WHO Norms and Standards: Blood Products & related Biologicals Dr Ana Padilla Blood Products & related Biologicals WHO/HIS/EMP/RHT

Outline  Blood Products and related Biologicals  Introduction  RWHA63.12: availability, safety and quality of blood products  Blood and Blood Components are Essential Medicines:  The need for national blood regulatory systems  WHO Biological Reference preparations

3 |3 | Blood Products & related Biologicals Animal-derived immunoglobulins  Anti-rabies  Snake anti-venoms  Anti-tetanus toxin  Anti-diphteria toxin  Anti-botulism toxin Human blood derived products  Blood components (red cells, platelets, plasma)  Blood Coagulation Factors  Polyvalent Immunoglobulins (IV, IM)  Specific Immunoglobulins  Anti-hepatitis B  Anti-rabies  Anti-tetanus  Anti-rhesus (anti-D)  Albumin  In vitro biological diagnostic devices (IVDs): Priority: blood safety, public health, support harmonization of international regulations Other biological products Anticoagulant & fibrinolysis biological therapeutic products

Introduction (1) The overall goal is to promote and enhance the quality, availability, and safety of blood products and associated in vitro diagnostic devices (IVDs). Prevention of the transmission of blood-borne infections and emerging agents worldwide is paramount. Specific strategies are considered where needed

Introduction (2) The blood products and related biologicals programme is providing Member States with the tools needed - to meet international validated standards for production and control of those products - to promote enforcement and implementation of appropriate production processes and effective quality assurance regulations - to support technical capacity building where needed

Introduction (3) Quality assurance and regulatory tools to achieve the goals:  WHO Guidelines for the manufacture and control of blood products;  WHO International biological reference preparations (international standards, reference panels);  Regular evaluation of transmission of blood-borne emerging infectious agents with the collaboration of WHO disease control Departments and the WHO Blood Regulators Network (BRN) and other specialized expert groups;  International coordination of standards setting organizations and promotion of the biological standardization principles;

Blood Products: Life-Saving Medicines WHA Resolution 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).

8 |8 | Blood Products: Life-Saving Medicines WHA Resolution  Blood and blood components –Whole blood collected into containers, anticoagulant to prevent clotting, cold chain –Blood components, obtained from whole blood by separation (centrifuge or apheresis): Red blood cells: Oxygen transport Platelets: Hemostasis, preventing bleeding Plasma: clotting factors, immunoglobulins etc. Cryoprecipitate, FVIII source  Plasma derived products Plasma for "fractionation“, further purification of plasma proteins, e.g. Blood Coagulation Factors, e.g. Factor VIII for treatment of hemophilia A Specific Immunoglobulins, e.g. anti-hepatitis B, anti-rabies, anti-tetanus, anti-D IM and IV normal IgG Albumin, involved in regulation of body fluids

9 |9 | WHO Essential Medicines List  Human derived blood products – Blood and Blood components Whole blood, red blood cells, platelets, fresh frozen plasma – Blood Coagulation Factors: FVIII, PCC – Human Normal Immunoglobulin (IV and IM) – Anti-D immunoglobulin – Anti-tetanus immunoglobulin

10 | TRACEABILITY FROM DONOR TO PATIENT Blood donation Plasma for Fractionation Blood Components Plasma-Derived Medicinal Product Patients DONATION INFORMATION donor population donor selection collection process COMPONENTS PREPARATION, e.g. production process testing process control release storage & transport FRACTIONATION, e.g. production process technology impact viral inactivation QC & release storage & transport GMP BEGMP PP

Suitability of plasma depends on meeting production standards for blood collection and component manufacturing Control of processes required for production of all blood components in blood establishments Blood establishment: production processes

Regulatory oversight serves to ensure that blood collectors, plasma derivatives manufacturers and care providers –have control of the entire process (donor to patient) –monitor the safety and quality of products, and –take appropriate action if adverse events occur Regulation assures that blood standards are met and is needed to assure that unused plasma is suitable for fractionation but itself depends on empowerment through a legislative framework Resolution WHA 63.12* Resolution WHA 63.12* The Need for Blood Regulation

Resolution WHA63.12* Resolution WHA63.12* The Need for Blood Regulation – I 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.” *Availability, quality and safety of blood products, May 2010

Resolution WHA63.12* Resolution WHA63.12* The Need for Blood Regulation – II 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 *Availability, quality and safety of blood products, May 2010

Resolution WHA63.12 Availability, safety and quality of blood products  Points out the need to support improvements in the availability, safety and quality of blood products  In particular, the Resolution draws attention to the large volumes of human plasma, that have been separated from whole blood, and currently go to waste  Yet, the plasma wasted could be used as a starting material for the manufacture of essential plasma-derived medicinal products unavailable today for treatment of local populations

Improving Access to Safe Blood Products Whole Blood and Blood Components as Essential Medicines

TRACEABILITY FROM DONOR TO PATIENT Blood donation Plasma for Fractionation Blood Components Plasma-Derived Medicinal Product Patients DONATION INFORMATION donor population donor selection collection process COMPONENTS PREPARATION, e.g. production process testing process control release storage & transport FRACTIONATION, e.g. production process technology impact viral inactivation QC & release storage & transport GMP BEGMP PP

Blood and Blood Components are Essential Medicines: Product Characteristics (I) Under internationally recognized standards, blood/blood components share fundamental features of medicines: – Manufacturing processes akin to other medicines, e.g. Raw material qualification (i.e. donor selection and testing), in-process quarantines, quality controls (e.g. temperature monitoring, visual inspection), product release, expiration dating, traceability, etc. – Administration only on a doctor’s order or prescription – Defined medical indications and contra-indications – Labeling for identity, content and intended use Additionally, blood/blood components delivered contain recognized medicines (e.g. anticoagulants, buffers, preservative solutions, etc.)

Blood and Blood Components are Essential Medicines: Product Characteristics (II) Examples of international product standards for the manufacture of blood components include: WHO Technical Report Series, No. 840, 1994, Annex 2 “Requirements for the collection processing and quality control of blood, blood components and plasma derivatives” WHO Catalogue of International Biological Reference Preparations Council of Europe, EDQM “Guide to the preparation, use and quality assurance of blood components – 16 th Ed.” National laws (e.g. Australia, Canada, Germany, Japan, Switzerland, USA etc.)

Importance of Listing Blood and Blood Components as Essential Medicines (I) Having Blood and BC on WHO’s Model List of Essential Medicines (EML), would help governments to justify increased efforts in blood donor recruitment and blood collection, which would improve medical care in the population. – If the medicine is deemed “essential,” steps will be taken to increase awareness, assure availability, and thereby prevent deaths and disabilities from blood shortages Listing of Blood and BC on WHO's EML would be especially important to address unmet needs for effective treatment of hemorrhage and anemia in many developing countries

In considering listing of Blood and BC as Essential Medicines, WHO and MS should take notice of the needs: – To establish and strengthen National Blood Regulatory Systems through education and technical support to regulators of medicines and blood operators – To promote establishment of adequate blood system infrastructures – To assist Member States to avoid potential unintended consequences to existing blood systems Importance of Listing Blood and Blood Components as Essential Medicines (II)

WHO available tools  The mandate  WHA on availability, quality and safety of blood products  The tools (internationally agreed standards)  Assessment criteria for national blood regulatory systems  WHO Guidelines on GMP for blood establishments  WHO Guidelines on Production, control & regulation plasma for fractionation  WHO Guidelines on Viral Inactivation and Removal procedures  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)

Overview of activities undertaken by WHO to assess the need to support local production of quality recovered plasma by blood establishments in LMIC* as a means to improve access to safe blood products *LMIC: Low and middle income countries

What we have learned (1) Significant volumes of plasma are discarded in multiple countries with no/poor access to PDMP Such plasma, when meeting GMP requirements could be used to treat patients with bleeding disorders and primary immunodeficiencies if fractionated Need for cost-benefit analysis in blood establishments and opportunities for technology transfer and potential fractionation of plasma

What we have learned (2) Implementation and upgrading of production standards for recovered plasma in blood establishments can lead to an upgrade in the overall blood establishment and benefit to public health Public health benefit includes: – provision of better epidemiology data for the population – reduction in transmission of infectious diseases by blood transfusion (e.g., HIV and hepatitis) from red blood cells, platelets and plasma transfused as blood components Cost-benefit analysis is essential

What we have learned (3) The precise selection of viral test kits should take into account several scientifically-based aspects including: –Specificity/sensitivity of tests, including that of local 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 knowing the limitations of the assays Importance of international standards & reference preparations developed and established by WHO

WHA 63.12: Availability, quality and safety of blood products 2. REQUESTS the Director-General: 2. (4) to ensure sustainable development and provision of WHO International Biological Reference Preparations for use in the quality control and regulation of blood products and related in vitro diagnostic devices; (5) to improve access by developing countries to WHO International Biological Reference Preparations and to the scientific information obtained in their validation in order to assure appropriate use of these preparations

Examples of contract fractionation programmes A contract fractionation programme in large countries such as Brazil and Iran, with government commitment, allows reduction by about 30-40% in the cost of similar amount of imported products Products made from local plasma may induce lower imported price, due to competition Closer collaboration and coordination between NRA of the plasma fractionator and NRA of the plasma supplier (convergence of regulation) is needed

Plasma Contract Fractionation Programs - Need for GMP implementation in BE - GMP Licensing GMP Licensing Quality Assurance Program across countries PLASMA SUPPLIER FRACTIONATOR Nat.Reg. Authority Nat.Reg. Authority GMP- common principles

WHO Biological Reference Preparations

The WHO International Biological Reference Preparations (IBRP) serve as reference sources for biologically defined activity expressed in an internationally agreed unit or specific level of reactivity. Regulators define requirements for blood therapeutic products and blood safety IVD related requirements on the basis of these preparations allowing international harmonisation/convergence of regulations. WHO Biological Reference Materials

WHO Biological Reference Preparations* Global measurement standards (IS)  Tool for comparison of biological measurement results worldwide  Facilitate transfer of laboratory science into worldwide clinical practice  Underpin apropriate clinical dosage  Support regulatory convergence of international regulations (e.g. blood products; IVDs – infectious agents) *Established by the Expert Committee on Biological Standardization

130 Reference preparations: 65% IS/Ref Panels established between : 60% new preparations (36% BS, 22% HT, 30% IP/IM) 40% replacements (19% BS, 67% HT, 14% IP/IM) 130 Reference preparations: 65% IS/Ref Panels established between : 60% new preparations (36% BS, 22% HT, 30% IP/IM) 40% replacements (19% BS, 67% HT, 14% IP/IM)

Documents

- First line detection of infectious agents - Crucial for the prevention of transmission of blood-borne pathogens - Significant impact on appropriate control of safety of blood and blood products Testing strategies and national control of blood safety related in vitro-diagnostic tests, a priority

In vitro diagnostic devices (IVDs)* Medical devices used in vitro for the examination of human specimens  IVDs for infectious markers  Viruses, bacteria, parasites, unconventional agents  IVDs for  Blood/plasma screening (blood safety)  Confirmation of infection  Diagnosis and monitoring  Tests methods  Serological assays (e. g. ELISA)  Nucleic acid amplification techniques (NAT) *Priority: impact on blood safety, public health issues and international regulations

ECBS: HIV (IVD Technologies) WHO International Standard or Reference Panel UsersCurrentTest Test developers, manufacturers, regulators, blood establishments, fractionators, reference laboratories, diagnostic laboratories HIV-1 p24 antigen, 1 st IS (IU)Serology Anti-HIV, 1 st Ref Panel (no unitage) (HIV-1 subtypes: A, B, C, CRF_01, O; HIV-2) HIV-1 RNA 2 nd IS (IU)NAT HIV-1 RNA Genotype 2 nd Ref Panel (no unitage) (A,B,C,D, AE, F, G, AG-GH, groups N & O) HIV-1 Circulating Recombinant Forms (CRFs) RNA 1 st Reference Panel (no unitage) HIV-2 RNA 1st IS (IU)

ECBS: Hepatitis related reference standards WHO International Standard or Reference Panel UsersCurrentTest Test developers, manufacturers, regulators, blood establishments, fractionators, reference laboratories, diagnostic laboratories Hepatitis B surface antigen (HBsAg), 2 nd IS (IU)+dilutional panel Serology HBsAg genotypes, 1st Reference Panel (15 members) Hepatitis B virus “e” antigen (HBeAg), 1st IS (IU) Anti-Hepatitis B virus “e” antibodies (anti-HBeAg), 1 st IS (IU) Anti-Hepatitis B virus core antibodies, 1 st IS (IU) Hepatitis B immunoglobulin, 2 nd IS (IU) Hepatitis A virus RNA 1 st IS (IU) NAT Hepatitis B virus DNA 2 nd IS (IU) Hepatitis B virus DNA Genotype 1 st Reference Panel Genotypes A, B, C, D, E, F, G (8 members) Hepatitis C virus RNA 2 nd IS (IU) Hepatitis D virus (HDV) RNA 1st IS (IU)

Immunotherapy; Hemostasis/Thrombosis −Blood group reagents – Blood Coagulation Factors* (e.g. FactorVIII, IX, vWF, PCC) – Human immunoglobulins (e.g. anti-D, hepatitis B, rabies, tetanus, rubella, varicella zoster etc.) – Protease inhibitors (AT, C1esterase inh; alpha1-antitrypsin) – Albumin – Other blood related biologicals (e.g. Unfractionated and LMW Heparin; Streptokinase; Urokinase; Tissue Plasminogen Activator) (*)Plasma Reference Materials applied to the Diagnosis of Blood Coagulation Disorders

Main achievements –The required IBRPs for the detection of microbial agents with an impact on the regulation and control of the safety of blood and blood products have been established. –The development of WHO reference panels designed for the determination of efficiency of Hepatitis and HIV diagnostic kits to detect the genotypes/subtypes prevalent in the different regions was high priority. –The reference panels as well as the international standards have been a fundamental tool in the on-going development and improvement of assays for the control of quality and safety of blood products.

Coordination of setting standards activities required –WHO CC plans of work in the development of IVD IRPs Updates on emerging/re-emerging pathogens New test strategies & emerging technologies Selection of priority projects supporting IVD & blood safety regulations –WHO disease control programmes (infectious diseases): Overview of global epidemiological data –Collaboration of Regional Offices: participating laboratories and identification of candidate materials –Coordination with other standard setting organizations and international organizations: ISO, BPM, European Commission etc.

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