Injectable Drug Sterilization: Key Challenges and Strategies

Lifecore Injectables CDMO is a Minnesota-based CDMO specialized in the development, fill/finish and commercialization of sterile injectable drugs, biologics, medical devices and combination products. The company supports global customers of all sizes in pre-clinical, clinical, and commercial stages with expertise in straightforward to highly complex formulations. Backed by over four decades of global regulatory success, Lifecore strives to meet challenges head-on and develop robust, efficient processes that scale.

In this conversation with Contract Pharma, Nathan Meehan, Process Engineer, Lifecore Injectables CDMO, highlights the organization’s sterilization strategies in injectable manufacturing. He explores how the company overcomes the challenges that make sterilization difficult, changing regulatory expectations, how sterilization affects formulation and process design, future trends and more.

Contract Pharma: Why is sterilization such a challenging aspect of injectable drug product manufacturing?

Nathan Meehan: Sterilization is inherently challenging because it is, by nature, destructive. It is designed to remove and/or destroy microorganisms, and that same mechanism can damage drug products. Many injectable formulations, particularly biologics, peptides, polymers, and other complex molecules, are sensitive to heat, pressure, radiation, or chemicals. As a result, sterilization methods can impact product parameters such as stability, viscosity, molecular weight, or overall chemical function.

From a CDMO perspective, sterilization is not a one-size-fits-all decision. Each product brings its own sensitivities and constraints, which means sterilization strategy must be considered early in development. At Lifecore Injectables CDMO, we frequently help clients determine how various sterilization options may influence formulation process design, process parameters, and final specifications.

CP: How have regulatory expectations around sterility assurance evolved in recent years?

Meehan: Sterility assurance expectations are tightening, with a greater focus on minimized human intervention. The EU’s latest Annex 1 requirements have increased the adoption of isolators and other technologies that offer greater contamination control. In recent years at Lifecore, we increased our sterile filling capacity with a high-speed isolator-based filling line. In addition, we installed isolator-based microbial testing equipment. Whether guarding products from contamination or protecting sample integrity, reduced exposure to human contact has a substantial impact on sterility.

In addition, the EU’s PUPSIT (Pre-Use Post-Sterilization Integrity Testing) requirement has clarified expectations for filter testing. Although PUPSIT is not a new concept for sterile manufacturers, the requirements and reasoning behind them are now more explicit. We interpret this as a sign of greater scrutiny around PUPSIT compliance by EU regulators.

CP: What is the primary sterilization option you typically evaluate for a new injectable solution?

Meehan: Terminal sterilization of the final product is always the preferred method by regulatory bodies. However, when that is not feasible, the first option we evaluate is almost always sterile filtration. If a product can be passed through a sterilizing-grade filter without significant fouling or loss of product, it is generally the least destructive and most straightforward approach. In sterile filtration, bacteria are physically retained by the filter while the product passes through, minimizing chemical or thermal stress.

However, not all products are good candidates for filtration. Non-soluble suspended APIs, for example, may be unable to pass through a filter within suspension. Larger molecular structures may have fast filter fouling and the associated low throughput volumes can make filtration ineffective at scale. When sterile filtration presents challenges, we work with clients to explore alternative options.

CP: What alternatives are available when sterile filtration is not feasible?

Meehan: One option is separating the formulation components and sterilizing each separately. Returning to our API suspension example, the excipients could be filtered while sourcing or sterilizing the API separately. The sterile API can then be added to the filtered formulation through aseptic processing. In some cases, we work with qualified external partners to support sterilization steps such as ethylene oxide (EtO) treatment for APIs or components that cannot be sourced sterilized. The sterile API can then be aseptically dosed to a sterile mix tank containing the filtered excipients.

Other approaches include specialized steam sterilization. If the API can withstand heat but cannot pass through a filter, there could be an opportunity to heat the formulated product to a sterilizing temperature utilizing a steam jacket on the mix vessel. Processing steps such as nitrogen overlay may assist the API’s heat tolerance and maintain the product’s desired specifications throughout the sterilization process.

CP: How can understanding the effects of sterilization on a product inform process design?

Meehan: Sterilization methods can alter physical and chemical properties, particularly for polymers and long-chain molecules. Heat can break molecular chains, leading to reduced viscosity, or filter membranes may alter a polymer’s molecular weight distribution as only a certain chain length of polymer will pass through the filter. These effects are often predictable, but they must be anticipated during process design and modeled during early development.

As an injectable CDMO, we help clients incorporate these effects into their development strategy. Products may be formulated at higher initial viscosity or molecular weight outside of the final specification range so that, after sterilization, they fall within the desired specification.

CP: What should sponsors look for in a CDMO when evaluating sterilization capabilities?

Meehan: Sponsors should partner with CDMOs that possess experience across a comprehensive sterilization “tool kit,” as sterilization strategies can vary significantly depending on the product. Additionally, sponsors should seek CDMOs with a demonstrated track record of successfully implementing these strategies, including validated processes that have withstood regulatory audit scrutiny.

CP: How can a CDMO support the use of customer-owned equipment in injectable manufacturing while ensuring sterility, validation, and regulatory compliance?

Meehan: Provided sterility and compliance are fully addressed, bringing customer-owned equipment in-house can be a highly effective way to maintain process familiarity, control costs, and scale efficiently. Customer-owned stainless-steel equipment can be integrated into our operations and validated using our steam-in-place (SIP) capabilities, which are designed to confirm that steam reaches all critical surfaces and achieves effective sterilization. This includes rigorous validation activities such as biological challenge studies to demonstrate microbial removal.

In parallel, we apply established cleaning validation protocols to ensure all product-contact surfaces meet predefined cleanliness before use. By combining SIP validation, cleaning validation, and in-process controls, we can confidently incorporate customer-owned equipment into aseptic processing workflows.

CP: Looking ahead, what trends or innovations do you see shaping sterilization strategies for injectable manufacturing over the next five to ten years?

Meehan: As mentioned, the use of isolator technology is expected to continue to increase. More broadly, facilities appear to be investing more in automation, robotics, and intervention-less designs to reduce reliance on manual operations. Not only do many of these technologies ensure better sterility, but they often offer benefits like driving manufacturing efficiencies and enhancing performance.