Both aseptic processing and terminal sterilization remove contamination from drug products, but the two methods are not the same, and they are not interchangeable.
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The end goal of all pharmaceutical manufacturers is the same: to produce safe and effective products free of pathogens or other contaminants. Therefore, drug product manufacturing operations must be carefully and intentionally designed to protect the quality and sterility of the product before it leaves the facility.
As manufacturers put in place contamination control strategies (CCS) for their facility and products, one of the first questions they should ask is whether a product should be produced by aseptic processing or terminal sterilization. The processes are not the same, and the right choice for a manufacturer depends on the characteristics of the active pharmaceutical ingredient (API) and drug product. Additionally, the method a manufacturer chooses has a significant impact on a facility’s capital and operational costs, profitability and risk, as well as its products’ ability to meet regulatory scrutiny. Given all the variables at play and the key differences between approaches, here’s how to make the right choice.
Bioburden and particulate types
In order to ensure their strength, purity, and quality, all final drug products must be free of foreign matter. However, the manufacturing environment, personnel and raw materials can all introduce contaminants—viable and non-viable particles—to a drug product throughout processing.
- Non-viable particles range from dust, pyrogens, fibers, or other particulates—any non-living thing that shouldn’t be in the final product.
- Viable particles are bacteria, molds, yeasts, viruses, and other microorganisms. These are also referred to as bioburden.
Regardless of the processing type—aseptic or sterile—it is critical to identify routes of particulate ingress to then determine the appropriate measures to mitigate contamination risk. Between the two options, the level of protection and the method of sterilization is what is different.
Terminal sterilization vs aseptic processing
Terminal sterilization and aseptic processing are both effective methods of producing safe, high-quality drugs. While aseptic processing aims to prevent contamination by maintaining a sterile environment throughout the critical processing steps, terminal sterilization controls bioburden accumulation and then performs a final sterilization step with heat or irradiation after filling is complete.
Products that are terminally sterilized use a sterilization step, based on a defined bioburden load, after filling is complete. Because it occurs at the end of the process, terminal sterilization provides a high level of sterility assurance and is preferred by regulatory agencies. In fact, the United States Food and Drug Administration (FDA) advises, “It is a well-accepted principle that sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible.”
Common sterilization methods include moist heat sterilization (such as a steam-air mixture or water cascade sterilizer) or irradiation. The chief limitation of terminal sterilization is product compatibility. It is not an option for sensitive APIs and drug products that are denatured or significantly degraded by the sterilization process. For this reason, terminal sterilization is typically used on simple solutions or small molecules.
Terminal sterilization is commonly used for:
- IV bag standard solutions (e.g., saline, dextrose, lactated ringers)
- Diluent solutions (e.g., water for injection, simple buffers or salts)
- Small molecule drugs not susceptible to heat
When using terminal sterilization, product formulation and filling can happen in a less rigidly controlled environment. This means that manufacturers can produce terminally sterilized products with less capital investment and at a lower operating cost.
Ultimately, if a drug product can withstand the sterilization step, terminal sterilization is the best option to achieve a high level of sterility assurance without adding complexity, cost, and extra regulatory scrutiny to a process.
Rather than sterilizing at the end of the process, aseptic processing involves sterilizing the manufacturing and packaging components prior to filling, and then assembling the drug product in a highly controlled environment; there is no sterilization at the end of the process. As such, a clearly defined sterile envelope is essential, and ideally, it is as small as possible. Adding unnecessary process steps to the aseptic environment creates excess complexity and cost.
To create a clean, contamination-free environment during aseptic operations, manufacturers employ uninterrupted, unidirectional HEPA-filtered air to create a Grade A/ISO 5 space. Aseptic fill lines also rely on barrier systems such as a Restricted Access Barrier System (RABS) or an isolator. These barrier systems provide a local Grade A environment and minimize the incursion of outside elements on the filling process.
With the rise of biologics as well as cell and gene therapies, there is an ever-growing list of drugs that require aseptic processing since they cannot withstand irradiation or a heat sterilization step.
Aseptic processing is often used for:
- Monoclonal antibodies
- Antibody-drug conjugates
- mRNA and oligonucleotides
- Cell and Gene therapies
Although aseptic processing lacks a final sterilization step, thoughtful facility and equipment design, paired with robust quality processes, produce safe and effective drug products that would otherwise be incompatible with parenteral delivery.
Capital and operational considerations
Terminal sterilization is more cost-effective than aseptic processing from both a capital and operations standpoint, largely due to its less stringent regulatory requirements. Aseptic processing includes investment in expensive equipment, such as isolators, which require specialized operators. Additionally, HVAC costs rise because it requires higher cleanroom classifications. For example, terminally sterilized products may be filled in a Grade C/ISO 8 (in operation) environment, whereas aseptic filling must be done in Grade A/ISO 5.
Which method is right for you?
There isn’t a one-size-fits-all solution when it comes to choosing between terminal sterilization and aseptic processing. However, our team has seen a tendency to default to aseptic processing because it’s more compatible with sensitive products. As the number of large molecule and biologic APIs continue to rise, the number of products requiring aseptic processing methods will likewise grow. Nonetheless, because terminal sterilization offers significant advantages in cost, simplicity, and regulatory requirements, it should be the preferred option for parenteral drug manufacturing whenever possible.
Integral to a robust contamination control strategy is selecting the proper filling method for your product portfolio. But what if you have a diverse portfolio and products that fall into both categories? At this stage, a cost/benefit analysis will uncover the best fit of all the available options. Does a single, large aseptic line meet your needs or would multiple smaller lines that are fit-for-purpose suit your operation better? Our CRB team is experienced in analyzing processes and guiding clients toward a facility that strikes the perfect balance between efficiency and compliance.