SSCI - Pharmaceutical Solids

May 13, 2005

-Polymorphism-
Interplay 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
Slide 1
 Overview of this Presentation
ICH Q6A Major Focus, with perspective from
Draft DS Guidance (2004) all below
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Draft Guidance on Polymorphism in ANDA (Dec 2004)
Slide 2
 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 Slide 3
 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

Slide 4
 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
Slide 5
 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.)
Slide 6
 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?

Slide 7
 ICH Q6A: Decision Tree #4 - Part 1

What is a reasonable polymorph screen for a given

drug?
Slide 8
 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)
Slide 9
 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)
Slide 10
Risk-Based Approach to Polymorph Screening

Simpler Solution drug products with

Polymorph drug load well below saturation
Screen High solubility*solid drug products

Low solubility*solid oral products

More
Suspension drug products
Thorough
Polymorph Solution drug products with drug load
Screen approaching saturation
Soft gelatin capsules

BCS Biopharmaceutics Classification System

http://www.fda.gov/cder/guidance/3618fnl.pdf
Slide 11
 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
Slide 12
Where does this fit in a CTD-Formatted Application?

Physicochemical
Characterization
Section S.3.1

Slide 13
ICH Q6A: Decision Tree #4 - Part 2
How Different?

Slide 14
ICH Q6A: Decision Tree #4 - Part 2

Solution DP
Other situations?

Slide 15
ICH Q6A: Decision Tree #4 - Part 2

Qualitative Control?
versus
Quantitative Control?

Slide 16
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

Slide 17
 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)
Slide 18
 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
Slide 20
 Appropriate Level
Process Understanding
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

Slide 21
Where does this fit in a CTD-Formatted Application?

DP Studies Saturation Level

Explained in
Sometimes for Solution DP
Justification of
Warranted
Specification
Discuss in Section S.4.5
Section P.2.1.1 Section P.2.2.3

Sections S.4.1 and S.4.5 Slide 22

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.
Slide 23
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

Slide 24
 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)

Slide 25
Where does this fit in a CTD-Formatted Application?
Address Justification
Parameters of DP Spec
Relevant to DP
Performance
Section P.2.2.3 Section P.5.6

Slide 26
 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
Slide 27
 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 1-
136

Slide 28
 Acknowledgements
Ivan Santos Ko-Yu Lo
Tim Wozniak Kathy Woodland-Outlaw
Scott Furness Nashed Nashed
John Smith Edwin Ramos
Andre Raw Chuck Hoiberg
Tony Decamp Chi-wan Chen
Lawrence Yu Yuan-yuan Chiu
Richard Adams Moheb Nasr
Slide 29