1. Influenza Vaccine Manufacturing Industry Perspective Tony Colegate Novartis Vaccines and Diagnostics Prepared by PhRMA Vaccine Technical Committee for presentation to VRBPAC Meeting 21 February 2008

2. Influenza Vaccine Manufacturing – Critical Factors Growth potential of seed virus –The quantity of trivalent influenza vaccine that can be produced is limited by the least productive monovalent strain Timing of strain selection –Available production time is limited due to necessity of distributing and administering vaccine prior to influenza season –Working seeds require at least 4 weeks (from receipt of seed candidate) for development prior to use in large-scale manufacturing Potency test reagents –Required to determine the potency of monovalent components prior to formulation of trivalent vaccine (SRID) –Must be produced/standardized for new strains Timing of Annual License Supplement Approval –Product release

3. Influenza Vaccine Manufacturing Model Timeline Jan Dec 2006Nov 2007 FebMarAprMayJunJulAugSepOct Manufacture Strain 1Manufacture Strain 2 Distribute VaccineStrain Balancing Produce & Standardize Potency Reagents Annual License Approval Formulate Bulk Trivalent Vaccine Fill & Package Manufacture Strain 3 Produce Working Seed Produce Reassortant

4. Current Manufacturing Status Production of monovalent strain(s) is underway –Production initiated “at risk of the strain(s) not being selected” for 2008 – 2009 Northern Hemisphere Influenza Vaccine to ensure sufficient vaccine supply. –Based on the publicly available surveillance information, manufacturers have chosen to produce the A/H1N1 A/Solomon Islands/3/2006 and/or B/Florida/4/2006-like strain(s) at-risk. –However WHO have not recommended A/Solomon Islands/3/2006 for the 2008 – 2009 season. –Three new strains for 2008 – 2009 Northern Hemisphere Influenza season is unprecedented for Northern Hemisphere in the last 20 years and will make it a very challenging year.

5. Evaluation of potential new strains H1N1 IVR 148 A/Brisbane/59/2007 received by most manufacturers only recently and is currently still under evaluation. Hy A/South Dakota/06/2007, NYMC X-173, X-173A, X-173B and X-173C shipped to manufacturers Monday & Tuesday this week. B strains Both B/Florida/4/06 and B/Brisbane/3/07 were used in production for the Southern Hemisphere. Other viruses recently provided by CDC/NIBSC - B/Bangladesh/3333/2007, B/Delaware/01/2007 and B/Pennsylvania/7/2007 do not appear to offer any yield advantage." H3N2 IVR 147 A/Brisbane/10/2007 is not a viable candidate for NH production due to low yield demonstrated during Southern Hemisphere production. X 171B A/Brisbane/10/2007 gives acceptable yield but has A198DEL –Additional serological studies taking place at CDC. A/Uruguay/716/2007 –CSL, NIBSC and NYMC all have promising reassortants in progress. »NYMC due to ship 25 & 26 February »CSL & NIBSC should be available latest - week commencing 3 March 2008

6. Public/Private Cooperation is necessary for successful Influenza Vaccine production & supply Timely Committee selection of the appropriate antigens –Consideration of antigenic match as well as growth potential Availability of seed viruses –Especially High Growth Reassortants –Opportunity for manufacturers to evaluate growth characteristics of potential strain candidates Availability of potency test reagents for all three strains by early June. Timely approval of Annual License Supplement

7. YearStrainChange 1989 FormulationA/Taiwan/1/86 (H1N1) [A/Singapore/6/86 (H1N1) - Like] 1990 FormulationA/Taiwan/1/86 (H1N1) [A/Singapore/6/86 (H1N1) - Like] 1991 FormulationA/Taiwan/1/86 (H1N1) [A/Singapore/6/86 (H1N1) - Like] 1992 FormulationA/Taiwan/1/86 (H1N1) [A/Singapore/6/86 (H1N1) - Like] 1993 FormulationA/Taiwan/1/86 (H1N1) [A/Singapore/6/86 (H1N1) - Like] 1994 FormulationA/Texas/36/91 (H1N1) [A/Singapore/6/86 (H1N1) - Like]X 1995 FormulationA/Texas/36/91 (H1N1) [A/Singapore/6/86 (H1N1) - Like] 1996 FormulationA/Texas/36/91 (H1N1) [A/Singapore/6/86 (H1N1) - Like] 1997 FormulationA/Texas/36/91 (H1N1) [A/Singapore/6/86 (H1N1) - Like] 1998 FormulationA/Beijing/262/95 X-127 (H1N1) [A/Beijing/262/95 (H1N1) - Like](Johannesburg NIB39)X 1999 FormulationA/Beijing/262/95 X-127 (H1N1) [A/Beijing/262/95 (H1N1) - Like](Johannesburg NIB39) 2000 FormulationA/New Caledonia/20/99 IVR-116 (H1N1) [A/New Caledonia/20/99 (H1N1) - Like]X 2001 FormulationA/New Caledonia/20/99 IVR-116 (H1N1) [A/New Caledonia/20/99 (H1N1) - Like] 2002 FormulationA/New Caledonia/20/99 IVR-116 (H1N1) [A/New Caledonia/20/99 (H1N1) - Like] 2003 FormulationA/New Caledonia/20/99 IVR-116 (H1N1) [A/New Caledonia/20/99 (H1N1) - Like] 2004 FormulationA/New Caledonia/20/99 IVR-116 (H1N1) [A/New Caledonia/20/99 (H1N1) - Like] 2005 FormulationA/New Caledonia/20/99 IVR-116 (H1N1) [A/New Caledonia/20/99 (H1N1) - Like] 2006 FormulationA/New Caledonia/20/99 IVR-116 (H1N1) [A/New Caledonia/20/99 (H1N1) - Like] 2007 FormulationA/Solomon Islands/3/2006 (H1N1)-like virusX 2008 FormulationA/Brisbane/59/2007 (H1N1)-like virusX 5 changes H1N1 NH strain changes since 1989

8. YearStrainChange 1989 FormulationA/OMS/5389/88 (WIC 160) (H3N2) [A/Shanghai/11/87 - Like] 1990 FormulationA/Shanghai/16/89 (NIB 24) (H3N2) [A/Guizhou/54/89 - Like]X 1991 FormulationA/Beijing/353/89 (H3N2)X 1992 FormulationA/Beijing/353/89 (H3N2) 1993 FormulationA/Beijing/353/89 (H3N2) 1994 FormulationA/Shangdong/9/93 (H3N2)X 1995 FormulationA/Johannesburg/33/94 (H3N2)X 1996 FormulationA/Nanchang/933/95 (H3N2) [A/Wuhan/359/95 (H3N2) - Like]X 1997 FormulationA/Nanchang/933/95 (H3N2) [A/Wuhan/359/95 (H3N2) - Like] 1998 FormulationA/Sydney/5/97 RESVIR -13 (H3N2) [A/Sydney/5/97 (H3N2) - Like]X 1999 FormulationA/Sydney/5/97 RESVIR -13 (H3N2) [A/Sydney/5/97 (H3N2) - Like] 2000 FormulationA/Sydney/5/97 RESVIR -13 (H3N2) [A/Sydney/5/97 (H3N2) - Like] 2001 FormulationA/Moscow/10/99 (H3N2) - Like (A/Panama/2007/99 RESVIR 17)X 2002 FormulationA/Moscow/10/99 (H3N2) - Like (A/Panama/2007/99 RESVIR 17) 2003 FormulationA/Moscow/10/99 (H3N2) - Like (A/Panama/2007/99 RESVIR 17) 2004 FormulationA/Fujian/411/2002-like (H3N2) [A/Wyoming/3/2003]X 2005 FormulationA/California/7/2004-like (H3N2) [A/New York/55/2004]X 2006 FormulationA/Wisconsin/67/2005 (H3N2)-likeX 2007 FormulationA/Wisconsin/67/2005 (H3N2)-like 2008 FormulationA/Brisbane/10/2007 (H3N2)-like virusX 11 changes H3N2 NH strain changes since 1989

9. B strain NH changes since 1989 YearSreainChange 1989 FormulationB/Yamagata/16/88 1990 FormulationB/Yamagata/16/88 1991 FormulationB/Yamagata/16/88 1992 FormulationB/Yamagata/16/88 1993 FormulationB/Panama/45/90X 1994 FormulationB/Panama/45/90 1995 FormulationB/Harbin/7/94 [B/Beijing/184/93 - Like]X 1996 FormulationB/Harbin/7/94 [B/Beijing/184/93 - Like] 1997 FormulationB/Harbin/7/94 [B/Beijing/184/93 - Like] 1998 FormulationB/Harbin/7/94 [B/Beijing/184/93 - Like] 1999 FormulationB/Yamanashi/166/98 [B/Beijing/184/93 - Like]X 2000 FormulationB/Yamanashi/166/98 [B/Beijing/184/93 - Like] 2001 FormulationB/Sichuan/379/99 - Like (B/Guangdong/120/00)X 2002 FormulationB/Hong Kong/330/01X 2003 FormulationB/Hong Kong/330/01 2004 FormulationB/Shanghai/361/2002-like [B/Jiangsu/10/2003]X 2005 FormulationB/Shanghai/361/2002-like [B/Jiangsu/10/2003] 2006 FormulationB/Malaysia/2506/2004X 2007 FormulationB/Malaysia/2506/2004 2008 FormulationB/Florida/4/2006-like virusX 8 changes

10. Summary Years covered20 H1N1 changes5 H1N1 change rate (yrs between changes)4.00 H3N2 changes11 H3N2 change rate (yrs between changes)1.82 B changes8 B change rate (yrs between changes)2.50 Zero strain changes in a single year4 times 1 strain change in a single year9 times 2 strain changes in a single year6 times 3 strain changes in a single year1 (2008-09?) Summary - NH strain changes since 1989