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BehavioralEconomicsand
Managementof Pharmaceutical
QualitybyDesign
Ajaz S. Hussain, Ph.D.
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 1
Pharmaceutical
knowledge pyramid
can be toppled easily!
Serendipitousintersectionof
BehavioralEconomics&CGMP
The Context
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 2
Breach of Data Integrity: one
of the most important and
relevant topics currently
Could we have anticipated it?
..a lot going on underneath
Open question - effective
CAPA?
Example observations
Symptom or cause?
Context
Publications:
CultureofPharmaceuticalQuality:
ConnectingtheDots.BiopharmaAsia
September/October2015
CultureofPharmaceuticalQuality
ManagementSystem.BiopharmaAsia
November/December2015
CultureofPharmaceuticalQuality:
PersonnelDevelopment.BiopharmaAsia
March/April2016
LinkedInPosts:
https://www.linkedin.com/in/ajazshussain
Slideshare:
http://www.slideshare.net/a2zpharmsci
Serendipitous intersection of Behavioral
Economics & CGMP
An urgent
request, in 2014,
to develop and
conduct a
training on
Culture of
Pharmaceutical
Quality for
management
and staff at
facilities in India
FDA observations alleged serious breach in data integrity
The program aimed at addressing behaviors; it included case
examples (a collection from my FDA experience) of blind-spots in
understanding of CGMP and the potential for adverse consequence to
patients when we deviate
Behavioral economics (per appreciation gained during a project at a
tobacco company), and not Ethics/Morality, informed the design of
course content; not to “point finger” and to discuss “uncomfortable”
topics
Similar training conducted at several companies all across India,
6000+ individuals participating. Follow-up surveys . LinkedIn &
Slideshare for updates/discussion.
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 3
Breach of Data
Integrity
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 ..
500
1000
1500
2000
2500
3000
3500
2008 2010 2012 2014 2016
FDA CGMP Inspections
Overseas Drug Facilities
?
Carmelo Rosa. DIA Multicenter International Data Integrity Workshop. 13-14, Nov. 2014. Bangalore, India.
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 4
"Dataintegrity[issues]reallysoundsoff
alarmbellsforus...ifyouseedata
integrity[issues]onthesurface,thereis
likelyalotgoingonunderneath.“
Thomas Cosgrove, FDA; on Observations related to
Breaches in Data Integrity
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 5
Could we have
anticipated it?
..a lot going on
underneath..
FDASIA
New Office of
Product Quality @
CDER/FDA
“One QualityVoice”
Will these changes get to
the root-cause?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 6
Latent factors and a globalized supply chain…
Variance and skewness of latent factors
TheGoldSheet.
28 March 2014.
Asharpincreaseindata
integrityfindingshasraised
questionsaboutthequality
ofpharmaceutical
manufacturinginIndia.
What’shappeningandwhy,
who’sresponsible,andhow
candrugmakersandthe
regulatoryagenciesthat
watchoverthemputastop
toit?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 7
• Look Out for
These Data
Integrity Issues
• Focus on India
Masks the Real
Data Integrity
Problems
• Data Integrity
Requires
Stronger Local
Enforcement
Thakur Cahilly
Takahashi
Theseviolations
cause your drug
products to be
adulteratedwithin
the meaning of
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.
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 8
Directive 2003/94/EC
GMPCWithdrawn!
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 9
 Evidence of data
integrity issues
within GMP
documentations,
buildings were also
falsified to
mislead……
WHO Prequalification
Team - Inspection
Services
Seriousconcerns regardingthe
integrity,reliabilityand
accuracyofthedata
generatedandavailableat
yourmanufacturingsiteand
onyourabilitytoprevent
contaminationandcross
contaminationofyour
products.
 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
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 10
Breach –to actcontrary
to (law,promise)
BDI -anewtrendand/or
improveddetectability?
Errors vs. malicious?
Operationsvs.
Development?
Genericvs. Brand?
Domesticvs.Foreign?
Symptom or a cause?
 Consequence (severity),
likelihood, detectability of
DI errors or breaches?
 Individuals, their company,
shareholders
 Regulators (CGMP
inspection, CMC review,
Management, local
authorities vs international)
 Competing companies and
the pharma sector
 Insurance companies and
payors
 Public (within a country,
global)
 Patients and their family
members
Degree of cognitive
dissonance?
• Sufficient to motivate
a change?
• Ample reasons to
rationalize away
dissonance?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 11
 Serendipitous intersection of Behavioral
Economics & CGMP
 Why attentiontoBehavioralEconomicscan
improveourmanagementofQbDwork-streams?
 How? What (benefits)?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 12
https://www.pinterest.com/pin/313563192778012694/
Journey across India
Insights from CPQTraining
Reaction of
participants to
FDA WL’s vary
Difficult to comprehend why now; occasional suspicion of FDA’s intent
Regulator heterogeneity (US FDAVs. MHRA, ..) difficult to reconcile
Quality = Meeting specifications and it is generally good; sincere belief
Growing recognition - importance of documentation and ALCOA in need
for significant attention; malicious intent a rare exception
Good technical
abilities;
attention on
communication
& experience
needed
For the paradigm “Quality = ConformingTest Results “
Ability to design/plan for effective SOP’s in need for attention
Hierarchal organizations, distance from supervisor and management
Over-optimistic expectations (e.g., RFT = 100%) common; can be
rationalized via “FDA Approved/Inspected” and “Process isValidated”
“Looking & Being Good = Meeting Expectations”; How to “Do Good” ?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 13
Dominant Paradigm
Ontology:Whatis
pharmaceuticalquality?
Epistemology: Howdo
youknowwhat youknow?
Methodology: Whatis
yourplanofaction(e.g.,in
caseofOOS)?
Methods: Whatdoyou
usetocollectdata?
Conforming toTest Results
 Conforming to specifications
per ANDA/USP
 Consulted USP & followed
instructions (SOPs); who wrote
the SOP and how? Was it
“validated” for your QC?
 File a deviation report and
follow SOP for investigation
(Phase I then, if necessary
Phase II)
 Check the methods used
before; resampling/testing in
Phase II
A hypothetical case example
to illustrate one challenge
 Makes analysts (and
supervisors) “accountable”
 But we only define
responsibilities for analysts and
supervisors?
 Types of human errors inQC
plus the stress of
inappropriate method
reproducibility & repeatability?
 Efforts needed for “Full
Investigation” and its potential
consequence?
 Re-testing and Re-sampling?
 Corrective and preventive
action plans?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 14
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 15
Head of
Operations
(the Boss)
B.Pharm/MBA
Experience in
Pharma 20
Years
Calls the
analyst and
supervisor
On several previous occasion after a lengthy investigation it turned out to
be analyst’s error. “Complete the investigation quickly and
release the batch on time!” The product is FDA approved and
process validated.TheQC lab is not well managed! (thoughts)
Head of
Analytical
Ph.D. (GC-MS)
Experience in
Pharma 15Years
X
When the CEO of the company will learn about this it will not look-good for
me and the Analytical Department. “Add as many resources you
need; complete the investigation quickly!“
Supervisor
(QC)
M. Pharm.
Experience in
QC 10Years
SOPTraining
Per SOP,
Deviation
Report.
This is not a GC test. I don't know how to speedup OOS investigations.
What if the root cause is unknown; again?
“We are looking bad!”
Amos Tversky and Daniel Kahneman. The framing of decisions
and the psychology of choice. Science. 1981 Jan 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.
Analyst
(QC)
M. Pharm.
Experience in
QC 1Year
SOP Training
Ooops! OOS!
Modified ReleaseTab.
DissolutionTest
Hussain, A. S. Culture of Pharmaceutical Quality: Connecting the Dots. BioPharma Asia September/October 2015
On the framing of decisions and the psychology of choice
Start here START
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 16
Framing & “Testing intoCompliance” DissolutionTesting :
Many reasons to rationalize away dissonance
“Testing into compliance”
In general – low
empowerment is a
significant challenge (low
perceived behavioral
control); plus reasons to
rationalize….
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 (local)
Documentation
not critical
Compendial
testing
sufficient
Regulators
collect & test
samples – no
issue there
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 17
Searching for answers after failing!
“we can be blind
to the obvious,
and we are also
blind to our
blindness.”
―DanielKahneman,
Thinking,FastandSlow
 July 10, 2015
 RE: USP PrednisoneTablets Reference
Standard (Catalog #1559505 Lot R001B0)
 Dear USP Customer
 Our records indicate that you have recently
purchased USP PrednisoneTablets Reference….
Recent evaluation…..Lot R001B0 is no longer
suitable for its intended … use. USP regrets
issuing this notice after the valid use date has
passed; please be assured that USP makes every
effort not to do so. A new lot is expected to be
available no later than July 31, 2015.
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 18
My personal
realization of a
“streetlight
effect”
A slide from my
presentation at
the FDA’s ACPS
Meeting, May
2005
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 19
Our cognitive biases:Can keep us busy
reacting to ‘common cause’ variation
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 20
 We keep using “market standards” as batch release
tests; when there are alternative approaches
 Critical importance of reproducibility and repeatability
of our test methods - for physical quality attributes is
widely underappreciated
 Although we are starting to realize that we can no
longer afford the inefficiency it imposes; our focus
remains on the least common denominators
 Outsourcing for lower costs with an expectation of
efficiency is our collective “streetlight effect”
600 days*
Good Developmentto
Good Manufacturing
Practices
PAT,ICHQ 8-11,PV2011
ManagementofQbD
Paradigm
[Ontology]
[Epistemology]
Methodology (ICHQ8;QbR)
[Methods]
[Needspecificattention]
Product & Process
Development
• Stage 1: Process
Design
Scale-up ,Transfer,
Validation
• Stage 2: Process
Qualification
Commercial
Manufacturing
• Stage 3:
Continued
Process
Verification
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 21
10X, 3 batches?
Monitoring & Control
Validated ranges
Process Performance
Explicit assurance of DI
Statistical Confidence
State of Control; Capability
Common vs. Special Cause
Effective CAPA
Explicit assurance of DI
Continual Improvement
1 batch, 3 batches
Patient failure modes?
Manufacturability?
Complex generics:
Totality of evidence
New Products New & Existing Products
Changing regulatory defaults & expectations: Heterogeneity during transition process
We must confront this
irrationality; starting with
how we establish regulatory
specifications – before not
after the product has been
developed!
 “Therefore, we propose that the
sponsor’s specification of Q=80% at 60
min should be changed to a
specification of Q=80% at 30 min.”
 Was the product designed and
developed with the FDA proposed spec.
as the target? If not, why would you
accept it – just to get the approval?
How should you make the case for the
right specification?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 22
A slide from my presentation at the FDA’s ACPS Meeting, May 2005
Black-box
(beforeICHQ8)
Process Capability and MeasurementProcess Capability and Measurement
Capability: Dissolution TestCapability: Dissolution Test
•• When we evaluate process capability byWhen we evaluate process capability by
measuring variability in the productmeasuring variability in the product
producedproduced
•• Total variabilityTotal variability σσ
22
TotalTotal
•• Assuming independent variable (if not independentAssuming independent variable (if not independent
for example interaction between measurement andfor example interaction between measurement and
product a covariance term needs to be included)product a covariance term needs to be included)
•• σσ
22
TotalTotal == σσ
22
ProductProduct ++ σσ
22
MeasurementMeasurement
•• σσ
22
MeasurementMeasurement == σσ
22
RepeatabilityRepeatability ++ σσ
22
ReprodicibilityReprodicibility
© Light Pharma
Process Capability: If you can’t measure it, you can’t improve it
Process Capability Roadmap:
1
Has Measurement
System capability
been verified?
STOP!
Do not compute
Proc. Cap. statistics.
Improve the Meas. System.
No
2
Is the process stable
or unstable via SPC?
Yes
STOP!
Do not compute
Proc. Cap. statistics.
Investigate special causes.
Improve process stability.
3
Is the data normal
“enough” via the
Normality Test?
STOP!
Transform data.
No
4
Compute
Cpk
Yes
Unstable
Stable
0
Challenge
Specs!
p-value < 0.05
p-value > 0.05
Gage R&R
& Calibration
SPC Charts
Scott Tarpley, UK Arden House 2004
SlidesfrommypresentationatUSPAnnualScientificMeeting"The
ScienceofQuality“.September26–30,2004:Biopharmaceuticsand
DrugProductQuality:PerformanceTests forDrugProducts,ALook
IntotheFuture.
And,fromamorerecentvisit(below)….
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 23
Management ofQbD
can be far from ideal
UnaccountedCognitive
Biases:Blindspots,
Streetlighteffect,….
Marketfailure
Information asymmetry
Decisionsunderrisk
Manyreasonsto
rationalizeaway
dissonance
QbD a Paradigm
• Origin “quality cannot be tested into products, it has to be
built-in by design” (FDA 1987 ProcessValidation Guidance),
adopted in the FDA’s PAT Guidance (2004)
Ontology?
• What is pharmaceutical quality? What is Assurance? Why is
CGMP & DI critically important?
• When a placebo effect is very significant, and generics are
promoted as cheap – how effective will be the generic on
substitution?
• From an IT perspective – what is the current status of our
Inactive Ingredient Guide? Are excipients truly inactive? What
about functionality?
Epistemology?
• How do you know what you know? Regulatory defaults: 10X, 3
batches, file first and figure it out later – will you?
Methodology for
QbD
• ICH Q8 outlined a methodology that facilitates regulatory
communication of scientific understanding of critical factors
and their risk-based controls in the CTD-P2 section of
regulatory submissions
Methods?
• Are our methods for physical attributes appropriately
validated for use in QC? Do we understand DOE?.......
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 24
Market failure
Information
asymmetry
Decisions under risk
Unaccounted
Cognitive Biases
Many reasons to
rationalize away
dissonance
 Clinical & Quality disconnect; quality = specifications, lack of
pharmacovigilence signal= quality is good; placebo effect
 Risk-uncertain:CQA’s, CPP’s,CMA’s (certificate of analysis); SOP’s
≠ CPP;Training on SOP for 15 minutes; Validation = state of
control; Rate of right first time often in 60-90% range; assumed to
be 100%; , Market standards for batch release; OOS root-cause
often “unknown”; Common cause –to- special cause confusion;
CAPA for common cause change SOP/re-train; System = folder of
policies and SOP’s written for regulators
 Regulatory defaults: 10X scale-up factor, 3 batches, bio-batch, 80-
125%, Pharmaceutical equivalence, File –first and figure it out later
works!; Regulator knows best why should I do more?
 Nudges and frames targeted towards FDA Approval, PassingGMP
inspection, business targets with less than optimal focus on
patients
 Significant Framing Effects, recurring OOS with root cause
unknown, time and $ spent in Operations = Costs (R&D $ =
investment) & regulator heterogeneity
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 25
Wearefinally beginningto
understandthat
irrationalityisthereal
invisiblehandthatdrives
humandecisionmaking.
TheEndofRationalEconomics.
HBRJuly-August2009
Because self-interest of
organizations does not
assure protection of their
own shareholders ($ -
measurable); what about
the interest of patients
(which is not easy to
measure; “market failure”)?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 26
Despite the progress in regulatory & pharmaceutical science
Pharmaceutical knowledge pyramid can be toppled easily!
Why attentionto BehavioralEconomicscanimproveour
managementofQbDwork-streams? Because…..
“we can be blind to the obvious, and we are also blind to our blindness.”
―DanielKahneman,Thinking,FastandSlow
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 27
Unaccounted Cognitive Biases &
Many reasons to rationalize away dissonance
 Serendipitous intersection of Behavioral
Economics & CGMP
 Why attentiontoBehavioralEconomicscan
improveourmanagementofQbDwork-streams?
 How? What (benefits)?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 28
https://www.pinterest.com/pin/313563192778012694/
Illustrationofatypicalapplicationof
Behavioral Economics
DefaultOption:
Generic Medication
Prescription Rates
Patel MS, Day SC, Halpern SD, et
al. Generic Medication
Prescription Rates After Health
System–Wide Redesign of Default
Options Within the Electronic
Health Record. JAMA Intern
Med. 2016;176(6):847-848.
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 29
The overall generic prescribing rate increased significantly from75.3%
during the 10-month pre-intervention period to 98.4%
There was less of an increase for levothyroxine representing a greater
proportion of opt-outs (95% CI, −16.4 to −14.8; P < .001)
Levothyroxine
Human development:
Ability forsystem or
integrative thinking
Is your team at 3rd
Order of
Consciousness?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 30
Needtoaccountfor
variance&skewnessinthe
distributedunderstanding
of pharmaceuticalquality
Globalizedsupplychain,
regulator heterogeneity,
demographics:Isthe
currentapproachto
education,training&
experience adequate?
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 31
Elephant in the dark or
men with blindfolds on?
ExpressPharma16May2016
A 21st Century Fable about Pharmaceutical Quality
and Preventing a Clash of Cultures
Integrating Big Ideas: Fisher,
Shewhart, Deming,Juran, Kegan,
Kahneman,..
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 32
 Epistemology essential in human development (to
higher Orders of Consciousness) and for overcoming
Immunity to Change (Professor Kegan)
 Human irrationality (Prof. Kahneman, Ariely and
others)
 “For instance, few realize that we are changing the
brains of schoolchildren through medication in order to
make them adjust to the curriculum, rather than the
reverse.” ― Nassim NicholasTaleb,The Bed of Procrustes:
Philosophical and Practical Aphorisms
Advice &Solutions:
Informed&Guidedby
Behavioral Economics
Re-building or
strengthening
Culture of
Pharmaceutical
Quality
• Training program with a focus on blind-spots and other
prevalent biases, Score-card, Pledges, Nudges
• For several companies
Question based
Development
Management
• Breakthrough therapy orphan drug, complex generics &
biosimilars
• Asking the right question at the right time; explicitly
stating/tracking assumptions accepted, pre-defining the
precision for the answers sought (stage-n-gate criteria)
Technology
transfer,
knowledge
management and
ProcessValidation
per 2011 Guidance
• A framework to risk-assessment & mitigation for current
products (without a comprehensive development
report) and for new products
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 33
CPQ: Founded on
the paradigm of
Quality 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.
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 34
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 35
Framework:Culture of PharmaceuticalQuality (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
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 36
Score-card; KeyAreas
of Improvement and
Recommendations
 Illustrative Score Card: For a
company currently in cGMP
remediation.
 Stars & color codes
Good progress, continue efforts
already initiated
Blind-spots, current efforts need
additional considerations
Blind-spot + new targeted
projects/efforts needed
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 37
An illustrative impact of training (survey via Survey Monkey® 3 months after training)
Rigorousadherence to
sciencewith effective
peerreview would
make adiscussionon
behavioral economics -
irrational!
Current (regulatory) defaults can become cognitive biases which
accumulate silently because there is no clearance mechanism -
eventually knowledge pyramid is toppled!
Specifically for breakthrough drugs (rapid
development), ComplexGenerics, Biosimilars,…
Time-crunch and/or increased complexity!
ICH Q8 outlined a methodology. Certain gaps remain in
our ontology (e.g., excipient functionality),
epistemology (e.g., blindly following FDA guidance/USP
monographs) and methods (e.g., physical attributes)
Many aspects of our
pharmaceutical &
regulatory science is not
rigorous!
Watch out! Some
current regulatory
defaults can become
cognitive biases!
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 38
Additional
Information
• http://www.slideshare.net/a2zpharmsci/
complex-generics-developing-
defensible-statistical-analyses-and-
acceptance-criteria
Complex Generics
Developing Defensible
Statistical Analyses and
Acceptance Criteria
• http://www.slideshare.net/a2zpharmsci/
biosimilar-development-eptm-2015
Biosimilar Development
EPTM 2015
• http://www.slideshare.net/a2zpharmsci/
breakthrough-designation-
opportunities-challenges-ajaz-hussain
Breakthrough Designation
Opportunities Challenges
AAPS 2014
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 39
We shallnot cease from exploration,
and the end of all our exploring will be
to arrive where we startedand know
the place for the first time.T.S. Eliot
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 40
 Between stimulus and response
there is a space. In that space is our
power to choose our response. In
our response lies our growth and
our freedom.Viktor E. Frankl
Thank you
8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 41
 Between regulatory
query and response
there is Design
Space. In that
space is our
comparability
protocol…

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Behavioral Economics and Managment of Pharmaceutical QbD 25 August 2016

  • 1. BehavioralEconomicsand Managementof Pharmaceutical QualitybyDesign Ajaz S. Hussain, Ph.D. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 1 Pharmaceutical knowledge pyramid can be toppled easily!
  • 2. Serendipitousintersectionof BehavioralEconomics&CGMP The Context 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 2 Breach of Data Integrity: one of the most important and relevant topics currently Could we have anticipated it? ..a lot going on underneath Open question - effective CAPA? Example observations Symptom or cause?
  • 3. Context Publications: CultureofPharmaceuticalQuality: ConnectingtheDots.BiopharmaAsia September/October2015 CultureofPharmaceuticalQuality ManagementSystem.BiopharmaAsia November/December2015 CultureofPharmaceuticalQuality: PersonnelDevelopment.BiopharmaAsia March/April2016 LinkedInPosts: https://www.linkedin.com/in/ajazshussain Slideshare: http://www.slideshare.net/a2zpharmsci Serendipitous intersection of Behavioral Economics & CGMP An urgent request, in 2014, to develop and conduct a training on Culture of Pharmaceutical Quality for management and staff at facilities in India FDA observations alleged serious breach in data integrity The program aimed at addressing behaviors; it included case examples (a collection from my FDA experience) of blind-spots in understanding of CGMP and the potential for adverse consequence to patients when we deviate Behavioral economics (per appreciation gained during a project at a tobacco company), and not Ethics/Morality, informed the design of course content; not to “point finger” and to discuss “uncomfortable” topics Similar training conducted at several companies all across India, 6000+ individuals participating. Follow-up surveys . LinkedIn & Slideshare for updates/discussion. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 3
  • 4. Breach of Data Integrity 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 .. 500 1000 1500 2000 2500 3000 3500 2008 2010 2012 2014 2016 FDA CGMP Inspections Overseas Drug Facilities ? Carmelo Rosa. DIA Multicenter International Data Integrity Workshop. 13-14, Nov. 2014. Bangalore, India. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 4
  • 5. "Dataintegrity[issues]reallysoundsoff alarmbellsforus...ifyouseedata integrity[issues]onthesurface,thereis likelyalotgoingonunderneath.“ Thomas Cosgrove, FDA; on Observations related to Breaches in Data Integrity 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 5 Could we have anticipated it?
  • 6. ..a lot going on underneath.. FDASIA New Office of Product Quality @ CDER/FDA “One QualityVoice” Will these changes get to the root-cause? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 6 Latent factors and a globalized supply chain… Variance and skewness of latent factors
  • 7. TheGoldSheet. 28 March 2014. Asharpincreaseindata integrityfindingshasraised questionsaboutthequality ofpharmaceutical manufacturinginIndia. What’shappeningandwhy, who’sresponsible,andhow candrugmakersandthe regulatoryagenciesthat watchoverthemputastop toit? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 7 • Look Out for These Data Integrity Issues • Focus on India Masks the Real Data Integrity Problems • Data Integrity Requires Stronger Local Enforcement Thakur Cahilly Takahashi
  • 8. Theseviolations cause your drug products to be adulteratedwithin the meaning of 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. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 8
  • 9. Directive 2003/94/EC GMPCWithdrawn! 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 9  Evidence of data integrity issues within GMP documentations, buildings were also falsified to mislead……
  • 10. WHO Prequalification Team - Inspection Services Seriousconcerns regardingthe integrity,reliabilityand accuracyofthedata generatedandavailableat yourmanufacturingsiteand onyourabilitytoprevent contaminationandcross contaminationofyour products.  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 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 10
  • 11. Breach –to actcontrary to (law,promise) BDI -anewtrendand/or improveddetectability? Errors vs. malicious? Operationsvs. Development? Genericvs. Brand? Domesticvs.Foreign? Symptom or a cause?  Consequence (severity), likelihood, detectability of DI errors or breaches?  Individuals, their company, shareholders  Regulators (CGMP inspection, CMC review, Management, local authorities vs international)  Competing companies and the pharma sector  Insurance companies and payors  Public (within a country, global)  Patients and their family members Degree of cognitive dissonance? • Sufficient to motivate a change? • Ample reasons to rationalize away dissonance? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 11
  • 12.  Serendipitous intersection of Behavioral Economics & CGMP  Why attentiontoBehavioralEconomicscan improveourmanagementofQbDwork-streams?  How? What (benefits)? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 12 https://www.pinterest.com/pin/313563192778012694/
  • 13. Journey across India Insights from CPQTraining Reaction of participants to FDA WL’s vary Difficult to comprehend why now; occasional suspicion of FDA’s intent Regulator heterogeneity (US FDAVs. MHRA, ..) difficult to reconcile Quality = Meeting specifications and it is generally good; sincere belief Growing recognition - importance of documentation and ALCOA in need for significant attention; malicious intent a rare exception Good technical abilities; attention on communication & experience needed For the paradigm “Quality = ConformingTest Results “ Ability to design/plan for effective SOP’s in need for attention Hierarchal organizations, distance from supervisor and management Over-optimistic expectations (e.g., RFT = 100%) common; can be rationalized via “FDA Approved/Inspected” and “Process isValidated” “Looking & Being Good = Meeting Expectations”; How to “Do Good” ? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 13
  • 14. Dominant Paradigm Ontology:Whatis pharmaceuticalquality? Epistemology: Howdo youknowwhat youknow? Methodology: Whatis yourplanofaction(e.g.,in caseofOOS)? Methods: Whatdoyou usetocollectdata? Conforming toTest Results  Conforming to specifications per ANDA/USP  Consulted USP & followed instructions (SOPs); who wrote the SOP and how? Was it “validated” for your QC?  File a deviation report and follow SOP for investigation (Phase I then, if necessary Phase II)  Check the methods used before; resampling/testing in Phase II A hypothetical case example to illustrate one challenge  Makes analysts (and supervisors) “accountable”  But we only define responsibilities for analysts and supervisors?  Types of human errors inQC plus the stress of inappropriate method reproducibility & repeatability?  Efforts needed for “Full Investigation” and its potential consequence?  Re-testing and Re-sampling?  Corrective and preventive action plans? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 14
  • 15. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 15 Head of Operations (the Boss) B.Pharm/MBA Experience in Pharma 20 Years Calls the analyst and supervisor On several previous occasion after a lengthy investigation it turned out to be analyst’s error. “Complete the investigation quickly and release the batch on time!” The product is FDA approved and process validated.TheQC lab is not well managed! (thoughts) Head of Analytical Ph.D. (GC-MS) Experience in Pharma 15Years X When the CEO of the company will learn about this it will not look-good for me and the Analytical Department. “Add as many resources you need; complete the investigation quickly!“ Supervisor (QC) M. Pharm. Experience in QC 10Years SOPTraining Per SOP, Deviation Report. This is not a GC test. I don't know how to speedup OOS investigations. What if the root cause is unknown; again? “We are looking bad!” Amos Tversky and Daniel Kahneman. The framing of decisions and the psychology of choice. Science. 1981 Jan 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. Analyst (QC) M. Pharm. Experience in QC 1Year SOP Training Ooops! OOS! Modified ReleaseTab. DissolutionTest Hussain, A. S. Culture of Pharmaceutical Quality: Connecting the Dots. BioPharma Asia September/October 2015 On the framing of decisions and the psychology of choice Start here START
  • 16. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 16 Framing & “Testing intoCompliance” DissolutionTesting : Many reasons to rationalize away dissonance “Testing into compliance” In general – low empowerment is a significant challenge (low perceived behavioral control); plus reasons to rationalize…. 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 (local) Documentation not critical Compendial testing sufficient Regulators collect & test samples – no issue there
  • 17. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 17 Searching for answers after failing!
  • 18. “we can be blind to the obvious, and we are also blind to our blindness.” ―DanielKahneman, Thinking,FastandSlow  July 10, 2015  RE: USP PrednisoneTablets Reference Standard (Catalog #1559505 Lot R001B0)  Dear USP Customer  Our records indicate that you have recently purchased USP PrednisoneTablets Reference…. Recent evaluation…..Lot R001B0 is no longer suitable for its intended … use. USP regrets issuing this notice after the valid use date has passed; please be assured that USP makes every effort not to do so. A new lot is expected to be available no later than July 31, 2015. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 18
  • 19. My personal realization of a “streetlight effect” A slide from my presentation at the FDA’s ACPS Meeting, May 2005 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 19
  • 20. Our cognitive biases:Can keep us busy reacting to ‘common cause’ variation 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 20  We keep using “market standards” as batch release tests; when there are alternative approaches  Critical importance of reproducibility and repeatability of our test methods - for physical quality attributes is widely underappreciated  Although we are starting to realize that we can no longer afford the inefficiency it imposes; our focus remains on the least common denominators  Outsourcing for lower costs with an expectation of efficiency is our collective “streetlight effect” 600 days*
  • 21. Good Developmentto Good Manufacturing Practices PAT,ICHQ 8-11,PV2011 ManagementofQbD Paradigm [Ontology] [Epistemology] Methodology (ICHQ8;QbR) [Methods] [Needspecificattention] Product & Process Development • Stage 1: Process Design Scale-up ,Transfer, Validation • Stage 2: Process Qualification Commercial Manufacturing • Stage 3: Continued Process Verification 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 21 10X, 3 batches? Monitoring & Control Validated ranges Process Performance Explicit assurance of DI Statistical Confidence State of Control; Capability Common vs. Special Cause Effective CAPA Explicit assurance of DI Continual Improvement 1 batch, 3 batches Patient failure modes? Manufacturability? Complex generics: Totality of evidence New Products New & Existing Products Changing regulatory defaults & expectations: Heterogeneity during transition process
  • 22. We must confront this irrationality; starting with how we establish regulatory specifications – before not after the product has been developed!  “Therefore, we propose that the sponsor’s specification of Q=80% at 60 min should be changed to a specification of Q=80% at 30 min.”  Was the product designed and developed with the FDA proposed spec. as the target? If not, why would you accept it – just to get the approval? How should you make the case for the right specification? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 22 A slide from my presentation at the FDA’s ACPS Meeting, May 2005 Black-box (beforeICHQ8)
  • 23. Process Capability and MeasurementProcess Capability and Measurement Capability: Dissolution TestCapability: Dissolution Test •• When we evaluate process capability byWhen we evaluate process capability by measuring variability in the productmeasuring variability in the product producedproduced •• Total variabilityTotal variability σσ 22 TotalTotal •• Assuming independent variable (if not independentAssuming independent variable (if not independent for example interaction between measurement andfor example interaction between measurement and product a covariance term needs to be included)product a covariance term needs to be included) •• σσ 22 TotalTotal == σσ 22 ProductProduct ++ σσ 22 MeasurementMeasurement •• σσ 22 MeasurementMeasurement == σσ 22 RepeatabilityRepeatability ++ σσ 22 ReprodicibilityReprodicibility © Light Pharma Process Capability: If you can’t measure it, you can’t improve it Process Capability Roadmap: 1 Has Measurement System capability been verified? STOP! Do not compute Proc. Cap. statistics. Improve the Meas. System. No 2 Is the process stable or unstable via SPC? Yes STOP! Do not compute Proc. Cap. statistics. Investigate special causes. Improve process stability. 3 Is the data normal “enough” via the Normality Test? STOP! Transform data. No 4 Compute Cpk Yes Unstable Stable 0 Challenge Specs! p-value < 0.05 p-value > 0.05 Gage R&R & Calibration SPC Charts Scott Tarpley, UK Arden House 2004 SlidesfrommypresentationatUSPAnnualScientificMeeting"The ScienceofQuality“.September26–30,2004:Biopharmaceuticsand DrugProductQuality:PerformanceTests forDrugProducts,ALook IntotheFuture. And,fromamorerecentvisit(below)…. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 23
  • 24. Management ofQbD can be far from ideal UnaccountedCognitive Biases:Blindspots, Streetlighteffect,…. Marketfailure Information asymmetry Decisionsunderrisk Manyreasonsto rationalizeaway dissonance QbD a Paradigm • Origin “quality cannot be tested into products, it has to be built-in by design” (FDA 1987 ProcessValidation Guidance), adopted in the FDA’s PAT Guidance (2004) Ontology? • What is pharmaceutical quality? What is Assurance? Why is CGMP & DI critically important? • When a placebo effect is very significant, and generics are promoted as cheap – how effective will be the generic on substitution? • From an IT perspective – what is the current status of our Inactive Ingredient Guide? Are excipients truly inactive? What about functionality? Epistemology? • How do you know what you know? Regulatory defaults: 10X, 3 batches, file first and figure it out later – will you? Methodology for QbD • ICH Q8 outlined a methodology that facilitates regulatory communication of scientific understanding of critical factors and their risk-based controls in the CTD-P2 section of regulatory submissions Methods? • Are our methods for physical attributes appropriately validated for use in QC? Do we understand DOE?....... 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 24
  • 25. Market failure Information asymmetry Decisions under risk Unaccounted Cognitive Biases Many reasons to rationalize away dissonance  Clinical & Quality disconnect; quality = specifications, lack of pharmacovigilence signal= quality is good; placebo effect  Risk-uncertain:CQA’s, CPP’s,CMA’s (certificate of analysis); SOP’s ≠ CPP;Training on SOP for 15 minutes; Validation = state of control; Rate of right first time often in 60-90% range; assumed to be 100%; , Market standards for batch release; OOS root-cause often “unknown”; Common cause –to- special cause confusion; CAPA for common cause change SOP/re-train; System = folder of policies and SOP’s written for regulators  Regulatory defaults: 10X scale-up factor, 3 batches, bio-batch, 80- 125%, Pharmaceutical equivalence, File –first and figure it out later works!; Regulator knows best why should I do more?  Nudges and frames targeted towards FDA Approval, PassingGMP inspection, business targets with less than optimal focus on patients  Significant Framing Effects, recurring OOS with root cause unknown, time and $ spent in Operations = Costs (R&D $ = investment) & regulator heterogeneity 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 25
  • 26. Wearefinally beginningto understandthat irrationalityisthereal invisiblehandthatdrives humandecisionmaking. TheEndofRationalEconomics. HBRJuly-August2009 Because self-interest of organizations does not assure protection of their own shareholders ($ - measurable); what about the interest of patients (which is not easy to measure; “market failure”)? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 26 Despite the progress in regulatory & pharmaceutical science Pharmaceutical knowledge pyramid can be toppled easily!
  • 27. Why attentionto BehavioralEconomicscanimproveour managementofQbDwork-streams? Because….. “we can be blind to the obvious, and we are also blind to our blindness.” ―DanielKahneman,Thinking,FastandSlow 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 27 Unaccounted Cognitive Biases & Many reasons to rationalize away dissonance
  • 28.  Serendipitous intersection of Behavioral Economics & CGMP  Why attentiontoBehavioralEconomicscan improveourmanagementofQbDwork-streams?  How? What (benefits)? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 28 https://www.pinterest.com/pin/313563192778012694/
  • 29. Illustrationofatypicalapplicationof Behavioral Economics DefaultOption: Generic Medication Prescription Rates Patel MS, Day SC, Halpern SD, et al. Generic Medication Prescription Rates After Health System–Wide Redesign of Default Options Within the Electronic Health Record. JAMA Intern Med. 2016;176(6):847-848. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 29 The overall generic prescribing rate increased significantly from75.3% during the 10-month pre-intervention period to 98.4% There was less of an increase for levothyroxine representing a greater proportion of opt-outs (95% CI, −16.4 to −14.8; P < .001) Levothyroxine
  • 30. Human development: Ability forsystem or integrative thinking Is your team at 3rd Order of Consciousness? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 30
  • 31. Needtoaccountfor variance&skewnessinthe distributedunderstanding of pharmaceuticalquality Globalizedsupplychain, regulator heterogeneity, demographics:Isthe currentapproachto education,training& experience adequate? 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 31 Elephant in the dark or men with blindfolds on? ExpressPharma16May2016 A 21st Century Fable about Pharmaceutical Quality and Preventing a Clash of Cultures
  • 32. Integrating Big Ideas: Fisher, Shewhart, Deming,Juran, Kegan, Kahneman,.. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 32  Epistemology essential in human development (to higher Orders of Consciousness) and for overcoming Immunity to Change (Professor Kegan)  Human irrationality (Prof. Kahneman, Ariely and others)  “For instance, few realize that we are changing the brains of schoolchildren through medication in order to make them adjust to the curriculum, rather than the reverse.” ― Nassim NicholasTaleb,The Bed of Procrustes: Philosophical and Practical Aphorisms
  • 33. Advice &Solutions: Informed&Guidedby Behavioral Economics Re-building or strengthening Culture of Pharmaceutical Quality • Training program with a focus on blind-spots and other prevalent biases, Score-card, Pledges, Nudges • For several companies Question based Development Management • Breakthrough therapy orphan drug, complex generics & biosimilars • Asking the right question at the right time; explicitly stating/tracking assumptions accepted, pre-defining the precision for the answers sought (stage-n-gate criteria) Technology transfer, knowledge management and ProcessValidation per 2011 Guidance • A framework to risk-assessment & mitigation for current products (without a comprehensive development report) and for new products 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 33
  • 34. CPQ: Founded on the paradigm of Quality 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. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 34
  • 35. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 35 Framework:Culture of PharmaceuticalQuality (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
  • 36. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 36 Score-card; KeyAreas of Improvement and Recommendations  Illustrative Score Card: For a company currently in cGMP remediation.  Stars & color codes Good progress, continue efforts already initiated Blind-spots, current efforts need additional considerations Blind-spot + new targeted projects/efforts needed
  • 37. 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 37 An illustrative impact of training (survey via Survey Monkey® 3 months after training)
  • 38. Rigorousadherence to sciencewith effective peerreview would make adiscussionon behavioral economics - irrational! Current (regulatory) defaults can become cognitive biases which accumulate silently because there is no clearance mechanism - eventually knowledge pyramid is toppled! Specifically for breakthrough drugs (rapid development), ComplexGenerics, Biosimilars,… Time-crunch and/or increased complexity! ICH Q8 outlined a methodology. Certain gaps remain in our ontology (e.g., excipient functionality), epistemology (e.g., blindly following FDA guidance/USP monographs) and methods (e.g., physical attributes) Many aspects of our pharmaceutical & regulatory science is not rigorous! Watch out! Some current regulatory defaults can become cognitive biases! 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 38
  • 39. Additional Information • http://www.slideshare.net/a2zpharmsci/ complex-generics-developing- defensible-statistical-analyses-and- acceptance-criteria Complex Generics Developing Defensible Statistical Analyses and Acceptance Criteria • http://www.slideshare.net/a2zpharmsci/ biosimilar-development-eptm-2015 Biosimilar Development EPTM 2015 • http://www.slideshare.net/a2zpharmsci/ breakthrough-designation- opportunities-challenges-ajaz-hussain Breakthrough Designation Opportunities Challenges AAPS 2014 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 39
  • 40. We shallnot cease from exploration, and the end of all our exploring will be to arrive where we startedand know the place for the first time.T.S. Eliot 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 40  Between stimulus and response there is a space. In that space is our power to choose our response. In our response lies our growth and our freedom.Viktor E. Frankl
  • 41. Thank you 8/25/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 41  Between regulatory query and response there is Design Space. In that space is our comparability protocol…