Administering Files, Records, and Grants

Plasma products and clinical applications[footnoteRef:1] [1: Adapted from: Ala, F, Burnouf T, El-Nageh M. Plasma fractionation programmes for developing economies. Technical aspects and organizational requirements. Cairo, WHO Regional Publications, 1999 (Eastern Mediterranean Series).]

a Some factor VIII concentrates containing von Willebrand factor are effective for the treatment of von Willebrand disease

b Prothrombin complex contains factor II, factor VII, factor IX, and factor X. The content of factor VII may vary depending upon products.

c May be used, in the absence of purifi ed plasma products, for substitutive therapy in factor VII, factor X, or protein C defi ciency. Whenever available, purifi ed factor IX should be used to treat haemophilia B. d Product obtained by mixing a concentrate rich in fi brinogen and a concentrate rich in thrombin.

Appendix 2

Donor selection

1 Preamble

2 Information to donors

3 Compliance with donor selection criteria

3.1 Identifi cation of donors

3.2 Confi dentiality

3.3 Questionnaire and interview

3.4 Physical examination, acceptance and deferral criteria

1. Preamble

Recognizing the importance of the provision of safe blood, blood components and plasma derivatives, the 58th World Health Assembly in 2005 (WHA Resolution 58.13) (1) expressed its support for “the full implementation of well-organized, nationally coordinated and sustainable blood programmes with appropriate regulatory systems” and stressed the role of “voluntary, non-remunerated blood donors from low-risk populations”. The provision of blood, blood components and plasma derivatives from voluntary, non remunerated donors should be the aim of all countries.

2. Information to donors

Candidate donors should receive an explanation, ideally both verbally and in writing, or by any other appropriate means such as a self-administered questionnaire, that answers to questions about their medical history and personal behaviour are necessary to determine whether they are eligible to donate blood or plasma. Written information can be in the form of a leafl et explaining the risks of infection associated with blood and plasma products; impact of social behaviour on risks of infection and risk factors for infection. This information is generally given by a licensed physician, or by a person under the direct supervision of a licensed physician, who should explain the exclusion criteria for donating blood and plasma. A convenient communication system should ensure that risk factors are well understood by the candidate donor.

Additionally, the donor should be asked to inform the blood centre if he or she feels unwell after the donation or if he or she forgot to mention a possible risk factor. This is of special importance for a donation used to prepare plasma for fractionation as it is important to be able to remove at-risk donations prior to the industrial pooling stage to avoid the potential need to destroy the plasma pool or the intermediates or products derived from it.

3. Compliance with donor selection criteria

3.1 Positive identifi cation of donors

Upon presentation at the blood/plasma collection site, donors should be asked to identify themselves by stating their name, address and date of birth, and to supply proof of a permanent place of residence to establish a reliable means of contact, including, for example, a telephone number where they can be contacted after donation, if needed. Proof of identity (such as identity card, passport or driving licence) should be provided. Identifi cation of donors should also take place immediately before venipuncture.

3.2 Confi dentiality

The premises and setting of the blood/plasma collection centre (or the mobile collection unit) should allow for adequate confi dentiality during the donor’s interview and the selection process so that the candidate donor will not avoid answering questions on his or her personal or private behaviour, which otherwise would compromise the safety of the plasma donation used for the fractionation process .

3.3 Questionnaire and interview

The assessment of each donor should be carried out by a suitably qualifi ed person, trained in use of donor selection criteria and will involve an interview, a questionnaire and further direct questions if necessary. In order to obtain relevant and consistent information about the donor’s medical history and general health, it is recommended that the donor can review, complete and sign a pre-printed questionnaire (computer-assisted self-administered interviewing (CASI) is being developed in some regions), adapted to the type of donor (for instance, fi rst-time donor versus regular donor). The questionnaire should be drafted in such a way that donors may easily identify whether they are in good health.

Candidate donors who are at risk of carrying a disease transmissible by blood/plasma derived products should be able to exclude themselves voluntarily after reading and responding to the donor information and/or the questionnaire. Such confi dential self-exclusion should also be possible after the donation (e.g. by telephone).

The candidate donor should be asked to sign an informed consent to give blood/plasma in which he or she acknowledges an understanding of the moral responsibility behind the donation of blood/plasma.

3.4 Physical examination, acceptance and deferral criteria

3.4.1 Physical examination

Prior to the fi rst donation and before subsequent blood donations and in case of plasmapheresis at regular intervals, a physical examination should be carried out by a licensed physician or a physician substitute following an established procedure. Local national regulatory authorities, usually after consultation with the blood establishment, should determine the health criteria and the respective acceptable limits to be taken into consideration during physical examination, such as measurement of weight, blood pressure, pulse rate and temperature, or any other criteria considered to affect the safety of plasma-derived products or the donor.

3.4.2 Records and traceability

An appropriate computerized or, if not available, manual system should exist to keep records of the donors, of their medical history and health status, and to ensure effi cient traceability of their donations. Such information provides historical perspective on the health status of the donors, including previous temporary deferrals (should they exist), and contributes to reinforcing the judgement as to whether the donation would present a risk to the quality and safety of plasma for fractionation.

3.4.3 Selection and exclusion criteria

The following elements have been recognized as playing a role in selecting the safest donors:

Establishment of exclusion criteria: Relevant acceptance, deferral and exclusion criteria for the donation of blood/plasma used for fractionation should be formulated by the national regulatory authority and be applicable nationwide, as national requirements. Within the scope of their role to establish and implement effective national regulations, local national regulatory authorities should enforce such criteria. Based on the characteristics of the production process used to manufacture plasma-derived products, the plasma fractionator may suggest additional or alternative exclusion criteria. For instance, in some countries, the plasma from fi rst-time donors is not used.

Deferral : A defi ned list of permanent or temporary deferral criteria used for candidate donors from which the plasma would be used for fractionation, should be clearly stated, made public, and incorporated in the donor educational material. The physician performing the physical examination should be able to identify whether the donor has been previously deferred and, if so, for what reason. Examples of the major permanent deferral criteria found in international guidelines include:

· clinical or laboratory evidence of blood-borne infectious diseases, e.g.

infection with HIV, HBV or HCV;

· past or present intravenous drug use.

Other exclusion criteria, either permanent or temporary, may include:

· sexual relationship between men;

· men or women who are engaged in prostitution;

· subjects with haemophilia or other clotting-factor defects, in particular if treated with clotting factors;

· sexual partners of any of the above or of someone the donor suspects may carry the above risk factors;

· jaundice within the 12 months prior to donation, as it may be a clinical sign of hepatitis A, B or C;

· transfusion with blood, blood components, or plasma products in the 12 months previous to donation, as blood transfusion is a risk factor for all blood-borne infections;

· tattooing, scarifi cation, ear piercing, acupuncture in the 12 months prior to donation. These practices may be a vehicle for the transmission of viral diseases unless clear evidence is provided that the procedure was carried out under sterile conditions;

· a particular policy may be required with regard to the exclusion criteria for a risk factor relevant to the safety of cellular blood components although it does not create safety issues for the preparation of plasma for fractionation and plasma derived products. For instance, risk factors for HTLV infection (e.g. due to travel in countries where the prevalence is high) may be an exclusion criterion for the donation of blood components, but this virus cannot be transmitted by plasma products. It is however not advisable to introduce two screening and quality standards for products separated from a whole blood unit (e.g. red cell concentrates and plasma for fractionation) as this may in itself create a risk of mishandling and error at the blood collection centre.

3.4.4 Reinstatement

When temporary deferral criteria are applied, a specifi c procedure conducted by trained personnel should be in place for reinstatement of donors. Some exclusion criteria are temporary (e.g. as long as a risk factor has been identifi ed) and can be waived once additional checks on the donor have been made, or the time period for exclusion has passed.

3.4.5 Procedures

Based on such criteria, a written procedure should be in place at the blood/plasma collection centre to control donor acceptance and deferral criteria. The procedure should comply with the requirements of the national regulatory authority and fractionator. Abnormal conditions should be referred to the physician who has the responsibility of making the fi nal decision on the donor suitability. If the physician has any doubt about the donor’s suitability, donation should be deferred.

Reference

1. Resolution WHA58.13. Blood safety: proposal to establish World Blood Donor Day. In: Fifty-eighth World Health Assembly. Geneva, World Health Organization, 2005.

Appendix 3

Donor immunization and plasmapheresis for the manufacture of specifi c immunoglobulins

There is a need for hyperimmune plasma for the manufacture of specifi c immunoglobulins that are clinically valid for therapeutic and prophylactic uses.

Donors with acquired antibodies

Plasma may be collected by plasmapheresis from donors who have acquired immunity through natural infection or through active immunization with approved vaccines for their own protection. Donors with medically useful plasma may be identifi ed by screening whole blood donations or by testing the plasma of convalescent patients or vaccinated individuals who have produced high-titre antibodies with the desired specifi city, for example, patients recovering from varicella-zoster infection or donors who have been immunized with rabies vaccine. Unnecessary primary immunizations can be avoided by this approach. Donation of plasma following natural infection should be deferred until the potential donor is asymptomatic, and non-viraemic.

Donors who require immunization

To ensure a suffi cient supply of life-saving immunoglobulins to treat patients, deliberate immunization of healthy volunteers may be necessary in addition to collection of plasma from convalescent patients and donors selected by screening for high levels of specifi c antibodies. The immunization of donors requires informed consent in writing and should take into consideration all the requirements of this Annex.

Donors should be immunized with antigens only when suffi cient supplies of material of suitable quality cannot be obtained from other appropriate donors, or from donations selected by screening. Donors should be fully informed of the risk of any proposed immunization procedure, and pressure should not be brought to bear on a donor to agree to immunization. Women capable of child-bearing should not be immunized with erythrocytes or other antigens that may produce antibodies harmful to the fetus. Donors with known allergies should preferably not be recruited.

Every effort should be made to use the minimum dose of antigen and number of injections. In any immunization programme, the following should be taken into consideration as a minimum:

— the antibody assay;

— the minimum level of antibody required;

— data showing that the dose, the intervals between injections and the total dosage proposed for each antigen are appropriate; and

— the criteria for considering a prospective donor a non-responder for a given antigen.

A donor could be hyperimmunized with more than one immunizing preparation as long as the safety of the procedure of multiple immunizations is demonstrated.

Potential donors should be:

· informed by a licensed physician of the procedures, risks and possible sequelae and how to report any adverse effects, and encouraged to take part in a free discussion (which, in some countries, takes place with small groups of potential donors);

· informed that they are free to withdraw their consent at any time.

In addition, donors may also be:

· encouraged to seek advice from their family doctor, or from an independent competent counsellor, before agreeing to immunization; and

· informed that any licensed physician of their choice will be sent all the information about the proposed immunization procedure.

All vaccines used for immunizing donors should be approved by the national regulatory authority. Special care should be taken to ensure the safety of the donor when a vaccine is administered at doses or according to schedules that differ from those recommended for routine prophylactic immunization. Erythrocyte and other cellular antigens should be obtained from an establishment approved by the national regulatory authority. Donors should be observed for approximately 30 min following any immunization in order to determine whether an adverse reaction takes place. Because reactions often occur 2–3 h after immunization, donors should be advised of this possibility and instructed to contact the facility’s physician if a reaction is suspected in the fi rst 12 h after immunization. Reactions may be local or systemic. Local reactions, which may be immediate or delayed, take the form of redness, swelling or pain at the injection site. Systemic reactions may include fever, chills, malaise, arthralgia, anorexia, shortness of breath and wheezing. An insurance system should be in place to compensate for side-effects to the donor.

Immunization with human erythrocytes

Erythrocyte donors

A donor of erythrocytes for the purposes of immunization should meet all the general health criteria for donors (see Appendix 2). Relevant measures should be taken to limit the risk of infectious diseases; these may vary from country to country taking into consideration the relevant risks. For instance, in some countries, the donor should never have had a blood transfusion in order to reduce risks of vCJD. Prior to the fi rst donation, the donor should be found to be negative for relevant markers, which may include the following: syphilis, HBsAg, anti-HIV, antibody to hepatitis B core antigen (anti-HBc), anti-HCV and antibodies to human T-cell lymphotropic viruses (anti-HTLV), and the serum level of aminotransferases should be within normal limits as established by the national control authority. Erythrocyte phenotyping should be done for ABO as well as for C, D, E, c and e. It is advantageous to select red cells expressing high amounts of RhD antigen, e.g. homozygous D or Rho, for immunization. Phenotyping for other clinically relevant specifi cities is also required , especially for Kell, Fya/Fyb, Jka/Jkb and S/s. The volume of erythrocytes drawn from a donor should not exceed 450–500 ml of whole blood in any 12 week period. Shorter intervals may induce iron defi ciency and, possibly, anaemia. Erythrocytes obtained for immunization purposes should be frozen (at least for 6–12 months depending upon the sensitivity and range of the tests performed, e.g. the use of NAT) before use and the donor should be retested and shown to be negative for the above markers of infection before the stored cells are released and used for immunization. Prestorage leukoreduction of donations is considered desirable, and NAT testing for HBV, HCV and HIV would give an additional level of safety.

Collection and storage of erythrocytes

Erythrocytes should be collected under aseptic conditions into sterile pyrogen-free containers in an appropriate proportion of an approved anticoagulant. They may then be dispensed in aliquots under aseptic conditions into single-dose sterile, pyrogen-free containers for storage. The microbiological safety of the dispensing environment should be validated. The method selected should have been shown to provide acceptable cell recovery in vitro (80%) or in vivo (70%). Erythrocytes should be washed after storage to remove the cryoprotective agent (e.g. glycerol). Adequate sterility data to support the shelf-life for stored erythrocytes should be kept on fi le. A test for bacterial and fungal contamination should be done on all blood dispensed in aliquots in an open system. The test should also be performed on at least one single-dose vial from each lot of whole blood that has been stored unfrozen for more than seven days. The test should be done on the eighth day after collection and again on the expiry date. Sterility tests should be performed following an approved procedure.

Erythrocyte recipients

The following additional testing of erythrocyte recipients is necessary:

· The recipient should be phenotyped for ABO, Rh, Kell Fya/Fyb, Jka/Jkb and S/s antigens before immunization. The red cell donor and the recipient should be matched as far as possible for major blood group antigens other than RhD. Only ABO-compatible erythrocytes may be transfused. Whereas mismatching within the Rh system for C and or E is acceptable, mismatching in the Kell, Fy, Jk and S/s systems is unacceptable.

· Screening for unexpected antibodies by methods that demonstrate coating and haemolvtic antibodies should use the antiglobulin method or a procedure of equivalent sensitivity.

Prospective erythrocyte recipients in whom antibody screening tests demonstrate the presence of erythrocyte antibodies (other than those deliberately stimulated through immunization by the plasmapheresis centre) should be asked whether they have ever been pregnant or had a blood transfusion, a tissue graft or an injection of erythrocytes for any reason. This history should form part of the permanent record and should identify the cause of immunization as clearly as possible. Recipients should be notifi ed in writing of any specifi c antibodies they have developed after injection of erythrocytes. The plasma centre should maintain records, which should be reviewed during inspection. The immunized donor should carry a card or medicalert bracelet specifying the antibodies. These measures allow optimal care of immunized donors who may require an emergency transfusion, (e.g. following a road traffi c accident) at some future time, and for whom knowledge of the antibody status, especially mixtures of antibodies, is important.

Immunization schedules

Erythrocytes used for immunization purposes should not be administered as part of any plasmapheresis procedure. Such immunization may be performed on the same day as plasmapheresis, but only after it and as a separate procedure.

To minimize the risk of infection to the donor, the immunization schedule should involve as few doses of erythrocytes as possible. Wherever possible, the same red cell donor should be used throughout the immunization programme of an individual plasma donor.

For primary immunization two injections of erythrocytes, each of a volume of about 2–5 ml and given 3 months apart, elicit antibody formation within three months of the second injection. Different schedules may be used for de novo immunization. It is advantageous to choose as donors of anti-D (anti-Rho) volunteers who are already immunized, because useful levels of anti-D are then usually attained within a few weeks of reimmunization with 2–5 ml of erythrocytes. About 70% of immunized volunteers eventually produce antibody levels well above 100 IU/ml. The baseline antibody titre of every recipient of erythrocytes should be established, and the antibody response, including both type and titre, should be monitored monthly to establish the peak level of anti-D and duration of the response. The response of each recipient is individual, and additional injections of erythrocytes may be required at intervals of 2–9 months to maintain anti-D levels (1). If injections of erythrocytes are discontinued, antibody levels usually fall appreciably within 6-12 months. Erythrocytes to be used for immunization purposes should be selected, for each recipient, by a licensed physician or a suitably trained and qualifi ed person.

Donors undergoing primary immunization who have not responded to a total of up to 150 ml erythrocytes are likely to be ‘non-responders’ and should be removed from the panel.

Plasmapheresis schedules

Donors should comply with the requirements for health screening and maximum plasma donation allowed by their national authorities.

Risks to recipients

Recipients of erythrocytes for immunization purposes may be at risk of:

— viral hepatitis (B and C) and HIV infection;

— other infectious diseases;

— HLA immunization;

— the production of unwanted erythrocyte antibodies that may complicate any future blood transfusion;

— a febrile haemolytic reaction if the antigen dose is too high; — vCJD in countries where this is endemic.

Record-keeping

Records of erythrocyte donors and of the recipients of their erythrocytes should be maintained and cross-referenced and stored at least for the minimum time required for blood transfusion recipients by the national authorities.

Reference

1. Cook I et al. Frozen red cells in Rhesus immunization. British Journal of Haematology, 1980, 44:627.

Appendix 4

Contract plasma fractionation programme

The fractionation of plasma requires specialized facilities, with provision for large-scale protein separation, purifi cation, virus inactivation and formulation, as well as for aseptic fi nishing and freeze-drying. The preparation of plasma-derived products should be governed by the same regulatory considerations that are applied to medicines. Manufacturers are required to obtain manufacturing licences which should cover the method of preparation and product characteristics. To obtain a licence, it is necessary to demonstrate adherence to GMP. Considerable technological, pharmaceutical and scientifi c expertise is required to meet these demands. Since key utilities (such as heating, ventilation and air-conditioning (HVAC), refrigeration and water for injection) should be maintained operational even when the facility is not fractionating plasma, the investment in and running costs of fractionation are substantial. The economic viability of a fractionation facility will be determined by:

· the cost of the plasma for fractionation (in particular cost-allocation of the whole blood collection system on plasma versus labile components);

· the operating capacity of the facility; and

· plasma availability and product demand to allow the facility to operate continuously at near to maximum capacity.

The break-even point for minimum annual plasma throughput for economic viability may vary greatly according to a set of parameters, these including plasma cost, product portfolio, adequacy of the various plasma products versus the plasma needed to cover those needs, and product yield. Therefore such projects require a careful feasibility study.

Countries which cannot justify building and operating a fractionation facility, may opt to have plasma collected locally and shipped for processing in an independent facility—so-called contract or toll fractionation. Plasmaderived products are then returned to the originating country on payment of a fee (toll). Such arrangements can work well, subject to specifi c provisions being made and adhered to. These include:

· commercial and quality agreements defi ning the responsibilities of both parties (the contract giver and the contract acceptor);

· clearly defi ned requirements for plasma quality (including the arrangements for donor selection, testing and traceability);

· provision for audit of the plasma collection centre (by the fractionator) and inspection by an appropriate regulatory body;

· formal approval of the contract plasma fractionation activities by the regulatory authority of the fractionator;

· a contractual commitment to supply agreed quantities of plasma. The annual minimal volume is dependent upon the fractionator’s overall free capacity and specifi c aspects of production such as plasma pool and product batch size;

· agreement on the arrangements for storage and shipment of plasma, with defi ned provisions for monitoring and control (typically transport by sea, at –20 °C or below);

· agreement on the range of products to be manufactured; and

· agreement on specifi c aspects of plasma processing (including batch size, possible requirements for segregation of processing, agreed use or destruction of excess intermediates, expected yield and toll fees).

Plasma products made from local plasma need to receive a specifi c registration, even if the same products made from foreign plasma are already licensed in the country of origin.

The regulatory authorities of the country where the plasma is collected may require inspection of the fractionation centre. Table 1 summarizes the responsibilities and roles of each party.

Table 1

Responsibilities and roles of blood establishment, plasma fractionator, and regulatory authorities

a See sections 7 and 8 of this annex.

Appendix 5

Technical points to consider in establishing plasma specifi cations criteria and obligations between blood establishment and plasma fractionator

The purpose of the contract is to have a “legally binding” document between the plasma supplier and the fractionator.

The following is an example of the quality control and documentation required by a plasma fractionator to acquire plasma for fractionation from a blood establishment. It is not meant to represent the only possible way to defi ne plasma specifi cations criteria and obligations between a blood establishment and a plasma fractionator. Depending upon the prevalence of blood-borne diseases in a country, additional safety requirements on donor selection and testing should be considered.

General specifi cations

Donors

Reference should be made to local regulations pertaining to the selection, eligibility, and exclusion criteria for donors of blood or plasma used for the manufacture of blood components and plasma derivatives. Newly introduced criteria may be spelled out (such as travel restrictions related to vCJD).

Blood establishments

Reference should be made to the offi cial legislation of blood establishments in the country of origin and to relevant legislation relating to plasma fractionation.

Donation process and plasma unit specifi cations

The contract should cover the following aspects of the donation process and plasma unit specifi cations.

• Collection process of the blood/plasma units:

— containers, collection sets and anticoagulants with relevant registration;

— duration of the whole blood collection (e.g. less than 15 minutes (1) for recovered plasma);

— guarantee that blood will be mixed with the anticoagulant as soon as the collection starts, by regular manual shaking or using a validated automated method (1);

— prior to freezing, plasma is clear (light opalescence may be allowed), yellow to — green in colour, with no sign of haemolysis or presence of red cells (2); and

— acceptable citrate concentration range.

· Infectious markers:

— test kits used should be of acceptable sensitivity and be agreed with manufacturer;

— anti-HIV 1 and 2, anti-HCV and HBsAg should be absent, and there should be no laboratory evidence of syphilis;

— when applicable: specifi c handling of anti-HBc positive donations (e.g. accepted only if anti-HBs antibody titre > 0.050 IU/ml and HBsAg negative); and

— HCV NAT and HIV tests must be negative (i.e. when a blood establishment organization performs NAT for HCV and HIV for blood components).

· Immunohaematological markers

— anti-A and anti-B titre < 1/64 using a validated assay;

— special requirements relative to the absence of irregular antibodies.

· Cellular content and haemoglobin

— statistical records of blood cell contamination showing that the relevant specifi cations are met. Some countries/fractionators have set specifi c limits on the residual leukocyte content of plasma for fractionation;

— statistical records of haemoglobin contamination showing that the relevant specifi cations are met.

· Protein quality control

— protein content ≥ 50 g/l after mixture with the anticoagulant;

— when plasma is used for production of factor VIII concentrate; minimum factor VIII content to be specifi ed for a pool sample of a defi ned number of donations

· Other criteria

— minimal acceptable volume of plasma per container;

— plasma freezing conditions: core temperature, time taken to freeze, and absence of folding to avoid a thin plasma layer that would be more susceptible to thawing during subsequent handling;

— maximum acceptable thickness of plasma containers;

— positioning of the donation identifi cation label (number and bar code);

— plasma storage temperature;

— plasma density (used to determine the volume of plasma shipped to/ received by fractionator);

— maximum time elapsed between donation and shipment to the fractionator.

Standard plasma

Plasma types

Plasma categories vary depending upon fractionator and local regulations. For instance, some fractionators may classify as plasma, either from whole blood or from apheresis, based on the time interval between the collection procedure and freezing.

Examples of plasma categories include:

· Category A: apheresis plasma frozen within 6 hours, with a factor VIII content ≥ 0.7 IU/ml;

· Category B: Recovered plasma with a factor VIII content ≥ 0.7 IU/ml, obtained from whole blood kept at 20–22 °C and frozen within 6 hours (in the absence of devices to maintain blood temperature), or frozen within 20 hours (if devices to maintain blood temperature are used);

· Category C: Plasma frozen within 24 hours after collection, or plasma initially categorized as A or B but containing ≤ 0.7 IU factor VIII/ml. This plasma is used to produce immunoglobulins and albumin only.

Hyperimmune plasma

Quality criteria

Acceptable criteria include:

· protein content, factor VIII, haemoglobin: usually the same as for standard plasma;

· a minimum potency level will be set for each antibody type. Where possible, the required potency will be specifi ed in IU per ml when assayed using an agreed method which includes an agreed reference control calibrated in IU/ml. Examples of limits are as follows:

— anti-tetanus: 10 IU/ml;

— anti-varicella/zoster: 10 IU/ml;

— anti-HBs: 25 IU/ml;

· Indication of the assay procedure, procurement of standards, test laboratory and communication procedure of the data.

Documentation

Each blood establishment delivering plasma should have an approved organizational chart, and changes should be communicated to the plasma fractionation centre according to an agreed procedure.

Shipping documentation should include:

· dated shipping document signed by responsible person;

· certifi cate of origin and control of the plasma, stating for each donation the:

— collection date;

— carton number;

— results of virology and immunohaematology screening;

— test kits used and their batch number;

— signature of the director or an authorized person;

· password-protected electronic fi le of the plasma donations and samples sent, stating for each donation collection date (this needs to be agreed with the fractionator):

— carton number;

— results of virology and immunohaematology screening;

— test kits used and their batch number;

· upon request, additional information on viral screening tests and confi rmatory assays can be provided to the fractionator;

· epidemiology data should be made available as appropriate, e.g. annually.

Shipment

Specifi cations relating to shipment include the following:

Plasma donations

· Broken plasma containers are not acceptable.

· When applicable, specifi cations of “pig tail” used for additional screening tests by the fractionator (e.g. length of 10–20 cm, attached to the plasma donation, and ideally, identifi ed with the donation number).

· Specifi cation of the plasma container identifi cation (labels and barcode).

· Specifi cation on potential additional samples sent with the shipment for additional screening tests such as NAT or for the look-back procedure.

· Statement on minimal number of plasma containers per shipping box or carton, and positioning.

Containers for shipment

Auditing programme

The contract should cover the following aspects of the auditing programme:

· obligation of the blood establishment to be subjected to auditing by the fractionator;

· routine auditing performed by the fractionator should follow an internally approved and regularly revised procedure with an established list of questions and check-points;

· special auditing performed annually/biannually based on a programme previously communicated to the director of the blood establishment;

· audit reports are communicated to the director of the blood establishment;

· list of reference documents (such as internal acceptance criteria for the preparation of plasma for fractionation).

Notifi cation obligations

Notifi cation obligations cover the following:

· obligation to notify the fractionator each time the safety of a previous donation may be questionable;

· obligation to notify the fractionator when:

— a unit positive for viral markers such as HBsAg, HIV-1 and HIV-2 antibodies, HCV antibody or syphilis has been sent by mistake;

— a deviation is subsequently discovered in any of the screening tests performed on the plasma units supplied. In this situation, the blood establishment should attempt to retest the implicated units if suitable library samples are available;

— a regular donor is found to be positive for a marker although the previous donation was found to be negative;

— the blood establishment is informed that a donor, previously contributing to plasma for fractionator, has developed an infectious disease potentially transmissible by plasma;

— a donation is found to have transmitted an infectious disease, or there is strong evidence implicating a donation in disease transmission;

— the blood establishment is informed that a donor previously contributing to plasma for fractionation: (a) has developed CJD or vCJD (in such a case the report with the pathological fi ndings should be provided if available); (b) has risk factors for vCJD; or (c) is identifi ed as exhibiting risk behaviour or other factors that affect the safety of the plasma;

— the blood establishment is informed that a patient has developed posttransfusion infection following transfusion of blood component(s) obtained from a donor who has also donated one or more units of plasma for fractionation.

Notifi cations should provide the list of all donations made within a 6-month period prior to the last donation found to be negative. The period of time depends on local regulations and the type of disease. The fractionator may request additional data on previous donations when thought necessary.

A communication procedure must be in place indicating information that must be provided. This should include:

· name of qualifi ed person at the fractionator to be contacted;

· reasons and description of the problem (under confi dentiality clauses);

· the time period between information being known and communication to the fractionator;

· if the problem is related to an infectious disease, a list of all plasma for fractionation donations made in the defi ned period prior to the last donation found negative;

· name of the blood establishment, director, donation number, carton number as indicated on the electronic fi le sent with the shipment, date of shipment, date of notifi cation and signature of the responsible person or his or her delegate.

References

1. Anonymous. Guide to the preparation, use and quality assurance of blood components. 13th ed. Strasbourg, Council of Europe Publishing, 2007.

2. Anonymous. Monograph of human plasma for fractionation 01/2005:0853 corrected. European Pharmacopoeia, Strasbourg, 2005.

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