1. Safety of IVIgG Elspeth McIntosh SNBTS Medical Information and Pharmacovigilance Manager

2. Plasma “Non-UK” Plasma - USA or Germany All suppliers audited by SNBTS and approved by the MHRA Unpaid donors wherever possible Meet Red Book/EU Blood Directive and/or FDA requirements Donor selection as per the UK Epidemiological data satisfactory

3. Plasma Testing Plasma tested for –HBsAg –Anti- HCV –Anti-HIV –ALT –PCR for HCV, HBV, HIV, Parvovirus B19 Plasma pools tested for –HBsAg –Anti- HCV –Anti-HIV –PCR for HCV, HBV, HIV, Parvovirus B19

4. Product Safety Full Traceability From Donor To Final Product Notification System For Advising Of Post Donation Infections Validated Virus Elimination Step(s) Control Of Process To Prevent Re- contamination After Virus Elimination Step Clinical Trial Data Post Marketing Surveillance

5. Virus Inactivation and Removal  Devise methods that will selectively inactivate and/or remove viruses without undue product damage/loss.  Study relevant test viruses in scaled-down process.  Ensure that method is capable of giving the degree of virus inactivation/removal required.

6. Virus Inactivation and Removal  Scale-up the process to ensure that the small- scale results can be fully reproduced at production scale.  Validate the production scale operation to ensure that this has been achieved.  Monitor and control the operations to prove that the procedure has been accomplished correctly on every occasion.

8. Virus Safety Cold ethanol fractionation pH4/pepsin virus inactivation effective against –enveloped viruses e.g. HIV, Hep B and C –and non-enveloped viruses e.g. Hep A

9. vCJD Precautions All PFC plasma imported from countries with no vCJD cases and little or no BSE. Donors selection processes designed to exclude those who may represent a risk. Decontamination of UK fractionation facilities before processing of non-UK plasma in 1998.

10. vCJD Precautions Very low level of infectivity in plasma pool should an infective donation be processed. Research work identifies the potential for prion reduction during manufacturing. So Very low risk of vCJD being transmitted via PFC products.

11. SNBTS IVIgG Clinical Use SNBTS IVIgG supplied since 1985 270kgs used every year Licensed for use in –1 o and 2 o Hypogammaglobulinaemia –Children with HIV –Bone Marrow Transplant –Kawasaki Disease –ITP –Guillain Barre Syndrome

12. Antibody Profile Adenovirus Chlamydia CMV Coxsackie B 2 Epstein Barr Herpes Simplex Influenza A + B Measles Mumps Mycoplasma Q fever RSV Rotavirus Varicella Zoster

13. Serious ADRs Serious Reactions to IVIgG are rare but the follwing are well described. –Acute Renal Failure –Anaphylaxis/Anaphylactoid Reactions –Aseptic Meningitis –Hypertension –Haemolytic Reactions

14. Non Serious ADRs Idiosyncratic batch related reactions - –One or more of the following symptoms: pyrexia, rigors, backache, nausea/vomiting, malaise, breathlessness, rash, hyper or hypotension, headache.

15. IVIgG for Neonatal Use ~ 6000 patients, 32 studies. Cochrane Review - Prevention of infection in pre-term/LBW infants Cochrane Review - Treatment of infection in neonates. Cochrane Reviews - Isoimmune haemolytic jaundice in neonates

16. Neonatal Use - SNBTS IVIgG Small trial early 1990s Randomised to IVIgG or 5% Dextrose Study to small to produce significant results No product related adverse events AND No reports of neonatal reactions in routine use.

17. Neonatal ADRs Cochrane Reports –No Serious Adverse Reactions. –Non-serious Adverse Reactions transient, included hypotension, tachycardia, and haemolysis –related to too rapid infusion of placebo or immunoglobulins. One study - increase in respiratory rate following the first infusion of IVIG

18. Causality Temporal relationship Pharmacological plausibility Recognised class effect Dechallenge/rechallenge Underlying illness and medications Irreversible events Transient/episodic events

19. Topics covered Plasma selection Virus safety vCJD Clinical use of SNBTS IVIgG Neonatal experience Adverse reactions

20. Conclusion SNBTS IVIgG is a well established product. Steps in place to reduce risk of virus transmission/vCJD. Low overall risk of adverse reactions.