# Presentation: 167778

## Scientific Considerations of Polymorphism in ANDAs

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

**Scientific Considerations of Polymorphism in ANDAs**

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

**Notes:**
Karen, Many thanks for your excellent introduction. Many thanks for Helen for giving us your full support and opening remarks. I would like to spend next 30 min to discuss with you polymorphism in ANDA review process. The ANDA polymorphism guidance is in draft stage. Good guidance practice does not allow us to share the draft guidance with you. Therefore, I conclude my talk in series of questions regarding polymorphism in ANDAs.

## 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?**

**Notes:**
Basically, I will discuss four aspects of polymorphism. Why... ANDAs?

## What is Polymorphism?

## 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 **

## Pharm. Properties Exhibited by Different Polymorphs

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

## Effect of Polymorphism on Melting Point

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

**Temperature (****o****C)**

**Watts/g**

## Effect of Polymorphism on Hygroscopicity

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

- Form III

- Form I

**Relative Humidity**

**Weight Gain % w/w**

## Effect of Polymorphism on Apparent Solubility

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

## Effect of Polymorphism on   Intrinsic Dissolution

**Form I**

**Form II**

**Dihydrate**

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

## Effect of Polymorphism on Bioavailability: Low Solubility Drugs

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

**Dihydrate**

**Form I**

**Solution**

## Polymorphic Form Conversion During Manufacturing

**Milling/micronization **
**Wet granulation**
**Inter-conversions between anhydrates and hydrates, or between different hydrates **
**Spray-drying**
**Amorphous form**

## 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)**

## ICH Q6A: Decision Tree #4Investigating 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?**

## Limits to Oral Drug Absorption

**Gastric**
**Emptying**

**Transit**

**Absorption**

**Dissolution**

**Metabolism**

**Dissolution Rate = D *S/h (C****s**** - C****l****)**
**D - diffusion coefficient**
**S - dissolution surface area**
**h - Aqueous boundary thickness**
**Cs - ****Solubility**
**Cl - Concentration in dissolution media**
**Absorption: ****Permeability**

## What is the BCS?

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

## Slide 16

## 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**

## 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**

## 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**

## Polymorph Appearing and Disappearing

**Benzylidine-dl-piperitone**
**Polymorph       ********                ********                   ******
**M. P. (****o****C)      59-60         63-64             69-70**
**1921 ******** and ******** in Australia, ******** ******** ******
**1936 ******** in Scotland, ******** or ******** ******** ******
**1987 ******** in India no ********, ******** not mentioned**

- From David Grant

## BACPAC I Guidance (2001)Bulk Actives Postapproval Changes:Chemistry, 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,...”**

## 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 DS

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

## 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?**

**YES**

**No need to set polymorphic**
**acceptance 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 or**
**2) The form is used in a previously commercialized product**

##  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.**

**Does**
**the drug product**
**dissolution testing**
**provide adequate controls if**
**the polymorphic ratio**
**changes?**

**NO**

**Set acceptance criteria for the**
**drug product dissolution testing**
**as a surrogate for polymorph**
**control in the drug product**

**END**

**YES**

**Previous Slide**

**Set acceptance criteria for the**
**drug product using other**
**approaches, 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.”**** **

## 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?**

**Notes:**
Basically, I will discuss four aspects of polymorphism. Why... ANDAs?

## 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 Tree#1. 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?**** **

## Questions

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