecting data integrity problems (contd.)  Determine whether other evidence supports the information gathered during the interviews, and determine whether additional facilities were involved in or affected by inaccurate data reporting.  Use organizational charts and SOPs to identify the specific managers in place when the inaccurate data reporting was occurring and determine the extent of top and middle management involvement in, or awareness of, data manipulation. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 50
  51. 51. US FDA: Remediation expectations (Warning Letter)  Third party auditor with experience in detecting data integrity problems (contd.)  Determine whether any individual managers identified in item (5) above are still in a position to influence data integrity with respect to CGMP requirements or the submission of applications; and establish procedures to expand your internal review to any other facilities determined to be involved in, or affected by, the inaccurate data reporting. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 51
  52. 52. US FDA: Remediation expectations (Warning Letter)  Third party auditor with experience in detecting data integrity problems (contd.)  As part of this comprehensive data integrity audit of your laboratory, your audit report also should include any discrepancies between data or information identified in approved applications (including Drug Master Files), and the actual results, methods, or testing conditions submitted to the Agency. Include an explanation of the impact of all discrepancies. Provide a corrective action operating plan describing the specific procedures, actions and controls that your firm will implement to ensure integrity of the data in each application currently submitted to the Agency and all future applications.This should not only cover methods validation, but any other testing (e.g., stability tests, release tests) or operations you have performed for customers that may have been used to support a drug application-related submission to the agency. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 52
  53. 53. US FDA: Remediation expectations (Progress reports)  Provide an update on the status of your on-going review of data generated from your chromatographic systems that have XXX installed.  Provide a detailed description of the process followed by 3rd Party during their review of batch production and electronic laboratory records and the batch certification process.  Provide your third party assessment and certification of the integrity of data in previously approved drug applications. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 53
  54. 54. US FDA: Remediation expectations (Progress reports – extended to applications)  Provide details on the following items in your response (note these elements requested are the baseline expectations for each application and we may request additional clarification or information to support the review of your applications):  Should you decide to commercialize any of your terminated products that are affected by this data integrity issue, we expect you to provide the analysis consistent with the expectations listed above (Part A) for these applications.  For already approved applications affected by data integrity breaches, we expect you to provide an analysis consistent with the expectations listed above (Part A) for these applications.  You may provide this package for selected priority applications in advance of a follow up inspection to allow FDA to prepare for possible outcomes following the re-inspection. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 54
  55. 55. US FDA: Remediation expectations (Progress reports)  Provide verification that metadata files not identified by the algorithm were correctly rejected.  For the metadata files that the algorithm did not flag, split the data into two groups for data integrity review.  One group should be a random sample of records from analysts previously identified as involved in questionable laboratory practices.  The second group should randomly sample records from analysts not previously identified as involved in questionable practices. Provide the protocol, the sample size, and justification of the proposed sampling plans. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 55
  56. 56. US FDA: Remediation expectations (Reminder)  Note that the FDA will refuse to approve an abbreviated application for a new drug under section 505(j) of the act for any of the following reasons: the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug product are inadequate to ensure and preserve its identity, strength, quality, and purity; i.e. if any pertinent xxx facility is named in the application, the application cannot be approved as long as it has an unacceptable compliance status. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 56
  57. 57. Outline (contd.) WhyanincreaseinBDI? Howto ensureeffective CAPA? Whatwillpromote confidence?  Evaluate the Global Regulatory Landscape  Historical perspective  Current context & trends (483’s &Warning Letters)  Global regulatory expectations  Assess EU statements of non-compliance with  GMP andWHO notices of concern  Understand FDA regulations and draft guidance  Expectations of the 2016 FDA Draft Guidance  What does the draft guidance really tell us?  What to expect for the full implementation of this guidance  How to implement meaningful and effective strategies that align with cGMP 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 57
  58. 58. Outline (contd.) Whyconfidence is a CQA? How confidence is achieved & sustained? What confidence contributes to top& bottom-line?  Overcome Top Challenges  Understand human factors — Cognitive biases and ‘blind spots’  How does these factors contribute to breaches in assurance of data integrity?  Implement appropriate (soft and hardware) controls to ensure an effective quality management system  Simplify the framework for the culture of pharmaceutical quality  Proactive Approach to Assurance of Data Integrity  Expected challenges in remediating breaches in data integrity  How to conduct effective investigations  How to make the necessary corrections  How to measure effectiveness and assess confidence to prevent reoccurrence  Effective communication — Credibility and rebuilding trust with FDA 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 58
  59. 59. Stance: Advisor (Industry) Effective Remediation to Proactive Compliance Global Regulatory Landscape FDA Draft Guidance 2016 Top Challenges Culture of Pharmaceutical Quality (Bonus) 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 59 Why confidence is a CQA? How confidence is achieved & sustained? What confidence (should) contribute to top & bottom-line?
  60. 60. Quality = Meeting Specifications Central drug controller unveils ‘world’s biggest’ quality check This survey is likely to make or break India’s reputation as one of the leading manufacturers of generic drugs in the world. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 60 http://indianexpress.com/article/india/india-others/central-drug-controller-unveils-worlds-biggest-quality-check/
  61. 61. Importance ofCGMP & Documentation  Past tragedies that occurred with products that “met specifications”  Limitations of pharmacovigilance  Basic duty of care for patients we serve  Not making false claims  Epistemic trust  Even playing field 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 60
  62. 62. India has the second-largest number of manufacturing facilities outside of theUS registered with theUS FDA Key highlights: Absence of quality process and procedures Technology upgrade is the need of the hour Work pressure and shortage of manpower affect quality compliance Lapses in data integrity continue to rise Setting up whistle-blowing frameworks – work in progress 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 62 EY Survey: The state of data integrity compliance; Indian Pharma http://www.ey.com/IN/en/Services/Assurance/Fraud-Investigation---Dispute-Services/ey-data- integrity-compliance-in-the-pharma-industry (June 2015) Following CGMPs IS a commitment, it saves lives. We make medicines – our first promise is – ‘Do No Harm’. With our skills, awareness, and commitment to a culture of quality – we work to provide the ‘healing touch’ – Confidence and Authenticity.” Ajaz S. Hussain
  63. 63. Indianpharmaceutical, majorstridesto becoming proactive Over one-third of the total data integrity reviews conducted by EY are done proactively 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 63 http://www.ey.com/IN/en/Services/Assurance/Fraud-Investigation---Dispute-Services/ey-data-integrity-compliance-in- the-pharma-industry (June 2015)
  64. 64. Streetlight effect  A policeman sees a drunk man searching for something under a streetlight and asks the drunk what he’s lost.  The drunk says, “I lost my keys,” and they both look under the streetlight together.  After a few minutes, the policeman asks if he’s sure he lost them here.  The drunk replies, “No, I lost them in the park.”  The policeman asks, “Why are you searching here then?”  The drunk replies, “This is where the light is. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 64 David H. Freedman (August 1, 2010)."The Streetlight Effect". Discover magazine Why Is The Placebo Effect Exploding In The U.S. But Nowhere Else? Forbes |Pharma & Healthcare OCT 7, 2015 We are finally beginning to understand that irrationality is the real invisible hand that drives human decision making. The End of Rational Economics. HBR July-August 2009
  65. 65. Humans are predictably irrational; some are capableof deliberately poisoningothers to make money  Daniel Kahneman and AmosTversky. ProspectTheory: An Analysis of Decision under Risk. Econometrica, 47(2), pp. 263-291, March 1979  Losses have a bigger emotional impact than an equivalent amount of gain. People often make decisions to avoid a loss (short- term) at the expense of gains (often long-term)  Company finances are allocated differently – R&D is a “Gain” or “Investment” whereas Operations are “Costs” or “Losses”  AmosTversky and Daniel Kahneman.The framing of decisions and the psychology of choice.Science. 1981Jan 30;211(4481):453-8  The psychological principles that govern the perception of decision problems and the evaluation of probabilities and outcomes produce predictable shifts of preference when the same problem is framed in different ways. Reversals of preference are demonstrated in choices regarding monetary outcomes, both hypothetical and real, and in questions pertaining to the loss of human lives. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 65
  66. 66. From “Art” to“Science” ofpharmaceutical product andprocess development 21st Century Desired State: Strengthen scientific foundation to facilitate risk-based orientation Current State: Majority still at the bottom of the pyramid + regulatory heterogeneity 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 66
  67. 67. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 67 Attitude/drivers: Output oriented Non-compliance Slow to fill gaps in IT controls & other safeguards Poor staff training , inability to escalate issues Inadequate QA & supervisory oversight & planning Lack of Sr. Mgmt. involvement in quality; not asking the right questions Human factors that undermine a QMS Culture of Pharmaceutical Quality (latent factors) Production pressures; weak leadership skills; silos Overwork, fear of error, low empowerment Reliance on previous audits (reactive); not-broken – why fix it? Ineffective root-cause investigations & CAPA If “a lot going on underneath” – What is the root cause? Set ofWhys Set ofWhys Set of Whys Set of Whys
  68. 68. Individual & Organizational Behavior 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 68 Attitude & Rationalization Incentive & Pressure Governance & Disregard/Neglect
  69. 69. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 69 Anatomy ofTesting intoCompliance (dissolution) Attitude toward performing the behavior Process validation is done so quality is good; Test prone to error “Batch failure means I made a mistake” Subjective norm Documentation not critical; Compendial testing sufficient Regulators collect & test samples – no issue there “Testing into compliance” In general – low empowerment is a significant challenge (low perceived behavioral control); plus reasons to rationalize…. Anatomy ofTesting into Compliance (dissolution)
  70. 70. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 70 Pharma patterns suggestive of ‘intentional holes’“….records not completed contemporaneously” “…observed analyst back-date logbooks” “…trial injections…..” “…results failing specifications are retested until acceptable results are obtained….” “…over-writing electronic raw data…..” “…OOS not investigates per XYZ SOP” “…appropriate controls not established….” Each additional observation adds reasons to confirm that this is very likely a system with intentional ‘holes’ in its defenses. A pattern suggestive of ‘intentional disregard’: Cheating by Design
  71. 71. Predictably irrational: Cognitive biases,…..  The cGMP issues with BDI currently being noted “new”?  Not likely – rigor and frequency of US FDA inspections is changing; more “unannounced” inspections at foreign facilities  Improving ability & capacity to conduct a thorough DI & IT system audit; Large “regulator heterogeneity” reducing (slowly)  Incorrect organizational assumptions – “FDA Approved”, “Process Validated”; push for “speed” and uninformed “Lean” programs to improve efficiency – ineffective management focus/support  Additionally, lax local regulatory norms (foreign facilities) providing reasons to rationalize deviations from cGMPs with a preferred narrow interpretation of “adulteration” to analytics  Systemic weakness in QMS – inadequate systems thinking  A general disregard for the intrinsic (as opposed to just satisfy FDA) value of documentation and assurance of data integrity; Quality by Design - much misunderstood & “file first and figure it out later” business model 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 71
  72. 72. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 72 Epistemic Trust Toppled Knowledge Pyramid: Preventing a Complete Collapse Re-building ‘epistemic trust” is difficult; First Principle is Culture of Quality !
  73. 73. “a lot going on underneath…” 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 73  To understand FDA regulations we must take a systems perspective when reviewing the draft guidance – Data Integrity and Compliance with CGMP  Re-organization at FDA: OPQ & One Quality Voice  Quality Metrics & Culture of Quality  ProcessValidations:General Principles & Practices  CGMPs for the 21st Century & the PAT Initiatives
  74. 74. Outline (contd.) Whyconfidence is a CQA? How confidence is achieved & sustained? What confidence contributes to top& bottom-line?  Overcome Top Challenges  Understand human factors — Cognitive biases and ‘blind spots’  How does these factors contribute to breaches in assurance of data integrity?  Implement appropriate (soft and hardware) controls to ensure an effective quality management system  Simplify the framework for the culture of pharmaceutical quality  Proactive Approach to Assurance of Data Integrity  Expected challenges in remediating breaches in data integrity  How to conduct effective investigations  How to make the necessary corrections  How to measure effectiveness and assess confidence to prevent reoccurrence  Effective communication — Credibility and rebuilding trust with FDA 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 74
  75. 75. Frameworkdevelopedfor Culture of Pharmaceutical Quality Bonus Material 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 75
  76. 76. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 76 Framework: Culture of Pharmaceutica lQuality (CPQ) Culture – Pharma Quality Quality is Normal Quality is Easy Quality is Rewarding System- QMS Appreciate System Theory of Knowledge Knowledge ofVariation Psychology of Change Practices- GXPs Fear Removed Mastery Awareness Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment Connect to CultureConnect to Practice Quality by Design
  77. 77. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 77 Attribute Rating Good progress, continue efforts already initiated Blind-spots, current efforts need additional considerations Blind-spot + new targeted projects /efforts needed CPQ Score-card • Leadership emphasis • Message credibility • Peer involvement • Employee empowerment Re-shaping the Environment • Quality is normal • Quality is easy • Quality is rewarding Re-setting the Norms • Commitment to the System • Knowledge based • Understanding & controlling variations • Safe-guards + pride of workmanship Ensuring effective QMS • Fear removed • Mastery • Awareness Promoting proactive behaviors Peer Involvement: It is essential that all functions recognize that “Quality is everyone's responsibility”. Employee Empowerment: However, class discussions suggested that the level of empowerment is variable within functions. This may be a ‘blind-spot’. Perhaps the high attrition rate in certain functions may be suggestive of this variability. High attrition rates (> 35%), in and of itself, is a reason for concern.
  78. 78. WhyCulture of Pharmaceutica lQuality (CPQ)? FDA inspections are Periodic, of limited duration, face information asymmetry, are heterogeneous,.. • Environment facilitates human behavior to do the right thing when no one is looking • Effective QMS • Compliance to GXP CPQ Safeguard for Pre- conditions to Malice or Disregard • Attitude & Rationalization • Pressure & Incentive • Opportunity – “holes” in QMS, supervision, policies,… 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 78 At minimum It is and must be much more… takes a human development stance for sustainable betterment!
  79. 79. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 79 Building the connect the dots framework Pharmaceutical GXPs – Rational, Proactive, Practices How proactive compliance is achieved? X,Y, Z Pharmaceutical Quality Management System What makes a QMS reliable? A, B, C, D Culture of Pharmaceutical Quality Why people change their behavior: 1, 2, 3 Attitude - Behavior Predictors of Culture of Quality
  80. 80. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 80 Culture – Pharma Quality Quality is Normal Quality is Easy Quality is Rewarding System- QMS Appreciate System Theory of Knowledge Knowledge ofVariation Psychology of Change Practices- GXPs X Y Z Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment Connect to CultureConnect to Practice Quality by Design Creating a Culture of Quality: Financial incentives don’t reduce errors. Employees must be passionate about eliminating mistakes. Ashwin Srinivasan and Bryan Kurey. Harvard Business Review, April 2014.
  81. 81. Going beyond rules pays.. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 81
  82. 82. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 82 Predictors of Culture of Quality Only four attributes actually predict a culture of quality: Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment People will change their behavior if they see the new behavior as Normal (1) Easy (2) Rewarding (3) Creating aCulture of Quality: Financial incentives don’t reduce errors. Employees must be passionate about eliminating mistakes. AshwinSrinivasan and Bryan Kurey. Harvard Business Review,April 2014.
  83. 83. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 83 Specific considerations for Pharmaceuticals:We make two inter- linked products; medicinal product & evidence Culture – Pharma Quality Quality is Normal Quality is Easy Quality is Rewarding System- QMS Appreciate System Theory of Knowledge Knowledge ofVariation Psychology of Change Practices- GXPs X Y Z Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment Connect to CultureConnect to Practice Quality by Design
  84. 84. Important to account for pharmaceutical ‘market failure’, ‘information asymmetry’ & cognitive biases (blind-spots) 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 84 ExpressPharma16May2016 Elephant in the dark or men with blindfolds on?
  85. 85. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 85 Struggle for effective cGMP remediation Company 1: Struggling Company 2: Progressing • Focus on ‘Root Cause’ • System wide improvements • Management metrics & data • Inadequate Investigations • Inadequate focus on System • Superficial Management Commitment
  86. 86. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 86 US FDA’s emphasis on management responsibility Richard L. Friedman, M.S. Management Oversight and LifecycleQualityAssurance. FDLIWorkshop, Washington DC, 14-15 July, 2014
  87. 87. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 87 US FDA’s evolving thinking on maturity ofQMS Richard L. Friedman, M.S. Management Oversight and LifecycleQualityAssurance. FDLI Workshop,Washington DC, 14-15 July, 2014
  88. 88. Historically resolution of process problems slow 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 88
  89. 89. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 89 Multiple causes; getting to “root” is difficult
  90. 90. Specific considerations for ‘Pharmaceuticals’ Sector-wide issues  Market failure and information asymmetry  Two products – API or medicinal product and documented evidence of compliance; any non-compliance = adulterated under the US FD&CAct  State of control of manufacturing process often not quantified (e.g., via control charts and statistical process control) and right-first-time (i.e., withoutSOP deviations and/or out of specification results) for dosage form manufacturing at about 60-70%  Investigation predominantly end in “root cause unknown”; often confusion between common and special cause  Likelihood of incorrect assumption of a simple or complicated process for which “Good” practices such as SOP’s, project management are reliable tools; i.e., given a specified starting conditions adherence to SOP will reliably deliver expected results  Market standards (Pharmacopeia tests) predominantly used as “release test”; posing many challenges with respect to method validation (particularly of test methods for physical attributes) and root-cause investigations  Variable interpretation of US FDA comments in 483 andWarning Letters; work- flow often targeting to achieve minimal regulatory requirements  Lack of verifiable knowledge bases and knowledge sharing between R&D and operations  Common usage of “this is FDA approved” or “the process is validated” or “we have not received any complaints” to justify that all is well 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 90
  91. 91. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 91 Principles of “Out of theCrisis” byW. Edward Deming MITPress (2000) The journey requires leadership with Profound Knowledge as a guide. • As leaders responsible for system change, top management is most in need of profound knowledge • Quality is often determined in the boardroom. • Problems arise when management reacts to common cause or chance variation as if it were special cause variation • Prediction based in theory provides a foundation for planning a course of action. Plan – Do –Check –Act • The leader serves the people with clear vision and guidance to empower them.To be empowered is to share ownership in the identity • Giving people a certain degree of control over their work fulfills the need for freedom and provides opportunity for taking joy in work
  92. 92. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 92 Pharmaceutical Quality for 21st Century had intended to limit the “crisis”; FDA now accelerating OneQualityVoice Paradigm It has to be built consciously – by design QMS Q7, Quality Systems Approach to cGMPs, ICH Q10 ICH Q 8 and ICH Q11; linking API to Formulation FDA’s Process Validation Guidance (2011) Revision of European Commission Guidelines on GMP Risk-based ICH Q9. Life cycle approach Continued ProcessVerification – process performance and capability; statisticalconfidence One Quality Voice OPQ, ……Culture,……QualityMetrics Integrated Question Based Review & Inspection Appreciation for a System Theory of Knowledge Knowledge about Variation Human Behavior - Psychology of Change
  93. 93. A, B,C, D 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 93 • Appreciation for System • Organization viewed as a system; an orchestraA • Theory of Knowledge • Without theory – there is no learning;Asking the right questions; Plan-Do-Check-Act B • Knowledge ofVariation • Common cause and special cause variability; control chartsC • Human behavior (pride/satisfaction + conscious/subconsciousbiases) • System support and safe guards; system for error management D
  94. 94. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 94 CPQ: Need for Emphasizing SystemsThinking & Practices;QbD is the foundation (Plan-Do-Check-Act) Culture – Pharma Quality Quality is Normal Quality is Easy Quality is Rewarding System- QMS Appreciate System Theory of Knowledge Knowledge ofVariation Psychology of Change Practices- GXPs X Y Z Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment Connect to CultureConnect to Practice Quality by Design
  95. 95. The Power of Habit:WhyWe Do WhatWe Do in Life and Business. CharlesDuhigg(2012) • Scientific methodology • Engineering Design • Plan-Do-Check-Act Consciously • Habits (work to get rid of bad ones) • Habits (work to cultivate good one) • Keystone habits (Safety @ Alcoa; A.L.C.O.A. of data integrity) Subconsciously 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 95 B
  96. 96. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 96 Maturity Level &Assurance ofQuality Managed Characterized, but reactive High risk of ‘Cheating by Design’ “Trail Injections” “Testing in to Compliance” Defined Characterized; proactive Lower level of assurance Stopping & Correcting Batch Rejection Measured & Controlled In control Quality by Design Quality Assured Improvement Opportunities C &D Integrated implementation of FDA’s PAT guidance, ICH Q8-11 and FDA’s Process Validation Guidance (2011) essential.
  97. 97. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 97 X,Y &Z: Reduce Fear,Awareness & Mastery Reduce Fear of Errors Error strain Covering up Awareness Anticipation Risk taking Mastery orientation QbD/RFT Error detection Escalating Analyzing errors Correction & PreventionHigh turn-over On-boarding new hires “Re-set” for current staff Low awareness; passive waiting to be told Anticipation, visualization, prevention attitude Empowerment to fail and take risk Accurate RFT estimate Correct analysis of knowledge Effective investigations Effective communication Statistical know-how Engineering know-how
  98. 98. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 98 Framework: Culture of Pharmaceutical Quality (CPQ) Culture – Pharma Quality Quality is Normal Quality is Easy Quality is Rewarding System- QMS Appreciate System Theory of Knowledge Knowledge ofVariation Psychology of Change Practices- GXPs Fear Removed Mastery Awareness Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment Connect to CultureConnect to Practice Quality by Design
  99. 99. CPQ: Founded onQuality by Design  We do our best to develop medicines and the evidence needed to satisfy the needs of patients – we develop these products consciously, recognizing that quality cannot be tested into our products .  We know that nothing is perfect and there will be some errors in our design, systems and procedures, or we may make mistakes in following set procedures.  It is normal, easy and rewarding to work within our quality management system, without fear, to detect, correct and to learn from our mistakes.  In doing so we act consciously in the interest of patients – especially when no one else is looking, and we continually improve our quality by design and aim for right first time. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 99
  100. 100. From “Art” to“Science” ofpharmaceutical product andprocess development 21st Century Desired State: Strengthen scientific foundation to facilitate risk-based orientation Current State: Majority still at the bottom of the pyramid + regulatory heterogeneity 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 100
  101. 101. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 101 Epistemic Trust Toppled Knowledge Pyramid: Preventing a Complete Collapse Re-building ‘epistemic trust” is difficult; First Principle is Culture of Quality !
  102. 102. We will never solve the problems tomorrow with the same order of consciousness we are using to create the problems of today Assurance is predominantly in the documented evidence of adherence to cGMPs Inspectional observations and warnings undermine public’s confidence Deviations from SOP’s are widespread A high demand on operators to work consciously, often under fear of not delivering expected results. Matching order of consciousness with complexity of task and the level of assurance needed is increasingly difficult. 8/24/2016 ©Ajaz S. Hussain | Insight,Advice & Solutions LLC 102 ajaz@ajazhussain.com +12404577064

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