WHO TRS (Technical Report Series) 996, 2016 Annex 9

Sathyanarayana M.Sc.

WHO TRS (Technical Report Series) 996, 2016 Annex 9

Guidance for organizations performing in vivo bioequivalence studies


During an informal consultation held in 2014, and at the forty-ninth meeting of the World Health Organization (WHO) Expert Committee on Specifications for Pharmaceutical Preparations, discussion took place regarding the possible revision of the guidance for organizations performing in vivo bioequivalence studies (WHO Technical Report Series, No. 937, Annex 9, 2006). The WHO Expert Committee on Specifications for Pharmaceutical Preparations agreed that in light of the new developments a draft for revision would be prepared.

These new guidelines take into consideration the revision of the multisource guidelines, as well as the creation of new guidance on good data management. The revision will also take into account the experience accumulated in the area of assessing and inspecting bioequivalence (BE) studies since 2006. In areas where the same problems are repeatedly identified by inspectors, the new guidelines provide clarifications, and supplementary details have been added on bioanalysis. The guidelines also put increased emphasis on subject safety and data integrity.

Based on the first working document: this second version incorporates the numerous comments and the feedback received from the public consultation, the WHO Prequalification Team (PQT) and from the Consultation on data management, bioequivalence, GMP and medicines’ inspection held in 2015.

WHO/PQT was set up in 2001 to assure that medicinal products supplied for procurement meet WHO norms and standards with respect to quality, safety and efficacy (http://www.who.int/prequal/). Specifically, there is a requirement that the submitted product dossier with all its necessary contents is assessed and found acceptable, and that the manufacturing sites for the finished pharmaceutical product (FPP), as well as the active pharmaceutical ingredient (API), are inspected and found to comply with WHO good manufacturing practices (GMP). 

Since products submitted to WHO/PQT are usually multisource (generic) products, therapeutic equivalence is generally demonstrated by performing a BE study, for example in a contract research organization (also known as a clinical research organization)(CRO). For prequalification of such a product it is vital that, in addition to the above-mentioned requirements, the CRO used by the sponsor for BE studies complies with WHO good clinical practices (GCP) and considers relevant elements from WHO good laboratory practices (GLP) and good practices for quality control (QC) laboratories to ensure integrity and traceability of data. 

In addition, if local legal provisions exist, CROs should be licensed by the respective national medicines authority. Where required by national regulations, BE studies should be authorized by the national regulatory authority. Those involved in the conduct and analysis of BE studies on products to be submitted for prequalification therefore need to ensure that they comply with the relevant WHO norms and standards so that they can be prepared for any inspections by WHO.

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Table of contents 


1. Scope 

2. Glossary 


3. Organization and management 

4. Computer systems

5. Quality management 

6. Archive facilities 

7. Premises 

8. Personnel 


9. Clinical phase 

10. Clinical laboratory 

11. Ethics

12. Monitoring 

13. Investigators

14. Receiving, storage and handling of investigational products 

15. Case report forms 

16. Volunteers and recruitment methods 

17. Food and fluids 

18. Safety, adverse events and adverse event reporting


19. Method development 

20. Method validation

21. Sample collection, storage and handling of biological material

22. Analysis of study samples

23. Data processing and documentation

24. Good laboratory practices


25. Pharmacokinetic and statistical calculations 

26. Study report 


Appendix 1 Example list of standard operating procedures at a contract research organization

WHO TRS (Technical Report Series) 996, 2016 Annex 9:


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