Parenteral drugs are infused or injected either intravenously, intramuscularly, or subcutaneously into the body to treat a wide range of diseases and conditions. Injectables are the second fastest growing segment in the drug delivery technology market and are expected to reach sales of nearly USD 620 billion in 2023.1 A large volume parenteral (LVP) is defined as a unit dose of greater than 100 ml, while small volume parenterals (SVP) is a broad category that encompasses all non-LVP parenterals. LVPs include nutritional and electrolyte infusions, dialysis solutions, plasma substitution, and irrigation solutions. In contrast, drug formulations such as anesthetics, vaccines and diagnostic agents are SVPs.
Parenteral therapy is particularly useful when a patient is unable or unwilling to take an oral medication or when rapid onset of therapeutic action is necessary such as administration of epinephrine to a patient experiencing a severe allergic reaction. Parenteral administration also enables delivery of high concentrations of a therapy such as that needed with chemotherapy. This is achieved, in part, by avoiding first-pass metabolism, which affects oral medications. Medications delivered orally are absorbed by the digestive tract and metabolized by the liver, reducing the amount of drug that reaches the systemic circulation. In contrast, nearly all of an injected drug reaches the circulation.
Figure 1 summarizes the formulation, filtration, and filling stages of the parenteral manufacturing workflow. During formulation, excipients with the necessary specifications and quality attributes for the formulation are selected. Identification of the most suitable excipients for a particular formulation can help to reduce risk, simplify processes, ensure reliable performance of the final drug product, and ensure speed to market. Proper mixing and sterile sampling are essential attributes for parenteral formulations. Sterile sampling during formulation and filtration should consider operator safety, maintain process sterility, and enable collection of representative samples. During the filling process, a completely closed flow path is necessary and the risk of contamination can be minimized with use of aseptic connections.
Orally administered drugs in the form of tablets and capsules pass through the intestine, which helps to prevent microbial contaminants from entering the bloodstream. Because parenteral medications are injected, and in the case of intravenous delivery, delivered directly into the bloodstream, the potential for contaminating microbes to cause harm is increased. As such, these injectables are considered to be high-risk, and there are significant regulations and strict controls for parenteral drugs and parenteral drug manufacturers. The final drug must be evaluated according to pharmacopeial tests for sterility, endotoxin and pyrogen content, and particle contamination. Guidelines on testing of parenteral dosage forms also exist. The higher risk to patients is reflected in the mandatory risk assessment which involves selection and testing of the raw materials.
There are many ways in which a parenteral drug formulation may become contaminated with microorganisms. Microbes may be introduced from the environment in which the manufacturing takes place, including from personnel and any equipment that is in contact with the product. The water used in manufacturing processes also presents a contamination risk, because whenever water is present, there is the potential for bacterial growth.
Finally, the raw materials used in drug production can be a source of microbial contamination. This is why high-quality raw materials designed specifically for high-risk formulations exist; comprehensive and transparent information on these raw materials should be available from your supplier.
While some parenteral products can be sterilized at the end of the production process, terminal sterilization via steam treatment is not possible for others because the drug substances and/or other ingredients in the formulation are heat sensitive. In these cases, sterile filtration is often the only solution and it must be used along with strict control measures to ensure product quality and prevent introduction of contamination at every production step.
It is important to note, however, that there are many aspects to be taken into consideration to establish a process which is compliant to good manufacturing practice (GMP) principles. One key principle is that a single control measure like terminal sterilization or testing alone is not a sufficient approach to ensure sterility and quality. A terminal sterilization method, for instance, may have a capability threshold, and a high bioburden may exceed the quantity of microorganisms that can be removed. As such, it is important that the level of bioburden must be determined prior to terminal sterilization to ensure that it is not too high for the technique being used. Testing after sterilization can also be an issue, as sterility assays have limitations in terms of specificity and sensitivity.
A high bioburden also creates a risk for endotoxin contamination because endotoxins originate in bacterial cells. Even if the bacteria are killed in the process of manufacturing the raw material or final drug, subcellular components may still be present in the formulation, leading to unacceptable levels of endotoxins and pyrogenic compounds in the final drug product. For these reasons, terminal sterilization is not an effective solution on its own and a comprehensive approach to ensuring sterility is necessary. Aseptic filtration followed by terminal sterilization is an ideal way to ensure sterility and compliant endotoxin levels.
The potential presence of endotoxin and other contaminants in excipients can be minimized by using high-quality raw materials from a trusted supplier; in this case, terminal sterilization becomes a risk mitigation strategy. In addition to helping to ensure product safety, your supplier should offer supply chain transparency and provide the detailed information needed to facilitate quality risk assessment.
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