# Presentation: 670666

## 
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

**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

## 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

- 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

## Influenza Vaccine Manufacturing Model Timeline

**Jan**

**Dec 2006**

**Nov 2007**

**Feb**

**Mar**

**Apr**

**May**

**Jun**

**Jul**

**Aug**

**Sep**

**Oct**

## 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.

**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.

## 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

**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

##    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

**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**

## H1N1 	NH strain changes since 1989

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

**H1N1 ****	****NH strain changes since 1989**

## H3N2 	NH strain changes since 1989

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

**H3N2 ****	****NH strain changes since 1989**

## B strain 	NH changes since 1989

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

## Summary - NH strain changes since 1989

| Summary |  |
| --- | --- |
| Years covered | 20 |
|  |  |
| H1N1 changes | 5 |
| H1N1 change rate (yrs between changes) | 4.00 |
|  |  |
| H3N2 changes | 11 |
| H3N2 change rate (yrs between changes) | 1.82 |
|  |  |
| B changes | 8 |
| B change rate (yrs between changes) | 2.50 |
|  |  |
| Zero strain changes in a single year | 4 times |
| 1 strain change in a single year | 9 times |
| 2 strain changes in a single year | 6 times |
| 3 strain changes in a single year | 1 (2008-09?) |

**Summary - NH strain changes since 1989**