Annex 4 Guidelines on viral inactivation and removal ...

1 150 GAnnex 4 Guidelines on viral inactivation and removalprocedures intended to assure the viral safetyof human blood plasma productsList of abbreviations and definitions used in this and , viral burden and screening infectious of viral inactivation and removal of well-recognized methods for viral inactivation and of of virus trials to assess in a manufacturing inactivated plasma for or donor-retested blue and visible of newer viral inactivation methods under fresh frozen light fresh frozen Secretariat213 References213 AppendixExample of a study on the inactivation of human immuodeficiencyvirus-1 by treating a therapeutic plasma protein preparation withtri(n-butyl)phosphate and Tween 80219 World Health OrganizationWHO Technical Report, Series No.

2 924, 2004 ECB text19/11/2004, 09:49 AM150 Black151 GList of abbreviations and definitions used in this AnnexThe definitions given below apply to the terms used in these Guidelines . They mayhave different meanings in other factor. Blood coagulationfactor VIII, missing in patients with componentsThese typically refer to red blood cellconcentrates, platelet concentrates enterovirus. A non-enveloped, single-stranded RNA virus used as a model forhepatitis A viral diarrhoea virus. An enveloped,single-stranded RNA virus used as a model forhepatitis C An enveloped, double-stranded DNA virus, typically virusA non-enveloped, single-stranded RNA parvovirus. A non-enveloped, single-stranded DNA retested plasmaA process for reducing window periodtransmissions whereby fresh frozen plasma isheld in the inventory for a designated period oftime until the donor returns and tests negativefor virus exposure.

3 The initial unit is thenreleased for use. Also called heatA process of heating protein followinglyophilization, typically at 80 C or barr virus. An enveloped, double-stranded DNA virus, typically virus. A non-enveloped,single-stranded, RNA IXBlood coagulation factor IX, missing in patientswith haemophilia VIIIB lood coagulation factor VIII, missing inpatients with haemophilia A. Also calledantihaemophilic frozen total quantity of light delivered. Expressedin process of virus inactivation or bacterialsterilization using gamma-irradiation of liquid,frozen or lyophilized text19/11/2004, 09:49 AM151 Black152 GGEG enome equivalents. The amount of nucleicacid of a particular virus assessed usingnucleic acid manufacturing practices.

4 Sometimesreferred to as current good A virus. A non-enveloped, single-stranded RNA B surface antigen. The antigen on theperiphery of hepatitis B B virus. An enveloped, double-stranded DNA C virus. An enveloped, single-stranded, RNA delta virus. A defective virus whichrequires co-infection by hepatitis B purity factor VIIIF actor VIII concentrate with a specific activitytypically greater than 100 immunodeficiency virus. An enveloped,single-stranded RNA simplex virus. An enveloped, double-stranded DNA virus, typically 1 and 2 Human T-cell lymphotropic virus, types 1 and2. Enveloped, single-stranded RNA viruses,typically quantity of virus or other infectious agentthat will infect 50% of subjects or tissuecultures.

5 Frequently expressed on a log scale;thus, 6 log10 ID50 represents 1 million the formation of antibody. Harshprocessing conditions may modify thestructure of a protein so as to make purity factor VIIIF actor VIII concentrate with a specific activitybetween 1 and 50 dilutionA way of determining titre by diluting thesample continually until the positive signal reduction factor. The quantity of virus,expressed on a log 10 scale, inactivated text19/11/2004, 09:49 AM152 Black153 GMB-plasmaMethylene blue-treated plasma intended as asubstitute for fresh frozen that usually have effective pore sizes of50 nm or less, designed to remove virusesfrom protein acid testing, using amplificationtechniques such as polymerase chain process of heating protein in solution,typically at 60 virusA non-enveloped, single-stranded, RNA pseudorabies virus.

6 An enveloped,double-stranded DNA parvovirus. A non-enveloped, single-stranded DNA infectious particle associated withtransmissible spongiform encephalopathies. Itis believed to consist only of protein and tocontain no nucleic virus. An enveloped, double-stranded DNA furocoumarin ring structure, which whenexposed to light, cross-links nucleic plasmaSee donor retested type 3. A non-enveloped, double-stranded RNA flavonoid used as an antioxidant thatreduces the action of reactive oxygen treatmentA process of treating protein in solution,usually with the organic solvent, tri(n-butyl)phosphate, and a detergent such asTween 80 or Triton plasma intended asa substitute for virusAn enveloped, single-stranded RNA forest virus.

7 An enveloped, single-stranded, RNA quantity of virus, typically expressed on alog10 scale. Six logs of virus are equal to 1million infectious (n-butyl)phosphate. The organic solventused with solvent/detergent X-100A non-ionic detergent frequently used as partof solvent/detergent text19/11/2004, 09:49 AM153 Black154 GTween 80A non-ionic detergent frequently used as partof solvent/detergent irradiation, usually at a wavelengthof 254 virusAn enveloped, double-stranded DNA heatingA process of heating protein followinglyophilization and then reintroducing moisturenormally at 60 C and in some cases at 80 inactivationA process of enhancing viral safety in whichvirus is intentionally killed.

8 viral removalA process of enhancing viral safety byremoving or separating the virus from theprotein(s) of stomatitis virus. An enveloped,single-stranded RNA Nile virusAn enveloped, single-stranded RNA and scopeHuman blood is the source of a wide range of medicinal products usedfor the prevention and treatment of a variety of often life-threateninginjuries and diseases. Despite measures such as donor selection, test-ing of donations and of plasma pools, the transmission of blood-borneviruses by plasma and purified plasma products is still considered toconstitute a risk to patients. Over the past 15 20 years, the transmis-sion of the principal viral threats historically associated with theseproducts hepatitis B virus (HBV), hepatitis C virus (HCV) andhuman immunodeficiency virus (HIV) has been greatly reduced oreliminated in many areas of the world.

9 This is a consequence of themore sensitive methods being used to screen donated blood andplasma pools, and of the establishment of manufacturing practicesthat lead to significant virus inactivation and removal . Several proce-dures for virus inactivation and removal have proven to be robustand to contribute substantially to blood product safety. viral inactiva-tion methods should be applied to all blood plasma-derived concerns about the quality and safety of plasma-derivedmedicinal products have resulted in a number of urgent requests fromMember States for support and advice from WHO. Moreover, theWorld Health Assembly Resolution No , of 13 May 1997 on the Quality of biological products moving in international commerce ,requested WHO to extend the assistance offered to Member States toECB text19/11/2004, 09.

10 49 AM154 Black155 Gdevelop and to strengthen their national regulatory authorities andcontrol laboratories to increase competence in the area, and to extendefforts to upgrade the quality and safety of all biological present WHO Guidelines on viral inactivation and removal pro-cedures intended to assure the viral safety of human blood plasmaproducts were developed to complement the WHO Requirements forthe collection, processing and quality control of blood, blood compo-nents and plasma derivatives (1), in response to the above Guidelines pertain to the validation and assessment of the stepsfor viral inactivation and removal employed in the manufacture ofhuman blood plasma derivatives and virally inactivated plasma fortransfusion, prepared either from plasma pools or from It is hoped that this document, by summarizing currentexperience with well recognized methods, will help set expectations,serve as a guide to speed implementation, and ensure that implemen-tation is , individual countries may formulate different policies, notonly in relation to procedures for validation and control.