Tourcoing, 20th of November 2015
Following the report of a case of apparent failure of viral inactivation with methylene blue, Macopharma contests the analysis provided in the Transfusion journal and asserts the efficacy of their pathogen inactivation procedure on HIV as long as it is used properly.
As announced today in the « Early View » of the Transfusion journal, an article by Alvarez et al. is published online ahead of print, reporting a case of HIV-1 transmission through plasma treated with methylene blue and visible light in Valencia’s blood centre, in Spain. Macopharma has submitted their answer to this « Case Report » to the Transfusion journal for publication in their next edition. Several points can already be clarified to obviate any misinterpretation of this article.
This case, which dates back to more than 10 years ago and has already been mentioned in a congress poster and a review article, is the only case of HIV transmission reported to date since the development and use of methylene blue inactivation, more than twenty years ago.
Following the report of the case in 2009, a deeper investigation was conducted in close cooperation with Valencia’s blood centre. It was not possible to identify the origin of the fault with certainty, due to the very long time span between the transfusion itself and the detection of transmission, but also because the blood centre was not able to provide the necessary internal traceability elements to either confirm or invalidate the fact that the plasma bag had been properly treated prior to transfusion.
However, the studies allowed us to confirm the following:
- On the one hand, the implicated batch of bags presented no defect, nor did the illumination device used on the concerned bag,
- On the other hand, HIV-1 cannot escape methylene blue inactivation, even at a very low level of viral particles diluted in a large volume of plasma. Additional investigations led after this case – whose results are included in Macopharma’s reply to the Transfusion journal – demonstrate the full efficacy of the THERAFLEX MB-Plasma procedure.
Accordingly, it appears that in all likelihood, the transmission of HIV-1 could be linked to wrong manipulation, and not to a failure of the THERAFLEX MB-Plasma system.
Nevertheless, Macopharma has implemented additional safety procedures to fully guarantee the quality of the devices provided to users. Macopharma has also renewed the training of staff from Valencia’s blood centre, who is still using methylene blue inactivation today.
To conclude, since 1992, more than 6.5 million units of plasma treated with methylene blue have been transfused in different clinical settings. Macopharma confirms that the THERAFLEX MB-Plasma system provides the highest guarantees in terms of safety and efficacy. Macopharma’s priority remains to meet at best the expectations of their partners and to work towards the safety of transfused patients, as demonstrated by the vote of confidence granted to the THERAFLEX MB-Plasma procedure by 120 customers in 19 countries.
Tourcoing, le 20 novembre 2015
Suite à l’annonce d’un cas de défaillance apparente de l’inactivation virale au bleu de méthylène, Macopharma conteste l’analyse livrée dans la revue Transfusion et rappelle l’efficacité de son dispositif d’inactivation des pathogènes sur le VIH dès lors qu’il est correctement utilisé.
Un article d’Alvarez et al., annoncé aujourd’hui dans la section « Early View » de la revue Transfusion, et à paraître dans la prochaine édition papier, rapporte un cas de transmission de VIH-1 par du plasma traité au bleu de méthylène et à la lumière visible, au centre de transfusion de Valence en Espagne. Macopharma a soumis au journal Transfusion sa réponse à ce « Case Report », pour publication dans la prochaine édition de la revue. Plusieurs points peuvent d’ores et déjà être précisés pour prévenir toute interprétation erronée de cet article.
Ce cas, remontant à plus de dix ans et ayant déjà été cité dans deux publications, constitue le seul et unique cas signalé à ce jour, depuis le développement et l’utilisation de l’inactivation au bleu de méthylène il y a plus de vingt ans.
Une enquête approfondie a été menée suite au signalement du cas en 2009, en coopération étroite avec le centre de transfusion de Valence. L’origine de la défaillance n’a pas pu être identifiée avec certitude, en raison du délai très long entre la transfusion et l’identification de la contamination, mais aussi car le centre n’a pas été en mesure de fournir les éléments de traçabilité internes qui permettent de confirmer ou pas que la poche de plasma a été correctement traitée avant la transfusion.
Les différentes études ont toutefois permis de confirmer que :
- D’une part, le lot de poches ne présentait aucune anomalie, pas plus que l’appareil d’illumination utilisé pour la poche concernée,
- D’autre part, le VIH-1 ne peut échapper à l’inactivation au bleu de méthylène, fut-ce à un niveau très faible de particules virales diluées dans un volume de plasma important. Des investigations supplémentaires conduites suite à ce cas, dont les résultats figurent dans la réponse de Macopharma à la revue Transfusion, démontrent la pleine efficacité du système.
En conséquence, il apparaît que selon toute probabilité, la transmission du VIH-1 serait ici liée à une erreur de manipulation, et non à une défaillance du THERAFLEX MB-Plasma.
Macopharma a néanmoins mis en place des procédures de sécurité supplémentaires pour garantir à 100% la qualité des dispositifs livrés aux utilisateurs. Macopharma a par ailleurs formé une nouvelle fois les personnels du centre de Valence, qui continue à utiliser aujourd’hui l’inactivation au bleu de méthylène.
En conclusion, depuis 1992, plus de 6.5 millions d’unités de plasma traité au bleu de méthylène ont été transfusées dans des milieux cliniques divers. Macopharma confirme que le THERAFLEX MB-Plasma présente les garanties les plus fortes en termes de sécurité et d’efficacité. Sa priorité reste de satisfaire au mieux les attentes de ses partenaires et à agir pour la sécurité des patients transfusés. La confiance de ses 120 clients dans 19 pays en témoigne.
Tourcoing — September 9th, 2015 –
Macopharma today announced the finalization of the European prospective non-interventional study for THERAFLEX MB-Plasma that has started in collaboration with an international CRO (contract research organization) SynteractHCR in November 2013, with the first patient enrolment in Spain.
The aim of this post marketing surveillance study was to collect, during a period of at least one year, adverse events related to MB-treated plasma transfusions in seven key European hospitals in Belgium, UK, Spain and Greece where MB-treated plasma is in routine use.
Last patient enrolment was in March 2015.
In this study the outcome of a total of 19,315 transfused units of MB plasma (3,780 transfusions) was observed. This number is considered adequate to determine the safety of MB plasma. The incidence of serious Adverse Transfusion Reactions (ATRs) was 1 per 19,315 transfused units of MB plasma which is similar to the incidence for untreated fresh frozen plasma reported by the French national authority ANSM. There were no ATRs reported in Greece where 9,241 units of MB plasma were transfused nor in the UK where 434 units were transfused during the observation period.
“We are very happy of the outcome of this study; this observational trial in patients confirms that Methylene Blue plasma is a safe product” Macopharma Clinical Research Manager Dr. Ignacio Alvarez, said. “We are also very satisfied about the great collaboration we had with SynteractHCR.”
Macopharma SA (“Macopharma”) (www.macopharma.com) is an innovator in global healthcare with expertise in the fields of transfusion and infusion. The company has become the largest supplier of in-line leucodepletion filtration sets in Europe. It is expanding its efforts in the fields of respiratory masks and cellular therapy by developing products for cell expansion, in addition to cell/organ processing and freezing. Headquartered in the Lille metropolitan area (France), Macopharma has four manufacturing facilities in Europe and its products are sold into more than 70 countries worldwide. One of Macopharma’s aims is to provide a comprehensive range for the pathogen reduction of infectious agents in plasma, platelets and red cells. This is aligned with Macopharma’s product development strategy of the continuous quest, through partnerships, for improved safety, efficacy, and quality of transfusion, infusion, masks and cellular therapy.
About THERAFLEX MB-Plasma
The THERAFLEX MB-Plasma System has a Class III CE Mark (available for sale in countries where the CE mark is accepted) and is not currently available for sale in the United States. It is a user-friendly in-house treatment for single units of plasma. The GMP-conforming procedure is adapted for the inactivation of FFP from aphaeresis or whole blood plasma. The MB-plasma system uses a combination of a membrane filter Plasmaflex PLAS4, (which removes residual leucocytes, red cells, platelets and aggregates, intra-cellular viruses and minimises the amount of microvesicles and microparticles), a dry Methylene Blue pill, visible light, and a Blueflex Methylene Blue removal filter.
See www.bloodsafety.macopharma.com for more information.
SynteractHCR is a full-service contract research organization with a successful two-decade track record supporting biotechnology, medical device and pharmaceutical companies in all phases of clinical development. SynteractHCR has conducted Phase I-IV studies on six continents and in more than 50 countries, offering expertise across multiple therapeutic areas and with notable depth in oncology, CNS, infectious disease, endocrinology, cardiovascular and respiratory, among other indications. With its “Shared Work – Shared Vision” philosophy and ICD+ approach, SynteractHCR provides customized services collaboratively and cost effectively, ensuring on-time delivery of quality data so clients get to decision points faster.
See www.SynteractHCR.com, for more information.
On 29th June 2015, a Macopharma lunch symposium took place during the ISBT congress in London, dealing with blood safety and especially with the THERAFLEX MB-Plasma technology, a photodynamic procedure using Methylene Blue and visible light for the inactivation of pathogens in plasma.
About 150 people attended the symposium. During this session, Macopharma shared two major topics with the scientific community: an international prospective clinical study on MB-treated Plasma and the safety profile of THERAFLEX MB-Plasma.
Dr. Hafiz Qureshi from the University Hospitals of Leicester presented the results of a prospective non-interventional study to evaluate the safety of Methylene Blue Plasma. This was an open label, multi-centre, non-controlled, non-randomized, non-interventional study, in 7 hospitals from 4 countries: Belgium, Greece, Spain and the United Kingdom. The aim of this investigation was:
- to gather data on adverse reactions occurring with MB plasma administered in a routine clinical practice environment
- to know more about their characteristics and behaviour, and the possible factors that may influence their presentation and evolution.
Prof. Axel Seltsam from the German Red Cross blood center NSTOB elaborated on the safety profile of THERAFLEX MB-Plasma. He showed that the THERAFLEX MB-Plasma procedure also reduces bacteria including bacterial spores. Moreover, the inactivation capacity of the procedure on viruses can compensate for reduced transparency of the plasma due to lipaemia.
Dr. Denese Marks from the Australian Red Cross Blood Service added information about the inactivation capacity on Dengue viruses. Inactivation of all four DENV types reached the detection limit of the assay already at half the standard illumination dose.
Moderators, namely Prof. Jean-Pierre Allain (Emeritus Professor of Transfusion Medicine at the Department of Hematology at the University of Cambridge in the United Kingdom) and Prof. Olivier Garraud (Senior Consultant, International Affairs, the Institut National de la Transfusion Sanguine (INTS), France) also contributed to the success of the symposium due to high quality questions,various exchanges and experience feedback.
Many thanks to the presenters, moderators and participants of our symposium on blood safety!
Click here to get access to the abstract book
Tourcoing — April 22, 2015 - Macopharma is pleased to inform you that a current article, entitled “Challenge study of the pathogen reduction capacity of the THERAFLEX MB-Plasma technology” has been recently published in the journal “Vox Sanguinis” 1.
Aim of the study was to investigate the bacterial reduction capacity of the THERAFLEX MB-Plasma treatment process. Moreover, the virus inactivation capacity in lipaemic plasma was explored.
The filtration steps of the procedure resulted in efficient bacteria reduction of transfusion-relevant strains like Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Bacillus cereus and Klebsiella pneumoniae ≥ 4.8 logs i.e. to the limit of detection (LOD). In addition, bacterial spores of Bacillus subtilis were eliminated. The overall reduction capacity of the THERAFLEX MB-Plasma technology is expected to be sufficient to prevent transfusion-transmitted bacterial infections, taking into account the concentration of bacteria normally present in contaminated therapeutic plasma.
HIV-1 and model viruses for HBV and HCV were efficiently inactivated by the MB/ light procedure independent of the degree of lipaemia. Its virus inactivation capacity is sufficient to compensate for reduced light transparency caused by intense lipaemia. This underlines the robustness of the system for natural plasma variation.
Macopharma SA (“Macopharma”) (www.macopharma.com) is an innovator in global healthcare with expertise in the fields of transfusion, infusion and biotherapy. The company has become the largest supplier of in-line leucodepletion filtration sets in Europe.
It is expanding its efforts in the fields of respiratory masks and cellular therapy by developing products for cell expansion, in addition to cell/organ processing and freezing. Headquartered in the Lille metropolitan area (France), Macopharma has four manufacturing facilities in Europe and their products are sold into more than 100 countries worldwide. One of Macopharma’s aims is to provide a comprehensive range for the pathogen reduction of infectious agents in plasma, platelets and red cells. This is aligned with Macopharma’s product development strategy of the continuous quest, through partnerships, for improved safety, efficiency, and quality of transfusion, infusion, masks and cellular therapy.
About THERAFLEX MB-Plasma
The THERAFLEX MB-Plasma System has a Class III CE Mark (available for sale in countries where the CE mark is accepted) and is not currently available for sale in the United States. It is a user-friendly in-house treatment for single units of plasma. The GMP-conforming procedure is adapted for the inactivation of FFP from aphaeresis or whole blood plasma. The MB plasma system uses a combination of a membrane filter Plasmaflex PLAS4, (which removes residual leucocytes, red cells, platelets and aggregates, intra-cellular viruses and minimises the amount of microvesicles and microparticles), a dry Methylene Blue pill, visible light and a Blueflex Methylene Blue removal filter.
See www.bloodsafety.macopharma.com, for more information.
1Reichenberg S, Gravemann U, Sumian C, Seltsam A. Challenge study of the pathogen reduction capacity of the THERAFLEX MB-Plasma technology. Vox Sanguinis 2015: DOI: 10.1111/vox.12257
Tourcoing and Fontenay-aux-roses —February 2015 – Macopharma and the Department of prion and atypical infections research (SEPIA, Institute of Emerging Diseases and Innovative therapies (iMETI), French Alternative Energies and Atomic Energy Commission (CEA), are pleased to announce the publication of new and compelling data on the performance of the Macopharma prion removal filter for red cell concentrates (P-Capt®) in a primate model. The article entitled “Evaluation of the protection of primates transfused with vCJD-infected blood products filtered with prion removal devices: a five years update” has been recently published online in the journal “Transfusion”.
The lack of an established detection method for infectious prions (PrPres) in human blood means animal bioassays must be used to demonstrate the ability of prion removal filters to capture and remove endogenous blood-borne infectivity from leucoreduced red blood cell concentrate.
The new study, undertaken by Macopharma and scientists from CEA / iMETI / SEPIA, comprised the collection of blood from cynomolgus macaques infected with either BSE or vCJD and the processing of the infected blood to provide leucoreduced (L-RBC) or non-leucoreduced (NL-RBC) red cell concentrates using standard methods established for the processing of human blood. L-RBC and NL-RBC were transfused into two healthy primates and red cell concentrates that had been subjected to P-Capt or prototype combined filter were transfused into three healthy primates, respectively.
Among the six macaques transfused with non-filtered samples, five developed neurological signs but only four exhibited peripheral detectable PrPres accumulation.
All three animals in the P-Capt-filtered L-RBC group remained asymptomatic after 74 months.
About variant Creutzfeldt-Jakob Disease
Variant Creutzfeldt-Jakob Disease (vCJD) is characterized by the accumulation of large deposits of misfolded prion protein in the brain and the nervous system and the appearance of sponge-like holes in the brain causing a fatal degenerative CNS disorder. Such abnormal prion proteins may be sufficient to transmit the disease. Although some people’s genetic make-up may protect them, at least 89% of the population may be susceptible to vCJD. vCJD was initially transmitted to humans from BSE infected cows presumably by the consumption of BSE contaminated meat, but a secondary route of transmission by the transfusion of blood units from asymptomatic vCJD individuals threatens to increase the prevalence of the fatal disease.
P-Capt® is a single-use sterile device which was awarded CE mark approval in September 2006. Red blood cells are passed through the filter under gravity and a highly specific affinity adsorbent material captures and removes vCJD prion protein.
P-Capt® is the only approved product proven to be effective for the removal of prion infectivity from red blood cell concentrate prior to transfusion. It has been evaluated extensively by the UK Blood Services, the Irish Blood Transfusion Service and the British Health Protection Agency since 2006 and has achieved all of the required performance and safety requirements and met all benchmarks. The P-Capt® filter incorporates a prion-specific affinity resin and is manufactured and distributed by Macopharma.
About Macopharma SA
Macopharma SA (“Macopharma”) (www.macopharma.com) is an innovator in global healthcare with expertise in the fields of transfusion and infusion. It has become the largest supplier of in-line leucoreduction filtration sets in Europe and is expanding its efforts into the cellular therapy field by developing products for cell expansion, in addition to cell/organ processing and freezing. Headquartered in the Lille metropolitan area (France), Macopharma has three manufacturing facilities in Europe and their products are sold into more than 70 countries worldwide.