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Free download or read online Intercepted pdf (ePUB) book. The first edition of the novel was published in September 11th 2018, and was written by Alexa Martin. The book was published in multiple languages including English, consists of 308 pages and is available in Paperback format. The main characters of this romance, contemporary story are Marlee Harper, Gavin Pope.

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Transfusion and Apheresis Science 52 (2015) 240–244
Contents lists available at ScienceDirect
Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i
Review
Update on pathogen inactivation treatment of plasma, with the INTERCEPT Blood System: Current position on methodological, clinical and regulatory aspects Johannes Irsch a,*, Jerard Seghatchian b a b
Cerus BV, Amersfoort, The Netherlands International Consultancy in Blood Components Quality/Safety Improvement, Audit/Inspection, and DDR Strategy, London, UK
A R T I C L E
I N F O
A B S T R A C T
After the INTERCEPT Blood System for pathogen inactivation (PI) of plasma was locally validated and approved and is now in routine use in Portugal, a conference was arranged in Portugal, by the IPST, in Coimbra, on 19th November 2014. One of the presentations informed about the current status of the INTERCEPT technology for plasma and a subsequent round table discussion, focused on the methodological and logistical aspects as well as on the experience from clinical studies and routine therapeutic use of INTERCEPT treated plasma units. Moreover, in view of current interests, both the global regulatory issues and hemovigilance data obtained were highlighted. This manuscript provides a brief summary of what has been discussed during presentations and the Q/A round table session. It was agreed between speaker and the moderator of the session to report a consensus opinion on the importance of INTERCEPT to improve the safety of plasma products in a standardized way in terms of quality indicators of hemostasis and the clinical effectiveness as well as the reliability of the technology for plasma pathogen inactivation, to be reported as part of a theme section from Portugal and to be published in Transfusion Apheresis Science in early 2015. The session started showing the beneficial advantages of the INTERCEPT technology, which has already become the standard of practice in Portugal and in more than 20 other countries, and then highlighted some of the methodological and global quality/clinical aspects, which are not usually discussed. We hope the topic discussed here would be of interest to readers of Transfusion Apheresis Science. © 2015 Elsevier Ltd. All rights reserved.
Contents Background ........................................................................................................................................................................................................................... The INTERCEPT Blood System ........................................................................................................................................................................................ Current regulatory status ................................................................................................................................................................................................ INTERCEPT procedure ....................................................................................................................................................................................................... Clinical experience .............................................................................................................................................................................................................
* Corresponding author. Cerus BV, Stationstraat 79D, 3811 Amersfoort, The Netherlands. Tel.: +0031-334960600; fax: +0031-334960606. E-mail address: [email protected] (J. Irsch). http://dx.doi.org/10.1016/j.transci.2015.02.013 1473-0502/© 2015 Elsevier Ltd. All rights reserved.
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Other applications for INTERCEPT plasma ................................................................................................................................................................ 243 Discussion ............................................................................................................................................................................................................................. 243 References ............................................................................................................................................................................................................................. 244
Background Although transfusion-transmitted infections (TTI) have been reduced due to strict donor selection or donor deferrals and the increased use of screening/testing procedures, ongoing development of quality/safety improvements is still warranted [1–4]. The continuous implementation of new testing methods not only poses logistical and economic problems, but it also represents only a reactive approach with all its limitations. The limited sensitivity of such tests as well as the window period pose continued threats to recipients of therapeutic plasma units. The development of tests for new pathogens on average takes more than 1 year even after the pathogen has been discovered and described. Additionally, test manufacturers have to prioritize the development of tests for new pathogens based on the market opportunity it presents. The development of new tests for pathogens, for which no high level of crisis would be foreseen, may be considered as of low priority as a good return on the investment for their development may not be expected. Pathogen inactivation (PI) on the other hand represents a pro-active approach and an additional safety measure as the mechanism of action for PI regardless of the technology is independent of the nature of the pathogen. A pro-active approach to blood safety has become even more important since the import of new or re-emerging pathogens as a result of climate changes and increased world-wide traveling. There is consensus that the introduction of any PI technology requires a thorough safety profile and minimal effect on the blood product efficacy. These should be validated with a comprehensive pre-clinical and clinical development program, covering all routine and potential clinical applications of the treated blood component, as well as a continuing hemovigilance program post approval [5]. The INTERCEPT Blood System The INTERCEPT Blood System for plasma (Cerus Europe BV, Amersfoort, The Netherlands) inactivates a broad range of pathogens, including viruses, bacteria, protozoa, and white blood cells (WBCs) [6,7]. The system is based on the photochemical treatment (PCT) with amotosalen (also known as S-59) and UVA light (320–400 nm) to treat plasma. Amotosalen reversibly intercalates into helical regions of DNA and RNA. Upon illumination with UVA light, covalent bonds are formed between amotosalen and pyrimidine bases in the nucleic acids. The genomes of the pathogens and WBC modified this way can no longer be replicated or transcribed [7,8]. The high specificity of amotosalen to pyrimidine bases and the fact that the reaction requires UVA light represents a major advantage over other technologies as it minimizes non-specific reactions and thus preserves the proteins in the blood product [9]. Other technologies developed for the PI of plasma differ widely in the range of pathogens they are capable of inactivating and in the safety and feasibility of
the procedures [10–13]. The INTERCEPT treatment process does not depend on reactive oxygen species (ROS) for its function, which represents another major difference to some other technologies currently available [14]. The absence of uncontrollable side-reactions that can occur due to ROS represents a desirable feature that preserves the quality of the treated component described by different authors [14,15]. The safety profile of the INTERCEPT technology has been demonstrated in a broad range of pharmacokinetic and toxicological studies [16,17]. Current regulatory status The INTERCEPT Blood System for plasma has been CE marked in Europe as a class III medical device since 2006 and received additional approvals by European authorities including the ANSM (formerly Afssaps, France), the PEI (Paul Ehrlich Institute, Germany) and the Swissmedic (Switzerland). Most recently, the FDA approved its use in the United States of America. It is in routine use in Europe for the treatment of fresh frozen plasma (FFP) and previously frozen plasma either from apheresis or whole blood collections. About 1 million plasma units have been treated to date worldwide, and used in a wide range of clinical treatments. There is no patient exclusion, i.e. all patient groups including pediatric patients can be transfused with INTERCEPT treated plasma. INTERCEPT procedure The INTERCEPT system is capable of treating plasma units with volumes between 385 and 650 ml. In the standard routine operation the plasma product (either from apheresis or 2–3 pooled whole blood collections) is sterile connected to an integrated disposable set (Fig. 1). Several variants of the pooling assembly exist, making the system fit local purposes, as discussed below. The device consists of an integrated disposable set and an illuminator. The integrated disposable set is a closed system comprised of connected containers. The plasma is sequentially passed through these containers by gravity flow with the first pouch containing the amotosalen. The process consists of 3 steps: the plasma is mixed with amotosalen, it is illuminated after transferring the suspension into the illumination container and after illumination the photoproducts are adsorbed in a flow-through compound adsorption device (CAD) before transfer into up to three storage containers (Fig. 1). The hands-on time for the entire process for the treatment of 2 plasma units, i.e. for the production of up to 6 therapeutic units, takes less than 10 minutes and the CAD step also requires approximately 10 minutes. The UVA illuminator is a microprocessor-controlled device capable of delivering the target UVA dose and illuminating two plasma units simultaneously [7]. The process has been validated in blood centers to verify the performance of the PCT system under different routine operating conditions [18,19]. These centers’ validations
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Fig. 1. The INTERCEPT Blood System for plasma consists of a UVA illuminator and an integrated disposable set. Upper part: The disposable set. The collected plasma product is sterile-connected to the integrated disposable set which consists of a pouch containing the active compound amotosalen (S-59), the illumination bag, the compound adsorption device (CAD, in which S-59 and photoproducts are removed in approx. 10 minutes) and 3 storage bags for up to 3 therapeutic units of plasma. Lower part: The illuminator in which two products can be treated simultaneously.
demonstrated that coagulation factor levels meet European and national standards and the product has a very good performance in routine use. It is important to highlight that anti-thrombotic factors like Protein S, Protein C, Antithrombin and Antitrypsin are also retained similar to untreated plasma in contrast to the results for other technologies, and consistent with the lack of observation of thrombotic events in routine use (Table 1).
Table 1 From Ref. 9. (a) Pre- and post-treatment values for coagulation factors and relative retention in FFP after INTERCEPT treatment compared with values before treatment (mean values, n = 6). (b) Pre- and post-treatment values for coagulation inhibitors and relative retention in FFP after INTERCEPT treatment (mean values, n = 6). Analyte (a) Fibrinogen (mg/dl) Factor II (IU/dl) Factor V (IU/dl) Factor VII (IU/dl) Factor VIII (IU/dl) Factor IX (IU/dl) Factor X (IU/dl) Factor XI (IU/dl) Factor XIII (IU/dl) (b) Antithrombin (IU/dl) Protein C (IU/dl) Protein S (IU/dl) Antitrypsin (mg/dl) Antiplasmin (IU/dl) Plasminogen (IU/dl)
Pretreatment mean value
Posttreatment mean value
% Retention
307.2 103.0 136.0 116.5 151.7 111.3 99.2 106.7 114.5
235.8 92.3 125.8 90.2 118.0 92.5 87.2 92.7 105.0
77 ± 3 90 ± 3 92 ± 2 78 ± 3 78 ± 5 83 ± 2 88 ± 2 87 ± 2 92 ± 3
95.5
92.5
97 ± 4
121.3 111.7 90.0 92.3 97.2
113.3 112.0 87.5 72.2 91
93 ± 4 100 ± 6 97 ± 1 78 ± 6 94 ± 5
Clinical experience An effective PI technology for plasma must be capable of inactivating a broad range of pathogens while retaining enough hemostatic function in the labile blood product to be suitable for therapeutic support [9]. The INTERCEPT Blood System for plasma has undergone a very thorough clinical study program covering key areas of applications for therapeutic plasma. Two clinical trials in 42 healthy subjects and four clinical trials in 203 patients have been conducted to evaluate the safety and efficacy of INTERCEPT treated plasma. The 3 phase III clinical studies covered the treatment of congenital coagulopathies, acquired coagulopathies, as well as therapeutic plasma exchange for thrombotic thrombocytopenic purpura (TTP). These studies have demonstrated that the INTERCEPT treated plasma units are comparable to the conventional plasma units in terms of safety and efficacy in the support of the patients [20–22]. Additional, larger phase IV retrospective clinical studies have been successfully performed in the TTP and liver transplantation settings [23,24]. The set of clinical trials performed encompasses most of the routine applications for INTERCEPT treated plasma. Other treatment areas include trauma and surgery as well as the therapeutic plasma exchange to treat hemolytic uremic syndrome (HUS). An active hemovigilance (HV) program performed in several centers (Table 2) [25] shows a very impressive safety profile for INTERCEPT plasma in routine clinical use for all patients. In addition to the HV program summary the national HV programs from France (Table 3), Switzerland and other countries demonstrate a safe and efficacious profile for the treated plasma units for all patient groups including pediatric patients. According to the French report the adverse event profile emerging for INTERCEPT plasma is comparable to quarantine and favorable compared to some other pathogen inactivation technology [26].
J. Irsch, J. Seghatchian/Transfusion and Apheresis Science 52 (2015) 240–244
243
Table 2 Summary of the clinical characteristics of all adverse events (AEs) reported in the INTERCEPT plasma HV program from participating routine production centers. From Ref. 25. On a per-transfusion basis, n (% = n ¥ 100/7483)
Variable
Number (%) with at least one AE Signs and/or symptomsc Chills Urticaria Tachycardia Hypotension Skin rash Itching Nausea Facial edema Fever Laryngeal edema Bronchospasm Dyspnea a b c
On a per-patient basis, n (% = n ¥ 100/3232)
AEs attributed to PCT-plasma (ATR)a
SAEsb attributed to PCT-plasma (ATR)
AEs attributed to PCT-plasma (ATR)a
SAEsb attributed to PCT-plasma (ATR)
8 (0.11)
3 (0.04)
8 (0.25)
3 (0.09)
3 (0.04) 3 (0.04) 3 (0.04) 3 (0.04) 2 (0.03) 2 (0.03) 2 (0.03) 2 (0.03) 1 (0.01) 1 (0.01) 1 (0.01) 1 (0.01)
1 (0.01) 1 (0.01) 3 (0.04) 3 (0.04) 1 (0.01) 2 (0.03) 1 (0.01) 1 (0.01) 0 (0) 1 (0.01) 1 (0.01) 1 (0.01)
3 (0.09) 3 (0.09) 3 (0.09) 3 (0.09) 2 (0.06) 2 (0.06) 2 (0.06) 2 (0.06) 1 (0.03) 1 (0.03) 1 (0.03) 1 (0.03)
1 (0.03) 1 (0.03) 3 (0.09) 3 (0.09) 1 (0.03) 2 (0.06) 1 (0.03) 1 (0.03) 1 (0.03) 1 (0.03) 1 (0.03) 1 (0.03)
All AEs reported in this study were classified as possibly related, probably related, or related to PCT- plasma transfusion. SAE = long-term life-threatening, immediate life-threatening, or death. Number of symptoms can exceed the number of transfusion reactions due to multiple observed symptoms per reaction.
Table 3 Frequency of ATR per 1000 plasma components transfused (ANSM Annual Reports 2009–2011) IBS Plasma = INTERCEPT treated plasma. Year
Product
ATR
Components
ATR/103
2009
Other plasmaa IBS plasma Other plasmaa IBS plasma Other plasmaa IBS plasma
191b 12 195c 25c 98 21
348,725 22,933 329,757 52,692 311,482 68,440
0.55d 0.52d 0.59e 0.47e 0.31f 0.31f
2010 2011
a Includes quarantine plasma, methylene blue treated plasma and solventdetergent treated plasma. b Excluding irregular antibody (RAI: apparition d’anticorps irrreguliers). c Excluding allo-immunization. d ATR: Acute transfusion reaction, all grades, imputability 2–4. e ATR: Acute transfusion reaction, all grades, imputability 1–3. f ATR: Allergic transfusion reactions only, all grades, imputability 2–3.
The production of cryo-precipitate is of utmost importance in several European countries including the UK, Portugal and others as there is a big demand from the clinics. In in vitro studies the quality of cryo-precipitate produced from INTERCEPT treated plasma has been demonstrated [30,31]. Most recently the INTERCEPT treatment has been shown to be very helpful in the preparation of safe convalescent plasma from donors who survived an infection with Ebola virus. Here the aim is not to inactivate Ebola per se, but to decrease the risk of the recipient to be exposed to other pathogens the unscreened donor might be infected with while retaining the protective antibodies in the convalescent plasma [32]. Discussion
Other applications for INTERCEPT plasma The INTERCEPT treated therapeutic plasma units in routine production are derived from either apheresis collection or from a pool of 2–3 whole blood-derived plasma donations. More recently a novel approach to the generation of small plasma pools has been successfully introduced. For this application, 5 whole blood plasma collections are pooled using a pooling device (Plasmix, Grifols, Barcelona, Spain) to generate 6 therapeutic units of plasma. Studies have shown a good retention of the coagulation factors and furthermore a better standardization of the final products. In addition, this approach has shown economical benefits presented in the literature. This approach is also implemented in Portugal [27,28]. The succesful preparation of PI treated, universal lyophilized plasma pools for the early emergency treatment of trauma patients, such as in combat situations, has been demonstrated with INTERCEPT treated plasma. Its use for the support of trauma patients has been evaluated in the field in Afghanistan by the French Special Forces [29].
The transmission of pathogens via the transfusion of labile blood components is an ongoing threat [33,34]. On the one hand donor selection and development of testing systems has significantly lowered that risk. On the other hand changes in climate and increased worldwide traveling have increased the risks of exposure to new or reemerging pathogens. In some countries deferrals of donors who have traveled to endemic areas are intended to lower the risk in the donation pool. Such policies have negative consequences on the availability of plasma and other blood products due to low specificity. The INTERCEPT Blood System for pathogen inactivation of plasma has been shown to inactivate the broadest panel of pathogens including bacteria, protozoa, viruses as well as leukocytes. The preparation of pathogen-inactivated plasma with INTERCEPT results in a good retention of the coagulation factors and anti-thrombotic factors and does not lead to activation of complement. The mechanism of action has been described in detail and pharmacological and toxicological studies demonstrate high safety margins [16]. The safety and efficacy of the INTERCEPT Blood System has been
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demonstrated in a series of pre-clinical studies as well as in the largest clinical program for any pathogen inactivation or reduction technology. The results of an ongoing active hemovigilance program underline the safety of the treated products in routine use. The INTERCEPT system represents a very versatile technology capable of treating a broad range of plasma products including apheresis collections, whole blood derived plasma pools from fresh, as well as previously frozen plasma. It has been officially approved as a class III medical device and its official label claims allow PI use as alternative to gamma-irradiation to lower the risk of GVHD. Also, PI with INTERCEPT can be used to replace CMV testing. Some potential risks not addressed by PI with INTERCEPT are the transmission of prions and certain nonenveloped viruses. Prions do not contain nucleic acids and as such are not amenable to inactivation by INTERCEPT. On the other hand, the importance of transfusion as route of transmission of prions is still a matter of debate. Similar limitations exist for other PI technologies. Technologies utilizing filters for prion-removal have the disadvantage of pooling very high numbers of donations thus introducing an increased risk for contamination just by the pool size, which is counteracting the risk reduction due to prion-filters. In addition to standard procedures the production of cryo-precipitates or lyophilized plasma products has been successfully demonstrated with INTERCEPT treated plasma. Main advantages include the good retention of coagulation factors as well as anti-thrombotic factors. The introduction of INTERCEPT has made quarantine storage obsolete in many blood banks. The utilization of small pools of whole blood derived plasma donations (<12) in addition to logistical benefits leads to a better standardization of coagulation factors. Also, different from technologies based on the pooling of several hundred or thousand donations this approach enables for the preparation of male-only plasma. This approach also allows the production of therapeutic units at the blood bank center maintaining control of local resources (donations) without the need to ship donations to external production plants. In the panel discussion following the presentations during the Coimbra meeting a few questions were addressed from the audience. Regarding the removal of amotosalen and residual photoproducts it was discussed that with the compound adsorption device (CAD) nearly all the free amotosalen and photoproducts are removed in a process only taking ten minutes. Also it was explained that pharmacological and toxicological studies, performed according to the ICH guidelines, showed very high safety margins for the treated products. The detailed analyses are part of the approval by the regulatory authorities and have been published in several key reviewed publications [16]. [34] One question was concerning a potential generation of reactive oxygen species (ROS) during the INTERCEPT process. In contrast to other technologies, the generation of ROS is not an integral part of the mechanism of action for INTERCEPT and only minor amounts are generated [7,14–17]. It was asked whether the passage of the plasma through the CAD had any negative effect on the plasma like for
example the activation of complement factors. In in-vitro studies the very high percentage of retention for a large panel of coagulation factors and antithrombotic factors was shown. One study also demonstrated that complement was not activated during the INTERCEPT process [7]. In addition a proteomic analysis demonstrated hardly any differences between INTERCEPT treated and conventional plasma [34,35]. Overall, the best evidence that the treatment of plasma with INTERCEPT is safe and that the units are efficient in different clinical settings comes from the large experience from clinical studies and from routine use. References [1] Hambleton J, Wages D, Radu-Radulescu L, Adams M, Mackenzie M, Shafer S, et al. Transfusion 2002;42:1302–7. [2] Dodd RY, Leiby D. Emerging infectious threats to the blood supply. Annu Rev Med 2004;55:191–207. [3] Dodd R. Curr Opin Hematol 2007;14:671–6. [4] Stramer S, Blaine Hollinger F, Katz L, Kleinman S, Metzel P, Gregory K, et al. Transfusion 2009;49:1S–29S. [5] Klein H, Anderson D, Bernardi M, Cable R, Hoch J, Robitaille N, et al. Transfusion 2008;48:697–705. [6] Singh Y, Sawyer L, Pinkoski L, Dupuis K, Hsu J, Lin L, et al. Transfusion 2006;46:1168–77. [7] Irsch J, Lin L. Transfus Med Hemother 2011;38:19–31. [8] Wollowitz S. Semin Hematol 2001;38(4):4–11. [9] Irsch J, Pinkoski L, Corash L, Lin L. Vox Sang 2010;98:47–55. [10] Hellstern P, Solheim B. Transfus Med Hemother 2011;38:65–70. [11] Marschner S, Goodrich R. Transfus Med Hemother 2011;38:8–18. [12] Seghatchian J, Struff W, Reichenberg S. Transfus Med Hemother 2011;38:55–64. [13] Prowse C. Vox Sang 2012;doi:10.1111/j.1423-0410.2012.01662.x. [14] Feys H, Van Aelst B, Devreese K, Devloo R, Coene J, Vandekerckhove P, et al. Vox Sang 2013;doi:10.1111/vox.12106. [15] Coene J, Devreese K, Sabot B, Feys H, Vandekerckhove P, Compernolle C. Transfusion 2013;doi:10.1111/trf.12460. [16] Ciaravino V, McCullough T, Cimino G, Sullivan T. Vox Sang 2003;85:171–82. [17] Heiden M, Seitz R. ISBT Sci Ser 2010;5:279–81. [18] Schlenke P, Hervig T, Isola H, Wiesel M.L, Kientz D, Pinkoski L, et al. Transfusion 2008;48:697–705. [19] Osselaer JC, Debry C, Goffaux M, Pineau J, Calomme G, Dubuc E, et al. Transfusion 2007;doi:10.1111/j.1537-2995.2007.01488.x. [20] Mintz PD, Bass N.M, Petz LD, Steadman R, Streiff M, McCullough J, et al. Blood 2006;107:3753–60. [21] Mintz PD, Neff A, MacKenzie M, Goodnough LT, Llyer C, Kessler C, et al. Transfusion 2006;46:1693–704. [22] de Alarcon P, Benjamin R, Dugdale M, Kessler C, Shopnick R, Smith P, et al. Transfusion 2005;45:1362–72. [23] Cinqualbre J, Kientz D, Remy E, Huanq N, Corash L, Cazenave J.P. Transfusion 2015;in press. [24] Herbrecht R, et al. Manuscript in preparation, 2015. [25] Cazenave JP, Waller C, Kientz D, Mendel I, Lin L, Jacquet M, et al. An active hemovigilance program characterizing the safety profile of 7483 transfusions with plasma components prepared with amotosalen and UVA photochemical treatment. Transfusion 2009;50(6):doi:10.1111/ j.1537-2995.2009.02579.x. [26] Afssaps Rapport Annuel Hemovigilance. p 56; Commission Nationale d’Hemovigilancecompte-Rendu de Reunion du 1er février 2011.

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