1. Influenza Vaccine Manufacturing Industry perspective for 2012-2013 influenza vaccine supply VRBPAC, 28 February 2012 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

2. 2011-2012 Influenza Vaccine Production Successful manufacturing campaign On February 25th, 2011, VRBPAC recommended that vaccines to be used in the 2011-2012 influenza season in the U.S. contain the same virus strains that were used for the 2010-2011 influenza season – Vaccine strains and reagents readily available Challenges – Inconsistent potency values for some manufacturers when using reagents from different sources – Moderate yields of the H3 component VRBPAC, 28 February 2012 2

3. Influenza vaccine strain changes SeasonStrain changes H1N1H3N2B 2011-2012No strain change 2010-2011 2009-2010  2008-2009  Three strain changes 2007-2008  2006-2007 2005-2006  2004-2005 2003-2004No strain change 2002-2003  2001-2002  3

4. Influenza Vaccine Manufacturing Cycle 4

5. Influenza Vaccine Manufacturing Critical Factors Global timing of strain selection – Available time to manufacture influenza vaccine is determined by distribution & administration 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 confirmed – 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 VRBPAC, 28 February 2012 5

6. Examples of Vaccine Strains under Consideration/Evaluation for 2012-2013 NH Vaccine Manufacture H1N1: an A/California/7/2009-like strain – A/California/7/2009 X-179A – A/California/7/2009, NYMC X-181 – A/Christchurch/16/2010, NIB-74 – A/Brisbane/10/2010 (LAIV) – A/California/7/2009 (LAIV) H3N2: an A/Victoria/361/2011-like strain – A/Victoria/361/2011 IVR-165 – A/Rhode Island/1/2010 (LAIV) 6 VRBPAC, 28 February 2012

7. Examples of Vaccine Strains under Consideration/Evaluation for 2012-2013 NH Vaccine Manufacture B/Yamagata lineage: a B/Wisconsin/1/2010-like strain – B/Wisconsin/1/2010 (TIV, LAIV) – B/Wisconsin/1/2010 BX-41 – B/Hubei-Wujiagang/158/2009 – B/Hubei-Wujiagang/158/2009 BX-39 – B/Stockholm/12/2011 – B/Texas/6/2011 7 VRBPAC, 28 February 2012

8. Influenza Vaccine Manufacturing Cycle 8

9. Vaccine strains under Consideration/Evaluation for 2012-2013 NH Vaccine Manufacture Some manufacturers are developing a quadrivalent Influenza Vaccine that includes a strain of the B/Victoria and B/Yamagata lineage In 2011, a new reference strain, B/Wisconsin/1/2010, was identified for the B/Yamagata lineage – New reference strain not included in the vaccine – Vaccine candidate strains were prepared, including reassortant strain B/Hubei- Wujiagang/158/2009 NYMC BX-39 – A reassortant strain of B/Hubei-Wujiagang/158/2009 was also prepared for LAIV – SRID reagents for B/Hubei-Wujiangang/158/2009 BX-39 were prepared by CBER in support of clinical development In 2012, B/Brisbane/60/2008 remains the reference strain for the B/Victoria lineage VRBPAC, 28 February 2012 9

10. Shared Responsibility of Public and Private Sector is Necessary for Successful Influenza Vaccine Production and Supply Timely communication of surveillance data and new candidate viruses Timely selection of appropriate virus strains, considering antigenic match as well as growth potential Early availability of wild-type viruses for reassortant production – Access of reassortant labs (NYMC, NIBSC, CSL, MedImmune, others) to wild-type strains has been a rate-limiting step – Opportunity for manufacturers to evaluate growth potential of candidate strains Availability of potency test reagents for new strains by May/June Timely approval of Annual License Supplement Lot review and release process in-season 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) 10 VRBPAC, 28 February 2012

11. RecipientPurposeTotal New York Medical College Development of high growth reassortants Isolation of seasonal influenza viruses in eggs For 2011: estimated US$ 2.05 million (1,893,934 Swiss Francs) WHO Essential Regulatory Lab - NIBSC WHO Influenza CC - Australia WHO Influenza CC – CDC Atlanta WHO Influenza CC – NIMR London Note: CSL also contributes as an independently funded reassortant laboratory Financial contributions to GISRS made by IFPMA IVS members

12. Industry contributes to improving number of quality isolates for development of candidate vaccine viruses Significant financial and technical contributions to improve the number of quality isolates for development of candidate vaccine viruses Providing feedback on growth characteristics of candidate strains Collaborating on initiatives in key areas such as synthetic seeds, FCC isolates and alternative assays for potency Continuing to be engaged in collaborative projects to improve all aspects of Influenza manufacturing