Administering Files, Records, and Grants

Examples of anticoagulant solutions commonly used in the preparation of plasma for fractionation

(×), seldom used; ×, commonly used.

6.4.2 Labelling of collection bags

There should be a secure system for procurement, printing and storing of the bar code labels used to identify the main collection bags and the satellite bags, associated samples and documentation to ensure full traceability at each stage of plasma production. There should be a defi ned procedure for labelling collection bags and samples — in particular to ensure that the labels correctly identify the association between samples and donations. Labelling should be performed in a secure manner, e.g. at the donor couch, prior to collection, or immediately after the start of collection, to avoid mislabelling. Duplicate number sets of bar code donation numbers should not be used. Information on the label of the donation should include: offi cial name of the product; volume or weight; unique donor identifi cation; name of the blood establishment; shelf-life or shelf term; shelf temperature; and name, content and volume of anticoagulant.

6.4.3 Equipment

Equipment used for the collection and further separation of blood should be maintained and calibrated regularly, and the collection and separation process needs to be validated. When validating the quality of the recovered plasma, a set of quality control tests, including measurement of total proteins, residual blood cells, haemoglobin, and relevant coagulation factors, such as Factor VIII, should be included. In addition, markers of activation of the coagulation and fi brinolytic systems may, if necessary, be performed with the support of the plasma fractionator based on the specifi cations of the plasma for fractionation set out by the fractionator and/or the national regulatory authority.

Likewise, apheresis equipment and apheresis procedures should be validated, maintained and serviced. Validation criteria for assessing the quality of plasma for fractionation also include protein recovery, residual content of blood cell and haemoglobin, and relevant coagulation factors. Validation studies of new apheresis procedures should also evaluate possible risks of activation of the coagulation, fi brinolysis, and complement systems potentially induced by the material in contact with blood (25, 35, 36); such studies are usually performed by the manufacturer of the apheresis machines.

6.4.4 Laboratory samples

Laboratory samples should be taken at the time of blood/plasma collection. Procedures should be designed to avoid any mix-up of samples and samples awaiting testing should be stored at an appropriate temperature, as specifi ed in the operating instructions of the test kits.

6.4.5 Volume of plasma per unit

The volume of recovered plasma per container varies depending upon the volume of whole blood collected, the respective haematocrit of the donor, and the volume of the anticoagulant solution. The volume of apheresis plasma per container depends directly upon the volume collected during the apheresis session and the volume of anticoagulant. The range of volume of blood and plasma collected per donor is usually defi ned in national regulations taking into consideration criteria such as the weight of the donor.

Although in most countries the volume of whole blood collected is close to 400–450 ml per donor, in some it may be as low as 200 ml (under those circumstances, the volume of anticoagulant solution is reduced so that the plasma:anticoagulant ratio is constant). As a result the volume of recovered plasma per unit (including anticoagulant) may vary from about 100 to 260 ml per container. In the case of plasmapheresis plasma, the volume may range from about 450 to 880 ml per container, depending upon the regulations in the country of collection.

The volume of plasma per container has direct practical impact on the fractionation process and manufacture of plasma products. Small-volume donations (e.g. 100 ml) will require more handling by the plasma fractionation operators at the stage of plasma preparation, at the container opening step, and during plasma thawing. The overall container opening process will take longer, requiring additional care to control bacterial contamination. Another consequence is that the number of donations contributing to a plasma pool will be higher (for instance, 20 000 plasma donations for a pool size of 2000 litres).

6.4.6 Secure holding and reconciliation

When the collection process is fi nished, it should be ensured that blood/ plasma donations are held at the donation site using a secure system to avoid mishandling.

Prior to dispatching the collected donations to the blood/plasma processing site, reconciliation of the collected donations should be performed according to a standardized procedure. The procedure should also specify the actions to be taken if there are found to be missing numbers or leaking containers. Documentation should accompany the donations to the plasma processing site, to account for all donations in the consignment.

6.4.7 Donor call-back system

A system should be in place in the blood establishment which allows recall of a donor if further analysis or investigation is necessary.

6.5 Separation of plasma

6.5.1 Premises

Blood processing should be carried out in adequate facilities suitable for the needs of the intended activity. The donor area and plasma processing areas should be separated whenever possible. Each area used for processing and storage should be secured against the entry or intervention of unauthorized persons and should be used only for the intended purpose. Laboratory areas and plasma storage areas should be separate from the donor and processing areas.

6.5.2 Intermediate storage and transport

Transport of the donations and samples to the processing site should be done according to procedures that ensure both constant approved temperature and secure confi nement. This is especially important when blood/plasma is transported from distant blood drive sessions.

Temperature monitoring is important to ensure optimal compliance and quality. One way is to use packaging methods that can keep the blood/ plasma within the required temperature limits. Portable temperature loggers can be used to monitor and record temperatures during the transportation of blood/plasma to the processing site.

6.5.3 Impact of whole-blood holding period

It has been shown that whole blood anticoagulated with CPD, transported and stored at 22 °C for up to 8 h prior to separation of plasma is suitable for the production of plasma for fractionation, but factor VIII activity is reduced by an additional 15–20% if blood is stored for 24 h (37). Rapid cooling of whole blood to 22 °C +/– 2 °C immediately after collection (e.g. using cooling units with butane-1,4-diol) (38) protects factor VIII and may allow storage of blood for 24 h (39). A temperature of 4 °C during transportation or storage of blood collected with either ACD, ACD-adenine, or CPD anticoagulants consistently appears to reduce the factor VIII content, but not necessarily that of other proteins, especially after 8 hrs of holding time (40–43). Holding blood at 4 °C for longer than 8 h is therefore not recommended when plasma is used for fractionation in the manufacture of factor VIII products.

6.5.4 Centrifugation of whole blood

Documentation on blood and plasma collection should be checked at the processing laboratory on receipt of the donations; reconciliation between consignment and documentation received should be performed. Blood separation procedures should be performed using a closed system and should be validated, documented and proven to ensure that containers are correctly identifi ed.

Reproducible production characteristics of the plasma for fractionation, following a validated procedure, should ensure consistency in the residual blood cell count and protein content and quality to meet the specifi cations set out by the blood establishment or the national regulatory authority and the plasma fractionator.

Comparisons have shown that CPD whole blood units that were centrifuged under conditions of low g force for a long time and those subjected to high g force for a short time yielded blood components of similar quality (44). Blood separation classically starts with the isolation of the platelet-rich plasma (PRP) fraction from whole blood by low-speed centrifugation. Subsequent high-speed centrifugation of PRP in turn yields the corresponding platelet concentrate and the plasma.

Fully automated systems for blood processing including removal of the buffy-coat layer have replaced manual extraction procedures. This allows standardized extraction and contributes to compliance with GMP in the preparation of blood components including plasma for fractionation (45). Blood component separation systems may be based on buffy coat extraction by the “top and bottom” technique (46). Its effi cacy in terms of yield, purity, and standardization of blood components has been well established.

Several technical approaches have been developed to separate blood components. The process may involve normal centrifugation to separate the blood components, which are subsequently squeezed out from the top and bottom simultaneously under control of a photocell. This primary separation step results in three components: a leukocyte-poor red-cell suspension, plasma, and a buffy-coat preparation (46). A multiple-bag system with top and bottom drainage of the primary bag allows automatic separation of blood components; plasma containing 14.6 ± 5.6 × 103 platelets/µl and 0.04 ± 0.035.6 × 103 leukocytes/µl is obtained (47). Blood components may be separated by initial high-speed centrifugation (4158 g, 14 min, 22 ºC) of whole blood in sealed triple or quadruple bag systems, followed by simultaneous extraction of fresh plasma at the top, and the red blood cell concentrate at the bottom, of the respective satellite bags that constitute the blood extraction bag system — keeping the leukocyte-platelet buffy coat layer stable throughout the process within the original extraction bag. The buffy coat component yields the platelet concentrate after low-speed centrifugation and removal of the plasma from the PRP. Automatic separators that subsequently express the various components into their respective satellite bags in top and bottom systems yield plasma containing 3 ± 3 × 106 leukocytes and 4 ± 3 × 109 platelets per unit (48). The “top and bottom” approach allows a marked reduction in leukocyte contamination of the different blood components (38, 49), and may yield optimal plasma volume (38).

6.5.5 Impact of leukoreduction

Recently, several countries have implemented universal leukoreduction of the blood supply (50, 51) to avoid cell-mediated adverse events or improve viral safety of blood components. It has also been considered as a precautionary measure against the risk of transmission of variant Creutzfeldt-Jakob disease (vCJD). A recent study in an endogenous animal infectivity model reports that leukoreduction of whole blood removes 42% of the vCJD infectivity associated with plasma (52), whereas further investigation by the same group found a ~70% removal of infectivity (R. Rohwer, unpublished data). The impact of leukoreduction on plasma protein recovery and activation markers appears to depend upon the chemical nature of the fi lters (53, 54). Some loss of coagulation factors and sometimes an increase in the markers of coagulation and complement activation has been found, although the impact on the quality of fractionated plasma derivatives is not known (54, 55).

Therefore, until more scientifi c data are gathered, the benefi ts of leukoreduction for the quality and safety of plasma products remains debated. The decision to leukoreduce plasma for fractionation should be assessed with the plasma fractionator and the national regulatory authority.

6.6 Freezing of plasma

Freezing is an important processing step that has an impact on some aspects of the quality of plasma for fractionation, in particular with regard to the content of factor VIII.

Several aspects of the freezing conditions of plasma for fractionation have been evaluated.

6.6.1 Holding time of plasma

Holding plasma, freshly harvested from CPD-whole blood, at ~ 4 °C for up to 24 h before freezing at –20 °C for 4 months was shown to induce almost 25% loss of factor VIII activity compared to that in plasma frozen immediately, whereas other coagulation factors were not affected (56). Storing plasma at 22 °C for 2–4 h does not seem to induce a signifi cant loss of factor VIII activity; however, after 4 h, some loss of activity takes place (41, 57).

Therefore, placing recovered plasma in a freezer as soon as possible, or at least within 4 h, after separation from cellular elements, would be favourable to the recovery of factor VIII. Similarly apheresis plasma should be frozen as soon as possible after completion of the collection procedure.

6.6.2 Freezing rate and freezing temperature

6.6.2.1 Freezing conditions

The regulatory requirements for the temperature at which plasma should be frozen vary (58), and depend upon the type of proteins fractionated.

The fractionator may also wish to specify freezing conditions depending on the intended use of the plasma.

The European pharmacopoeia currently states that recovered or apheresis plasma for fractionation to be used for the manufacturing of labile proteins (e.g. production of factor VIII concentrate) should be frozen rapidly, within 24 hours of collection, at –30 °C or colder (26), as this temperature has long been claimed to ensure complete solidifi cation (59), and to be needed for optimal freezing (60). However, freezing conditions are currently under debate and the wording used in the European pharmacopoeia monograph may be revised. Recovered plasma used to manufacture only stable plasma proteins (e.g. albumin and immunoglobulins) should be frozen within 72 h of collection at –20 °C or colder.

The US Code of Federal Regulations specify that plasma collected by apheresis and intended as source material for further manufacturing should be stored at –20 °C or colder immediately after collection.

The rate at which freezing proceeds is considered to be an important quality factor, at least when coagulation factors are intended to be produced (61, 62). Rapid freezing of plasma prevents or reduces loss of factor VIII in frozen plasma either recovered or obtained by apheresis (23, 63, 64), whereas slow freezing of plasma has been shown to infl uence the purity and recovery of factor VIII in cryoprecipitate (61, 64–66). An ice front velocity of 26 mm/h during freezing was recently shown to preserve factor VIII:C in plasma better than 9 mm/h or less (57).

Therefore, freezing plasma rapidly (typically in less than 2 h, so as to ensure a high ice front velocity) down to a core temperature of at least –20 °C, and preferably colder, appears to be the best approach for the preservation of labile proteins.

6.6.2.2 Impact of containers and equipment

To ensure optimal and consistent freezing and storage conditions, it is important to use standardized plasma containers as freezing time is infl uenced by container shape, volume and thickness (57, 64, 65).

Optimum conditions used by some plasma collectors to ensure reproducible freezing are achieved by freezing “well separated” plasma packs in a stream of moving cold air at the lowest temperature tolerable to the plastic of the pack (a so-called “blast freezer”), and then to store the frozen packs “closepacked” in a storage freezer at the agreed upon storage temperature. The worst case would be to place a large number of unfrozen plasma bags, close together, in a domestic (–18 °C to –22 °C) freezer, adding more plasma bags for freezing each day, and storing the plasma under these conditions for several months. With good practice at the time of loading (i.e. not putting too many packs in at the same time and keeping them separated), a walk-in freezer at a suitable temperature offers a workable compromise.

The plasma fractionator should specify precisely to the plasma collector, with the approval of the national regulatory authority, which precise freezing parameters to use.

6.6.2.3 Validation of the freezing process

Recovered plasma and apheresis plasma should be shown to be frozen in a consistent manner at the required temperature. A system should be in place for ensuring that plasma is frozen to the correct core temperature within the time limit agreed upon with the plasma fractionator, keeping in mind that the speed of freezing will be infl uenced by the type of plasma container as well as by the volume of plasma (64). Validation of the freezing process by recording the temperature of plasma donations during a freezing process allows evaluating the freezing capacity of the equipment to be evaluated. Validation studies should be available, and should demonstrate that the temperature of a frozen pack reaches the proposed storage temperature following the specifi cations agreed upon with the manufacturer.

As indicated above, the aim should be to achieve rapid freezing, and thereafter to minimize temperature changes to the frozen plasma.

6.7 Storage of plasma

6.7.1 Storage conditions and validation

Plasma for fractionation should be stored at –20 °C or colder.

A multicentre study showed no detectable storage-related changes in three pools of plasma (2 recovered CPD plasma and 1 apheresis plasma) that had been quick-frozen at –30 °C, or colder, and stored over a period of 36 months at –20 °C, -25 °C, -30 °C, or –40 °C. An 11% reduction in factor IX was found in one of the recovered plasma pools during storage at –20 °C for 2 years (67). The authors concluded that plasma may be stored at –20 °C for 2 years, or at –25 °C, –30 °C, or –40 °C for 3 years.

By keeping the average storage temperature of the frozen plasma as constant as possible, at or below –20 °C, the original quality of the plasma is maintained, without having any impact on the fractionation process, in particular the cryoprecipitation step (60, 61, 66).

The European pharmacopoeia has a provision stating that if the temperature of the plasma is between –20 °C and –15 °C for a maximum of 72 h, or if it is above –15 °C (but colder than –5 °C) in no more than one occurrence, the plasma can still be used for fractionation. Therefore, maintaining a constant storage temperature of –20 °C or colder is a recommended approach to ensure a consistent and optimal plasma quality.

6.7.2 Premises and equipment

Storage conditions should be controlled, monitored and checked. Temperature records should be available to prove that the full plasma containment is stored at the temperature agreed upon with the plasma fractionator throughout the storage area. Appropriate alarms should be present and regularly checked; the checks should be recorded. Appropriate actions on alarms should be defi ned. Areas for storage should be secured against the entry of unauthorised persons and should be used only for the intended purpose. Storage areas should provide effective segregation of quarantined and released materials or components. There should be a separate area for rejected components and material.

If a temporary breakdown of the freezing machine or failure of the electricity supply occurs (e.g. electricity used for the stored plasma), examination of the temperature records should be made together with the plasma fractionator to evaluate the impact on plasma quality.

6.7.3 Segregation procedures

The following should be taken into account in the storage and boxing of plasma for fractionation.

· Untested plasma and released plasma should be stored in separate freezers, or if both types of plasma are stored in a single freezer a secure segregation system should be used.

· Initially reactive plasma donations should be stored in a separate quarantine freezer or a secure system (e.g. validated computer hold system) should be used to prevent boxing of non-released plasma.

· Donations that are found to be unacceptable for fractionation should be retrieved, disinfected and discarded using a secure system.

· Plasma donations for shipment to the plasma fractionator should be boxed in a secure manner and an effective procedure (such as a computerized system) should exist to make sure that only fully tested and released plasma donations are boxed.

· Prior to shipment, plasma boxes should be reconciled appropriately.

· Prior to release of the plasma shipment to the fractionator, there should be a formal review of the documentation to ensure that the plasma shipped complies fully with the specifi cations agreed upon with the plasma fractionator.

The goal of the above-mentioned measures is to make sure that donations that do not comply with the specifi cations agreed upon with the fractionator will not be released and shipped, and that traceability of donations is ensured.

6.8 Compliance with plasma fractionator requirements

Any plasma collected and prepared for fractionation should meet the plasma product manufacturer requirements as the specifi cations of plasma for fractionation are part of the marketing authorization granted by the national regulatory authority for a specifi c plasma derivative. In addition, to the regulatory criteria related to donor selection and screening of donations, the quality specifi cations agreed upon with the fractionator may encompass:

— compliance with GMP during production and control;

— residual level of blood cells (platelets, leukocytes) that should be below a certain level that may vary depending upon the requirements of different countries or fractionators;

— protein content possibly including a minimal mean level of Factor VIII coagulation activity if this product is manufactured;

— guarantee of an appropriate ratio of plasma:anticoagulant solution (see Table 6) and evidence of appropriate mixing with the anticoagulant

during the collection process (for instance, clots should be absent);

— acceptable maximum titre of ABO blood group antibodies (risks of haemolytic reactions due to the presence of ABO antibodies, or antibodies to other blood group systems, in intravenous IgG and lowpurity factor VIII preparations have been described (68)). The European pharmacopoeia requires an ABO titre of less than 1:64 for the release of plasma products for intravenous use.

— maximum haemoglobin content;

— absence of haemolysis;

— colour;

— absence of opalescence (due to lipids);

— citrate (anticoagulant) range content (usually between 15 and 25 mM); and

— minimum titre of a specifi c antibody when the donation is used for the production of hyperimmune IgG such as anti-Rho, anti-HBs, anti-tetanus or anti-rabies.

6.9 Release of plasma for fractionation

Each blood establishment should be able to demonstrate that each unit of plasma has been formally approved for release by an authorized person preferably assisted by validated information technology (IT)-systems. The specifi cations for release of plasma for fractionation should be defi ned, validated, documented and approved by quality assurance and the fractionator.

There should be a system of administrative and physical quarantine for plasma units to ensure that they cannot be released until all mandatory requirements have been satisfi ed. In the absence of a computerized system for control of product status, the label of the plasma unit should identify the product status and should clearly distinguish released from non-released (quarantined) plasma. Records should demonstrate that before a plasma unit is released, all current declaration forms, relevant medical records and test results have been verifi ed by an authorized person.

Before fi nal product release, if plasma has been prepared from a donor who has donated on previous occasions, a comparison with previous records should be made to ensure that current records accurately refl ect the donor history.

In the event that the fi nal product is not released due to potential impact on plasma quality or safety, all other implicated components from the same donation should be identifi ed. A check should be made to ensure that (if relevant) other components from the same donation(s) and plasma units or other components prepared from previous donations from the same donor(s) are identifi ed. There should be an immediate update of the donor record(s) to ensure that the donor(s) cannot make a further donation, if appropriate.

6.9.1 Plasma release using electronic information systems

Special documented evidence is needed if release of plasma is subject to use of electronic information systems (EIS) to ensure that the system correctly releases plasma units only if all requirements are met. The following points should be checked:

· The EIS should be validated to be fully secure against the possibility of plasma which does not fulfi l all test or donor selection criteria, being released.

· The manual entry of critical data, such as laboratory test results, should require independent verifi cation by a second authorized person.

· There should be a hierarchy of personnel permitted access to enter, amend, read or print data. Methods of preventing unauthorized entry should be in place, such as personal identity codes or passwords which are changed regularly.

· The EIS should block the release of plasma or other blood components considered not to be acceptable for release. There should also be a means to block the release of any future donation from a donor.

6.10 Packaging of plasma

The packaging requirements should be specifi ed by the fractionator. The specifi cation should include the following information:

— how the plasma containers are to be packed to prevent damage during shipment;

— that plasma of different types should be kept discrete and packaged into separate cartons; and

— that each carton should have a unique identifi cation number or a bar code which should be clearly displayed on the carton and recorded in the shipping documentation.

6.11 Transportation of plasma

Although it is possible to think of transport as an extension of storage, some additional qualifi cation is appropriate. This need arises because of the additional requirements for risk management during transport. Plasma is at increased risk when:

· Responsibilities for storage and transportation conditions change (especially when handling is the responsibility of individuals with little understanding of the consequences of temperature elevation, as will often be the case with contract shippers).

· Plasma is moved from one freezer or container to another (especially if this involves even temporary exposure to ambient temperatures, as on the loading dock of a blood establishment or a fractionation facility).

· The usual provisions for backup in the event of failure of the refrigeration system are not available (as during sea-transportation of several weeks duration).

The recommendations for cold chain maintenance, as mentioned for plasma storage, should also apply during transportation of plasma. The arrangements for temperature control and monitoring during shipping should be clearly defi ned and documented. The requirements for number and location of temperature logging devices during shipping should be based on a documented assessment of risk throughout the process. The temperature to be maintained during transportation should be defi ned by the fractionator in accordance with relevant regulations.

The responsibilities of organizations and individuals during shipping should be identifi ed; in particular any requirements for documented handover checks should be specifi ed. The fi nal responsibility for acceptance of quality as compliant with specifi cation lies with the quality department of the fractionation facility.

Table 7 summarizes some recommendations on the handling of blood and plasma to optimize the recovery of labile proteins such as factor VIII in plasma. These recommendations should be examined keeping in mind that the relationship between the content of factor VIII in the starting plasma and its recovery in factor VIII concentrates is unclear (40, 69), possibly in part due to the loss of factor VIII that takes place during industrial cryoprecipitation (70) as well as during purifi cation and virus reduction procedures.

Table 7

Processing of plasma for fractionation to optimize factor VIII stability

a Collection of plasma by apheresis makes it possible to freeze plasma immediately after the end of the collection procedure by contrast to whole blood processing.

6.12 Recall system

In the case of known or suspected quality defects of a plasma unit that has already been shipped, a person within the blood establishment should be nominated to assess the need for product recall and to initiate and coordinate the necessary actions. An effective recall procedure should be in place, including a description of the responsibilities and actions to be taken. Actions should be taken within predefi ned periods of time and should include tracing all relevant components of the donation and, where applicable, should include look-back procedures.

7. Quality assurance system and Good Manufacturing Practices

Human plasma for fractionation is the single most critical raw material in the manufacture of plasma derivatives. Fractionators should only use plasma for fractionation from blood establishments that are subject to inspection and approved by a national regulatory authority. When the mandatory safety testing is outsourced, the laboratories need to be inspected and approved. The safety and quality of plasma for fractionation should be assured by implementation of standards at the blood establishment where plasma is prepared. These standards should be assured by implementation, at the blood establishment, of an effective QA system based on the principles of

GMP.

The QA system should ensure that all critical processes such as the purchase of raw materials, starting materials, selection of donors, collection of blood and plasma, production of plasma, storage, laboratory testing, dispatch and associated quality control measures, are specifi ed in appropriate instructions and are performed in accordance with the principles of GMP and comply with the appropriate regulations. The management should review the system regularly to verify the effectiveness and introduce corrective measures if deemed necessary.

Because the quality standards implemented at the blood establishment have such a profound impact on the quality of plasma, it is a requirement that their implementation be agreed between the blood establishment and the fractionator, under the terms of the contract for plasma supply (Appendix 5). Medicines regulatory authorities will verify that such a contract is in place and that it complies with the regulations in force.

A blood establishment should establish and maintain an active and operational quality assurance system covering all activities, and taking into account the principles of GMP. The following items are of special relevance as part of a QA system for the production of plasma for fractionation (71).

7.1 Organization and personnel

There should be an organization chart showing the hierarchical structure of the blood establishment and clear delineation of lines of responsibilities. All personnel should have appropriate qualifi cations and experience to enable them to perform their tasks and should be provided with initial and continued training. Only persons authorized by defi ned procedures and documented as such should be involved in the production and control of plasma. The tasks and responsibilities should be clearly documented and understood. All personnel should have clear, documented and up to date job descriptions.

Training programmes appropriate to the specifi c tasks of staff members should be in place, and should include at least:

— relevant principles of plasma production and plasma characteristics;

— quality assurance and GMP; and

— relevant knowledge of microbiology and hygiene.

Training should be documented and training records should be maintained. The contents of training programmes should be periodically assessed.

If certain tasks, such as separation of blood or viral safety testing, are performed externally, these should be subject to a specifi c written contract. The contract should ensure that the contract acceptor meets good practice requirements in all disciplines relevant to the contract giver’s activity.

7.2 Documentation system

Every activity that may affect the quality of the blood and/or blood component should be documented and recorded. The documentation should be designed to ensure that the work performed is standardized and that there is traceability of all steps in the process. The documentation should allow all steps and all data to be checked. All documentation should be traceable and reliable. A document control procedure should be established for review, revision history and archiving of documents. It should include a distribution list. All changes to documents should be acted upon promptly and should be reviewed, dated and signed by an authorized person. Documentation procedures should be designed, developed, validated and personnel trained in a consistent manner.

7.3 Premises and equipment

Premises should be located, constructed, adapted and maintained to suit the operations to be carried out. Premises should be designed to permit effective cleaning and maintenance to minimize risk of contamination. The tasks in each area should take place in a logical sequence to minimize the risk of errors.

All critical equipment should be designed, validated and maintained to suit its intended purpose and should not present any hazard to donors or operators. Maintenance, cleaning and calibration should be performed regularly and recorded. Instructions for use, maintenance, service, cleaning and sanitation should be available. There should be procedures for each type of equipment, detailing the action to be taken when malfunctions or failures occur. New and repaired equipment should meet qualifi cation requirements when installed and authorized before use. Qualifi cation results should be documented.

7.4 Materials

Only reagents and materials from approved suppliers that meet the documented requirements and specifi cations should be used. Where relevant, materials, reagents and equipment should meet the requirements of other local legislation for medical devices. Appropriate checks on goods received should be performed to confi rm that they meet specifi cations. Inventory records should be kept for traceability. Critical materials should be released under the responsibility of quality assurance function before use.

7.5 Validation programme

All processes and equipment involved in the production and control of plasma for fractionation should be validated. Data should be available to ensure that the fi nal product will be able to meet specifi cations.

7.6 Quality monitoring data

Quality control of plasma should be carried out according to a defi ned sampling plan taking into account different collection and production sites, modes of transport, methods of preparation and equipment used. Acceptance criteria should be based on a defi ned specifi cation for each type of plasma for fractionation. These data may include monitoring of factor VIII or any other protein quality criteria determined by the plasma fractionator, and monitoring of residual cell counts (platelets, leukocytes, erythrocytes) when requested by the plasma fractionator. All quality control procedures should be validated before use.

The viral safety testing should be performed in accordance with the recommendations of the manufacturers of the reagents and test kits. The work record should identify the test(s) employed to ensure that entries, such as the calculation of results, are available for review. The results of quality control testing should be subject to periodic review.

Test results that do not satisfy the specifi ed acceptance criteria should be clearly identifi ed to ensure that plasma from that donation remains in quarantine and that the relevant samples are kept for further testing. Where possible the performance of the testing procedures should be regularly assessed by participation in a formal system of profi ciency testing.

7.7 Virology safety testing

7.7.1 Sampling

The following are practical points to consider in ensuring that sampling is performed appropriately:

· Sampling machine:

— Automatic sampling: Test samples should be taken automatically and the donation number should be read from the barcode. In case of failure of the automatic system, an appropriate system for manual entry of records of donations should exist, and should require double entry with digit checks;

— Sampler validation: The sampling machine should be validated and a validation report should be available; and

— Calibration: The sampling machine should be calibrated on schedule and records available.

· Reconciliation: There should be a reconciliation of the samples received at the virology laboratory versus expected.

7.7.2 Test equipment

The following are practical points to consider in ensuring that the equipment used for the virology testing performs appropriately:

· Sample addition. The process of addition of samples to the test plates should be automatic and should include identifi cation of the barcode of the plates.

· Test processing. Ideally, the test processing should be automated. If addition of reagents is done manually, full documentation should be available

· Equipment. Pipettes, incubators and other items of equipment should be fully validated and routinely calibrated and appropriate records maintained.

7.7.3 Assay performance validation

The objective of validation of assay performance is to make sure that the performance of the virology assays, as carried out by the entity responsible for plasma collection, is satisfactory. Points to consider include:

· Each test run should include an independent control.

· Analysis of positive controls.

· Analysis of data on non-repeatable reactives (see 7.7.5 below).

· Evidence of satisfactory participation in external profi ciency schemes.

7.7.4 Test interpretation and downloading

The data from virology safety testing should be examined by the supervisor before being offi cially accepted. Accepted data should be downloaded directly to the mainframe computer, or there should be a secure system for manual download which ensures positive release of the samples. No transcription of results should be done as mistakes may be introduced.

7.7.5 Follow-up of reactives

The following should be given special attention:

· Identifi cation of initial reactives. They should be identifi ed using a secure system.

· Repeat reactives. An acceptable system should be in place to confi rm repeat reactives, including sampling, labelling, testing, and entry of results.

· Editing of repeat reactive. A computer algorithm should edit reactive status to repeat reactive, or the editing should be performed by two staff members.

· Deferral system. An appropriate deferral system should exist for repeat reactives.

· Re-entry of deferred donors. Appropriate documentation should be in place.

7.8 Electronic information system

Importance should be given to the introduction of an EIS for blood establishments involved in the preparation of plasma for fractionation and when possible linked to other establishments to facilitate and speed tracing of individual plasma donations. This will allow timely identifi cation of the location of donations in the chain of production of plasma products.

All software, hardware and backup procedures should be validated before use and checked at least once a year to ensure reliability. The system should prevent the use of duplicate donation numbers, or else the system should be able to deal with duplication without data corruption.

Hardware and software should be protected against unauthorized use or changes (e.g. by password protection of key functions). There should be procedures for each type of software and hardware, detailing the action to be taken when malfunctions or failures occur.

A backup procedure should be in place to prevent loss of records during expected and unexpected downtime or function failures. Changes in computerized systems should be validated, applicable documentation revised and personnel trained, before the change is introduced into routine use. The EIS should be maintained in a validated state.

7.9 Storage and transport

Storage and distribution routines should take place in a safe and controlled way to assure product quality throughout storage and transport and to exclude identifi cation errors of plasma units. Intermediate storage and transport should be carried out under defi ned conditions to ensure that set requirements are met.

7.10 Change control system

A formal change control system should be in place for planning, evaluating and documenting all changes that may affect the quality, traceability, availability or effect of components or safety of components, donors or patients. The potential impact of the proposed change should be evaluated.

The need for additional testing and validation should be determined.

7.11 Quality assurance auditing

In order to monitor the implementation and compliance with the blood establishment quality management system, regular internal audits are needed. These should be conducted independently by trained and competent persons from within the organization, according to approved protocols. Inter-institutional audits should be actively promoted.

All audit results should be documented and reported to management. Appropriate corrective actions should be taken. Preventive and corrective actions should be documented and assessed for effectiveness after implementation. In general the blood establishment should have procedures for systematic improvement. Input for this process can come from complaints, errors, inspections, audits and suggestions.

7.12 Defect reporting system

There should be systems in place to ensure that complaints, all types of quality defects (e.g. in blood bags or test kits), and adverse events or reactions are documented, carefully investigated for causative factors and, where necessary, followed by the implementation of corrective actions to prevent recurrence. This also applies to “near miss events”. The corrective and preventive action system should ensure that nonconformity of the product or quality problems are corrected, that recurrence of the problem is prevented, and that the plasma fractionator is notifi ed according to the agreed procedure. The blood establishment should have methods and procedures in place to channel product or quality problems into the corrective and preventive action system.

7.13 Quality agreement between blood establishment and fractionator

The important elements of a blood establishment quality system with critical implications for plasma quality, will normally be addressed in a quality agreement — an addendum to the contract for plasma supply. The quality agreement should address at least the following areas of concern:

· agreement on specifi c donor selection criteria (with approval of the national regulatory authority);

· schedule of requirements for exclusion or acceptance of donors, including the arrangements for establishing donor identity and the provision for possibility of self-exclusion;

· arrangements for monitoring and reporting the epidemiology of the donor population;

· location of blood establishments (and of any facility to which a quality-critical function, for example donation testing, has been outsourced);

· frequency of donation and the system for ensuring that donations are not taken more frequently than allowed;

· requirements for donor screening and for donation testing, including any provision for the preparation and testing of mini-pools;

· procedure for validation and approval of relevant test reagents and kits;

· record-keeping, including the arrangements for traceability of donors and donations;

· specifi cations of plasma to be supplied, including any arrangements for verifying compliance with specifi cations and documentation of compliance;

· specifi cations of containers to be used for blood/plasma collection and supply;

· detailed requirements for labelling of individual plasma units (the adhesive used for the labels should not compromise the quality of the plasma products);

· arrangements for freezing, storage and shipment of plasma;

· notifi able events, including the arrangements for post-donation notifi cation;

· procedure for review and approval of any proposal for procedural change;

· procedure and agreed frequency for audit of blood establishments by the fractionator; and

· arrangements for notifying the fractionator of a proposed regulatory inspection, its periodicity, and of the outcome of such an inspection.

7.14 Blood/plasma establishment audit and inspection

It is a requirement of GMP that the regulatory authorities and the plasma fractionator should establish the basis of confi dence in the quality of critical raw materials. In the case of plasma, this is achieved by four basic provisions:

· maintenance of a list of blood establishments approved (by the fractionator and the regulatory authorities) for supply of plasma;

· agreement in a contract, or in the technical agreement to a contract of supply, of the quality arrangements made at each blood establishment approved for supply of plasma;

· regular audit of blood establishments to confi rm satisfactory implementation of the quality arrangements (these audits should be reported in writing to the blood/plasma establishment and any remedial actions confi rmed); and

· monitoring of the quality of plasma supplied, with trending of quality-critical parameters.

There will normally be a requirement for independent inspection and approval of each blood establishment by the relevant regulatory authority (see below). Such inspections should be provided for in any contract between the plasma supplier and the fractionator, and will normally be undertaken by the responsible authority in the country where plasma preparation is performed. Written reports of such inspections should be made available to the blood establishment and a remediation plan agreed upon. Reports of regulatory inspections and associated remediation plans should be made available to the fractionator under the terms of the contract for plasma supply.

8. Regulatory control of plasma for fractionation

8.1 Role of national regulatory authority

According to the WHO Guidelines for national regulatory authorities on quality assurance of biological products (72, 73), national regulatory authorities have the duty to ensure that available biological products, whether imported or manufactured locally, are of good quality, safe and effi cacious, and should thus ensure that manufacturers adhere to approved standards of quality assurance and GMP. The responsibilities of the national regulatory authority should also include the enforcement and implementation of effective national regulations, and the setting of appropriate standards and control measures. The evaluation and control of the quality, safety and consistency of production of blood products involve the evaluation of the starting material, production processes and the test methods to characterize batches of the product. This requires specialist expertise by the national regulatory authority.

8.2 Establishment licence and inspections

In many countries, national regulatory authorities have implemented a control system based on licensing the establishments, inspecting them regularly, and enforcing the implementation of the legal requirements and applicable standards.

According to international GMP standards for the manufacturing of blood products, the following two main principles are important for the control of plasma as starting material:

· Quality assurance should cover all stages leading to the fi nished product, from collection (including donor selection) to storage, transport, processing, quality control and delivery of the fi nished product.

· Blood or plasma used as a source material for the manufacture of medicinal products should be collected by establishments and be tested in laboratories which are subject to inspection and approved by a national regulatory authority.

These two points in the GMP requirements summarize an important basic principle which is relevant for the manufacture of plasma derivatives and the control of plasma as starting material. Most national regulations therefore require that the establishments involved in the collection and storage of plasma as a source material (e.g. plasmapheresis centres and blood establishments) need to have an establishment licence and need to be inspected by the competent national regulatory authority. To obtain the licence the establishments have to fulfi l a defi ned set of requirements to guarantee that the plasma collected is safe and of good quality. Since each unit collected represents a single batch, a marketing authorization for the plasma as a “product“ is not required in all countries. Under the latter condition, a “system control”, instead of a “product control”, may be more appropriate. In addition to the establishment licensing system some countries have also introduced a product-specifi c approval system for blood components.

8.3 Impact of good manufacturing practices

The approach of implementing the principles of GMP in the production of medicinal products is not new, and it is widely acknowledged that it is essential in assuring the quality and safety of medicinal products. For blood products, GMP becomes even more important and more complex due to the biological nature of the products. Therefore, taking into account the principles of GMP and the existence of an appropriate system of quality assurance to address and implement these requirements in the manufacturing steps of blood products should be a pivotal element of the preparation of plasma for fractionation. As outlined in the previous sections, implementation of GMP in the manufacture of blood products is essential, and quality assurance and GMP should cover all stages, including the collection of plasma as starting material. The implementation and enforcement of GMP in blood establishments therefore has the following impact:

— introduces the application of quality assurance principles in all steps involved in the collection, preparation and testing of blood components;

— supports systematic application of donor selection criteria for each donation;

— reduces errors and technical problems in collection, preparation, testing, and distribution;

— contributes to the release of products which comply with safety and quality requirements;

— ensures adequate documentation and full traceability for each donation and product;

— enables continuous improvement in collection, preparation and testing of starting material;

— supports regional cooperation networks that may result in the formation of centres of competence by centralizing activities in order to reach compliance at the required level (cost-benefi t for implementing quality assurance measures);

— provides suitable tools for the national regulatory authority to assess the compliance of a plasma collection centre.

An establishment licensing system for blood establishments by the competent national regulatory authorities should therefore exist. The main requirements for obtaining an establishment licence may include:

· Application of quality assurance system and GMP to all steps from donation, to preparation, storage, testing and distribution of plasma.

· Personnel directly involved in the collection, testing, processing, storage and distribution of plasma need to be appropriately qualifi ed and provided with timely and relevant training.

· Adequate premises and equipment should be available.

· An adequate system to ensure traceability of plasma should be established; traceability should be enforced through accurate donor, donation, product and laboratory sample identifi cation procedures, through record maintenance and use of an appropriate labelling system.

· Requirements for selection of donors, including exclusion criteria for donors with risk behaviours; provision of information to donors on risk situations and the donation in general; and the use of a questionnaire to obtain information on donor’s health.

· Requirements for testing of each donation.

· Requirements regarding traceability and documentation.

· Post-donation information system.

8.4 Inspections

In conducting regular inspections as part of the licensing procedure, enforcement of the implementation of GMP is required aiming to ensure the compliance of the blood establishments with the existing provisions. It is the responsibility of the inspector from the national regulatory authority to ensure that the manufacturers and the blood and plasma establishments adhere to the approved standards of GMP and quality assurance, including at sites where plasma is collected as starting material.

The inspections should be carried out by offi cials representing the competent national regulatory authority. These offi cials should be specialized inspectors, trained in GMP inspections, and they should be familiar with blood bank technologies and the special features of quality assurance in the collection of plasma. Inspections may follow common inspection procedures, including:

· an opening meeting;

· a blood establishment tour;

· inspection of main areas and activities;

— donor acceptance and identifi cation

— donor suitability

— collection process

— processing and sampling

— plasma freezing

— testing and availability of test results

— release of plasma units

— storage, transportation and shipment

— quality assurance (including self inspection and change control)

— documentation (standard operating procedures, records, donor record fi les and log books)

— personnel and organization

— qualifi cation and process validations

— error and corrective action system

— look-back information, recalls and complaints

— product quality controls

• a fi nal meeting summarizing the inspection outcome.

A thorough inspection includes the observation of staff during performance operation and comparison with defi ned written procedures. In a “system control”, the inspection can be considered not only as a GMP inspection, but also as an indirect product quality assessment by checking productspecifi c validation and quality control data.

A written report should summarize the main aspects of the inspection including its scope, a description of the company, the defi ciencies listed, specifi ed and classifi ed (e.g. as critical, major or minor), and a conclusion. The written report will be sent to the company. The companies are requested to notify the national regulatory authority about the specifi c steps which are taken or planned to correct the failures and to prevent their recurrence. If necessary, follow-up inspections should be performed e.g. to check that specifi c corrective actions have been implementd.

The national regulatory authority should have the authority to withdraw an establishment licence in a case where inspection results showed critical non-compliance with the requirements or product specifi cations.

Information on the collection and control of the starting material, human blood or plasma, and on the procedures conducted during the preparation of the fi nal blood derived medicinal product have to be documented as part of the dossier in the marketing authorization.

In summary, the implementation of licensing and inspection systems for blood establishments has become an important tool through which the national regulatory authorities confi rm the assurance of quality of plasma as starting material for fractionation. The use of international standards not only further promotes harmonization, but also facilitates regional collaboration and information exchange between the national regulatory authorities.

Authors

The drafts of these guidelines were prepared by:

Dr T. Burnouf, Human Plasma Product Services, Lille, France; Dr A. Padilla, World Health Organization, Geneva, Switzerland; Dr C. Schärer, Swissmedic, Swiss Agency for Therapeutic Products, Bern, Switzerland; Dr T. Snape, Consultant, Pickering, North Yorkshire, UK; Dr P. Strengers, International Society of Blood Transfusion, Amsterdam, the Netherlands; Professor S. Urbaniak, Regional Transfusion Centre, Aberdeen, UK; Professor W.G. van Aken, Professor of Medicine, Amsterdam, the Netherlands.

The Drafts prepared were circulated for Consultation to Representatives of National Regulatory Authorities, National Blood Programs and to the respective WHO Regional Advisors in all the WHO Regional Offi ces. Plasma fractionators were consulted through their respective plasma fractionation associations or through the regulatory agencies in their countries. Both the Plasma Protein Therapeutic Association and the International Plasma Fractionation Association presented consolidated comments of their Members.

Acknowledgements are due to the following experts for their comments, advice and information given during the preparation and consultation process of these Guidelines:

Lic. M. P. Alvarez, Departamento Biológicos, CECMED, Havana, Cuba; Dr. R. S. Ajmani, Intas Pharmaceuticals Ltd, Chinubhai Centre, Ahmedabad, India; Dr D. Armstrong, Natal Bioproducts, South Africa; Dr. T. Barrowcliffe, National Institute for Biological Standards, Potters Bar, Herts, UK; Dr C. Bianco, America's Blood Centers, Washington DC, USA; Dr R. Büchel, Plasma Protein Therapeutics Association (PPTA) Source, Brussels, Belgium; Dr E. A. Burgstaler, Transfusion Medicine, Mayo Clinic, Rochester, Minnesota, USA; Mr A. Cadiz, Empresa Productora de Sueros y Hemoderivados, La Habana, Cuba; Dr F. Cardoso de Melo, Agencia Nacional de Vigilancia Sanitaria, Ministerio da Saude, Brasilia, Brazil; Dr B. Cuthbertson, Scottish National Blood Transfusion Service, Edinburgh, UK; Dr A. M. Cheraghali, Iran Blood Transfusion Organization, Tehran, Iran; Dr N. Choudhury, Prathama Blood Center, Vasna, Ahmedabad, India; Dr J. R. Cruz, Regional Advisor Laboratory and Blood Services, AMRO/PAHO, Washington, USA; Dr. F Décary, Héma-Québec, Canada; Dr N. Dhingra, World Health Organization, Geneva, Switzerland; Dr R. Dodd, American Red Cross, USA; Dr J. Epstein, Offi ce of Blood Research and Review, FDA Center for Biologics Evaluation and Research, Bethesda, Maryland, USA; Mr T. Evers, International Plasma Fractionation Association (IPFA), Amsterdam, the Netherlands; Ms M. Farag, Egyptian Regulatory

Authority, Cairo, Egypt; Professor A. Farrugia, Offi ce of Devices, Blood and Tissues, Therapeutic Goods Administration, Woden, Australia; Dr B. Flan, Laboratoire Français du Fractionnement et des Biotechnologies, les Ulis, France; Dr J. C. Goldsmith, Offi ce of Blood Research and Review, FDA Center for Biologics Evaluation and Research, Bethesda, Maryland, USA; Ms K. Gregory, AABB, Bethesda, MD, USA; Ms M. Gustafson, Plasma Protein Therapeutics Association, Washington, USA; Mrs T. Jivapaisarnpong, Department of Medical Sciences,

Ministry of Public Health, Nonthaburi, Thailand; Dr H. Klein, National Institutes of Health, Clinical Research Center, Transfusion Medicine, Bethesda, MD, USA; Dr. J. Kurz, Federal Ministry of Health and Women, Medicines & Medical Devices Inspectorate, Vienna, Austria; Professor J. Löwer, Paul Ehrlich Institute, Langen, Germany; Mrs B. Mac Dowell Soares, Agencia Nacional de Vigilancia Sanitaria, Brasilia, Brazil; Dr E. Al Mansoori, Drug Control Department, Ministry of Health, United Arab Emirates; Dr M. Maschio, Plan Nacional de Sangre, Buenos Aires, Argentina; Dr A. Miller, Blood National Program, Montevideo, Uruguay; Dr S. Park, Korea Food and Drug Administration, Seoul, South Korea; Professor I. Peake, International Society on Thrombosis and Haemostasis, University of Sheffi eld, Sheffi eld, UK; Dr F. Reigel, Swissmedic, Swiss Agency for Therapeutic Products, Bern, Switzerland; Dr A. Robinson, NHS Blood and Transplant, National Health Service, UK; Mr D. Sato, Ministry of Health and Welfare, Japan; Professor E. Seifried, German Red Cross, Institute of Transfusion Medicine and Immunohaematology, Frankfurt/Main, Germany; Professor R. Seitz, Paul Ehrlich Institute, Langen, Germany; Dr G. Silvester; European Medicines Evaluation Agency, London, UK; Dr L. S. Slamet, National Agency of Drug and Food Control, Indonesia; Dr T Simon, Tricore, USA; Professor J.-H. Trouvin, Afssaps, Paris, France; Dr F. Vericat, Grifols, Barcelona, Spain; Dr E. Voets, Biological Standardization, Scientifi c Institute of Public Health, Federal Public Service Health, Brussels, Belgium; Professor G. N. Vyas, University of California, San Francisco, California, USA; Dr M. Weinstein, Offi ce of Blood Research and Review, FDA Center for Biologics Evaluation and Research, Rockville, Maryland, USA; Mrs M. Wortley, Haemonetics, Braintree USA; Professor H. Yin, Biological Products, State of Food and Drug Administration, Beijing, People’s Republic of China; Dr Mei-Ying Yu, Offi ce of Blood Research and Review, FDA Center for Biologics Evaluation and Research, Rockville, Maryland, USA.

Special thanks are also due to Dr T. Burnouf for the compilation and professional follow up of the signifi cant number of contributions received during the Consultation process. Dr T. Burnouf and Dr A. Padilla, WHO Project Leader prepared the fi nal manuscript of these Guidelines.

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Appendix 1

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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