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8/3/2019 Miller Poly

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Slide 1

-Polymorphism-

Interplay of Science and Regulation

Steve Miller, Ph.D.

Chemistry Team Leader for the Division ofAntiviral Drug Products

Office of New Drug Chemistry, CDER, FDA

SSCI - Pharmaceutical Solids

May 13, 2005


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Slide 2

Overview of this Presentation

ICH Q6A

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Draft Guidance on Polymorphism in ANDA (Dec 2004)

Major Focus, with perspective from

all below


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Slide 3

Definition of Polymorphism

(From Regulatory Perspective)ICH Q6A Setting Specs for New DS and New DP (2000)*

Polymorphism: The occurrence of different crystalline formsof the same drug substance. This may include solvation orhydration products (also known as pseudopolymorphs) and

amorphous forms.

My View:broad definition is valuable, because changes from onecrystalline form to another, to a solvate/hydrate, or to an amorphous formare 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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Slide 4

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 NewDrug 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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Slide 5

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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Slide 6

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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Slide 7

ICH Q6A: Decision Tree #4

Investigating the Need to Set AcceptanceCriteria 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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Slide 8

ICH Q6A: Decision Tree #4 - Part 1

What is a reasonable polymorph screen for a given

drug?


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Slide 9

AAPS/FDA Workshop

DS and DP SpecificationsMarch 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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Slide 10

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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Slide 11

Risk-Based Approach to Polymorph Screening

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

Simpler

Polymorph

Screen

MoreThorough

Polymorph

Screen

*

*

BCS Biopharmaceutics Classification System

http://www.fda.gov/cder/guidance/3618fnl.pdf


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Slide 12

Polymorph Screening - Byrn et al

1. Solvents and mixtures used in isolation and

purification of drug substance

Polymorphs or solvates present before finalcrystallization?

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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Slide 13

Where does this fit in a CTD-Formatted Application?

Physicochemical

Characterization

Section S.3.1


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Slide 14


How Different?


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Slide 15


Solution DP

Other situations?


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Slide 16


Qualitative Control?versusQuantitative Control?


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Slide 17

*Does the Manufacturing Process RoutinelyGive a Single Polymorph?

Yes - Qualitative Control (IR, etc)

No - Quantitative Control (XRD, etc)

* see S.Byrn et al, 1995



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Slide 18

Thoughts on Control of

Polymorphism in DS

What form(s) does manufacturing processproduce?

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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Slide 19

AAPS Workshop Conclusion:

Acceptance Criteria in DS Spec Qualitative test may be adequate when only

one of multiple polymorphs is consistentlyproduced

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 needbioavailability data to resolve

compare polymorph performance of mixtures

and pure forms


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Slide 20

Complicated Situations

(AAPS Workshop)

DS polymorph changes throughout amanufacturing process or during stability

Drug product containing DS with multiplepolymorphs 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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Slide 21

Process UnderstandingAppropriate 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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Slide 22

Explained in

Justification ofSpecification

Section S.4.5

Sections S.4.1 and S.4.5

DP Studies

Sometimes

Warranted

Saturation Level

for Solution DP

Section P.2.2.3

Discuss in

Section P.2.1.1



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Slide 23

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

Q6A: It is generally technically very difficult to measurepolymorphic changes in drug products. A surrogate test(e.g., dissolution) can generally be used to monitorproduct performance, and polymorph content should

only be used as a test and acceptance criterion of lastresort.

N.B.: Undertake the following processes only if technically

possible to measure polymorph content in the drug product.



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Slide 24


Does Change refer only to stability, ordoes it also include a change that

occurs during DP manufacture?

AAPS Workshop Conclusion:Change includes both DP manufactureand DP stability


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Slide 25

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 narrowtherapeutic range drugs)


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Slide 26

AddressParameters

Relevant to DP

Performance

Section P.2.2.3

Justification

of DP Spec

Section P.5.6



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Slide 27

Regulatory approaches should follow from goodscience:

Reasonably thorough screening study

Share the data with us; expect science-based regulatoryoutcomes

Collect data during IND phase (amount depends on DSand 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

Overall Conclusions


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Slide 28

References

Advanced Drug Delivery Reviews, 2004, 56, Issue

3, pages 235-414

Advanced Pharmaceutical Solids, Jens

Carstensen, Vol. 110 in Series: Drugs in thePharmaceutical Sciences, 2001, Marcel Dekker.

Adv. Drug Deliv. Rev., 2001, 48: Issue 1, pages 1-

136


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Slide 29

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 ChenLawrence Yu Yuan-yuan Chiu

Richard Adams Moheb Nasr

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