MB situation in France 

  1. What is therapeutic plasma?
  2. What types of therapeutic plasma exist?
  3. How is therapeutic plasma prepared in France?
  4. What are the three main technologies used in France for the Pathogen Reduction of Plasma?
  5. What is Methylene Blue?
  6. What is MB-treated plasma using the THERAFLEX MB-plasma process?
  7. Is therapeutic plasma allergic?
  8. Is Methylene Blue allergic?
  9. Could other Pathogen Inactivated Plasma be allergic?
  10. What are the potential risks for patients transfused with MB-treated plasma?
  11. Is Methylene Blue toxic?
  12. Is Methylene Blue removed from the treated plasma after the inactivation process?
  13. Where is MB-Plasma used outside of France?
  14. Which authorities have already given regulatory approval worldwide for the use of THERAFLEX MB-Plasma?
  15. Why have AFSSAPS decided to gradually stop the use of MB-plasma in France?
  16. Why have AFSSAPS decided not to immediately stop the use of MB plasma?
  17. Is there any variability in the concentration of fibrinogen in MB plasma compared to the other types of plasma marketed in France?
  18. What will be the consequences on the French therapeutic plasma supply?

 

1.  What is therapeutic plasma?

Therapeutic plasma is:

- The liquid portion of blood (straw-coloured clear liquid) which is a protein-salt solution within which blood cells (red and white blood cells and platelets) are suspended

- It constitutes 55%-60% of blood volume Plasma

Composition :

 

 2. What types of therapeutic plasma exist?

Three types of therapeutic plasma exist:- FFP: Fresh Frozen Plasma (prepared from Whole blood or Apheresis)- QFFP: Fresh Frozen Plasma (prepared from Whole blood or Apheresis) available after a 6 month quarantine storage period – Pathogen Inactivated Plasma: Fresh Frozen Plasma (prepared from Whole blood or Apheresis) exposed to pathogen reduction techniques.

 

 3. How is therapeutic plasma prepared in France?

Therapeutic plasma is prepared by EFS (French blood service) blood centres and the CTSA (Army blood bank) and sent to hospitals and clinics to be transfused to patients. There are two methods to produce plasma:

- from Whole Blood (donation of 1 unit of whole blood)

- from Aphaeresis (donation of 1 unit or a double dose unit of plasma)

In France, therapeutic plasma is only produced from Aphaeresis plasma and is 100% pathogen reducedo. Once prepared by the blood centre the pathogen-reduced plasma bags are sent to hospitals and clinics for storage and subsequent  transfusion.

Each year, the EFS distributes 370,000 bags of pathogen-reduced plasma to hospitals and clinics.

 

 4. What are the three main technologies used in France for the Pathogen Reduction of Plasma?

Due to stringent donor selection and testing procedures, therapeutic plasma in the developed world offers a high degree of viral safety.However, the current strategy can not eliminate all transfusion-transmitted infectious agents, i.e. not only known pathogens for which tests do not exist or are not used but also unknown new agents resulting in some patients being harmed before preventative measures are introduced. The EFS decided to implement 3 technologies to secure their plasma supply:

- Solvent-detergent (SD plasma, produced by EFS);

- Amotosalen (IA plasma, using Intercept technology – CERUS) ;

- Methylene blue (MB plasma, using THERAFLEX MB-Plasma technology – Macopharma)

 

 5. What is Methylene Blue (MB)?

Methylene blue is a phenothiazine-based photosensitizer with a particular affinity for guanosine-cytosine pairs.

Long History of Medical Application:

1) Staining (Paul Ehrlich, 1885)

2) Tissue staining (dissection of adenoids, lymph nodes, thyroid gland)

3) Antidote for Methemoglobinemia reversal (drug)

4) Antiseptic properties (drug)…

 

 6. What is MB-treated plasma using the THERAFLEX MB-Plasma process?

-       A pathogen reduction technology for therapeutic plasma

-       A photodynamic procedure using methylene blue (85µg/ unit of plasma) and visible light

-       Applied to single donor units of plasma

-       Methylene blue is a phenothiazine dye which intercalates into viral nucleic acid

-       Subsequent illumination generates singlet oxygen leading to guanosine oxidation and destruction of the viral nucleic acid preventing viral replication

-       Suitable for both whole blood and aphaeresis plasma

-       Combines the use of a fully integrated dockable disposable set and an illumination device

-       Class III CE marked (approved by AFSSAPS & most recent certification delivered by the notified body G-Med on September 28th, 2011)

 

7. Is therapeutic plasma allergic?

Most of the time after transfusion, adverse events are related to the transfusion of the therapeutic plasma itself (DONOR ≠ PATIENT). Allergic events due to transfusion of blood products are common but most of the time mild. Only one in 20.000 to 47.000 cases is severe. Often a pre-existing antibody in the recipient is reacting with a protein from the donor and triggers the reaction.

 

8. Is Methylene Blue allergic?

A very broad range of substances can be allergens to sensitive individuals. In addition to foreign proteins found in foreign serum (from blood transfusions) and vaccines, common allergens include:- Animal products: fur, wool, house dust mite excretion,- Drugs & chemicals: penicillin, aspirin, chlorine, methylene blue, – Foods: eggs, fruit, wheat, peanuts, – Insects stings: bee, wasp, mosquito, – Plant pollens (Hay fever): grass, weed, trees- Others: latex, metalIt is therefore possible that some patients could be allergic to MB in exactly the same way that a patient can be allergic to a drug or to other substances such as latex. For these patients it is not recommended to use MB plasma,as mentioned in the Instructions For Use (Notice) “CONTRAINDICATIONS : Do not use THERAFLEX MB-Plasma in case of allergic reactions to methylene blue or its derivatives.” Out of 2.5 million units of MB plasma which have been treated worldwide using the THERAFLEX MB-PLASMA process, 510 000 plasma units have been transfused in France between 2008 and 2010. So far, the only “more frequent serious allergic reports” are those observed by the French haemovigilance network.

 

 9. Could other Pathogen Inactivated Plasma be allergic?

For all three plasma types distributed in France severe allergic reactions were described in the last Haemovigilance Report 2010. Regarding Intercept plasma (IA plasma, Cerus) some severe cases were recently reported in the following article and poster:

-       “An active hemovigilance program characterizing the safety profile of 7483 transfusions with plasma components prepared with amotosalen and UVA photochemical treatment. Transfusion. 2010 Jan.”

-       “An Active Hemovigilance Program Provides Real-Time Data to Monitor the Safety of INTERCEPT Platelet and Plasma Components. Anne Elliott, Lily Lin, Meisa Propst and Laurence Corash in collaboration with the INTERCEPT Hemovigilance Study Centers, Cerus Corporation, Concord, USA” All three severe events included tachycardia and hypotension. At least one was judged as an allergic reaction.

 

10. What are the potential risks for patients transfused with MB-treated plasma?

If the patient is not allergic to MB there is no increased risk linked to MB-treated plasma. If the patient has a known allergy to MB, it is recommended not to transfuse them with MB-treated plasma. However, you can have some adverse events related to the transfusion of plasma itself (donor ≠ patient) which can occur both in the presence and absence of MB. Macopharma recommends using the Plas4 filter (already included in most of the kits, not in the French product code) in order to remove cells (a possible source of adverse events) in the plasma.In France, all of the therapeutic plasma is produced by apheresis machines. However, the authorisation file specifies the use of an integrated MB plasma kit (including Plas4 filter). Nevertheless the EFS decided not to use an MB plasma kit with the Plas4 filter as they consider that the apheresis machine provides the same leucoreduction efficiency as the plasma filter (plas4).

 

 11. Is Methylene Blue toxic?

There have not been any toxic effects reported linked to the Methylene Blue concentrations used with THERAFLEX MB-Plasma technology. Biocompatibility and toxicological studies were carried out by GLP laboratory, LEMI as part of the CE Marking File and registration process with no adverse results observed.

 

 12. Is Methylene Blue removed from the treated plasma after the inactivation process?

It depends. Some countries (Italy, Spain) are using the THERAFLEX MB-Plasma system without the Blueflex filter (90% MB removal) since more than 10 years. In some other countries (France, UK, Austria etc …), customers are using a Blueflex filter to remove residual MB and its photoderivatives from the plasma at the end of the process.

 

13. Where is MB-Plasma used outside of France?

THERAFLEX MB-Plasma is the most adopted pathogen reduction method for single plasma units Worldwide. This technology is authorized, accepted and used in the following countries: Germany, Belgium, Italy, Spain, UK, Greece, Brazil, Argentina, Malaysia, Hong Kong, Singapore, Armenia, Turkmenistan, Kazakhstan, Belarus, Poland, Austria and Russia. The technology has been used for: 12 years (Spain), 11 years (Greece), 10 years (UK & Italy), 7 years (Belgium), 6 years (Malaysia), 5 years (Russia), 4  years (Austria, Brazil & Singapore), 3 years (France & Poland)  ….

 

 14. Which authorities have already given regulatory approval worldwide for the use of THERAFLEX MB-Plasma?

Please find below all regulatory approvals for MB-treated plasma worldwide: Germany : PEIFrance : AFSSAPSSwitzerland : SwissmedicArgentina : ANMAT (Administracion Nacional de Medicamentos, Alimentos Macopharma Tecnologia Medica)Uruguay : Ministerio de Salud PublicaCanada : Santé CanadaRussia : Ministry of HealthMexico : Ministry of Health

Croatia : Agency for Medicinal Products and Medical DevicesUkraine: Ministry of HealthBrazil : ANVISAThailand : FDABelarus : Ministry of HealthKazakhstan : Ministry of HealthHong Kong : Medical Devices Control OfficeSingapore : HSA (Health Sciences Authority)

 

15. Why have AFSSAPS decided to gradually stop the use of MB plasma in France?

Afssaps have decided to gradually stop the use of MB plasma treated with methylene blue because of two reasons: the frequency of allergic reactions after MB plasma transfusion and variability in the concentration of fibrinogen in MB plasma compared to the other types of plasma marketed in France. However, Afssaps has apparently not taken into consideration the recommendations made by its own Allergy Working Group (GT) related to the last 2010 Haemovigilance  report: “GT experts recommend that the results (the results of the full analysis of all allergic cases related to plasma reported between 2005 and 2009) should be  interpreted with great caution, due to the following unresolved issues; exhaustivity of reporting, incomplete reports in some of the records (reporting before 2008) and because of the weakness of the analysis related to infrequent events.

 

 16.  Why have AFSSAPS decided not to immediately stop the use of MB plasma?

“In order to guarantee that plasma requirements are fully met, EFS in collaboration with Afssaps, will progressively substitute MB plasma by the two other types of plasma until March 2012.”Additionally, Afssaps have stated that they do not consider that MB-Plasma is a dangerous product. They simply believe that there is a greater risk of allergic reactions with MB-Plasma than with the other types of plasma based on their analysis of the Haemovigilance reports but that the risk is rare.

 

 17. Is there any variability in the concentration of fibrinogen in MB plasma compared to the other types of plasma marketed in France?

Fibrinogen is an important coagulation factor. However, there are no clinical studies demonstrating what mean concentration of fibrinogen is required in a therapeutic plasma unit. Additionally, according to French, European and American guidelines, the only indicator of quality which is considered for therapeutic plasma is factor VIII.During the last French transfusion congress (SFTS congress, Lyon, May 2011) Doctor Rachel Petermann (Afssaps) presented the quality control data of different therapeutic plasmas approved in France. The mean fibrinogen value for MB plasma was 2.3g/l ± 1 and 2.2g/l ± 0.8 for IA plasma. Based on Afssaps desire to have a mean value greater than 2g/l, it was calculated that 71.8% of MB plasma units were above this mean with only 60.9% for IA plasma. In conclusion the IA plasma fibrinogen rate is lower than for MB plasma.  Following various observations and internal validations by Macopharma, we can state that the variability in the concentration of fibrinogen in MB plasma cited by Afssaps can be explained by the fact that the analysis is based on inadequately prepared quality control plasma samples and not due to the therapeutic unit to be transfused.

 

 18. What will be the consequences on the French therapeutic plasma supply?

One of the consequences of ceasing to use MB plasma will be the increased use of other therapeutic plasmas that may not be any safer in terms of adverse events.

SD plasma technology used in France requires the pooling of plasma units from 100 donors. If one donor plasma unit is infected (within the mix of 100 plasma units) by a pathogen not susceptible for the process, e.g. a non-enveloped virus, the infection could subsequently be also present in all resulting plasma bags.

To date, the Intercept process marketed by the American company Cerus does not yet have FDA (American Drug Regulatory Authority) approval.

During 2010 in France, the volume of pathogen-reduced plasma using the Intercept process represented about 20% of the total amount of MB treated plasma with an equivalent frequency of reported severe allergic cases.

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