ACPS Advisory Committee Meeting ACPS Advisory Committee Meeting October 21 - 22, 2002October 21 - 22, 2002

ACPS Advisory Committee Meeting ACPS Advisory Committee Meeting October 21 - 22, 2002October 21 - 22, 2002

Scientific Considerations Scientific Considerations of Polymorphism in ANDAsof Polymorphism in ANDAs

Lawrence X. Yu, Ph. D.Lawrence X. Yu, Ph. D.Director for ScienceDirector for Science

Office of Generic DrugsOffice of Generic DrugsFood and Drug AdministrationFood and Drug Administration

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Presentation OutlinePresentation Outline What is polymorphism? What is polymorphism? How does polymorphism affect How does polymorphism affect

pharmaceutical properties of drugs?pharmaceutical properties of drugs? To what extent should scientific

considerations be given to polymorphism in ANDAs?

What is polymorphism? What is polymorphism? How does polymorphism affect How does polymorphism affect

pharmaceutical properties of drugs?pharmaceutical properties of drugs? To what extent should scientific

considerations be given to polymorphism in ANDAs?

3

What is Polymorphism?What is Polymorphism?

Habit

Single EntityPolym orphs

Channel Layer Cage(Clathrate)

Nonstoichiom etricInclusion Com pounds

Stoichiom etricSolvates (Hydrates)

M olecular Adducts

Crystalline Am orphous

Internal Structure

Chem ical Com pound

Habit

Single EntityPolym orphs

Channel Layer Cage(Clathrate)

Nonstoichiom etricInclusion Com pounds

Stoichiom etricSolvates (Hydrates)

M olecular Adducts

Crystalline Am orphous

Internal Structure

Chem ical Com pound

Haleblian JK. J. Pharm. Sci. 64:1269-88 (1975)

Orderedarrangement

Disorderedarrangement

ICH Definitionon Polymorphism

4

CharacterizationCharacterization Crystallography; x-ray diffraction pattern

Nonequivalent crystal structure Microscopy Thermal analysis; DSC and TGA Apparent solubility studies Intrinsic dissolution rate Infrared absorption, and Raman

spectroscopy Solid-state nuclear magnetic resonance

Crystallography; x-ray diffraction pattern Nonequivalent crystal structure

Microscopy Thermal analysis; DSC and TGA Apparent solubility studies Intrinsic dissolution rate Infrared absorption, and Raman

spectroscopy Solid-state nuclear magnetic resonance

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Pharm. Properties Exhibited Pharm. Properties Exhibited by Different Polymorphsby Different Polymorphs

Melting PointMelting Point HygroscopicityHygroscopicity Chemical and Physical StabilityChemical and Physical Stability Apparent Solubility and DissolutionApparent Solubility and Dissolution Bioavailability and BioequivalenceBioavailability and Bioequivalence Manufacturability Manufacturability

Melting PointMelting Point HygroscopicityHygroscopicity Chemical and Physical StabilityChemical and Physical Stability Apparent Solubility and DissolutionApparent Solubility and Dissolution Bioavailability and BioequivalenceBioavailability and Bioequivalence Manufacturability Manufacturability

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Effect of Polymorphism Effect of Polymorphism on Melting Pointon Melting Point

DSC profiles of the fluoroquinolone (US Patent 5,985,893)

Temperature (oC)

Wa

tts/

g

7

Effect of Polymorphism on Effect of Polymorphism on HygroscopicityHygroscopicity

Moisture sorption of the fluoroquinolone (US Patent 5,985,893)

Form III

Form I

Relative Humidity

We

igh

t G

ain

% w

/w

8

Effect of Polymorphism on Effect of Polymorphism on Apparent SolubilityApparent Solubility

0

0.5

1

1.5

2

2.5

3

3.5

Co

nce

ntr

atio

n (

mg

/mL

)

Form I Form III

One Hour

One Day

Three Days

0

0.5

1

1.5

2

2.5

3

3.5

Co

nce

ntr

atio

n (

mg

/mL

)

Form I Form III

One Hour

One Day

Three Days

Solubility of the fluoroquinolone (US Patent 5,985,893)

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Effect of Polymorphism on Effect of Polymorphism on Intrinsic DissolutionIntrinsic Dissolution

Form I

Form II

Dihydrate

Kabayashi et al. Int. J. Pharm. 193:137-146 (2000)

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Effect of Polymorphism on Effect of Polymorphism on BioavailabilityBioavailability: Low Solubility Drugs: Low Solubility Drugs

Kabayashi et al. Int. J. Pharm. 193:137-146 (2000)

Dihydrate

Form I

Solution

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Polymorphic Form Conversion Polymorphic Form Conversion During ManufacturingDuring Manufacturing

Milling/micronization Wet granulation

Inter-conversions between anhydrates and hydrates, or between different hydrates

Spray-drying Amorphous form

Milling/micronization Wet granulation

Inter-conversions between anhydrates and hydrates, or between different hydrates

Spray-drying Amorphous form

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Decision Tree Development on Decision Tree Development on Polymorphism in ANDAsPolymorphism in ANDAs

Process for evaluating when and how Process for evaluating when and how polymorphs of drug substances in ANDAs polymorphs of drug substances in ANDAs should be monitored and controlledshould be monitored and controlled Based on the ICH Guidance Q6A decision Based on the ICH Guidance Q6A decision

trees on polymorphismtrees on polymorphism Biopharmaceutics Classification System Biopharmaceutics Classification System

(BCS)(BCS)

Process for evaluating when and how Process for evaluating when and how polymorphs of drug substances in ANDAs polymorphs of drug substances in ANDAs should be monitored and controlledshould be monitored and controlled Based on the ICH Guidance Q6A decision Based on the ICH Guidance Q6A decision

trees on polymorphismtrees on polymorphism Biopharmaceutics Classification System Biopharmaceutics Classification System

(BCS)(BCS)

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ICH Q6A: Decision Tree #4ICH Q6A: Decision Tree #4Investigating the Need to Set Acceptance Criteria Investigating the Need to Set Acceptance Criteria

for Polymorphism in DS and DP for NDAsfor Polymorphism in DS and DP for NDAs Part 1Part 1

Do multiple polymorphic forms exist? Do multiple polymorphic forms exist? Part 2 Part 2

Is routine polymorph testing of DS valuable?Is routine polymorph testing of DS valuable? Part 3Part 3

Is routine polymorph testing of DP valuable?Is routine polymorph testing of DP valuable?

Part 1Part 1 Do multiple polymorphic forms exist? Do multiple polymorphic forms exist?

Part 2 Part 2 Is routine polymorph testing of DS valuable?Is routine polymorph testing of DS valuable?

Part 3Part 3 Is routine polymorph testing of DP valuable?Is routine polymorph testing of DP valuable?

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Limits to Oral Drug AbsorptionLimits to Oral Drug Absorption

GastricEmptying

Transit AbsorptionDissolution

Metabolism

Dissolution Rate = D *S/h (CDissolution Rate = D *S/h (Css - C - Cll)) D - diffusion coefficientD - diffusion coefficient S - dissolution surface areaS - dissolution surface area h - Aqueous boundary thicknessh - Aqueous boundary thickness

Cs - Cs - SolubilitySolubility Cl - Concentration in dissolution mediaCl - Concentration in dissolution media

Absorption: Absorption: PermeabilityPermeability

Dissolution Rate = D *S/h (CDissolution Rate = D *S/h (Css - C - Cll)) D - diffusion coefficientD - diffusion coefficient S - dissolution surface areaS - dissolution surface area h - Aqueous boundary thicknessh - Aqueous boundary thickness

Cs - Cs - SolubilitySolubility Cl - Concentration in dissolution mediaCl - Concentration in dissolution media

Absorption: Absorption: PermeabilityPermeability

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What is the BCS?What is the BCS?

BiopharmaceuticsClass

Solubility Permeability

I High High

II Low High

III High Low

IV Low Low

BiopharmaceuticsClass

Solubility Permeability

I High High

II Low High

III High Low

IV Low Low

The BCS is a scientific framework for classifying The BCS is a scientific framework for classifying drugs based on their aqueous solubility and drugs based on their aqueous solubility and intestinal permeability.intestinal permeability.

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17

Decision Trees on Decision Trees on Polymorphism in ANDAsPolymorphism in ANDAs

Decision Tree #1. Investigating the need to set acceptance criteria of polymorphs

Decision Tree #2. Investigating the need to set acceptance criteria of polymorphs for drug substance

Decision Tree #3. Investigating the need to set acceptance criteria of polymorphs for drug product

Decision Tree #1. Investigating the need to set acceptance criteria of polymorphs

Decision Tree #2. Investigating the need to set acceptance criteria of polymorphs for drug substance

Decision Tree #3. Investigating the need to set acceptance criteria of polymorphs for drug product

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Decision Tree #1. Investigating the Need to Set Acceptance Criteria of Polymorphs

Decision Tree # 2

START

Are there known polymorphs

with different apparentsolubility?

NO

YESEND

No further test or poly-morphic acceptance criteria for drug substance and drug product

Areall known

polymorphs highlysoluble?

NO

YES

Adequate knowledge of drug substance polymorphs is available by the time an ANDA is filed

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Drug Substance Polymorphism: Drug Substance Polymorphism: Knowledge versus ProcessKnowledge versus Process

FDA receives many ANDA applications for the same drug substance

Each applicant needs to have adequate knowledge on drug substance polymorphism to make appropriate decisions Each applicant has a unique approach to address

polymorphic issues Polymorphic information may come from literature,

patents, compendia, experience, or others

The Decision Tree # 1 emphasizes knowledge on polymorphism; not approaches used

FDA receives many ANDA applications for the same drug substance

Each applicant needs to have adequate knowledge on drug substance polymorphism to make appropriate decisions Each applicant has a unique approach to address

polymorphic issues Polymorphic information may come from literature,

patents, compendia, experience, or others

The Decision Tree # 1 emphasizes knowledge on polymorphism; not approaches used

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Polymorph Appearing and Polymorph Appearing and DisappearingDisappearing

Benzylidine-dl-piperitoneBenzylidine-dl-piperitone Polymorph Polymorph M. P. (M. P. (ooC) 59-60 63-64 69-70C) 59-60 63-64 69-70 1921 1921 and and in Australia, in Australia, 1936 1936 in Scotland, in Scotland, or or 1987 1987 in India no in India no , , not mentioned not mentioned

Benzylidine-dl-piperitoneBenzylidine-dl-piperitone Polymorph Polymorph M. P. (M. P. (ooC) 59-60 63-64 69-70C) 59-60 63-64 69-70 1921 1921 and and in Australia, in Australia, 1936 1936 in Scotland, in Scotland, or or 1987 1987 in India no in India no , , not mentioned not mentioned

From David Grant

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BACPAC I Guidance (2001)BACPAC I Guidance (2001)Bulk Actives Postapproval Changes:Bulk Actives Postapproval Changes:

Chemistry, Manufacturing, and Controls DocumentationChemistry, Manufacturing, and Controls Documentation

““Generally, only two physical properties of the Generally, only two physical properties of the drug substance, morphic form and particle size, drug substance, morphic form and particle size, are considered critical for evaluation of are considered critical for evaluation of equivalence.”equivalence.”

Equivalence of Physical PropertiesEquivalence of Physical Properties ““Conformance to established acceptance criteria Conformance to established acceptance criteria

for morphic form or, where acceptance criteria do for morphic form or, where acceptance criteria do not exist, the isolation of the same form or not exist, the isolation of the same form or mixture within the range of historical data,…”mixture within the range of historical data,…”

““Generally, only two physical properties of the Generally, only two physical properties of the drug substance, morphic form and particle size, drug substance, morphic form and particle size, are considered critical for evaluation of are considered critical for evaluation of equivalence.”equivalence.”

Equivalence of Physical PropertiesEquivalence of Physical Properties ““Conformance to established acceptance criteria Conformance to established acceptance criteria

for morphic form or, where acceptance criteria do for morphic form or, where acceptance criteria do not exist, the isolation of the same form or not exist, the isolation of the same form or mixture within the range of historical data,…”mixture within the range of historical data,…”

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Decision Tree #1. Investigating the Need to Set Acceptance Criteria of Polymorphs

Decision Tree # 2

START

Are there known polymorphs

with different apparentsolubility?

NO

YES

Initial scientific characterization of the form(s):

e. g., X-ray Powder Diffraction, DSC / Thermoanalysis, Microscopy, and/or Spectroscopy

END

No further test or poly-morphic acceptance criteria for drug substance and drug product

Areall known

polymorphs highlysoluble?

NO

YES

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Decision Tree #2. Investigating the Need to Set Acceptance Criteria of Polymorphs for DS

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

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Decision Tree #3. Investigating the Need to Set Acceptance Criteria of Polymorphs for DP

Decision Tree # 2

Is there sufficient

concern that polymorphicacceptance criteria for drug

product should be established?

YES

No need to set polymorphicacceptance criteria for drug product

END

NO

Next Slide

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

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Decision Tree #3. Investigating the Need to Set Acceptance Criteria of Polymorphs for DP (Continued)

Dissolution testing can frequently detect potential conversion of polymorphs. In rare cases, solid characterization methods have to be used.

Doesthe drug product

dissolution testingprovide adequate controls if

the polymorphic ratiochanges?

NO

Set acceptance criteria for thedrug product dissolution testingas a surrogate for polymorphcontrol in the drug product

END

YES

Previous Slide

Set acceptance criteria for thedrug product using otherapproaches, such as solid characterization method

END

FDA BA/BE Guidance: “It is recommended that the sponsor select the agitation speed and medium that provide adequate discriminating ability, taking into account all the available in vitro and in vivo data.”

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Presentation OutlinePresentation Outline What is polymorphism?What is polymorphism? How does polymorphism affect How does polymorphism affect

pharmaceutical properties of drugs?pharmaceutical properties of drugs? To what extent should scientific

considerations be given to polymorphism in ANDAs?

What is polymorphism?What is polymorphism? How does polymorphism affect How does polymorphism affect

pharmaceutical properties of drugs?pharmaceutical properties of drugs? To what extent should scientific

considerations be given to polymorphism in ANDAs?

27

QuestionsQuestions Do the proposed decision trees adequately address Do the proposed decision trees adequately address

the key polymorph issues (stability and the key polymorph issues (stability and bioavailability) that should be considered in FDA's bioavailability) that should be considered in FDA's regulatory assessment on an ANDA? regulatory assessment on an ANDA? Decision Tree#1. Are there other issues with respect to Decision Tree#1. Are there other issues with respect to

characterization of polymorphic forms that FDA should characterization of polymorphic forms that FDA should consider?consider?

Decision Tree #3 addresses the necessity of having a Decision Tree #3 addresses the necessity of having a polymorph spec for drug product when using the most polymorph spec for drug product when using the most stable or previously used form:stable or previously used form: Please comment on methods, approaches, and challenges for Please comment on methods, approaches, and challenges for

establishing specification for polymorphs in drug products. establishing specification for polymorphs in drug products. Also, in your experience, how often would you anticipate that Also, in your experience, how often would you anticipate that

such a specification necessary?such a specification necessary?

Do the proposed decision trees adequately address Do the proposed decision trees adequately address the key polymorph issues (stability and the key polymorph issues (stability and bioavailability) that should be considered in FDA's bioavailability) that should be considered in FDA's regulatory assessment on an ANDA? regulatory assessment on an ANDA? Decision Tree#1. Are there other issues with respect to Decision Tree#1. Are there other issues with respect to

characterization of polymorphic forms that FDA should characterization of polymorphic forms that FDA should consider?consider?

Decision Tree #3 addresses the necessity of having a Decision Tree #3 addresses the necessity of having a polymorph spec for drug product when using the most polymorph spec for drug product when using the most stable or previously used form:stable or previously used form: Please comment on methods, approaches, and challenges for Please comment on methods, approaches, and challenges for

establishing specification for polymorphs in drug products. establishing specification for polymorphs in drug products. Also, in your experience, how often would you anticipate that Also, in your experience, how often would you anticipate that

such a specification necessary?such a specification necessary?

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QuestionsQuestions

What additional considerations, if any, should be What additional considerations, if any, should be addressed on the issue of manufacture-ability or addressed on the issue of manufacture-ability or "process-ability" when different polymorph "process-ability" when different polymorph forms are present?forms are present?

What additional considerations, if any, should be What additional considerations, if any, should be addressed on the issue of manufacture-ability or addressed on the issue of manufacture-ability or "process-ability" when different polymorph "process-ability" when different polymorph forms are present?forms are present?