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EVALUTION OF DOSSIERS IN WHO-PREQUALIFICATION PROJECT MULTISOURCE TB-DRUGS. Evaluation of bioavailability/bioequivalence data Based, with some changes on a presentation by Anna-Karin Hamberg Medical products agency, Sweden Presented by Hans Kemmler Consultant to WHO

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evalution of dossiers in who prequalification project multisource tb drugs
EVALUTION OF DOSSIERS IN WHO-PREQUALIFICATION PROJECTMULTISOURCE TB-DRUGS

Evaluation of bioavailability/bioequivalence data

Based, with some changes on a presentation by Anna-Karin Hamberg

Medical products agency, Sweden

Presented by

Hans Kemmler

Consultant to WHO

(Clinical Reviewer, Swissmedic, Switzerland)

Malaysia, 2005-02-24

why do we need bioequivalence studies
Why do we need Bioequivalence studies?
  • No clinical studies have been performed in patients with the Generic Product to support its Efficacy and Safety.
  • With data to support similar in vivo performance (= Bioequivalence) Efficacy and Safety data can be extrapolated from the Innovator Product to the Generic Product.

Malaysia, 2005-02-24

overview
Overview
  • Definition of some important Bioequivalence [BE] terms
  • Key issues in the WHO Manual Annex 3 “Guidelines on Requirements to Establish Interchangeability”
  • Major Deficiencies in BE-Studies identified within the WHO Procurement, Quality and Sourcing Project: Tuberculosis Drugs

Malaysia, 2005-02-24

overview4
Overview
  • Comparison of WHO requirements with other (FDA and CPMP) Bioequivalence Guidelines
  • A Note on Choice of Reference Products
  • Present new WHO Template for Assessment of Bioequivalence data

Malaysia, 2005-02-24

bioavailability
Bioavailability
  • “ .. the extent and the rate at which a substance or its active moiety is delivered from a pharmaceutical form and becomes available in the general circulation.”

Reference:

intravenous administration = 100% bioavailability

Malaysia, 2005-02-24

plasma concentration time profile
Plasma concentration time profile

concentration

Cmax

AUC

time

Tmax

Malaysia, 2005-02-24

important pharmacokinetic parameters
Important Pharmacokinetic Parameters
  • AUC: area under the concentration-time curve  measure of the extent of bioavailability
  • Cmax: the observed maximum concentration of drug  measure of both the rate of absorption and the extent of bioavailability
  • tmax: the time after administration of drug at which Cmax is observed  measure of the rate of absorption

Malaysia, 2005-02-24

bioavailability8
Bioavailability
  • Absolute bioavailability (F):
  • Relative bioavailability (Frel)

Malaysia, 2005-02-24

bioavailability same dose
Bioavailability: Same Dose
  • Absolute bioavailability (F):
  • Relative bioavailability (Frel)

Malaysia, 2005-02-24

pharmaceutical equivalents
Pharmaceutical Equivalents
  • contain the same amount of the same active substance in the same dosage form
  • meet the same or comparable standards
  • intended to be administered by the same route

Pharmaceutical equivalence by itself does notnecessarily imply therapeutic equivalence

Malaysia, 2005-02-24

pharmaceutical equivalents11
Pharmaceutical Equivalents

Test

Reference

Possible Differences

  • Drug particle size
  • Excipients
  • Manufacturing Equipment or Process
  • Site of manufacture

Could lead to differences in product performance in vivo

 Possible Bioinequivalence

Malaysia, 2005-02-24

bioequivalence
Bioequivalence

Two products are bioequivalent if

  • they are pharmaceutically equivalent
  • bioavailabilities (both rate and extent) after administration in the same molar dose are similar to such a degree that their effects can be expected to be essentially the same

Malaysia, 2005-02-24

therapeutic equivalence
Therapeutic equivalence

Two products are therapeutically equivalent if

  • pharmaceutically equivalent
  • their effects, with respect to both efficacy and safety, will be essentially the same as derived from appropriate studies
    • bioequivalence studies
    • pharmacodynamic studies
    • clinical studies
    • in vitro studies

Malaysia, 2005-02-24

interchangeable pharmaceutical products
Interchangeable pharmaceutical products

If a product is demonstrated to be

therapeutically equivalent to a reference

product, then the products are considered

interchangeable.

Malaysia, 2005-02-24

bioanalytical method validation
Bioanalytical Method Validation

Quantitative determinations of drugs

in biological samples, such as blood

or plasma, play a significant role in

evaluation and interpretation of

bioequivalence data.

Malaysia, 2005-02-24

bioanalytical method validation16
Bioanalytical Method Validation

Essential to use a well-characterised

and fully validated analytical method

to yield reliable results.

Malaysia, 2005-02-24

bioanalytical method validation17
Bioanalytical Method Validation
  • Method Validation should include
    • Accuracy
    • Precision
    • Sensitivity
    • Specificity
    • Recovery
    • Stability

Malaysia, 2005-02-24

bioanalytical method validation18
Bioanalytical Method Validation

Accuracy

Closeness of determined value to the true value. The acceptance criteria is mean value  15% deviation from true value. At LOQ, 20% deviation is acceptable.

Malaysia, 2005-02-24

bioanalytical method validation19
Bioanalytical Method Validation

Precision

The closeness of replicate determinations of a sample by an assay. The acceptance criteria is  15% CV. At LOQ, 20% deviation is acceptable.

Malaysia, 2005-02-24

bioanalytical method validation20
Bioanalytical Method Validation

Sensitivity

The limit of quantitation (LOQ) is the lowest concentration which can be measured with acceptable accuracy and precision.

Malaysia, 2005-02-24

bioanalytical method validation21
Bioanalytical Method Validation

Specificity (selectivity)

Ability of the method to measure only what it is intended to measure in the presence of other components in the sample. Blank samples of the biological matrix should be tested for interfering peaks.

Malaysia, 2005-02-24

bioanalytical method validation22
Bioanalytical Method Validation

Recovery

The extraction efficiency of an analytical process, reported as a percentage of the known amount of an analyte carried through the sample extraction and processing steps of the method. Recovery does not have to be 100%, but the extent of recovery of an analyte and of the internal standard should be consistent.

Malaysia, 2005-02-24

bioanalytical method validation23
Bioanalytical Method Validation

Stability

Stability of the drug in the biological matrix during

the collection process,

the sample storage period and

sample analysis,

should be established.

Malaysia, 2005-02-24

bioanalytical method validation24
Bioanalytical Method Validation

Useful references:

FDA Guidance for Industry

  • Bioanalytical Method Validation (May 2001)(http://www.fda.gov/cder/guidance/4252fnl.pdf)

Published Workshop Reports

  • Shah, V.P. et al, Pharmaceutical Research: 1992; 9:588-592
  • Shah, V.P. et al, Pharmaceutical Research: 2000; 17: 1551-1557

Malaysia, 2005-02-24

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