1. 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

2. 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

3. 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

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

5. 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)

6. 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

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

8. 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.

9. 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 !!!

10. 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: ≈ mL
pH: 1-3
Residence Time: T½ ≈ min
Permeability: Low
- Volume: ≈ mL SI
pH: 3-8
Residence Time: ≈ 2-4 Hours (Fasting)
Capability of absorption (Permeability): High (SI 80 m² exchange surface)

11. 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: ≈ mL
pH: 1-3
Residence Time: T½ ≈ min
Permeability: Low
- Volume: ≈ mL SI
pH: 3-8
Residence Time: ≈ 2-4 Hours (Fasting)
Capability of absorption (Permeability): High (SI 80 m² exchange surface)

12. 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: ≈ mL
pH: 1-3
Residence Time: T½ ≈ min
Permeability: Low
- Volume: ≈ mL SI
pH: 3-8
Residence Time: ≈ 2-4 Hours (Fasting)
Capability of absorption (Permeability): High (SI 80 m² exchange surface)

13. 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

14. 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

15. 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

16. 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)

17. 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

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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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)

25. Biowaiver for Generics: EMA Policy
Merci pour l’attention Thank you for your attention