Report from the GHPP-BloodTrain inspection workshop in Harare the 20th to the 24th of May 2019.

During the training workshop on Inspection of Blood Establishments, which was hosted by the PEI GHPP BloodTrain in Harare from the 20th to the 24th of May 2019, participants from the National Regulatory Authorities from seven Sub-Sahara African countries presented their current experiences related to regulation and inspection of blood establishments in their respective countries. While in all seven countries regulation and inspection of conventional medicinal products manufacturer is performed, the regulatory situation of blood and blood components as well as inspection of blood establishments is still heterogeneous.

Requirements for blood and blood components intended for transfusion or for further manufacturing use. Final rule.

The Food and Drug Administration (FDA) is amending the regulations applicable to blood and blood components, including Source Plasma, to make the donor eligibility and testing requirements more consistent with current practices in the blood industry, to more closely align the regulations with current FDA recommendations, and to provide flexibility to accommodate advancing technology. In order to better assure the safety of the nation's blood supply and to help protect donor health, FDA is revising the requirements for blood establishments to test donors for infectious disease, and to determine that donors are eligible to donate and that donations are suitable for transfusion or further manufacture. FDA is also requiring establishments to evaluate donors for factors that may adversely affect the safety, purity, and potency of blood and blood components or the health of a donor during the donation process. Accordingly, these regulations establish requirements for donor education, donor history, and donor testing. These regulations also implement a flexible framework to help both FDA and industry to more effectively respond to new or emerging infectious agents that may affect blood product safety.

European definitions, current use, and EMA stance of platelet-rich plasma in sports medicine.

Platelet-rich plasma has been the focus of much attention over the last few years as an appealing biological approach to favor the healing of tissues otherwise doomed by a low healing potential. In Europe, the regulatory framework concerning the blood system is currently disciplined by Directive 2002/98/EC of the European Parliament and Council of January 27, 2003, which sets out quality and safety rules for collecting, controlling, processing, preserving, and distributing human blood and its components, acknowledged in the various States of the Union with internal regulations. This lack of homogeneity in the European legal landscape will probably lead the Community legislature to intervene in the near future, to even out the "rules of engagement" of this peculiar class of biomaterials.

[Testing of medicinal products produced from pooled plasma]. / Prüfung von aus gepooltem Plasma hergestellten Produkten.

Medicinal products produced from human plasma fall under the administrative batch release procedure of the competent authority. In Germany, this has been carried out since 1995 by the Paul Ehrlich Institute (PEI), the responsible state control agency for blood products. Medicinal products released for the European and national market are tested for quality, efficacy and safety. Experimental testing of the final product and the starting materials, the plasma pools, as well as control of the production documentation guarantee a constantly high product safety. In the 28,000 batches tested since the beginning of the state controlled batch release testing of these blood products at the PEI, there has been no transmission of infectious viruses (HIV, HBV and HCV) to any patient. The batch release has made a contribution to the improvement of product quality. This procedure is still an important tool to ensure safety of blood products. The PEI is integrated in the batch release network of the European Directorate for the Quality of Medicines & Health Care (EDQM) in Strasbourg. Regulations and guidelines for official control authority batch release (OCABR) ensure harmonized procedures for mutual recognition of batch release on the European level. The EU certificates and German national certificates are requested and accepted in over 70 countries worldwide. Experimental testing in the EU and the requisite certificates have developed into a seal of quality for the world market.

Regulation of cell-based therapeutic products intended for human applications in the EU.

AIMS: Recent developments in the field of cell-based therapeutic products (CBTPs) have forced the EU to revise its legislation on therapeutic products by enacting several new legal instruments. In this study, we investigate how CBTPs are regulated and what determines their regulatory classification. Furthermore, we compare the regulatory burden between CBTPs in different product categories. MATERIALS & METHODS: Product categories covering CBTPs were identified and characteristics critical for the regulatory classification of a CBTP were determined in each category. The effect of the critical characteristics on the classification was evaluated by constructing a decision tree that covers all possible combinations of the critical characteristics. Differences in the regulatory burden between CBTPs were evaluated by comparing regulations crucial for placing a therapeutic product on the EU market between the product categories. RESULTS: Regulation of CBTPs has been divided between the main product categories of the EU legal framework for therapeutic products on the basis of the characteristics of the cells that the CBTPs contain. The regulatory burden is lowest for CBTPs regulated as blood, cells or tissues, and highest for CBTPs regulated as medicinal products. CONCLUSION: CBTPs exist in all product categories of the EU legal framework for therapeutic products. However, the current framework does not cover all possible CBTPs. Furthermore, our results indicate that the regulatory burden of a CBTP is related to the risk it may pose to the health and safety of recipients.

Does a liberal national transfusion law assure blood safety? A survey of blood bank directors' perspectives in Lebanon.

In transfusion medicine today, 'zero risk' has become a universal objective. Thus, we investigated whether the level of blood safety as defined by Lebanese legislation is satisfactory. Our work covered the period from September 2008 to June 2012. First, we studied each chapter in law and regulations, and compared them with the latest French regulations. The standards of Good Manufacturing Practice, characteristics of blood products and their storage, and the overall organization and haemovigilance for recipients and donors are not defined. Our analysis revealed numerous problems in today's blood safety situation. There is, for example, no clear definition or identification of the different blood safety components. Then, we conducted a national survey of blood bank directors to assess their perception of blood safety in Lebanon. Our survey revealed a negative perception (52.4 per cent) of the current blood safety situation, with more than 90 per cent of respondents in favor of national regulatory improvements.

Viral safety of human plasma-derived medicinal products: impact of regulation requirements.

The viral safety of plasma-derived medicinal products is of paramount importance. This article aims to provide insight into the relative impact of different safety measures on achieving viral safety of finished products, derived from human plasma. Virus removal and/or inactivation during the production process is the most important safety measure, and model-based risk estimates show that with current safety measures, the risk of transmission of known blood-borne pathogens to plasma product recipients is extremely low. However, because the residual risk of virus transmissions is also influenced by the incidence rate of infection in the donor population, it makes sense to control these incidence rates, as well. The current measures are aiming in the right direction, but integration of guidelines is required to adequately address their common goal: controlling the risk of infectious disease transmission by plasma-derived medicinal products. By integration of guidelines, the combination of various types of safety measures to prevent virus transmission-donor selection, donation screening, quarantining, and virus removal and/or inactivation during production-may be consistently interpreted and adequately assessed.

Platelet-rich plasma and blood components for non-transfusion use: technical and medicolegal aspects.

There are a large number of publications describing the use of platelet-rich plasma (PRP) in multiple fields of application. These illustrate a large number of therapeutic elements with different and specific actions within 'platelet gel' (this term is used in the current regulations to define this product). This term, however, lacks specificity and, depending on the method used in its production is variable both in its blood composition and in platelet concentration, and several publications consider better and easier methods of platelet gel production, which may or may not lead to greater standardization in the product. The authors illustrate the general aspects of PRP and other blood components for non-transfusion use, briefly touching on the history and different fields of application and the rational of for its use. Given the increased use of such preparations, the authors describe critically the regulations in force in Europe and propose a new regulatory framework aimed to simplify and facilitate the use of such material as a therapeutic agent within medicine.

The Wildbad Kreuth initiative: European current practices and recommendations for optimal use of blood components.

With the aging population in Europe it is anticipated that the growing demand for blood products will not be met by the estimated supply. Therefore up-to-date recommendations for optimal administration of blood products in hemotherapy are needed. Ten years after the first meeting on optimal use of blood products at Wildbad Kreuth, Germany, a second symposium was organized to convene leading experts from the clinical, regulatory and economic perspective. The aim was to re-evaluate the existing state of hemotherapy, identify areas where further studies are needed, and to provide up-dated recommendations. A preparatory survey by questionnaire concerning guidelines, quality management in clinical use of blood products, provision of products in the individual countries and re-evaluation of the 1999 Wildbad Kreuth recommendations was completed in advance. The second Kreuth Meeting in April 2009 was attended by 110 experts in transfusion medicine, regulators and regulatory authorities from 38 countries. By consensus, 20 new recommendations were adopted. Most of the 1999 recommendations were found to still be valid 10 years later. But their realization and implementation on the levels of clinical practice, regulatory authorities and health policy decision makers is still lagging behind leaving an important task to accomplish. The Kreuth initiative toward optimal use of blood products should continue.

[European regulation on blood and blood components]. / Réglementation Européenne relative au sang et à ses composants: déclinaison au niveau de la réglementation Française.

The European regulation on blood and blood components is declined in four directives: the Directive 2002/98/EC known as "mother Directive" and three directives called "daughter Directives" 2004/33/EC, 2005/61/EC and 2005/62/EC. It constitutes a common basis of provisions of quality and safety of blood in the European Union (EU), thus guaranteeing this safety and this quality with the whole of the citizens circulating in Member States of the Union. It cannot prevent a Member State for maintaining or introducing more stringent protective measures. It encourages the anonymous, voluntary and unpaid blood donations. It envisages many provisions for the prospective blood donor eligibility, the blood collection, the testing, processing, storage, transport, distribution and issuing of blood and blood components and the haemovigilance. In the field of the haemovigilance, this European regulation widened the field of competence of the national systems to the notification of serious adverse events of the transfusion chain and the serious adverse reactions, which have occurred in the blood donors. The European directives were transposed in the French national law between 2004 and 2007 by legislative and lawful ways.

[Report on notifications pursuant to Section 21 of the German Transfusion Act for the years 2008 and 2009]. / Bericht zur Meldung nach § 21 TFG für die Jahre 2008 und 2009.

This report contains the data collected in 2008 and 2009, pursuant to Section 21 of the German Transfusion Act (Transfusionsgesetz), as well as an overview of the supply situation during the last 10 years. In 2009, blood donation services reported a total of 7.5 million donations--the largest amount since 2000. At the same time, more than 4.7 million red blood cell concentrates and more than 500,000 platelet concentrates were available. The number of therapeutic single plasma units decreased to 1.1 million units in 2009. The loss rate for red blood cell concentrates is still between 3% and 4% for the users, while for the manufacturers, it has decreased slightly to 1.4%. The loss rate, for platelet concentrates, on the other hand, increased in 2009, and--what is noteworthy--especially for manufacturers of pooled platelet concentrates. The loss rate for apheresis platelet concentrates accounted for 5.2% compared to 17.5% for pooled platelet concentrates. As far as the users were concerned, loss rates for platelet concentrates largely remained unchanged with rates between 5% and 6%. Based on the data collected, the supply of blood components for transfusion can be regarded as assured. Nearly 2.9 million liters of plasma for fractionation were collected in Germany in 2009. According to reports from the pharmaceutical industry, of these, 2.6 million liters remained on the German market, of which only 56% were fractionated in this country; no statement can be made on the use of the remaining amount. Many plasma derivatives are not manufactured in Germany, despite the large amount of plasma collected. The supply with these products, however, is assured by imports. Overall, 16,409 autologous and 9,435 allogeneic hematopoietic stem cell preparations were manufactured in 2009, of which 3,382 allogeneic preparations were exported. A total of 3,181 autologous and 2,374 allogeneic preparations were transplanted; 187 of these products from imports. The large number of exported stem cells and the small number of imported stem cells suggest that no serious shortages are to be expected for the supply with these products.

Transfusão de hemocomponentes na urgência / Blood transfusion in emergency

A transfusão de hemocomponentes possui grande importância como recurso terapêutico nos atendimentos de urgência seja pela frequência ou importância na estabilização hemodinâmica de pacientes graves. É importante considerar, entretanto, os riscos associados a esse procedimento, uma vez que consiste em forma de transplante alogênico, o que expõe o receptor a potenciais complicações. Os hemocomponentes mais utilizados em urgência são o concentrado de hemácias, o plasma fresco congelado e o concentrado de plaquetas. O conhecimento da regulamentação, indicações e riscos relacionados à prática transfusional possui importância na prática clínica no sentido de orientar as decisões acerca da necessidade de transfusão sanguínea. É importante, ainda, atentar para as perspectivas de terapêuticas alternativas à transfusão heteróloga, representadas pela transfusão autóloga intraoperatória e pelos substitutos de hemocomponentes, práticas que podem contribuir para a redução dos riscos transfusionais.

Blood transfusion has great importance as a therapeutic resource in emergency rooms for both its frequency and its importance in the hemodynamic stabilization of critically ill patients. However, it is important to consider the risks associated with these procedures, since they consist of forms of allogeneic transplant and, as such, exposes the recipient to potential complications. The blood products used in urgencies are the red blood cells, fresh frozen plasma and platelet concentrate. The knowledge of regulations, indications and risks related to blood transfusion has great importance in clinical practice to guide decisions about the need for blood transfusion when it occurs. It is also important to pay attention to the prospects for therapeutic alternatives to heterologous transfusion represented here by the hemoglobin substitutes and the autologous transfusions, practices that may contribute to the reduction of transfusion risks.

[Report on notifications pursuant to Section 21 German Transfusion Act for 2007]. / Bericht zur Meldung nach section sign 21 TFG für das Jahr 2007.

The present report contains the data collected in 2007, pursuant to Section 21 Transfusionsgesetz (German Transfusion Act), and an analysis of the supply situation over the past eight years. The recording of the data by online reporting is in the meantime well established and generally accepted. As in previous years, all blood donation centers located in Germany transmitted data on the collection, manufacture, import and export of blood components for transfusion, so that meaningful data are available. According to these data, a total of 6.7 million blood collections were performed in 2007. The number of whole blood donations was at the level of previous years, with 4.7 million, whereas the number of apheresis donations rose again, to 1.9 million. The portion of autologous blood collections accounts for only 1.1% and thus continues to decline. Since 2003, the number of red blood cell concentrates prepared has been a constant 4.5 million transfusion units. The decrease in the portion of decay of red blood cell concentrates on the user side is particularly good news. In 2000, it accounted for 5% and in 2007, it was just above 3%, referred to the total quantity of data reported as transfused and decayed. The manufacture of platelet concentrates rose from 366,000 to 480,000 transfusion units between 2003 and 2007. The production of therapeutic single plasmas also markedly increased in 2007 compared with previous years, accounting for 1.2 million transfusion units. In 2007, 2.2 million liters of plasma for fractionation were collected in Germany. This trend went hand in hand with the increasing number of apheresis donations that year. In addition, 1.0 million liters were imported, and, at the same time, 1.8 million liters were exported. The quantity available in Germany from a pure arithmetic point of view of 1.4 million liters was almost entirely allocated to basic fractionation, so that a sufficient plasma supply can be assumed. The assessment of the degree of self-sufficiency is made difficult because of the influence of imports and exports; however, the results show no deficit for plasma derivatives. Due to the fact that manufacturing capacities are still lacking in Germany, recombinant factors need to be imported in their entirety. Since 2003, Germany has by far been the leader in Europe with more than 20 liters of fractionation plasma collected per 1,000 inhabitants. Furthermore, regarding the manufacturing figures of red blood cell concentrates, platelet concentrates, and therapeutic single plasma, Germany is in the top third for all these products compared with other European countries. The manufacture of allogeneic stem cell products for hematopoietic reconstitution, obtained by apheresis, has continuously risen to 4,700 in the reporting year. A large portion of this, 1,810 transplants could be exported while only a small number, 179 preparations, had to be imported. The manufacture of autologous stem cell preparations from cord blood also rose drastically compared with 2006, to more than 10,000 in 2007. It must be emphasized that these products were entirely placed into stock; none were transplanted in the reporting year. The interest in the figures collected in compliance with Section 21, Transfusion Act remains high both in Germany and at the international level. Reliable data are available thanks to the evaluations of trends over years, above all on the availability of blood components for transfusion. In addition, the Paul Ehrlich Institute will continue to strive to meet the demands for high-quality information on the supply situation in the future.

[For a reform of the legislation applied to plasma derivatives]. / Pour une réforme de la législation applicable aux médicaments dérivés du plasma.

The French system of law concerning marketing authorisations for blood-derived medicines is currently being contested by foreign laboratories claiming that our legislation limits the importation of medicines developed from remunerated blood and plasma donation. This criticism is not entirely founded; nonetheless, it would be judicious to bring about at least three reforms of the system of production and sales of blood-derived medicines in order to improve its safety and effectiveness while at the same time creating conditions necessary for ethical competition between different laboratories.

[Understanding the role of the European public institutions in blood transfusion]. / Comprendre le rôle des institutions publiques européennes en transfusion sanguine.

In the context of increased demand of blood components, it is highly desirable to ensure development and implementation of established standards for ethical, organisational and regulatory fields in order to guarantee the sufficiency, quality and safety of blood components and their derivatives as well as the protection of donors and recipients. In Europe, the contributions of the European public institutions is fundamental for the achievement of these goals and for the harmonisation of practices inherent to transfusional medicine activities. The Council of Europe with its 47 member states constitutes the ideal platform to tackle these themes: for half a century, its public health and bioethics experts have contributed to the elaboration of conventions and recommendations which serve as a model to elaboration of national or European regulations relevant to this field.