Inspection Waiver Memo - IXIARO

MEMORANDUM


Date:
March 26, 2009 

From:
Destry Sillivan, HFM-676, Facilities Reviewer 

To:
BLA File – STN 125280/0 

Subject: 
Recommendation to waive a pre-license inspection of ---------(b)(4)-------------- ------------------------------------------------ , the contract filler for Intercell AG for the product Japanese Encephalitis Virus (JEV) Vaccine, Inactivated 

Sponsor:
Intercell AG 

Product:
JEV Vaccine, Inactivated 

Indication:
Indicated for active immunization against JEV for persons aged eighteen years and older 

Through:
David Doleski, Acting Branch Chief, OCBQ/DMPQ/MRB-II/ HFM-676 

Concurrent Clearance Routing

____________________________       ___________        ___________           ___________
John A. Eltermann, Jr., R.Ph. M.S            CONCUR           DO NOT CONCUR           DATE

Director
Division of Manufacturing and Product Quality, HFM-670
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

____________________________      ___________       ___________           ___________
Jerry P. Weir, Ph.D.                         CONCUR              DO NOT CONCUR            DATE
Director
Division of Viral Products, HFM-445
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research

Summary:

This memorandum recommends that a pre-license inspection be waived for ------(b)(4)------ ---------------------------------- in ----------(b)(4)----------- for contract filling of the drug product JEV Vaccine.

FDA’s Office of Regulatory Affairs (ORA) performed a GMP inspection of the facility, including aseptic filling, on (b)(4)-----------------. Nine 483 observations were made. ------(b)(5)------- --------------------------------------------------------------------------------------.

Brief History

Intercell AG submitted an original Biologics License Application for JEV Vaccine. The BLA listed ---------------------------(b)(4)----------------------------- as the contract manufacturer responsible for filling of the drug product.

Facility Information

The filling facility was originally approved for manufacture of US products in 1998. The most recent biennial FDA inspection occurred on ---------(b)(4)---------- --------------(b)(5)--------------------------------------------------------------------------------

The aseptic filling is performed in building -------------(b)(4)-------------- and associated rooms. The facilities for manufacture of JEV Vaccine pre-filled syringes at -(b)(4)- consist of material preparation area, material and personnel airlocks and clean room -(b)(4)- filling areas. All rooms involved in production have proper air cascades and pressure differentials to facilitate the flow of air from critical to less critical areas. -(b)(4)- performs all operations where the product is exposed in ----(b)(4)-----. A ---------(b)(4)------------ system is installed around the Grade -(b)(4)- (Class -(b)(4)-, ISO Class -(b)(4)-) ----(b)(4)----- area of the filling line. Filling line manipulations are only performed using ----(b)(4)------. The handling of the -------(b)(4)--------- --------------- syringes in ------(b)(4)--------- after loading onto the ------(b)(4)------ for removal of the --(b)(4)-- after which filling is a fully automated process.

Controls employed during fill to assure sterile, contaminate free filled syringes include viable (------(b)(4)----------) and non-viable particulate (--(b)(4)--) monitoring. Operators are also monitored routinely.

Process

Shipment to Contract Filler:

Post-manufacturing, Intercell processes the ----(b)(4)----- containing the Final Bulk Vaccine by ------------------------(b)(4)----------------------------, followed by labeling and placement into a -------(b)(4)------- which is --(b)(4)-- sealed and stored at -(b)(4)-. Intercell then ships Final Bulk Vaccine from Intercell Biomedical, in Livingston, Scotland, to ------------- -(b)(4)--------- -, in ---------(b)(4)------------- in a temperature controlled container at --(b)(4)--.

Filling Facility and Equipment:

As noted above, -(b)(4)- performs all operations where the product is exposed in --(b)(4)-------------- areas. Filling is accomplished in Clean Room -(b)(4)-, in a -------(b)(4)--------- system installed around the Grade -(b)(4)- (Class -(b)(4)-, ISO Class -(b)(4)-) ----(b)(4)---- area of the filling line. Filling line manipulations are only performed using ---(b)(4)---- -(b)(4)-. The handling of the ---------------(b)(4)---------------- syringes in ---(b)(4)------- after loading onto the ------(b)(4)------ for removal of the ---(b)(4)-- after which filling is a fully automated process.

Equipment which comes in contact with the product is dedicated or single use equipment, and all production steps are performed in closed systems. The connection between the - -(b)(4)-- which contains the FBV and the filling line is made -------------(b)(4)-------------------------- in an ISO Class -(b)(4)- background. Processes where product and sterilized components are exposed to the environment are performed under Grade ------(b)(4)--------------.

Major equipment utilized for filling are a ---(b)(4)---- to ensure homogeneity, a ---(b)(4)-- and ---(b)(4)--- autoclave for sterilization of equipment, and a ---(b)(4)--- filling and stoppering machine. The equipment has been qualified, and that all initial qualifications were performed no earlier than 2005, and that scheduled re-qualifications have all been performed. Equipment is cleaned either manually or in an equipment washing machine according to defined procedures, and that a product specific cleaning validation was performed for -(b)(4)- filling equipment. Results of this validation study have been reviewed and are acceptable.

Utilities

Utilities include a heating, ventilation and air conditioning (HVAC) system with major components dedicated to sterile suites, as well as WFI systems.

Supporting Information

The basis for this waiver is based on criteria outlined in CBER SOPP 8410 “Determining When Pre-Licensing/Pre-Approval Inspections (PLI/PAI) are necessary.” As stated in the aforementioned SOPP, it is CBER’s policy that a pre-license or pre-approval inspection will generally be necessary for a supplement if any of the following criteria in bold are not met:
1.The facility does not hold an active US license.

The FEI number for the -(b)(4)- facility is ---(b)(4)---
2.The facility has not been inspected in the last two years by the FDA.

The most recent FDA inspection occurred --------(b)(4)----------, --------------(b)(5)---------------- -----------------------.
3.The establishment is performing significant manufacturing step(s) in new (unlicensed) areas using different equipment (representing a process change). This would include areas that are currently dedicated areas that have not been approved as multi-product facilities/buildings/areas.

-(b)(4)- is not performing significant manufacturing step(s) in new (unlicensed) areas using different equipment (representing a process change).
4.The previous inspection revealed significant GMP deficiencies in areas related to the processes in the application/supplement (similar processes) or systemic problems, such as QC/QA oversight. 

During the ------(b)(4)------- inspection, -(b)(4)- was initially cited with objectionable conditions meriting, -------------------------------------------(b)(5)--------------------------------------------- -------------------------------------------------------------------------------------------------------------- ------------------. Therefore, significant GMP deficiencies areas related to the processes in the application were not observed.
5.The manufacturing process is sufficiently different (new production methods), specialized equipment or facilities) from that of other approved products produced by the establishment. 

The manufacturing of the Product is not sufficiently different from that of other approved products produced by the establishment.

Waiver Recommendation:

This memorandum recommends that a pre-license inspection be waived for -(b)(4)- for fill of the drug product JEV Vaccine product based on the information provided in the Biologics License Application, and the previous inspection reports

Signed:

__________________________
Destry Sillivan
Facilities Reviewer
Division of Manufacturing and Product Quality, HFM-676
