The New EMA Bioequivalence Guideline: Key Considerations

Aug 01, 2010

A new guideline1 for conducting bioequivalence studies was adopted by the Committee for Proprietary Medicinal Products (CPMP) in January this year and it becomes fully effective as of 1 August 2010. The guideline (CPMP/QWP/EWP/1401/98 Rev. 1), which specifies the requirements for the design, conduct and evaluation of bioequivalence studies for immediate release dosage forms incorporating APIs with systemic action, will replace the "Note for guidance on the investigation of bioavailability and bioequivalence" (CPMP/QWP/EWP/1401/98) and the related Q&A document (CHMP/EWP/40326/06 ).

The Biopharmaceutics and Pharmacokinetics Focus Group of the International Association for Pharmaceutical Technology (APV), among other organisations, had the opportunity to comment on the Draft version of the guidance,2 thus leading to this final version.

Overall, key changes have been made to the design and conduct of bioequivalence studies, the application of statistical acceptance criteria and the biowaiver options available in order to replace in vivo bioequivalence trials by in vitro studies.

Important changes

The question of how to demonstrate and evaluate bioequivalence for drug products is of importance to both innovator and generic drug companies. While previously an in vivo bioequivalence study in humans was required by regulatory bodies to demonstrate bioequivalence, today several alternatives (biowaivers) have been developed to avoid these time consuming and costly studies.

As a result of these modified requirements, APV organised a seminar on 14 June 2010 in Titisee, Germany to discuss "The New EMA Bioequivalence Guideline — What's in it, how to implement it?" A panel of experts, including those actively involved in the development of the guideline revision from industry, academia and regulatory agencies, explained the changes in the regulatory and scientific requirements to meeting attendees.

Peter Langguth, Professor at Johannes Gutenberg-Universität in Mainz, Germany, head of the Focus Group and one of the seminar workshop leaders explained: "In order to substantiate the claims on the product label, bioequivalence is a key requirement; it justifies changes in the formulation of drug products from early clinical batches to the marketed drug product and also in the substitution of products containing the same active ingredients. That's why the new guideline effective in August 2010 is of particular importance. The guideline not only provides a thorough description of how pharmacokinetic-based bioequivalence studies should be conducted and evaluated but it also includes recommendations on biowaivers".

The APV seminar has clarified and provided case examples for the additions and modifications made in the latest guidelines. The most important changes that have been incorporated into the new guidance in comparison to the previous guidance are as follows:

  • New requirements including aspects on the non-necessity of a multiple dose study in demonstration of bioequivalence.
  • Recommendations on the conduct of study designs under fasting and fed conditions to evaluate the food effect for drug products.
  • Instructions on whether to measure parent compound or metabolite, racemate or enantiomers.
  • Introduction of bracketing approach for more than two strengths.
  • Narrowing of CI acceptance interval for AUC ranging from 90.00 to 111.11% instead of 80 to 125%.
  • Widening of CIs in case of highly variable drugs depending on the CV of the reference product from 69.84 to 144.19% maximum and according to the scaled average bioequivalence approach.
  • BCS based biowaivers and biowaivers based on in vitro/in vivo correlation further represent attractive options of reliably demonstrating bioequivalence without the necessity of conducting a clinical study.

The next project of interest for the Focus Group will be the CPMP announced revision of guidance for oral modified release and transdermal dosage forms. APV will shortly announce its activities encompassing the discussion of these updated guidelines.

APV (International Association for Pharmaceutical Technology) is a non-profit scientific association located in Mainz, Germany. The association publishes EJPB (European Journal of Pharmaceutics and Biopharmaceutics) and organises various events ranging from expert meetings and seminars to in-house trainings. APV also organises international scientific congresses, such as the PBP World Meeting, and is the conceptual sponsor of the TechnoPharm annual meeting in Nuremberg. The organisation is supported by experts from academia and industry.

For detailed information on the APV's workshop programme, please visit

Peter Langguth is Professor at the Department of Pharmaceutical Technology and Biopharmaceutics at Johannes Gutenberg University, Mainz, Germany and Head of the APV Focus Group Biopharmaceutics and Pharmacokinetics.


1. Guideline on the investigation of bioequivalence (Committee for Medicinal Products for Human Use, EMA, London, UK, 20 January 2010).

2. D. Barends, et al., Pharm. Ind. 71(2), 258–263 (2009).