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The safety and quality of plasma for fractionation results from the combination of several cumulative prevention measures

— appropriate selection of blood/plasma donors;

— testing of blood/plasma donations;

— epidemiological surveillance of the donor population; — strict adherence to GMP; and — post-donation information system.

Such information on collection and testing of plasma is requested by some regulatory authorities as part of a plasma master fi le (12) used in the evaluation of the marketing authorization of plasma-derived medicinal products. However, the plasma master fi le is not a universally used regulatory document.

5.1 Appropriate selection of blood/plasma donors

Plasma for fractionation should be obtained from carefully selected, healthy donors who, after review of their medical history (the donor questionnaire), medical examination and laboratory blood tests, would be considered not to present an increased risk for transmission of infectious agents by plasmaderived products (see Appendix 2). Local national regulatory authorities are pivotal in setting up at the national level a harmonized donor selection criteria framework appropriate to the country in which plasma is collected, taking into account the type of products to be manufactured, the relevant risks of infection, and the epidemiological situation. The local national regulatory authority should also be part of any decision making process intended to modify the donor selection and donation testing procedures. Specifi c selection criteria may be added by the plasma fractionator as part of the contractual agreement with the provider of plasma.

Regulatory agencies and a number of organizations have published regulations and recommendations concerning the criteria for the selection of donors of whole blood and of plasma obtained by apheresis (see for instance Guide to the preparation, use and quality assurance of blood components of the Council of Europe (13). In general these regulations and recommendations can be used as reference documents for the collection of plasma for fractionation, although some specifi cations may differ from those of plasma for transfusion. Examples of criteria for the selection of donors for the collection of plasma for fractionation are presented in Appendix 2. These are not intended to constitute an absolute reference or an exhaustive list of requirements, but rather to provide examples and explain critical points for consideration.

A regular donor is someone who routinely donates blood or plasma in the same centre in accordance with the minimum time intervals. The period taken into account may vary from country to country. A repeat donor is someone who has donated before in the same establishment, but not within the period of time required to be considered as regular donation. Plasma fractionators may implement their own criteria for donors’ eligibility to improve safety margins. Whenever possible, plasma for fractionation should be collected through a donation system that relies on regular and repeat donors. Obtaining plasma from regular and repeat donors makes a major contribution to ensuring optimal historical medical information about the donors, and therefore to detecting potential risk factors.

In some countries family or replacement donors may constitute a signifi cant proportion of the population of blood plasma donors, and — depending on the situations — have been found (14) or not (15) to be at a higher risk than regular/repeat donors of having markers of viral infections. The decision to use this plasma for fractionation is to be made jointly by the plasma fractionator and the national regulatory authorities and should be based on both a careful epidemiological assessment and the evaluation of other safety measures in place for screening of donations for viruses.

Plasma may be collected by plasmapheresis from donors who have acquired immunity through natural infection or through active immunization. Specifi c information on this issue can be found in Appendix 3.

5.2 Screening of blood/plasma donations for infectious markers

5.2.1 Screening tests

The following tests, considered mandatory by all regulatory agencies, are relevant to the preparation of plasma for fractionation and should be performed on each blood or plasma donation:

— an approved test for HBsAg;

— an approved test for anti-HIV; and — an approved test for anti-HCV.

The results of all three tests should be negative. Testing for HIV p24 antigen and HCV core antigens may increase the sensitivity. Initially reactive donations should be retested in duplicate by the same assay. A repeatedly reactive donation should not be used for therapeutic applications and should usually be destroyed unless useful for non-therapeutic use or investigations. A sample of the donation should be evaluated by a confi rmatory test and if confi rmation is positive a system should exist to notify and counsel the donor. It is recommended that national algorithms should be developed and used to enable consistent resolution of discordant or unconfi rmed results.

5.2.2 Other tests

The screening of plasma for fractionation for anti-human T-lymphotropic virus (HTLV) is not required as the virus is cell-associated and susceptible to inactivation by the freeze–thaw process.

In some countries, testing for anti-HBc is performed on whole blood donations as a means to reduce the risks of exposure to donations of blood components that are hepatitis B-positive (16). However, donations of plasma for fractionation obtained from whole blood that are both anti-HBc positive and HBsAg negative, and which contain a suffi cient titre of antibodies against hepatitis B surface antigen (anti-HBs) are usually used for fractionation: the scientifi c rationale is to maintain a suffi cient titre of anti-HBs antibody in the plasma pool to neutralize any HBV that may be present. The minimum titre of anti-HBs for an anti-HBc positive/HBsAg negative plasma donation to be accepted for fractionation may be specifi ed by the plasma fractionator and/or the national regulatory authority. Currently, the minimum titre of anti-HBs antibodies required by some plasma fractionators ranges from 50 to 100 IU/l. Alternatively, the plasma donation may be identifi ed by the plasma collector as being anti-HBc positive and the plasma fractionator may conduct additional tests. The setting of a minimum limit, if any, for the titre of anti-HBs antibody usually involves a risk assessment that takes into consideration the sensitivity of the HBsAg screening test, the testing or not of HBV by nucleic acid testing (NAT), and the effi ciency of the viral reduction techniques (3, 17).

Additional testing for other agents or markers may be required by the national regulatory authority, taking into consideration the epidemiological situation in any given area or country, or the frequency of donating blood or plasma, and at the specifi c request of the plasma fractionator.

5.2.3 Nucleic acid testing

NAT of plasma for fractionation may be performed for the following viruses: HCV, HBV, HIV, HAV, and/or B19. If NAT is performed by the fractionator, following current practice using mini-pool samples, a specifi c logistics system may have to be developed at the blood establishments to collect and provide labelled samples in a form suitable for the test. In addition to performing mini-pool testing, fractionators re-test the plasma manufacturing pool for the absence of various viral markers.

5.2.4 Test kits

A system should exist in the country or region for approval of tests kits, such as an offi cial approval system by the national regulatory agency or a delegated laboratory. The required sensitivity of the tests for the different antigens or antibodies should be determined by the national regulatory authority. In addition, the test kits to be used should be agreed by the fractionator that will receive the plasma for fractionation.

5.2.5 Quality control of screening

The quality of the screening of blood/plasma donations relies on a number of measures, such as:

— validation of new techniques before implementation;

— internal control of reagents and techniques on a daily basis;

— confi rmation of positive tests by an appropriate laboratory; and

— external profi ciency testing which involves the testing of a panel of sera circulated to laboratories by an approved reference institution.

Details on sampling, test equipment, validation of performance of assays, test interpretation and downloading and follow-up of reactives can be found in section 7 on QA and GMP in these guidelines.

5.2.6 Look-back

A system should be in place to perform a look-back procedure, preferably using a computer database. A look-back is a procedure to be followed if it is found retrospectively that a donation should have been excluded from processing, e.g. because that unit was collected from a donor who was subsequently rejected because of reactive viral marker, risk behaviour, exposure to CJD/vCJD or other risks related to infectious diseases. The blood establishment should then transmit this information to the fractionator according to the agreements in place, and to the national regulatory authority. Donor notifi cation and counselling are recommended both for purposes of donor health and for the safety of the blood supply.

5.3 Epidemiological surveillance of donor population

To ensure optimal long-term safety of plasma for fractionation, it is highly recommended to establish continuous epidemiological surveillance of the donor population This is not a requirement in all regions of the world. The objective of this survey is to know, as precisely as possible, the prevalence and incidence, and their trends, of infectious markers that are relevant to the safety of medicinal plasma products so that counter-measures can be taken in a timely fashion.

The system should not only be able to gather epidemiological data at the national and regional level but also among the donor populations that are providing blood or plasma for fractionation at individual blood establishments within a country or a region.

The information from the epidemiological surveillance can furthermore be used:

· to detect differences among donor populations of various collection centres which may be associated with objective differences in viral markers within donor populations or may refl ect differences in the process of donor selection and screening among collection centres;

· to detect trends in infectious markers which may refl ect either a change in the rate of viral markers in the population or a possible deviation in the donor selection or screening process at specifi c collection sites;

· to assess the relevance of any prevention measures such as a strengthened donor selection process, additional exclusion criteria, or implementation of additional screening tests to avoid contamination of plasma products.

When donations from fi rst-time donors are used to prepare plasma for fractionation, epidemiological data on this specifi c group of donors should be included in the estimation of the risk for infectious diseases transmitted by blood. Indeed, it has been shown that fi rst-time donors, who may occasionally include test-seeking individuals, constitute a group which in some situations is more likely to have blood-borne viral markers than regular donors group who have already gone through a selection or deferral process (18–21). Some plasma fractionators do not fractionate plasma from fi rst-time donors as prevalence of infectious diseases may be higher in this donor group. Currently, it is advisable to collect and analyse epidemiological data at the collection sites for anti-HIV-1 and antiHIV-2, anti-HCV and HBsAg, since, historically, they represent the major pathogenic risks associated with plasma products. It is the responsibility of the local national regulatory authority to determine whether the list should be modifi ed or should include additional criteria, such as emerging infectious agents, based on local or regional epidemiology. For the three currently recommended markers, only confi rmed positive tests (i.e. tests that are repeatedly reactive in a screening test and positive in at least one confi rmatory test) should be recorded. When the plasma fractionator performs additional tests (such as NAT tests) on donations which gave negative results in serological tests, the results should be reported.

Recent guidelines published by the European Medicines Agency (EMEA) entitled Guideline on epidemiological data on blood transmissible infections (22) describe how to conduct epidemiological surveillance of the donor population.

5.4 Strict adherence to good manufacturing practices

Because the pooling of thousands of plasma donations is required for the manufacture of plasma derived medicinal products, it is necessary to ensure full traceability between individual blood/plasma units collected and the fi nal plasma products manufactured. This is important to enable any quality and safety problems, in particular problems related to infectious risks, to be traced back to individual blood/plasma donations and to allow relevant measures to be taken to protect the donors as well as the patients who received the plasma-derived medicinal products.

The donor selection process, the collection of blood or plasma and the processing of the donation, in order to obtain plasma for fractionation, represent the fi rst steps in the manufacturing of plasma-derived medicinal products, and therefore should be performed in compliance with GMP. Strict adherence to the principles of GMP and the implementation of a QA system to address and comply with the requirements of GMP is crucial at all stages of the production of plasma for fractionation (See section 7 on QA and GMP in these Guidelines).

5.5 Post-donation events

There should be a system to ensure effective communication between the blood establishment and the fractionator so that information on signifi cant post-donation events may be immediately transmitted to the fractionator and the national regulatory authority. In particular, this procedure should allow early and effective communication of any evidence for the presence of blood-transmissible infection in a donor whose plasma has been sent for fractionation.

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