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Plasma ProductsIndustrially purified preparations (e.g. coagulationsfactors, antibodies) are manufactured from pooledplasma froma great number of donors
In the past, patients suffering from haemophiliahad to face pain, impairments and death at an earlyage; modern medicinal products help improve their
quality of life and increase their life expectancy
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Blood as a Medicinal Product
Blood donations are processed tobecome blood components :Red blood cells, platelets (for
haemostatis), plasma
Blood transfusionsare indispensible inmodern medicine!
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Regulatory Control of Medicinal Products in
Europe: National and EC ActivitiesMarketing authorizationOfficial batch release
Plasma derivatives, not recombinant productsRegular surveillance inspectionsEnsuring e.g. Good Manufacturing Practice(GMP)
Postmarketing surveillanceCAP (Centrally Authorised Products) testing:spot checks with random sampling from themarket
PharmacovigilanceReports of adverse events, regulatory measuresPeriodic Safety Update Reports (PSUR)
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Challenges / past events
overview
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Safety Problems
Pathogen transmissionVirus infections:
Human immune deficiency virus(HIV) Liver infection: Hepatitis B (HBV),
Hepatitis C (HCV)Prions ? Creutzfeldt-Jakob-Disease
Immunological incompatibility or allergicreactionsBlood clotting (thromboses)
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WHO Global Database 2001 - 2002
On the basis of 81 million donations per year in 178 countries worldwide onlyaround 60% would be subject to stringent safety requirements. Deficient
regulatory systems or lack of appropriate tests still account for about 40% ofdonations globally, i.e.
32 million donations are not or not completely testedhttp://www.who.int/bloodproducts/ivd/en/
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WHO Global Database 2001 - 2002
Virus / Bacterium Donations Not
Tested
Deficient Testing
(about 35%)HIV 357.036HBV 401.933HCV 1.948.933Treponema pallidum(Syphilis)
2.595.34428.802.809
Data: http://www.who.int/bloodsafety/GDBS_Report_2001-2002.pdfand http://www.who.int/bloodproducts/ivd/en/
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Risk of Pathogen Transmission byBlood Products per Year
Virus /Disease
Prevalencein Donor
Blood
Minimum Risk ofInfection
(no test at all)
Maximum Risk ofInfection
(no test plus deficient testing)
HIV 1/1.000 1/10.000 35 357 2.915 30.000
HBV 1/ 10.000 40 3.000HCV 1/50-1/100 19.489 38.978 307.517 615.034
Syphilis no data no data no data
Epidemiology varies in different countries/continents Other viruses may have to be considered in other countries/continents
B19 infections are only serious for certain risk groups(e. g. sickle cell anaemia in Africa, pregnant women) Virulence may depend on epidemiological factors (e. g. HAV) HTLV (I + II) and HCMV are mainly cell associated.
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Regulation of Blood Screening in Germany
Viralmarker
Licence Dateof First Assay
Introductionof Testing
Test MandatorySince
HBsAg 1 Mar 1976 End ofseventies 1980
Anti-HIV 5 Jun 1985 immediately 1 Oct 1985
Anti- HCV 5 Jan 1990 1992 1 Jan 1993
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Virus Transmissions by Blood Productsin Germany since 1985
Group ofProduct
Method ofInactivation
TransmittedVirus
Number ofTransmissions
Year
PPSB PL, UV HIV >10 1989/90
Factor VIII S/D-treatment HAV >80 1991 ff.
iv-IgG Cohnfractionation
HCV >250 1993/94
PPSB Pasteurisation HBV >30 1994
Factor VIII S/D-treatment HAV 6 1997
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Transmission of vCJD by Blood TransfusionThree cases of probable transmission of vCJD byblood transfusions have been observed in the UK.They were detected since blood donations, whichvCJD patients had given before illness, are followedup
Patient diagnosed with vCJD 6.5 years after redblood cells from a donor with vCJD 3.5 years
after donationPatient having received red blood cells fromdonor with vCJD 18 months after donation, died5 years later from unrelated cause; autopsy
vCJD pathogen (prions) in his lymphatic tissuePatient diagnosed with vCJD 8 years after redblood cells from a donor with vCJD 20 monthsafter donation
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vCJD Risk of Blood Products?
Red cell transfusions are large-volume, non-processed single donor blood components
If a donor is incubating vCJD, his/her blood
may contain prionsThere is no dilution, nor sufficiently effectiveremoval of prions
Plasma products are manufactured from largepools of donations, the haemophilia products arehighly processed (fractionation, purification)
If a donor is incubating vCJD, his/her plasmawould be diluted in a large poolFor several steps of manufacture, effectiveremoval of prions has been demonstratedexperimentally
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Precautions
Refrain from using UK plasma for fractionationExclusion of donors possibly at risk
CJD or vCJD of donor or in familyTreatment with human pituitary hormone, TXof dura mater or corneaAfter cumulative stay for X (*) months in UKbetween 1980 and 1996After operation/transfusion in the UKRecipients of blood transfusions (*)
Recall of products, if vCJD donor identified(*) The measures taken may vary by memberstate
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CPMP POSITION STATEMENT ON CREUTZFELDT-JAKOBDISEASE and PLASMA-DERIVED AND URINE-DERIVED
MEDICINAL PRODUCTSLondon, 23 June 2004, EMEA/CPMP/BWP/2879/02 rev 1
Available data indicate that the manufacturing
processes for plasma-derived medicinal productswould reduce infectivity if it were present inhuman plasma . Manufacturers are now requiredto estimate the potential of their specificmanufacturing processes A CHPM Note for guidance on the investigation ofmanufacturing steps came into force in October
2004http://www.emea.eu.int/pdfs/human/bwp/513603en.pdf
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Bakterial Transfusion Reactions1995 - 2005
Total Suspected Cases 92Causal relationship likely 45
Contamination of the sample 42Unrecognised infection of the donor (Yersiniaenterocolica, E. coli, Malaria)
3
Total - fatal outcome 15Sepsis by pathogens detected in the bag containingresidual sample(Yersinia (2x), Staph. aureus, Klebsiella pneumoni-ae, Proteus vulgaris, Enterobacter cloacae,Strept.pyogenes)
7
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Approaches to Control Potential ViralContamination of Biologicals
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Three principal complementary approaches can be adopted
to control potential viral contamination of biologicals:
selecting and testing source material for the absence ofviruses,
testing the capacity of the production processes to remove orinactivate viruses,and testing the product at appropriate stages of production forfreedom from contaminating viruses.
Approaches to Control Potential ViralContamination of Biologicals
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Donor Criteria
Directive 2004/33/EC provides legally binding criteria inits ANNEX III: ELIGIBILITY CRITERIA FOR DONORS OFWHOLE BLOOD AND BLOOD COMPONENTS
These state-of-the art requirements build on previousEC Recommendation 98/463/EC on the suitability ofblood and plasma donors and the screening of donatedblood, the Council of Europe guide, the monographs ofthe European Pharmacopoeia, particularly in respect ofblood or blood components as a starting material, andrecommendations of the World Health Organisation(WHO)They apply to the collection and testing of human bloodand blood components, whatever their intendedpurpose, including plasma for fractionation
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Diagnostic Window in HIV Detection
NAT
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Diagnostic Window in HCV Detection
NAT
HCV core Antigen
HCV 2.0
Day delay in detection of HCV
Current CE-marked Anti-HCV assays by PEI/NB since 2003
up to 2003
after re-evaluation PEI 1998
CE-marked in 2005 not by PEI
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Summary IQuality Control of Screening Tests
Crucial parameters: sensitivity and specificity
Sensitivity: crucial for safetySensitivity: close to 100% with clearly positivesamplesBiological sensitivity: seroconversion panels
Analytical sensitivity: dilution seriesFor antibody tests, analytical sensitivity does notcorrelate with biological sensitivityAnalytical sensitivity should not be used for
comparison of assays, but for control ofconsistency of batches
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Summary IIQuality Control of Screening Tests
Specificity: largely economical, logistical andpsychological issue, less for safetySpecificity: >95% with large number of negative
samplesSpecificity: >95% with tricky samples
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1,0E+00
1,0E+011,0E+021,0E+031,0E+041,0E+051,0E+06
1,0E+071,0E+081,0E+091,0E+10
0 10 20 30 40 50 60 70 80 90
Days after infection
H C V - R
N A ( c o p i e s / m l )
0,00
0,50
1,00
1,50
2,00
2,50
3,00
an
t i - H C V ( s
/ c o )
59 days
HCV NAT reduces the window period by ca. 60days
M. Nbling et al.
The PEI mandated in Germany the NAT-testing for HCV (1 April 1999) andHIV (1 May 2004) of all donations fortransfusion
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Initial anti-HCVscreening test
Anti-HCV positivepools
(anti-HCV 2nd)
No. of plasmapools tested
No. of HCV-PCRpositive plasma
pools
none +++ 8 8 (100%)
anti-HCV 1st +/- 85 65 (76%)
anti-HCV 2nd - 123 49 (39%)
HCV NAT in Plasma Pools
M. Nbling et al.
After introduction of HCV NAT, the HCV burden in all plasmapools used in the EC is below the detection limit, ensuring ahigh safety margin for the virus inactivation steps.
Pools before HCV NAT:
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Nucleic Acid Amplification Tests:
Events in Europe21 February 1994 Withdrawal of license for Gammagard
24 November 1994 NAT in plasma pools for certain IVIG
27 April 1995 NAT in plasma pools for certain IMIG
14 September 1995 NAT in plasma pools for certain IMIG
7 May 1996 Commitment for HCV NAT in plasmapools (EAPPI)
12 February 1997 Commitment for HCV NAT in plasmapools (EPFA)
21 October 1997 CPMP recommendation for HCV NATin plasma pools from 1 January 1999
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1. Single donation
2. Testing pools3. Minipools4. Production pools
5. Intermediate products6. Final products
NAT: Appropriate Stage for Testing forFreedom from Contaminating Viruses
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Appropriate Stage for Testing for Freedomfrom Contaminating Viruses
It is due to statistics (Poisson distribution)that testing of final products for the presence of
viruses (antigen tests, NAT)cannot ensure freedom from contaminating agents .
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Viral Safety of Blood Transfusions afterIntroduction of NAT
The selection of healthy donors and highly developedtesting methods have reduced the risk drasticallyThe residual risk of contracting a virus infection
through a blood transfusion is extremely low and canonly be assessed very roughly:
For HIV and HCV it is markedly below 1 : 3,000,000For HBV, NAT is difficult to perform and is notobligatory; in spite of this, only isolatedtransmissions HBV occur; testing for anti-HBc iscurrently introduced
Experience will show whether new developments inthe pathogen inactivation of blood components willbring about further progress
S R f b bl T i i f
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Spontaneous Reports of probable Transmissions ofHepatitis C Virus via Transfusions 1990-2005 (n =
60)
0
2
4
6
8
10
12
14
16
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005Year of Transfusion
Introduction of NAT
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Summary: Importance of in vitroDiagnostics
First line detection of infectious agents (highestprobability in blood donations)Crucial for the prevention of transmission ofblood-borne pathogensAvoiding new starting points for transmission
chainsImpact appropriate control on safety of blood andblood products
Independent control = unbiased control
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Principles in the regulatory (independent)evaluation of IVD tests
Licensing
Verification of documentsLaboratory control
Official batch (lot) releaseVerification of documents
Laboratory controlEmergency cases methods
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Three principal complementary approaches can be adoptedto control potential viral contamination of biologicals:
selecting and testing source material for the absence ofviruses,
testing the capacity of the production processes to remove orinactivate viruses,and testing the product at appropriate stages of production forfreedom from contaminating viruses.
Approaches to Control Potential Viral
Contamination of Biologicals
Testing of blood donations with serological and NA tests
Virus validation studies
Plasma pool testing with NA tests