NIBSC is the world’s major producer and distributor of WHO international standards and reference materials (supplying over 95% of standards).
The effective use of vaccines, most biotechnology products in therapy and many other biological medicines and disease markers (biologicals) depends on the availability of international biological standards supplied by NIBSC.
The complex assays used to assure the potency of biologicals require the use of a standard of biological activity (a batch of a substance that has been assigned units of activity and is used as a ’benchmark’).
The system of World Health Organisation (WHO) international standards provides a set of common standards that are essential if quality testing results from different parts of the world are to be comparable. International standards are the ‘gold standards’ from which countries and manufacturers can calibrate their own working standards for biological testing.
International standards manufactured according to WHO guidelines and are calibrated in units of biological activity which are assigned following extensive studies involving multiple international laboratories. They are then formally established following review by the WHO Expert Committee on Biological Standardisation (ECBS) at its annual meeting in October.
NIBSC aims to remain the world’s leading developer and supplier of high-quality international reference materials for biological medicines and to be recognised as the world’s foremost centre of expertise and excellence in biological standardisation.
There are currently over 330 international standards, reference reagents and panels available.
International units (IU) are assigned to international standards or other reference materials to allow the assessment of ‘biologicals’ in a consistent internationally-agreed manner.
Biological reference materials, with an assigned value in IU, may be used in situations where physico-chemical determination of international standard units, eg mass, is not possible or not appropriate. There may be no agreed validated reference methods of determination available, or a simple mass unit may not adequately define a clinically-relevant measure of activity eg glycoprotein hormones.
The World Health Organisation (WHO) provides biological reference materials which serve as reference sources of defined biological activity expressed in internationally agreed units. Their use should lead to improved agreement between laboratories and increased patient safety, by helping clinicians, scientists, regulatory authorities and manufacturers compare data from clinical trials or research publications, and to provide regulatory limits and guidelines for treatment regimes, using a common agreed unit. They are intended for the calibration of secondary reference materials (national or manufacturer) rather than routine inclusion as run controls.
The international standard will usually be assigned a value after a multi-centre international collaborative study. The role of the collaborative study is to characterise the performance of the reference material and determine whether it is ‘fit for purpose’. The study will be designed to include a wide representation of assay methods, types of laboratory, and countries.
Other samples may be included in the study to assess the effectiveness of the candidate reference material to improve between-laboratory agreement. The study should determine whether a single reference material and unit can be used for the available range of assay methods.
The results of the study determine whether the candidate reference material is suitable for adoption as a WHO international standard. This is the formal responsibility of the WHO Expert Committee on Biological Standardisation (ECBS). If the reference material is found to be suitable, and there is no pre-existing standard, the reference will be assigned an arbitrary value in international inits. The IU is defined by the contents of the ampoule or vial, and is not usually dependent on the particular assay method used.
As the reference material is a physical entity that is supplied to users, the stocks will eventually be depleted. A replacement standard will then be made. A further multi-centre collaborative study will be carried out to characterise the candidate replacement standard, and to compare it directly to the existing current standard.
The value assigned to the replacement standard, in IU, will be based on a consensus calibration of the candidate replacement to the existing international standard. This is to ensure that, as far as possible, the biological activity of an IU remains the same even though there may be a different number of IU per ampoule.
In a strict metrological sense, the replacement IU is defined by the contents of the ampoule of the new standard. Every effort is made to maintain the continuity of the IU, but the replacement IU is not formally traceable to the first IS, only to the physical content of the replacement IS. For this reason, no uncertainty of measurement is applied to the replacement IS.
Reports of many recent collaborative studies, containing details of the results from all participating laboratories and methods, are available on the WHO website, and summaries are often published in appropriate journals.
It is WHO’s policy not to assign an expiry date to their international reference materials. They remain valid with the assigned potency and status until withdrawn or amended.
International standards or other biological reference materials are provided as a physical entity with a defined content. They are manufactured under carefully controlled conditions to ensure homogeneity within the production batch, and stability for both long-term storage and transportation. Where possible, they will often be freeze-dried to improve stability. Sufficient numbers will be produced to provide many years supply for any particular reference material. Reference materials are held at NIBSC within assured, temperature-controlled storage facilities. Stability is monitored, and provided that it remains stable, the IS will remain available for as long as stocks last.
Storage instructions are shown on the label of the preparation. Where available, stability information about a particular preparation is detailed on the ‘Instructions for use’ supplied with the preparation. Once reconstituted, diluted or aliquoted, users should determine the stability of the material according to their own method of preparation, storage and use. Users who have data supporting any deterioration in the characteristics of any reference preparation are encouraged to contact us by emailing firstname.lastname@example.org.