WHO Norms and Standards: Blood Products & related Biologicals Dr Ana Padilla Blood Products &...

WHO Norms and Standards: WHO Norms and Standards:

Blood Products & related BiologicalsBlood Products & related Biologicals

Dr Ana Padilla Blood Products & related Biologicals

Quality and Safety: MedicinesEssential Medicines and Pharmaceutical Policies Department

Health Services and Systems Cluster World Health Organization

HTP/PSM/QSD: WHO/UNICEF TB, 18.11. 082 |

Biological Standardization (*)

Constitutional responsibilityBiological 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


- implemented for more than 50 years - mandated by Member States

- implemented for more than 50 years - mandated by Member States

International Biological Standardization by WHO

WHO is expected to be both a driving forceand a key reference point on biological

standardization issues


Implementation of strategic objective for quality of biologicals (WHO/HQ)

Implementation of strategic objective for quality of biologicals (WHO/HQ)

T w o u n its b u t a fu n ctio na lly in te g ra ted ap p roa ch to b io log ica l s tan d ard isa tion

Q S S /IV B /F C H)V a ccin e s , c yto kin e s , g ro w th fa cto rs ,en d o crin e s (

Q S M /E M P /H S S)B lo od p rod u c ts, in vitro d ia g n os tic s (

B io log ica l s ta n da rd isa tionC o vers vacc ine s , b lo o d p rod u c ts , o th e r b io lo g ica ls

a n d in v itro d ia g n os tics


Blood Products & related BiologicalsBlood 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

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

Other related products Anticoagulant & fibrinolysis biological therapeutic products


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


Blood Products & related Biologicals Blood Products & related Biologicals Strategic Plan Strategic Plan (approved at 57(approved at 57thth ECBS, 2006) ECBS, 2006) Blood Products & related Biologicals Blood Products & related Biologicals

Strategic Plan Strategic Plan (approved at 57(approved at 57thth ECBS, 2006) ECBS, 2006)

WHO Essential Medicines List: o Animal derived sera )IgS(:

Snake antivenom and anti-rabies immunoglobulinso Human blood derived products:

GMP production of plasma for fractionation

WHO Biological Reference Standards for regulation and control of in vitro )biological( diagnostic tests

o Standardization of traditional and new technologies


WHO Essential Medicines List (I)WHO Essential Medicines List (I)

Animal derived blood products – Snake anti-venom immunoglobulins – Anti-rabies imunoglobulins

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


n

Courtesy Prof D Warrell, Nuffield Department of Clinical Medicine, Oxford

Antivenom sera are essential to prevent long-term disability & death

Antivenom sera are essential to prevent long-term disability & death


Component 1: Global Quality Assurance GuidanceComponent 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


Countries representedJakarta, May 2008

Countries representedJakarta, May 2008

SEAROWPRO

Bangladesh

India

Indonesia

Nepal

Thailand

Australia

Cambodia

Japan

Malaysia

Papua New Guinea

China

Philippines

Vietnam


Countries representedAddis Ababa, July 2008

Countries representedAddis Ababa, July 2008

AFROEMROBenin, 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


Fragility of production systems in developing world

The document has been discussed in the field:

Bi-Regional Workshops in Aisa and Africa: - Jakarta, May 2008 - Addis Ababa, June 2008

Global experts consultation

Adoption requested to the 59th ECBS )2008(

FINAL REVISED UPDATED VERSION WHO/BS/08.2088

ENGLISH ONLY

EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION (ECBS)

Geneva, 13 to 17 October 2008

Proposed WHO Guidelines for the Production, Control and Regulation of Snake Antivenom

Immunoglobulins

ADOPTED BY ECBS on 17 October 2008

NOTE: This document has been prepared for the purpose of inviting comments on the proposals contained therein, and for the preparation of the materials to be considered by the Expert Committee on Biological Standardization. Comments proposing modifications for this text MUST be received by 1 October 2008 and should be addressed to the attention of Dr Ana Padilla, World Health Organization, at the following e-mail address [email protected], with copy to [email protected], or by fax at the number +41 22 791 4889.


Antivenom Is the Only Specific Antidote to Snake Venom

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


Clinical Assessment: Need of Efficacy Test(reported by Dr Thapa, Nepal)

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(


Major issues about antivenom preparations

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


LiteratureLiterature


Literature Literature

A - Collection of venoms

B – Horse ImmunizationProtocols

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)


3 major instruments to inform about potency and efficacy of Antivenoms

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

Capacity Capacity building for snake venoms building for snake venoms production and antivenoms production and antivenoms

preclinical evaluation: preclinical evaluation: a proposal to strenghten national capacitiesa proposal to strenghten national capacities


Venoms production: Basic problemsVenoms 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.


Consequences…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.


Consequences…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.


Component 2: national/regional capacity building on venoms production

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.


Components of the WHO proposal(Proposed WHO Consultation, 2009)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


Expected outcomesExpected 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.


WHO Essential Medicines List (II)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


Blood Plasma: a valuable human resourceBlood Plasma: a valuable human resource

Medicinal products derived from human donations of blood and plasma play a critical role in health care

The ‘Achilles’ project: The ‘Achilles’ project:

a WHO initiative to assure safety and a WHO initiative to assure safety and availability of blood products in availability of blood products in

developing countries developing countries


What is the global situation ?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 Background



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 Background



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? What are the problems?


Increase availability of safe blood derived products by: Supporting implementation of national validated quality and safety standards for blood establishmentsRaising the manufacturing activities of blood establishments to international standardsUsing 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 establishmentsUsing expertise and experience gained from developed countries

WHO “Achilles” project: Expected Outcomes


The “Achilles” project: Project Goals

The “Achilles” project: Project Goals


GMP implementation in Blood/Plasma Establishments: a key element to

Quality and safety of plasma for fractionationPlasma contract fractionation programs

Supporting access to blood plasma products

Good Manufacturing Practices (GMP): an essential tool for improvement of safety


TRACEABILITYTRACEABILITY FROM DONOR TO PATIENTFROM DONOR TO PATIENT

TRACEABILITYTRACEABILITY FROM DONOR TO PATIENTFROM DONOR TO PATIENT

COMPONENTS PREPARATION

DONATIONINFORMATION

FRACTIONATIONVIRAL INACTIVATION

TREATMENT

Good Manufacturing Practices

Blood/Plasma donation

Plasma for Fractionation

Blood Components

Plasma-Derived Medicinal Product

PatientsPatients


Plasma Contract Fractionation Programs(Need for GMP implementation)

Plasma Contract Fractionation Programs(Need for GMP implementation)

GM

PL

ice

ns

ing GM

PL

ice

ns

ing

Quality Assurance Program

across countries

PLASMASUPPLIER FRACTIONATOR

Nat.Reg.Authority

Nat.Reg.Authority

GMP- common principles


WHO “Achilles” projectAction Plan )demonstration project(

WHO “Achilles” projectAction 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 (*)WHO “Achilles” project (*)

)*(Demonstration project: First steps action plan 2009


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 Biological Reference PreparationsWHO Biological Reference PreparationsGlobal Measurement StandardsGlobal Measurement Standards


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


WHO Biological Reference PreparationsStrategic Plan

WHO Biological Reference PreparationsStrategic 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!"


WHO Biological Reference PreparationsBlood Products and related Biologicals

WHO Biological Reference PreparationsBlood Products and related Biologicals

0

20

40

60

80

100

120

Nu

mb

er o

f p

rep

arat

ion

s

Medical field application

In vitro Diagnostic Tests 52 15 10 75

Therapeutic products 0 20 7 27

Blood Safety and General

Hematology

Blood Coagul. and Thrombotic Agents

Immunological Reagents

Total

WHO Catalogue of Biological Reference Preparations: www.who.int/bloodproductsWHO Catalogue of Biological Reference Preparations: www.who.int/bloodproducts


Web site addresses


Priority Projects for Biological Reference Preparations Priority Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007)WHO Collaborating Centres' Meeting (29-30 January 2007)

Priority Projects for Biological Reference Preparations Priority Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007)WHO Collaborating Centres' Meeting (29-30 January 2007)

200720082009ECBS

HCV RNA (3rd)*2007

Anti-Syphilitic (2nd)*2007

Anti-HBs (2nd)*2008

Anti-HBc*2008

HIV-1 gt1 (2nd)**2009

HIV-2 RNA* 2009

HBV gt2**2009

Anti-HCV**2009

Anti-T. cruzi** 2009

Consultation

Feasibility studies

Collaborative study

1the anti-HIV antibody panel will also be extended; 2two panels for HBsAg- and NAT-tests

*IS**Panel

WHO Recommendations: Annex 2, WHO TRS, No 932, 2005


WHO IVD StandardizationWHO IVD StandardizationPriorities 2009

WHO IVD StandardizationWHO IVD StandardizationPriorities 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


Migration Flows from Latin AmericaChagas disease

Migration Flows from Latin AmericaChagas disease

ource:

Europe 1985-1992250,000

Australia 199080,000

Australia 2005/200665,707

Spain 2005>1 million

Legal 640,000Canada 2001216,975

USAUp 1989:2,459,000

90s: legal 7,036,000

Up 2005: legal 7,486,643

Undocumented2000: 5,6 million2006: 8,9 million

Japan 1990 150,000

Japan 1994 250,000

ource:

Europe 1985-1992250,000

Australia 199080,000

Australia 2005/200665,707

Spain 2005>1 million

Legal 640,000Canada 2001216,975

USAUp 1989:2,459,000

90s: legal 7,036,000

Up 2005: legal 7,486,643

Undocumented2000: 5,6 million2006: 8,9 million

Japan 1990 150,000

Japan 1994 250,000

Technical capacity of National Technical capacity of National Regulatory AuthoritiesRegulatory Authorities

Blood Products RegulationsBlood Products Regulations


International Conference of Drug Regulatory International Conference of Drug Regulatory AuthoritiesAuthorities (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


Quality Assurance & Safety: Blood Products and Quality Assurance & Safety: Blood Products and related Biologicals. related Biologicals. Programme OverviewProgramme Overview

Quality Assurance & Safety: Blood Products and Quality Assurance & Safety: Blood Products and related Biologicals. related Biologicals. Programme OverviewProgramme 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


National/Regional Reg. Authorities

Other Standardsetting Organizations

(e.g.BIPM, EDQM, ISO)

Experts Partners & Collaborations

Industry: ManufacturersAssociations

Intnal Scientific Societies

(e.g. ISTH, ISBT, IFCC)

Research& Public Health

Institutions

WHO ECBSExpert Advisory Panels

WHO Working Groups

WHO CC for Biological

Standards & Quality Assurance

WHO Consultations


www.who.int/bloodproductswww.who.int/biologicalswww.who.int/medicines

Web site addresses

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