Guide for the Assessment of Clotting Factor Concentrates

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Table 2: Advantages and other points to consider when selecting viral reduction treatmentsof factor concentratesTreatment Advantages Points to considerSolvent-detergent (SD)Treatment with a mixture of chemicals – solventsand detergents – which inactivate virusesthrough removal of the lipid envelope whichcoats some types of viruses. Hence it is noteffective against agents which lack this envelope. Extremely efficient againstenveloped viruses Relatively simple equipment Non denaturing effect on proteins High recovery of protein functionalactivity Requires a subsequentmanufacturing step toeliminate the SD agents Not effective against nonenvelopedviruses, e.g. B19or HAVPasteurisationThis is a generic term for heat treatment of aprotein in solution at 60 o C for 10 hours. Itsefficacy in inactivating viruses is dependent onthe exact conditions under which it is performed.When it is used to treat proteins which arefragile, such as clotting factors, the solution hasto include protective chemicals so as to preservethe protein; these may also preserve the virus. Potential to inactivate envelopedand non-lipid enveloped viruses,including HAV. Each processneeds to be evaluated on thebasis of the data submitted bythe manufacturer. Relatively simple equipment Dependent on conditions Protein stabilizers mayprotect viruses Does not inactivate B19 Low recovery of fragilecoagulation factors Potential generation ofneoantigensVapor-heatCurrently restricted to one manufacturer. May inactivate enveloped andnon-enveloped viruses, includingHAV Possible risk of transmissionof HCV and HBV Does not inactivate B19Terminal dry-heat This involves heating the final product inthe lyophilized state in the container used toissue and reconstitute the concentrate. Theefficacy of viral kill is strongly dependent onthe exact combination of time and temperaturewhich the product is exposed to. These conditionshave been described by manufacturers: May inactivate enveloped andnon enveloped viruses, includingHAV Treatment applied on the finalcontainer Does not inactivate B19 10 to 20% loss of coagulationfactor activity Requires strict control ofresidual moisture content60 o C for 72 hours80 o C for 72 hours100 o C for 30 minutes100 o C for 120 minutes65 o C for 96 hoursFor example, 60 o C is known to be less effectivethan 80 o C for similar lengths of time. Eachprocess needs to be evaluated on the basis ofthe data submitted by the manufacturer.8 Guide for the Assessment of Clotting Factor Concentrates
Treatment Advantages Points to considerNanofiltration on 15 nm membranesNanofiltration on 35 nm membranes Elimination of viruses based onsize-exclusion effect. Eliminate all major virusesincluding HAV and B19. May possibly eliminate prions Filter’s integrity and removalcapacity is validated after use High recovery of protein activity Non denaturing for proteins Risks of downstream contaminationare limited when filtration isperformed prior to aseptic filling Filters are commercially available;no royalties Similar to 15 nm membranes Applicable to some factor VIIIand von Willebrand factorconcentrates Non applicable to highmolecular weight proteinconcentrate (without significantprotein loss) Elimination of small virusesnot totalAdapted from: Ala F, Burnouf T, and El Nagueh M, Plasma Fractionation Programmes for Developing Countries,WHO RegionalPublications, Eastern Mediterranean Series, No. 22, 1999, and Burnouf T and Radosevich M,“Reducing the risk of infectionfrom plasma products; specific preventative strategies,” Blood Reviews, 2000, 14: 94-110.Authorities faced with making a decision on excluding donors at risk of vCJD need to assess carefullythe effect of such deferral measures on the overall blood supply. In many developing countries, bloodis in short supply and these countries cannot afford to lose donors because of possible vCJD risk. Also,in areas of high prevalence for other more established risks, such as HIV and HCV infection, the deferralof well-accredited repeat donors because of possible vCJD risk may mean that new donors with ahigher prevalence of these established infections are used instead. New donors always have higherviral marker rates than repeat donors, and authorities in developing countries, where selection andscreening procedures may not be optimized, need to ensure that unproven risks are not replaced byreal ones.A test for vCJD is currently unavailable, and is unlikely to be available for some years, despite considerableeffort to develop such a test. The exclusion of infective donations to the extent that pooled plasmaproducts are rendered safe is probably not achievable through selection and testing measures, if theexperience with viral infections is any guide 2 .This leaves the clearance of infectivity through the manufacturing process as the main route for minimizingthe risk of vCJD from plasma products.The level of clearance attained by different processes is considerable and has probably contributed tothe absence of vCJD infection in recipients of plasma products, including people with hemophilia,observed so far. It is known that plasma from people who subsequently developed vCJD has been2 Infections such as HIV and HCV continued to be transmitted through hemophilia products after the introduction of selectionand testing measures, which are generally of insufficient sensitivity to exclude infected donations from being included inplasma pools containing thousands of units.Guide for the Assessment of Clotting Factor Concentrates 9
Page 1: GUIDE FOR THE ASSESSMENTOF CLOTTING
Page 5 and 6: INTRODUCTIONSelecting therapeutic p
Page 7 and 8: SECTION 1FACTORS AFFECTING THE QUAL
Page 9 and 10: and authorities need to assess each
Page 11: There are a number of different vir
Page 15: measures may have only limited bene
Page 18 and 19: • FDA draft guidelines• FDA ins
Page 20 and 21: Common strengths of U.S. & EU regul
Page 22 and 23: • Audit potential suppliers who m
Page 24 and 25: on HCV reactivity in product sample
Page 26 and 27: Basic requirementsThere are a numbe
Page 28 and 29: treatment, and therefore samples sh
Page 30 and 31: EvaluationSome of the consideration
Page 32 and 33: Figure 2: Production of cryoprecipi
Page 34 and 35: Some measures which should be inclu
Page 37 and 38: APPENDIX 1REGISTRY OF CLOTTING FACT
Page 39 and 40: TABLE 1A: SEROLOGIC TESTS ON INDIVI
Page 41 and 42: TABLE 2. FACTOR VIII CONCENTRATES M
Page 43 and 44: BRAND COMPANY SITE OF MANU-FACTUREP
Page 45 and 46: TABLE 7: OTHER CLOTTING FACTOR CONC
Page 47 and 48: APPENDIX 2MODEL PRODUCT ASSESSMENT
Page 49: (D) STABILITY AND SHELF LIFEInclude
Page 52 and 53: Nucleic acid testing (NAT): Testing
Page 56: World Federation of Hemophilia1425

Guide for the Assessment of Clotting Factor Concentrates

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