Scientific rationale for EU regulatory expectations concerning product composition in case of Class-I and Class-III medicinal products Dr Ridha BELAIBA PharmD, PhD ANSM (French Medicines Agency) Senior Scientist: Team Leader PK-PD Evaluation Directorate-France PK-WP membre EMA (London) HRB Amman 2-3 May

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

BCS-Based BW Class I & Class III Composition EU Rational Concept of BW BW means Bioequivalence demonstration is not required Evidence of BE is always required for Generic drug products BE becomes self-evident in views of the Drug attributes and in vitro testing

BCS-Based BW Class I & Class III Composition EU Rational Concept of BW: BCS-Based BW BW for other considerations: 100 50 25

Concept of BCS-BW: Absorption Boundaries Dissolution (Drug Product) i Is not a limiting Step Is not a limiting Step (Drug Substance) Solubility Is not a limiting Step Permeability (Absorption)

BCS-Based BW Class I & Class III Composition EU Rational Concept of BCS-BW: Absorption Boundaries If a Drug Substance (DS) is Highly permeable, And If DS is soluble along the range of conditions encountered in the Gastro-intestinal truct The only limitation for absorption is the Drug Product Dissolution The Comparison of the rate dissolution could be a surrogate for the comparison of absorption profiles

Biowaiver for Generics: EMA Policy BCS Classification: Class 3 Poorly permeable Highly soluble Class 2 Highly permeable Poorly soluble Class 4 Class 1

BCS-Based BW Class I & Class III Composition EU Rational Solubility ALL 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.

BCS-Based BW Class I & Class III Composition EU Rational Solubility Dissolution: Micronization enhances considerably the solubility of the drug This Tablet is highly Soluble !!!

Biowaiver for Generics: EMA Policy The Highest Single dose is soluble: in 250 mL of aqueous Media Under pH range 1 To 6.8 At 37°C Solubility Relevant Physiological parameters for BCS: Volume: ≈ 250-300 mL pH: 1-3 Residence Time: T½ ≈ 15-30 min Permeability: Low - Volume: ≈ + 500 mL SI pH: 3-8 Residence Time: ≈ 2-4 Hours (Fasting) Capability of absorption (Permeability): High (SI 80 m² exchange surface)

Biowaiver for Generics: EMA Policy 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. Permeability Relevant Physiological parameters for BCS: Volume: ≈ 250-300 mL pH: 1-3 Residence Time: T½ ≈ 15-30 min Permeability: Low - Volume: ≈ + 500 mL SI pH: 3-8 Residence Time: ≈ 2-4 Hours (Fasting) Capability of absorption (Permeability): High (SI 80 m² exchange surface)

Biowaiver for Generics: EMA Policy - Very : Very rapidly Dissolving 85% within 15 min. Rapidly dissolving: 85% within 30 min. Dissolution Relevant Physiological parameters for BCS: Volume: ≈ 250-300 mL pH: 1-3 Residence Time: T½ ≈ 15-30 min Permeability: Low - Volume: ≈ + 500 mL SI pH: 3-8 Residence Time: ≈ 2-4 Hours (Fasting) Capability of absorption (Permeability): High (SI 80 m² exchange surface)

Unlikely to be influenced by excipients Class I Drug Substance Dissolution could be a surrogate for the comparison of absorption profiles Drug Substances: Class 1 Drug Products: Very & rapidly Dissolving Valid } Unlikely to be influenced by excipients

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 1

Biowaiver for Generics: EMA Policy EMA Recommendations: Using the same excipients is advisable Differences in excipients is acceptable. But The excipients that could impact: gastrointestinal motility susceptibility of interactions with the drug substance (e.g. complexation) drug permeability Interaction with membrane transporters. Must be quantitatively & qualitatively the same. BCS-Class 1

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)

Class III Drug Substance Dissolution could be a surrogate for the comparison of absorption profiles Drug Substances: Class 3 Drug Products: Very & rapidly Dissolving Valid } Unlikely to be influenced by excipients

Biowaiver for Generics: EMA Policy How excipients could influence the absorption: Greater number of potential mechanisms. Not always predictible. BCS-Class 3

Biowaiver for Generics: EMA Policy Dissolution could be a surrogate for the comparison of absorption profiles Drug Substances: Class 3 Drug Products: Very & rapidly Dissolving Valid } If no excipients influencing the permeability

Biowaiver for Generics: EMA Policy EMA Recommendations: All the excipients must be qualitatively the same and quantitatively very similar The excipients that could impact: gastrointestinal motility susceptibility of interactions with the drug substance (e.g. complexation) drug permeability Interaction with membrane transporters. Must be quantitatively & qualitatively the same. BCS-Class 3

Biowaiver for Generics: EMA Policy EMA Recommendations: What is very similar means The difference in ratio AS/each excipient between the Test & Reference should not be > 5% BCS-Class 3

Biowaiver for Generics: EMA Policy EXAMPLE Colonne1 Mass % 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

Biowaiver for Generics: EMA Policy Lyoequivalence as a surrogate for BE NO YES BIOEQUIVALENT Dissolution Tests: Over-Discriminating Dissolution Tests: Do not detect Bioinequivalence: IVIVC not known YES NO DISSOLUTION Tests

Biowaiver for Generics: EMA Policy LYOEQUIVALENCE (In vitro) As A Surrogate for BE In-Vitro data are not predictive of in vivo performances Consumer Risk (public health concern) IVIVC is seldom established. IVIVC Is product specific (generally not performed for IR formulations)

Biowaiver for Generics: EMA Policy Merci pour l’attention Thank you for your attention ridha.belaiba@ansm.sante.fr