Transcript Discussion Questions of Polymorphism in ANDAs Ken Morris Industrial and Physical Pharmacy

Purdue University – Industrial and Physical Pharmacy - Morris
Discussion Questions of Polymorphism in
ANDAs
Ken Morris
Industrial and Physical Pharmacy
Purdue University
Purdue University – Industrial and Physical Pharmacy - Morris
Questions for the SAB
A. Do the proposed decision trees adequately address the key polymorph
issues (stability and bioavailability) that should be considered in FDA's
regulatory assessment on an ANDA?
B. Decision Tree#1. Are there other issues with respect to characterization
of polymorphic forms that FDA should consider?
C. Decision Tree #3 addresses the necessity of having a polymorph spec
for drug product when using the most stable or previously used form:
– Please comment on methods, approaches, and challenges for
establishing specification for polymorphs in drug products. Also,
in your experience, how often would you anticipate that such a
specification necessary?
D. What additional considerations, if any, should be addressed on the issue
of manufacture-ability or "process-ability" when different polymorph
forms are present?
Purdue University – Industrial and Physical Pharmacy - Morris
Decision Trees in My Opinion
• Represent a huge mentality advance over “check list”
approach
• Encourages inclusion of proper scientific processes
• Removes incentive for “testing into compliance”
• Allows the industrial scientist to logically develop appropriate
tests
• Facilitates rationale risk assessment by regulatory and
management
• Levels the playing field for Generic companies by allowing the
establishment of reasonable expectations based on the science
Purdue University – Industrial and Physical Pharmacy - Morris
A. Do the proposed decision trees adequately address the
key polymorph issues …
B. Decision Tree#1. Are there other issues with respect to
characterization of polymorphic forms that FDA should
consider?
In the context of sameness including amorphous, solvates
(stoichiometric and variable), adducts, etc.. under the
#1
umbrella of polymorphs: questions/caveats.
START
1. If polymorphs are not known or no
monograph is available, do they have to be
screened for? If so, this should be in the
table.
2. The solubility determination of meta-stable
forms must be scrutinized for conversion
artifact.
Are there
known polymorphs
with different apparent
solubility?
YES
Are
all known
polymorphs highly
soluble?
NO
Decision Tree # 2
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Decision Tree # 1
• MP as an ID test for all of the
forms under polymorphs is
often problematic: it must be
carried out and analyzed
carefully to avoid confusion
if it is to be the only test.
#2
Is there a
polymorphic specification
in the USP? (e.g.,
melting point)
NO
YES
Is the USP
polymorphic
specification
adequate?
NO
Set new polymorphic
acceptance criteria for
drug substance
YES
Set the same polymorphic
acceptance criteria for
drug substance as the USP
Decision Tree # 3
More revealing yet
common tests may be
much less ambiguous
and require similar
resources
Matsuda et.a.
#2
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Decision Tree # 1
• Tighter specs may
have to be negotiated
with changing
suppliers.
• Includes differences
in impurity profiles
• Final crystallization
and drying conditions
Is there a
polymorphic specification
in the USP? (e.g.,
melting point)
NO
YES
Is the USP
polymorphic specification
adequate?
NO
Set new polymorphic
acceptance criteria for
drug substance
YES
Set the same polymorphic
acceptance criteria for
drug substance as the USP
1) Different
polymorphic form
2) Allow to establish
tight specification
Decision Tree # 3
Purdue University – Industrial and Physical Pharmacy - Morris
Levels of Difficulty: Reasonable Expectation in
Characterization of Polymorphs
• Routine
– Identification and quantitation of mixed phases in API
• XRD, DSC, IR, NIR
– Identification of “high” levels of mixed phase in Product
• Difficult (sometimes unreasonable on a case by case basis)
– Quantitation of trace amounts of phases in API/product
• Synchrotron
• Raman mapping
• Advanced PXRD
– Quantitation of phases in Drug Product
• Particularly amorphous
• Cutting Edge
– Prediction of crystal structures from powder XRD patterns
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What to Expect from the Different Solid Phases
Solid Phase Properties Relative to Crystalline, Room Temperature Stable Forms
Solubility Dissolution
X-ray Diffraction
DSC/TGA
Infra-Red
Mechanical
Polymorphs
Higher for metastable forms
Different peaks
Different melting
and enthalpies
Hydrate
Usually lower
some exceptions
Usually Higher for
organics, but
can be lower
Higher
Variable water
loss
and melting;
Weight loss
Different melting
and enthalpy
Often different
compression
characteristics
Usually different
compression
characteristics
Solid Solution
(crystalline)
Different peaks
possible
“dehydrated
hydrates”
Variably shifted
dep. on conc of
guest
Same as physical
mixture
Sometimes
differences due
to H-bond
O-H stretch
HOH scissors
New
absorptions
from “guest”
Same as
physical mixture
Often different
compression
characteristics
Usually
compressible
Variable but
similar due to
chemical
structure
Shifts in
interacting
frequencies
Highly
compressible
Solid
Modification
Eutectic
Amorphous
Higher often with
rapid transformation
or crystallization
No or few peaks
Glass Solution
“Mixed Glass”
(amorphous)
Higher often with
rapid transformation
or crystallization
No or few peaks
Eutectic and
abundant
compound
melting –
constant enthalpy
Glass transition
w/
possible re-xtal /
melt
One intermediate
Tg until phase
separation
Highly
compressible
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#3
Dissolution testing may often be
correlated to KNOWN
transformations.
Given a demonstrated liability,
should the statistics be improved?
Are other techniques less resource
intensive than dissolution allowing
better statistics with less
incremental investment?
Previous Slide
Does
the drug product
dissolution testing
provide adequate controls if
the polymorphic ratio
changes?
NO
Set acceptance criteria for the
drug product using other
approaches, such as solid
characterization method
END
“Dissolution testing can frequently detect
potential conversion of polymorphs. In
rare cases, solid characterization methods
have to be used.”
Purdue University – Industrial and Physical Pharmacy - Morris
#3
“In general, there should not be a concern if
1) The most stable polymorphic form is used or
2) The form is used in a previously commercialized product”
• Here we need caveats for point 2 around amorphous and
hydrated “polymorphs”.
– Amorphous forms may have been stabilized by unique
formulation/processing strategies not easily reproduced and
should include a cautionary statement.
– Hydrates may be easily altered in subsequent processing
– There should be a recognition of the possible need to “build
in” in product characterization for meta-stable forms
subjected to processing conditions producing conditions
conducive to transformation
C. Approaches, and challenges for establishing specification for polymorphs in
drug products. Also, in your experience, how often would you anticipate that
such a specification necessary? (I’d say only occasionally to the last part)
• PXRD method
– Range 3-30 % form A
– Method RSD 5%
– Good percent recovery
Calibration
form A/form B peak height
3.50
y = 0.111x - 0.2501
R2 = 0.959
3.00
2.50
2.00
1.50
1.00
0.50
0.00
0
18.0
5
10
15
20
25
30
35
-0.50
percent form A
16.0
Predicted Form A Concentration (% w/w)
Purdue University – Industrial and Physical Pharmacy - Morris
4.00
Validation
14.0
R2 = 0.975
12.0
Percent Peak height form A/ Calculated Percent
form A peak height formB % Form A Recovery
4.4
0.27
4.6
105
8.0
0.58
7.4
93
10.1
1.00
11.3
112
13.0
1.38
14.7
113
10.0
8.0
6.0
4.0
2.0
0.0
0
2
4
6
8
10
12
14
Input Form A Concentration (% w/w)
Newman and Bugay
Calibration Curves of Glycine Compacts
90%
80%
70%
60%
50%
40%
30%
20%
10%
180000
g form
y = 167451x
R2 = 0.998
100000
0%
150000
80000
120000
60000
90000
40000
60000
a form
20000
30000
Integrated peak intensity (g form)
100%
120000
Integrated peak intensity a
( form)
Purdue University – Industrial and Physical Pharmacy - Morris
Glycine g form concentration
y = 114141x
R2 = 0.9994
0
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
0
100%
Glycine a form concentration
Calculated detection limit: 0.5 % wt (g form), 0.8 % wt (a form)
Cao and Morris (in press, JPharm Biomed Anal.)
Purdue University – Industrial and Physical Pharmacy - Morris
Questions for the SAB
D. What additional considerations, if any, should be addressed
on the issue of manufacture-ability or "process-ability"
when different polymorph forms are present?
1. Subject of ongoing research (Minnesota, Purdue,
Companies)
2. Issues should be addressed when potential is identified in
formulation/process development. This could be
acknowledged in charts.
• Maybe valuable as background for companies in
subsequent trouble shooting