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Guidance Requirement
For
Evaluation of
Similarity Factor (F2) Across
Global Regulatory Market
Vivek Singh Rathore
Research Scientist
R&D-Formulation
17013200
Jubilant Generics Pvt. Ltd.
INDEX
 1. Introduction
 2. Dissolution Profile Comparison
 3. Model Independent Approach Using a Similarity Factor
 4. Recommended f2 Harmonized Criteria
 5. Recommendation for Evaluation of Similarity Factor (F2)
for US Market
 6. Recommendation for Evaluation of Similarity Factor (F2)
for EU Market
 7. Similarities and Differences in Criteria for Exemptions
from f2 Comparisons
 8. Similarities and Differences in the Minimum Number of
Time Points Required for an f2 Calculation
 9. Similarities and Differences in Determination of the Last
Time Point for an f2 Calculation
 10. Similarities and Differences in Coefficient of Variation
Criteria
 11. References
1. INTRODUCTION
 DISSOLUTION PROFILE COMPARASION
 For major changes, a dissolution profile comparison
performed under identical conditions for the product
before and after the change(s) is recommended (see
SUPAC-IR).
 Dissolution profiles may be considered similar by virtue
of:
i. Overall profile similarity and
ii. Similarity at every dissolution sample time point.
 The dissolution profile comparison may be carried out
using model independent or model dependent methods.
2. DISSOLUTION PROFILE COMPARASION
DISSOLUTION PROFILE
COMPARASION
Model Independent
Approach Using a
Similarity Factor
Model Independent
Multivariate Confidence
Region Procedure
Model Dependent
Approaches
3. MODEL INDEPENDENT APPROACH
USING A SIMILARITY FACTOR
 A simple model independent approach uses a difference factor
(f1) and a similarity factor (f2) to compare dissolution profiles
(Moore 1996).
 Difference factor (f1): calculates the percent (%) difference
between the two curves at each time point and is a
measurement of the relative error between the two curves:
 Where n is the number of time points, Rt is the dissolution
value of the reference (prechange) batch at time t, and Tt is
the dissolution value of the test (postchange) batch at time t.
3. MODEL INDEPENDENT APPROACH
USING A SIMILARITY FACTOR
 Similarity factor (f2): is a logarithmic reciprocal square root
transformation of the sum of squared error and is a
measurement of the similarity in the percent (%) dissolution
between the two curves.:
3. MODEL INDEPENDENT APPROACH
USING A SIMILARITY FACTOR
 A specific procedure to determine difference and
similarity factors is as follows:
 Determine the dissolution profile of two products (12 units
each) of the test and reference products.
 Using the mean dissolution values from both curves at each
time interval, calculate the difference factor (f1) and similarity
factor (f2) using the above equations.
 For curves to be considered similar, f1 values should be close
to 0, and f2 values should be close to 100. Generally, f1
values up to 15 (0-15) and f2 values greater than 50 (50-
100) ensure sameness or equivalence of the two curves and
thus, of the performance of the test and reference products.
4. RECOMMENDED F2 HARMONIZED CRITERIA
Parameter Recommended criteria
Number of units
for test and
reference
12 unless otherwise justified
f2 value to claim
similarity
50–100
Criteria for f2
exemption
Where more than 85% of the drug is dissolved for both
test and reference products within 15 min, dissolution
profiles may be accepted as similar without further
mathematical evaluation.
Early time points For immediate-release products, early time points are
those that are less than or equal to 15 min. For modified-
release products, early time points should be based on
the shape of the profile (e.g., on the mean dissolution
results).
Number of time
points
At least five sampling time points must be selected to
characterize the dissolution profiles.Only two points
should be on the plateau of the curve and the other three
should be distributed between the ascending and
inflection portions of the profiles.
5. RECOMMENDATION FOR EVALUATION OF
SIMILARITY FACTOR (F2) FOR
US/CANADA/BRAZIL MARKET
 The dissolution measurements of the test and reference
batches should be made under exactly the same conditions.
 The dissolution time points for both the profiles should be the
same (e.g., 15, 30, 45, 60 minutes). The reference batch used
should be the most recently manufactured product.
 Only one measurement should be considered after
85% dissolution of both the products (Reference &
Test).
 To allow use of mean data, the percent coefficient of variation
at the earlier time points (e.g., 15 minutes) should not be
more than 20%, and at other time points should not be more
than 10%.
6. RECOMMENDATION FOR EVALUATION OF
SIMILARITY FACTOR (F2) FOR EU/AUS
MARKET
 A minimum of three time points (zero excluded).
 The time points should be the same for the two formulations
 Twelve individual values for every time point for each
formulation.
 Not more than one mean value of > 85%
dissolved for any of the formulations (Reference &
Test).
 The relative standard deviation or coefficient of variation of
any product should be less than 20% for the first point and
less than 10% from second to last time point.
7. SIMILARITIES AND DIFFERENCES IN CRITERIA
FOR EXEMPTIONS FROM F2 COMPARISONS
Country Criteria for f2 exemptions
United States, Europe,
Thailand, Russia, Turkey,
South Africa, China, South
Korea, Canada, Australia,
Mexico.
Where more than 85% of the drug is dissolved for
both test and reference products within 15 min,
dissolution profiles may be accepted as similar
without further mathematical evaluation.
Brazil It is necessary to prove the very rapid dissolution
products, by the curve graphic, performing
collections at, for example 5, 10, 15, 20, and 30
min.
The variation coefficient, at the 15-min point, may
not exceed 10%. If the reference comparator drug
presents mean dissolution of 85% in 30 min (rapid
dissolution), then the test drug must also present
rapid dissolution.
Japan Detail descriptions of the exemptions are provided
in the Japanese Guideline for Bioequivalence
Studies.
India Not provided in the guidance.
8. SIMILARITIES AND DIFFERENCES IN THE MINIMUM NUMBER
OF TIME POINTS REQUIRED FOR AN F2 CALCULATION
Country Minimum number of time points
China A minimum of three time points (zero excluded) until
drugs undergo more than 90% dissolution or reaches
dissolution platform.
Europe, Australia,
Russia, Turkey
A minimum of three time points (zero excluded).
South Africa, Thailand,
United States
A minimum of three time points
Canada Adequate sampling should be performed until either
90% of drug from the drug product is dissolved or an
asymptote is reached.
Brazil A minimum of five time points (zero excluded)
Mexico At least five sampling points. Only two points will be
on the plateau of the curve and the other three will be
distributed between the ascending stage and the
inflection stage.
To be continue…
8. SIMILARITIES AND DIFFERENCES IN THE MINIMUM NUMBER
OF TIME POINTS REQUIRED FOR AN F2 CALCULATION
Country Minimum number of time points
Japan •% Dissolution ≥85% in 15–30 min: three time points.
•% Dissolution is ≥85% at 120 min in pH 1.2 and 360 min in
other media: four time points.
•% Dissolution is 50–85% between 30 and 120 min in pH 1.2
and 30–360 min in other media: eight time points.
•% Disso <50% between 30 and 120 min in pH 1.2 and 30–360
min in other media: eight time points.
South Korea •If the mean dissolution rate of reference drug is NLT 85%
within 15~30 min: 15, 30, 45 min (three time points).
•If the mean dissolution rate of reference drug is not less than
85% after 30 min but within specified test time: Ta/4, 2Ta/4,
3Ta/4. Ta, where Ta is the time point when the mean dissolution
rate of reference drug is approx 85%.
•If the mean dissolution rate of reference drug is less than 85%
within the specified test time: Ta/4, 2Ta/4, 3Ta/4. Ta, where Ta
is the time point when the mean dissolution rate of reference
drug is approx 85% with the test time.
India Suitably spaced time points to provide a profile for each batch
(e.g., 10, 20, 30 min) to achieve virtually complete dissolution.
9. SIMILARITIES AND DIFFERENCES IN DETERMINATION
OF THE LAST TIME POINT FOR AN F2 CALCULATION
Country Last time point/Measurement to include in an f2
analysis
Japan The reference drug has reached 85% dissolution. Drug
substance percent dissolved at final time point (or first point of
plateau is acceptable)
Europe,
Australia,
Russia, Turkey
Any one of the reference or test product has reached 85%
dissolution (or asymptote is reached)
Thailand,
Brazil, United
States,
South Africa,
Canada
Only one measurement should be included after 85%
dissolution of the test and reference products.
China Drug dissolution is allowed to reach more than 90% only in one
time point
South Korea,
Mexico
The reference drug reached 85% dissolution
India Achieve virtually complete dissolution
10. SIMILARITIES AND DIFFERENCES IN
COEFFICIENT OF VARIATION CRITERIA
Country Coefficient of variation criteria
United States,
Canada,
South Africa,
Brazil*
The percent coefficient of variation at the earlier
time points should be not more than 20%, and at
other time points should be not more than 10%.
*For Brazil, the first 40% of time points are
considered “earlier time points”
Europe, Australia,
Russia, China,
Mexico, Turkey
The percent coefficient of variation at the first
time point should be not more than 20%, and at
other time points should be not more than 10%
South Korea The percent coefficient of variation should be not
more than 15% at all time points.
Thailand The percent coefficient of variation should be not
more than 10% from second to last time points
Japan The absolute difference of mean is applied in the
Japanese guidance
11. REFERENCES
 1. FDA Guidance for Industry Dissolution Testing of Immediate
Release Solid Oral Dosage Forms.
 2. European Medicines Agency. Committee for medicinal products
for human use. Guideline on the investigation of bioequivalence
 3. 15.2 Comparative dissolution profiles for biopharmaceutic studies
(TGA).
 4. Biopharmaceutics Classification System Based Biowaiver (Health
Canada).
 5. Health Canada. Drugs and Health Products. Post-Notice of
Compliance (NOC) Changes: Quality document. 2013; File Number
13-107786-650.
 6. National Health Surveillance Agency, Brazil. About the studies of
pharmaceutical equivalence and comparative dissolution profile.
Collegiate Directory. 2010 August; Resolution-RDC No. 31.
 7. China FDA Center for Drug Evaluation. Technical guidelines for
supplementary application of chemical drugs (The Second Draft).
2015 March.
 8. Central Drugs Standard Control Organization, Ministry of Health
and Family Welfare, Government of India. Guideline for bioavailability
and bioequivalence studies. 2005.
11. REFERENCES
 9. Pharmaceutical Food and Safety Bureau, Japan. Guideline for
Bioequivalence Studies of Oral Solid Formulations with Formulation
Changes. 2000 February; PMSB/ELD Notification Number 67,
Revised November 2006.
 10. Drug Control Division, Thailand. Guidelines for the Conduct of
Bioavailability and Bioequivalence Studies Adopted from “ASEAN
Guidelines for the Conduct of Bioavailability and Bioequivalence
Studies. 2009.
 11. Ministry of Health, Republic of Turkey. Pharmaceuticals and
pharmacy general directorate number B.10.0.IEG.0.10.00.03-
301.99 On Bioequivalence Files 24305.
 12. Medicines Control Council, Department of Health, Republic of
South Africa. Registration of Medicines: Dissolution. 2007 June;
Version 2.
 13. Korea Ministry of Food and Drug Safety. KFDA guidelines for
comparative dissolution test. 2010 June; KFDA Notification No.
2010-44.
 14. Dissolution Similarity Requirements: How Similar or Dissimilar
Are the Global Regulatory Expectations?

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Guidance requirement for evaluation of similarity factor (f2) across global regulatory market

  • 1. Guidance Requirement For Evaluation of Similarity Factor (F2) Across Global Regulatory Market Vivek Singh Rathore Research Scientist R&D-Formulation 17013200 Jubilant Generics Pvt. Ltd.
  • 2. INDEX  1. Introduction  2. Dissolution Profile Comparison  3. Model Independent Approach Using a Similarity Factor  4. Recommended f2 Harmonized Criteria  5. Recommendation for Evaluation of Similarity Factor (F2) for US Market  6. Recommendation for Evaluation of Similarity Factor (F2) for EU Market  7. Similarities and Differences in Criteria for Exemptions from f2 Comparisons  8. Similarities and Differences in the Minimum Number of Time Points Required for an f2 Calculation  9. Similarities and Differences in Determination of the Last Time Point for an f2 Calculation  10. Similarities and Differences in Coefficient of Variation Criteria  11. References
  • 3. 1. INTRODUCTION  DISSOLUTION PROFILE COMPARASION  For major changes, a dissolution profile comparison performed under identical conditions for the product before and after the change(s) is recommended (see SUPAC-IR).  Dissolution profiles may be considered similar by virtue of: i. Overall profile similarity and ii. Similarity at every dissolution sample time point.  The dissolution profile comparison may be carried out using model independent or model dependent methods.
  • 4. 2. DISSOLUTION PROFILE COMPARASION DISSOLUTION PROFILE COMPARASION Model Independent Approach Using a Similarity Factor Model Independent Multivariate Confidence Region Procedure Model Dependent Approaches
  • 5. 3. MODEL INDEPENDENT APPROACH USING A SIMILARITY FACTOR  A simple model independent approach uses a difference factor (f1) and a similarity factor (f2) to compare dissolution profiles (Moore 1996).  Difference factor (f1): calculates the percent (%) difference between the two curves at each time point and is a measurement of the relative error between the two curves:  Where n is the number of time points, Rt is the dissolution value of the reference (prechange) batch at time t, and Tt is the dissolution value of the test (postchange) batch at time t.
  • 6. 3. MODEL INDEPENDENT APPROACH USING A SIMILARITY FACTOR  Similarity factor (f2): is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) dissolution between the two curves.:
  • 7. 3. MODEL INDEPENDENT APPROACH USING A SIMILARITY FACTOR  A specific procedure to determine difference and similarity factors is as follows:  Determine the dissolution profile of two products (12 units each) of the test and reference products.  Using the mean dissolution values from both curves at each time interval, calculate the difference factor (f1) and similarity factor (f2) using the above equations.  For curves to be considered similar, f1 values should be close to 0, and f2 values should be close to 100. Generally, f1 values up to 15 (0-15) and f2 values greater than 50 (50- 100) ensure sameness or equivalence of the two curves and thus, of the performance of the test and reference products.
  • 8. 4. RECOMMENDED F2 HARMONIZED CRITERIA Parameter Recommended criteria Number of units for test and reference 12 unless otherwise justified f2 value to claim similarity 50–100 Criteria for f2 exemption Where more than 85% of the drug is dissolved for both test and reference products within 15 min, dissolution profiles may be accepted as similar without further mathematical evaluation. Early time points For immediate-release products, early time points are those that are less than or equal to 15 min. For modified- release products, early time points should be based on the shape of the profile (e.g., on the mean dissolution results). Number of time points At least five sampling time points must be selected to characterize the dissolution profiles.Only two points should be on the plateau of the curve and the other three should be distributed between the ascending and inflection portions of the profiles.
  • 9. 5. RECOMMENDATION FOR EVALUATION OF SIMILARITY FACTOR (F2) FOR US/CANADA/BRAZIL MARKET  The dissolution measurements of the test and reference batches should be made under exactly the same conditions.  The dissolution time points for both the profiles should be the same (e.g., 15, 30, 45, 60 minutes). The reference batch used should be the most recently manufactured product.  Only one measurement should be considered after 85% dissolution of both the products (Reference & Test).  To allow use of mean data, the percent coefficient of variation at the earlier time points (e.g., 15 minutes) should not be more than 20%, and at other time points should not be more than 10%.
  • 10. 6. RECOMMENDATION FOR EVALUATION OF SIMILARITY FACTOR (F2) FOR EU/AUS MARKET  A minimum of three time points (zero excluded).  The time points should be the same for the two formulations  Twelve individual values for every time point for each formulation.  Not more than one mean value of > 85% dissolved for any of the formulations (Reference & Test).  The relative standard deviation or coefficient of variation of any product should be less than 20% for the first point and less than 10% from second to last time point.
  • 11. 7. SIMILARITIES AND DIFFERENCES IN CRITERIA FOR EXEMPTIONS FROM F2 COMPARISONS Country Criteria for f2 exemptions United States, Europe, Thailand, Russia, Turkey, South Africa, China, South Korea, Canada, Australia, Mexico. Where more than 85% of the drug is dissolved for both test and reference products within 15 min, dissolution profiles may be accepted as similar without further mathematical evaluation. Brazil It is necessary to prove the very rapid dissolution products, by the curve graphic, performing collections at, for example 5, 10, 15, 20, and 30 min. The variation coefficient, at the 15-min point, may not exceed 10%. If the reference comparator drug presents mean dissolution of 85% in 30 min (rapid dissolution), then the test drug must also present rapid dissolution. Japan Detail descriptions of the exemptions are provided in the Japanese Guideline for Bioequivalence Studies. India Not provided in the guidance.
  • 12. 8. SIMILARITIES AND DIFFERENCES IN THE MINIMUM NUMBER OF TIME POINTS REQUIRED FOR AN F2 CALCULATION Country Minimum number of time points China A minimum of three time points (zero excluded) until drugs undergo more than 90% dissolution or reaches dissolution platform. Europe, Australia, Russia, Turkey A minimum of three time points (zero excluded). South Africa, Thailand, United States A minimum of three time points Canada Adequate sampling should be performed until either 90% of drug from the drug product is dissolved or an asymptote is reached. Brazil A minimum of five time points (zero excluded) Mexico At least five sampling points. Only two points will be on the plateau of the curve and the other three will be distributed between the ascending stage and the inflection stage. To be continue…
  • 13. 8. SIMILARITIES AND DIFFERENCES IN THE MINIMUM NUMBER OF TIME POINTS REQUIRED FOR AN F2 CALCULATION Country Minimum number of time points Japan •% Dissolution ≥85% in 15–30 min: three time points. •% Dissolution is ≥85% at 120 min in pH 1.2 and 360 min in other media: four time points. •% Dissolution is 50–85% between 30 and 120 min in pH 1.2 and 30–360 min in other media: eight time points. •% Disso <50% between 30 and 120 min in pH 1.2 and 30–360 min in other media: eight time points. South Korea •If the mean dissolution rate of reference drug is NLT 85% within 15~30 min: 15, 30, 45 min (three time points). •If the mean dissolution rate of reference drug is not less than 85% after 30 min but within specified test time: Ta/4, 2Ta/4, 3Ta/4. Ta, where Ta is the time point when the mean dissolution rate of reference drug is approx 85%. •If the mean dissolution rate of reference drug is less than 85% within the specified test time: Ta/4, 2Ta/4, 3Ta/4. Ta, where Ta is the time point when the mean dissolution rate of reference drug is approx 85% with the test time. India Suitably spaced time points to provide a profile for each batch (e.g., 10, 20, 30 min) to achieve virtually complete dissolution.
  • 14. 9. SIMILARITIES AND DIFFERENCES IN DETERMINATION OF THE LAST TIME POINT FOR AN F2 CALCULATION Country Last time point/Measurement to include in an f2 analysis Japan The reference drug has reached 85% dissolution. Drug substance percent dissolved at final time point (or first point of plateau is acceptable) Europe, Australia, Russia, Turkey Any one of the reference or test product has reached 85% dissolution (or asymptote is reached) Thailand, Brazil, United States, South Africa, Canada Only one measurement should be included after 85% dissolution of the test and reference products. China Drug dissolution is allowed to reach more than 90% only in one time point South Korea, Mexico The reference drug reached 85% dissolution India Achieve virtually complete dissolution
  • 15. 10. SIMILARITIES AND DIFFERENCES IN COEFFICIENT OF VARIATION CRITERIA Country Coefficient of variation criteria United States, Canada, South Africa, Brazil* The percent coefficient of variation at the earlier time points should be not more than 20%, and at other time points should be not more than 10%. *For Brazil, the first 40% of time points are considered “earlier time points” Europe, Australia, Russia, China, Mexico, Turkey The percent coefficient of variation at the first time point should be not more than 20%, and at other time points should be not more than 10% South Korea The percent coefficient of variation should be not more than 15% at all time points. Thailand The percent coefficient of variation should be not more than 10% from second to last time points Japan The absolute difference of mean is applied in the Japanese guidance
  • 16. 11. REFERENCES  1. FDA Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms.  2. European Medicines Agency. Committee for medicinal products for human use. Guideline on the investigation of bioequivalence  3. 15.2 Comparative dissolution profiles for biopharmaceutic studies (TGA).  4. Biopharmaceutics Classification System Based Biowaiver (Health Canada).  5. Health Canada. Drugs and Health Products. Post-Notice of Compliance (NOC) Changes: Quality document. 2013; File Number 13-107786-650.  6. National Health Surveillance Agency, Brazil. About the studies of pharmaceutical equivalence and comparative dissolution profile. Collegiate Directory. 2010 August; Resolution-RDC No. 31.  7. China FDA Center for Drug Evaluation. Technical guidelines for supplementary application of chemical drugs (The Second Draft). 2015 March.  8. Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, Government of India. Guideline for bioavailability and bioequivalence studies. 2005.
  • 17. 11. REFERENCES  9. Pharmaceutical Food and Safety Bureau, Japan. Guideline for Bioequivalence Studies of Oral Solid Formulations with Formulation Changes. 2000 February; PMSB/ELD Notification Number 67, Revised November 2006.  10. Drug Control Division, Thailand. Guidelines for the Conduct of Bioavailability and Bioequivalence Studies Adopted from “ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies. 2009.  11. Ministry of Health, Republic of Turkey. Pharmaceuticals and pharmacy general directorate number B.10.0.IEG.0.10.00.03- 301.99 On Bioequivalence Files 24305.  12. Medicines Control Council, Department of Health, Republic of South Africa. Registration of Medicines: Dissolution. 2007 June; Version 2.  13. Korea Ministry of Food and Drug Safety. KFDA guidelines for comparative dissolution test. 2010 June; KFDA Notification No. 2010-44.  14. Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations?