BIOAVAILABILITY:

Rate and extent to which the active pharmaceutical ingredient is absorbed

From the pharmaceutical dosage form and becomes available at the site of

Action/in the general circulation

BIOEQUIVALENCE

Two pharmaceutical products are bio-eqivalent if they are

pharmaceutical

Equivalent,and their biovailability in terms of peak(Cmax,Tmax) and total

Exposure (AUC) after administration of same molar dose under same

Conditions are similar

DOCUMENTATION OF EQUIVALENCE FOR MARKETING

AUTHORISATION:

1. Comparative Pharmacokinetic Studies—Tmax.Cmax,AUC

2 Comparative Pharmacodynamic Studies

3. Comparative Clinical Trials

4. Comparative In-vitro Studies

EQUIVALENCE STUDIES NOT NECESSARY:

Same active pharmaceutical Ingredient in the same molar concentration,

As the comparator Product—Aqueous Solutions

1. Aqueous Parenterals—Intravenous, intramuscular, Subcutaneous

2. Syrups, Elixirs, Tinctures—not Suspensions

3. Powders to be reconstituted in aqueous solutions

4. Gases

5. Otics, Opthalmic, topical, Nebulisers, nasal sprays-in aqueous

solutions

Applicant to demonstrate that the excipients used are same, and in

Exact concentrations as in comparative product

INVIVO BIOEQUIVALENCE STUDIES REQUIRED:

1.Oral immediate release: Critical Use Medicines

Drugs with narrow therapeutic range

BA problems with active chemical (<70%)

Polymorphs of API/ Excipients

Changes in Manufacturing Scales

2. Non- oral , Non parenteral products for systemic absorption:

transdermal patches, testosterone gels, nicotine chewing gums etc.

3. Modified Release products for Systemic Absorption

4. Fixed dose combinations for systemic absorption—at least 1

ingredient BE

5. Non aqueous solutions for non systemic use: nasal, oral,

ocular ,dermal. Rectal etc

ISSUES IN BIOEQUIVALENCE STUDIES:

STUDY DESIGN:

1. Two-period, two sequence, crossover randomized

Washout period: 5 times the half-life (generally 7 days)

2. Too toxic or Very Potent Drugs

Lower doses in volunteers

Multiple dose steady state cross over in patients

Parallel group in patients

 3 Drugs with long half life:

Cross over with adequate washout period (< 3-4 weeks)

Parallel design—another alternative

4. Modified dosage release

@ Single dose cross over with highest dose of product/comparator

@ Study in fasting/fed state

@ Multiple dose steady state of MDR with equivalent strength

comparator ,given in recommended dose

SUBJECTS:

# Numbers of healthy volunteers as per statistical considerations

12-----18------24,depending on drug variability

select extra for contingency

# Healthy volunteers 18—55 years. Normal range of average weight

could be either sex—not mandatory

# Phenotyping of Volunteers: Slow and fast metabolisers of drugs

Parallel group to even out the above types

STUDY STANDARDISATION:

---Minimise variability

---overnight fasting 10-12 hours

---Product with 240 ml water

--- All meals standardized

--- Fed state study if product advised with meals

INVESTIGATIONAL PRODUCT:

@ Identical to available comparator product

@ QC control data for the Batch

@ Samples to from Normal Production Batch, or Pilot Batch Production

equivalent to 10 % of production batch, or 10,000 units whichever is

higher

@ In vitro dissolution study with comparator

COMPARATOR PRODUCT:

1. Innovator product from Country of Origin or from India ,if marketed

 2. WHO comparator product, or alternative marketed from well
regulated country(following ICH Guidelines)

3. Locally available first generic

SAMPLING TIME SCHEDULE:

 fasting state(Predose), 1-2 points before Cmax,

 2 points near Cmax
 3-4 points during elimination
 Up to 80 % of AUC time
 Generally not required after 72 hours

PARAMETERS FOR ASSESSMENT:

Single Dose: C max, T max, AUC (o-t)

Half Life

Mutidose : AUC over one dosing interval at steady state

C max, C min-concentration at end of dosing interval

Peak-trough fluctuation--% difference ( C max, C min)

Urine Examination: Cumulative urine recovery

Maximum urinary excretion rate

STUDY OF METABOLITES:
  Product is a pro drug

 Active metabolites contribute to safety and

efficacy

 Measurement of parent drug too low

FED STATE STUDIES: ^ Product with reported interaction with food

^ Product has GI disturbances on admnistration

^ Labelling advises intake with food

^ Modified Release Dosages-to avoid *dose-

dumping*

FIXED DOSE COMBINATION PRODUCT:

BE of the Test Product should be compared with the same fixed dose
combination available in Market

In absence of its being marketed ,the same ingredients in same strengths

can be given as a single dose

Assay all the ingredients, or the most important therapeutic ingredient

Consent of Regulatory for this

DIFFERENT STRENGTH OF SAME FORMULATIONS;

If Pharmacokinetics are linear, only one strength for BE(usually higher)

PHARMACODYNAMIC STUDIES:
Study the Pharmacologic effect of the drug in healthy volunteer/patients

This is Necessasary when quantitative analysis of the API/Metabolite in

serum or urine difficult ,due to lack of accurate or sensitive assay methods

Also for products given locally(inhalers),that work after absorption

The response measured should be relevant to the

therapeutic claim

Rule out subjects who are non-responders and who show placebo response

INVITRO TESTING:

Comparative In-Vitro dissolution profile similarity between the Test and

Comparator, could be used to document Bio-equivalence

In vitro tests should be with standard methods at ph 1.2,4.5.6.8

The tests are categorized as :

Very Rapid: 80 % drug dissolves in 15 minutes

Rapid: 80 % drug dissolves in 30 minutes

Not Rapid: Not fulfilling above criteria

BIOPHARMACEUTICS CLASSIFICATION SYSTEM:

BCS is based on aqueous solubility and intestinal permeability of the drug

CLASS 1. High Solubility, High Permeability

CLASS 2. Low Solubility, High Permeability

CLASS 3. High solubility, Low Permeability

CLASS 4. Low Solubility, Low Permeability

BIOWAVER:

On the basis of Dissolution Profile and principles of Solubility and

Permeability, BCS approach provides an opportunity for waiver of Bio-

equivalence Testing for certain categories of Immediate Release Drugs

Qualification for Biowaver: Conditions considered ;

1. Solubility and Permeability of the chemical

2. Dissolution Profile similarity at three different ph

3. Excipients used in formulations

Biowaver decisions are not applied to drugs meant for treating Critical
conditions, and for drugs having narrow therapeutic index

SURVEILLANCE:
 1. Monitoring of each and every BE study to be mandatory

2. Reports of each study should carry monitors report, as well as Audit

Reports of the sponsor

Clinical Monitoring; M.D., M.Pharm., Phd in Pharmacology

Analytical Monitoring: M.Sc., Phd, in Analytical Chemistry

VALIDATION:

All analytical tests used to determine the active chemical in the bio-logical
fluids must be well characterized, fully validated and documented

It should be reliable and Reproducible

Principles of GLP should be followed

Validation comprises before study and within study phases

If an essay has to be used at different sites, it must be validated at each site

All the samples of same subject should be analysed in the same analytical
run

Validation procedures, methodology and acceptance criteria .should be

specified in the Test procedures and be part of the Protocol