WHO Technical Specifications and Pre-Qualification

1. WHO Technical Specifications and Pre-Qualification UNICEF Vaccine Pre-Tender 2010-2012 Copenhagen Denmark 10 December 2008 Dr. Nora Dellepiane, Scientist WHO/IVB/QSS Carmen Rodriguez, Scientist WHO/IVB/QSS 10 December 2008

2. Outline of presentation • Introduction • UN tender specifications and WHO recommendations • Changing landscape • WHO approaches to address challenges • Head-ups on Scientific Opinion and Expedited Review Procedures • Challenges faced with novel vaccines • Main shortcomings and proposed solutions • Last comments

3. Purpose of WHO prequalification • A service provided to UN purchasing agencies. • Provide Independent opinion/ advice on the quality, safety and efficacy of vaccines for purchase • Ensure that candidate vaccines are suitable for the target population and meet the needs of the programme • Ensure continuing compliance with specifications and established standards of quality

4. Status of WHO prequalified vaccines 12 industrialized country mfrs 6 developing country mfrs 21 manufacturers 82 pre-qualified vaccines used in 112 countries 53% total population

5. Principles GMP Clinical data Consistency of final product characteristics Consistency of final product characteristics Meeting WHO requirements and tender specs Reliance on NRA

6. Conditions for PQ evaluation • NRA of record fully functional • Vaccine is licensed by the responsible NRA (Scientific opinion by EMEA accepted) • WHO guidelines/recommendations available • Listed in the vaccine priority list (low priority vaccines may be postponed)

7. Conditions for prequalification Ongoing oversight and commitments by the NRA Inspections at regular Intervals. Inform WHO of serious GMP deviations Lot to lot release Post-marketing surveillance for safety and efficacy Inform WHO in case of reports of serious AEFI Inform WHO in case of withdrawals or recalls of lots and license suspensions

8. Conditions for PQ evaluation Commitments from the manufacturer Inform of WHO of problems that may impact the quality, safety, efficacy or timely supply of product Report variations to WHO Communicating with WHO Report serious AEFI Provide regular updates Of safety profile

9. Specific aspects considered • General understanding of production process and quality control methods • Clinical data relevant for the target population in the recommended schedules • Production consistency at commercial scale (assessed by testing of samples of final product) • Compliance with GMP • Compliance with WHO recommendations and UN tender specifications including labels and inserts • Programmatically suitable presentation

10. Technical WHO recommendations Good Manufacturing Practices • Good Manufacturing Practices for Biological Products (WHO Technical Report Series No. 822, 1992) and Guideline for National Authorities on Quality Assurance for Biological Products (WHO Technical Report Series No. 822, 1992). • Good Manufacturing Practices for pharmaceutical manufacturers (WHO Technical Report Series No. 823, 1992). • WHO Good Manufacturing Practices: Main principles for pharmaceutical products (WHO Technical Report Series No. 908, 2003). Regulation and licensing • Regulation and licensing of biological products in countries with newly developing Regulatory Authorities (WHO Technical Report Series No. 858, 1995) • Guidelines for national authorities on quality assurance for biological products; (WHO Technical Report Series No. No 822, 1992)

11. Technical WHO recommendations • General Requirements for the Sterility of Biological Substances (WHO Technical Report Series No. 530. 1973), Amendment 1995 (WHO Technical Report Series No. 872, 1998) • Requirements for the use of animal cells as in vitro substrates for the production of biologicals (WHO Technical Report Series No. 878, 1998) • Report of a WHO Consultation on Medicinal and other Products in relation to Human and Animal Transmissible Spongiform Encephalopaties. WHO/BLG/97.2 • Recommendations on risk of transmitting animal spongiform encephalopathy agents via medicinal products (WHO Technical Report Series No. 908, 2003) • Guidelines on regulatory expectations related to the elimination, reduction or replace of thiomersal in vaccines, (WHO Technical Report Series No. 926, 2004) • Guidelines on stability evaluation of vaccines (WHO/BS/06.2049 2006)

12. Technical WHO recommendations Clinical • Guidelines on clinical evaluation of vaccines: regulatory expectations(WHO Technical Report Series No. TRS 924, 2004) Non clinical • WHO guidelines on nonclinical evaluation of vaccines (WHO Technical Report Series No. 927, 2005)

13. Technical WHO recommendations • Revised requirements for dried BCG vaccine (revised 1985) (WHO Technical Report Series No. 745, 1987), Amendment 1987 (WHO Technical Report Series No. 771, 1988) • Requirements for Diphtheria, Tetanus, Pertussis, and Combined vaccines (Revised 1989) (WHO Technical Report Series No. 800, 1990) Amendment 2003 WHO Technical Report Series, No. 927, 2005) • Recommendations for whole cell pertussis vaccine (WHO Technical Report Series No. 941, 2007) • Requirements for Haemophilus Type B conjugate vaccine (WHO Technical Report Series No. 814, 1991). Revision, 1998 Recommendations (WHO Technical Report Series No. 897, 2000).

14. Technical WHO recommendations • Revised requirements for Hepatitis B vaccine made by recombinant DNA techniques (WHO Technical Report Series No. 786, 1989). Amendment (WHO Technical Report Series No. 889, 1999) • Biological products prepared by recombinant DNA technology (WHO Technical Report Series No. 814, 1991) • Revised requirements for Hepatitis B vaccine prepared from plasma. Revised 1987 (WHO Technical Report Series No. 771, 1988). Amendment (WHO Technical Report Series No. 858, 1995) • Requirements for Measles, mumps and rubella vaccines and combined vaccines, freeze dried (Live) (WHO Technical Report Series No. 840, 1994) (WHO Technical Report Series No. 848, 1994) • Requirements for Yellow Fever vaccine (WHO Technical Report Series No. 872, 1998)

15. Technical WHO recommendations • Requirements for Meningococcal Polysaccharide vaccine (WHO Technical Report Series No. 594, 1975) Amendment (WHO Technical Report Series No. 658, 1980), Amendment (WHO Technical Report Series No. 904, 2002) • Recommendations for the production and control of Meningococcal group C conjugate vaccines, (WHO Technical Report Series No. 924, 2004) Amendment (WHO Technical Report Series No. 926, 2004) • Recommendations to assure the quality, safety and efficacy of Group A Meningococcal Conjugate vaccines WHO/BS/06.2041-2006) • Recommendations for the production and control of pneumococcal conjugate vaccines WHO Technical Report Series, No. 927, 2005)

16. Technical WHO recommendations • Guidelines to assure the Quality, safety and efficacy of recombinant Human Papillomavirus virus-like particle vaccines, WHO/BS/06.2050, 2006 • Guidelines to assure the quality, safety and efficacy of live attenuated rotavirus vaccines (oral) (WHO Technical Report Series No. 941, 2007)

17. Shipping Guidelines • Guidelines on the international packaging and shipping of vaccines WHO/IVB/05.23 • International shipping guidelines to be revised in 2009 with a target to publish the revised version in Q3. • WHO-UNICEF policy statement on the use of vaccine vial monitors in immunization services • VVM PQS performance specification WHO/PQS/E06/IN05.1

18. Model inserts • Traditional vaccines: No changes foreseen • Novel vaccines: Model inserts under preparation

19. PREQUALIFICATION STEPS • Scientific review of quality dossier • Testing of samples • Consultation with responsible NRA • Site visit to manufacturing facilities • Scientific review of clinical data http://www.who.int/immunization_standards/vaccine_quality/pq_suppliers/en/index.html

20. Changing landscape(Partners perspective) GAVI- expanding vaccine portfolio (support for 7 new vaccines) Efforts made to accelerate introduction of underutilized vaccines Efforts made to increase coverage to achieve measles elimination/control goal Increased demand for concerned vaccines Expectations of expanding PQ portfolio and of accelerating (fast tracking) prequalification procedure

21. Changing landscape(Manufactures & respective NRAs perspective) Challenge for producers to ensure adequate/std processes and procedures across sites Challenging Regulatory Pathways New partnerships to produce combination and novel vaccines (multiple sites) Demonstration/assessment of quality, safety and efficacy is challenging, in addition assessment of programmatic suitability is a challenge No "One size fits all" possible Sophisticated technologies, issues with consistency, presentation, stability, other? PMS monitoring for safety and efficacy is an issue Since they are novel, no performance experience May not be licensed in country of origin or licensed for export purposes only Some novel vaccines not required in country of origin NRA in country of origin may not have required expertise, enough human resources challenging testing methods Additional expertise and resources required for their regulation

22. Changing landscape(User countries perspective) Direct procuring countries purchasing such vaccines may find their regulation quite challenging New partnerships to produce combination and novel vaccines (multiple sites) Product profile may not be fully suitable to the conditions of the country and represent a challenge for introduction Sophisticated technologies, issues with consistency, presentation, stability, other? PMS monitoring for safety and efficacy is an issue Since they are novel, no performance experience If not licensed in country of origin or licensed only for export, importing country may not be able to license Some novel vaccines not required in country of origin Licensing novel vaccines may be challenging, lack of expertise and the required resources Additional expertise and resources required for their regulation

23. WHO approach: regulatory oversight MAA PMS Regulatory inspections Licensure For export Country of origin NRA Manufacturer Lot release certificate Art. 58 Lot release certificate Documentation samples MAA thru WHO Expedited procedure Receiving country PMS WHO Sentinel Network

24. What is the CHMP Scientific Opinion procedure (Art. 58) • It is an opinion issued by the CHMP, the scientific committee of the EMEA, in collaboration with the WHO. This opinion is based on the evaluation of an application containing data on the quality, safety and efficacy of the product, and concludes on the benefit-risk of the product

25. What is the CHMP Scientific Opinion procedure (Art. 58) • It is a procedure applicable exclusively to products (vaccines and other medicines) designated as "eligible" by WHO • WHO "eligibility" for vaccine products applies to vaccines to be used in the Expanded Programme on Immunization for protection against a WHO public health priority disease • Applicants or their contact points must be established in the EEA (Member State of the EU , Norway, Iceland or Liechtenstein) • Procedure mimics the EMEA centralized procedure for MA

26. Two important features • WHO observers and representatives from NRAs from target countries take part in the procedure • The assessment of clinical data takes into consideration the target population and the epidemiology in target countries Concluding remarks: CHMP has established a procedure that is of the same standard as the centralized procedure for registration of medicines in Europe, which has the additional benefit of taking into consideration suitability of data for target population Prequalification process can be streamlined

27. Procedure for expedited review of PQd vaccinesSCOPE AND CONDITIONS • Intended for countries that source their vaccines through UN agencies, or that use the WHO prequalification as a basis for selection of vaccines for purchase • Guidance on how NRAs of such countries can expedite the regulatory review for such products. • Applies to vaccines used in National Immunization Programmes • Not intended to affect post-approval activities in these countries • For adoption, national regulations must contain provisions to allow to shorten the normal regulatory approval process. Details of the "Procedure for expedited review of imported prequalified vaccines for use in national immunization programmes. WHO/IVB/07.08 at http://www.who.int/immunization_standards/vaccine_quality/pq_suppliers/en/index.html

28. Novel vaccines- Challenges for evaluation by WHO (1) • Need to ensure that adequate regulatory pathway is in place, that product is licensed or licensable, continuous regulatory oversight in place • Need to ensure supply through existence of long term agreement • Need to assess quality • Adequacy of production process • Adequacy of quality control methods and specifications • Stability data • Transferability of testing methods to NCL and independent labs • Consistency of production • GMP compliance, adequate Quality Management System in place

29. Novel vaccines- Challenges for evaluation by WHO (2) • Need to assess suitability of clinical data • Adequacy of available clinical trial protocols and data • Relevance of existing data for target population and immunization schedules • Co-administration with other EPI vaccines or other interventions • Immunization schedules, route of administration, etc • Inter-changeability with other brands of same vaccine • Safety profile. Phase IV studies may be required, strong pharmaco-vigilance system in place crucial. • Indications, labelling and inserts

30. Novel vaccines- Challenges for evaluation by WHO (3) • Need to assess programmatic suitability • Tender specifications met • Adequacy of presentation • Cold chain requirements, stability profile • Temperature indicators: VVMs, data loggers for shipment, etc

31. Main shortcomings and solutions Testing methodologies not always available in independent labs Need to start transfer of methods at the beginning of evaluation or before this is started Meetings with manufacturers ahead of submission and during evaluation highly recommended

32. Main shortcomings and solutions Available clinical information not always sufficient/adequate For combination vaccines all existing clinical info for the same antigens in different products taken as supportive evidence, this is not applicable to novel products Meetings with manufacturers highly recommended

33. Main shortcomings and solutions Some novel products do not fully meet the programmatic needs but are still considered useful for countries in absence of the ideal alternative Recommended for use rather than prequalified Increased demand for evaluation Acceleration of introduction Some products are not "mature" at time of submission. Submission In parallel with licensure has not been successful Target timelines for evaluation established Need for clinical protocols/data at time of submission

34. Last comments Need to revise multidose vial policy. Need for solution for small multidose vials without preservative Ongoing, will take time Interim solution, Add thiomersal Addition of text on labels, boxes and inserts (not encouraged) + training + VVM on cap + colour? New webpage under development Thanks to all manufacturers for information provided Publication of basis for PQ (WHO PARs) under consideration Addressing information issue Web list Advocacy with partners, NGOs and receiving countries NRAs

35. Dr. Nora Dellepiane, Scientist WHO/IVB/QSS dellepianen@who.int • Ms Carmen Rodriguez, Scientist WHO/IVB/QSS rodriguezhernandezc@who.int