The IFPAC Session: Controlling excipient impact during the product lifecycle. Excipients enable the delivery of actives as a pharmaceutical product. Quality by Design requires that the impact of excipient variability on finished product quality be minimized, or, as paraphrased by Tobyn: - What matters doesn’t vary, and what varies doesn’t matter. This parallels the current practice of categorizing excipients into critical vs non-critical, the assumption being that the latter do not impact the finished product Critical Quality Attributes. This binary classification of criticality has been criticized as too simple and it is not uncommon to observe excursions in finished product quality correlating with variability of a so-called non-critical excipient. The complexity of the excipients, and the products into which they are formulated, contributes to this uncertainty. For excipients, what varies may not have mattered prior to approval, but may come to matter later in the product lifecycle, especially for continuously manufactured products with real time release. Excipients, even if fully compliant and manufactured under GMP, represent a reservoir of special cause variability in finished product quality. By definition this can only be addressed via the Control Strategy. Risk management requires continuous multivariate monitoring of finished product and raw materials to maintain quality and model fidelity.

1. Ajaz S. Hussain, Ph.D. and Vadim Gurvich, Ph.D.
The National Institute of Pharmaceutical Technology & Education, Inc.

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Excipients: IFPAC 2017
Chair: Brian Carlin

3. Background: NIPTE 2016
NIPTE resurgence, passion, and
expansion (new members)
Expansion of stakeholders beyond US
FDA; while maintaining commitment to
FDA collaboration
Reflection on roadblocks and strategies
for roadmap 2017
This presentation co-author:
Dr. Vadim Gurvich, Executive Director
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4. Presenter (Ajaz): Declaring my interests
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Insight Advice & Solutions LLC
Advisory and Consulting Practice
Complex Generics, Biosimilars & Orphan Drugs
Advisory Boards: Several Companies
When requested:
Systems approach - CGMP Remediation (strategy)
Culture of Pharmaceutical Quality Training
with Emphasis on Data Integrity
President
Share my understanding of challenges
in the assurance of "Pharmaceutical Quality”
Strategic planning and NIPTE advocacy.
Programing and other executive functions.

5. Legislative recognition: 2006 to 2016
FDA leadership, FDA Grants,…..
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2006: Federal investments in a major pharmaceutical technology and education initiative led by the Food
and Drug Administration in collaboration with university research partners will produce multiple
benefits in health care quality and access.
2016: FDA may award grants to institutions of higher education and nonprofit organizations for the
purpose of studying and recommending improvements to the process of continuous manufacturing of drugs
and biological products and similar innovative monitoring and control techniques.

6. Organizational Maturity, Epistemology and Continuous
Improvement Transformation: Biotech “Tipping Point”
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Martin VanTrieste, R. Ph. Improving the Quality of
Investigations. PIA Meeting – June 21, 2012
3 September 2003

7. Solid Dosage Form Manufacturing: “Tipping Point” not
feasible without an “Angle of Repose”
• Certificate of Analysis
• Uncertainty in solid-state material attributes
• Research laboratory measurement systems
• Life-cycle stability and reproducibility in QC?
• Fixed equipment and process parameters
• Committed in submissions, difficult to change post
approval; why bother finding the real cause?
• Uncertainty in the stability and capability of
measurements and manufacturing process
• Raises questions on adequacy of sampling and
obstructs risk-based decisions
• Globalization – variable empowerment/oversight
• “FDA Approved” and “Validated”; frames the
mindset and provides reasons to rationalization
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8. Repeating deviations and errors & ineffective investigations
point to cognitive biases and risk of irrational behaviors
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600 days

9. GXPs & Adult Human Development:
The Subjective Dimension [my learning & focus]
An ancient Indian board
game: Snakes & Ladder
(in the USA: Chutes and
Ladder)
An ancient Indian story:
Elephant in the Dark (in
the USA: Six Blind Men &
the Elephant)
Integrating: “Orders of
Consciousness” (Prof.
Robert Kegan) &
“Thinking, Fast and Slow”
(Nobel Laureate Prof.
Kahneman)
A journey – “I know it
when I see it” to “I can
see clearly now”
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Paradigm, Ontology, Epistemology, Methodology, Methods

10. “Angle of Repose”: Adaptive learning challenges
Solid Oral Dosage Form Manufacturing
At a Tipping Point
• NDA 26038; Orkambi®, Vertex Pharmaceuticals. 25 June 2015
• Post-approval change: NDA 021976 Prezista® , Janssen. 12 April 2016 (Continuous manufacturing with
RTRT)
Progress and set-backs
• Several, ….others (new drugs); generics faced OGD push-back
• 2006 MSD/Merck
The Beginning
• 2004-2005 Sanofi-Aventis Comparability Protocol (FDA Approved - Not Implemented)
• (Late 1990’s: Medical Gas; Air Separation Units)
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11. Angle of Repose & Tipping Point
From “Don’t use or Don’t tell”* to problem-solving mindset,……
PAT-Continuous Manufacturing
– RTRT platforms for rapid
product development, control
strategy, and Design Space
• Multiple companies and Schools passionately perusing this opportunity with regulatory
encouragement and acknowledgment of its potential for higher level of assurance
• Enforcement of Continued Process Verification (PV 2011) now becoming apparent in the
USA; adds an emphasis on statistical confidence and process stability and capability
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1
2
3
From: Martin Warman, Kelly Swinney and Justin Pritchard. PAT for In Process Control (IPC) and Real Time Release Testing (RTRT) in Continuous Manufacturing. 7th Pharmaceutical Technology Conference on Continuous Manufacturing, Japan (December 2015)
http://www.fda.gov/ohrms/dockets/ac/02/briefing/3841B1_05_PFIZER.PDF ; FDA Science Board 16 November 2001

12. Angle of Repose to Tipping Point: Journey needs to now go
from extraordinary to normal, easy and rewarding
Technical Learning
• Control strategies (with “new”
measurement systems)
• Engineering skills
• Statistics (Chemometrics)
Adaptive Learning
• Culture/Mindset change: reactive to
proactive
• Cross-functional collaboration
• Systems thinking, understanding
effective QMS, and change
management system
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Angle of Repose Tipping Point
Sufficient to achieve?
Law of the Few,
the Stickiness Factor and
the Power of Context

13. Make the journey normal, easy and rewarding
Societal need (e.g.,
FDASIA) for confidence in
[our] assurance of quality
• Confident assurance of quality across a global supply chain; risk ranking
• Recognition that early detection of issues necessary; effective investigations
• Delay insp. = adulteration; explicit assurance of data integrity
Increased appreciation of
PAT-QbD-Lifecycle
Approach to Validation
needed for effective QMS
• Operational inefficiency and an apparent inability to improve after regulatory
approval can have many consequences
• Outsourcing without an objective assessment of QMS effectiveness is not a
solution
PAT-Continuous
Manufacturing – RTRT
platforms for rapid product
development, control
strategy, and Design Space
• Multiple companies and Engineering & Pharmacy Schools, a critical mass (?),
passionately perusing this opportunity with regulatory encouragement and
acknowledgment of its potential for higher level of assurance
• Enforcement of Continued Process Verification (PV 2011) now becoming
apparent in the USA; adds an emphasis on statistical confidence and process
stability and capability
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14. Today NIPTE’s mission cannot be
clearer and its resolve stronger
The strategic themes identified in 2016 are very relevant to address several
roadblocks in the progress of NIPTE
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15. Roadblocks to the “+”
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• NIPTE = Integrative + Adaptive + Centralized
• What is NIPTE (centralized)? What it should
standardize?
2016 Strategic Themes
1. Team Science
2. Centers of Excellence
3. Certification of Education & New Prior
Knowledge
Roadmap 2017 How to…?
With 2020 Vision?

16. Roadmap 2017: Road mapping process
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17. Team science, Centers of Excellence & Certification
• NIPTE Roadmap 2017 steps towards becoming the 3rd leg of the stool starting 2020
• [Six ways President Trump can create a tipping point for a renaissance of pharmaceutical
manufacturing in the USA ]
-----------------------------------------Currently Outside NIPTE------------------------------------------------------
• USP & C-SOPS Roadmap of Transforming Pharmaceutical Manufacturing from Batch to
Continuous (not part of NIPTE; Pro bono advisory support to USP)
------------------------------------------Ajaz’s Advisory & Consulting Practice -----------------------------------
• Note for Disclosure & Transparency: Important elements of my consulting practice:
• Making Quality by Design normal easy and rewarding; cheating-by-design not profitable
• Advisor CONTINUUS Pharmaceuticals (recipient of $4.4 M Contract with US FDA)
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18. Centralize and standardize
How to…?
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 Instill/practice
— Key message to all: You are NIPTE & NIPTE is You
— Support Individualistic/Adaptive Goals and encourage/facilitate/recognize
Collaborative/Integrative practices and contributions
— Adopt NCI Team Science Toolkit
 Establish Charter, Process, & Leaders
— NIPTE “Think Tanks” to strengthen the Voice of NIPTE
— Senior Faculty led Center that work in their particular areas of interest (e.g.,
Pediatric Formulation)
— Governing Charter and process for “NIPTE Brand Endorsement”
 Develop, Evaluate, Scale-up, & Execute
— Plan/focus on success of Sun-Pharma Program
— NIPTE QbD Education Curricula and Certification
— New Prior Knowledge: New, Generic & Biosimilar applications
Team Science
2020
Vision
NIPTE
Certification
Centers of
Excellence

19. 3rd leg of the stool?
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 User fee
commitments.
 “fire-fighting” to
minimize impact of
(fewer) failures
 New policies,
practices & staff
 Research priorities
 Why NIPTE?
 What will NIPTE
contribute?
 How will NIPTE
contribute?
 Roadmap 2017
 The ‘Third-leg of
the stool”?
 Push for faster
approvals
 Pressures to reduce
price of medicines
 Reduce regulatory
burden
 Revitalize US
manufacturing
Pharmaceutical Technology Research & Education
Needs of the Nation
FDANIPTE: 2020?
Macro-
environment

20. Summary & Next Steps
• NIPTE Roadmap 2017
• NIPTE Advocacy
• Expanding stakeholders and
collaborations
• We celebrate successes of
pharmaceutical technology!
• You are NIPTE and NIPTE is you!
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