1. ECBS: Vaccines and Biotherapeutic products
EMP Technical Briefing Seminar
ECBS: Vaccines and Biotherapeutic products
Dr Ivana Knezevic TSN/EMP/HIS
WHO, Geneva, 5th November 2014

2. Outline Norms and standards for biologicals in the context of WHO
Strategic drivers and issues
WHO International Standards
- written (eg, Guidelines, Recommendations)
- measurement (Int. Standards and Reference Preparations)
ECBS 2014 – main outcomes
Biotherapeutic Products (BTP)
Similar Biotherapeutic Products (Biosimilars)
Collaborating Centers

3. World Health Organization (WHO)
WHO is a specialised agency of the UN serving as the directing and coordinating authority for international health matters and public health on behalf of its 194 Member States.
Principle objective - the attainment by all people of the highest possible level of health.
WHO is responsible for providing leadership on global health matters, shaping the health research agenda, setting norms and standards, articulating evidence-based policy options, providing technical support to countries and monitoring and assessing health trends.
Setting norms and standards and promoting their implementation is one of WHO core functions.

4. WHO Biological Standardization
WHO has played a key role for over 60 years in establishing the WHO Biological Reference Materials necessary to standardize biological materials as well as developing WHO guidelines and recommendations to assure the quality, safety, and efficacy of biological products.
These norms and standards, based on scientific consensus achieved through international consultations, assist WHO Member States in ensuring the quality and safety of biological medicines and related in vitro biological diagnostic tests worldwide.
The Organization accomplishes this biological standardization work through
its biological programme coordinated by a Secretariat at WHO HQ;
the WHO Expert Committee on Biological Standardization (ECBS) selected from an Expert Advisory Panel on Biological Standardization; and
WHO Collaborating Centres for Biological Standardization.

5. Key strategic drivers Global public health WHO context
Universal health coverage
Regulatory convergence
Regulatory science
WHO context
WHO reform
EMP reorganization
ICDRA 2014
New WHA resolutions
Scope of the ECBS

6. New Resolutions: BTP and RSS
New Resolution on biotherapeutic product (BTP)
Discussed at the 134th Executive Board meeting, Jan 2014: EB134.R19
Decision/adoption to be made: by 67th World Health Assembly in May 2014: WHA67.21
New Resolution on RSS (Regulatory System Strengthening)

7. 16th ICDRA recommendations
Feedback from ICDRA and pre-ICDRA meetings are two sources of additional information regarding the regulatory practices in WHO member states:
16th meeting of the International Conference of Drug Regulatory Authorities (ICDRA) – held in Rio de Janeiro, August 2014, hosted by ANVISA
ICDRA recommendations published at:
  ion2014_Vol28-3/en/
Selected topics of interest:
Strengthening regulatory systems for medicinal products
Biosimilars
Advanced therapies
Clinical trial regulation
Pre-ICDRA meeting on biosimilars – held on August 2014
Info doc

8. WHO norms and standards for biologicals
Global written standards
Global measurement
standards
Scientific evidence
Standardization of assays
Further development
and refinement of QC tests
3) Scientific basis for setting
specifications
Reference preparations for
vaccines and biotherapeutics
Measurement
standards:
essential elements for development, licensing
and lot release

9. Development of measurement standards for Vaccines, 2013 - 2016
1. Tetanus toxoid for flocculation assay (3rd IS)
2. Anti-Toxoplasma Serum, Human (2nd IS)
3. Typhoid Vi Polysaccharide (1st IS)
1. Trivalent inactivated polio vaccine (TIPV) for D antigen assay (3rd IS)
2013
2014
2015
2016 ?
1. Human serum anti-malaria Plasmodium falciparum (1st RR)
2. Haemophilus influenzae b polyribosylribitol phosphate polysaccharide (2nd IS)
1. Japanese Encephalitis Vaccine (1st IS)
2. Bordetella pertussis Toxin (2nd IS)
3. Rabies vaccines (7th IS)
4. Meningococcal serogroup X polysaccharide (1st IS)
5. Antibody to A (H7N9 Influenza virus (1st IS)

10. Development of measurement standards for biotherapeutics, 2013 - 2016
1. Etanercept (1st IS)
2. Human antibodies to EPO (1st monoclonal antibody reference panel)
1. TNF alpha, recombinant, non-glycosylated (3rd IS)
2. PEG G-CSF (1st IS)
2013
2014
2015
2016
1. Luteinizing Hormone, human pituitary (3rd IS)
2. Human proinsulin (1st IS)
1. Rituximab (1st RR)
2. Batroxobin (1st RR)
3. Biosynthetic human insulin (1st IS)

11. Guidelines/ recommendations under development/ revision
ECBS 2014
Recommendations for IPV vaccines
Regulatory evaluation of post-approval changes
Regulatory Risk Evaluation on Finding an Adventitious Agent in a Marketed Vaccine - Scientific Principles to Consider
ECBS 2015
GMP for biologicals
HPV
Regulatory Risk Assessment of Biotherapeutic Products
Regulatory expectations for CTC
ECBS 2016
Guidelines on clinical evaluation of vaccines
Guidelines on flu vaccines for non-producing countries

12. Timeline for WHO Written Standards:
Vaccines
2013
2014
2015
2016
Typhoid
NC of adjuvanted
IPV
Rev of TRS 926
Post-app. Changes
RRA for AAs
GMP
HPV
CTC
Clinical
Flu label – Pregnant
Flu – non-producing
Cell substrates
Others
STB LR
DTP
MAL LR
Informal consultation
ECBS submission
Implementation workshop

13. Timeline for WHO Written Standards:
Biotherapeutics
2014
2015
2016
2017
rDNA
RERA for BTP
SBP
Informal consultation
ECBS submission
Implementation workshop

14. Timeline for Written Standards Projects with unclear timeline/ format
Vaccines
Influenza vaccines for pregnant and lactating women
Safe production of IPV – revision of TRS 926
Meningitis B, Meningitis X
Vector based vaccines
RSV Hep E
Biotherapeutic Products
Amendment on Similar Biotherapeutic Products (SBP) - mab
Cell therapies/ Advanced therapies

15. Implementation of standards - tools
Implementation workshops:
Lectures on selected topics
Case studies
Work in groups of 6-8 participants where regulators and manufacturers discuss application of guiding principles to specific examples
Facilitators help clarifying the points needed for discussion and each group comes up with a conclusion and key arguments that support their opinion
In some cases, there is no consensus but options for proceeding further
Good learning opportunity but limited to certain number of workshop participants (eg participants)
Publications – meeting reports, case studies from implementation workshops
Special issue in Biologicals – Vaccine Stability and Similar Biotherapeutic Products
E-learning tools, Webinars

16. Implementation of standards – 2013-2016
General Topics
Stability Evaluation of Vaccines – 2013
Evaluation of Cell Substrates
Vaccine Lot Release
Post approval changes of vaccines
Specific issues related to Vaccines or Biotherapeutic Products
Selected vaccines with complex issues such as:
Evaluation of combined vaccines based on DTP – Indonesia, May, 2014
Typhoid conjugate vaccine – China, November, 2014
Malaria vaccine – South Africa, November, 2014
HPV
Evaluation of Biotherapeutic Products
Evaluation of SBP

17. Implementation of standards – case studies
Implementation workshops provide:
Good learning opportunity for participants
Among all materials, case studies were recognized as preferred format for illustrating application of WHO guiding principles
Publications:
Meeting report from implementation workshop on evaluation of combined vaccines based on DTP – available at
Case studies from implementation workshops on cell substrates – as an example
Adventitious agents in viral vaccines: Lessons learnt from 4 case studies (Biologicals 42 (2014) )
E-learning tools – to be developed for BTP, SBP, vaccine stability, cell substrates, vaccine lot release in ; other topics to be considered

23. Collaborating Centers
Recent designations:
NIFDC – Jan 2013
PEI – Aug 2013
Recent re-designations:
NIBSC – July 2013
NIID – Aug 2014
TGA – Aug 2014
Current status: 8 CCs for standardization and evaluation of vaccines
Additional expertise and broader experience available in CCs which has increased capacity for responding to expectations of the users of standards
Concept of global CC with technical support to various regional and inter-country networks of regulators
Information on WHO web site for biologicals – revision of the page for CCs to provide regular update on the activities of CCs

24. WHO Network of Collaborating Centers
1st meeting held in April 2012 – meeting report published in Biologicals 40 (2012),
2nd meeting of the CC network on vaccine standardization, March 2014 at PEI, Langen, Germany:
main issues discussed: 1) current ToR of individual CCs, 2) criteria for success of the CC network, 3) key areas where the network should focus its efforts and 4) priorities for coming years
good opportunity for CCs to understand current approach and needs of one global and several regional regulatory networks that WHO supports
agreed that the CC network should focus on standards, both written and measurement, as well as their practical application to support WHO initiative in promoting science based regulation of vaccines worldwide
all CCs confirmed commitment to help WHO to improve efficiency in responding to the needs of its member states. In particular, development of new vaccines was recognized as an area where the CC network can provide more valuable support than the individual CCs.
Consensus reached that the CC network will focus on the following:
Improve approaches to support implementation of WHO standards into regulatory practice
Improve the efficiency of the global standards setting process, and
Identify gaps in WHO standards and set regulatory science agenda to address gaps

25. Further information and contact
Biological standardization website:
Immunization website:
Contact details:
Dr Ivana Knezevic (