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4.1 Range of products made from human blood and plasma

Human blood is the source of a range of medicinal products. Blood products obtained from the processing of single donations of blood or plasma, generally known as blood components, include red cell concentrates, platelet concentrates, leukocyte concentrates and plasma for transfusion. Small pools, usually of less than 10 donations, mainly for the production of platelet concentrates, can also be prepared by blood establishments. Small pool cryoprecipitate is produced in some countries. The safety of these blood components depends largely on the criteria used for selection of the donors and the screening of donations.

Other blood products are obtained by the industrial processing of plasma of a large number of donations (up to tens of thousands) that are pooled together. These products include pooled virally-inactivated plasma for transfusion that is not fractionated, and the purifi ed plasma products, also known as plasma derivatives, that are obtained by a fractionation process that combines protein purifi cation and viral inactivation and removal steps.

Table 1 summarizes the range of products made from human blood and plasma, illustrating the diversity of source material and manufacturing methods involved, and, consequently, the complex regulation needed to ensure their quality and safety, in particular with regard to the control of risks of infection.

Plasma-derived products are regarded as medicinal products worldwide and their marketing authorization, which involves the offi cial approval of the production process and quality assurance (QA) system used as well as of product effi cacy, should be the responsibility of the national regulatory authority in all Member States. The national regulatory authority has the duty to enforce regulations, to evaluate the quality and safety of products, and to conduct regular assessment and inspection of the manufacturing sites.

An important part of the evaluation of the marketing authorization for plasma products relates to the production and control of the starting plasma used for fractionation, and is the focus of these Guidelines.

4.2 Composition of human plasma

Human plasma is a complex biological material composed of hundreds of biochemical entities, some of which have not yet been fully characterized. Among these are albumin, various classes of immunoglobulins, coagulation factors, anticoagulants, protease inhibitors, and growth factors. The complexity of plasma is illustrated in the Table 2.

The concentrations of the various protein components vary from about 40 g/litre (albumin) down to a few nanograms/ml for some coagulation factors. Plasma protein molecular mass varies from several million daltons (the von Willebrand multimer complex) to tens of thousands Daltons (for example, albumin).

Table 1

Range of blood/plasma products derived from single donor or pooled donations

a Usually 4–10 platelet concentrates derived either from platelet-rich-plasma or from buffy coats.

b Rarely produced. Pooled cryoprecipitate should ideally be subjected to a viral inactivation treatment. Also used as a fi brinogen source for fi brin sealant (fi brin glue).

Human plasma for fractionation is the starting material for the manufacture of a range of medicinal products used for the treatment of a variety of lifethreatening injuries and diseases. A list which includes the most established clinical use of these products is provided in Appendix 1.

4.3 Pathogens present in blood and plasma

A number of infectious agents can be present in human blood but not all blood-borne pathogens can be transmitted by plasma for transfusion or by plasma derivatives (7). Some pathogens are exclusively associated with blood cells, or are at least partially sensitive to the freeze–thaw process that takes place during the manufacture of plasma and plasma products. In addition, the multiple sterilizing fi ltration steps systematically included in the manufacture of plasma products, as for any other parenteral preparation, eliminate micro-organisms larger than 0.2 µm. Table 3 summarizes the major infectious risks linked to blood-borne pathogens and presents the current evidence on risks of infection from cellular components, plasma and fractionated plasma products.

Table 2

Selected proteins of human plasma

Source: Adapted from references 5 and 6.

a Factor II is the zymogen plasma protein which upon activation generates thrombin, one of the components of fi brin sealant (fi brin glue).

b There are several cytokines present in traces in plasma. G-CSF and erythropoietin for therapeutic use are obtained by recombinant technology.

Some of the viruses listed in Table 3 are highly pathogenic (e.g. HIV, HCV and HBV), others are pathogenic only in certain recipient populations (e.g. cytomegalovirus (CMV) and B19) and a few are currently considered to be non-pathogenic (HGV and TTV).

Historically, clinical use of single-donor blood components and pooled plasma products (plasma derivatives) has been associated with transmission of blood-borne viruses (HBV, HCV, HIV, HAV and B19) (3). The implementation of validated virus inactivation and removal steps into the manufacturing process of plasma derivatives has now virtually eliminated the risks of infection from HIV, HBV, and HCV (3) and has also avoided the transmission of some emerging infectious agents, such as WNV (8, 9).

The infective agents for the bacterial and parasitic infections most commonly associated with transfusions of cellular blood components are reliably removed during the processing and aseptic fi ltration of plasma products, as are residual blood cells.

Table 3

Evidence of transmission of infectious agents by human blooda

HIV, human immunodefi ciency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HAV, hepatitis A virus; HEV, hepatitis E virus; HGV, hepatitis G virus; TSE, transmissible spongiform encephalopathies.

+, evidence of transmission; –, no evidence of transmission; ?, questionable or unknown.

a Most viral transmissions associated with plasma products took place prior to the introduction of effi cient viral inactivation or removal procedures.

b Transmitted by contact with animal blood but not reported to follow transfusion.

c Limited epidemiological surveys have not revealed transmission of SARS coronavirus by transfusion but further confi rmation may be needed.

d Investigational studies performed by plasma fractionators using spiked TSE agents indicate that several purifi cation steps used in the manufacture of some plasma products are likely to remove prion agents. These data may not necessarily be extrapolated to clearance of the endogenous form of the TSE agent in human blood.

4.4 Strategies to ensure safety of plasma products

A combination of measures to exclude infectious donations, together with steps to inactivate or remove potential contaminating viruses during processing, has signifi cantly reduced the risk of disease transmission by plasma products.

There are four distinct complementary approaches to virus risk reduction for plasma products:

· minimizing the virus content of the plasma pool by:

— implementing a quality system to select donors;

— screening blood/plasma donations; and

— performing plasma manufacturing pool testing.

· inactivating and removing residual viruses during plasma fractionation and processing (3);

· adherence to GMP at all steps of the production; and

· recognizing and responding appropriately to post-donation events affecting plasma donations that have already been processed.

In-process and fi nished product virus inactivation and/or removal procedures have been shown to play a powerful role in ensuring the viral safety of plasma products, in particular from HIV, HBV, and HCV risks (3). Those procedures have also recently been shown to provide a suffi cient margin of safety against emerging lipid-enveloped viruses, such as WNV (8, 9).

Although procedures for the inactivation and removal of viruses may therefore seem to offer the fractionator an ideal means for counterbalancing occasional lapses in the identifi cation of risk donations, such an assumption would be incorrect. As powerful as the contribution of properly validated and implemented steps for virus inactivation and removal has been shown to be, it remains essential to limit the virus load at the stage of the plasma pool by avoiding, through donor selection and donation screenings, the inclusion of a high-titre infectious donation. The synergistic effects of reduced viral load in the plasma pool and validated viral inactivation and removal procedures are well illustrated for resistant non-enveloped viruses, such as parvovirus B19, for which viral reduction procedures used during fractionation alone may not be suffi cient to ensure safety (10, 11).

Exclusion of infectious donations, and retrospective identifi cation of any infectious donation that would have passed undetected through the screening and testing nets, require the highest priority at the blood establishment. The blood establishment should establish a reliable mechanism to ensure consistent identifi cation of such donations.

Neither of the sets of measures described above can, in isolation, provide suffi cient assurance of safety against all potential blood-borne pathogens.

For this reason, the manufacture of plasma for fractionation according to Good Manufacturing Practices (GMP) is necessary to ensure the optimal quality and margin of safety of this raw material for the manufacture of medicinal plasma products.

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