1. Y. B. Chavan College of Pharmacy,
BCS: a regulatory tool for getting bio-waiver in generic products development
Dr. S. R. Lahoti
Professor
Y. B. Chavan College of Pharmacy,
Aurangabad

2. Snapshots Basic criterias and understanding BCS
Regulatory criteria for BCS
Dissolution
Permeability determination
Bio-waiver
BCS based bio-waiver
Challenges and issues in bio-waiver

3. Basic criterias and understanding
Highly Soluble
Rapidly Dissolving
High permeability
Absorption Number
Dissolution number
Dose Number
Pharmaceutical equivalent
Bioequivalent
Bio-waiver

4. BCS pillars
Solubility
Permeability
Dissolution

5. BCS: basic concept Two types for absorption: Dissolution limited
Permeability limited
BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.

6. BCS: basic concept cont….
Class-I:
High permeability, high solubility
High absorption number and a high dissolution number
Formulated as immediate release products
Dissolution rate generally exceeds gastric emptying
At least 85% of a product dissolves within 30 min
Bio-waiver can be obtained
IVIVC expected
IR and CR products.
Ex: Metoprolol, Diltiazem,Verapamil, Propranolol.

7. BCS: basic concept cont….
Class-II:
High permeability, low solubility
High absorption number but a low dissolution number.
Dissolution is then a rate limiting step for absorption except at a
Very high dose number.
IVIVC expected.
Challenges to increase dissolution and retention time
Ex: Phenytoin, Ketoconazole, Mefenamic acid, Nifedinpine
Class-III:
Low permeability, high solubility
Permeability is rate limiting step
High variation in the rate and extent of drug absorption
No IVIVC
Permeation Enhancement strategies.
Ex: Cimetidine, Acyclovir, Captopril

8. BCS: basic concept cont….
Class-IV
Low Permeability, Low Solubility
have a poor and variable oral bioavailability
Very difficult to formulate
Parenteral formulations
No IVIVC
Ex: Hydroclorthiaziade, Fourth and fifth generation Cephalosporines.
Class-V
Not actually part of BCS
Metabolically or chemically unstable
Limited and variable Bioavailability
Prodrugs, enteric coating, enzyme inhibition, lipid technologies

9. Bio-waiver a useful tool
CURRENT PEDESTALS OF BIOWAIVERS Applications for bio-waivers are granted on the basis of: BCS: Considers the dose: solubility ratio, permeability and dissolution IVIVC : Based on correlation between in vitro data and in vivo profile. Composition Proportionality: New product is qualitatively same and quantitatively proportional to bio-batch. Bio-waiver is needed: IND, NDA, ANDA and Post approval changes (SUPAC).

10. BCS bases bio-waiver
A bio-waiver based on solubility and permeability consideration of active pharmaceutical ingredient, as well as dissolution profile similarity of the multisource (test) and the comparator (reference) product in pH 1.2, 4.5 and 6.8 media.
Bio-waiver criterias:
Class-I drug
IR product
Dissolution greater than 85% in 30 min.
F2 > 50
Drug should not have narrow therapeutic index
Expient used approved for IR product
Drug stable GI T
Product not for oral cavity absorption.

11. Steps for BCS bio-waiver cont…
Determination of equilibrium solubility:
The pH-solubility profile of the test drug substance should be determined at 37 ± 1oC in aqueous media with a pH in the range of ( The number of pH conditions based on the ionization ie Pka)
Ex: pKa of a drug is in the range of 3-5, solubility should be determined at pH = pKa, pH = pKa +1, pH = pKa-1, and at pH = 1 and
Minimum of three replicate in each pH conditions.
The solubility class should be determined by calculating the volume of an aqueous medium sufficient to dissolve the highest dose strength in the pH range of
Shake-flask method for saturation solubility studies.
Analysis by validated stability-indicating assay.

12. Steps for BCS bio-waiver cont…
Permeability Determination:
Pharmacokinetic studies in humans:
Mass-balance studies
Absolute bioavailability studies
Intestinal permeability methods:
In vivo intestinal perfusions studies in humans
In vivo or in situ intestinal perfusion studies in animals
In vitro permeation experiments with excised human or animal intestinal tissue
In vitro permeation experiments across epithelial cell monolayers
Instability in the Gastrointestinal Tract
Accounts for extent of degradation of a drug in the GI fluid prior to intestinal membrane permeability.

13. Steps for BCS bio-waiver
Criterias for permeability study:
A linear (pharmacokinetic) relationship between the dose (e.g., relevant clinical dose range) and measures of BA (area under the concentration-time curve) of a drug is demonstrated.
Lack of dependence of the measured in vivo or in situ permeability is demonstrated in an animal model on initial drug concentration.
No statistically significant difference in the rate of transport between the apical-to-basolateral and basolateral-to-apical direction for the drug concentrations selected .
Suitability of a Permeability model must be validated using model drugs of a range of low (e.g., < 50%), moderate (e.g., %), and high (≥ 90%) absorption.
Drug concentrations should then be determined using a validated stability-indicating assay method. Significant degradation (>5%) of a drug in this protocol could suggest potential instability.

14. Model drugs suggested by WHO for use in establishing suitability of a permeability method.
IS = Internal standard for Permeability
studies
ES =Efflux pump substrates

15. Steps for BCS bio-waiver cont…
Dissolution profile study:
USP Apparatus I at 100 rpm or Apparatus II at 50 rpm using 900 ml of the following dissolution media:
(1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes;
(2) a pH 4.5 buffer;
(3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes. (For capsules and tablets with gelatin coating, Simulated Gastric and Intestinal Fluids USP (with enzymes) can be used.)
A minimum of 12 dosage units of a drug product should be evaluated to support a bio-waiver request.

16. World Health Organization
14 September, 2018

17. World Health Organization
14 September, 2018

18. World Health Organization
14 September, 2018
When the two profiles are identical, f2 = An average difference of 10% at all measured time points results in a f2 value of 50. FDA has set a public standard of f2 value between to indicate similarity between two dissolution Profiles.

19. Bio-waiver of Class-II
As per USFDA no bio-waiver.
But at higher PH of intestine fast and reliable dissolution.
After Gastric emptying behaves as Class-I
If solubility/ Dose ratio is > 1 completely absorbed.
In-vivo solubility is higher because of bile salts.
If dissolution and solubility is enhanced by various techniques.
Bio-waiver of Class-III
The absorption is permeability limited , so less depend upon formulation aspects.
If dissolution is faster at all physiological PH then behaves as Oral solution in-vivo and solutions gets bio-waiver.
If excipients used are not affecting absorption and dissolution is > 85% in 15 min.
The permeability is low but uniform through GIT.
But if drug shows gradient permeability, absorption window, excipients affect contact time and residence time in GIT no bio-waiver.

20. BCS Bio-waiver argument issues
As per BCS the drug should be soluble in PH range 1 to 7.5, the physiological PH under fasting and Fed state is 1.4 to So the BCS requirement should be relaxed accordingly.
250 ML is volume for solubility, but in-vivo volume is higher.
Presence of bile salts .
90% absorption criteria is High, as more than 85% absorption is considered to be complete absorption.
Process of dissolution also based on Dose, in addition to solubility. The drug is available in various strengths, so if Solubility /Dose ratio is considered it will be more appropriate.
Effect of food, transporters, efflux, rout of elimination /metabolism not considered.

21. Bio-waiver exclusions
Locally applied, systemically acting products
Non-oral immediate release forms with systemic action
Modified release products
Transdermal products

22. Extension of BCS SIX class BCS : Given by Bergstrom in 2003.
Solubility : Low and High
Permeability: Low, Intermediate and High.
Q BCS (RINAKI et al ):
BCS based upon Solubility /Dose ratio Vs Permeability.
If dose is less complete absorption.
Four classes accordingly.
BDDCS:
Most popular extension given by Chi-Yuan Wu in 2005.
The classification based on Solubility Vs Metabolism.
If > 70% Drug excreted as metabolite extensive metabolism
If > 50% drug excreted as unchanged poor metabolism.
Accordingly four classes.

23. ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER
Excipients :
Can sometimes affect the rate and extent of drug absorption.
Currently in FDA-approved IR solid oral dosage .
Quantity of excipients in the IR drug product should be consistent with the intended function
New excipients or atypically large amounts of commonly used excipients are included in an IR solid dosage form, additional information documenting the absence of an impact on BA of the drug may be requested by the Agency. Such information can be provided with a relative BA study using a simple aqueous solution as the reference product.
Large quantities of certain excipients, such as surfactants (e.g., polysorbate 80) and sweeteners (e.g., mannitol or sorbitol) may be problematic.

24. ADDITIONAL CONSIDERATIONS
Pro-drugs :
Permeability of pro-drugs will depend on the mechanism and (anatomical) site of conversion to the drug substance. When the pro- drug-to-drug conversion is shown to occur predominantly after intestinal membrane permeation, the permeability of the pro-drug should be measured. When this conversion occurs prior to intestinal permeation, the permeability of the drug should be determined. Dissolution and pH-solubility data on both pro-drug and drug can be relevant.

25. Conclusion
BCS based biowaiver has major advantage of cost and resource reduction. It avoids ethical problem comes with unnecessary testing of drugs on human subjects. Logically small change in formulation should not affect the performance of drug so similarity can be proved with in vitro dissolution study. The regulatory authorities have given certain guidelines for carrying out the bio-waiver study, along with criteria for drug for study. The difference in regulatory allowance still is major part of discussion. It is expected in upcoming time the regulatory authorities will consider other classes of BCS for bio-waiver study based on risk assessment. The lowering of regulatory burden will result in regulatory relief without loss of product quality. The regulatory authority still reviewing several drugs for bio-waiver study but still distance to go for product approval based on in vitro data.