Plasma-derived medicinal products are pharmaceuticals produced out of human plasma.
Plasma is the liquid part of the blood and consists of approx. 90% water. It contains over 120 different proteins that take on functions vital to life such as fighting infections or the clotting of blood to stop bleeding after an injury. Over 20 different proteins can be isolated for the production of plasma-derived medicinal products such as albumin, immunoglobulin, clotting factors, fibrinogens, etc.
Collection of the starting material (plasma and blood donation) is the first step of a complex manufacturing process: Isolation of proteins is most commonly performed by the so called COHN process (and processes derived thereof), developed by Edwin Cohn in 1940. Out of frozen plasma, which is thawed in the first place, different proteins are isolated by means of precipitations, adsorptions, filtrations, centrifugations, and chromatography. After that, further manufacturing steps such as purification, lyophilization, formulation and filling may be performed (see Safety of plasma derived products).
Marketing authorisation of plasma-derived products
Marketing Authorisation of plasma-derived medicinal products
In contrast to other pharmaceuticals, marketing authorization of plasma-derived medicinal products includes authorization of the so called Plasma Master File (PMF).
Safety of plasma-derived medicinal products
Viruses, bacteria, fungi and prions may be transmitted via human blood/plasma.
Measures taken to prevent transmission of infection by plasma-derived medicinal products include
- selection of donors
- screening of donations/pools
- inactivation or removal of viruses during the manufacturing process.
Regarding selection of donors and screening please refer to Plasma Master File (PMF).
Fungi as well as bacteria are removed by sterile filtration, always undertaken during manufacture.
The manufacturing process plays a central role and is of great significance with regard to viral safety. Implementation of effective steps for inactivation/removal of a wide range of viruses of diverse physico-chemical characteristics improved the safety of plasma-derived medicinal products significantly. Two distinct inactivation/removal steps which complement each other in their mode of action shall ensure that any virus surviving the first step would be effectively inactivated/removed by the second. Heat treatments, nanofiltrations and application of chemical substances are well-known examples for such effective process steps.
Before marketing authorization, studies of the process for the ability to inactivate/remove virus infectivity are subject to particularly careful assessment by regulatory authorities.
Transmissible Spongiform Encephalopathies (TSEs) are chronic degenerative nervous diseases characterized by the accumulation of an abnormal isoform of a cellular glycoprotein (known as prion protein). Prions are considered to be the infective agents responsible for transmitting TSE disease. In humans, TSE disease includes inter alia different forms of Creutzfeld-Jakob Disease (CJD). v(variant)CJD is most likely caused by exposure to BSE (bovine TSE) contaminated food. The infectious prions of vCJD may therefore be present in human plasma/blood.
Measures taken to manage the risk of transmitting vCJD via medicinal products are of great importance and include
- selection of donors
- inactivation or removal of prions during manufacturing process
Until now, no adequate testing for prions in human blood/plasma can be performed.
Regarding selection of donors please refer to Plasma Master File (PMF).
Similar to viruses, manufacturers have to investigate every manufacturing process of a plasma-derived medicinal product for its ability to reduce prions.
Before marketing authorization, studies of the process for the ability to reduce prions are subject to particularly careful assessment by the regulatory authorities.
Obligation for batch release
Medicinal products that are made from human plasma (plasma products), have to be approved by an Official Medicines Control Laboratory (OMCL) before allowed be placed by the manufacturer or marketing authorization holder in Austria on the market. The Austrian OMCL is part of the BASG / AGES medicines and medical devices agency.
For plasma products that are licensed in Austria, also batch release certificates from other OMCLs within the EU/ EEA countries and Switzerland are accepted if the specifications laid down in the marketing authorization of the releasing country are consistent with the Austrian marketing authorization.
For an application for batch release batch records describing the starting material, the production and the test results as well as test samples (e.g. plasma pools and final products) have to be submitted to the OMCL by the manufacturer.
Consequently the OMCL does an assessment whether the submitted batch meets the requirements of applicable monographs of the European Pharmacopoeia and is in compliance with the specifications as laid down in the respective marketing authorization. Furthermore, samples are tested for phase I tests laid down in the product specific guidelines elaborated by the EDQM and confirmed that the product specifications are met. Phase I tests are usually tests for identity, purity and assays for potency determination. As a safety measure plasma pools are tested for viral markers.
If the batch records and the test results of the OMCL are in compliance, an EU-Official Control Authority Batch Release (OCABR) certificate is issued, which is recognized by other OMCLs in the EU and the EEA and Switzerland.
If there is an objection to the batch, the applicant will be contacted by the OMCL and informed of the reasons for the objection.
If the batch gets finally rejected, the OMCL informs the Federal Office for Safety in Health Care (BASG) about the rejection and the reasons for it. The applicant receives the objection in written form. The applicant may request the BASG to revise the decision to reject the batch. This has to be done by BASG within 30 days. Requests for further data (including analytical test results) prolong the deadline.
The rejection of a batch has to be reported to the European OMCL-network by the OMCL which did the assessment (Rapid Information).