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Discussion Questions of Polymorphism in ANDAs

Ken Morris

Industrial and Physical Pharmacy

Purdue University

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Questions for the SABA. 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?

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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

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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 umbrella of polymorphs: questions/caveats.

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.

Decision Tree # 2

START

Are there known polymorphs

with different apparentsolubility?

YES

Areall known

polymorphs highlysoluble?

NO

#1

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is• 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.

More revealing yet common tests may be much less ambiguous and require similar resources

Matsuda et.a.

Decision Tree # 1

Is there apolymorphic specification

in the USP? (e.g.,melting point)

Set new polymorphicacceptance criteria fordrug substance

Is the USPpolymorphic specification

adequate?

NO

YES

NO

YES

Set the same polymorphicacceptance criteria fordrug substance as the USP Decision Tree # 3

#2

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is • Tighter specs may have to be negotiated with changing suppliers.

• Includes differences in impurity profiles

• Final crystallization and drying conditions

Decision Tree # 1

Is there apolymorphic specification

in the USP? (e.g.,melting point)

Set new polymorphicacceptance criteria fordrug substance

Is the USPpolymorphic specification

adequate?

NO

YES

NO

YES

Set the same polymorphicacceptance criteria fordrug substance as the USP Decision Tree # 3

1) Different polymorphic form 2) Allow to establish tight specification

#2

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isLevels 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

Solid Modification

Solubility - Dissolution

X-ray Diffraction DSC/TGA Infra-Red Mechanical

Polymorphs Higher for meta- stable forms

Different peaks Different melting and enthalpies

Sometimes differences due

to H-bond

Often different compression

characteristics Hydrate Usually lower

some exceptions Different peaks

possible “dehydrated

hydrates”

Variable water loss

and melting; Weight loss

O-H stretch HOH scissors

Usually different compression

characteristics

Solid Solution (crystalline)

Usually Higher for organics, but can be lower

Variably shifted dep. on conc of

guest

Different melting and enthalpy

New absorptions from “guest”

Often different compression

characteristics Eutectic Higher

Same as physical

mixture Eutectic and

abundant compound melting –

constant enthalpy

Same as physical mixture

Usually compressible

Amorphous Higher often with rapid transformation

or crystallization

No or few peaks Glass transition w/

possible re-xtal / melt

Variable but similar due to

chemical structure

Highly compressible

Glass Solution “Mixed Glass” (amorphous)

Higher often with rapid transformation

or crystallization

No or few peaks One intermediate Tg until phase

separation

Shifts in interacting frequencies

Highly compressible

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is 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?

Doesthe drug product

dissolution testingprovide adequate controls if

the polymorphic ratiochanges?

NO

Previous Slide

Set acceptance criteria for thedrug product using otherapproaches, 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.”

#3

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• 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

“In general, there should not be a concern if 1) The most stable polymorphic form is used or2) The form is used in a previously commercialized product”

#3

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isC. 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

y = 0.111x - 0.2501R2 = 0.959

-0.50

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

0 5 10 15 20 25 30 35

percent form A

form

A/f

orm

B p

eak

hei

gh

t

Calibration

R2 = 0.975

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0

0 2 4 6 8 10 12 14

Input Form A Concentration (% w/w)

Pre

dic

ted

Fo

rm A

Co

nc

en

tra

tio

n (

% w

/w) Validation

Newman and Bugay

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Calibration Curves of Glycine Compacts

Calculated detection limit: 0.5 % wt ( form), 0.8 % wt ( form)

y = 114141x

R2 = 0.9994

y = 167451x

R2 = 0.998

0

20000

40000

60000

80000

100000

120000

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Glycine form concentration

Inte

gra

ted

peak i

nte

nsit

y ( f

orm

)

0

30000

60000

90000

120000

150000

180000

0%10%20%30%40%50%60%70%80%90%100%

Glycine form concentration

Inte

gra

ted

pe

ak

inte

ns

ity

( fo

rm)

form

form

Cao and Morris (in press, JPharm Biomed Anal.)

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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