Plasma derived products
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).
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 and bacteria
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 authorisation, studies of the process for the ability to reduce prions are subject to particularly careful assessment by the regulatory authorities.
Requirement 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 the medicines control laboratory of the BASG.
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).
Plasma Master File
For marketing authorization of a plasma-derived medicinal product, the so called PMF has to be submitted to regulatory authorities. The PMF is a compilation of all the required scientific data on the quality and safety of human plasma relevant to the medicines, medical devices and investigational products that use human plasma in their manufacture. These data cover all aspects of the use of plasma, from collection to plasma pool – such as:
- Selection of donors: Selection of donors is regulated by European law. Criteria that shall ensure safety of the donation’s recipient are divided into permanent and temporary deferral criteria.
- Blood/plasma donation: Plasma for the manufacture of plasma-derived medicinal products can be sourced from whole blood donation (recovered plasma) or by plasmapheresis (source plasma). During plasmapheresis, a needle is inserted as it is done for blood donation. By centrifugation and filtration the blood is separated into blood cells and plasma components. While the plasma is collected in a container, the blood cells are returned to the donor by the extraction tube immediately.
- Recovered plasma is collected through whole blood donation in which plasma is separated from its cellular components by filtration, centrifugation and separation. Resulting from this, the plasma may be shock frozen and used for fractionation of plasma-derived medicinal products (Fresh Frozen Plasma) and the cellular components (red blood cell concentrate) is used for transfusion.
- Screening of donations: Donations from first time donors are screened by licensed test kits/systems to ensure quality and safety. Not until the same donor turns up for a second donation which as well turns out to be of adequate quality and safety, the first donation is released for further production/use. Screening is performed for HIV, HBV, HCV and other infectious agents. Donations revealing a positive screening result are discarded.
- Epidemiological data on blood transmissible infections: By collecting and reporting these data, information on the infection risk in a specific donor population shall be obtained to ensure that donations do not come from donors with a high probability of being infected with blood transmissible agents. Data on prevalence and incidence of transfusion transmissible infectious markers in donors and the estimated risk of infectious donations entering the plasma supply have to be presented and discussed on a yearly basis.
- Screening of plasma pools: At the manufacturing site the frozen single plasma units are unpacked, pooled, and thawed under stirring. Plasma pool samples are drawn for screening to ensure quality and safety. Screening is performed using licensed test kits/systems. Screening of pool samples is not only performed by the manufacturer, but also by an EU competent authority (see Plasma pool testing by Official Medicines Control Laboratory).
- Look-back system: Traceability has to be ensured from the plasma pool to the individual donation and vice versa.
- Blood collection sites, testing laboratories, transport organizations, plasma storage sites (EU and third countries): All these sites have to be listed by name, address and last inspection by an EEA competent authority.
In 2004 a special EU-wide authorization process for the PMF data-package was implemented. This special procedure is called “PMF certification” and is coordinated by EMA (European Medicines Agency). Following a positive evaluation, the PMF data-package is certified by EMA and thus licensed throughout the EU. A PMF certificate is valid for one year. Every year the whole data-package has to be updated by the PMF-Holder and re-evaluated by EMA (“PMF Annual Update procedure”). To date, 14 PMFs have been certified using this EU certification procedure.
BASG is one of the PMF Coordinators significantly involved in this PMF-EU certification procedure by evaluating the scientific data as well as by performing the relevant inspections of collection sites, testing labs, transport organizations and storage sites within Austria and third countries (mostly USA). Last but not least the OMCL (Official Medicines Control Laboratory) of BASG performs Plasma pool testing as described below.
Plasma pool testing by Official Medicines Control Laboratory (OMCL)
Samples for screening are drawn from the first homogenous plasma pool. For Human Plasma for Fractionation laboratory tests are carried out to detect antibodies against HIV 1 and 2 (human immunodeficiency virus), HBsAg (hepatitis B surface antigen) and HCV (hepatitis C virus) RNA by NAT (nucleic amplification technique).
On manufacturing pools for Human Plasma Pooled and Treated for Virus Inactivation additionally Parvovirus B19, HAV (hepatitis A virus) RNA and HEV (hepatitis E virus) RNA are determined.
Manufacturing pools for Human anti-D Immunoglobulin are screened in the same way as Human Plasma for Fractionation but also including determination of Parvovirus B19.
In case that all specifications are met, the OMCL approves the respective plasma pool and hence enables the manufacturer to release this plasma for manufacture.