Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability-Annex 6
Republication of Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability, WHO Technical Report Series, No. 992, Annex 7 with a new Appendix 2
Background
Following the publication of the Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability in 2015, it was noted that a text on equilibrium solubility experiments for the purpose of classification of active pharmaceutical ingredients (APIs) according to the Biopharmaceutics Classification System (BCS) would be a useful addition. The method for determination of equilibrium solubility was suggested to be added as an appendix to the above-mentioned guidelines.
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TABLE OF CONTENTS
3. Documentation of equivalence for marketing authorization
4. When equivalence studies are not necessary
5. When equivalence studies are necessary and types of study required
6. In vivo equivalence studies in humans
6.1.1 Provisions for studies in humans
6.1.2 Justification of human bioequivalence studies
6.1.3 Selection of investigators
7. Pharmacokinetic comparative bioavailability (bioequivalence) studies in humans
7.1 Design of pharmacokinetic studies
7.1.1 Alternative study designs for studies in patients
7.1.2 Considerations for active pharmaceutical ingredients with long elimination half-lives
7.1.3 Considerations for multiple-dose studies
7.1.4 Considerations for modified-release products
7.2.2 Drop-outs and withdrawals
7.2.3 Exclusion of subject data
7.2.5 Monitoring the health of subjects during the study
7.2.6 Considerations for genetic phenotyping
7.3.1 Multisource pharmaceutical product
7.3.2 Choice of comparator product
7.4.1.1 Non-linear pharmacokinetics
7.4.3 Co-administration of food and fluid with the dose
7.4.3.1 Immediate-release formulations
7.4.3.2 Modified-release formulations
7.4.6 Sample fluids and their collection
7.4.7 Parameters to be assessed
7.4.9 Measurement of individual enantiomers
7.5 Quantification of active pharmaceutical ingredient
7.6.1 Two-stage sequential design
7.9.1 Fixed-dose combination products
7.9.2 Clinically important variations in bioavailability
7.9.3 “Highly variable active pharmaceutical ingredients”
8. Pharmacodynamic equivalence studies
9. Clinical equivalence studies
10. In vitro equivalence testing
10.1 In vitro equivalence testing in the context of the Biopharmaceutics Classification System
10.1.1 Biopharmaceutics Classification System
10.1.2.1 Very rapidly dissolving
10.2 Qualification for a biowaiver based on the Biopharmaceutics Classification System
10.3 In vitro equivalence testing based on dose- proportionality of formulations
10.3.1 Proportional formulations
10.3.2 Qualification for biowaivers based on dose-proportionality of formulations
10.3.2.1 Immediate-release tablets
10.3.2.2 Delayed-release tablets and capsules
10.3.2.3 Extended-release tablets and capsules
10.3.3 Dissolution profile comparison for biowaivers based on dose-proportionality of formulations
10.4 In vitro equivalence testing for non-oral dosage forms
10.5 In vitro equivalence testing for scale-up and post-approval changes
Appendix 1 Recommendations for conducting and assessing comparative dissolution profiles
WHO TRS (Technical Report Series) 1003, 2017 Annex 6
