Invest in analytics, mathematics & statistics, and large sample sizes; and in systems/integrative thinking and data integration. Get to know the RLD – multiple lots; open the door with large sample size. Ability to justify measured RLD variability is relevant to development of the proposed generic. Exquisite regulatory communication strategy. This is not a ‘complicated process’ for which typical ‘good practices” work (e.g., typical project management approach). This is a complex process – with multiple interactions and “emergent properties”; treat it as it is - a complex process and plan to anticipate and address “emergent issues” - in technical, regulatory and legal dimensions; at a certain point be prepared for stakeholder (payers, patient groups,..) communications.

1. Pharmaceutical
Equivalence:Opportunities,
Challenges, andSolutions
forANDA and 505(b)(2)
Ajaz S. Hussain, Ph.D., Insight Advice & Solutions LLC
ajaz@ajazhussain.com
2nd Annual Symposium on
Development of Generics
& 505(b)(2):
‘New Frontiers for
Complex Drug Products
and BCS Based
Biowaivers’
DoubleTree Hotel
Somerset, NJ
Ajaz S. Hussain| Insight Advice & Solutions LLC 1

2. Outline
 Greetings fromToronto, Canada; sincere apology for not being
with you in person to deliver this talk. At IGPA later today we will
be discussing Building a Culture of Quality; a topic that is also
relevant to the audience in NJ
 Why I firmly believe that for Complex Generics it is
“Pharmaceutical Equivalence” that is the ‘Elephant in the Dark’ ?
 What I have learned specifically that reaffirms the Why?
 Examples while at FDA, Examples from Sandoz (Omnitrope® - US
505(b)(2), Generic Enoxaparin and Glatiramer acetate), other
examples
 How many companies fail to leverage this “billion(s) dollar”
opportunity?
Ajaz S. Hussain| Insight Advice & Solutions LLC 2

3. Our “generic”
paradigm:
Interchangeability
with confidence
Pharmaceutical
Equivalence
Bio-
equivalence
Practices >
Confidence
Therapeutic
Equivalence
Ajaz S. Hussain| Insight Advice & Solutions LLC 3

4. This paradigm
has been
tested and
“knocked on
its head”
 “It still is solid” but in need for attention –
particularly in the realm of complex generics
 “Knocks on the head”
 Generic Drug Scandal
 Failures to detect obvious errors/flaws
 Recent failures and manufacturing challenges
 Tested – numerous prospective studies to
assess therapeutic equivalence
Ajaz S. Hussain| Insight Advice & Solutions LLC 4

5. “Knocks on the
head” erode
confidence and
increase nocebo
effects!
 “Knocks on the head” have occurred
 When we failed to appreciate a systems approach to development,
review, process validation, and inspections (GLP/GCP/CGMPs)
 When we ignored to ask the ‘right question’ and in the ‘right
sequence’
 When we did not question assumptions we take for granted
 Most of these relate to Pharmaceutical Equivalence
 PE = dosage form (irrespective of color, shape, mechanism of
release,….);
 A clear liquid in a bottle is a “solution”: e.g., cyclosporine micro
emulsion, and low-permeability excipients (e.g., sorbitol)
 Consider current examples….ER failures and AB to BX downgrades
 Our incorrect thinking – “BE is the pivotal evidence”; instead of
integrating PE,BE, Practices – as in a system
Ajaz S. Hussain| Insight Advice & Solutions LLC 5

6. “Pharmaceutical
Equivalence”
that is the
‘Elephantin the
Dark’
 Q1/Q2
 Q1/Q2/Q3, ……
 Today … Color, Shape,…..moving towards same mechanism of
release?
 Today we are back to “subjectXformulation” interaction – once
again in healthy subjects?
 Isn't this just an assumption?Which, politely, is not a part of “our
elephant” but what comes out of it when we don’t pay attention to
PE!
 We lack consensus on a set of principles to integrate across
multiple, orthogonal, analytical characterization tools for physical
attributes and physical performance (e.g., size, shape, charge,
flow, plume, …)
 This is a “billion dollar” opportunity; but only for certain
companies
Ajaz S. Hussain| Insight Advice & Solutions LLC 6

7. generics are for minor
but not serious
illnesses;… and poor
people are forced to
‘settle’ for generics.
What do people really think of generic medicines? A systematic review and
critical appraisal of literature on stakeholder perceptions of generic drugs. BMC Medicine 2015, 13:173
36 % of the patients reported negative
experiences after medication substitution
89 % of pharmacists reported
receiving patient complaints
regarding use of generic medicine,
although 64 % suggested that this
was due to a nocebo effect
Only 50.2 % of the surveyed pharmacists
agreed that all products that were
approved as generic equivalents can be
considered therapeutically equivalent.
Just 6 % of pharmacists
considered that dry powder
inhalers were interchangeable.
While acceptance of generic medications is improving, substantial mistrust and lack of confidence remains,
particularly within the patient and, to a lesser extent, physician groups.
Nearly half the patients stated they
would refuse generic substitution when it
became available if this was just to save
the health authority money.
Generic medicines were
considered to be poor quality
and treated with suspicion.
Ajaz S. Hussain| Insight Advice & Solutions LLC 7

8. The “how” is very
difficult because of
“culture” and
“mind-set”
Example: Equivalence
ofGlatopa® and
Copaxone®
Characteri-
zation of
Brand
Copaxone
Thorough
understandingof
reference listed
drug (Copaxone)
required.
Review available
scientific, patent,
and regulatory
literatureon
Copaxone.
Characterizationby
more than 60
physicochemical,
biological, and
immunological
methods.
Multiplelots (up to
50 for some
attributes) were
studiedover several
years probing the
range and diversity
of the commercial
lots, as well as
evaluatingthe
effects of lot aging.
Four-Point
Criteria for
Demonstration
of Equivalence
of Glatopa and
Copaxone
Equivalenceof
startingmaterials
and basic
chemistry.
Equivalenceof
structural
signaturesfor
polymerization,
depolymerization,
and purification.
Equivalenceof
physicochemical
properties.
Equivalenceof
biological and
immunological
properties.
http://www.momentapharma.com/AAN-Equivalence-Glatopa-Poster-6x4-PRESS.pdf(accessed 16 September 2015)
Ajaz S. Hussain| Insight Advice & Solutions LLC 8

9. To leveragethe
“billion(s)dollar”
opportunity:
Put R back in
R&D & recognize
it is a “complex”
productand
process!
 Invest in analytics, mathematics & statistics, and large sample
sizes; and in systems/integrative thinking and data integration
 Get to know the RLD – multiple lots; open the door with large
sample size
 Ability to justify measured RLD variability is relevant to
development of the proposed generic
 Exquisite regulatory communication strategy
 This is not a ‘complicated process’ for which typical ‘good
practices” work (e.g., typical project management approach)
 This is a complex process – with multiple interactions and
“emergent properties”; treat it as it is - a complex process and
plan to anticipate and address “emergent issues” - in technical,
regulatory and legal dimensions; at a certain point be prepared for
stakeholder (payers, patient groups,..) communications
Ajaz S. Hussain| Insight Advice & Solutions LLC 9

10. Related talks
that you may
find of some
interest
 Please see past presentations @
http://www.slideshare.net/a2zpharmsci/
 Product Quality & Patient Safety USP Workshop, Mumbai, 12 June
2015
 Excipient Knowledge Management, Mumbai, 12 March 2015
 QbD and CoQ IDMA, Mumbai, 24 March 2015
 QbR to QbD to CPV; 16 February 2015
 Bioequivalence – Still a Quality Achilles’ Heel? 16 October 2014
 A Historical Document on Subject By Formulation Interaction
 Voices of/for Patients
 Voice of the Patient
 Reducing technical and regulatory uncertainty in biosimilar
development
 Biopharmaceutics Classification System (BCS) &Waiver of
Bioequivalence
Ajaz S. Hussain| Insight Advice & Solutions LLC 10