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

This document provides guidance on evaluating the similarity factor (F2) across global regulatory markets. It discusses the model independent approach using F2 to compare dissolution profiles, with recommended F2 criteria of 50-100 indicating similarity. There are some variations in criteria for exemptions from F2 comparisons, minimum time points required, when to end comparisons, and coefficient of variation thresholds across different countries. Overall the guidelines aim to harmonize F2 evaluation globally while accounting for some regional regulatory differences.

Health & Medicineā—¦
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 ļ‚— 1. Introduction ļ‚— 2. Dissolution Profile Comparison ļ‚— 3. Model Independent Approach Using a Similarity Factor ļ‚— 4. Recommended f2 Harmonized Criteria ļ‚— 5. Recommendation for Evaluation of Similarity Factor (F2) for US Market ļ‚— 6. Recommendation for Evaluation of Similarity Factor (F2) for EU Market ļ‚— 7. Similarities and Differences in Criteria for Exemptions from f2 Comparisons ļ‚— 8. Similarities and Differences in the Minimum Number of Time Points Required for an f2 Calculation ļ‚— 9. Similarities and Differences in Determination of the Last Time Point for an f2 Calculation ļ‚— 10. Similarities and Differences in Coefficient of Variation Criteria ļ‚— 11. References
1. INTRODUCTION ļ‚— DISSOLUTION PROFILE COMPARASION ļ‚— 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). ļ‚— Dissolution profiles may be considered similar by virtue of: i. Overall profile similarity and ii. Similarity at every dissolution sample time point. ļ‚— 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 ļ‚— A simple model independent approach uses a difference factor (f1) and a similarity factor (f2) to compare dissolution profiles (Moore 1996). ļ‚— 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: ļ‚— 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 ļ‚— 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 ļ‚— A specific procedure to determine difference and similarity factors is as follows: ļ‚— Determine the dissolution profile of two products (12 units each) of the test and reference products. ļ‚— 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. ļ‚— 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 50ā€“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 ļ‚— The dissolution measurements of the test and reference batches should be made under exactly the same conditions. ļ‚— 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. ļ‚— Only one measurement should be considered after 85% dissolution of both the products (Reference & Test). ļ‚— 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 ļ‚— A minimum of three time points (zero excluded). ļ‚— The time points should be the same for the two formulations ļ‚— Twelve individual values for every time point for each formulation. ļ‚— Not more than one mean value of > 85% dissolved for any of the formulations (Reference & Test). ļ‚— 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 continueā€¦
8. SIMILARITIES AND DIFFERENCES IN THE MINIMUM NUMBER OF TIME POINTS REQUIRED FOR AN F2 CALCULATION Country Minimum number of time points Japan ā€¢% Dissolution ā‰„85% in 15ā€“30 min: three time points. ā€¢% Dissolution is ā‰„85% at 120 min in pH 1.2 and 360 min in other media: four time points. ā€¢% Dissolution is 50ā€“85% between 30 and 120 min in pH 1.2 and 30ā€“360 min in other media: eight time points. ā€¢% Disso <50% between 30 and 120 min in pH 1.2 and 30ā€“360 min in other media: eight time points. South Korea ā€¢If the mean dissolution rate of reference drug is NLT 85% within 15~30 min: 15, 30, 45 min (three time points). ā€¢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%. ā€¢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 ā€œearlier time pointsā€ 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 ļ‚— 1. FDA Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms. ļ‚— 2. European Medicines Agency. Committee for medicinal products for human use. Guideline on the investigation of bioequivalence ļ‚— 3. 15.2 Comparative dissolution profiles for biopharmaceutic studies (TGA). ļ‚— 4. Biopharmaceutics Classification System Based Biowaiver (Health Canada). ļ‚— 5. Health Canada. Drugs and Health Products. Post-Notice of Compliance (NOC) Changes: Quality document. 2013; File Number 13-107786-650. ļ‚— 6. National Health Surveillance Agency, Brazil. About the studies of pharmaceutical equivalence and comparative dissolution profile. Collegiate Directory. 2010 August; Resolution-RDC No. 31. ļ‚— 7. China FDA Center for Drug Evaluation. Technical guidelines for supplementary application of chemical drugs (The Second Draft). 2015 March. ļ‚— 8. Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, Government of India. Guideline for bioavailability and bioequivalence studies. 2005.
11. REFERENCES ļ‚— 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. ļ‚— 10. Drug Control Division, Thailand. Guidelines for the Conduct of Bioavailability and Bioequivalence Studies Adopted from ā€œASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies. 2009. ļ‚— 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. ļ‚— 12. Medicines Control Council, Department of Health, Republic of South Africa. Registration of Medicines: Dissolution. 2007 June; Version 2. ļ‚— 13. Korea Ministry of Food and Drug Safety. KFDA guidelines for comparative dissolution test. 2010 June; KFDA Notification No. 2010-44. ļ‚— 14. Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations?