European Medicines Agency reminds marketing-authorisation holders about revised monographs for human normal immunoglobulin

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28/09/2012

European Medicines Agency reminds marketing-authorisation holders about revised monographs for human normal immunoglobulin

The European Medicines Agency reminds marketing-authorisation holders of human immunoglobulin-containing medicines that they need to investigate their manufacturing processes to determine if any changes are required to comply with the revised European Pharmacopoeia monograph on human normal immunoglobulin.

Monograph 0338, which was recently revised in response to thromboembolic events associated with an immunoglobulin preparation, now states that:

For preparations intended for subcutaneous administration, the method of preparation also includes a step or steps that have been shown to remove thrombosis-generating agents. Emphasis is given to the identification of activated coagulation factors and their zymogens and process steps that may cause their activation. Consideration is also to be given to other procoagulant agents that could be introduced by the manufacturing process.

The implementation date for this change is 1 January 2013.

The Agency is writing to all marketing-authorisation holders (MAHs) of relevant centrally authorised medicines to inform them of these changes. If manufacturing changes are needed, the MAHs will need to submit a variation to the Agency together with supporting validation data by 1 July 2013, so that the marketing authorisations can be updated.

If the manufacturing process already includes steps that have been shown to remove thrombosis-generating agents, the relevant validation data will have to be submitted as a type-II variation by 1 July 2013. A single type-II variation under B.III.2.z may be submitted.

The Agency also requires MAHs to submit an analysis of pharmacovigilance data for thromboembolic events in parallel to the type-II variations.

Any signal of thromboembolic events or indications of thrombogenic activity in a centrally authorised human immunoglobulin product (normal or specific) for subcutaneous administration should be immediately reported to the Agency.

The update to monograph 0338 follows the revision for human normal immunoglobulin for intravenous administration (monograph 0918). To understand the suitability of methods used to detect procoagulant activity or factor XIa, a reference preparation is desirable. A National Institute for Biological Standards and Control (NIBSC) reference reagent for factor XIa is now available. The Agency requests MAHs of intravenously and subcutaneously administered immunoglobulins to provide information on the performance of their methods in terms of this reference reagent, with a particular emphasis on sensitivity.

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