Good practice in plasma collection and fractionation
XXXIst International Congress of the ISBT, Berlin (Germany), June 26-July 1, 2010.
Session 15: Regulation of plasma derivatives.
Christian Schärer, Swissmedic, Swiss Agency for Therapeutic Products, Bern, Switzerland
The control strategy to ensure safety of blood products includes a combination of measures focusing on ensuring the quality and safety of starting material by careful donor selection and testing strategies at different levels, together with validated manufacturing processes, including steps to inactivate or remove potential contaminating agents. Using an approach based on good manufacturing practice (GMP) provides a manufacturing model that allows for a documented system of incorporating quality throughout the entire manufacturing process and describes the activities and controls needed to consistently produce products that comply with specifications and are safe for use. There are no doubts that the aim of providing safe and high-quality product to the patients should be the same for all products derived from human blood, independent of its use either as a blood component for direct transfusion or as industrially manufactured product. It would be difficult to justify whether for blood components the good practice standards and for plasma derivatives the GMP standards for manufacturing would not ensure equivalent levels of quality and safety. To ensure a high level of quality and safety of blood components and plasma derivatives, the implementation of double standards in blood establishments and fractionation industry would not be effective and should be avoided. Harmonized standards and good practices for collection and fractionation, based on the principles of GMP, should be envisaged in the whole chain of manufacturing blood components and plasma derivatives. Global initiatives to further promote the implementation of harmonized GMP for the collection in blood establishments and a stringent regulatory control are ongoing. This would further contribute to the global availability of plasma-derived medicinal products.
Before the industrial revolution, craft workers made their products and only those products that fulfilled their requirements were sold (100% quality control). With the introduction of bulk production, 100% quality control became quite expensive and no longer feasible. Statistical quality control was introduced. With the increase of product reliability, the system of quality assurance or good manufacturing practice (GMP)  was introduced in the pharmaceutical industry. In many countries, by law, the pharmaceutical industry must comply with the requirements of GMP and they are regularly inspected by competent authorities. International collaboration between inspectorates of competent authorities is based on a common harmonized understanding of GMP.
Quality Management versus GMP
Quality assurance is that part of quality management that ensures that all critical processes are specified in appropriate written instructions, are performed in accordance with the principles of GMP and comply with the appropriate regulations. Quality assurance incorporating GMP is a wide-ranging concept covering all matters that individually or collectively influence the quality of the product. It is the totality of arrangements made with the objective of ensuring that the products are of the quality required for their intended use. In addition, it may also include other factors that are less product oriented or services outside the scope of the manufacturing activities. GMP is that part of quality assurance which ensures that the products are consistently produced and controlled to the quality standards appropriate to their intended use, as required by product specification and, if applicable, by the marketing authorization. For blood components, GMP is aimed primarily at diminishing the risks inherent in any blood establishment operation, such as contamination (including cross-contamination), mix-ups, disease transmission or other unexpected adverse outcomes from the use of blood components. GMP is concerned with both production and quality control.
Basic requirements of GMP are that:
- 1 All manufacturing processes are clearly defined by policies and procedures, systematically reviewed in the light of experiences and shown to be capable of consistently manufacturing products of the required quality complying with their specifications.
- 2 Qualification of equipment and reagents and validation of processes and methods are performed prior to use in the manufacturing of products intended for transfusion or infusion.
- 3 All necessary resources are provided, including appropriately qualified and trained personnel, adequate premises, suitable equipment, appropriate materials, approved procedures and instructions, suitable storage and transport.
- 4 A system is available to maintain traceability of all products and materials to facilitate recall of any suspected non-conforming product, if necessary, and a system to handle complaints.
- 5 A system that addresses process and quality improvement functions and activities.
The current GMP principles are based on long experience in manufacturing medicinal products, and newer concepts, such as quality risk management, periodic quality review, quality by design, are going to be incorporated into the basic GMP requirements.
Product reliability consequences made manufacturers aware of their responsibilities when selling a product to their clients. Although the activities of a blood establishment, especially in a hospital setting, may be closely linked to the clinical application of the blood components, these special concerns of responsibility of the manufacturer could not completely be withdrawn. In many countries, this has led in the past 15 years to a change of culture also in blood establishments, moving the blood collection from being a medical service towards preparation of blood components being a manufacturing activity. The role and responsibilities as manufacturer had thereby been taken into consideration when setting up quality management systems to address specifically product quality aspects by implementing GMP principles.
GMP for industrial manufacturing of blood products
Blood products are considered to be biological medicinal products, and the starting materials include biological substances, such as cells or fluids (including blood or plasma) of human origin. Certain special features arise from the biological nature of the source material. For example, disease-transmitting agents, especially viruses, may contaminate the source material. The quality and safety of these products relies therefore on the control of source materials and their origin as well as on the subsequent manufacturing procedures, including infectious marker testing, virus removal and virus inactivation. In principle, active substances used as starting material for medicinal products must comply with the principles and guidelines of GMP. This applies equally to starting material derived from human blood and plasma.
Human blood is a source of a range of therapeutic products; they are either obtained from the processing of single donations of blood or plasma, generally known as blood components, or obtained by an industrial fractionation process of large numbers of plasma units that combines protein purification and viral inactivation and removal steps, also called plasma derivatives.
During the (industrial) manufacturing process itself, the implementation of GMP is already a well-accepted basic element involved in ensuring technical quality and safety of medicinal products; it is also applicable to its starting materials. The control of the starting material and its traceability throughout the supply chain is very well developed when compared to other medicinal products.
In the EU, medicinal products derived from human blood or plasma (and their active substances which are used as starting materials) must comply with the principles and guidelines of GMP (as laid down in Commission Directive 2003/94/EC and the EU Guidelines on GMP published by the European Commission) and the relevant marketing authorization (Directive 2001/83/EC, Art. 46, 51). Equivalent GMP standards apply in the participating authorities within the Pharmaceutical Inspection Cooperation Scheme (PIC/S; http://www.picscheme.org), which encompasses more than 35 competent authorities. An additional specific importance of GMP in relation to blood products needs to be mentioned with regard to the virus inactivation steps: As powerful as the contribution of properly validated and implemented steps for virus inactivation and removal has been shown to be, it remains essential to limit the virus load at the stage of the donation by avoiding, through donor selection and donation screenings, the inclusion of a high-titre infectious donation. Only with strict adherence to GMP, the efficiency of a validated virus inactivation step is ensured. Furthermore, GMP helps to establish a well-defined contract while regulating duties and responsibilities of the contract giver (fractionator) and the contract acceptor (plasma supplier) .
Blood product manufacturing fits the paradigm for using a GMP approach to consistently manufacture blood products, including blood components, that meet predetermined specifications and customer’s expectations. This approach provides a manufacturing model that allows for a documented system of incorporating quality throughout the entire manufacturing process and describes the activities and controls needed to consistently produce products that comply with specifications and are safe for use.
GMP for blood establishments is not new
Already 20 years ago, in the absence of specific harmonized GMP standards for blood establishments, the specific annex of the EU or PIC/S GMP Guide related to the manufacturing of products derived from human blood or human plasma was used as a basic standard for blood establishments, especially because they needed an establishment licence for supplying plasma as a starting material for further fractionation. Compliance with GMP was already required at that time. The GMP annex, however, mainly addresses industrial manufacturing processes and less the technologies used in blood establishments. In 1990, a first edition of guidelines of the United Kingdom Blood Transfusion Service (UKBTS) was published . In 1992, the Blood Transfusion Council of the Netherlands Red Cross published a GMP Guideline for Blood Banks , which supported the blood bank in implementing GMP in blood banks. Both guidelines were intended to be used in conjunction with the current Guide to GMP and other documents from World Health Organisation  or the Council of Europe .
In 1994, an Expert Circle on Human Blood within the PIC/S was created to build up specific expertise in the field of inspection of blood establishments and blood product manufacturer. The implementation of GMP by blood establishments as well as the inspection of blood establishments by Competent Health Authorities was relatively new in many countries at that time. As a result, it was considered by the PIC/S Blood Expert Circle that a comprehensive GMP guide for blood components was missing and that as a consequence the implementation of GMP as well as the harmonization of inspections was impeded. Therefore, the PIC/S Blood Expert Circle undertook in 1996 the task of drafting a specific GMP guide for blood establishments and blood components, which was published in 2001 . As a consequence, this document was used in many PIC/S participating authorities as their GMP standard in blood establishment. Even in many non-PIC/S countries, the document was considered to be a useful guidance and reference document representing a broadly harmonized basis.
According to European or most national legislation, blood establishments should establish and maintain quality systems involving all activities that determine the quality policy objectives and responsibilities and implement them by such means as quality planning, quality control, quality assurance and quality improvement within the quality system, taking into account the principles of GMP. With the implementation of Good Practices during plasma collection procedures, a systematic approach should ensure, e.g., the application of donor selection criteria for each donation prevents the occurrence of errors during testing, or supports traceability by adequate documentation of all important steps, and that the whole chain of processes in the production of blood components, i.e. correct processing, labelling, storage and transportation, are covered by relevant, reliable quality assurance systems.
For blood establishments, the European Union has accepted Directive 2005/62/EU  containing the quality system requirements for blood establishments. The corresponding Good Practice Guidelines for blood establishments, however, are currently still pending but the development of these Good Practice Guidelines should fully take into account the detailed principles of GMP as referred to in EU Directive 2001/83/EC.
A global issue
Plasma-derived medicinal products for the treatment of haemophilia and immune diseases are included in the WHO Model List of Essential Medicines, and there is a need to facilitate access to these products by developing countries. A major factor limiting the global availability of plasma-derived medicinal products is an inadequate supply of plasma meeting internationally recognized standards for fractionation. Bearing in mind that treatment using labile blood components is gradually being included in medical practice in developing countries and that thereby increased quantities of recovered plasma should become available for fractionation into plasma-derived medicinal products to meet their needs.
In developing countries, blood components’ separation technology and fractionation capacity are lacking, and because of insufficient regulatory controls and failure to implement appropriate practices in blood establishments, plasma from developing countries is often unacceptable for contract fractionation, with considerable wastage of plasma as a result.
The capacity to collect plasma is limited and would not suffice to produce enough essential medicines to cover global needs. It is therefore essential that all countries have local capacity to collect plasma of acceptable quality and safety to meet their needs. Where national plasma fractionation capacities are lacking, there should be an option for supply of fractionation capacity in other countries, it should be ensured that the supply of plasma-derived medicinal products can be made available to meet local needs in the country of the plasma supplier.
In recent years, guidance on GMP for blood establishments was considered of highest priority for the WHO following request from Member States at the International Conferences of Drug Regulatory Authorities. There is a widely recognized need for an internationally agreed upon GMP guideline for Blood Establishments, as blood components, including plasma for fractionation, should meet agreed upon global quality standards to ensure recipient safety and are being increasingly shared all over the world.
Just recently, WHO was considering a resolution on availability, quality and safety of blood products. Among other points, this resolution urges Member States to establish quality systems for the processing of whole blood and blood components, GMP for the production of plasma-derived medicinal products and appropriate regulatory control.