Scientific rationale for EU regulatory expectations concerning product composition in - PowerPoint Presentation

Slide1

Scientific rationale for EU regulatory expectations concerning product composition in case of Class-I and Class-III medicinal products

Dr Ridha BELAIBA PharmD, PhDANSM (French Medicines Agency)Senior Scientist: Team Leader PK-PDEvaluation Directorate-FrancePK-WP membre EMA (London)

HRB Amman 2-3 MaySlide2

BCS-

Based BW Class I & Class IIIComposition EU RationalConcept of the BCS-Based BioWaiver (BW):Current Regulatory situation in Europe:Scientific Rational For the current requirements regarding generic drug products compositionSlide3

BCS-

Based BW Class I & Class IIIComposition EU RationalConcept of BWBW means Bioequivalence demonstration is not requiredBE becomes self-evident in views of the Drug attributes and in vitro testingEvidence of BE is always required for Generic drug productsSlide4

BCS-

Based BW Class I & Class IIIComposition EU RationalConcept of BW: BCS-Based BW BW for other considerations:

100

50

25Slide5

Concept of BCS-BW: Absorption Boundaries

5Dissolution(Drug Product)Solubility(Drug Substance)Permeability(Absorption)iIs not a limiting StepIs not a limiting StepIs not a limiting StepSlide6

BCS-

Based BW Class I & Class IIIComposition EU RationalConcept of BCS-BW: Absorption BoundariesThe only limitation for absorption is the Drug Product DissolutionIf a Drug Substance (DS) is Highly permeable,AndIf DS is soluble along the range of conditions encountered in the Gastro-intestinal tructThe Comparison of the rate dissolution could

be

a

surrogate

for the

comparison

of absorption profiles Slide7

Biowaiver for Generics: EMA Policy

BCS Classification:Class 3Poorly permeableHighly soluble

Class 2

Highly permeable

Poorly soluble

Class 4

Poorly permeable

Poorly soluble

Class 1

Highly permeable

Highly solubleSlide8

BCS-

Based BW Class I & Class IIIComposition EU RationalSolubilityALL is about the Drug Substance only: Maximum dissolved dose in water per Volume Unit (mg/mL).Is a physical property of the molecule (finger print)Independent from particle morphe or size:Dependent upon temperature & pH conditions Dissolution:All is about the Drug Product,Largely dependent upon the formulation,Expressed as the dissolved fraction of the drug/ Unit Time (%/min)Solubility is always the limiting factor (prerequisite) for dissolution.8Slide9

BCS-

Based BW Class I & Class IIIComposition EU RationalSolubilityDissolution:9This Tablet is highly Soluble !!!Micronization enhances considerably the solubility of the drugSlide10

Biowaiver for Generics: EMA Policy

- Volume: ≈ + 500 mL SIpH: 3-8Residence Time: ≈ 2-4 Hours (Fasting)Capability of absorption (Permeability): High (SI 80 m² exchange surface)Relevant Physiological parameters for BCS:Volume: ≈ 250-300 mLpH: 1-3

Residence Time: T½ ≈ 15-30 min

Permeability: Low

The Highest Single dose is soluble:

in 250 mL of aqueous Media

Under pH range 1 To 6.8

At 37°C

SolubilitySlide11

Biowaiver for Generics: EMA Policy

- Volume: ≈ + 500 mL SIpH: 3-8Residence Time: ≈ 2-4 Hours (Fasting)Capability of absorption (Permeability): High (SI 80 m² exchange surface)Relevant Physiological parameters for BCS:Volume: ≈ 250-300 mLpH: 1-3

Residence Time: T½ ≈ 15-30 min

Permeability: Low

High permeability means complete absorption.

Absorption is considered complete if the extent of absorption is > 85%.

Only reliable investigations in human are taken into account for the classification.

PermeabilitySlide12

Biowaiver for Generics: EMA Policy

- Volume: ≈ + 500 mL SIpH: 3-8Residence Time: ≈ 2-4 Hours (Fasting)Capability of absorption (Permeability): High (SI 80 m² exchange surface)Relevant Physiological parameters for BCS:Volume: ≈ 250-300 mLpH: 1-3

Residence Time: T½ ≈ 15-30 min

Permeability: Low

-

Very :

Very rapidly Dissolving 85% within 15

min.

Rapidly dissolving:

85

% within 30

min.

DissolutionSlide13

Class I Drug Substance

Dissolution could be a surrogate for the comparison of absorption profiles Drug Substances: Class 1Drug Products: Very & rapidly DissolvingValid}

Unlikely

to

be

influenced

by excipients Slide14

Biowaiver for Generics: EMA Policy

How excipients could influence the absorption:The drug is subject to active uptake: excipient inhibit the transporter.The drug is rapidly absorbed: excipients modulating the gastric emptying time or the intestinal transit time.BCS-Class 1Slide15

Biowaiver for Generics: EMA Policy

EMA Recommendations:Using the same excipients is advisableDifferences in excipients is acceptable.ButThe excipients that could impact:gastrointestinal motilitysusceptibility of interactions with the drug substance (e.g. complexation)drug permeabilityInteraction with membrane transporters. Must be quantitatively & qualitatively the same.BCS-Class 1Slide16

Class

III Drug Substance Permeability is low:The drug is subject to transporter mediated efflux (PgP).Low passive diffusion,Site-Specific absorption (absorption window)Permeability (Absorption)Slide17

Class III Drug Substance

Dissolution could be a surrogate for the comparison of absorption profiles Drug Substances: Class 3Drug Products: Very & rapidly DissolvingValid}

Unlikely

to

be

influenced

by excipients Slide18

Biowaiver for Generics: EMA Policy

How excipients could influence the absorption:Greater number of potential mechanisms.Not always predictible.BCS-Class 3Slide19

Biowaiver for

Generics: EMA PolicyDissolution could be a surrogate for the comparison of absorption profiles Drug Substances: Class 3Drug Products: Very & rapidly DissolvingValid}

If no excipients

influencing

the

permeabilitySlide20

Biowaiver for Generics: EMA Policy

EMA Recommendations:All the excipients must be qualitatively the same and quantitatively very similarThe excipients that could impact:gastrointestinal motilitysusceptibility of interactions with the drug substance (e.g. complexation)drug permeabilityInteraction with membrane transporters. Must be quantitatively & qualitatively the same.BCS-Class 3Slide21

Biowaiver for Generics: EMA Policy

EMA Recommendations:What is very similar meansThe difference in ratio AS/each excipient between the Test & Reference should not be > 5%BCS-Class 3Slide22

Biowaiver for Generics: EMA Policy

Colonne1Mass%Lower bound %Lower Bound (g)Higher Bound (%)Higher Bound (g)AS

200

Filler

700

350%

332.5

665

367.5

735

Desitegrating

Agent

90

45

4.275

85.5

4.725

105

Lubrificant

10

5

0.475

9.5

5.25

10.5

Total Mass

1000

960

1050.5

EXAMPLESlide23

Biowaiver for Generics: EMA Policy

Lyoequivalence as a surrogate for BEDissolution Tests:Over-DiscriminatingDissolution Tests:Do not detect Bioinequivalence:IVIVC not knownNOYESBIOEQUIVALENT

DISSOLUTION Tests

YES

NOSlide24

Biowaiver for Generics: EMA Policy

LYOEQUIVALENCE (In vitro) As A Surrogate for BEIn-Vitro data are not predictive of in vivo performancesConsumer Risk (public health concern) IVIVC is seldom established.IVIVC Is product specific (generally not performed for IR formulations)Slide25

Merci pour l’attention

Thank you for your attentionridha.belaiba@ansm.sante.frBiowaiver for Generics: EMA Policy