generic substitution and biowaver

COMPUTER AIDED DRUG DEVELOPMENT ,GENERIC SUBSTITUTION.BIOWAVERS, BSC BASED BIOWAVERS'CRITERIA

1. Presented by SUJITHA MARY PHARMACEUTICS ST JOSEPH COLLEGE OF PHARMACY GENERIC SUBSTITUTION AND BIOWAIVER

2. CONTENTS Introduction Generic substitution Biowaiver BCS based biowaiver Criteria for biowaiver Conclusion Reference

3. GENERIC SUBSTITUTION

4. To contain drug costs, most state have adopted generic substitution laws to allow pharmacist to dispense a generic drug product for a brand-name drug product that has been prescribed. Some states have adopted positive formulary , which lists therapeutically equivalent or interchangeable drug product that pharmacist may dispense . Others use a negative formulary, which lists drug products that are not therapeutically equivalent, or interchange of which is prohibited. And if the drug is not negative formulary , the unlisted generic drug products are assumed to be therapeutically equivalent and may not be interchanged.

5. Approved Drug Products With Therapeutic Equivalence Evaluation Orange book contains therapeutic equivalence evaluations for approved drug products made by various manufacturers. These marketed products are evaluated according to specific criteria, the evaluation codes used for these drugs are listed A code Drug products considered to be therapeutically equivalent to other PE products AA Products in conventional dosage forms not presenting bioequivalence problems. AB Products meeting bioequivalence requirements. AN Solution and powders for aerosolization AO Injectable oil solutions AP Injectable aqueous solutions AT Topical products

6. B codes Drug products that the FDA does not consider to be therapeutically equivalent to other PE products B* Drug products requiring further FDA investigation and review to determine therapeutic equivalence BC Extended –release tablets, extended –release capsules, and extended- release injectable BD Active ingredients and dosage forms with documented bioequivalence problems BE Delayed –release oral dosage forms BT Topical products with bioequivalence issues BS Products having drug standard deficiencies BN Products in aerosol-nebulizer drug delivery systems

7. The concept of therapeutic equivalence as used to develop the Orange Book applies only to drug products containing the same active ingredient. And does not encompass a comparison of different therapeutic agents used for same condition. Eg : propoxyphene HCL versus pentazocine HCL for treatment of pain.

8. Generic Substitution Of Modified- Release Drug Products Generic extended- release drug products may have different release mechanism compared to brand drug product. The modified drug release drug products have different pharmacokinetic profiles. And even different clinical efficacy compared to conventional form of the drug given in the same daily dose. Since the pharmacokinetic profile may differ, the practitioner needs to consult the FDA publication, approved Drug Products with Therapeutic Equivalence Evaluation(Orange Book),to determine which of these drugs can be substituted.

9. BIOWAIVER Biowaivers are considered as the waivers of clinical bioequivalence study. BE studies are vital concern in drug development process. It eliminates unnecessary exposure of healthy subjects to in vitro studies. Instead of conducting expensive and time consuming in vivo studies, a dissolution test could be adopted as the surrogate basis for the decision as to whether the two pharmaceutical products are equivalent.

10. What is BCS ? It is a scientific frame work which divides APIs into four groups, according to their solubility and permeability properties.

11. BCS –BASED ‘ BIOWAIVER’ It is defined as Comparison of test and reference. In vitro instead of invivo BE testing. BCS – based biowaiver are intended only for BE studies.

12. Solubility To determine equilibrium solubility of a drug substance under physiological pH conditions. pH –solubility profile of test drug at 37 C Highly soluble: highest dose strength is soluble in ≤ 250 ml aqueous media over a pH range of 1-7.5, 37±1 C Permeability A drug substance is considered HIGHLY PERMEABLE when extent of absorption in humans is determined to be > 85% of an administered dose . It is based on a mass balance determination or in comparison to an administered reference dose

13. Dissolution USP apparatus 1 (basket) at 100 rpm or USP apparatus 2 (paddle) at 50 rpm. Dissolution media (900ml) A pH 1,2-0.1 N HCL or simulated gastric fluid USP, A pH 4.5 buffer, A pH 6.8 buffer or simulated intestinal fluid USP compare dissolution profiles of test and reference products using a similarity factor f2

14. Biowaiver criteria BCS based biowaiver - No Invivo /BA/BE study needed Rapid dissolution relative to gastric emptying Class 1: high solubility, high permeability Wide therapeutic window Excipients used in dosage form should be used previously in FDA approved immediate release (IR) solid dosage forms Prodrugs ; buccal absorption eg ; sublingual tablets

15. No biowaiver for Locally applied Systemically acting products Non- oral immediate release forms with systemic action Modified release products transdermal products

16. Biowaiver class 2 drugs Some drugs that are currently classified as class 2 are consistently and currently absorbed after oral administration.

17. Biowaiver extension potential for class 3 drugs Absorption of class 3 drugs is limited by its permeability and less dependent upon its formulation. BA is determined by its in vivo permeability pattern.

18. Potential excipient effect on motility/permeability

19. CONCLUSION Drug product selection and generic substitution are important responsibilities of the pharmacists. A listing of approved drug products of generic drug products of generic drug products that may be safely substituted is available in ORANGE BOOK. BCS is employed to waive in vivo BE testing(i.e. provide “ biowaiver ”) for new & generic drugs. Granting biowaiver under systems such as BCS , eliminates unnecessary drug exposure to healthy subject standard for therapeutic equivalence.

20. REFERENCE Shargel L., Andrew B.C. Applied Biopharmaceutics and Pharmacokinetics, 7 th edn . Mc Graw Hill Education, INC., singapore , 2016. Page No.437-444. Harle NU, Gaikwad NJ, Principles and Industrial Applications of Pharmacokinetics and Biopharmaceutics . 2 nd edn . Nirali prakashan ; 2012. P. 2.11-2.17.