Depyrogenation Tunnel

Installation Qualification In addition to the common requirements outlined in the "General" section, the tunnel and conveyor belt must be at least 304 stainless steel. The unit is supplied with heat resistant HEPA filters Operational Qualification In addition to the common requirements outlined in the "General" section, the tunnel differential pressures prevent air travel from the dirty to clean areas. Critical Areas should have laminar airflow of 90 fpm ± 20%, or 28 m/min ± 20% The tunnel must meet specifications for total particulates for a Class 100 area. Rate of speed, minimum, maximum and nominal, will be measured and verified. Physical handling of containers will be monitored. No containers should be damaged, none hung up, or dislodged. The tunnel will be temperature mapped to demonstrate consistency. During the temperature mapping period, the temperature readings for the temperature recording chart and the average chamber temperature for tunnels at 250*C and greater are consistently ± 15.0*C of each other throughout the study. The temperature range among thermocouples for ovens at 250*C and greater, for each five minute interval, is ± 15.0*C of the average temperature throughout the study. Average is ± 15.0*C of the setpoint. Note: Infrared tunnels, which heat components, not the air, cannot be mapped in the absence of bottles. The mapping is therefore performed in the PQ. OQ Acceptance Criteria Setpoints Differential Pressure Air Velocity Laminarity Smoke Testing Record the ammeter values and differential pressures. The Tunnel zones are balanced per the manufacturer specifications. Air does not move from dirty to clean. Critical Areas should have laminar airflow of 90 fpm ± 20%, or 28 m/min ± 20% The entry hot and cooling zones demonstrate laminar air flow.

The oven must meet specifications for total particulates, . less than or equal Total Particulate to 100 for less than 0.5 micron per ft3 or less than or equal to 3,500 for less Counts than 0.5 micron per m3 and 0 for 5 micron per m3 All thermocouples will calibrate within ± 0.5*C of the reference temperatures before protocol execution and verify within ± 0.5*C of the high reference temperature after protocol execution. Thermocouple Calibration Eighty-five percent of thermocouples used must be operational upon completion of the study. All critical thermocouples (i.e. thermocouples with specific acceptance

criteria, such as cold spots or adjacent to a controller)must be operational upon completion of the study. During the mapping period, the temperature readings for the temperature recording chart and the average chamber temperature for Tunnels at 250*C and greater are consistently ± 15.0*C of each other throughout the study: Temperature Mapping Temperature range among thermocouples for Tunnels at 250*C and greater, for each five minute interval, is ± 15.0*C of the average temperature throughout the study. The average temperature for Tunnels at 250*C and greater at each interval is ± 15.0*C of setpoint temperature

Performance Qualification During the PQ, each vial size that will be used during production will be qualified. The study method employed will be that described in Validation of Dry Heat Processes Used For Sterilization and Depyrogenation, Technical Report No. 3, Parenteral Drug Association, 1981. At least one heat penetration study using thermocouples will be performed on each vial size. Temperature uniformity and delivery of heat will be documented. At least three endotoxin studies will be performed on each bottle size. Heat delivery and depyrogenation will be monitored by thermocouples and endotoxin reduction respectively. A minimum of a three log reduction in endotoxin must be demonstrated. PQ Acceptance Criteria Temperature To determine cold spots. Mapping, Specific Loads Monitor Tunnel differential pressure during the depyrogenation period. Inoculate glassware or vials with a minimum of 5,000 EU of E. coli lipopolysaccharide. All inoculated glassware placed must demonstrate, at minimum, a three-log reduction in endotoxin. Positive controls must demonstrate a minimum recoverable 1,000 EU, per Validation of Dry Heat Processes Used for Sterilization and Depyrogenation, PDA Technical Report Number 3. Negative controls (pyrogen free water) must not exhibit a level of endotoxin above the minimum sensitivity of the reagent used. Minimum cumulative FH location will be determined for informational purposes only. Distribution thermocouples are within a range of ± 15.0* C from the

Endotoxin Studies, done in triplicate