SSCI - Pharmaceutical Solids May 13, 2005

-PolymorphismInterplay of Science and Regulation

Steve Miller, Ph.D. Chemistry Team Leader for the Division of Antiviral Drug Products Office of New Drug Chemistry, CDER, FDA
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Overview of this Presentation

ICH Q6A Major Focus, with perspective from all below Draft DS Guidance (2004) Byrn, Hoiberg, et al Pharm. Res., 12, 945-54 (1995) AAPS Workshop on DS/DP Specs (2002) Personal Review Experience (94-04) Other sources
BACPAC-I (2001) and II (under development) Draft DP Guidance (2003) Articles from generic drug perspective Draft Guidance on Polymorphism in ANDA (Dec 2004)
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Definition of Polymorphism (From Regulatory Perspective)

ICH Q6A Setting Specs for New DS and New DP (2000)* Polymorphism: The occurrence of different crystalline forms of the same drug substance. This may include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms.
My View: broad definition is valuable, because changes from one crystalline form to another, to a solvate/hydrate, or to an amorphous form are similar from both the Scientific perspective (all can affect dosage form performance), and Regulatory perspective (need for data to show whether they do affect performance for this particular DS and DP)
* http://www.fda.gov/OHRMS/DOCKETS/98fr/122900d.pdf
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Definition of Polymorphism
(From Regulatory Perspective - Continued)
Similar broad usage of Polymorphism (including solvates/hydrates and amorphous forms) in other regulatory documents:
BACPAC-1 (post-approval changes for DS) http://www.fda.gov/cder/guidance/3629fnl.pdf ICH Q3A (impurities in DS) http://www.fda.gov/cder/guidance/4164fnl.doc Scientific Considerations of Pharmaceutical Solid Polymorphism in Abbreviated New Drug Applications, Yu et al, Pharmaceutical Research, 2003, Vol. 20, No.4, 531-536. Draft Drug Substance: Chemistry, Manufacturing, and Controls Information (issued for public comments Jan 2004) http://www.fda.gov/cder/guidance/3969dft.doc Draft ANDAs: Pharmaceutical Solid Polymorphism (issued for public comments Dec 2004) http://www.fda.gov/cder/guidance/6154dft.doc

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ICH Q6A Guidance on

Specifications for New DS & New DP Specification Setting for Drug Substance (DS)
Does this test need to be performed (before each lot is released)? If so, what acceptance criterion is appropriate?

Specification Setting for Drug Product (DP)

Same two issues
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ICH Q6A
Specifications for New DS & New DP Drug Substance Specification
Identity; Assay; Impurities (related substances, volatile organics) Physical tests (morphic form, particle size, etc.)

Drug Product Specification

Identity; Assay; Dose Uniformity Degradants Physical tests (dissolution, morphic form, etc.)
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ICH Q6A: Decision Tree #4 Investigating the Need to Set Acceptance Criteria for Polymorphism in DS and DP Part 1
Do multiple polymorphic forms exist?

Part 2
Is routine polymorph testing of DS necessary?

Part 3
Is routine polymorph testing of DP necessary?
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ICH Q6A: Decision Tree #4 - Part 1

What is a reasonable polymorph screen for a given drug?

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AAPS/FDA Workshop DS and DP Specifications March 2002

Breakout Session on Physical Properties: Particle Size, Polymorphs and Q6A Decision Trees Moderators Ivan Santos (Merck) Tim Wozniak (Lilly) Jon Clark (CDER) Steve Miller (CDER)
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AAPS Workshop Conclusion: Screening for Polymorphs

Diversity in approaches
Focus on DS manufacturing process solvents Investigate beyond solvents in DS manufacturing process; impact on DP process (e.g., hydrate)

Reviewers want assurance of due diligence

describe solvents/conditions used in screen

How close is solution dosage form to saturation solubility for least soluble polymorph
forced crystallization from DP vehicle (draft DP Guide)
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Risk-Based Approach to Polymorph Screening

Simpler Polymorph Screen Solution drug products with drug load well below saturation High solubility*solid drug products Low solubility*solid oral products Suspension drug products Solution drug products with drug load approaching saturation Soft gelatin capsules

More Thorough Polymorph Screen

BCS Biopharmaceutics Classification System http://www.fda.gov/cder/guidance/3618fnl.pdf

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Polymorph Screening - Byrn et al

1. Solvents and mixtures used in isolation and purification of drug substance Polymorphs or solvates present before final crystallization? Solvate as actual form of DS before drying? 2. Crystallize from water or aqueous mixtures Formation of hydrate on storage of DS or DP? 3. Representative solvents of different polarities More desirable polymorph available? Early warning of problematic polymorph
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Where does this fit in a CTD-Formatted Application?

Physicochemical Characterization Section S.3.1

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ICH Q6A: Decision Tree #4 - Part 2

How Different?

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ICH Q6A: Decision Tree #4 - Part 2

Solution DP Other situations?

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ICH Q6A: Decision Tree #4 - Part 2

Qualitative Control? versus Quantitative Control?

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ICH Q6A: Decision Tree #4 - Part 2

*Does the Manufacturing Process Routinely Give a Single Polymorph? Yes - Qualitative Control (IR, etc) No - Quantitative Control (XRD, etc)

* see S.Byrn et al, 1995

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Thoughts on Control of Polymorphism in DS

What form(s) does manufacturing process produce? One-time studies during IND phase Use control strategy that makes sense:
Quantitative (or limit) test in DS specification Qualitative (ID) test in DS specification Process Test (e.g., endpoint test for drying) Process Parameter (solvent composition)
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AAPS Workshop Conclusion: Acceptance Criteria in DS Spec

Qualitative test may be adequate when only one of multiple polymorphs is consistently produced
E.g., ID by IR: Conforms to Form 2 Sunset or Skip/PQIT testing might be an option after demonstration of control

More complicated situations may need bioavailability data to resolve

compare polymorph performance of mixtures and pure forms Slide 19

Complicated Situations (AAPS Workshop)

DS polymorph changes throughout a manufacturing process or during stability Drug product containing DS with multiple polymorphs having different bioavailability Significant amount of amorphous form in DS Important to discuss data and plan regulatory approaches in End of Phase-2 meeting
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Process Understanding

Appropriate Level of Control

Is the DP manufacturing process robust towards polymorphic form of DS? What parameters control the DP performance? (quality for patients = safety and efficacy)

Risk-Based Approach to Regulation

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Where does this fit in a CTD-Formatted Application?

DP Studies Sometimes Warranted Discuss in Section P.2.1.1

Saturation Level for Solution DP

Explained in Justification of Specification Section S.4.5

Section P.2.2.3

Sections S.4.1 and S.4.5

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ICH Q6A: Decision Tree #4 - Part 3

N.B.: Undertake the following processes only if technically possible to measure polymorph content in the drug product.

Q6A: Part 3 of Decision Tree #4 should only be applied when polymorphism has been demonstrated for the DS, and shown to affect properties of the DP.

Q6A: It is generally technically very difficult to measure polymorphic changes in drug products. A surrogate test (e.g., dissolution) can generally be used to monitor product performance, and polymorph content should only be used as a test and acceptance criterion of last resort.
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ICH Q6A: Decision Tree #4 - Part 3

Does Change refer only to stability, or does it also include a change that occurs during DP manufacture?

AAPS Workshop Conclusion: Change includes both DP manufacture and DP stability

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Polymorphism Issues for DP

Usually dissolution or other in vitro release test provides sufficient assurance of polymorph control Special situations may benefit from 1-time studies (or routine testing) of polymorphic form in DP; for example: Amorphous DS Data suggests inconsistent polymorphic change during DP manufacture (especially for narrow therapeutic range drugs)
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Where does this fit in a CTD-Formatted Application?

Address Parameters Relevant to DP Performance Section P.2.2.3 Justification of DP Spec

Section P.5.6

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Overall Conclusions
Regulatory approaches should follow from good science:
Reasonably thorough screening study Share the data with us; expect science-based regulatory outcomes Collect data during IND phase (amount depends on DS and DP) Use data to justify adequacy of control strategy for polymorphism in commercial manufacturing

Use End-of-Phase 2 and PreNDA meetings to reach agreement on data needed for NDA
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References
Advanced Drug Delivery Reviews, 2004, 56, Issue 3, pages 235-414 Advanced Pharmaceutical Solids, Jens Carstensen, Vol. 110 in Series: Drugs in the Pharmaceutical Sciences, 2001, Marcel Dekker. Adv. Drug Deliv. Rev., 2001, 48: Issue 1, pages 1136

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Acknowledgements
Ivan Santos Tim Wozniak Scott Furness John Smith Andre Raw Tony Decamp Lawrence Yu Richard Adams Ko-Yu Lo Kathy Woodland-Outlaw Nashed Nashed Edwin Ramos Chuck Hoiberg Chi-wan Chen Yuan-yuan Chiu Moheb Nasr
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