For the next few years, experts expect the demand for plasma for fractionation to increase. Human plasma contains proteins that are processed for life-saving medicines – including coagulation factor concentrates – immunoglobulins, albumin and plasma, and is subjected to at least one industrial process, e.g. solvent/detergent plasma.
The supply of this valuable ‘commodity’ essentially depends on two factors: the donor’s willingness to donate and the suitability of the blood/plasma donation. Here, the selection of the donor plays an important role, i.e. the registration of their history and the examination of exclusion factors such as neurological disorders, viral infections (HIV, HBV) or drug abuse.
Donor registration and donor management are the first important steps in ensuring the supply and safety
Donor registration and donor management are thus the first important steps in ensuring the supply and safety. There must also be full traceability in the supply chain: it must be possible to track at any point which donations and from which donor a plasma product has originated from, thus enabling a connection between a plasma donor and the patient who received a specific batch of plasma product(s).
Another important factor is the testing of the products for any transmissible diseases, especially viral markers, by means of ELISA or Polymerase Chain Reaction/Nucleic Acid Amplification Technology methods. This is followed by further processing for virus removal or inactivation measures in the plasma fractionation process and includes the following methods:
Cold ethanol precipitation: For this method the earlier mentioned separation processes apply. But it is worth noting that ethanol/low pH show antiseptic effects at room temperature. However, plasma fractionation occurs at much lower temperatures, and thus this fact cannot be used. It is therefore advisable to use pre-filters in filtration steps as they prevent premature filter blockage and therefore increase virus removal.
Pasteurisation: heat treatment of the finished product in aqueous solution (10hrs at +60°C) is the European Pharmacopoeia method for albumin. It is also used for bulk preparations and other plasma products. Pasteurisation is effective against coated and some uncoated viruses. The efficiency of the step is dependent on the product composition, temperature and time. Stabilisers are needed here to minimise the formation of neo antigens.
Heat treatment of lyophilised products: Lyophilised products are exposed to high temperatures under defined pressure for a certain time. For these methods it is necessary to observe in particular the residual moisture content, protein integrity and a possible aggregate formation. The residual moisture should be determined at each individual final product container using non-invasive methods, e.g. Near Infrared Spectroscopy.
Solvent/detergent (S/D) process: treatment with solvents and detergents very effectively inactivates coated viruses by breaking and destroying their lipid shell. Often a filtration step is preceded by a S/D procedure to remove any virus-containing aggregates. A homogeneous distribution of the S/D reagents in the test material is essential. S/D treatment is not effective against uncoated virus.
Nano filtration: This method is used especially for the enrichment of smaller, uncoated viruses such as HAV and B19V, against which other methods are not very effective or even ineffective. This step is not suitable for all products because the molecular size of the active substance (factor VIII, for example, is a very large molecule) and those of the viruses can vary greatly; in such cases small viruses are enriched effectively, but so is the main active ingredient. Certain filter types are also able to activate udesireable clotting factors.
Low pH: Low pH values prove to be effective against coated and some uncoated viruses (B19V under certain conditions, but not HAV) and is used in the production of immunoglobulins.
Generally, robustness studies are also required, which constitute so-called ‘worst case’ conditions: it should be shown that viruses are inactivated/removed effectively even under altered, unfavourable production conditions such as lower S/D reaction times or different temperatures, pressure or pH value.
In the case of positive tests on pool donations, all involved donations in the past six months have to be retested and quarantine action taken
Due to the above mentioned testing and the requirement for traceability, it is possible to determine a potential transfer route for viral infections to patients through the administered drug. Such records must be kept for at least 30 years after plasma donation. Plasma pool samples for testing must be kept for at least one year after the end of the shelf-life of the medicinal plasma product that has been held for the longest. In addition, in the case of positive tests on pool donations, all involved donations in the past six months have to be retested and quarantine action taken.
Furthermore, due to globalisation and increased import and export of plasma worldwide, uniform quality and safety standards have grown in importance within Europe as well as for trade with non-European countries such as the US. This is also reflected in the relevant guidelines, e.g. the EMA Guideline on plasma-derived medicinal products.
Many additional guidance and regulatory documents are now also important, including:
- Directive 2002/98/EC setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC
- Plasma Master File
- European Pharmacopoeia (EP)
- EDQM Guide for the preparation, use and quality assurance of blood components
Generally, the relevant monographs of the EP requirements for the manufacture of plasma products have to be applied.
As in many other areas of the manufacture of medicinal products and medical devices, risk evaluation plays an important role in plasma derivatives. This is also addressed by the above mentioned guideline on plasma-derived medicinal products (previously described in the guideline CPMP/BWP/5180/03).
A review of all steps and considerations affecting the virus security is mandatory. Such steps include information on the epidemiological situation of the donor population; the selection and testing of appropriate donors and raw material; knowledge about the so-called ‘window periods’ of certain viruses (i.e. the period in which viral antigens in the plasma are no longer detectable and specific antibodies are not yet detectable); and the enrichment/inactivation capacity of the manufacturing process.
A theoretical calculation of the viral residual risk in the final product must also be adjusted, based on the overall viral reduction. A formula for calculating the residual viral risk can be found in the guideline CPMP/ICH/295/95.
Generally speaking, the elimination capacity should always be higher than the amount of virus that can potentially be included in the plasma. Information on the safety and potential residual risk must be included in the instructions for use.
The risk assessment for the viruses HIV, HAV, HBV, HCV and B19V applies to all new registrations except for albumin; according to Cohn or Kistler/Nitschmann, for albumin, no such evaluation is necessary if the production follows the EP. Regarding this point there is a standard clause in the core Summary of Product Characteristics (SPC) for albumins.
For already approved products, a risk evaluation for HAV and B19V is required if information on the viral safety of these two viruses is included in the prescribing information.
If plasma products are used as excipients or as part of medical devices, the same requirements in terms of quality and specifications apply as for approved medicinal products
Clinical experience regarding viral transmission through plasma products also has to be taken into account. The viral safety of a product cannot be considered as a given even when previously no viral transfers were observed. This applies particularly to unexpected/unknown, so far risk-free or not specifically studied viruses.
Plasma products also play a role as part of medical devices or as excipients. If plasma products are used as excipients or as part of medical devices, the same requirements in terms of quality and specifications apply as for approved medicinal products, and the full quality documentation must be included in the marketing authorisation dossier. It may be waived if a valid approval and/or Plasma Master File for the respective excipient can be referenced.
In such cases it is sufficient to provide a flowchart for the manufacturing process, the final product specifications, a summary of the stability data including run time, viral risk assessment and the qualitative and quantitative composition of the product.
As for approved plasma products, the batch release by a state-authorised control lab is required as well. Any manufacturer using plasma products as excipients or in medical devices is required to synchronise the expiration date of the final product/medical device with that of the excipient. In some cases compliance with this requirement can prove difficult. Deviations from it can, however, be accepted if appropriately justified within the approval process.
Issues surrounding quality and safety are at the centre of the ECA Conference Blood, Blood Products and Plasma on the 19–20 May, 2016, in Vienna, Austria. Experts from the competent European and US authorities, donor establishments and fractionation companies will discuss the current state of science and technology in this area.