Ajaz Hussain discusses the importance of excipient knowledge management, particularly regarding physical functionality and performance. He notes that many drug products now require precise control of complex material attributes supplied by excipients. Effective knowledge management is needed to understand and control excipient variability. Hussain also highlights current regulatory trends and the need to improve databases on inactive ingredients to better track excipient functionality.

1. [‘Excipient’] Knowledge
Management: 2015 & Beyond
Ajaz S. Hussain, Ph.D.
Insight, Advice & Solutions LLC
Maryland, USA
Executive Director, the National Institute for
Pharmaceutical Technology & Education
3/12/2015 Ajaz S. Hussain, Ph.D. 1

2. Acknowledgment
• Thanks to Arihant Innochem Pvt. Ltd. for inviting me to speak and also
for accepting my requests to; (a) expand the program and include
other speakers, and (b) inviting faculty members from local schools of
pharmacy
• For me this is an opportunity to share my insights on excipients and,
more importantly, learn something about excipient supplier – Pharma
interactions in India
• Arihant Innochem Pvt. Ltd. made the travel arrangements for my trip
to Mumbai. We have no other business or financial relationship. They
did not request to see, nor did I provide, an advance copy of my slides.
3/12/2015 Ajaz S. Hussain, Ph.D. 2

3. Insights
• Why attention to excipient
knowledge management
(specifically their
functionality) is critical to
mitigating risks (or to leverage
opportunities) posed by the
rapidly increasing complexity
and uncertainty
• Note: Knowledge management in
the context of ‘intellectual
property’ is not the focus of this
talk
• In the second talk, end of the
day, I plan to discuss how
certain management practices
can impact effectiveness of
knowledge management
• Note: Knowledge management is
a combination of both IT and
human aspects; I intend to focus
on ‘human factors’
3/12/2015 Ajaz S. Hussain, Ph.D. 3

4. Outline
• Declaring my interests, acknowledging experiences contributing to
my current thinking
• Current hot topics – ‘excipients’, regulatory trends & insights
• Why attention to (excipient) knowledge management (specifically
physical functionality/performance) is critical
3/12/2015 Ajaz S. Hussain, Ph.D. 4

5. My interest in [‘excipients’] KM
acknowledging experiences contributing to my current thinking
• Business decisions
• Regulatory research, policy & enforcement
• Academic research
3/12/2015 Ajaz S. Hussain, Ph.D. 5

6. Business decisions
• Management responsibilities
• VP & Global Head Biopharmaceutical Development @ Sandoz (2005-2009)
• Development/regulatory submission: Omnitrope®, Binocrit®, Zarzio®, Generic
Enoxaparin & Glatiramer acetate
• VP Next Generation Product Assessment & CSO @ Philip Morris
International (2009 -2012)
• Development/evidence quality/regulatory strategy: Plant based vaccines &
assessment of products intended for tobacco harm reduction
• President Biotechnology & CSO @ Wockhardt (2012-2013)
• Biosimilar and Complex Generic Strategy Improvement
• Advisory/Consulting (2013 – currently)
• Mitigating risks in development of complex products, Framework for
effective compliance & remediation, Strengthening Culture of Quality
3/12/2015 Ajaz S. Hussain, Ph.D. 6

7. Regulatory research, policy & enforcement
support @ US FDA (1995 – 2005)
• Research to Policy
• SUPAC, BCS, IVIVC, ….Topical Microbicides,…several others
• Policy
• SUPAC-MR, IVIVC, BCS, …….., PAT, @ ICH FDA Lead (Quality) –
“desired state for 21st Century”, ICH Q8 – 10
• Enforcement Support
• Expert witness for the prosecution (1995)
• Facilitating resolution of difficult WLs linked to shortages
3/12/2015 Ajaz S. Hussain, Ph.D. 7

8. Knowledge to inform policy improvement
3/12/2015 Ajaz S. Hussain, Ph.D. 8

9. Physical Attributes: Can be critical for
safety, efficacy and quality
3/12/2015 Ajaz S. Hussain, Ph.D. 9
July 15, 2005 FDA
Public Health
Advisory: Safety
Warnings Regarding
Use of Fentanyl
Transdermal (Skin)
Patches.

10. Also, relevant today: Pattern Recognition
3/12/2015 Ajaz S. Hussain, Ph.D. 10
Preliminary, illustration of a concept. Going forward expect to see regulators utilize state-of –the –art pattern
recognition and modeling systems.
Effective Regulatory System: Importance of Process Understanding and Quality by Design
Ajaz Hussain, Pharmaceutical Quality Forum: 3rd Symposium November 2004, Tokyo, Japan

11. Academic research
University of Cincinnati (1989-1994)
• Formulation design
• Several projects – oral, topical and
transdermal
• Example: Elaborating the utility of
Transcutol® (Gattefossé)
• Computer aided formulation
design
• Artificial Neural Network based
‘expert systems’
• Example: Prototype for ‘Technical
Service Support’ (funding - Aqualon)
NIPTE (Currently)
• NIPTE’s Excipient Knowledge
base
• Available since 2007; at
http://pharmahub.org/
• The goal of this project is to
share information and modeling
tools to support pharmaceutical
product
3/12/2015 Ajaz S. Hussain, Ph.D. 11

12. Prototype for ‘Technical Service Support’
3/12/2015 Ajaz S. Hussain, Ph.D. 12
From a ‘Database’ to
a ‘Knowledge base’
• ‘Look-up tables’ to
‘Ability to Predict’
• Ability to predict =
generate hypotheses
• Ability (simulate) ask
questions - what if?

13. NIPTE * Knowledge Management
3/12/2015 Ajaz S. Hussain, Ph.D. 13

14. Contact Prof. Hoag @ Univ. Maryland, shoag@rx.umaryland.edu
3/12/2015 Ajaz S. Hussain, Ph.D. 14

15. NIPTE * Knowledge Management
This study was funded by the FDA-sponsored contract “Development of Quality by Design (QbD) Guidance Elements on Design Specifications across Scales
with Stability Considerations” (contract number HHSF223200819929C).
3/12/2015 Ajaz S. Hussain, Ph.D. 15

16. Current hot topics –’excipients’,
regulatory trends & insights
@ ExcipientFest on 28-29 April 2015 in Washington, Organizational Changes @
CDER/FDA, and Inspectional Trends,…..(Complex Generics,…., Continuous
Manufacturing)
3/12/2015 Ajaz S. Hussain, Ph.D. 16

17. Current experience with ‘Supplier
Qualification’?
• Recent observations are
summarized in this
report by ECA Academy
(21/01/2015), Areas of
attention:
• Accuracy and completeness of
administrative documentation
• Evidence to justify excipient
and supplier qualification
• Risk-assessment and effective
integration within in QMS
• Quality agreements
• Going forward, I envision a
need to emphasize a life-
cycle approach (e.g., linking
to CAPA, change control)
3/12/2015 Ajaz S. Hussain, Ph.D. 17

18. FDA’s Inactive Ingredient Database -
status?
• Substance Registration System (SRS)
• Generic listing vs. Specific Grade listing for commonly used excipients –
max. precedent levels
• Listing of Mixtures?
• The UNII code confusing, the National Library of Medicine yet to finalize
standards for assigning UNII codes for polymers
• Individual Grades vs. Family Data
• Legal status of the IID, and FDA communications of changes to the IID
• DMF Implications
• Impact on ANDAs – ‘Delays’ & ‘Refuse to File Letters’
3/12/2015 Ajaz S. Hussain, Ph.D. 18

19. 3/12/2015 Ajaz S. Hussain, Ph.D. 19
Inactive Ingredients’ to ‘Excipients’ to ‘Functionality’
Where are we in this journey?‘
Status of ‘Substances In Regulatory Practice’
Clearly we need a global database with
improved precision and accuracy of
naming (and coding) to identify,
describe, compare and link (to
products and AERs)
INDs, NDAs, BLAs, CFR’s; Orphan Drug Applications
Products that Contain Each Substance
Pharmacological Classification
Active Moieties, Related Moieties and Salts
LADMER
Metabolites
Metabolic Enzymes, Transporters, and Effects
Drug target (therapeutic and other), type of interaction
Solubility and Permeability (BCS)
Protein Binding
Impurities and Related Substance
ISO 11238 (ISO IDMP), some challenges
Both substances & specified substances
Implementation in EU; EMA Task force
Global Ingredients Archive System (GInAS)

20. 3/12/2015 Ajaz S. Hussain, Ph.D. 20
The War Against Fake Medicines, Update on FDASIA- Guidance and Impact on Excipient Suppliers and
Users, QbD Sampling Guidelines, The NSF/IPEC/ANSI 363 2014 GMP standards
explained, Good Supply Practices – Using Cross Industry Knowledge to Devise Pragmatic Solutions, Impact
of Non-harmonized Standards and What is Needed to Achieve Harmonization, Advancements in the Question
Based Review approach and various other excipient specific related topics, An Overview of the FDA OGD
IID EWG activities, Effective Sourcing and Purchasing of Excipients,
Industry Collaboration for Science Based
Implementation of Elemental Impurities, Challenges And Opportunities In Developing
And Modernizing Public Standards For NF Excipients Monographs For Regulated Drug
Products Marketed In The USA, Future Pharma Manufacturing Efficiencies and the Role of
Innovative Excipient Technologies.
IPEC ExcipientFest 2015
Current Hot Topics @ ExcipientFest on 28-29 April 2015 in Washington

21. 3/12/2015 Ajaz S. Hussain, Ph.D. 21
The War Against Fake Medicines, Update on FDASIA- Guidance and Impact on Excipient
Suppliers and Users, QbD Sampling Guidelines, The NSF/IPEC/ANSI 363 2014 GMP
standards explained, Good Supply Practices – Using Cross Industry Knowledge to Devise
Pragmatic Solutions, Impact of Non-harmonized Standards and What is Needed to Achieve
Harmonization, Advancements in the Question Based Review approach and various other
excipient specific related topics, An Overview of the FDA OGD IID EWG activities, Effective
Sourcing and Purchasing of Excipients, Industry Collaboration for
Science Based Implementation of Elemental Impurities, Challenges And
Opportunities In Developing And Modernizing Public Standards For NF Excipients
Monographs For Regulated Drug Products Marketed In The USA, Future Pharma
Manufacturing Efficiencies and the Role of Innovative Excipient
Technologies.
IPEC ExcipientFest 2015
Inspectional trends in data
integrity (Bangalore, Nov
2014)
22(d)
192
100(a)
160(b)
110(a)
67(b)
68(a)
25(a)
67(a)
100(b)
Recurring 483 Observations:
Top 10
22(d) 192 100(a) 160(b)
110(a) 67(b) 68(a) 25(a)
67(a) 100(b)
Jeff Medwid NIPTE-FDA Conference 13 June 2012
International Society for Pharmaceutical Engineering (ISPE),
in conjunction with McKinsey & Co., will release preliminary
data and findings from its Quality Metrics Pilot Program at
the ISPE Quality Metrics Summit on April 21–22 in Baltimore
FDA Launches New Drug Quality
Office, With Goal of Improving the
Pharmaceutical Industry
Posted 13 January 2015By Alexander
Gaffney, RAC
FDA’s New
Pharma Quality
Office Will Take a
Team Approach:
Yu Explains
Regulatory Recon: Investigations Find
Major Quality Problems at Indian
Pharma Companies (3 December 2014)
Posted 03 December 2014By Alexander
Gaffney, RAC
Currently the environment is complex, there is high uncertainty
Don’tforgetfunctionality
ofexcipientsisimportant!

22. 3/12/2015 Ajaz S. Hussain, Ph.D. 22
Need for urgent progress: ‘Inactive Ingredients’ to ‘Excipients’ to ‘Functional Excipients’
Importance of
assuring quality
and controlling
variability of
excipients,
including their
‘functionality’, has
long been
recognized
• Increasing complexity of drugs, their
delivery, and failure modes
• Patient (e.g., pediatric) relevant failure
modes
• Simple generics to complex generics &
biosimilars
Urgent need to address gaps in the FDA’s Inactive Ingredient Database

23. 3/12/2015 Ajaz S. Hussain, Ph.D. 23
Trends: Lab & Manufacturing
“Deletion of Data”
“Testing Into Compliance”
“BMR manipulation is a
slippery slope”
“Suggestive of faulty
manufacturing process or
practices, even if this is not the
case”
“It is top management’s
responsibility to ensure the
training program is robust and
effective!”
Inspectional trends in data integrity (Bangalore, Nov 13 2014 - Nov 14 2014)
Growing concern @ some
companies “data looks too good
to be true”

24. 3/12/2015 Ajaz S. Hussain, Ph.D. 24
GMP Compliance & Remediation
Jeff Medwid NIPTE-FDA Conference 13 June 2012
QbD & QbR: Clarity on Critical
Functionality
FDA’s New
Pharma
Quality
Office Will
Take a
Team
Approach:
Yu Explains
Carmelo Rosa, M.S., Psy.D. November 2014
Urgent Need & Opportunity:
To align & ensure sound scientific basis of these critical regulatory decisions

25. FDA CDER OPQ Plans for Surveillance of
Pharmaceutical Quality
Teresa Mullin, Ph.D. December 2014
3/12/2015 Ajaz S. Hussain, Ph.D. 25

26. Need for a comprehensive (excipient)
knowledge base
Teresa Mullin, Ph.D. December 2014
3/12/2015 Ajaz S. Hussain, Ph.D. 26

27. Why attention to (excipient)
knowledge management is
critical
Specifically for physical attributes, functionality, performance
3/12/2015 Ajaz S. Hussain, Ph.D. 27

28. 3/12/2015 Ajaz S. Hussain, Ph.D. 28
Today there are several
product categories
(e.g., controlled release,
inhalation products,
DPI’s, topical,
transdermal, liposomal
products, etc.,) which
requires an exquisite
control of complex
physical material and
product attributes
(functionality)
Many of our current measurement systems need
improvement
We depend on these to ensure control of lot-lot variability
Measurement system capability must be confirmed to be
able to assess process capability (calibration & Gauge R&R)
Life-cycle approach to quality; continued process
verification (FDA’s Process Validation, 2011) is a safety net.
Supplier & Excipient Qualification & Process Validation

29. Measurement System Analysis
• From ‘calibration’ to ‘Gauge R&R’
Particularly for physical
attributes; destructive analysis
• Many (including regulators) have not yet
understood its importance
Gauge R&R well established
but not commonly practiced
• Measurement system in a state of control;
effective CAPA, quality metrics, Culture of Quality
With the move towards
Statistical Process Control
• Demonstrate equivalent in vitro performance;
more exacting criteria
Development of complex
generic products (ER,
Injectable, Inhalation, etc.)
3/12/2015 Ajaz S. Hussain, Ph.D. 29

30. Process Validation (2011), Statistical
Confidence, Continued Process Verification…
3/12/2015 Ajaz S. Hussain, Ph.D. 30
http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004
(accessed 6 December 2014)

31. 3/12/2015 Ajaz S. Hussain, Ph.D. 31
Supplier & Excipient Qualification & CAPA
Out of Specification events
are difficult to resolve
Excipient functionality can
be a significant
contributing factor
Sometimes, reluctantly,
have to settle with - “Root
cause unknown
600 days*
*I have inserted the “600 days’, on the figure – this is based on cases I have seen while at FDA)

32. 3/12/2015 Ajaz S. Hussain, Ph.D. 32
Prevention of OOS and Effective CAPA needs a focus on critical functional attributes
Out of Specification events
are difficult to resolve
Excipient functionality can
be a significant
contributing factor
Sometimes, reluctantly,
have to settle with - “Root
cause unknown

33. Compendial standards and manufacturing
3/12/2015 Ajaz S. Hussain, Ph.D. 33

34. Practice, Control, Process: Maturity
Initial
• Unpredictable
Managed
• Characterized,
but reactive
Defined
• Characterized;
proactive
Measured &
Controlled
• In control
Optimizing
• Focus on
improvement
3/12/2015 Ajaz S. Hussain, Ph.D. 34
Capability Maturity Model Integration; Carnegie Mellon University
A validated process?

35. Maturity Level & Assurance of Quality
Managed Characterized,
but reactive
High perceived
risk of
‘Cheating by
Design’
“Trial
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
3/12/2015 Ajaz S. Hussain, Ph.D. 35

36. At the individual level, in QC function– how
often does this occur?
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
Indian
regulators
collect & test
samples – no
issue there!
3/12/2015 Ajaz S. Hussain, Ph.D. 36
“Testing into compliance”
In general – low empowerment
is a significant challenge (low
perceived behavioral control);
plus reasons to rationalize….

37. Excipient Functionality: Can be critical for
safety, efficacy and quality
3/12/2015 Ajaz S. Hussain, Ph.D. 37
July 15, 2005 FDA
Public Health
Advisory: Safety
Warnings Regarding
Use of Fentanyl
Transdermal (Skin)
Patches.

38. A pattern of failure: Pharmaceutical
Equivalence by Design? (2004)
3/12/2015 Ajaz S. Hussain, Ph.D. 38
http://www.nihs.go.jp/drug/PhForum/documents041122/Hussain041122.pdf

39. An attempt to correct
3/12/2015 Ajaz S. Hussain, Ph.D. 39
http://ipecamericas.org/system/files/KeyNoteEF13May11LawrenceYu(FDA).pdf

40. Recent challenges
3/12/2015 Ajaz S. Hussain, Ph.D. 40
TheVoiceoftheAmerican
PsychiatricAssociationandthe
PsychiatricCommunity Physicians Question FDA's Confidence in Generic
Drugs' Safety, Efficacy (OCTOBER 24, 2014)
• “most patients” is not the same as“ all patients,” and whether the 24
to 36 normal subjects used in the agency's bioequivalency tests
represents the full range of individual variation in the way drugs are
absorbed across the pharmaceutical using population is uncertain
• Individuals can sometimes be allergic and react differently to
whatever substance goes into making up the capsule or the tablet
FDA Flags Generic Versions of ADHD Medication
(NOVEMBER 14, 2014)
• FDA changed the therapeutic equivalence (TE) rating from AB to
BX—meaning that the products are still approved and can be
prescribed, but are no longer recommended as automatic substitutes

41. RLD Variability: Can be a block-buster
opportunity
Focus on ‘control strategy’
• Overcoming CP & IP; provide FDA a
submission they need to address CP
• Then begin with QTPP; CQA’s, … skip
‘design space’ and focus on ‘control strategy
• The entire development team should read
the complete package insert of RLD
• Discuss to ensure a common understanding
• Failure modes & intended use
• Pharmaceutical Equivalence
• Bioequivalence
• Other studies
QbD Challenges
3/12/2015 Ajaz S. Hussain, Ph.D. 41
New
Regulators are not prepared to handle
QbD applications
New
Misalignment of international regulatory
authorities
New and
Generics
R&D incentivized for ‘shots on the goal’;
not QbD
Generics
Lack of belief in business case – ‘Generics
are all about file first; figure out later’
Biologics Lack of technology to execute
Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee

42. Summary
• Excipient functionality can contribute in critical ways to product
quality & performance; adequate control is necessary
• Our databases, tools, and knowledge are lagging behind the
rapidly increasing complexity and uncertainty
• Risk to quality and to business is increasing and regulatory
transitions pose additional difficulties
• Effective knowledge management – IT and Human practices – is
critical for organizational ‘bottom-line’
• We all must come together, collaboratively, to address the urgent
needs; we owe it to the patients we serve
3/12/2015 Ajaz S. Hussain, Ph.D. 42

43. Knowledge Management &
Culture of Quality
Ajaz S. Hussain, Ph.D.
Insight, Advice & Solutions LLC
Maryland, USA
Executive Director, the National Institute for
Pharmaceutical Technology & Education
3/12/2015 Ajaz S. Hussain, Ph.D. 43

44. 3/12/2015 Ajaz S. Hussain, Ph.D. 44
Life-cycle approach needed for knowledge management
Investigational Products
cGMPs
Development
Technology
Transfer
Commercial
Manufacturing
Discontinuation
Management Responsibility
Process Performance & Product Quality Monitoring System
CAPA, Change Management, Management Review
PQS
Elements
Knowledge Management
Quality Risk ManagementEnablers
ICH Q10: KM is a systematic approach to acquiring, analyzing, storing and disseminating
information related to products, manufacturing processes and components.
Based on ICH Q10

45. “we can be blind to the
obvious, and we are also
blind to our blindness.”
Daniel Kahneman, Thinking, Fast and Slow
3/14/2015 Ajaz@ajazhussain.com 45
http://web.mit.edu/persci/people/adelson/checkershadow_proof.html

46. 3/12/2015 Ajaz S. Hussain, Ph.D. 46
1938 The Federal Food,
Drug, and Cosmetic
(FDC)
• 1937 Elixir of
Sulfanilamide
1962 Kefauver-Harris
Drug Amendments
• 1962
Thalidomide
• 1960 Color Additive
Amendment
• 1958 Food Additives
Amendment; GRAS
• 1960 Color Additive
Amendment
• 1958 Food Additives
Amendment; GRAS
1992 Generic Drug
Enforcement Act
•1989 L-Tryptophan
• 1989: Generic
Drug Scandal
• 1988 Food and Drug
Administration Act
• 1984 Fines Enhancement Laws;
Drug Price Competition and
Patent Term Restoration Act
2012 Food and Drug
Administration Safety
and Innovation Act
(FDASIA).
• 2007:
Heparin
Disaster
2013 Pandemic and
All-Hazards
Preparedness
Reauthorization Act
(PAHPRA) Drug
Quality and Security
Act.
• 2012: The
Deadly
Meningitis
Outbreak
Past 70 years: 1937 – 2007; The diethylene glycol (DEG) narrative

47. 3/12/2015 Ajaz S. Hussain, Ph.D. 47
0
5
10
15
20
25
30
35
Years
DEG: Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths
1937:ElixirofSulfanilamide
2007:Tootpastecontamination
0 70 years 0 70 years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair –IPECAmericas 2009
Past 70+ years: DEG contamination or economically motivated adulteration

48. 3/12/2015 Ajaz S. Hussain, Ph.D. 48
Reported cases underestimate the real tragedy; rapid intervention may not occur !
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning. JAMA. 1998;279(15):1175-1180.
doi:10.1001/jama.279.15.1175
Month of hospital admission for children with
acute renal failure, Haiti
October 1995-October 1996.
Diethylene glycol poisoning in Gurgaon, India, 1998
Bulletin of the World Health Organization, 2001, 79: 88–95.
We report a second episode of poisoning occurring in 1998 in
India as a result of children ingesting diethylene glycol; at
least 33 children are known to have died.
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in
children.
A brand of cough expectorant manufactured by a local
pharmaceutical company was found by the Central Drugs
Laboratory, Calcutta, to contain 17.5% (v/v) diethylene
glycol.
The district and state drug controller had tested many
samples using thin layer chromatography before a sample of
medicine tested positive for diethylene glycol at the Central
Drugs Laboratory. None of the earlier samples was found to
be contaminated.

49. 3/12/2015 Ajaz S. Hussain, Ph.D. 49
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1. Manufacturers did not perform full
identity testing on the glycerin raw
material, including tests to quantify
the amount of DEG
2. Relied on the certificate of analysis
(COA)
3. The origin of the glycerin was not
easily apparent from the COA.
4. The COA was often a copy of a COA
on the letterhead of the distributor
5. The chain of custody or distribution
history of the glycerin was also not
readily known
USP Glycerin Monograph
Type of Posting: Revision Bulletin
Posting Date: 04–Feb–2009
Official Date: 01–May–2009
Because of the serious hazards
associated with…., and in response to
recommendations set forth in the
FDA Guidance for Industry, "Testing
of Glycerin for Diethylene Glycol"
published in May 2007, USP has
revised the USP Glycerin monograph..
Because diethylene glycol and
ethylene glycol are considered
unacceptable toxic substances, the
testing of USP Glycerin should
demonstrate the absence of these
substances.
April 2007: FDA request to
USP to revise the Glycerin
monograph’s
IDENTIFICATION section.
Revision includes: adding –
Identification test B. LIMIT OF
DIETHYLENE GLYCOLAND
ETHYLENE GLYCOL to detect
and quantify DEG/EG in Glycerin.
− Is no longer part of the impurity
testing,
“Limit of DEG and Related
Compounds”. − Introduces a
capillary gas-chromatographic
(GC) method with flame ionization
detection (FID). − Limit of NMT
0.10% each for diethylene glycol
and ethylene glycol is found.
70+ years to get here; how difficult will it be to change habits such as ‘blind reliance of COA’?

50. 3/12/2015 Ajaz S. Hussain, Ph.D. 50
Personality and Habitual Frame Biases
Myers Brigs: ENTJ (first tested at FDA)
S
TF
Expanded frame,
future
possibilities
objective, ‘cause
and effect’
Expanded frame,
future
possibilities
people and
relationships.
Narrow frame,
the present,
individuals and
relationships.
Narrow frame,
the present,
objective,
cause and
effect.
N
Based on Stanford Webinar - How to Overcome the Top 3 MegaBiases in Decision-Making
Stanford University’s Strategic Decision and Risk Management certificate program
From Mapping a Manager's Brain on Incentives
Social
influences
Relative
thinking
Uncertainty
Complexity

51. By Design: Intention to act consciously
• In the interest of patients, and to continually improve this ability
• To provide a healing touch – one life at a time, in what we do, and how we
do it.
12/9/2014 Ajaz@ajazhussain.com 51
Consciously
Scientific methodology
Engineering Design
Plan-Do-Check-Act
Subconsciously
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)
The Power of Habit: Why We Do What We Do in Life and Business. Charles Duhigg (2012)
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality

52. What does it take to come out of the cGMP
crisis?
Persuasive demonstration of:
(1) Ability to face facts
(2) Legal & regulatory
requirements,
3) Systems approach to
quality,
4) Changing behavior
& culture
What is often missed or
is unconvincing is how
you will strengthen
culture of quality.
“Let one who wants to
move and convince
others, first be convinced
and moved themselves.”
Thomas Carlyle
Signals that question the
competence, motivation,
and/or integrity of company
personnel
Do not defend the plainly
indefensible; it adds further
serious credibility costs
3/14/2015 Ajaz@ajazhussain.com 52

53. Quality is everyone's responsibility
Lack of
knowledge... that is
the problem.
If you do not know
how to ask the
right question, you
discover nothing.
If you can't
describe what you
are doing as a
process, you don't
know what you're
doing.
Rational behavior
requires theory.
Reactive behavior
requires only reflex
action.
Whenever there is
fear, you will get
wrong figures.
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Selected quotes, W. Edwards Deming

54. 3/14/2015 Ajaz@ajazhussain.com 54
Organization (Policies
& Sr. Mgmt.)
Technology
(Constraints & Controls)
Individual
(Training & Certification)
Team & Supervisor
(Soft Defenses)
Defenses
(Quality Management System)
Error
Latent अप्रकट conditions Goal conflicts & mixed messages
Design flaws
Production pressures
Fear of error
“WE CANNOT CHANGE THE HUMAN CONDITION. BUT…WE CAN
CHANGE THE CONDITIONS UNDER WHICH HUMANS WORK”
JAMES REASON

55. Disregard to Malice?
3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 55
“….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.

56. Preconditions
Rationalization &
Attitude
Pressure &
Incentive
Opportunity –
‘holes in the QMS”
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57. 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 57
Attitude towards
the behavior
Subjective norm
Perceived
behavioral
control
Intention
Future
Behavior
usually found to predict behavioral
intentions with a high degree of
accuracy
intentions, in combination with
perceived behavioral control, can
account for a considerable
proportion of variance in behavior.
Past
Behavior
Ajen, I. The theory of planned behavior. ORGANIZATIONAL BEHAVIOR AND
HUMAN DECISION PROCESSES 50, 179-211 (1991)

58. Heparin tragedy 2007 and 2008
FDA reports 149 deaths with
allergic or hypersensitivity
symptoms during that period
• Contaminated heparin from China
QC Testing
• Initial testing failed to detect the
contaminant
Pharmacovigilence
• Signals in the pharmacovigilence
systems responded slowly and
Eventually, the severity of
reactions associated made it
likely that the contamination
would be detected
• too late for those who died or were
injured
3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 58

59. Congressman Shimkus: When the drug safety
system fails, people get sick. Some die.
• Some of these people are already very vulnerable, and proving the
cause of harm from impurities, adulteration, and counterfeits can be
elusive.
It is hard to detect harm
• Certainly the companies are obligated to ensure a culture of quality and
maintain vigilance as well. This reflects a systems approach to safety.
FDA inspectors look for a
culture of quality at
manufacturing facilities.
• FDA policies led to the failure to inspect the Chinese plant.
This system approach wasn't at
play here.
• While it doesn't deny the counterfeit source, tries to say that
counterfeits didn't cause the reaction, as if the adulteration itself was
no big deal. Is this an acceptable mindset? ……….
This brings me to China and its
quality culture or lack thereof.
3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 59
ONE HUNDRED TENTH CONGRESS SECOND SESSION. APRIL 29, 2008. Serial No. 110-109

60. 21 CFR PART 211: SUBPARTS -
Deviations signal gaps in CoQ
•GENERAL PROVISIONSA
•ORGANIZATION AND PERSONNELB
•BUILDINGS AND FACILITIESC
•EQUIPMENTD
•CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURESE
•PRODUCTION AND PROCESS CONTROLSF
•PACKAGING AND LABELING CONTROLG
•HOLDING AND DISTRIBUTIONH
•LABORATORY CONTROLSI
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For example the combination….

61. The Power of Habit: Why We Do What We
Do in Life and Business. Charles Duhigg (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
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62. CoQ: How?
•What are the predictors of CoQ?
CoQ Manifests by Design -
‘quality by design’ the
foundation
•1, 2, 3When do people change their
behaviors?
•A, B, C, D (any body can dance)What makes a QMS effective?
•X, Y, ZWhen proactive compliance
occurs?
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63. Going beyond rules pays..
3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 63

64. Human behavior:
Connecting the
Dots; With the Right
Connectors
GXPs – rational behaviors
How proactive compliance is achieved? X, Y, Z
Quality Management System
What makes a QMS reliable? A, B, C, D
Culture of Quality
Why people change their behavior: 1, 2, 3
Human Behaviors Beyond GXPs
Predictors of Culture of Quality
Why, What, and How of
Culture of Quality?
9/19/2014 © Ajaz S. Hussain | INSIGHT, ADVICE & SOLUTIONS LLC 64

65. Predictors of CoQ
Act consciously in the interest of patients – when no one is looking.
3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 65
Only four
attributes
actually predict
a culture of
quality:
Leadership
Emphasis
Message
Credibility
Peer
Involvement
Employee
Empower-ment
People will
change their
behavior if they
see the new
behavior as
Normal
(1)
Rewarding
(2)
Easy
(3)

66. Dr. W. Edwards Deming’s - “Out of the crisis”
3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 66
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

67. Profound Knowledge as a guide
3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 67
Appreciation
for a System
Theory of
Knowledge
Knowledge
about
Variation
Human
Behavior -
Psychology
of Change
A
B
C
D+

68. Systems Approach for Error/Deviation
Management
3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 68
Organization
(Policies & Sr. Mgmt.)
Technology
(Constraints & Controls)
Individual
(Training & Certification)
Team & Supervisor
(Soft Defenses)
Defenses
(Quality Management System)
Error
Latent अप्रकट conditions
Goal conflicts & mixed messages
Design flaws
Production pressures
Fear of error
Human error: models and
management. J. Reason. BMJ. 320:
768–770 (2000).
D+

69. Culture of Error Management प्रबंधन
• Error strain
• Covering up
Fear of Errors
• Anticipation
• Risk taking
Awareness
• Development QbD/RFT
• Error detection, Communication
• Analyzing errors, Correction
Mastery
orientation
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70. Dots & Connections
3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 70
CoQ
1
2
3
QMS
A
B
C
D
GXP
Behaviors
X
Y
Z

71. 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 71
Culture of
Quality
Normal
Rewarding
Easy
QMS
System
Knowledge
Variation
Behavior
Behavior -
GXPs
Fear
Removed
Mastery
Awareness
Environment
Leadership
Emphasis
Message
Credibility
Peer
Involvement
Employee
Empowerment
Connect
to CoQ
Connect
to GXPs
A Framework and a Tool (for gap analysis)