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
Drug product selection &generic drug product substitution
are major responsibilities for physicians ,pharmacists and
others who prescribes dispense or purchase drugs.
• To facilitate that FDA published, Approved Drug
Products with Therapeutic Equivalence Evaluations
Orange book which identifies drug products approved on the
basis of safety and effectiveness.
• They serve as public information and advice to health
agencies, prescribers and pharmacists to promote
public education in the area of drug product selection.

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 370 C
 Highly soluble: highest dose strength is soluble in ≤ 250 ml
aqueous media over a pH range of 1-7.5, 37±10 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.
Poorly soluble weak acids
with pka values of ≤ 4.5
Intrinsic solubility is of ≥
0.01mg/ml
At pH values of fasted state in the
jejenum (pH about 6.5)-solubility
of ≥ 1mg/ml
Currently they are class 2
drugs ,which are poorly
soluble at gastric pH and
small intestinal transit time
In fasted state longer the gastric residence time, drugs with these
physical characteristics will have amble time to be dissolved.
As long as they meet permeability criteria ,biowaiver extension
potentail is possible

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.
If dissolution is
rapid-under all
physiologic pH
condition-
determined by in
vivo permeability
Expect to behave
like an oral solution
in vivo
BE are
generally
waived for
oral solution –
DR is
immediate.

18. Potential excipient effect on
motility/permeability
Class 3 drugs exhibit site dependent absorption properties-transit
time through specific regions of upper intestine may be critical for
BE
More stringent dissolution criteria is suggested to ensure
complete dissolution in stomach.
Eg: poorly absorbed sugars alcohols like mannitol &
sorbitol decrease intestinal transit time
Therefore class 3 drug with significant amount of transit-
influence of excipients should be excluded from biowaiver
considerations.

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