Data Integrity Validation Keynote Address Boston August 2016

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Compliance Draft Guidance and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Draft Guidance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

Since20o8FDAhasbeen
increasingthenumberof
inspections atforeign
facilities;parity(per
FDASIA)with frequencyof
domesticinspectionsby
2017?
Whatabout‘rigorof
inspections’-
unannounced
inspections?
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
?

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

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

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.”

"Dataintegrity[issues]reallysoundsoff
alarmbellsforus...ifyouseedata
integrity[issues]on thesurface,thereis
likelyalotgoingonunderneath.“
ThomasCosgrove, FDA on Observations related to Breaches
of Data Integrity (BDI)I
The FDA issued warnings
to 10 drug companies in
2015 for data integrity
violations – the most in
at least 10 years.

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

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.
http://www.pharmacompass.com/pharma-news/18-reasons-
spelt-out-by-peter-j-werth-to-delete-analytical-data
Acceptable reasons for deleting?

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.
http://indianexpress.com/article/india/india-others/central-drug-controller-unveils-worlds-biggest-quality-check/

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)

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 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 biases
(blind-spots)

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

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)

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.
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

Outline: Keynote
Effective
Remediation,
Proactive Compliance
Global Regulatory
Landscape
FDA Draft Guidance
2016
Top Challenges
Culture of
Pharmaceutical
Quality

Keynote Stance:
Attitude of a person
or organization
towards CGMP
Stance
Ex-
Regulator
Advisor
Patient
Questions
Why?
How?
What?

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?

Stance:
Ex-Regulator
Effective Remediation
to Proactive
Compliance
Global Regulatory
Landscape
FDA Draft Guidance
2016
Top Challenges
Culture of
Pharmaceutical
Quality (Bonus)
Why an increase in BDI?
How to ensure effective CAPA?
What will promote confidence?

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

Stance:
Advisor (Industry)
to Proactive
Compliance
Global Regulatory
Landscape
FDA Draft Guidance
2016
Top Challenges
Culture of
Pharmaceutical
Quality (Bonus)
Why confidence is a CQA?
How confidence is achieved & sustained?
What confidence (should)
contribute
to top &
bottom-line?

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

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

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

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 )

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)

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

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)?

§ 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
Company Date Issuer Subject
RL
Posted Closeout

Review selectedWLs &
NOCs
US FDA, EU (MHRA/EMA) ,WHO
Prior to issuance of
DI guidance (drafts)

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)).

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.

Statement of Non-
compliance with
GMP
Exchangeofinformation
betweenregulators

Evidenceof data integrity issues withinGMP documentations,
buildings were also falsified to mislead……
Directive 2003/94/EC GMPCWithdrawn!

Nature of non-
compliance
Major deficiencies
Data falsification in
relation to training
records
Not routinely recording
unplanned deviations
Poor QA oversight

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

Notice ofConcern
Steps taken by
inspectors
 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

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.

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
“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”

EudraGMDP
(Public Site)
 GMP Non-
Compliance Search
Results
 Total Records: 104,
Wed Aug 03
01:51:46 BST 2016

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

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).

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?

Data Integrity &
Compliance withCGMP
April 2016 DraftGuidance
To understand FDA
regulations we must
take a systems
perspective when
reviewing

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.

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.)”

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.”

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.

US FDA:
Remediation
expectations
(Warning Letter)
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.

US FDA:
Remediation
expectations
(Warning Letter)
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.

US FDA:
Remediation
expectations
(Warning Letter)
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.

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.

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.

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.

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.

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

Outline (contd.)
Whyconfidence is a
CQA?
How confidence is
What confidence
contributes to top&
bottom-line?
integrity?
reoccurrence

Stance:
Advisor (Industry)
to Proactive
Compliance
Global Regulatory
Landscape
FDA Draft Guidance
2016
Top Challenges
Culture of
Pharmaceutical
Quality (Bonus)
Why confidence is a CQA?
How confidence is achieved & sustained?
What confidence (should)
contribute
to top &
bottom-line?

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.
http://indianexpress.com/article/india/india-others/central-drug-controller-unveils-worlds-biggest-quality-check/

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

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
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

Indianpharmaceutical,
majorstridesto becoming
proactive
Over one-third of the total
data integrity reviews
conducted by EY are done
proactively
http://www.ey.com/IN/en/Services/Assurance/Fraud-Investigation---Dispute-Services/ey-data-integrity-compliance-in-
the-pharma-industry (June 2015)

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.
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

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.

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

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
(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

Individual &
Organizational
Behavior
Attitude &
Rationalization
Incentive &
Pressure
Governance &
Disregard/Neglect

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)

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

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

Epistemic Trust
Toppled Knowledge Pyramid: Preventing a Complete Collapse
Re-building ‘epistemic trust” is
difficult; First Principle is Culture
of Quality !

“a lot going on
underneath…”
 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

Outline (contd.)
Whyconfidence is a
CQA?
How confidence is
What confidence
contributes to top&
bottom-line?
integrity?
reoccurrence

Frameworkdevelopedfor
Culture of Pharmaceutical
Quality
Bonus Material

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

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.

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,…
At minimum
It is and must be much more… takes a
human development stance for
sustainable betterment!

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
Why people change their behavior: 1, 2, 3
Attitude - Behavior
Predictors of Culture of Quality

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
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.

Going beyond
rules pays..

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.

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

Important to
account for
pharmaceutical
‘market failure’,
‘information
asymmetry’ &
cognitive biases
(blind-spots)
ExpressPharma16May2016
Elephant in the dark or men with blindfolds on?

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

US FDA’s
emphasis on
management
responsibility
Richard L. Friedman, M.S. Management Oversight and LifecycleQualityAssurance. FDLIWorkshop,
Washington DC, 14-15 July, 2014

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

Historically
resolution of
process problems
slow

Multiple
causes; getting
to “root” is
difficult

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

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

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

A, B,C, D
• 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

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

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
B

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.

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

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

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.

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

Epistemic Trust
Toppled Knowledge Pyramid: Preventing a Complete Collapse
Re-building ‘epistemic trust” is
difficult; First Principle is Culture
of Quality !

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.
ajaz@ajazhussain.com +12404577064

Data Integrity Validation Keynote Address Boston August 2016

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Data Integrity Validation Keynote Address Boston August 2016