Administering Files, Records, and Grants

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.

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