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Objective risk assessment via asking the right
question at the right time:
Knowledge based decisions for dosage form
design/development/control
Ken Morris, Ph.D.
University Professor and
Director Lachman Institute for Pharmaceutical Analysis
Long Island University – Brooklyn Campus
Arnold & Marie Schwartz College of Pharmacy and Health Sciences
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Patient related failure modes as the basis for
development, risk assessment and equivalence
Examples Patient Failure
mode
Efficacy
Toxicity
Side effects
Compliance
Dosing regime
Route of administration
Examples of Pharmaceutical
Source(s) of variability
Stability (phys-chem)
Cp vs. time
t½
Dissolution
Processing changes
Company changes
From where does the knowledge come?
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Implementation of the Generic Drug User Fee Amendments of 2012
(GDUFA)
Testimony of Janet Woodcock, M.D.
Before the Committee on Oversight and Government Reform
United States House of Representatives, February 4, 2016
Ongoing Challenges
…”Second, there is a need for more research in the
generics space. Some drugs lack generic competition
because there is no convincing bioequivalence test
method available. … Similarly, methods for showing
chemical sameness for certain complex drugs are not
available…”
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Pharmaceutical Science for Generic Drugs: The
Science of Equivalence
Robert Lionberger, Ph.D., 4/30/15 (slide 26)
Three for the Future of NIPTE
• Ensure modern manufacturing for the 5 out of 6
products that are generics
• Advance the science of equivalence:
– Prioritize tools and science that make equivalence
evaluation clear and development easier
– Product design for human use
• Engage with GDUFA regulatory science
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The Science of Equivalence: Therapeutic and Bio-Equivalence
are only as good as the Pharmaceutical Equivalence
• BE is limited in scope (low variability normal healthy
subjects) and relies on a clear definition and
understanding of the PE to be of use
• Relying on BE in the absence of PE is a no-starter, TE
assumes PE/BE/GMP
• Hence the need to set meaningful specifications for a
product before it goes to the clinic (incl. est. shelf life)
• PE must be strong in prod/process understanding and
inform SOP design
• Pharmaceutical Equivalence needs to move from the 19thcentury classification (tablet, elixir, etc.) to 21st Century
Classification
– New drugs get the right CQA’s – considering patient needs and
related failure modes. Same CQA’s and lot-lot variability for
Generics.
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RQRT #1: Levothyroxine Sodium Pentahydrate
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• Symptoms vs. problems
• Adherence vs. compliance
– How do I know what I know?
• Critique the methodology
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Eric Duffy – CDER-FDA
8
•
Impact of the Solid State on Chemical Stability: Dehydration (Solid
16.11
State Chemistry of Drugs, Byrn 1999)
OXIDATION REACTIONS PRECEDED BY LOSS OF SOLVENT
Although not extensively studied, there are several solid-state oxidation reactions that
are preceded by and may indeed require prior loss of solvent of crystallization.
CO 2–
A. Dihydrophenylalanine
H
+
NH3
dihydrophenylalanine
CO –2
O2
H
+
NH3
phenylalanine
• Impact of the Solid State: Crystalline Hydrate Classification System
(Morris and Rodriguez 1993, Morris and Brittain1998)
Dehydration can lead to
amorphous material, new
crystal structures,
dehydrated hydrates
which maintain the
packing motif of the
original structure, or
mixed structures
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Dehydration of l-TH can produce a dehydrated hydrate which maintain the packing
motif of the original structure as shown
Katrusiak and Katrusiak, 93(12), JPS 2004
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Does Dehydration
Precede
Degradation?
Control
fit to Control
RT / 0% O2
fit to RT / 0% O2
Does O2 Cause
Degradation?
Pharm Dev and Tech Vol. 20(3), pgs.314-319 May 2015
% Levothyroxine Sodium Remaining
105
100
60oC / 0% O2
fit to 60oC / 0% O2
RT / 21% O2
fit to RT / 21% O2
95
90
60oC / 21% O2
fit to RT / 21% O2
85
80
75
70
65
60
0
2
4
6
Time (Days)
8
10
11 12
So a lot was known or discoverable about levo’s properties and issues
– NTI (narrow therapeutic index drug)
– Very low dose, 25-300ug
– Chemically labile
• Stable if hydrated but oxidized if dehydrated/disordered
• Processing effected stability (ala structure) – Cincinati thesis
• Excipient interaction (often via pH)-thesis, Mansoor’s papers
– Long PK t½ of approximately 7 days
Yet products were developed and approved apparently oblivious of
the prior knowledge and/or logical concerns
• This illustrates the point that for generic products, the dosage form
quality specs need to be developed at the preclinical or pre-biostudy stage (QTPP – Q8 -ala Q6A)
• Otherwise, you can’t know what variability is due to the patient
variability or PD issues instead of the variability in the dosage form?
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What are some of the right question(s) at the right time: during
development and ANDA review for levothyroxine sodium pentahydrate?
•
•
•
•
•
•
•
Development
What are the patient failure
modes used in product design
What does the literature say
about the science and API
What are the CQAs
Is the API chemically stable
What is the solid form of the
API and is it physically stable
over the shelf life
Does the process compromise
API stability
Specs and Risk Assessment
•
•
•
•
•
•
Review
Is the DH complete (including
problems observed)
What is the API
characterization process
Are the analytical methods
really targeting CQAs
Are the specifications relevant
Are the process controls
sufficient to insure integrity of
the API
Is the dosage form PE to the
RLD
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NTI quality classification: knowledge base development
(generating “new” prior knowledge)
Drug
Oral Dose
(mg)
Stability
Cp t1/2
(hr)
Solubility
(mg/mL)
Product Recall Basis
(2012 - 2016)
Mol. Wt
(g/mol)
Prazosin
1
Light Sensitive
2.5
0.5 (HCl salt)
-
383.4
Warfarin
1
Temperature
sensitive
40
0.017
Super potetnt, CU,
Stability
308.33
Clonidine
0.1
+
14
50
-
230.09
Valproic Acid
125
Light and
Temperature
Sensitive
12.5
50
Failed Dissolution
144.21
Digoxin
0.05
Light Sensitive
42
0.0648
-
580.94
Levothyroxine
0.025
168
0.000105
0.15 (salt)
Subpotent, stability,
(45)
776.87
Phenytoin
30
17
0.032
Failed dissolution
252.27
Isoetharine
Mesylate
0.35
3.18
-
335.42
Disopyramide
100
0.0449
Failed dissolution
339.47
Light Sensitive,
Oxidation
Temperature
sensitive
Temperature
sensitive
+
6.7
Many more descriptors are relatively straight forward to obtain or generate
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RQRT #2: Methylphenidate
• [11-13-2014] FDA concerns about therapeutic equivalence with two generic
versions of Concerta tablets (methylphenidate hydrochloride extendedrelease)Based on an analysis of data, FDA has concerns about whether or not two approved
generic versions of Concerta tablets (methylphenidate hydrochloride extended-release tablets),
used to treat attention-deficit hyperactivity disorder in adults and children, are therapeutically
equivalent tothe brand-name drug.
• In some individuals, the Mallinckrodt and Kudco products may deliver
drug in the body at a slower rate during the 7- to 12-hour range. The
diminished release rate may result in patients not having the desired
effect.
• As a result, the FDA has changed the therapeutic equivalence (TE) rating
for the Mallinckrodt and Kudco products from AB to BX. This means the
Mallinckrodt and Kudco products are still approved and can be
prescribed, but are no longer recommended as automatically
substitutable at the pharmacy (or by a pharmacist) for Concerta.
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Methylphenidate
(Clinical Therapeutics, 34(5), p1170, 2012)
Therapeutically equivalent?
Not always
Pharmaceutically equivalent?
Not really
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What are some of the right question(s) at the right time: during
development and ANDA review for methylphenidate?
Development
• What are the patient failure
modes used in product design
• What does the literature say
about the API/dosage forms
• What is the mechanism of
modifying the release profile
• What are the controls for the
consistency of the modified
release coating
• What constitutes adherence to
PE principles
• What are the specs and risk
assessment
•
•
•
•
•
Review
Is the DH complete
Were the patient failure
modes used appropriate
What’s the BE vs. the target
demographic
Does the level of PE cover all
marketed dosage forms
What is the appropriate RLD
and has PE been established
for it
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RQRT #3: Mesalamine, RLD variable, generics?
Asacol—Average dissolution curves for three different lots
measured at (a) pH 6.5, (b) pH 6.8 (c) pH 7.2, JPS, 97(4), 4/08
Mean dissolution time as a function of the overall mean tablet
coating thickness measured by terahertz pulsed imaging
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Draft
Guidance on
Mesalamine
It’s known that the dissolution
is dependent on coating
thickness, what good is BE w/o
PE?
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What are some of the right question(s) at the right time: during
development and NDA or ANDA review for mesalamine?
•
•
•
•
•
Development
What are the patient failure
modes used in product
design
What does the literature say
about the API/dosage forms
What is the mechanism of
modifying the release
profile
What are the CQAs and the
controls for consistency of
the modified release
coating (deign space)
What is the risk assessment
•
•
•
•
•
Review
Is the DH complete
What is the scale-up strategy
Is the CQA monitoring
technology sufficient to
assess process capability
Is the use test (dissolution)
sufficiently powered to
detect variability at the
appropriate level
Should a bio-waiver be
possible for the RLD and/or a
generic
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RQRT #4: Fosinopril Sodium: NCE
• ACE inhibitor NCE successfully developed in the 80’s
• NDAs are more complicated and there’s less prior
knowledge
• However, using scientific principles and experience
several challenges (all public) were addressed
• A Chemical stability and excipient interaction
illustrates RQRT principles
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Fosinopril
Sodium (JPS
88(7), 1999, p696)
Hypothesized reaction pathway(s) and excipient (MgSt)
interaction was tested when observed in later
development
Kinetics/risk analyses
showed the effect was
not significant to selflife
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What are some of the right question(s) at the right time: for stability
issues during development and NDA review for fosinopril sodium?
•
•
•
•
•
Development
What are the patient failure
modes used in product
design
What does the literature
and paper chemistry say
about the API
What excipient interactions
might be expected
What applicable ICH Q6A
tenets apply
What are the specs and risk
assessment
•
•
•
•
•
Review
Is the DH complete
Were the risks identified
sufficiently explored
Were the observed
problems explained and
supported by data/models
Were corrective actions
required
Does the risk analysis and
monitoring support the
decision(s)
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Right Question at the Right Time – Sponsors in practice
• The development history/report should be a log of the rationale and,
therefore, the internal science and risk assessment questions are
asked at the time
• Documenting unexpected or out of spec/trend results is essential in
supporting decisions made and addressing related questions and
“information requests”
• Every development history becomes part of the institutional
knowledge base and an integral part of risk assessment, reduction
and/or mitigation
• Adherence to the precepts of QbD and not just simple compliance
with regulations and quidances is the most efficient method for
quality product development
• Right question at the right time should lead to “Right the First Time”
approvable applications on the first cycle
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Right Question at the Right Time - FDA in practice
• FDA’s asking the right question – at the right time – critically
contributes to effective and efficient development of pharmaceutical
products and incorporates science and risk assessment
• To ask the right question at the right time FDA needs portions of
development report available for review by reviewers with the
necessary ‘peer’ expertise, the earlier the better and reviewed with a
mind willing to understand
• Even with ICH Q8 – effective/congruent review of new drug
development reports is yet to be achieved across the ICH regions, so
the time is right to encourage this in the U.S.
• With the formation of OPQ and the efforts to align new and generic
(including biotech) CMC review processes, the QbD-QbR approach
holds promise but is in need of significant attention to ensure it is
really using the knowledge gained to assess risk and incorporate the
principles QbD
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From where does the knowledge come?
Knowledge Bases and Knowledge Management
• A Development History captured in the Development Report is the
key to both guiding development and being ready for review.
• Essential aspects of the development history (DH) include:
– The rationale for all phases of development
• Fundamental principles, prior knowledge, heuristics
• Adherence (not just compliance!) to Q8 and Q6 tenets are
implicit in DH
– The knowledge base created and effectively curated
• Makes the DH an electronic living document capturing all
changes
• Usage of new and prior knowledge to make decisions
• Capturing of failure modes (patient/product) and sharing of
knowledge between FDA review and inspection
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What can you do with a knowledge base?
Manufacturing Science in the 21st Century Pharmaceutical: A Case
Study on Quality by Design
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What can you do with a knowledge base?
“Ontological informatics infrastructure for pharmaceutical
product development and manufacturing”
Venkatasubramanian et al., Computers and Chemical Engineering 30 (2006) 1482
An ontology is a formal, explicit specification of a shared conceptualization
• Conceptualization refers to an abstract model of some phenomenon in
the world by having identified the relevant concepts of that
phenomenon.
• Explicit means that the type of concepts used, and the constraints on
their use are explicitly defined.
• Formal refers to the fact that the ontology should be machine-readable.
• Shared reflects the notion that an ontology captures consensual
knowledge i.e. it is not private to an individual, but accepted by a group
Formalizes asking the right question at the right time!
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Summary: Needs and NIPTE/FDA Approaches
• EPISTOMOLOGY
– Understanding of patient failure modes
• Epistemology
– Objective risk assessment
• Ontology
– what is the “nature” of
pharmaceutical knowledge
and information
• Methodology
– How are data generated
and analyzed to create new
knowledge
• Determination of modes attributable to
pharmaceutical properties/behavior
• Establishment of CQAs for design
– Science of Equivalence – PE to TE, generics
• Basic research in materials DF design
• Establish PE for known CQAs
• Specifications and controls before clinicals
• ONTOLOGY
– Knowledge curation and management
• Curation center for scientific and prior knowledge
management – generalizable, reusable
• Bayesian – generate “new” prior knowledge
• Tipping point analysis and opportunities
– Synthesis
• RQRT – Educational Initiatives
• METHODOLOGY
– 21st century analytical methodology and new
technology
– Science and Risk-based cGMPs and SOPs
• Adherence directed compliance
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