Vaccine standardization in

the context of PQ

Vaccine standardization in Vaccine standardization in

the context of PQthe context of PQ

Dr Ivana Knezevic

Quality, Safety and Standards

WHO, Geneva

OutlineOutline

�� WHO standards for vaccines WHO standards for vaccines

�� Vaccines of assured qualityVaccines of assured quality

�� Written and measurement standards Written and measurement standards –– 40 years 40 years analysisanalysis

�� Basis for vaccine PQBasis for vaccine PQ

�� Development of new and revision of existing Development of new and revision of existing standardsstandards –– plan for 2011/2013plan for 2011/2013

�� SummarySummary

�� Way forwardWay forward

Source data Modified

WHO Biological Standardization WHO Biological Standardization

Global consensusGlobal consensus

Global written standardsGlobal written standards Global measurement standardsGlobal measurement standards

370 WHOmeasurementStandards

are available;define the IU

1) Standardization of assays

2) Development and refinement of

QC tests3) Scientific basis

for setting specifications

http://www.who.int/biologicals/en/

Evolving concept

67 WHOWritten Standards

Biological Standardization as Biological Standardization as constitutional responsibilityconstitutional responsibility

�� WHO is mandated by its Member States to WHO is mandated by its Member States to ""……develop, establish and promote develop, establish and promote international international standards for biological productsstandards for biological products""

�� Biological products for WHO cover vaccines, Biological products for WHO cover vaccines, biological therapeutics, blood products and biological therapeutics, blood products and selected in vitro diagnosticsselected in vitro diagnostics

�� Implemented by Expert Advisory Panel (EAP) and Implemented by Expert Advisory Panel (EAP) and Expert Committee on Biological Standardisation Expert Committee on Biological Standardisation (ECBS) (ECBS)

�� Served by secretariat in the Quality Safety & Served by secretariat in the Quality Safety & Standards (QSS) TeamStandards (QSS) Team

WHO Collaborating Centres for WHO Collaborating Centres for biological standardizationbiological standardization

�� NIBSC (all biologicals)NIBSC (all biologicals)�� CBER/FDA (all biologicals)CBER/FDA (all biologicals)�� PEI (blood products and related IVDs PEI (blood products and related IVDs –– expansion expansion to vaccines under consideration)to vaccines under consideration)

�� NIID, Japan (vaccines)NIID, Japan (vaccines)�� TGA (vaccines)TGA (vaccines)�� KFDA (Korea) KFDA (Korea) –– designated in 2011 (vaccines and designated in 2011 (vaccines and biotherapeutics)biotherapeutics)

�� Under consideration: BTGD (Canada); NICPBP Under consideration: BTGD (Canada); NICPBP (China); Thai NCL(China); Thai NCL

�� Strategic direction: synchronized approach for the Strategic direction: synchronized approach for the network of CCs for Biological Standardizationnetwork of CCs for Biological Standardization

WHO Written Standards for WHO Written Standards for VaccinesVaccines

�� Technical specifications that help define safe and Technical specifications that help define safe and efficacious vaccinesefficacious vaccines

�� Intended to be scientific and advisory in natureIntended to be scientific and advisory in nature

�� Basis forBasis for vaccine prequalificationvaccine prequalification

�� Guidance for NRAs and manufacturers on international Guidance for NRAs and manufacturers on international regulatory expectations for the regulatory expectations for the production and quality production and quality control of vaccines, noncontrol of vaccines, non--clinical and clinical evaluation of clinical and clinical evaluation of vaccinesvaccines

�� Facilitating international harmonization of vaccine licensure Facilitating international harmonization of vaccine licensure

�� Living documents revised in response to scientific advancesLiving documents revised in response to scientific advances

Scope: Recommendations to assure quality, safety and efficacy of pneumococcal conjugate vaccine (an example)

Development and endorsement of Development and endorsement of WHO written standardsWHO written standards

�� Drafting group meeting to initiate drafting (scope, structure, Drafting group meeting to initiate drafting (scope, structure, approach, and major scientific/technical issues)approach, and major scientific/technical issues)

�� Informal consultation (regulators, academicians, industry Informal consultation (regulators, academicians, industry experts)experts)

�� Web publication of a draft: call for comments (*new Web publication of a draft: call for comments (*new procedure since 2009)procedure since 2009)

�� Distribution to EAP and Member States as "BS document" to Distribution to EAP and Member States as "BS document" to obtain commentsobtain comments

�� ECBS review ECBS review -- discussion, revision, and decision (discussion, revision, and decision (--> report to > report to SAGE & Exec Board)SAGE & Exec Board)

�� Internal clearance (DGO approval)Internal clearance (DGO approval)�� Web publication of electronic document (final document Web publication of electronic document (final document

available)available)�� Editing & proofreadingEditing & proofreading�� Printing as Annex to WHO TRSPrinting as Annex to WHO TRS

World Health Organization GoalWorld Health Organization Goal

Definition Definition �� National Regulatory Authority (NRA) National Regulatory Authority (NRA) independently controls the quality of independently controls the quality of vaccines in accordance with the six vaccines in accordance with the six specified functions defined by WHOspecified functions defined by WHO

�� No unresolved confirmed reports of No unresolved confirmed reports of quality related problemsquality related problems

Guided by WHO Expert Guided by WHO Expert Committee on Biological Committee on Biological Standardization ECBS): Standardization ECBS): RecommendationsRecommendationsto assureto assure quality, quality, safetysafety and and efficacy efficacy of of vaccinesvaccines (WHO (WHO Technical Report Series Technical Report Series (TRS)(TRS)

Ensure that ““100%100%”” of vaccines used in all national immunization programmes are of assured quality

Written Standards Written Standards

Established/Revised for Vaccines Established/Revised for Vaccines

& Biologicals& Biologicals

No. of Written Standards for Vaccines & Biologicals

for 4 Decades (N=174)

35

56

4038

0

10

20

30

40

50

60

1971-1980 1981-1990 1991-2000 2001-2010

Ph

7%

V

72%

BL

8%

Bi

13%Count of Category

No. of Written Standards for Vaccines & Biologicals for 4 DecadNo. of Written Standards for Vaccines & Biologicals for 4 Decades (N=174):es (N=174):

Analysis by AreaAnalysis by Area

V, Vaccine; Bi, Biologicals; BL, Blood; Ph, Pharmaceuticals

6 7 8

1

3 22

7

37

11

29

39

27 31

0

10

20

30

40

50

60

1970s 1980s 1990s 2000s

V

Ph

BL

Bi

Count of Category

Decade

Category

No. of Written Standards for Vaccines & Biologicals for 4 DecadNo. of Written Standards for Vaccines & Biologicals for 4 Decades (N=174):es (N=174):

Trend Analysis by AreaTrend Analysis by Area

Living Written Standards for Vaccines & Biologicals Living Written Standards for Vaccines & Biologicals

(1948 (1948 –– present, N=67): Basis for Vaccine PQpresent, N=67): Basis for Vaccine PQ

0

5

10

15

20

25

30

35

40

45

50

Bi BL V VB VBPh

PQ

Other

Count of PQ

Category

PQ

Bi, Biotherapeutics other than blood; BL, Blood Products; V, Vaccine; VB, Vaccine+Biologicals; VBPh, Vaccine+Biologicals+Pharmaceuticals

WHO International WHO International

Biological Reference Biological Reference

Preparations (Preparations (IBRPsIBRPs):):

An analysis of 10An analysis of 10--year datayear data

Living Measurement Standards for Vaccines & Biologicals Living Measurement Standards for Vaccines & Biologicals

(1948 (1948 –– present, N=370)present, N=370)

Vaccines / Toxoids /

Toxins

16%

Cytokines, Growth

Factors Endocrine

24%

Blood Products

28%Others

32% Sum of Numbers

Blood

33%

Stability in-use

1%

Vaccine - serology

(Antibodies)

6%

CyGFEndo

20%

Antibiotics

1%Vaccine-related antigens

22%

All biologicals

3%

IVD

14%

Sum of Number

WHO International Biological Reference Preparations (WHO International Biological Reference Preparations (IBRPsIBRPs) )

Established in 2001Established in 2001--2010: Analysis for Proportion by Area2010: Analysis for Proportion by Area

Revision of written standards Revision of written standards –– current status and plan for 2011current status and plan for 2011--2013 2013 --

20112011

2012/2012/20132013

5. Dengue (TRS 932) 5. Dengue (TRS 932) 6. 6. BCG (TRS 745 and 771) BCG (TRS 745 and 771) 7. Acellular pertussis vaccine (TRS 878) 7. Acellular pertussis vaccine (TRS 878) 8. DTP vaccines (TRS 800)8. DTP vaccines (TRS 800)9. Combined vaccines based on DTP 9. Combined vaccines based on DTP –– newnew10. OPV (TRS 904 and 910)10. OPV (TRS 904 and 910)11. IPV (TRS 926)11. IPV (TRS 926)12. Malaria vaccine 12. Malaria vaccine –– newnew13. Risk assessment 13. Risk assessment -- newnew

201020101. Cell substrates (TRS 878) 1. Cell substrates (TRS 878) 2. Yellow Fever Vaccine (TRS 872) 2. Yellow Fever Vaccine (TRS 872) 3. Hepatitis B recombinant (TRS 786, 889)3. Hepatitis B recombinant (TRS 786, 889)4. Independent vaccine lot release (new)4. Independent vaccine lot release (new)

ECBSECBSRecommendations/ GuidelinesRecommendations/ Guidelines

Adopted

SummarySummary

�� Total no of living WHO Written Standards for vaccines Total no of living WHO Written Standards for vaccines and other biologicals is 67 as of 2010and other biologicals is 67 as of 2010

�� Development of Written Standards for vaccines has Development of Written Standards for vaccines has been major part of work, comprising 72% of total written been major part of work, comprising 72% of total written standards in the previous 4 decades. standards in the previous 4 decades.

�� 85% of them (57/67) have served as the basis for WHO 85% of them (57/67) have served as the basis for WHO prequalification of vaccinesprequalification of vaccines

�� Total no of living WHO Measurement Standards for Total no of living WHO Measurement Standards for vaccines and biologicals is 370 as of 2010.vaccines and biologicals is 370 as of 2010.

�� An analysis of the latest 10An analysis of the latest 10--year data on the year data on the establishment of Vaccineestablishment of Vaccine--related antigen preparations related antigen preparations comprise 22% (33 of N=152 2001comprise 22% (33 of N=152 2001--2010)2010)

Way forwardWay forward

�� Issues of importance for defining strategic Issues of importance for defining strategic direction for coming 10 years and beyond: direction for coming 10 years and beyond: �� Better way for measuring impact of WHO standards in Better way for measuring impact of WHO standards in

the regulation of vaccines the regulation of vaccines

�� More precise indicatorsMore precise indicators

�� Link with NRA strengthening Link with NRA strengthening

�� Use of WHO standards for vaccine PQUse of WHO standards for vaccine PQ

�� Scope of workScope of work•• Vaccines, some biotherapeutics, biologicals in generalVaccines, some biotherapeutics, biologicals in general

•• PrePre--normative, normative and postnormative, normative and post--normativenormative

�� Collaboration with other standard setting bodiesCollaboration with other standard setting bodies

�� Funding of vaccine standardization Funding of vaccine standardization

Many thanksMany thanks

�� To all collaborators who contributed to the To all collaborators who contributed to the

development of standardsdevelopment of standards

�� To my colleagues Jinho Shin, Christoph To my colleagues Jinho Shin, Christoph

Conrad and Sue Jenner for the analysis of Conrad and Sue Jenner for the analysis of

40 years data40 years data

�� Colleagues from PQ team Nora Dellepiane Colleagues from PQ team Nora Dellepiane

and Sergio Nishiokaand Sergio Nishioka