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TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE

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TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE & BIOEQUIVALENCE Validation of Analytical Methods Used For Bioequivalence Studies – PowerPoint PPT presentation

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Title: TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE


1
TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD
MANUFACTURING PRACTICE BIOEQUIVALENCE
  • Validation of Analytical Methods Used For
    Bioequivalence Studies
  • Presented by
  • John Gordon, Ph.D.
  • Consultant to WHO
  • e-mail john_gordon_at_hc-sc.gc.ca

2
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.

3
Bioanalytical Method Validation
  • Essential to use a well-characterised
  • and fully validated analytical method
  • to yield reliable results.

4
Development / Use of a Bioanalytical Method
  • Reference standard preparation
  • Method procedure development
  • Application of validated method to routine
    analysis

5
Reference Standards
  • Calibration standards / Quality control samples
  • Authenticated reference
  • Known identity
  • Known purity
  • Reference standard should be identical to
    analyte, if possible

6
Method Development
  • Chromatographic assays
  • e.g., gas chromatography, liquid chromatography
  • Ligand-binding assays
  • e.g., radioimmunoassay (RIA)

7
Bioanalytical Method Validation
  • Method Validation should include
  • Accuracy
  • Precision
  • Sensitivity
  • Specificity
  • Recovery
  • Stability

8
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.

9
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.

10
Bioanalytical Method Validation
  • Sensitivity
  • The limit of quantitation (LOQ) is the lowest
    concentration which can be measured with
    acceptable accuracy and precision.

11
Bioanalytical Method Validation
  • Calibration Curve
  • Sufficient number of calibration standards must
    be employed
  • Typically 6 8 non-zero standards
  • Blank sample
  • Zero sample
  • Lower Limit of Quantification (LLOQ)
  • Goodness of fit statistics

12
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.

13
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.

14
Bioanalytical Method Validation
  • Stability
  • Stability of the analyte in the biological matrix
  • Sample collection
  • Sample storage
  • Sample analysis

15
Bioanalytical Method Validation
  • Stability
  • Freeze-thaw stability
  • Short-term stability
  • Long-term stability
  • Post-preparation stability
  • Stock solution stability

16
Bioanalytical Method Validation
  • Dilution integrity
  • Confirm ability to dilute samples above Upper
    Limit of Quantitation (ULOQ)
  • Accuracy and precision

17
Bioanalytical Method Validation
  • Additional considerations for ligand-binding
    assays
  • Cross-reactivity
  • Matrix effects
  • Concentration-response relationship

18
Clinical Sample Analysis
  • Single determination of calibration standards
  • Calibration curve for each analytical run
  • Extrapolation below or above calibration range
    not acceptable

19
Clinical Sample Analysis
  • Quality control (QC)
  • At least three concentrations
  • Low concentration
  • Midrange concentration
  • High concentration
  • Duplicate determinations
  • 4 out of 6 QC samples must be ? 15 of nominal
    value two outside cannot be at the same
    concentration

20
Clinical Sample Analysis
  • Repeat sample analysis
  • Clear SOP and acceptance criteria
  • Reasons for re-analysis
  • Analytical issues
  • Problematic pharmacokinetic fit
  • Explanation for missing samples

21
Standard Operating Procedures
  • Complete written set of SOPs
  • Quality control and assurance
  • All aspects of analysis should be covered
    including
  • Record keeping
  • Security
  • Chain of sample custody
  • Sample preparation
  • Analytical tools
  • Procedures for quality control and verification
    of results

22
Full / Partial Validation
  • Full validation
  • During method development
  • Partial validation
  • Transfer between laboratories
  • Change in instrument / software
  • Change in anticoagulant
  • Minor changes in sample processing procedures

23
Bioanalytical Method Validation
  • Useful references
  • FDA Guidance for Industry
  • Bioanalytical Method Validation (May
    2001) (http//www.fda.gov/cder/guidance/4252fnl.pd
    f)
  • Published Workshop Reports
  • Shah, V.P. et al, Pharmaceutical Research 1992
    9588-592
  • Shah, V.P. et al, Pharmaceutical Research 2000
    17 1551-1557
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