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					World Health Organization
 International Biological
        Standards

              Elwyn Griffiths

Biologics and Genetic Therapies Directorate


    Health Santé
    Canada Canada
WHO’S BIOLOGICAL
STANDARDIZATION
PROGRAMME
   Develops Recommendations
    (Requirements) and Guidelines on the
    production and control of specific
    biologicals (Written standards)

   Develops and establishes International
    Biological Standards and Reference
    Reagents (Physical standards)
WHO’S BIOLOGICAL
STANDARDIZATION
PROGRAMME

 Work part of Constitution of WHO
  (1946)
 Inherited from League of Nations
 International Biological Standardization
  initiated under League of Nations in
  1920s – Commission on Biological
  Standardization
     FIRST BIOLOGICAL
 1890’s Diphtheria antitoxin (Germany)
 Tremendous achievement
 France successful/ England not
 Attributed to “weak sera”
 Paul Ehrlich found answer –
  STANDARD ANTITOXIN
  PREPARATION - Units
 Standard used to calibrate future
  batches
    INSULIN STANDARD

 Henry Dale (London) applied concept to
  insulin and other biologics (1920s)
 Banting & Best discovered insulin in
  Toronto but STANDARDIZATION
  CRITICAL for clinical usefulness
 Need for INTERNATIONAL oversight
 INTERNATIONAL STANDARD /
  INTERNATIONAL UNITS (IU) as
  measure of “strength” or “activity”
WHO Standard Setting Process

 Expert Committee on Biological
  Standardization (1st meeting 1947)
 Biologicals Unit (Quality & Safety of
  Biologicals/Quality & Safety of Plasma
  Derivatives) ( Secretariat)
 WHO International Laboratories for
  Biological Standards/ Collaborating
  Centres
    WHO Laboratories and
    Collaborating Centres
 *National Institute for Biological Standards
  and Control , Potters Bar , UK ( NIBSC)
 *Sanquin-Central Laboratory Netherlands
  Red Cross Blood Transfusion Service ( CLB)
 Center for Biologics Evaluation and Research
  FDA, Bethesda, USA (CBER)

* Hold and distribute international standards
         Collaboration
 Other standard setting bodies eg Council of
  Europe/European Department for the Quality
  of Medicines: USP/International Standards
  Organization (ISO)
 National Regulatory Authorities/National
  Control Laboratories
 Scientific Societies/Associations
 Manufacturers Associations ( International
  Federation of Pharmaceutical Manufacturers
  Associations)
Types of WHO biological
reference materials
     International         Reference Reagents
       Standards            differ from
 enable the activity of     International
  biological                 Standards in the
  preparations to be         extent of
  expressed in the           characterisation and
  same way globally          intended use
 mostly in (IUs)           not assigned IU’s
  International Units       Interim
Types of WHO biological
reference materials
 International Reference Panels
 Group of reference materials
  established to collectively aid evaluation
  of assays or diagnostic tests.
 Comply with requirements for WHO
   reference standards/reagents
Examples of WHO Standards
relevant to in vitro diagnostics
   HBsAg, subtype adw2 genotype A (33
    IU/vial) 2nd IS 2003
    Hep B virus DNA (500,000 IU/vial) 1st IS
    1999
   Hep C RNA ( 50,000 IU/vial) 1st IS 1997
   HIV-1 p24 Ag ( 1000 IU/ampoule) 1st Int Ref
    Reagent 1992
   HIV-1 RNA ( 100,000 IU/vial) 1st IS 1999
   HIV-1 genotype Reference Panel 2003
            Biologicals -
         What’s the Problem?
   Special consideration/ challenges

   Inherent variability of biological systems,
    including biological and immunological
    assays

   Potential for microbial contamination

   Complex macromolecules/systems
         Biologicals –
      What’s the Problem?


   Cannot be adequately characterised by
    chemical and/or physical means alone

   Used in prophylaxis, therapy or
    diagnosis of human diseases
    (in vitro diagnostics)
    WHO biological reference
          materials
   Play a vital role in facilitating transfer of
    laboratory science into worldwide
    clinical practice

   Contribute to development and on going
    use of safe and effective biologicals and
    reliable diagnostics
      Use of WHO International
        Reference Materials

   Form basis of quality control, regulation
    and clinical dosing for biological
    medicines

   Form basis of quality control and
    regulation of in vitro diagnostic
    devices
Biotechnology Derived Products

 Past 20 years seen explosion in
  molecular biology/novel bioproduction
  methods
 Opened new possibilities for disease
  diagnosis/treatment /prevention
 Cutting - edge of biomedical research
 Economically fastest growing sector in
  pharmaceuticals
Regulatory Developments in
standardisation
 International Standards Organisation
  developed written standards for
  establishment of reference materials
 European Commission adopted ISO
  standards for in vitro diagnostic devices
 Implications for WHO biological
  reference preparations
Regulatory Developments in
standardisation

   Issue - extent to which principles for
    characterization of reference materials
    in other fields can be applied to
    biological reference materials

   Much debated.
ISO requirements for reference
materials
 Apply to ALL reference materials ,
  chemical and biological,
 Following ISO/WHO discussions
  recognized biologicals “different”
 Biological standards were not
  considered “primary” standards
  because could not meet all metrological
  principles – confusion
ISO requirements for reference
materials
 Metrological principles - primary
  standards established in SI units
 Single method
 Measurement uncertainty
 Commutability
 Traceability to previous standard
 DOES NOT MAKE SENSE FOR ALL
  BIOLOGICAL SITUATIONS
         Biological Situation
   Many biologicals exist in both active and
    inactive states in plasma

   Activity (IU) rather than content (mol)
    may better reflect the clinical situation

   Calibration in less precise biological
    units (IU) more appropriate than
    calibration in more precise, but
    clinically irrelevant SI units
          Biological Situation



   Conversely, situations exists where
    measurement of inactive or total (active
    plus inactive) analyte (mol) may be
    more clinically relevant than activity (IU)
ISO requirements for reference
materials
   Placed WHO standardization activities
    outside accepted metrological principles

   Made compliance with some external
    requirements (eg EU in vitro diagnostic
    devices directive) problematic
International Consultations –
            on in vitro diagnostics
 WHO worked with ISO, other standard
  setting bodies, regulatory authorities,
  scientific community and users
 Through series of consultations
  reviewed scientific basis for the
  preparation and characterization of
  biological reference materials.
International Consultations –
            on in vitro diagnostics



   WHO Consultation on Global
    Measurement Standards and their use
    in the in vitro Biological Diagnostic Field

                June 2004
International Consultations –
            on in vitro diagnostics
 Re-affirmation that concepts used by
  WHO for biological standardization still
  appropriate
 Re-affirmation of the continued need
  and usefulness of this class of reference
  materials
 Need for improved clarity in explaining
  principles used to establish WHO
  International Standards
Preparation, characterisation and
establishment of WHO biological
reference preparations

 Guidelines in WHO Technical Report
  Series,1978, revised in 1986 ,1990.
 Have now been updated taking into
  consideration recent developments
  and need for improved clarity
 Adopted as Recommendations by
  Expert Committee on Biological
  Standardization, November 2004
Recommendations not Guidelines

   For Preparation, Characterization and
    Establishment of International and other
    Biological Reference Standards

   Comprehensive document

   As usual considerable consultation in
    their development
      New Recommendations
   Choice of unit ( IU/SI /none ) -
    should be based on the biological,
    medical and physicochemical
    information available on a case-by-
    case basis

   Where it is appropriate for WHO
    biological standard to be calibrated in SI
    units, principles of ISO 17511 to be
    followed
      New Recommendations

   Deal with number of Issues/principles
    such as:
    Methods – single or multiple
    Measurement uncertainty
    Commutability in vitro diagnostics field
    (deals with matrix issues)
    Traceability
    Definitions
      New Recommendations

   Sections include -
    Quality Assurance
    Treatment of bulk liquid
    Quality of final containers
    Freeze drying
    Characterization / Stability
    International collaborative studies
    Use
     New Recommendations

   WHO biological standards cover a
    broad range of uses

   range of options should continue to be
    used in their characterisation.
     New Recommendations

   Essential to define the intended use of a
    standard prior to initiation of studies -
    aids in design the studies to
    characterise the material and in the
    eventual value assignment to the
    material.
    Assessment of need formalized

 Not all requests for development of
  international standards are appropriate.
 Need to assess priority in establishing
  International Standards/Reference materials
 Decision tree developed ( Appendix 1)
 ECBS is the decision making body, but with
  advice from other bodies and consultations
  eg SoGAT
European Commission – Common
Technical Document
   Clarification of process and background
    to development and establishment of
    WHO International Standards

   Enabled EC to adopt WHO International
    Standard for Hepatitis B ( calibrated in
    IU) as the standard required to fulfil
    Common Technical Document
European Commission – Common
Technical Document
   Legally binding in EC

   Further collaboration with the EC on
    going regarding adoption of other WHO
    International Standards for in vitro
    diagnostics.
Keeping Pace with Developments

   WHO needs to keep pace with
    developments in all biologicals fields

   SoGAT valuable venue to discuss
    scientific developments in NAT assays,
    to look to the future and to support the
    work of the ECBS
     WHO Biologicals Field
   Information re WHO activities in biologicals
    field found on internet :

 www.who.int / biologicals
 www. who.int / bloodproducts/en/


   Catalogue of International Standards
    and Reference Reagent on line
WHO Consultation June 2003

 Review the scientific basis for
  preparation and characterisation of
  WHO biological reference materials
 review a draft revision of the WHO
  guidelines
 make recommendations to WHO to
  ensure that WHO biological reference
  materials retain the widest acceptance
  of fitness of purpose
     prEN/ISO 17511                                   WHO

Calibration of standards           WHO guidelines produce standards:
   (prEN/ISO
17511) requires:
                                   1 calibrated in a multi-method study
1 Single method studies              (rather than a single, reference
  (conventionally agreed or,         method)
  where possible reference
  method)

                                   2 With values assigned in
2 SI units rather than IU (where     International units (rather than
  possible)                          mg/ml)


2     Traceability to previous
    standard, with defined         •     With no imprecision assigned to
    uncertainty                        the ampoule content
Method bias, and single method vs multi method calibration

Calibration of the current International Reference Preparation for TSH


                                         Deviation of any assay result from the
                                         mean is composed of two elements;
                                         the assay imprecision, and the bias:

                                         The WHO multi-method approach, by
                                         including all assays, seeks to average
                                          out, and therefore eliminate the bias
                                         effect.

                                         The WHO approach will provide an
                                         estimate which is “accurate” but not
                                         “precise”

                                         The “reference-method approach will
                                         provide an estimate which may be
                                         “precise”, but not
                                         “accurate”
Single or multi-method
calibration studies
 June 2003 consultation:
“the choice of method depends on
  whether the most important
  consideration is metrological to
  minimise imprecision, in which case a
  single method should be used, or is
  biological to achieve a “true” overall
  value, in which case multiple methods
  should be used”.
   To measure in activity (IU) or content (SI units)?


• Many biologicals exist in both active and inactive
  states in plasma, where the activity (IU) rather than
  content (mol) reflects the clinical situation of the
  patient. Calibration in less precise biological units
  would hence be more appropriate than calibration in
  more precise, clinically irrelevant SI units

2 Conversely, situations exists where measurement of
  inactive or total (active plus inactive) analyte (mol)
  may be more clinically relevant that activity (IU)
The case of the drifting hepatitis
B nanogram
 The 1st HBsAg IS was assigned an IU
  value
 Used to calibrate immonoassays
 Some users also assigned a ng value
 A recent WHO collaborative study
  showed differences between ng
  assignments of some secondary
  standards
Drift in the HBsAg “ng”

Unit                 Unitage equivalent   IU equivalent to 1   Potency of the Candidate
                     to 1 IU              unit of each         IS (00/588) in each
                                          reference            unitage
                                          preparation
International Unit   1.0                  1.0                  33
PEI units primary    0.584                1.713                19.3
PEI units current    0.427                2.341                14.1
French ng            1.931                0.518                63.7
Abbott ng            5.587                0.179                184.4
Choice of units

   June 2003 consultation

“the choice of unit should be based on
  biological, medical and physico-
  chemical criteria and not by perceived
  metrological status”
    Assignment of uncertainty
 WHO standards are established either:
  - as the first International Standard for
  any given analyte, in which case in
  which case the international unit is
  arbitrarily established for the first time
  - or as replacement international
  standards, in which case it is necessary
  to ensure continuity of the value of the
  unit;
 two approaches - calibration or value
Calibration approach

   the second standard is calibrated in
    terms of the first standard, preserving a
    line of metrological traceability of the
    international unit. This approach
    requires assignment of uncertainty, and
    the minimization of that uncertainty
    through the use of defined or even
    reference methods
Calibration approach
        Advantages                  Disadvantages
   compliance with the          a significant range of
    metrological principles       uncertainty would
    established in various        provide difficulties for
    ISO standards                 the users
                                 for some standards (eg
                                  NAT standards) the
                                  uncertainties would run
                                  into orders of
                                  magnitudes
                                 for frequently replaced
                                  standards (eg factor
                                  VIII), the accumulated
Value assignment approach

   the second standard is arbitrarily assigned a
    value intended to preserve as closely as
    possible the value of the unit, but where
    traceability to the first IS is discontinued and
    re-established to the second. This approach
    requires an arbitrary assignment without
    uncertainty, as wide a range of methods as
    possible, and sometimes reference to
    additional factors outside the collaborative
    study (eg standard plasma pools for factor
    VIII)
Value assignment approach
      Advantages              Disadvantages
 it works                 places WHO
 the observed              standardization
  variation in a study      activities outside
  is verified               currently accepted
  statistically to fall     metrological
  within acceptable         principles
  ranges and               makes compliance
  confidence limits for     with external
  the assay methods         requirements (eg
  used                      EU in vitro
 very little evidence      diagnostic devices
Next steps concerning
uncertainty
 WHO will convene further meetings
  - with the in vitro diagnostics regulators
  - a WHO working group on uncertainty
  - with ISO
 The next ECBS will be asked to
  consider stating some elements of
  uncertainty (imprecision of fill; predicted
  loss of activity on storage) in the
  memoranda that accompany standards
Other recommendations from
June 2003 meeting
 WHO should make further use of
  experts in different specialities to plan
  the study design and evaluation of study
  results prior to submission of studies to
  the ECBS
 Additional guidance should be provided
  by WHO on the stability testing of
  international standards, but it is not
  appropriate to assign expiry dates to
Conclusions from June meeting

   The continued usefulness of WHO
    biological standards shows that the
    approaches taken by WHO to biological
    standardisation have served well over a
    long period of time. The current two
    classes of reference preparation, the
    International Standard and WHO
    Reference Reagents should be
    maintianed.
Conclusions from June meeting

   As WHO biological standards cover a
    broad range of uses a range of options
    should continue to be used in their
    characterisation. It is essential to define
    the intended use of a standard prior to
    initiation of studies. This is to aid in the
    design of the studies to characterise the
    material and in the eventual value
    assignment to the material.

				
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