Summary of Technical and Risk Assessment for VPHP Decontamination and H2O2 Uptake in the Isolator for Filling Operation
| Process Parameters | Impact to H2O2 Uptake by Open, Filled Vials (YES/NO) | Impact on H2O2 Uptake by Tubing Assembly (YES/NO) | Impact Rationale | Interaction with Other Process Parameters | Considered in the Study (YES/NO) | Studies Required |
|---|---|---|---|---|---|---|
| General | ||||||
| Product sensitivity to H2O2 | Y | Y | Product is more sensitive to H2O2 and has a lower allowable H2O2 limit, which may substantially constrain the manufacturing process. | None | Y | Small-scale H2O2 spiking study in vials |
| VPHP Decontamination Phase | ||||||
| Decontamination parameters (i.e., amount H2O2 vaporized, decontamination duration, etc.) | N | Y | The tubing assembly is set up prior to decontamination and may absorb a large amount of H2O2. Decontamination is a validated process where all parameters are fixed. | Tubing size | N | None |
| Tubing size (ID and WT) | N | Y | Smaller and thicker tubing absorbs more H2O2.a | Residual VPHP level in isolator air, interruption time | Y (ID)/N (WT) | Small-scale and manufacturing-scale uptake studies |
| VPHP Aeration Phase | ||||||
| Aeration parameters (i.e., air flow rate, duration, etc.) | N | Y | Aeration is a validated process where all parameters are fixed. Aeration is considered complete when the sensor detects the VPHP level is below 300 ppb. | None | N | None |
| SIP/CIP/Drying | N | Y | Tubing cleaning operation is a validated process where all parameters are fixed. All these operations may facilitate the removal of H2O2 from tubing. In the meanwhile, the tubing will continue to absorb VPHP from the isolator air. | Tubing size, residual VPHP level in isolator air | Y | Small-scale and manufacturing-scale uptake studies |
| Filling Operation | ||||||
| Filling starting time | Y | Y | Residual VPHP level continues decreasing after the aeration phase; filling begins immediately after aeration represents the worst-case condition. | Residual VPHP level in isolator air | N | None |
| Residual VPHP level in isolator air | Y | Y | The higher the VPHP level, the more/faster H2O2 uptake by open, filled vials and tubing. | Filling starting time, tubing size | Y | Small-scale studies (fixed); manufacturing-scale studies (monitored/not controlled) |
| Interruption time | Y | Y | Longer interruption times allow more H2O2 to be taken up by both open, filled vials and DP solution in tubing. | Residual VPHP level in isolator air | Y | Small-scale and manufacturing-scale studies |
DP, drug product; CIP, clean-in-place; ID, Internal diameter; SIP, steam-in-place; WT, wall thickness.
↵a Hubbard and Eppler, 2015 (21).