EMA Publish Guidance on Plasma-Derived Medicinal Products
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Human plasma contains many proteins which, following extraction, purification, and formulation into medicinal products are of great medical importance. Plasma-derived products provide life-saving therapies but the quantity of plasma for fractionation is limited by the number of donors. Therefore, the exchange of intermediates between manufacturers or the use of a variant manufacturing process (see below) may be possible to assure the best use of blood/plasma donations.
Although the therapeutic use of blood transfusion goes back to the beginning of the 20th century, it was not until the 1940s that the technique of plasma fractionation, devised by Cohn and colleagues, enabled the widespread use of medicinal products extracted from human plasma.
Improvements in protein purification and molecular separation technology have made available a wide variety of products, with medical applications covering a large field, and the therapeutic value of these is unquestioned. However, the potential for viral transmission is well recognised, and because of the large number of donations which are pooled, a single contaminated batch of a plasma-derived product, with the contamination possibly originating from a single donation, can transmit viral disease to a large number of recipients. The recognition in the mid-1980′s that plasma-derived medicinal products, in particular coagulation factor concentrates, had caused widespread transmission of human immunodeficiency virus (HIV) and hepatitis C (previously identified as non-A non-B hepatitis) resulted in major changes to the manufacturing processes, with the introduction of specific steps to inactivate or remove these and other blood-borne viruses. Infectious non-enveloped viruses were detected in certain plasma-derived medicinal products during the 1990’s and early 2000’s. Therefore, recent process development has been devoted to further reducing non-enveloped viruses such as hepatitis A (HAV) and parvovirus B19 (B19V).
Measures taken to prevent infection include selection of donors, screening of individual donations and plasma pools for markers of infection with known viruses and validation of the production process for inactivation or removal of viruses. From the 1990’s on, measures designed to minimise contamination of the starting plasma have been improved by the refinement of serological test kits and the use of nucleic acid amplification technology (NAT) for the testing of viral DNA and RNA, thereby shortening the window period during which infectious donations are not detected.
Recent cases of apparent iatrogenic variant Creutzfeldt-Jakob disease (vCJD) infection by blood transfusion in man in the UK provide strong evidence that vCJD is transmissible through blood transfusion. Precautionary measures to minimize the risk of transmission of infectivity by plasma-derived medicinal products were put in place by CHMP in 1998 following the identification of the first cases of vCJD and have been kept under review and updated as needed.
The legal basis for EU minimum standards for the quality and safety of the starting material for plasma-derived medicinal products has been established along with the pharmaceutical legislation and specific provisions have been laid down in the pharmaceutical Directive 2001/83/EC as amended. In this legislation the option of a centralised certification of Plasma Master File was established.
In 2003 the European Parliament and the Council have adopted the overarching Directive 2002/98/EC “Setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components…”, also known as the “Blood Directive”. Thereby, from 8 February 2005, Directive 2002/98/EC amending Directive 2001/83/EC establishes the requirements for the collection and testing of human blood and blood components whatever the intended purpose. In line with this Directive, the technical Directives 2004/33/EC, 2005/61/EC and 2005/62/EC have been issued by the Commission. Guidance is also provided by the “Guide to the Preparation, Use and Quality Assurance of Blood Components” of the Council of Europe which contains a compendium of measures designed to ensure the safety, efficacy and quality of blood components.
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