Scientific Considerations of Polymorphism in ANDAs

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Scientific Considerations of Polymorphism in ANDAs

• Lawrence X. Yu, Ph. D.
• Director for Science
• Office of Generic Drugs
• Food and Drug Administration

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

• What is polymorphism?
• How does polymorphism affect pharmaceutical
  properties of drugs?
• To what extent should scientific considerations
  be given to polymorphism in ANDAs?

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What is Polymorphism?
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Characterization

• 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 by Different
Polymorphs

• Melting Point
• Hygroscopicity
• Chemical and Physical Stability
• Apparent Solubility and Dissolution
• Bioavailability and Bioequivalence
• Manufacturability

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Effect of Polymorphism on Melting Point
DSC profiles of the fluoroquinolone (US Patent
5,985,893)
Watts/g
Temperature (oC)
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Effect of Polymorphism on Hygroscopicity
Moisture sorption of the fluoroquinolone (US
Patent 5,985,893)
Form I
Weight Gain w/w
Form III
Relative Humidity
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Effect of Polymorphism on Apparent Solubility
Solubility of the fluoroquinolone (US Patent
5,985,893)
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Effect of Polymorphism on Intrinsic Dissolution
Form I
Form II
Dihydrate
Kabayashi et al. Int. J. Pharm. 193137-146 (2000)
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Effect of Polymorphism on Bioavailability Low
Solubility Drugs
Kabayashi et al. Int. J. Pharm. 193137-146 (2000)
Solution
Form I
Dihydrate
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Polymorphic Form Conversion During Manufacturing

• 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 Polymorphism in
ANDAs

• Process for evaluating when and how polymorphs of
  drug substances in ANDAs should be monitored and
  controlled
• Based on the ICH Guidance Q6A decision trees on
  polymorphism
• Biopharmaceutics Classification System (BCS)

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ICH Q6A Decision Tree 4Investigating the Need
to Set Acceptance Criteria for Polymorphism in DS
and DP for NDAs

• Part 1
• Do multiple polymorphic forms exist?
• Part 2
• Is routine polymorph testing of DS valuable?
• Part 3
• Is routine polymorph testing of DP valuable?

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Limits to Oral Drug Absorption

• Dissolution Rate D S/h (Cs - Cl)
• D - diffusion coefficient
• S - dissolution surface area
• h - Aqueous boundary thickness
• Cs - Solubility
• Cl - Concentration in dissolution media
• Absorption Permeability

Gastric Emptying
Metabolism
Transit
Absorption
Dissolution
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What is the BCS?

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

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Decision Trees on Polymorphism 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

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Decision Tree 1. Investigating the Need to Set
Acceptance Criteria of Polymorphs
Adequate knowledge of drug substance polymorphs
is available by the time an ANDA is filed
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Drug Substance Polymorphism Knowledge 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

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Polymorph Appearing and Disappearing

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

From David Grant
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BACPAC I Guidance (2001)Bulk Actives
Postapproval ChangesChemistry, Manufacturing,
and Controls Documentation

• Generally, only two physical properties of the
  drug substance, morphic form and particle size,
  are considered critical for evaluation of
  equivalence.
• Equivalence of Physical Properties
• Conformance to established acceptance criteria
  for morphic form or, where acceptance criteria do
  not exist, the isolation of the same form or
  mixture within the range of historical data,

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Decision Tree 1. Investigating the Need to Set
Acceptance Criteria of Polymorphs
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Decision Tree 2. Investigating the Need to Set
Acceptance Criteria of Polymorphs for DS
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
polymorphic acceptance criteria for drug product
should be established?
No need to set polymorphic acceptance criteria
for drug product
NO
END
YES
Next Slide
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
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Decision Tree 3. Investigating the Need to Set
Acceptance Criteria of Polymorphs for DP
(Continued)
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.
Previous Slide
Does the drug product dissolution testing provide
adequate controls if the polymorphic
ratio changes?
Set acceptance criteria for the drug product
dissolution testing as a surrogate for
polymorph control in the drug product
YES
NO
END
Set acceptance criteria for the drug product
using other approaches, such as solid
characterization method
Dissolution testing can frequently detect
potential conversion of polymorphs. In rare
cases, solid characterization methods have to be
used.
END
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Presentation Outline

• What is polymorphism?
• How does polymorphism affect pharmaceutical
  properties of drugs?
• To what extent should scientific considerations
  be given to polymorphism in ANDAs?

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Questions

• 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?
• Decision Tree1. Are there other issues with
  respect to characterization of polymorphic forms
  that FDA should consider?
• 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?

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Questions

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