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Vaccines, Blood & Biologics

Executive Summary for the CMC Section of STN 125265/0 - Rotarix


DATE: March 28th, 2008

FROM: Dino Feigelstock

SUBJECT: Executive Summary for the CMC section of STN 125265/0: Rotarix, Human Rotavirus Vaccine Live, Oral, GlaxoSmithKline Biologicals.

TO: Laraine Henchal, OVRR, DVRPA

THROUGH: Stephen Feinstone, Robin Levis, Anissa Cheung, Phil Krause, Jerry Weir, DVP, OVRR

cc. Loris McVittie, DVRPA


GlaxoSmithKline Biologicals submitted a BLA seeking approval of Rotarix on June, 2007. I reviewed the CMC section.

Rotarix is a vaccine composed of a monovalent, live, attenuated rotavirus derived from the human 89-12 strain (isolated from a naturally infected child with rotavirus gastroenteritis). Rotarix is provided as a lyophilized cake contained in a glass vial and a liquid diluent (1mL) in a pre-filled oral glass applicator with a plunger stopper. The lyophilized vaccine contains live, attenuated rotavirus produced on Vero cells, amino acids, dextran, Dulbecco's Modified Eagle Medium (DMEM), sorbitol, and sucrose; the diluent contains calcium carbonate, sterile water, and xanthan. The vaccine is administered orally and contains no adjuvant.

Rotarix is derived from a single human attenuated rotavirus strain. This is different from Merck's FDA approved vaccine (RotaTeq) which is a "pentavalent" vaccine, composed of five reassortants rotavirus strains derived from a bovine strain (each of which contains a gene encoding VP4 or VP7 from human origin). Rotarix vaccine also contrasts with the RotaShield vaccine (which was withdrawn from the market in 1999); RotaShiled is composed of 4 human-simian reassortants containing four serotypically distinct VP7 components.

Rotarix has been approved for use in Mexico in 2004, and subsequently in other Latin American countries and Europe. Eight clinical trials performed in the USA, Latin America and Finland have shown that the vaccine is safe and protected children against rotavirus infection and against severe rotavirus gastroenteritis .

The sponsor shows data ensuring that master cells banks, working cells banks, virus master seeds, and virus working seeds used in the production of the vaccine are sterile and free of extraneous agents.

The sponsor shows data ensuring that end-of product cells are sterile and free of extraneous agents.

The sponsor shows data ensuring safety from TSE concerns.

The final vaccine formulation does not contain any new or hazardous excipients and is therefore considered devoid of any toxicity.

The sponsor presents results showing that the elimination of ------------------------- throughout the process is consistently higher than -------------------- content in commercial bulks is ------------- ng/ dose.

The vaccine manufacturing process is robust, and the titers achieved are highly consistent.

The sponsor performs testing at different stages of production to ensure that the product meets specifications and is consistent

Testing for Lot Release of final containers (rotavirus) includes: Description, identity, sterility, moisture content, ------, potency and loss of potency after - days at ----0C.

Testing for Lot Release of final containers (diluent) includes: Description, identity of ----------------, identity ------------------, volume, and calcium carbonate content.

Extensive studies have shown that the vaccine is genetically stable; the markers for attenuation are not yet identified.

The sponsor performed (and is performing) studies demonstrating the stability of the HRV lyophilized vaccine and the liquid diluent.

Regarding the potency of the vaccine, the sponsor has ------------------ specification of ----- CCID50 ------------------------------------------------------------------------------------ -------------------------------------------------------------------------------------------------------------

Regarding the lower limit specification, the sponsor has set a lower limit specification of ----- CCID50. This titer, according to calculations made by CBER reviewers, will ensure a titer of 106.0 CCID50 at the end of expiry period of 24 months. This titer is not consistent with the phase 3 clinical studies that have shown efficacy of the product at a dose of 106.5 CCID50. According to CBER clinical reviewers, phase 2 clinical studies have shown that the vaccine protects at lower doses. However, it is not clear the level of protection at the end of expiry dose (106.0 CCID50); therefore, I strongly recommend to clearly state in the label that phase 3 clinical trials were performed at a dose of 106.5 CCID50.

Based on the above statements, I recommend approval of the product.

Contact FDA

(800) 835-4709
(240) 402-8010
Consumer Affairs Branch (CBER)

Division of Communication and Consumer Affairs

Office of Communication, Outreach and Development

Food and Drug Administration

10903 New Hampshire Avenue

Building 71 Room 3103

Silver Spring, MD 20993-0002

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