Influenza Vaccine Manufacturing Industry perspective for influenza vaccine supply VRBPAC, 27 February 2013 The FDA CBER requested this annual summary of information from influenza vaccine manufacturers supplying the U.S., for purposes of a general presentation to the VRBPAC. This summary has been prepared from a variety of public sources, and was reviewed by GSK, Sanofi-Pasteur, Novartis, CSL, and MedImmune. 1

Northern Hemisphere Influenza Vaccine Strain Changes Season Strain changes H1N1H3N2B  Two strain changes No strain change    Three strain changes     No strain change   2 VRBPAC, 27 February 2013

Influenza Vaccine Production Successful manufacturing campaign Timely strain recommendation by VRBPAC for the season: – Trivalent commercial vaccines should contain two new strains A/Victoria/361/2011 (H3N2)-like and B/Wisconsin/1/2010-like (Yamagata lineage) – Quadrivalent investigational vaccines should contain the additional B/Brisbane/60/2008-like strain (Victoria lineage) strain Challenges – Late identification of new H3N2 strain (late flu season, H3N2 strains increasingly difficult to isolate in eggs) – At the time of the 2012 VRBPAC meeting IIV manufacturers had not received the H3N2 Victoria IIV reassortant, and LAIV manufacturer had not received the wild- type strain for reassortant production Manufacturing seeds not available No opportuity to evaluate/optimize vaccine strain in manufacturing processes Manufacturing of 3rd strain started later than usual H3N2 antigen and calibrated reagents were available later than usual CBER commitment to providing reagents and transparency regarding timing of reagent availability facilitated planning of manufacturing activities VRBPAC, 27 February

Influenza Manufacturing Cycle 4 Produce Reassortants Select Vaccine Strain(s) WHO-FDA Produce & Standardize Reagents Annual License Approval Produce Working Seeds (3 strains) Manufacture Strain 1 Manufacture Strain 2 Manufacture Strain 3 Strain Balancing Formulation, Fill, Packaging of Trivalent Vaccine Distribution Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Influenza Vaccine Manufacturing Critical Factors Global timing of strain selection ensures large vaccine supply – Available time to manufacture influenza vaccine is determined by Need to distribute & administer vaccine before the peak season Availability of last vaccine strain – To ensure timely availability of influenza vaccine, manufacturing of one strain starts at risk before final strain composition is made – Productivity of the least productive monovalent strain determines supply quantity Availability of Potency Test Reagents – Complex process to prepare and standardize potency reagents for new strains – Linked to global timing of strain selection for new strains – Availability of calibrated reagents determines start of influenza vaccine formulation 5 VRBPAC, 27 February 2013

Examples of Vaccine Strains under Consideration/Evaluation for NH Vaccine H1N1: A/California/7/2009-like – *A/California/7/2009 and reassortants (IIV and LAIV) – A/Christchurch/16/2010 and reassortants (IIV) H3N2: *A/Victoria/361/2011-like – A/Texas/50/2012 and reassortants (IIV and LAIV) 6 VRBPAC, 27 February 2013 * Indicates most recent H1N1pdm and H3N2 vaccine strains

Examples of Vaccine Strains under Consideration/Evaluation for NH Vaccine B Yamagata lineage: – B/Massachusetts/2/2012 and reassortants (IIV and LAIV) B Victoria lineage (for quadrivalent vaccines): – * B/Brisbane/60/2008 and reassortants (IIV and LAIV) – B/Nevada/3/2011 and reassortants (IIV and LAIV) – B/Hong Kong/259/2010 and reassortants (IIV) 7 VRBPAC, 27 February 2013 *Indicates most recent Victoria lineage vaccine strain

Influenza Manufacturing Cycle 8 Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Produce Reassortants Select Vaccine Strain(s) WHO-FDA Produce & Standardize Reagents Annual License Approval Produce Working Seeds (3 strains) Manufacture Strain 1 Manufacture Strain 2 Manufacture Strain 3 Strain Balancing Formulation, Fill, Packaging of Trivalent Vaccine Distribution

Shared Responsibility of Public and Private Sectors Timely communication of surveillance data and new candidate viruses Timely selection of vaccine strains, considering antigenic match and growth potential Early access of all reassortant labs (NYMC, NIBSC, CSL, MedImmune, others) to wild- type viruses for reassortant production – Opportunity for manufacturers to evaluate growth potential of candidate strains – Time for CDC to certify antigenic properties of new candidate strains Availability of potency test reagents for new strains by May/June Timely approval of Annual License Supplement Lot review and release Collaboration on key initiatives (e.g., improved SRID assay, alternative potency assays, cell culture isolates, synthetic seeds) Information sharing during telephone conferences, chaired by ERL or WHO, between WHO CCs, ERLs, reassortant producers and manufacturers has been key in challenging situations (e.g. 3 strain changes in one season) 9 VRBPAC, 27 February 2013