-Polymorphism- Interplay of Science and Regulation

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– Draft Guidance on Polymorphism in ANDA (Dec 2004)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

More • Low solubility*solid oral products
Thorough
Polymorph • Suspension drug products

Screen • Solution drug products with drug load
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

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

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
Section P.2.2.3 Section S.4.5
Discuss in
Section P.2.1.1 Slide 22

Sections S.4.1 and S.4.5

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.5.6

Section P.2.2.3

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