Formulation vessel design
The FV needs to be designed for its collective intended uses, which include sterilization (autoclave or SIP), preservation
of sterility following the sterilization, the aseptic-formulation process, and a robust means of aseptically transferring
the sterile contents of the FV to the filling machine. The product contact surfaces of the FV should be composed of electropolished
316-L stainless steel, or they should be glass-coated if the product is not compatible with stainless steel. The FV must be
sized to thoroughly mix and contain the final volume of formulated product but also able to fit through door openings within
the facility. The design of the FV should include load cells for weighing materials required by the formulation. Consideration
should be given to aseptic connections, in-process samples, and transferring formulated product from the FV to the filling
machine (via a dip tube or bottom-outlet port). The FV may need to be jacketed and rated for pressure and vacuum depending on the product
and process needs (e.g., cooling during formulation and SIP). To facilitate the performance of the process steps, various
fittings need to be connected to the FV (see Table I).
Table I: Fittings required.
In the event that SIP is the chosen sterilization method for the FV, the items identified in Table II should facilitate the
Table II: Components for sterilization in place.
Develop the aseptic formulation process
The existing facility, utilities, equipment, and regulations establish boundaries for the chosen aseptic formulation process.
In-house expertise in manufacturing, process development, and validation all factor into the success of the project. The primary
goal of the aseptic formulation process is to produce a sterile product. The following guidelines improve the chances of success:
- Minimizing the number of aseptic connections.
- Designing the FV in such a way so when sterilized, that all fittings needed in the aseptic formulation process are also sterilized
(e.g., filters, sampling devices and valves).
- Exposing the aseptic connection points to a constant supply of ISO 5 unidirectional airflow. Avoid having connection points
near the floor or in other areas where there is turbulent airflow (i.e., bottom-outlet valves may present aseptic connection
- Whenever the aseptic formulation process has been developed and validated, training is critical. Train multiple operators
on the "how's" as well as the "why's" of the process. If the operators fail to understand the "whys," recognizing deviations
and their impact during manufacturing will be difficult. It may be helpful to include these operators in the validation activities.
- Leveraging, whenever possible, existing processes and validations.
- Although not directly related to sterility assurance, one also must put into place a filter integrity-testing strategy. Filter
and immediately remove the filters to be postuse integrity-tested before proceeding; filter and proceed with the remainder
of the formulation before integrity-test results are known or redundantly filtered using a series of two filters. Table III
outlines advantages and disadvantages of the options.
Table III: Options in filter integrity testing.