Influenza Virus Vaccine - Fluvirin
Status: approved; marketed
Organizations involved:
Chiron Corp. – Manuf.; R&D; Tech.; World mark.
Novartis AG – Parent
FFF Enterprises Inc. – U.S. mark.
Evans Vaccines Ltd. – R&D; Tech.; Former
PowderJect Pharm. plc – Former
Medeva Pharmaceuticals, Inc. – Former
Celltech Group plc – Former
Lederle Laboratories – Former
Cross ref: See the Influenza Virus Vaccines entry (#470) and other influenza vaccine entries.
Description: Influenza Virus Vaccine or Fluvirin is a conventional injectable trivalent inactivated split (subvirion) influenza vaccine. Influenza virus hemagglutinin (HA) and neuraminidase (NA) virus surface antigens are purified from influenza virus strains cultured in embryonated chicken eggs, inactivated (killed) with beta-propriolactone, and split (disrupted) using nonylphenol ethoxylate (Triton N101), an nonionic surfactant. As exemplified by the 2003-2004 flu season formulation, each 0.5 mL dose contains 15 µg of HA from each of the three designated influenza virus strains.
Excipients are buffer solution (0.01M) composed of potassium dihydrogenphosphate, disodium hydrogenphosphate; sodium chloride, and Water for Injection. Thimerosal, a mercury derivative antimicrobial preservative (see #939), is added at a concentration of 0.01% or 24.5 µg of mercury per 0.5 mL dose. Others substances in trace amounts in the vaccine are sucrose, nonylphenol ethoxy-late, formaldehyde, beta-propiolactone (BPL) used for inactivation, ovalbumin, and the antibiotics neomycin and polymyxin. Neomycin, polymyxin, and beta-propiolactone are not detectable using current assays. Fluvirin is stored at 2-8˚C (refrigerated).
Nomenclature: Influenza Vaccine/Novartis UK [BIO]; Fluvirin [TR in U.S.]; Influenza Virus Vaccine [FDA USAN]; Inactivated Influenza Vaccine (Surface Antigen) [Eur. Pharm.]; Influenza Virus Vaccine USP [USP]; Evagrip [TR foreign]; Flu-Immune [TR former]; NDC 66521-105-10 [NDC]
Companies.: The vaccine was originally developed and manufactured by Evans Medical, Ltd. (CBER/FDA est. no. 1615), formerly a subsidiary of Med-eva PLC, became part of Celltech Group for a short period, then a subsidiary of PowderJect plc (acquired from Celltech in Sept. 2000), which was acquired by Chiron Corp., which merged into Novartis AG in Oct. 2005. Chiron Vaccines manufactures the vaccine at former Evans/Medeva facilities in Speke, U.K. This establishment is the sole manufacturer of human vaccines in the U.K. Chiron markets the vaccine in the U.S. and internationally.
Fluvirin from Evans/Medeva was marketed in the U.S. as Flu--Immune by Lederle Labs. (Wyeth) until 1991.
Chiron plans to manufacture 52 million doses for the 2004-2005 season, including 2 million doses later in the season for a national stockpile held by the U.S. Centers for Disease Control and Prevention (CDC). This record level of supply is an increase of more than one-third compared with Fluvirin deliveries during the last influenza season. Evans/PowderJect increased manufacturing capacity of Fluvirin to 27 million doses for the 2002-2003 flu season, completing a 3-year expansion program. Chiron (current owner) originally expected to manufacture 34 million doses for the 2003-2004 season (U.S. market), but produced 38 million doses, with about 98% shipped to the U.S. With conventional inactivated vaccine in short supply in late 2003, in Jan. 2004, Chiron prepared and sold to the Centers for Disease Control and Prevention (CDC) 363,200 doses of Fluvirin. Chiron is investing about $100 million to further increase manufacturing capacity by 25%.
Chiron Vaccines/Novartis is the world’s second-largest influenza vaccines manufacturer. In total for the 2003-2004 flu season, Chiron produced 75 million doses of its four brands of flu vaccine (Fluvirin, Agrippal, Begrivac and Fluad), with production facilities in Liverpool, U.K.; Marburg, Germany; and Siena and Rosia, Italy. Only the U.K. facility manufactures influenza vaccine for the U.S. market.
In April 2006, Novartis Vaccines concluded a three-year agreement with FFF Enterprises Inc for U.S. distribution of Fluvirin. FFF is “the nation’s leader in flu vaccine distribution.” FFF Enterprises’ unique distribution model entails purchasing products from manufacturers only and shipping only to healthcare providers, i.e., no sales to middle-men or other suppliers.
Manufacture: The viral strains are independently cultured in specific pathogen-free embryonated chicken eggs inoculated with a specific influenza virus strain suspension containing neomycin and polymyxin. The allantoic fluid containing the virus is harvested and clarified by centrifugation. The viruses are inactivated with beta-propiolactone (BPL), and concentrated and purified by zonal centrifugation. The HA and NA surface antigens are split from the virus outer membrane by centrifugation in the presence of Triton N101 (nonoxynol 101; nonyl-phenol ethoxylate; an nonionic surfactant), allowing removal of most of the viral internal proteins. The nonoxynol 101 is removed from the concentrated surface antigens, and the antigens are suspended in 0.01 M phosphate buffered saline. Thi-mer-osal is added at a concentration of 0.01%.
FDA class: Biologic PLA
CBER class: Viral And Rickettsial Vaccines
Approvals: Date = 19880812; first approval, PLA
Date = 19981103; licenses (PLA/ELA) revoked and granted (reissued) to new owner, Medeva Pharma Ltd.
Indications: see the other influenza vaccine entries.
Status: 2004/5 Flu Season Supply Problems: Chiron experienced bacterial contamination problems in the manufacture of its influenza vaccine for the 2004/5 flu season, and it vaccine was not released for marketing. Chiron had planned to supply the U.S. market with 46-48 million doses for the 2004/5 flu season. This left only one injectable vaccine to supply the entire U.S. market, Fluzone from Aventis Pasteur Inc. (now Sanofi Pasteur Inc.), and severe shortages occurred. It remains doubtful whether Chiron will be able to fix its problems with its vaccine manufacturing facility in the U.K. and receive FDA release (approval) of vaccine for the 2005/6 flu season, again leaving Sanofi Pasteur as the only supplier, which increased its manufacturing for the 2005/6 season.
In Aug. 2004, U.K. MHRA authorities inspected Chiron’s facilities and on Oct. 3 suspended the company’s license for three month and refused to release the 2004/5 flu season batches of Fluzone due to Serratia marcescens bacterial contamination and inability to assure lack of contamination. This effectively prevented Chiron from exporting 46 million doses of already-Manufactured vaccine allocated for the U.S. market, much of of already presold or ordered. In Oct., FDA inspected the Speke facilities. In Dec., Chiron was issued a warning letter by FDA requesting detail on investigations into cGMP deviations and the design and conduct of studies to aid investigations; and the U.K. MHRA extended the suspension of Chiron’s license for an additional three months. The MHRA suspension had been set to expire Jan. 4, 2005. Chiron wrote off (reported a loss of) $91 million related to its disposal of it unsold vaccine.
In March 2005, the U.K. MHRA lifted the license suspension for Chiron’s Speke/Liverpool facility to manufacture Fluvirin influenza vaccine. Chiron may begin full manufacturing subject to certain conditions, which include a high level commitment to the completion of a remediation plan and ongoing improvements, providing the MHRA with weekly updates, and possible further MHRA inspections.
In Oct. 2004, yet another popular book critical of vaccines, “Evidence of Harm - Mercury in Vaccines and the Autism Epidemic: A Medical Controversy,” simplistically and erroneously cited thimerosal, a mercury-based preservative (see related entry), as the cause of Chiron’s bacterial contamination problems, since Chiron used thimerosal as a sterilizing agent in its manufacturing facilities.
2005/6 Flu Season Supply Problems: After fixing its prior problems (see above), Chiron expected to be able to produce Fluvirin for the U.S. 2005/6 season. Chiron expected that the FDA would conduct an inspection between mid-June and mid-July 2005 to determine whether deficiencies noted in its warning letter of Dec. 2004 had been resolved.
However, Chiron was forced to reduce its manufacture of Fluvirin for the 2005/6 flu season, projecting18-26 million doses early in the season (but apparently not later disclosing actual production figures), because of delays related to remediation and lower production output associated with adaptation to new processes and procedures at the Liverpool plant. Chiron did not manufacture Fluvirin in prefilled syringes for general U.S. distribution for the 2005/6 flu season, just vials.
FDA approved Chiron’s Liverpool Fluvirin manufacturing facilities in late Aug. 2005. FDA had conducted an inspection in July 2005. By Oct. 2005, Chiron had received supplemental approvals for improvements to facilities, equipment and processes that were part of the company’s remediation plan, and the first three vaccine lots were approved by FDA in Oct. This, combined with the conclusion by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) in March 2005 that Chiron could conduct operations in accordance with GMP, meant that Chiron could proceed with its efforts to return Fluvirin to the market for the 2005/6 influenza season. Chiron manufactured and supplied reduced (undisclosed) number of doses for the 2005/6 flu season.
2006/7 Season: With its manufacturing and approvals in place, Chiron has been manufacturing vaccine for the 2006/7 flu season without incident, and expects to produce 40 million doses of Fluvirin for the 2006-07 season (less than it had previously planned for, including having expanded manufacturing capacity).
2007/8 Season: A total of 40 million doses were shipped to the U.S., and more than 30 million dose were produced for European markets.
2008/9 Season:
Market: Fluvirin is almost exclusively manufactured for the U.S. market.
Novartis Vaccines (formerly Chiron) plans to produce ~40 million doses of Fluvirin vaccine for distribution in the U.S. during the 2007/08 influenza season - a 30% increase in supply from Novartis compared to the 2006/7 season. Fluvirin is usually the second best selling influenza vaccine worldwide, with about 22% of the market. Presuming most sales at bulk prices in the range of $6/dose (although this could now be higher), 2007 sales are on the order of $240 million and 2006 sales were on the order of $168 million.
The 2007 Average Wholesale Price (AWP) is $182.40 for 10 prefilled adult single-dose syringes; and $148.10/10-dose vial ($104.68 in 2005; $106.25 in 2004) (Red Book, 2007).
As reported by the National Immunization Program (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the Private Sector Cost/Dose (average cost) per dose is $12.48 for 10-dose vials (containing thimerosal), and $15.54 for for 10-packs of preservative-free prefilled syringes. The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $12.48 for 10-dose vials (containing thimerosal), and $10.69 for 10-dose vials (containing thimerosal), and $12.61 for 10-packs of preservative-free prefilled syringes. These prices include the $0.75/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. Novartis’ contract with NIP, CDC, expires on Feb. 28, 2008.
In its March 22, 2006 price list, FFF Enterprises, a major biologics distributor, reported $103.70/10-dose vial ($73.80 in 2004), and $125.30/box of ten 0.5 mL single-dose syringes ($92.10 in 2005).
Chiron Vaccines/PowderJect invested about $20 million over three years to double manufacturing capacity by the 2004 flu season. PowderJect completed the first phase of this 3-year manufacturing capacity expansion program in 2002, increasing capacity to 27 million doses/season. PowderJect anticipated an increase of over 30% in 2003-4 season. The company planned to increase capacity to 35 million doses in 2003 and 45 million in 2004. However, with Wyeth abandoning manufacture of conventional influenza vaccine after 2002 (to concentrate on sales of FluMist), leaving only Aventis Pasteur/Sanofi Aventis and PowderJect/Chiron, PowderJect/Chiron further accelerated addition of more manufacturing capacity. However, as described above and in the Fluzone entry, the company has experienced major problems and has not been able to ramp up its manufacturing as much as it had expected.
In Jan. 2008, Novartis reported a Speke production record for Fluvirn, with Novartis the second largest supplier of influenza vaccine in the U.S. (after Sanofi Pasteur). The Speke plant produced 50 million doses, 20 million more than in 2006, and more than three times as many as in 2005 (the first production after losing all of the 2004 product to contamination problems). For the 2008/9 season, Novartis reported, "new facilities will have a capacity to annually produce approximately 100m doses of influenza vaccine."
R&D: Chiron Corp. is conducting Phase III trials with a cell cultured seasonal influenza vaccine. Also, Chiron (Novartis) and PowderMed Ltd. are developing needle-free injected powder influenza vaccines, both seasonal and pandemic (H5N1). PowderMed was spun-off from Chiron Vaccines in a management buy-out, with PowderMed assuming Pow-derJect’s original needless powder injection technology, and was acquired by Pfizer in Oct. 2006. Chiron is now merged into Novartis AG.
In Nov. 2006, Novartis announced plans to build the first cell culture-derived influenza vaccines manufacturing plant in the U.S. at a site in Holly Springs, North Carolina, with construction expected to begin in 2007
Companies involvement:
Full monograph
472 Influenza Vaccine/Novartis UK
Nomenclature:
Influenza Vaccine/Novartis UK [BIO]
Fluvirin [TR in U.S.]
Influenza Virus Vaccine [FDA USAN]
Inactivated Influenza Vaccine (Surface Antigen) [Eur. Pharm.]
Influenza Virus Vaccine USP [USP]
Evagrip [TR foreign]
Flu-Immune [TR former, reg. to Lederle Labs.]
NDC 66521-105-10 [NDC]
Influenza Vaccine/Evans [BIO former]
FDA Class: Biologic PLA
Year of approval (FDA) = 1988
Date of 1st FDA approval = 19880812
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
chicken source materials
vaccines, inactivated
vaccines, subunit
vaccines, viral
allantoic fluid
chicken embryo (egg) culture
influenza virus
virus culture
beta-propiolactone (BPL; beta propiolactone)
beta-propiolactone (BPL; beta propiolactone)
disodium hydrogen phosphate
formaldehyde
hemagglutinin (HA) antigen, influenza A virus
neomycin
nonoxynol 101 (Triton N101)
nonoxynol 101 (Triton N101)
polyethylene glycol (PEG)
polymyxin
potassium dihydrogen phosphate
sodium chloride
Sterile Water for Injection
sucrose
thimerosal (mercury derivative)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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