A Systems Perspective on Common and Special Excipients IFPAC 2019

A Systems Perspective on
Common and Special Excipients
Ajaz S. Hussain, Ph.D.
The National Institute of
Pharmaceutical Technology
and Education

A Modern
View of
Excipients
• Beyond Bioequivalence
3/5/2019 Ajaz S. Hussain, Ph.D. IFPAC 2019 2

A Systems Perspective: Common vs. Special Cause
A Systems Perspective on Common and Special Excipients
Nested Pharmaceutical Quality Management Systems: Individual, Corporate, National, ..
Common or Special Cause?
Common cause: Improve System(s) Special cause: Investigation & CAPA
[Critical] Attributes: Quality Control & Assurance
Measurements [and uncertainties]: Laboratory (QC) & Real-world (QA)

A Systems Perspective: Common vs. Special Cause
Nested Pharmaceutical Quality Management Systems: Individual, Corporate, National,....
Corporate pQMS : Continual
Improvement
Risk of recurring errors of commission
(CGMP) & omission (CMC)
Effective investigations & system wide
CAPA
SUPAC→ PAT/QbD → ICH Q8-11 → Process Validation:: OOS: Common or Special Cause?
“Inactive Ingredients” & “Certificate of Analysis”: Functionality & Measurement Uncertainties
1995 →→→ 2004 →→→→→ 2009 →→→→→→ 2011 →→→

Formulation
specific
criticality:
Errors of
omission
• “Considering the number of excipients in formulations, the number of
physicochemical parameters that may be studied, the difficulty of
obtaining or producing representative samples, and the interactions with
APIs and manufacturing processes, identifying excipients’ CMAs is not an
easy task.”
• Thoorens, G., Krier, F., Leclercq, B., Carlin, B. and Evrard, B., 2014. Microcrystalline
cellulose, a direct compression binder in a quality by design environment—A
review. International Journal of Pharmaceutics, 473(1-2), pp.64-72.
Ajaz S. Hussain, Ph.D. IFPAC 2019 5

Recipe for Chaos
Ajaz S. Hussain, Ph.D. IFPAC 2019
• The legacy approach to
development “file first and figure
it out later”
• Formulation specific critical
material attributes
• Fixed (in time) process
parameters
• Orchestrated “three process
qualification batches”
• Compendial tests as QC end-
product testing
• Belief based management –
“market failure”, “FDA Approved”,
“Validated” – OOS must be
“operator error”
• Chaos is not disorder; it is a
system, which beyond average, is
unpredictable due to extreme
sensitivity to initial conditions
(the Butterfly Effect); patterns
(non-linear and long-range) with
“strange attractors”
3/5/2019 6

Chaos, beyond average, unpredictable
Extreme sensitivity to initial conditions with patterns with “strange attractors”

Four islands called systems in a turbulent sea called disorder

Cause → Effect, Cause & Effect, Cause ? Effect, Cause */ Effect

For some the journey ahead: “666” –to- 2 σ –to- 6 σ

Therapeutic Equivalence
& Therapeutic Outcomes
• By definition Therapeutic Equivalence is an
“expectation” - four parts, pharmaceutical
equivalence, label, CGMP, when necessary
bioequivalence
• “Pivotal bio” mindset is “common” and a reason for
recurring errors which erode trust patients
• Understanding and practicing “totality of
evidence” is difficult for many
• A systems or “Totality of Evidence” mindset, not
“pivotal bio”, can and must be the path forward!
• QbD = Pharmaceutical Equivalence → reproducible
BE & Process Validation → repeatable CGMP →
Continuous Improvement → 6 σ
3/5/2019 © Copyright 2018-2020: Ajaz S. Hussain, Ph.D. 11
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“Value information about a drug (such as the price tag) can strongly
affect its therapeutic effect.”
3/5/2019 © Copyright 2018-2020: Ajaz S. Hussain, Ph.D. 12
Science. Vol. 358, Issue 6359, pp. 105-108. 06 Oct 2017

“Lactose out, mannitol
and citric acid in”!
In "Risks of reformulation: French patients complain after Merck
modifies levothyroxine pills" . BMJ 2018; 360 doi:
https://doi.org/10.1136/bmj.k714 (Published 16 February 2018)
Ajaz S. Hussain, Ph.D. IFPAC 2019 3/5/2019 13

Our legacy of insensitivity now
necessitates that we become
hypersensitivity to excipient issues
• Real world evidence, patient centric
development, personalized medicine in the
context of “exploding” placebo and nocebo
effects

For the sake
of patients we
must act now!

We cannot continue to ignore the
many inherent sensitivities to “initial
conditions” and “strange attractors”
• Purchase of ingredients predominantly based on price as long as
“Certificate of Analysis” per a compendial monograph
• Powder blend and dose content uniformity measured on chemical analysis
of only “active pharmaceutical ingredients.”
• Analytical methods for “critical” physical attributes “validated” based on
an assumption of “a stock solution” as in chemical solution analysis.
Gauge R&R? Is the reference material “stable” & “capable”?
• For decades manufacturing process “validation” hinged on 3 “qualifying
batches”; representative of “commercial manufacturing”? Many
struggling to adopt FDA’s 2011 Guidance.
• After “FDA approved” and “validated” too scared to take additional test
samples or to use new analytical methods (see US FDA’s PAT Guidance).
Investigation of OOS? Root cause – unknown? Normal, easy and rewarding
to cycle: blame it on “operator error”, GMP consultant tweak SOP, & re-
train?

BAD-I
• Companies Everywhere Copied
Japanese Manufacturing. Now
the Model Is Cracking (Wall Street
Journal, Feb. 4, 2018)
• “A string of scandals has tarnished
concepts celebrated in business
publications worldwide.”
• “Corporate wrongdoing occurs the world
over, but Japan’s scandals cut to the core
of what has kept Japanese brands popular,
as well as the country’s perception of
itself.”
17

Nested Pharmaceutical Quality
Management Systems: Individual,
Corporate, National, ..
• Pharmaceutical Quality Management
System (pQMS)
• A rule-based professional corporate system,
nested within other hierarchical systems,
that is built and maintained to consistently
provide pharmaceuticals conforming to
regulatory specifications with the assurance
needed to continually reaffirm claims
endorsed by public health officials and to
satisfy expectations of profit seekers,
patients, public, and professional
practitioners

Evidence based rules and
practices curtail human
irrationality
• Quality assurance allows patients to accept a
vulnerable position by assuming their best
interests and competence of professional
practitioners and public health officials
• Education and training of adults is diverse and
their experiences personal
• Asymmetries of information, knowledge, and
understanding of reality will persist (increase)
19

NIPTE: Proposed Solution #1
• Continuing education leveraging
experiential learning to facilitate
continuous professional
development; certification with
membership
• Course 1: Opportunity to
advance skills in Quality by
Design of solid oral delivery
systems that are integrated with
a life-cycle approach to Quality
Management System. Sharpen
skills as a solution provider on
industry pain points such as
multiple FDA’s Complete
Response Letters and Warning
Letters for ineffective Out of
Specification (OOS)
investigations.
3/5/2019 20

Adult development occurs in stages, by
overcoming “immunity to change”
(Constructive Development Theory, Prof. Kegan).
• Professional Development is to:
• Go beyond traditional education
& training
• Be self-authored in what we
know and how we know it
• Be self-transforming in filling
gaps between what we know
and what we can implement
• Feel the need, and know the
ways, to leverage our collective
experiential learning
• Understand the context for our
abstract nouns; increasing
Order of Consciousness
3/5/2019 21

An intrapersonal model to self-gauge our
“current” & “good” development stage
(Hussain A. S. How to build and maintain an effective pQMS? (2019))
• Feeling system: From the illusionary power of Procrustes, fear of
“looking bad,” seeking external validation, to ‘tribal passions” to
arrogance of “knowledge is power” with “internal validation,” to
understanding systems (remember “process understanding”)
• Change prevention system
• Procrustean or “one-size-fits-all” approach to specification setting,
insisting on the market or compendial standards (with “zero
tolerance” and built-in α & ß errors) as QTPP and QC tests and
“Default based Prior Approval Supplement” requirements
• Corporate management rewarding “file first – figure it out later”
stance and taking “FDA approved” and “Validated” as gospel and a
reason to “just do it” expecting “right first time every time”
• Regulators in asking more questions for “QbD applicants” in their
attempt to encourage “enabling regulatory considerations” (e.g., PAT
Guidance and ICH Q8) and making it easier to continue using the
minimum “check-the-box” approach.

• Team Science to generate new
knowledge needed to fill gaps
• Leveraging the expertise in its
18 member universities to
create a “critical mass” to
address the needs of the
Nation!
3/5/2019 24

Few examples…..

In-press in AAPS PharmSci Tech: Open Access (thanks AAPS!), please download and review.

Summary: Professional development, new and “new
prior knowledge” and a community of knowledge!
Nested Pharmaceutical Quality Management Systems: Individual, Corporate, National,....
Corporate pQMS : Continual
Improvement
Risk of recurring errors of commission
(CGMP) & omission (CMC)
Effective investigations & system wide
CAPA
SUPAC→ PAT/QbD → ICH Q8-11 → Process Validation:: OOS: Common or Special Cause?
“Inactive Ingredients” & “Certificate of Analysis”: Functionality & Measurement Uncertainties
1995 →→→ 2004 →→→→→ 2009 →→→→→→ 2011 →→→

A Systems Perspective on Common and Special Excipients IFPAC 2019

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A Systems Perspective on Common and Special Excipients IFPAC 2019