This article is part of PharmTech's supplement "Injectable Drug Delivery."

The formulation process for parenteral, or injectable, solutions often follows the overly simplified method of combining water for injection (WFI), active pharmaceutical ingredient (API) and excipients in a formulation vessel (FV) located within a formulation room and mixing until dissolved. The formulated solution is filtered through one or two sterilizing-grade (0.22 μm) membrane filters into a sterilized receiving vessel located in a traditional cleanroom with an International Organization for Standardization (ISO) Class 5 unidirectional airflow, isolator, or restricted access barrier system (RABS) (1). Occasionally, however, the formulated product includes a component that cannot be sterilized through filtration because the act of filtration would render the final product ineffective. These nonfilterable components may be insoluble particles suspended in a solution or they could be molecules too large to pass through a filter membrane. With the exception of terminal sterilization of the formulated or filled product, devising a means to formulate the product aseptically may be the only solution to ensure product sterility. Performing aseptic formulation requires consideration of several aspects for the entire process.

In making these evaluations, the analysis in this article assumes that the facility and equipment have been qualified and approved for parenteral production under good manufacturing practices (GMPs). The analysis takes the perspective of using a traditional cleanroom for manufacturing with the understanding that these approaches can be applied to advanced systems such as isolators or RABS and tailored as necessary.

The first step in determining the approach for an aseptic-formulation project is to learn the characteristics and limitations of the product. This determination will help guide the formulation process. The key elements are: the total volume to be formulated because this will influence the formulation vessel size and design; and the various components of the product capable and incapable of being sterile filtered.

The type, brand, and model of sterilizing filter selected may influence the sterilization process for the filters (autoclave or sterilization-in-place [SIP]) and may also influence the formulation process. Of those components that can be sterile filtered, it must be determined whether they should be filtered in series through the same set of filters or whether separate filters are needed for some or all components. This selection may influence the sterilization process for the filters and may also influence the formulation process.

For those components that cannot be sterile filtered, it is important to understand how those will be sterilized and where such sterilization will occur (presterilized or sterilized in-house). Sterilizing the material in house could add another layer of complexity and cost to the project, depending on the characteristics of the material. Also important to know are any specific temperature conditions required for the formulation process because these conditions will influence the FV design and potential heating and cooling equipment.

Assess existing capabilities

The existing facilities and available utilities may be adequate, may need to be modified, or may need to be designed and built to support aseptic formulation project needs. A source of clean, ISO 5-compliant, unidirectional airflow is critical for making aseptic connections and performing general aseptic operations. Additionally, some aseptic connection points may require the use of horizontal laminar airflow. Making the decision requires a good understanding of the aseptic formulation process as well as the intended sterilization process.

From a utilities perspective, if the FV will be sterilized through SIP, qualified pure-steam ports and inert-gas ports will be needed in the area intended for SIP. The pure steam-system pressure should be high enough (e.g., ≥ 40 psig) to ensure that sterilization within the FV can occur at the same time as supplying other steam-consuming equipment (e.g., autoclaves, sterilizers, and lyophilizers). The inert-gas distribution system pressure will likely exceed 100 psig. Therefore, regulators will be needed to reduce the pressure for use in drying the FV following SIP.