Australian Public Assessment Report for purified antigen fractions of inactivated split virion A/Indonesia/05/2005 (H5N1), as03 adjuvanted

II. Quality findings

Introduction (if applicable)

Prepandemrix is a split virion influenza vaccine against a strain of influenza derived from a currently circulating highly pathogenic avian influenza that has the potential to cause a pandemic. It is intended to be used according to the same dosing as the currently registered Pandemrix H5N1 (AUST R 145924).

Drug substance (active ingredient)

The vaccine is based on the reassortant strain A/Indonesia/05/2005 (H5N1)/PR8-IBCDC-RG2, developed by CDC using reverse genetics. It combines the H5 and N1 segments to the PR8 strain backbone. The H5 has been engineered to delete the polybasic stretch of amino acids at the HA cleavage site, to avert the virulence of the original strain.

The specifications for the drug are in line with the European Pharmacopeia (EP) Monograph 0158 on split, inactivated influenza vaccines. Appropriate validation data have been submitted for determination of HA content, viral inactivation, and sodium deoxycholate content and data presented to demonstrate the removal of process related impurities.

Stability results are provided for three batches of Thiomersal free split inactivated H5N1 monobulks (produced in Dresden, Germany) following storage at +2°C to +8°C. Results show the HA content is stable over the 24 month period tested and all other tests are compliant with the specifications of that test. Stability results are also provided for up to 18 months of storage at +2°C to +8°C for H5N1 A/Indonesia monobulks and A/Vietnam H5N1 split monovalent bulks manufactured by the thiomersal containing process. All results are acceptable. The monobulks can be stored in Type I glass bottles or Flexible (Flexboy) bags. Stability data is provided to support this storage and all issues have been resolved. Other parameters such as sterility, endotoxin content and pH are included in the stability plan and acceptable data is provided on three commercial batches.

The sponsor has assigned a shelf life of 12 months for monovalent bulks stored in flexible bags at +2°C to +8°C.

Drug product

Each 0.5 ml vaccine dose contains 3.75 µg HA of inactivated split virion of A/Indonesia/05/2005 (H5N1)/PR8-IBCDC-RG2 adjuvanted with AS03. It also contains the excipients Polysorbate 80, Octoxynol 10, Thiomersal, Sodium chloride, Disodium hydrogen phosphate, Potassium dihydrogen phosphate, Potassium chloride and Magnesium chloride and may contain residues of egg, Gentamicin sulphate, Formaldehyde, Sucrose and Sodium deoxycholate.

Thiomersal is present as a preservative at a concentration of 10 µg/ml (5 µg per dose) in the final adjuvanted H5N1 vaccine. The antimicrobial efficacy of the preservative in the finished product has been assessed at the end of the proposed in use shelf life of 24 h at 25°C following extemporaneous mixing. The results of the preservative efficacy testing are provided to demonstrate that 10 µg/ml of thiomersal in AS03 adjuvanted H5N1 Flu vaccine is efficacious throughout the shelf life of the mixed vaccine. All release tests are carried out on the antigen and adjuvant preparation separately; no release testing is performed on the combination (as per published guidelines).¹

The specifications for ovalbumin and formaldehyde in the product are within EU pharmacopoeial limits. EP 0158 recommends <0.2g/L of free formaldehyde and 1 µg per human dose of ovalbumin in split virion inactivated Influenza vaccines.

Data from accelerated and real time stability studies on the H5N1 final container lots are provided to support a shelf life of 60 months at 2-8°C. Stability indicating parameter is the HA content measurement by SRD tested at each time point. Other parameters investigated are sterility, thiomersal content, endotoxin content, pH, description and protein content. The sponsor has assigned shelf life for the inactivated split virion A/Indonesia H5N1 antigen component of 60 months. This is supported by real time stability data generated at +2°C to +8°C on final containers lots of A/Indonesia derived from:

thiomersal free monovalent bulk manufacturing process up to 60 months;

thiomersal containing monovalent bulk manufacturing process up to 60 months.

The sponsor has clarified that the first commercial filling of H5N1 A/Indonesia antigen lots (derived from thiomersal containing monobulks) occurred at the site in Canada, for which stability data are available until 60 months. Subsequently, the manufacturing strategy was modified: (1) thiomersal was removed from monobulks manufacturing process and (2) the site in Canada was no longer maintained as a filling, labelling and pre-packaging site for this antigen component sourced in Dresden. Consequently, no commercial H5N1 A/Indonesia antigen lots derived from thiomersal containing monobulks were filled in Belgium and/or England and stability data are only available for lots filled in Canada.

Biopharmaceutics

Not relevant for this product because it is a vaccine.

Quality summary and conclusions

The administrative, product usage, chemical, pharmaceutical, microbiological and biopharmaceutic data (as applicable) submitted in support of this application have been evaluated in accordance with the Australian legislation, pharmacopoeial standards and relevant technical guidelines adopted by the TGA.

A number of quality and sterility issues requiring resolution before the product can be recommended for approval, were identified during the evaluation and were referred to the applicant for comment or resolution. The sponsor responded to the issues raised and the responses have been evaluated. Consistency of production has been demonstrated over the two manufacturing buildings.

Stability data provided to support the storage of the H5N1 Monovalent bulk in s71-2 bags has been generated on the Pandemic A/California H1N1v strain stored in 50L Flexboy bags. The sponsor was requested to provide storage/stability data for A/Indonesia H5N1 (the drug substance). The sponsor has responded that stability studies have been initiated recently with two A/Indonesia H5N1 drug substance batches (AFLSEDA887 and AFLSEDA888), to validate a shelf life extension of the drug substance in bags beyond 12 months. Six month data will be available in March 2015, 12 month data in September 2015. The sponsor was contacted to discuss the availability of the stability data for two A/Indonesia H5N1 drug substance batches (AFLSEDA887 and AFLSEDA888). The sponsor provided a stability report for H5N1 monobulk with 4 months of real time data in January 2015, and informed that the 12 month data will be available in September 2015.

The evaluator recommends that Prepandemrix purified antigen fractions of inactivated split virion A/Indonesia/05/2005 (H5N1)/PR8-IBCDC-RG2 (H5N1) vaccine should be approved.