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Paul-Ehrlich-InstitutWHO Collaborative Centre for Quality Assurance of Blood Productsand in vitro Diagnostic Devices

2

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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3

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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4

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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5

Challenges / past events

overview

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6

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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Paul-Ehrlich-InstitutWHO Collaborative Centre for Quality Assurance of Blood Products

and in vitro Diagnostic Devices7

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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and in vitro Diagnostic Devices

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

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