Call Girls Ludhiana Just Call 9907093804 Top Class Call Girl Service Available
New WHO Guidance on Analytical Method Validation
1. This presentation is compiled by “ Drug Regulations”
a non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
2. This presentation is compiled from freely available resource
like the website of WHO specifically WHO Draft Guidance
Titled
GUIDELINES ON VALIDATION – APPENDIX 4 ANALYTICAL
METHOD VALIDATION
“Drug Regulations” is a non profit organization which
provides free online resource to the Pharmaceutical
Professional.
Visit Our Website GMP Training
for latest information from the world of Pharmaceuticals.
04-09-2016 2
Visit Our WEBSITE GMP Training
http://fdagmp.blogspot.in/
3. This presentation is based on WHO
Draft Guidance titled
GUIDELINES ON VALIDATION –
APPENDIX 4 ANALYTICAL METHOD
VALIDATION
04-09-2016 3Visit Our Website GMP Training
4. The need for revision of earlier
Supplementary guidelines on good
manufacturing practices: validation was
identified by the Prequalification of Medicines
Programme
A draft document was circulated for comment
in early 2013.
04-09-2016 4Visit Our Website GMP Training
5. The focus of the revision was the Appendix on non-
sterile process validation (Appendix 7), which had been
revised and was adopted by the Committee at its forty-
ninth meeting in October 2014.
◦ See our presentation here
Modified Appendix 4 on Analytical Method Validation is
now published in working document QAS/16.671.
04-09-2016 5Visit Our Website GMP Training
6. This guidance covers following
◦ Principle
◦ General
◦ Pharmacopoeial Methods
◦ Non Pharmacopoeial Methods
◦ Method Validation
◦ Method Verification
◦ Method Transfer
◦ Revalidation
◦ Characteristics of Analytical Methods
04-09-2016 6Visit Our Website GMP Training
7. This guidance presents information on
the characteristics that should be
considered during Analytical method
Validation.
04-09-2016 7Visit Our Website GMP Training
8. Approaches other than that specified in
this guidance can be adopted.
Manufacturers should choose validation
protocols and and procedures most
suitable for testing their products.
04-09-2016 8Visit Our Website GMP Training
9. It is essential to demonstrate that the
Analytical Procedure is suitable for
intended use.
All analytical methods should be
validated.
◦ Whether they are stability indicating or not
04-09-2016 9Visit Our Website GMP Training
10. Validation of Analytical method should be performed by
the R & D
There after the method can be transferred to Quality
Control.
Follow recommendations provided in Good Laboratory
practices guidance
Also follow the recommendations given in Transfer of
Technology Guidance.
04-09-2016 10Visit Our Website GMP Training
11. Have specifications for both materials
and products.
The tests to be performed should be
described in the documentation on
Standard Test Methods.
04-09-2016 11Visit Our Website GMP Training
12. Pharmacopeial or Non Pharmacopeial
Methods May be Used.
Well Characterized reference materials
with documented purity should be
used in analysis.
04-09-2016 12Visit Our Website GMP Training
13. Most common Analytical procedures Include
◦ Identification Tests
◦ Assay of Drug Substance
◦ Assay of Pharmaceutical Products
◦ Quantitative tests for content of Uniformities
◦ Limit Test for Impurities
◦ Dissolution Testing
◦ Determination of Particle Size.
04-09-2016 13Visit Our Website GMP Training
14. The Results of Analytical Procedures should be
◦ Legible
◦ Contemporaneous
◦ Original
◦ Reliable
◦ Reproducible
All Results should be archived for an appropriate period of
time.
They should be in compliance with NRA requirements
04-09-2016 14Visit Our Website GMP Training
15. The procedure should become part of
a continuous verification procedure
Demonstrate that it meets predefined
criteria over the life of the procedure.
04-09-2016 15Visit Our Website GMP Training
16. Perform following at intervals to
ensure that the method is appropriate
for its intended use.
◦ Trend Analysis
◦ Risk Assessment
04-09-2016 16Visit Our Website GMP Training
17. Manage changes to methods as per COC procedure
Consider following when methods are transferred from
one lab to another or when major pieces of analytical
equipment are changed:
◦ Variability of Reference materials.
◦ Changes in process of synthesis
◦ Changes in composition of the finished product
◦ Changes in Analytical Procedure
04-09-2016 17Visit Our Website GMP Training
18. The changes referred earlier should be
◦ Understood
◦ Controlled
◦ Where possible reduced.
Consider Verification or Revalidation
04-09-2016 18Visit Our Website GMP Training
19. Perform risk assessment for such
changes
Scope of verification & degree of
revalidation depend on
◦ Nature of changes
◦ Out come of risk assessment
04-09-2016 19Visit Our Website GMP Training
20. Analyst should be appropriately qualified.
Qualification should be documented
For certain tests conduct “Analyst Proficiency”
Data for method validation and verification should be covered
by GxP
Follow good data and record management.
Associated metadata should also be retained and be
subjected to good data and record management practices.
04-09-2016 20Visit Our Website GMP Training
21. Use of computerized systems should comply with
the principles given in Guidance for Computerized
Systems Validation.
Pay Adequate attention to sample preparation.
This step should be described in as much detail as
possible.
04-09-2016 21Visit Our Website GMP Training
22. Attention should be paid to factors such as :
◦ Sonification Time
◦ Sonification Bath Temperature
◦ Mixing
◦ Demixing where such is known to happen
04-09-2016 22Visit Our Website GMP Training
23. Document & report all failures during method validation.
Also document how these failures were overcome
It is not acceptable to give only passing results.
This will give biased information about reliability of the
method.
04-09-2016 23Visit Our Website GMP Training
24. When such method are used there should be evidence that such
methods are suitable for routine laboratory use.
i.e. The methods should be verified.
When such methods are used for determination of content or
impurities , the specificity of the methods should be demonstrated.
i.e. Specificity with respect to the substance under consideration –
no placebo interference.
04-09-2016 24Visit Our Website GMP Training
25. All Non Pharmacopoeial Methods should be
appropriately validated.
04-09-2016 25Visit Our Website GMP Training
26. Perform validation as per a protocol.
Protocol should include procedure and acceptance criteria for all
characteristics.
Results should be documented in the validation report.
Justification should be provided if Non Pharmacopoeial methods are
used when Pharmacopoeial are available.
Justification should include data for comparison with Pharmacopoeil
and other methods.
04-09-2016 26Visit Our Website GMP Training
27. Standard Test methods should be described in details.
They should provide sufficient information to allow a properly
trained analyst to perform analysis in reliable manner.
As a minimum, the description should include
chromatographic conditions, reagent needed, reference
standards, formulae for calculation of results and system
suitability tests.
04-09-2016 27Visit Our Website GMP Training
28. Method verification consists of partial velidation.
It should be performed for a validated method under following
conditions:
◦ When an already validated method is used on a product for the first time.
Change of active ingredient supplier, change in method of synthesis,
reformulation of a drug product
◦ When an already validated method is used in a laboratory for the first
time.
In some cases method transfer may be preferred.
04-09-2016 28Visit Our Website GMP Training
29. May include only the validation characteristics of relevance to
the particular change.
◦ In case of change in API supplier the expected change would be
impurity profile or solubility of the API.
◦ Therefore for an Related substances method there should be an
appropriate verification that the method is able to detect and
quantitate all potential impurities including the late eluting ones.
◦ Specificity should be amongst the tests considered.
04-09-2016 29Visit Our Website GMP Training
30. Method Verification is suitable
in lieu of method validation for
Pharmacopoeial methods.
04-09-2016 30Visit Our Website GMP Training
31. Methods should be maintained in validated state over the
life of the method.
Perform Revalidation when there are following changes:
◦ Changes to the Mobile Phase( Refer Pharmacopoeias for acceptance limits
beyond which revalidation must be performed.
◦ Changes to the column
◦ Changes to the temperature of the column
◦ Changes to the concentration/composition of the sample and standards
04-09-2016 31Visit Our Website GMP Training
32. Perform Revalidation when
there are following changes:
◦ Changes to the detector
Change in detector type
Wavelength of detection
04-09-2016 32Visit Our Website GMP Training
33. Perform Revalidation when there are
following changes:
◦ In cases of repeated system suitability failures
◦ In case of doubtful results
◦ In such cases perform an investigation to determine root
cause.
◦ Then make appropriate changes and revalidate the methods
04-09-2016 33Visit Our Website GMP Training
34. Perform revalidation according to a
period that is scientifically justifiable.
It is acceptable to include only the
validation characteristics of relevance to
the particular change and methods
04-09-2016 34Visit Our Website GMP Training
35. Establish Documented evidence that
◦ a method has equivalence performance
when used in a laboratory different from
that where it was originally validated.
04-09-2016 35Visit Our Website GMP Training
36. Generally it should be performed
◦ By comparing a set of results obtained by
an analyst in one laboratory
◦ to that obtained by another analyst at
the laboratory to which the method is
being transferred.
04-09-2016 36Visit Our Website GMP Training
37. Two set of results should be
statistically compared
The differences between the two
sets of test results should be
within an acceptable range.
04-09-2016 37Visit Our Website GMP Training
38. Method transfer should be performed before
testing of samples for obtaining critical data.
◦ For Dossier
◦ Process Validation
◦ Stability Studies
◦ For Routine use
04-09-2016 38Visit Our Website GMP Training
39. Follow a predetermined protocol which should include:
◦ A title
◦ Objective
◦ Scope
◦ Responsibilities of the sending unit & the receiving unit
◦ A specification of materials and methods
◦ Experimental design
◦ Acceptance criteria
04-09-2016 39Visit Our Website GMP Training
40. Follow a predetermined protocol which should include:
◦ Documentation: Information to be supplied with results, forms
etc.
◦ Deviation handling procedure
◦ References
◦ Details of Reference samples, starting materials, intermediates
and finished products
Protocol should be authorized and dated
04-09-2016 40Visit Our Website GMP Training
41. Independent Testing by a separate entity: National Quality
Control Testing Laboratory.
This may not be considered an obligation.
This may be considered an optional step when
encountering difficulties in applying a particular method.
◦ Refer WHO Guidance on technology Transfer
(See our Presentation)
04-09-2016 41Visit Our Website GMP Training
42. Consider following Characteristics while validation:
◦ Specificity
◦ Linearity
◦ Range
◦ Accuracy
◦ Precision
◦ Detection Limit
◦ Quantitation Limit
◦ Robustness
04-09-2016 42Visit Our Website GMP Training
43. Accuracy
◦ Degree of agreement of Test Results with the True Value
◦ Closeness of the results obtained by the procedure to the true
value.
◦ Generally established on samples of the material to be
examined that have been prepared to quantitative accuracy.
◦ Should be established across the range specified for the
analytical procedure.
04-09-2016 43Visit Our Website GMP Training
44. Accuracy
◦ Acceptable to use a spiked placebo
where a known quantity or
concentration of a reference material
is used.
04-09-2016 44Visit Our Website GMP Training
45. Precision
◦ Degree of agreement among individual results.
◦ Apply complete procedure repeatedly to separate
identical samples drawn from the same homogenous
batch of materials.
◦ Measured by the scatter of individual results from the
mean.
◦ Expressed as the Relative Standard Deviation-RSD
04-09-2016 45Visit Our Website GMP Training
46. Repeatability
◦ Determine using a minimum of nine
determinations covering the specified range for
the procedure.
◦ Three concentration/three replicates each or
◦ A minimum of six determinations at 100 % of the
test concentrations.
04-09-2016 46Visit Our Website GMP Training
47. Intermediate Precision
◦ This expresses within laboratory variations
Different days
Different analysts
Different equipment
◦ If reproducibility is assessed , a measure of
intermediate precision is not required.
04-09-2016 47Visit Our Website GMP Training
49. Robustness( or Ruggedness)
◦ Ability of the procedure to provide
analytical results of acceptable accuracy
and precision under a variety of
conditions.
04-09-2016 49Visit Our Website GMP Training
50. Robustness( or Ruggedness)
◦ Results from separate samples are influenced by
changes in the operational or environmental
conditions.
◦ Robustness should be considered during the
development phase
◦ Should show the reliability of an analysis when
deliberate variations are made in method parameters.
04-09-2016 50Visit Our Website GMP Training
51. Robustness( or Ruggedness)
◦ Verification of stability of analytical solutions is of importance.
◦ Other characteristics of robustness should include extraction
time.
◦ In case of Liquid chromatography robustness testing may also
include
Verification of the impact of changes in pH, temperature and
flow rate.
04-09-2016 51Visit Our Website GMP Training
52. ◦ Factors that can have an effect on robustness when performing
chromatographic analysis include:
Stability of standard & test solutions
Reagents
Different columns-different lots/suppliers
Extraction time
Variations of pH of mobile phase
Variations in mobile phase compositions
Temperature
Flow Rate
04-09-2016 52Visit Our Website GMP Training
53. Linearity
◦ Indicates ability to produce results that are directly
proportional to the concentration of the solution.
◦ Use samples in which the analyte concentrations span
the claimed range of the procedure.
◦ In case of a linear relationship use appropriate
statistical test to show linearity.
◦ A minimum of 5 concentrations should be used.
04-09-2016 53Visit Our Website GMP Training
54. Range
◦ Expression of the lowest and highest level
of analyte that have been demonstrated to
determinable for the product.
◦ Specified range is normally derived form
linearity study.
04-09-2016 54Visit Our Website GMP Training
55. Specificity ( selectivity)
◦ Ability to measure unequivocally the desired analyte
in the presence of components such as excipients and
impurities that may also be expected to be present.
◦ An investigation of specificity should be performed
during the validation of identification tests, the
determination of impurities and assay.
04-09-2016 55Visit Our Website GMP Training
56. Detection Limit ( Limit of Detection)
◦ Smallest quantity of analyte that can be detected and not necessarily
determined in a quantitative fashion.
◦ Approaches may include instrumental or non-instrumental procedures
◦ Could include those based on
Visual evaluation
Signal to noise
Standard deviation of the response and the slope
Standard deviation of the blank
Calibration curve
04-09-2016 56Visit Our Website GMP Training
57. Quantitation Limit ( Limit of Quantitation)
◦ Lowest concentration in a sample that may be determined with acceptable
accuracy and precision.
◦ Approaches may include instrumental or non instrumental procedures
◦ Could include those based on
Visual evaluation
Signal to noise
Standard deviation of the response and the slope
Standard deviation of the blank
Calibration curve
04-09-2016 57Visit Our Website GMP Training
59. Use appropriate statistical analysis to
evaluate validation characteristic against
predetermined acceptance criteria.
Use appropriately validated software
Consider appropriate number of samples to
provide adequate statistical power and range.
04-09-2016 59Visit Our Website GMP Training
60. Integral part of analytical testing procedure.
Tests are based on the concept that the
equipment, electronics, analytical operations
and samples to be analyzed constitute an
integral system that can be evaluated as such.
04-09-2016 60Visit Our Website GMP Training
61. SS parameters that need to be
established for a particular
procedure depend on the
◦ Type of procedure being evaluated
04-09-2016 61Visit Our Website GMP Training
62. Suitability of the entire system
should be confirmed prior to and
during method validation tests.
Similarly this should be done
during sample analysis.
04-09-2016 62Visit Our Website GMP Training
63. SS runs should include only established
standards or reference material of known
concentrations.
This provides appropriate comparator for
the potential variability of the
instrument.
04-09-2016 63Visit Our Website GMP Training
64. When a sample is used for system
suitability written procedures should be
established.
Results of all such trial runs should be
included in the results and data review
process.
04-09-2016 64Visit Our Website GMP Training
65. A sample can be used only if it is well
characterized material.
Characterization in such cases should
be performed prior to the use of this
sample as part of SS testing.
04-09-2016 65Visit Our Website GMP Training
66. The sample material or product under
test should not be used for trial run
purposes or to evaluate the SS.
Refer WHO guidelines on data and
record management.
◦ See our presentation here.
04-09-2016 66Visit Our Website GMP Training
67. This presentation is compiled from freely available resource
like the website of WHO specifically WHO Draft Guidance
Titled
GUIDELINES ON VALIDATION – APPENDIX 4 ANALYTICAL
METHOD VALIDATION
“Drug Regulations” is a non profit organization which
provides free online resource to the Pharmaceutical
Professional.
Visit Our Website GMP Training
for latest information from the world of Pharmaceuticals.
04-09-2016 67
Visit Our WEBSITE GMP Training
http://fdagmp.blogspot.in/