Overview of the Biological Standardisation Programme (BSP) · Overview of the Biological...

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Overview of the

Biological Standardisation Programme

(BSP)

Eriko Terao, PhDScientific Officer

Council of EuropeEuropean Directorate for the Quality of Medicines & HealthCare (EDQM)

Department of Biological Standardisation, OMCL Network & Healthcare (DBO)

Ph. Eur. Training sessionBiologicals

7 February 2017

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1. Biologicals : what’s so special ?

The Biological Standardisation Programme (BSP)

E Terao Training on Biologicals, 07-08/2/2017 ©2017 EDQM, Council of Europe. All rights reserved.2

2. Standardisation : why & what do we need ?

3. What is the BSP ?

4. BSP: how does it work ?

5. A glimpse of BSP projects: done, ongoing

6. How to participate in a BSP study ?

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• Vaccines & sera for human use Ph. Eur. Expert Group 15

• Biologicals Ph. Eur. Expert Group 6

hormones, cytokines, anticoagulants (heparins),…

Specific Working Groups• Miscellaneousendotoxins, mycoplasma,…

• Blood products Ph. Eur. Expert Group 6Bimmunoglobulins, coagulation factors,…

• Vaccines & sera for veterinary use Ph. Eur. Expert Group 15V

1. Biologicals: what’s so special? (1)


Biological products are substances


produced by a biological process

usually in living organisms

o purified , fractionated, concentrated,...

o human, animal, recombinant,…

o an inherent (biological) variation

reflecting molecular heterogeneity

o a chemical complexity

characterized by


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Assays

In vivo

- indirect : serology assays,...

In vitro

- physico-chemical characterisation

- specific activity

- ...

Variation sources

- animal strain & individuals,…

- immunisation design,…

- cell lines & culture conditions,…

- reagents, testing conditions,…

- sample preparation

- polydispersion, glycosylation,…

- conversion factors (IU-mg)

there is an inherent (biological) variation/heterogenicity

- of the samples - of the reagents, references, readout systems, assay conditions,...

- direct : challenge assays, body temperature,...

- cell culture assays

- immunoassays (ELISA, ToBI,...)

- nucleic acid amplification



need for comparison & trust in results obtained by different laboratories

- global markets- mutual recognition of control results- centrally authorised products

- public health crises (product adulteration, adverse effects with unidentified causes, …)

- stock shortages (due to production issues, emergencies: natural disasters or outbreaks,…)

- continuity of treatments (for travellers, for clinicians during stock shortages,…)

for rapid global exchange of data and medicines

clinicians & patients

2. Standardisation: why & what do we need ? (1)


between different sites of the same organisation

between control authorities & manufacturers

between control laboratories (OMCL network,…)

manufacturersnational control laboratories

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Common validated methods



Common - reference standards- critical reagents

Physico-chemical tests Chemical Reference Substances (CRS)

Biological assays Biological Reference Preparations (BRP)

Biological Reference Reagents (BRR)

- transferable- acceptable intra-laboratory variation- acceptable inter-laboratory variation- suitable for various products

are usually assigned an arbitrary unitage :

‘amount that induces a defined biological effect’

represent the average response

from a large number of assays from various laboratories

The International Units (IU) for biological activities

- are not part of the international system of units (SI)

- are defined by the World Health Organization (WHO)

through the establishement of preparations designated as

International Standards (IS)



Reference standards for use in biological assays

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- assigned with a content

• in IU (as appropriate)

• in Ph. Eur. Units when no IS was established

- calibrated against the corresponding WHO IS (when existing)

Ph. Eur. Reference standards for Biologicals are

- officially adopted by the Commission of the Ph. Eur.

- working standards for use in conjunction with the Ph Eur texts

The calibration of BRPs requires data from a large number of laboratories

need for coordinated international collaborative studies



1994 EU becomes full member of the Ph. Eur. Convention

Creation of the OMCL Network (66 OMCLs in 35 countries)

Foundation of the Council of Europe1949

The Ph. Eur. Convention, a Council of Europe partial agreement

Ph. Eur. texts are mandatory in member countries

1964

harmonisation of technical requirements for the autorisation and manufactureof medicinal products

37 members and 30 observers - including WHO

Biological Standardisation Programme (BSP)1991

agreement betweenthe Council of Europe (Strasbourg) & the EU Commission (Brussels)

47 member countries & 6 observer statesHuman Rights, Democracy, Rule of Law


3. What is the BSP ? (1)

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• Programme co-financed by

the Council of Europe (Strasbourg) and the EU Commission (Brussels)


• coordinates large collaborative studies to:

- establish of Ph. Eur. reference standards & reagents

- standardise / validate pharmacopoeial methods

including alternative 3R (refine, reduce, replace) methods to animal use

for the quality control of biologicals

• is independent: no financial interest, neutral focal point for open discussions

• aims at improving international harmonisation

by holding discussions with all interested parties (OMCLs, manufacturers, WHO, pharmacopeia,…)


Technical secretariat

- project coordination

Department of Biological Standardisation, OMCL network & HealthCare (DBO)

scientific administrators

biostatisticians

secretarial assistant

Steering Committee Non-EDQM experts

- scientific advice

- liaison with Ph. Eur. Groups of Experts

- liaison with other organisations for global harmonisation



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• Chairs of the Ph. Eur. Groups of Experts on Biologicals

- biological substances (6)- human blood & blood products (6B)- human sera and vaccines (15) - veterinary sera and vaccines (15V)

• Chairs of the Biological Working Groups of the European Medicines Agency- human use: BWP- veterinary use: IWP

• EDQM Director

• Representatives of - the EU Commission

- the European Medicines Agency (EMA)

- the World Health Organization (WHO)

• Co-opted experts in biologicals - for human use (2)

- for veterinary use (1)



3. Launch of a collaborative study

whenever possible, projects are run jointly with WHO, US-FDA, USP,…

to establish harmonised / common reference standards and methods


4. BSP: how does it work ? (1)

2. Discussion and decision by the BSP Steering Committee (BSP SC)

start of the project

nomination of the external Project Leader(s)

regular monitoring and discussion of the project

1. Proposal for a new project: reference standard or/and method validation

relevant to the Ph. Eur. mature method (no research/development) applicable to most products no proprietary method/reagent

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variable number of laboratories (up to 50)

depending on methods

- a common protocol, reagents (as needed) & reporting sheets

- a central analysis of the datasets

- an international panel of participants : OMCLs, manufacturers, authorities

• are characterised by

3. Collaborative studies

- calibrating / assigning a unitage to a (potential or candidate) RS- determining the transferability of a method

• aim at



- a review of the study report at successive levels:participants, relevant group of experts, BSP Steering Committee, Ph. Eur. Commission

- a publication

3. Collaborative studies

• Procurement of a starting material for the RS

• Production of batch(es) of candidate RS

• Pre-testing by a few laboratories

• Stability study (thermal stress)

• Elaboration of a study protocol for the study

• Preparation of the shipments (import permits,...)

• Invitations to laboratories : OMCLs, manufacturers from EU and other regions



Phase 1 : preparative phase - with the project leader(s)

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Phase 2 : collaborative study – with all participating laboratories

• distribution of a common study protocol

- materials and methods

- special instructions

- reporting sheets

- deadlines and contact details

• distribution of a common panel of samples

- calibrants : current WHO IS and/or Ph. Eur. Ref. Standard

- candidate replacement batch(es)

- additional samples

- critical reagents

Phase 3 (optional) : reporting phase - usually with manufacturersdata from routine production lots with a new method or ref. standard



In some cases (new method, global issue), a symposium is organised by EDQM

- submission to the Ph. Eur. Commission official adoption of the RS

- to the corresponding Ph. Eur. Expert Group

- to the BSP Steering Committee

revision of Ph. Eur. text as needed

liaison with EU/EMA, WHO

Distribution of an official study report

- to the study participants check of data by each participant

assignmentof a unitage to the candidate RS

evaluation of assay variation

Central statistical analysis

Monitoring of the stability of the RS regular testing of the RS



Publication of the study report

in Pharmeuropa Bio Scientific Notes open public access

from the EDQM website

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official name

cat. code

relatedPh. Eur. text

instructions for reconstitution, ...

approx. contentfor the customs

assigned potency


4. BSP: how does it work ? (6 - leaflets)

storage conditions(unopened vials)

publication of theBSP study report(open access)


4. BSP: how does it work ? (7 - leaflets)

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149 BSP projects 118 projects finalised, 24 projects currently ongoing

118 projects on BRP/CRSabout 100 batches of more than 60 different BRP/CRS

• Human vaccines Antigens, toxoids, toxinsAntisera,…

• Veterinary vaccines AntigensChallenge strainsReagents, antisera,…

• Blood products ImmunoglobulinsClotting factorsContaminants,..

• Miscellaneous Mycoplasma strains, allergens, endotoxins…

• Biotech products Erythropoietin, somatropin, heparins, etarnercept, influximab…

43 projects on method validation, 18 projects on 3R methods


5. A glimpse of BSP projects: done & ongoing (1)

mumps, measles, varicella,tetanus, diphtheria, acellular/whole cell pertussis,Haemophilus influenzae b, poliomyelitis (OPV, IPV), HAC, HBV, HCV,...

rabies, equine influenza, clostridiaswine erysipelas, Newcastle disease,tetanus toxoids,...

normal and specific Ig (tetanus, hepatitis,...)coagulation factors VII, VIII, IX, albumins,...HAV & HEV RNA, prekallikrein, isoagglutinins,...

Validation of improved & alternative 3R methods

• Human vaccines serology methods, alternative 3R in vitro assays,...

diphtheria, tetanus, acellular pertussis, influenza,…

hepatitis A, rabies vaccines,...

Inactivated Poliomyelitis Virus immunogenicity & antigen content,…

• Veterinary vaccines serology methods, alternative 3R in vitro assays

• Blood products improved agglutination method, alternative 3R potency assays

• Biologicalssomatropin, heparins, erythropoietin, INF alfa-2,…

43 projects on method validation

18 projects on 3R methods - to refine , reduce, replace animal use


5. A glimpse of BSP projects: done & ongoing (2)

rabies, Clostridium tetani, swine erysipelas, Newcastle disease,…

isoagglutinins direct method, Tetanus immunoglobulins,...

alternative 3R & improved physico-chemical tests

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Check the EDQM website for ongoing / future studies (BSP work programme)

• As participant

- if you perform the test

- if you use the Ph. Eur. RS

• laboratory from manufacturer / OMCL

• As project leader

- with wide knowledge of products / methods

• expert in the field

- if you developed a new method

- with access to a laboratory

Contact the EDQM/DBO/BSP (via Helpdesk on the EDQM website or direct contact)

• As donator of starting material • manufacturer


6. How to participate in a BSP project ?

evaluate a proposed new method/standard contribute to the calibration of a new batch of reference standard

Thank you for your attention


Overview of the Biological Standardisation Programme (BSP) · Overview of the Biological...

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