02/06/20151 combined vaccines with a hep b component the role of non-clinical testing in ensuring...

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COMBINED VACCINES WITH A HEP B COMPONENT

The role of non-clinical testing in ensuring their safety & efficacy

Roland Dobbelaer, Dr. Sc.,Head Biological Standardisation

Scientific Institute of Public HealthBrussels

Copyright, 1996 © Dale Carnegie & Associates, Inc.

Scientific Institute of Public Health - Louis PasteurWetenschappelijk Instituut Volksgezondheid - Louis PasteurInstitut Scientifique de Santé Publique - Louis PasteurBIOLOGICAL STANDARDISATION

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COMBINED VACCINES ARE NOT NEW: DISEASE COMBOS


Men A,C

Men A,C,W,Y

Pneu 23

Pneu conj 7, 11, 14

Flu A,A,B

OPV 1, 2, 3

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COMBINED VACCINES ARE NOT NEW: VIRAL COMBOS


Me

Mu

Ru

MMR

MMR+V

HepA/HepB

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COMBINED VACCINES ARE NOT NEW:BACTERIAL + VIRAL COMBOS


DT

D-HepB

DTP a,w/Hib

DTP a,w-HepB/Hib

DTP a,w-IPV 1,2,3/Hib

DTP a,w-IPV 1,2,3-HepB/Hib

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PhEur VACCINES FOR HUMAN USE Vaccina ad usum humanum


“For a combined vaccine, where there is no monograph to cover a particular combination, the vaccine complies with the monograph for each individual component, with any necessary modifications approved by the competent authority.”

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COMBINED VACCINES: Issues


PRO ISSUESLogistics for D, T,P, IPV, HepB, Hibin the first year:

15 injections (US)

11 injections (EU)

4 injections

Combining ismore than simply

mixing

Potentialimplications for:

Efficacy Reactivity Testing

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Combining is more than mixingFormulation issues of combined vaccines


pH Degree of adsorption Ionic strength & Osmolality Concentration and compatibility of:

adjuvant buffer salts antimicrobials residual CHOH, A-biotics, endotoxins, ...

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PhEur Characterisation HBsAg


– Complete protein, lipid and carbohydrate structure

– Morphological characteristics of particles (electron microscopy)

– Buoyant density (gradient centrifugation)– Antigenic epitopes– Primary structure (amino-acid composition &

sequence analysis, peptide mapping)

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PhEur HepB testing of culture and harvest and on purified antigen


CULTURE AND HARVEST– Identity, microbial purity, plasmid retention and

consistency of yield

PURIFIED ANTIGEN– Total protein– Antigen content and identy (RIA, ELISA with

MCl Ab against protective epitope)– Antigen/protein ratio

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PhEur HepB testing of culture and harvest and on purified antigen


PURIFIED ANTIGEN (ctd.)– Molecular weight– Antigenic purity (>= 95 % HBsAg).– Composition (proteins, lipids, NA and CH)– Host-cell- and vector-derived DNA (<=10

pg/shd)– Caesium and/or other chemicals– Sterility

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PhEur HepB testing of the final bulk and final lot


Final bulk– Antimicrobial preservative– Sterility

Final lot– Identity, Aluminium, Free formaldehyde, Antimicrobial

preservative, Sterility, Pyrogens

– Assay: either in vivo, by comparing its capacity to induce specific antibodies against hepatitis B surface antigen (HBsAg) in mice or guinea-pigs with the same capacity of a reference preparation, or in vitro, by an immunochemical determination of the antigen content.

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PhEu rHepB in-vivo assay: mouse immunogenicity

– Vaccinate

– Incubate

– Titrate

– Calculate

>


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PhEur HepB in-vitro assay: antigen content (ELISA)


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rDNA Hepatitis B ELISA assay

15

20

25

30

0%

20%

40%60%

80%

100%

120%

EstimateLower 95% fiducial limit (% of estimate)Upper 95% fiducial limit (% of estimate)

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TESTING TO ENSURE CONSISTENCY


What if possible interactions between antigens are observed?– HepB– Di & Te without Pw

– Te & HibTe conj.

– Hib & Pa Compare with clinical reference and

monitor consistency

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IMPORTANCE OF


Research into correlates/surrogates for protection and defining significance of observed differences

Defining how much info has to be available before licensing and what can be left to post-licensing

Close epidemiological monitoring of vaccine coverage and efficacy & adverse reactions, pathogen circulation upon introduction of new (combined) vaccines

Increased public sensitivity to safety standards

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Quality Surveillance of Biological Medicinal Products

*EDQM - OM CL's*Ph. Eur. (Exp. 15)*WHO (VSQ)

Rapporteurs and assessors

C(P)(V)M P & Working Parties

EM EA

DG Industry

SIPH-LP (OM CL)Biological Standardisation Section*Batch Release*Advising in licensing & inspection

Assesors

M edicines Board(s)

Pharmaceutical Inspectorate

Public Health

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BASIS FOR MUTUAL RECOGNITIONQUALITY

THE WORLD ACCORDING TO THE WORLD ACCORDING TO EN45001EN45001

EDQM “Joint audits”EDQM “Joint audits” EDQM proficiency studiesEDQM proficiency studies WHO auditsWHO audits

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CONTROL AUTHORITY BATCH RELEASE

PRODUCER-INDEPENDENT OMCL PRODUCER-INDEPENDENT OMCL PRE-MARKETINGPRE-MARKETING– RE-testing and critical RE-evaluation of

production & control protocol to verify & monitor conformity with to verify & monitor conformity with

MAA, Ph. Eur. & WHOMAA, Ph. Eur. & WHO

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M arketing Information Form and copy of certificateto im p ortin g cou n try

EU release certificate or notification of non-compliance(accompanies the batch)

Testing of samples and assessment of protocol

Submission of samples and protocol

Request for Batch Release

CONTROL AUTHORITY BATCH RELEASE PROCEDURE

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CONTROL AUTHORITY BATCH RELEASE

Hepatitis B (rDNA) Vaccine

On the bulk purified antigen: Identity and purity

On the final lot: Identity and Assay (the assay serves as an identity test) If an in vitro assay is used to determine the antigen

content, it must be done on the final lot. If an in vivo assay is used it is required only whenever a

new final bulk has been used.

02/06/20151 combined vaccines with a hep b component the role of non-clinical testing in ensuring...

Documents

hepb hib slide

monitor consistency

antigen content elisa

peptide mapping slide

pheur vaccines

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w hib dtp

pheur hepb testing of