WHO TRS (Technical Report Series) 1003, 2017 Annex 6

Sathyanarayana M.Sc.
0

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.


Click on the titles below for complete guidelines


TABLE OF CONTENTS


1. Introduction 

2. Glossary 

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 

5.1 In vivo studies 

5.2 In vitro studies 

6. In vivo equivalence studies in humans 

6.1 General considerations 

6.1.1 Provisions for studies in humans 

6.1.2 Justification of human bioequivalence studies 

6.1.3 Selection of investigators 

6.1.4 Study protocol

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 Subjects 

7.2.1 Number of subjects 

7.2.2 Drop-outs and withdrawals

7.2.3 Exclusion of subject data 

7.2.4 Selection of subjects

7.2.5 Monitoring the health of subjects during the study 

7.2.6 Considerations for genetic phenotyping 

7.3 Investigational product 

7.3.1 Multisource pharmaceutical product 

7.3.2 Choice of comparator product 

7.4 Study conduct 

7.4.1 Selection of strength 

7.4.1.1 Non-linear pharmacokinetics 

7.4.2 Study standardization 

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 

7.4.4 Wash-out interval 

7.4.5 Sampling times 

7.4.6 Sample fluids and their collection 

7.4.7 Parameters to be assessed 

7.4.8 Studies of metabolites

7.4.9 Measurement of individual enantiomers

7.5 Quantification of active pharmaceutical ingredient 

7.6 Statistical analysis 

7.6.1 Two-stage sequential design 

7.7 Acceptance ranges 

7.8 Reporting of results 

7.9 Special considerations 

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 

10.1.1.1 High solubility 

10.1.1.2 High permeability 

10.1.2 Determination of dissolution characteristics of multisource products in consideration of a biowaiver based on the Biopharmaceutics Classification System 

10.1.2.1 Very rapidly dissolving 

10.1.2.2 Rapidly dissolving 

10.2 Qualification for a biowaiver based on the Biopharmaceutics Classification System 

10.2.1 Dissolution criteria for biowaivers based on the Biopharmaceutics Classification System according to the properties of active pharmaceutical ingredients 

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 

References 

Appendix 1  Recommendations for conducting and assessing comparative dissolution profiles 

Appendix 2  Equilibrium solubility experiments for the purpose of classification of active pharmaceutical ingredients according to the biopharmaceutics classification system 


WHO TRS (Technical Report Series) 1003, 2017 Annex 6

Post a Comment

0Comments

Post a Comment (0)