biological standardisation programme who
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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 Standards
enable the activity of biological preparations to be expressed in the same way globally
mostly in (IUs) International Units
Reference Reagents differ from
International Standards in the extent of characterisation and intended use
not assigned IU’s 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
Calibration of standards (prEN/ISO
17511) requires:
1 Single method studies (conventionally agreed or,
where possible reference method)
2 SI units rather than IU (where possible)
2 Traceability to previous standard, with defined uncertainty
WHO guidelines produce standards:
1 calibrated in a multi-method study (rather than a single, reference method)
2 With values assigned in International units (rather than mg/ml)
• With no imprecision assigned to the ampoule content
prEN/ISO 17511 WHO
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”
Method bias, and single method vs multi method calibration
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)?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 equivalentto 1 IU
IU equivalent to 1unit of eachreferencepreparation
Potency of the CandidateIS (00/588) in eachunitage
International Unit 1.0 1.0 33PEI units primary 0.584 1.713 19.3PEI units current 0.427 2.341 14.1French ng 1.931 0.518 63.7Abbott 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 assignment
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 compliance with the
metrological principles established in various ISO standards
Disadvantages a significant range of
uncertainty would provide difficulties for 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 uncertainty would soon render the standard useless
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 approachAdvantages
it works the observed variation in
a study is verified statistically to fall within acceptable ranges and confidence limits for the assay methods used
very little evidence in significant drift in the value of the IU
Disadvantages places WHO
standardization activities outside currently accepted metrological principles
makes compliance with external requirements (eg EU in vitro diagnostic devices directive) problematic
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 biological reference materials.
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.