Table 1.

A comparison of the distinct roles of the reference medicinal product and the WHO International Standard.

Characteristic	Reference Medicinal Product	WHO International Standard
Authorisation	Approved by the relevant competent authorities for defined clinical indications	Established by the WHO Expert Committee for Biological Standardization
Product characteristics	Clinical product for human use. Has defined physicochemical and biological characteristics as per licence specifications extensive clinical history relating to its efficacy and safety	Not a product for clinical use in humans Manufactured as per WHO specifications for use as a primary reference standard for bioactivity
Regulatory role	Serves as a ‘comparator’ product for biosimilarity assessments as per biosimilar guidance	No formal regulatory rolea
Form/Presentation	Lyophilised/liquid in product specific formulation Vials or prefilled syringes, pen cartridge etc	Small amounts lyophilised in product specific formulation Glass ampoules
Labelling	Labelled and dosed in ‘mass’	International Units (IU) per ampoule with no stated ‘mass’
Bioactivity	Expressed in proprietary U/ml ± acceptance limits	Arbitrary IU/ampoule
Specific Activity	U/mg	Not applicable
Stability and Expiry date	Stable within expiration date (~ 2 years) if stored as per manufacturer’s recommended conditions	As defined in the ‘Instructions for Use’. Usually stable over many decades as predicted by accelerated degradation studies
Role in assay calibration, standardisation and data harmonization	None	As the highest order (primary) standard Supports bioassay performance, calibration and validation Supports calibration of secondary reference (national, pharmacopoieal, manufacturers) standards Facilitates comparability of bioassay data between different stakeholders
Availability	Restricted	Publicly available from a WHO custodian laboratory, e.g., NIBSC

^aProduct bioactivity expressed in units traceable to the IS can support regulatory decisions