Regulation of Plasma and Plasma Products How Should We Regulate Blood and Blood Products?

1. Regulation of Plasma and Plasma Products How Should We Regulate Blood and Blood Products? Dr Ana Padilla Blood Products and related Biologicals Quality Assurance and Safety: Medicines Essential Medicines and Health Products Kuwait, 30 November 2012

2. Outline • WHA Resolution 63.12 on blood products • Blood safety strategy • Criteria for suitability of recovered plasma • WHO assessment criteria for national blood regulatory systems • Summary

3. Blood Products: Life-Saving MedicinesWHA Resolution 63.12 Blood products are defined as therapeutic substances derived from human blood, including whole blood, labile blood components and plasma-derived medicinal products (WHA 63.12, adopted 2010).

5. The World Health Assembly (WHA) Resolution 63.12*:Need for Blood Products Regulation • WHA resolution 63.12 recognized that: • “stringent regulatory control is vital in assuring the quality and safety of blood products…” and • urged Member States to “update their national regulations … in order to ensure that regulatory control in the area of quality and safety of blood products across the entire transfusion chain meets internationally recognized standards.” • Strengthening regulatory systems for blood products and building technical capacity of national and regional blood regulatory authorities is recognized as a fundamental need to assure global availability of safe blood products *How to improve quality in BE for the production of BC, including plasma

6. TRACEABILITYFROM DONOR TO PATIENT Blood donation Blood Components Patients Plasma-Derived Medicinal Product Plasma for Fractionation FRACTIONATION VIRAL INACTIVATION DONATION INFORMATION COMPONENTS PREPARATION TREATMENT Good Manufacturing Practices

7. The General Blood Safety Strategy • Appropriate selection of blood donors • Volunteer, non-remunerated donors • Donor education and science-based risk factor screening • Medical interview and physical examination • Infectious disease testing on blood plasma donations: screening strategies and selection of test kits and validation • HIV, hepatitis B, hepatitis C • Additional testing is based on regional epidemiology (e.g. HTLV, West Nile Virus, T. cruzi) • Epidemiological surveillance of donor population • Adherence to GMP in blood collection and processing • Vigilance systems: adverse reactions in donors and recipients

8. Viral safety testing Individual donations/plasma units • Serological tests: blood establishment • HBsAg, HIV-Ab, HCV-Ab (§) • Nucleic acid based technology (NAT): • HCV in plasma pools (mini-pools) (§), • HIV*, Parvo B19*, HAV*, HBV* (§) mandatory tests; *additional tests may be required by some NRAs * some countries

9. Selection of viral test kits • The precise selection of viral test kits should take into account several scientifically-based aspects including: • Specificity/sensitivity of tests • Donor characteristics (e.g. first time vs repeat donors) • Local epidemiological situations (e.g. viral genotypes*) • Evolution of testing technologies • Understanding the risks and limitations of the assays *Relevant reference panels established by WHO: http://www.who.int/bloodproducts/catalogue/en/index.html

10. Residual Infectious Risk • Residual infectious risk due to: • Limitations of screening methods • Errors in blood/plasma virus testing • Plasma donation mishandling • Window period: test negative/virus present • Can be significant when subsequent pooling is used to prepare a manufacturing batch • Resulting products derived from a contaminated plasma pool may infect a large population of recipients • Finished product safety testing is not a substitute for effective quality systems and arrangements for regulation/control

11. Window period estimates • HIV - the infectious window periodis estimated to be: • 19 days for anti-HIV • 15 days for HIV p24 antigen and • 5 days for sensitive NAT testing • For HCV, the infectious window periodis estimated to be • 65 days for anti-HCV • 3 days for sensitive NAT testing • For HBV, the infectious window periodis estimated to be • 36 days for HBsAg and • 21 days for sensitive NAT testing.

12. Operational parameters affecting quality of plasma for fractionation • Plasma separation method • Anticoagulant • Time to separation from cells • Time and temperature from collection to freezing • Cell content • Rate of freezing • Storage time and temperature, including during transport

13. Types of plasmaWHO recommendations for Plasma for Fractionation

14. Freezing and storageWHO recommendations for Plasma for Fractionation • Whole blood holding time before plasma separation: • < 18 – 20 hrs at + 22˚C • < 8 hrs at + 4˚C • Plasma holding time and freezing conditions: • Freezing asap after separation • Freezing rapid rate, important quality factor (specified by the fractionators) • Validated freezing process: consistency • Storage and transportation at - 20˚C or colder, constant

15. Factors influencing quality and safety of Plasma Derivatives • Quality & safety of plasma (starting material)* • Process design: • Fractionation process • Viral Inactivation/Removal Procedures (#) • Strict adherence to GMP for production processes * WHO recommendations for production, control and regulation of plasma for fractionation (2007): http://www.who.int/entity/bloodproducts/publications/TRS941Annex4blood.pdf (#) WHO guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood plasma products (2005): http://www.who.int/entity/bloodproducts

16. Regulatory considerations • Regulatory oversight serves to ensure that blood establishments, plasma fractionators and care providers • have control of the entire production process • monitor the safety and quality of products, and • take appropriate action if adverse events occur • Regulation, national standards for blood establishments, is needed to assure that unused plasma is suitable for fractionation

17. Assessment Criteria for National Blood Regulatory Systems - I • Consistent with WHA Resolution 63.12, WHO has developed Assessment Criteria for National Blood Regulatory Systems • To provide a tool to assist capacity building of National Regulatory Authorities (NRAs) for blood and blood products • For both developed and developing countries, a benchmarking and/or assessment process that could serve to highlight strengths of the NRA while identifying gaps or areas for future development • Global criteria also promote international standardization, which may reduce burdens to product developers * WHO BRN includes representatives from Health Canada, ANSM, Paul Ehrlich Institute, Swissmedic, TGA Australia, US FDA and MHLWL Japan. WHO provides the Secretariat.

18. WHO Assessment Criteria for National Blood Regulatory Systems* - I To identify essential control functions that should be undertaken by an effective/functional NRA to assure the quality, safety and efficacy of blood and blood products as well as associated substances and medical devices including in vitro diagnostics To establish standard indicators for these essential functions in order to allow NRAs to assess their performance in the regulation of blood and blood products PURPOSE & OBJECTIVES 18

19. Two essential functions (National Regulatory System and National Regulatory Authority) Criteria and indicators Twelve Core functions Criteria and indicators WHO Assessment Criteria for National Blood Regulatory Systems* - II WHO STRUCTURE OF THE ASSESSMENT TOOL 19

20. National Blood Regulatory Systems: Core Functions Licensing/registration of blood establishments Licensing/registration of manufacturers and distributors of plasma derived products Approval of blood and blood components Approval of plasma derived products 20

21. National Blood Regulatory Systems: Core Functions Regulatory oversight of associated substances and medical devices including in vitro diagnostics Access to a laboratory independent of manufacturers Control of clinical trials System for lot release of plasma derived products 21

22. National Blood Regulatory Systems: Core Functions Regulatory inspections and enforcement activities Vigilance systems Ensuring traceability and record keeping by manufacturers for all regulated products International cooperation . 22

23. Conclusions – Blood Regulation • Blood regulation within a legal framework is an essential element of any national blood system • Meeting evidence based standards for blood collection and processing minimizes the inherent risks of blood transfusion • By assuring that standards are met, blood regulation serves to protect donors and to promote and maintain the quality and safety of both blood components for transfusion and plasma for fractionation • The acceptability of plasma for fractionation depends upon a system in which compliance with recognized standards is verified through regulation

24. Conclusions – Plasma Derivatives • Plasma for fractionation is needed to generate essential plasma-derived medicinal products (e.g. clotting factors and immune globulins) • National and global sufficiency in plasma products can be achieved only by reducing wastage of non-transfused plasma • Suitability of plasma for fractionation depends on meeting evidence based quality standards for blood collection and component manufacturing

25. National Regulation of Blood Components as Medicines Blood is regulated as a medicine in many jurisdictions, either directly or indirectly, e.g. • In the US, Canada, Germany and Switzerland, blood and blood components are directly regulated as biological medicines • In Japan, Blood and Blood Products are regulated as safety measures by the “Pharmaceutical Affairs Law” and under the “Law on Securing a Stable Supply of Safe Blood Products” • In Australia, blood component manufacturers are subject to licensing to assure that the products meet standards as per the Council of Europe “Guide” Common to all blood component regulations are requirements to assure that blood components meet product standards through controls on manufacturing, often explicitly stated as Good Manufacturing Practice requirements

26. The concept of Whole Blood and Blood Red Cells as Essential Medicines has been unanimously endorsed by the WHO ECBS*, the WHO BRN and the International Conference of Drug Regulatory Authorities (ICDRA)October 2012 *ECBS: WHO Expert Committee on Biological Standardization *BRN: WHO Blood Regulators Network

28. Overall objectives* • Assist countries to use recovered plasma to generate essential medicines • Assist countries to improve quality and safety of all blood components • Improve quality production systems in blood establishments * WHO Report to be published shortly

29. WHO available toolswww.who.int/bloodproducts • The mandate • WHA 63.12 on availability, quality and safety of blood products • The tools (internationally agreed standards) • Assessment criteria for national blood regulatory systems (2012) • WHO Guidelines on GMP for blood establishments (2011) • WHO Guidelines on Production, control & regulation plasma for fractionation (2007) • WHO Guidelines on Viral Inactivation and Removal procedures(2005) • WHO catalogue of biological reference materials: blood products and blood safety IVDs (on-going development and establishment) • Collaboration with government organizations: national regulatory authorities, national blood programmes and Inspectorate • Training experience strengthening implementation of regulatory systems • Wide international expert networks: ECBS, BRN, WHOCC, others • Worldwide network of National Regulatory Authorities (ICDRA)

30. WHO guidance documents: website addressed www.who.int/bloodproducts • Reference on GMP for blood establishments (2011): http://www.who.int/entity/bloodproducts/publications/GMP_Bloodestablishments.pdf • Reference on production, control and regulation of plasma for fractionation (2007): http://www.who.int/entity/bloodproducts/publications/TRS941Annex4blood.pdf • Reference on viral inactivation and removal procedures (2005): http://www.who.int/entity/bloodproducts/publications/GMP_Bloodestablishments.pdf • Catalogue of blood products and blood safety related reference materials: http://www.who.int/bloodproducts/catalogue/en/index.html

31. http:// www.who.int/bloodproducts

32. Web site addresses http://www.who.int/bloodproducts http://www.who.int/bloodproducts/catalogue