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.
Assess the product
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.
