Target Product Profile and technical requirements Pre-tender Meeting Pneumococcal Vaccines under the AMC Unicef Supply Division, Copenhagen 26 August 2009 Dr. Nora Dellepiane, Scientist Quality Safety and Standards Department of Immunization, Vaccines and Biologicals The thirteen attributes for AMC eligibility A. Vaccine serotypes H. Product presentation B. Immunogenicity I. Product formulation C. Target population/ target age groups J. Storage and cold chain requirements D. Safety, reactogenicity and contraindications K. Packaging and labelling E. Vaccine dosage schedules L. Product registration and prequalification F. Interference and co-administration M. Post Marketing Surveillance G. Route of administration 2 PRODUCT CHARACTERISTICS Attribute Minimally Acceptable Profile A. Vaccine serotypes The serotypes in the vaccine formulation must cover at least 60% of the invasive disease isolates in the target region, and must include serotypes 1, 5 and 14 which are the most frequent isolates in GAVI eligible countries. Serotypes 1 and 5: most common and epidemic-prone types in regions relevant to GAVI particularly Asia and Africa Serotype 14: most common serotype in children under 5 in all regions 60% coverage: balance between public health benefit and likelihood of success in developing pneumococcal vaccines for the GAVI market. A formulation covering 60% of invasive disease possible with only 6 serotypes. Less number of serotypes less complexity of the vaccine. 3 PRODUCT CHARACTERISTICS Attribute Minimally acceptable profile B. Immunogenicity Immunogenicity should be demonstrated in accordance with WHO criteria, which are based on non-inferiority to a licensed pneumococcal vaccine as outlined in WHO Recommendations for the production and control of pneumococcal conjugate vaccines. (WHO Technical Report Series, No 927, 2005 and any subsequent published guidance). The threshold antibody concentration for invasive disease is 0.35mg/ml (ELISA). Antibody titres of 0.20– 0.35mg/ml correlate well with opsonophagocytic antibody titre of 1:8, which correlates well with protective efficacy. 4 PRODUCT CHARACTERISTICS Attribute Minimally acceptable profile C. Target population/ The vaccine must be designed to prevent disease among children <5 target age groups years of age and in particularly be effective in those < 2 years of age. Pneumococcal disease rates are highest in children <5 years of age and in the elderly and in developing countries. (US 96/100,000 children <5 years before vaccine introduction vs estimated incidence in Kenya of 597/100,000 children <5 years of age per year). Pneumococcal conj vaccines maximal public health impact for disease prevention in children <5 years of age particularly in those < 2 years of age. 5 PRODUCT CHARACTERISTICS Attribute Minimally acceptable profile D. Safety, reactogenicity and contraindications The safety and reactogenicity profile should be comparable to, or better than that of the currently licensed pneumococcal conjugate vaccine. Contra-indications should be restricted to known hypersensitivity to any of the vaccine components. The WHO Global Advisory Committee on Vaccine Safety (GACVS) recently reviewed the current evidence on the safety of PCV7 and other pneumococcal conjugate vaccines and found it reassuring. Monitoring of unexpected effects after introduction in the target population remains critical. Since developing countries have a high prevalence of malnutrition and LBW infants, studies in those populations are important. 6 PRODUCT CHARACTERISTICS Attribute Minimally acceptable profile E. Vaccine dosage schedules Vaccine scheduling must be compatible with national infant immunization programmes and consist of not more than 3 doses in the first year of life. The first dose must be shown to be administrable at 6 weeks of life or earlier. The possibility of alternative schedules (e.g. two or less infant doses and a later dose at 912 months) should also be explored. Information on the need for booster doses may be desirable in the future to answer questions on herd immunity effects and persistence of protection. Data on immunogenicity of a single dose in older children is worth seeking. 7 PRODUCT CHARACTERISTICS 8 Attribute Minimally acceptable profile F. Interference and co-administration with other vaccines There should be no clinically significant interaction or interference in relation to safety and immunogenicity with concurrently administered vaccines. PRODUCT CHARACTERISTICS Attribute Minimally acceptable profile G. Route of administration Intramuscular or subcutaneous. Vaccine developers are encouraged to explore other routes of administration (intra/trans dermal, intranasal, aerosol, etc . 9 PRODUCT CHARACTERISTICS Attribute Minimally acceptable profile H. Product presentation The vaccine must be available in mono-dose or low multi-dose presentations. Mono-doses must be either in single dose vial or in autodisable compact pre-filled device. Low multi-dose presentations must be formulated and labelled in compliance with WHO policy or guidance. The preferred presentation for WHO is a monodose in vial or prefilled autodisable syringe or low multidose vial with preservative. If a low multi-dose vaccine contains no preservative, it needs to be discarded at the end of the immunization session, and at latest 6 hours after the vial has been opened. To distinguish such products from those containing preservative, specific labeling of the vial and training at field level will be required. WHO is currently revising its policy on the use of opened multi-dose vials (The use of opened multi-dose vials of vaccine in subsequent immunization sessions, WHO/V&B/00.09). A final position on acceptability of such presentations will be available shortly. 10 PRODUCT CHARACTERISTICS 11 Attribute Minimally acceptable profile I. Product formulation Liquid formulation with a standard volume of 0.5 ml/dose PRODUCT CHARACTERISTICS Attribute Minimally acceptable profile J. Storage and cold chain requirements The product must be stable at 2-8°C with a shelf-life of at least 24 months and a vaccine vial monitor should be attached as outlined in Making use of vaccine vial monitors. Flexible vaccine management for polio (WHO/V&B/00.14). Vaccines with increased shelf life and thermostability are desirable because they permit more flexible use of the vaccine and ideally, new vaccines would not need a cold chain. 12 PRODUCT CHARACTERISTICS 13 Attribute Minimally acceptable profile K. Packaging and labelling Name and labelling must be in accordance with WHO Recommendations for the production and control of pneumococcal conjugate vaccines. (WHO Technical Report Series, No 927, 2005). Packaging must ensure minimal storage space requirements as set out in Guidelines on the international packaging and shipping of vaccines (WHO/IVB/05.23). PRODUCT CHARACTERISTICS Attribute Minimally acceptable profile L. Product registration and prequalification The product must be WHO pre-qualified in accordance with Procedures for assessing the acceptability, in principle, of vaccines for purchase by United Nations agencies (WHO/IVB/05.19). A pre-requisite to prequalification is the licensure or Marketing Authorization by the responsible NRA or NRA of record, usually that of country of origin. For registration for the vaccine in user countries, WHO has developed guidelines on how to expedite registration of a pre-qualified vaccine (see Procedure for expedited review of imported prequalified vaccines for use in national immunization programmes (WHO/IVB/07.08)). 14 PRODUCT CHARACTERISTICS Attribute Minimally acceptable profile M. Post Marketing Surveillance Post-marketing surveillance should be conducted in accordance with national regulatory authorities and WHO prequalification requirements as set out in Guideline for preparation of the product summary file for vaccine prequalification (WHO/IVB/06.16) , Guidelines on clinical evaluation of vaccines: regulatory expectations (WHO Technical Report Series, No 924, 2004) and any relevant published guidance. Monitoring through PMS for safety, effectiveness in target population, herd immunity and potential serotype replacement following widespread use of the vaccine is critical. WHO has established a Post-Marketing Surveillance Network of 10 countries worldwide to monitor the safety of newly introduced vaccines. Individual countries need to continue efforts to strengthen their systems. For countries wishing to introduce low multidose vaccines without preservative the ability to detect AEFI should be extremely high because of the risks related with product contamination. Further strengthening of monitoring systems will require support from manufacturers, WHO and other partners 15 WHO PQ and AMC requirements Attribute WHO prequal Meet Meet TPP compliance Not meet Meet C. Target population/ target age groups Meet Meet D. Safety, reactogenicity and contraindications Meet Meet E. Vaccine dosage schedules Meet Meet Meet Meet A. Vaccine serotypes B. Immunogenicity F. Interference and coadministration with other vaccines 17 WHO PQ and AMC requirements Attribute WHO prequal Meet TPP compliance Not Meet H. Product presentation Meet Meet I. Formulation Meet Meet Not Meet Meet K. Packaging and labelling Meet Meet L. Product registration and prequalification Meet Meet M. Post Marketing Surveillance Meet Meet G. Route of administration J. Storage and cold chain requirements 18 Conditions for prequalification During the PQ evaluation, WHO will review all quality, safety and efficacy related data including the 13 attributes required by the AMC WHO will also review compliance with the UNICEF tender specifications When the process is completed, WHO will provide outcome of evaluation to GAVI in a report on the basis of each of the 13 attributes and any other relevant reasons (New procedure) WHO will provide a letter to UN indicating whether the vaccine is acceptable, in principle, for purchase by UN agencies or not as per normal practice The IAC will independently review the following attributes: – Vaccine serotypes – Target population/Target age groups – Product formulation – Dosage Schedule – Route of Administration On the basis of the WHO report plus their own assessment of the attributes above, the IAC will determine whether the product meets or not the TPP 19 Conditions for prequalification Tender specifications Compliance with – Good Manufacturing Practices TRS, 822, 823, 902 (Annexes 5 and 6), 908 (Annex 4) and 929 (Annexes 2 and 3) – General Requirements for Sterility of Biological Substances TRS 530 AND 872 – Recommendations on risk of TSE. TRS 908 – Regulatory expectations related to E/R/R of thiomersal in vaccines TRS 924 – Guidelines on stability evaluation of vaccines WHO/BS/06.2049 – Guidelines on clinical evaluation of vaccines TRS 924 – Guidelines on non-clinical evaluation of vaccines TRS 927 – Recommendations for production and control of pneumococcal conjugate vaccines TRS 927 20 Conditions for prequalification Tender specifications Changes in production method, formulation, equipment, facilities, etc, requiring approval from NRA should be communicated to WHO within one month of approval. If change does not require approval, WHO should be consulted in timely manner before changes are introduced. Primary container labels and diluent containers should be the same as agreed by WHO during the PQ process or as revised and approved by WHO. Affixed with water resistant adhesive. Adsorbed vaccines shall have the warning "DO NOT FREEZE" Package insert as approved by WHO during PQ process or as revised and approved printed in English, French, Portuguese and Russian. Closures should conform ISO standards 8362-2 to 7 Vaccine lots shall be subject to release by the NRA of record. 50 samples per lot to be retained for testing purposes 21 Conditions for prequalification Tender specifications Problems in production, control or release must be communicated to UNICEF and WHO/QSS in timely manner Supplier shall inform UNICEF and WHO/QSS of any serious issues regarding vaccine safety and provide information sufficient to consider such issues. UNICEF and WHO will rapidly notify the supplier in case of serious adverse events Supplier shall promptly notify WHO/QSS and UNICEF in case of recall or withdrawal of vaccine or any field alert regarding the vaccine Supplier shall permit access to UNICEF and WHO or its representatives to the manufacturing facilities to assess/reassess the vaccines Supplier shall comply with VVM labelling and WHO prequalified data loggers included in shipments. Remaining shelf life for pneumo vaccine should not be less than 20 months 22 at time of shipment.