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WHO Norms and Standards: Blood Products & related Biologicals Dr Ana Padilla Blood Products & related Biologicals Quality and Safety: Medicines Essential.

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Presentation on theme: "WHO Norms and Standards: Blood Products & related Biologicals Dr Ana Padilla Blood Products & related Biologicals Quality and Safety: Medicines Essential."— Presentation transcript:

1 WHO Norms and Standards: Blood Products & related Biologicals Dr Ana Padilla Blood Products & related Biologicals Quality and Safety: Medicines Essential Medicines and Pharmaceutical Policies Department Health Services and Systems Cluster World Health Organization

2 HTP/PSM/QSD: WHO/UNICEF TB, |2 | Biological Standardization (*) Constitutional responsibility WHO is mandated by it's Member States to "…develop, establish and promote international standards for biological products." In practice, biological products cover »Vaccines »Blood and blood products »In vitro biological diagnostic devices »Other biological products (*) Expert Committee for Biological Standardization

3 HTP/PSM/QSD: WHO/UNICEF TB, |3 | - implemented for more than 50 years - mandated by Member States International Biological Standardization by WHO WHO is expected to be both a driving force and a key reference point on biological standardization issues

4 HTP/PSM/QSD: WHO/UNICEF TB, |4 | Implementation of strategic objective for quality of biologicals (WHO/HQ)

5 HTP/PSM/QSD: WHO/UNICEF TB, |5 | Blood Products & related Biologicals Animal- derived sera Anti-rabies Anti-venoms (snake bites) Anti-tetanus toxins Anti-diphteria toxins Anti-botulism toxins 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 Priority: IVDs applied to the control of blood and blood products safety Other related products Anticoagulant & fibrinolysis biological therapeutic products

6 HTP/PSM/QSD: WHO/UNICEF TB, |6 | Quality Assurance and Safety: Blood Products and related biologicals WHO standard setting functions* : to establish WHO Biological Reference Preparations to develop evidence based WHO Guidelines on Quality Assurance and Safety of specific products to support implementation of WHO Norms and Standards: (strengthen technical/regulatory capacity of MRAs & NCLs) to support operational strategies to improve access to quality products (*) Expert Committee on Biological Standardization

7 HTP/PSM/QSD: WHO/UNICEF TB, |7 | Blood Products & related Biologicals Strategic Plan (approved at 57 th ECBS, 2006) WHO Essential Medicines List: oAnimal derived sera (IgS): Snake antivenom and anti-rabies immunoglobulins oHuman blood derived products: GMP production of plasma for fractionation WHO Biological Reference Standards for regulation and control of in vitro (biological) diagnostic tests oStandardization of traditional and new technologies

8 HTP/PSM/QSD: WHO/UNICEF TB, |8 | WHO Essential Medicines List (I) Animal derived blood products – Snake anti-venom immunoglobulins – Anti-rabies imunoglobulins

9 The Meeting urged WHO to: Improve availability of antisera by building technical capacity and expertise of regulatory authorities and manufacturers creating a prequalification system. Improve management of diseases through adequate distribution and improved clinical guidance. coordinate collaboration and partnerships (resource mobilization) 1 patient treated = 1 life saved or 1 permanent disability prevented

10 HTP/PSM/QSD: WHO/UNICEF TB, | n Courtesy Prof D Warrell, Nuffield Department of Clinical Medicine, Oxford Antivenom sera are essential to prevent long-term disability & death

11 HTP/PSM/QSD: WHO/UNICEF TB, | Component 1: Global Quality Assurance Guidance Development of WHO Guidelines on the Production, Control and Regulation of animal plasma-derived immunoglobulins (encompassing e.g. control of starting materials and large- scale implementation and control of manufacturing steps) Elaborated in parallel to, and as a result of, WHO Regional and Bi-Regional Workshops

12 HTP/PSM/QSD: WHO/UNICEF TB, | Countries represented Jakarta, May 2008 SEAROWPRO Bangladesh India Indonesia Nepal Thailand Australia Cambodia Japan Malaysia Papua New Guinea China Philippines Vietnam

13 HTP/PSM/QSD: WHO/UNICEF TB, | Countries represented Addis Ababa, July 2008 AFROEMRO Benin, Cameroon, Côte d'Ivoire, Democratic Republic of Congo Ghana, Guinea, Kenya Mali, Niger, Nigeria South Africa, Senegal Tanzania, Uganda Zimbabwe Egypt Morocco Pakistan Saudi Arabia Tunisia

14 HTP/PSM/QSD: WHO/UNICEF TB, | Fragility of production systems in developing world The document has been discussed in the field: Bi-Regional Workshops in Aisa and Africa: - Jakarta, May Addis Ababa, June 2008 Global experts consultation Adoption requested to the 59 th ECBS (2008)

15 HTP/PSM/QSD: WHO/UNICEF TB, | Antivenom Is the Only Specific Antidote to Snake Venom Most important decision in the management of a victim is whether or not to give antivenom From Dr Ariaratne, Sri Lanka

16 HTP/PSM/QSD: WHO/UNICEF TB, | Clinical Assessment: Need of Efficacy Test (reported by Dr Thapa, Nepal) 3 envenomed victims arrived in snakebite treatment center within half an hour but died during medication (Reported from Bharatpur Hospital during recent research) In Bhratpur Hospital, of the two cases, one with 98 ASV vials died but next with 94 vials survived (Pandey et al. 2007)

17 HTP/PSM/QSD: WHO/UNICEF TB, | Major issues about antivenom preparations Enormous doses, uncertain benefit Reaction rates are very high Takes time to dissolve, froth Changing the tender for AVS supply by the authorities Very poor regulatory control No definite way reporting adverse reaction

18 HTP/PSM/QSD: WHO/UNICEF TB, | Literature

19 HTP/PSM/QSD: WHO/UNICEF TB, | Literature

20 A - Collection of venoms B – Horse Immunization Protocols C – Starting material of animal derived sera D – Fractionation & Purification process PRODUCTION OF ANTIVENOM IMMUNOGLOBULINS: Technology in the public domain (not protected by intelectual property)

21 HTP/PSM/QSD: WHO/UNICEF TB, | 3 major instruments to inform about potency and efficacy of Antivenoms Pre-requisite: Preclinical assessment of all antivenoms, using local venoms or venoms likely to have close similarities Clinical assessement: safety & efficacy –Safety (reaction rates) –Dose finding studies –Observational prospective studies –Randomised control trials (when possible) Post-marketting surveillance

22 Capacity building for snake venoms production and antivenoms preclinical evaluation: a proposal to strenghten national capacities

23 HTP/PSM/QSD: WHO/UNICEF TB, | Venoms production: Basic problems Lack of adequate venom production: Venoms used for production need to have appropriate quality and to be representative of the snake populations. Lack of endogenous capacity to assess the neutralizing potency of antivenoms at the preclinical level.

24 HTP/PSM/QSD: WHO/UNICEF TB, | Consequences… The antivenoms produced using low quality, or non- representative venoms are deficient in terms of neutralizing potency and extent of coverage. The capacity to prepare high-quality venoms is a key component in any global strategy aimed at increasing the production and use of effective and safe antivenoms.

25 HTP/PSM/QSD: WHO/UNICEF TB, | Consequences… The lack of endogenous capacity in many countries to assess the preclinical efficacy of antivenoms results in the introduction of antivenoms which are not effective to neutralize the venoms of a particular country or region.

26 HTP/PSM/QSD: WHO/UNICEF TB, | Component 2: national/regional capacity building on venoms production To develop a programme to assist countries in the development of local snake venom production for antivenom manufacture, and in the development of local capacity for the preclinical assessment of antivenom efficacy using these venoms.

27 HTP/PSM/QSD: WHO/UNICEF TB, | Components of the WHO proposal (Proposed WHO Consultation, 2009) Assistance to identify in-country organisations to host snake venom production and preclinical testing of antivenoms; Mobilize international experts through regional workshops and via specific contracts for direct assistance in countries; Regional support for countries through funding of contracted, independent quality assurance services by recognised non- commercial laboratories; Training exchanges (i.e.: venom QA laboratory facilities, laboratories for preclinical testing of antivenoms); Assistance in leveraging funding support for snake venom production and preclinical assessment of antivenoms projects

28 HTP/PSM/QSD: WHO/UNICEF TB, | Expected outcomes A worldwide support in the availability of high-quality snake venom preparations for antivenom production and for preclinical assessment and quality control. Strenghtening of the endogenous national capacities to participate in antivenom production and control.

29 HTP/PSM/QSD: WHO/UNICEF TB, | WHO Essential Medicines List (II) Human derived blood plasma products – Plasma for Fractionation Blood Coagulation Factors: FVIII, PCC Human Normal Immunoglobulin (IV and IM) Anti-D immunoglobulin Anti-tetanus immunoglobulin Blood-derived medicinal products for the treatment of haemophilia and immune diseases are included in the WHO Model List of Essential Medicines

30 HTP/PSM/QSD: WHO/UNICEF TB, | Blood Plasma: a valuable human resource Medicinal products derived from human donations of blood and plasma play a critical role in health care

31 The Achilles project: a WHO initiative to assure safety and availability of blood products in developing countries

32 HTP/PSM/QSD: WHO/UNICEF TB, | What is the global situation ? Blood-derived products are often unavailable in developing countries: patients suffering from hereditary bleeding disorders or congenital and acquired immune diseases do not have access to treatment The global need for blood plasma products exceeds by far available supply No realistic possibility of generating surplus products in developed countries to meet developing countries needs and, even when available, would be unaffordable. Background

33 HTP/PSM/QSD: WHO/UNICEF TB, | What is the global situation ? Plasma for fractionation available in industrialized countries meet their needs "Developing countries will only be able to create an affordable and sustainable supply of blood derived products by using blood plasma collected in their own blood establishments and from their own populations" Plasma fractionation can be performed through plasma contract fractionation programs Background

34 HTP/PSM/QSD: WHO/UNICEF TB, | What is the global situation ? Wastage of blood plasma in developing countries: (does not currently meet the standards required for product manufacture) Risk of transfusion-transmitted diseases and cross-border threats: (increasing internationally mobility of populations highlights need to strengthen quality assurance systems globally) Need to introduce a "plasma production culture" (GMP culture in blood establishments) Poor regulation of blood and blood products: (need for update of legal provisions and strengthen MRAs technical capacity) What are the problems?

35 HTP/PSM/QSD: WHO/UNICEF TB, | Increase availability of safe blood derived products by: Supporting implementation of national validated quality and safety standards for blood establishments Raising the manufacturing activities of blood establishments to international standards Using reliable regulatory systems able to "prequalify" blood establishments: adherence to WHO standards for the manufacture of plasma for fractionation and to WHO GMP for blood establishments Using expertise and experience gained from developed countries WHO Achilles project: Expected Outcomes The Achilles project: Project Goals

36 HTP/PSM/QSD: WHO/UNICEF TB, | GMP implementation in Blood/Plasma Establishments: a key element to Quality and safety of plasma for fractionation Plasma contract fractionation programs Supporting access to blood plasma products Good Manufacturing Practices (GMP): an essential tool for improvement of safety

37 HTP/PSM/QSD: WHO/UNICEF TB, | TRACEABILITY FROM DONOR TO PATIENT COMPONENTS PREPARATION DONATION INFORMATION FRACTIONATION VIRAL INACTIVATION TREATMENT Good Manufacturing Practices Blood/Plasma donation Plasma for Fractionation Blood Components Plasma-Derived Medicinal Product Patients

38 HTP/PSM/QSD: WHO/UNICEF TB, | Plasma Contract Fractionation Programs (Need for GMP implementation) GMP Licensing GMP Licensing Quality Assurance Program across countries PLASMA SUPPLIER FRACTIONATOR Nat.Reg. Authority Nat.Reg. Authority GMP- common principles

39 HTP/PSM/QSD: WHO/UNICEF TB, | WHO Achilles project Action Plan (demonstration project) Development of comprehensive GMP guidelines to support training and inspection activities: GMP Guidelines for Blood Establishments (ECBS 2009) Development of Work Plans: upgrading quality assurance systems, regulatory expertise and national regulations initially in 2 pilot countries (ECBS 2009) Work Plans imply development of specific and measurable indicators to monitor success and progress with the pilot countries (e.g. regulations updated; BE GMP compliance; quality assurance officers trained; increase in plasma volume for fractionation…) WHO Achilles project (*) (*) Demonstration project: First steps action plan 2009

40 HTP/PSM/QSD: WHO/UNICEF TB, | Optimal use and benefit from donated blood plasma Use of local plasma to improve supply of blood derived medicinal products Increase quality and safety of all blood products in blood establishments Apply internationallly agreed standards for blood establishments Sustainable and affordable blood plasma derived essential medicines Potential application of QA and GMP principles to other medical disciplines Substantial contribution to public health programs WHO Achilles project: Expected Outcomes

41 WHO Biological Reference Preparations Global Measurement Standards

42 HTP/PSM/QSD: WHO/UNICEF TB, | WHO Biological Reference Preparations Global measurement standards Tool for comparison of biological measurement results worldwide To facilitate transfer of laboratory science into worldwide clinical practice To support harmonization of international regulations of blood products and high risk IVDs To accelerate transfer technology

43 HTP/PSM/QSD: WHO/UNICEF TB, | WHO Biological Reference Preparations Strategic Plan Impact of migrations: health safety/security Standardization of in vitro biological diagnostic technologies Convergence of regulatory policies Track and monitor blood safety "The battle against infections and the struggle for blood safety are closely interrelated!"

44 HTP/PSM/QSD: WHO/UNICEF TB, | WHO Biological Reference Preparations Blood Products and related Biologicals WHO Catalogue of Biological Reference Preparations:

45 HTP/PSM/QSD: WHO/UNICEF TB, | Web site addresses

46 HTP/PSM/QSD: WHO/UNICEF TB, | Priority Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007) ECBS HCV RNA (3 rd )* 2007 Anti-Syphilitic (2 nd ) * 2008 Anti-HBs (2 nd )* 2008 Anti-HBc* 2009 HIV-1 gt 1 (2 nd ) ** 2009 HIV-2 RNA * 2009 HBV gt 2** 2009 Anti-HCV** 2009 Anti-T. cruzi** Consultation Feasibility studies Collaborative study 1 the anti-HIV antibody panel will also be extended; 2 two panels for HBsAg- and NAT-tests *IS **Panel WHO Recommendations: Annex 2, WHO TRS, No 932, 2005

47 HTP/PSM/QSD: WHO/UNICEF TB, | WHO IVD Standardization WHO IVD Standardization Priorities 2009 WHO Collaborating Centres Meeting in 2009 Identify and coordinate needs/priorities within WHO Disease oriented Departments IHR-core laboratory capacity Anti-Trypanosma cruzi (Chagas) reference panel HBV genotype panel (DNA and HBsAg) H. Scheiblauer

48 HTP/PSM/QSD: WHO/UNICEF TB, | Migration Flows from Latin America Chagas disease

49 Technical capacity of National Regulatory Authorities Blood Products Regulations

50 HTP/PSM/QSD: WHO/UNICEF TB, | International Conference of Drug Regulatory Authorities International Conference of Drug Regulatory Authorities (ICDRA): Recommendations, Bern 2008 Recognizing the need worldwide for blood products regulation to ensure availability of safe blood and blood products in the face of known and emerging threats, including emerging infectious diseases, WHO should: » Take steps to further develop and strengthen national/regional blood regulatory authorities and to promote cooperation » Provide harmonized "assessment criteria for blood regulatory systems" (BRN): convene a consultation of NRAs to review Draft assessment tool » Prioritize development of Guidelines on GMP for Blood Establishments » Promote introduction of WHO recommended plasma standards by NRAs

51 HTP/PSM/QSD: WHO/UNICEF TB, | Quality Assurance & Safety: Blood Products and related Biologicals. Programme Overview WHO standard setting functions for Biological Products (WHO Constitution ……….) Global Norms and Standards: Quality Assurance regulatory and biological standardization functions Expert Committee on Biological Standardization WHO Essential Medicines List WHO Biological Standards for blood safety-related diagnostic tests Essential Element of a public health system

52 HTP/PSM/QSD: WHO/UNICEF TB, | National/Regional Reg. Authorities Other Standard setting Organizations (e.g.BIPM, EDQM, ISO) Experts Partners & Collaborations Industry: Manufacturers Associations Intnal Scientific Societies (e.g. ISTH, ISBT, IFCC) Research & Public Health Institutions WHO ECBS Expert Advisory Panels WHO Working Groups WHO CC for Biological Standards & Quality Assurance WHO Consultations

53 HTP/PSM/QSD: WHO/UNICEF TB, | Web site addresses

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