PharmTech: ER injectables cannot be terminally sterilized. Why is this the case, and what types of sterilization should be used instead?
(Herbert, Alkermes): The challenge with terminal sterilization is that the physical and chemical stability of the materials used ER injectables—drug
and polymers—do not generally withstand the temperatures required to effect terminal sterilization. Terminal sterilization
utilizes high temperatures or radiation to make the product sterile. These conditions are likely to affect the API, creating
some level of impurities. For polymer-based ER injectables, these high temperatures would melt the polymer, and radiation
would typically decrease the molecular weight.
Additional therapeutic areas for ER injectables
Aseptic processing is therefore used to produce sterile product in temperature- and radiation-sensitive products. Process
equipment is steam sterilized-in-place, and ingredients entering the process pass through sterilizing filters that remove
any organisms that might be in the ingredients. The majority of the processing takes place in closed equipment to prevent
human contact. Media simulations are conducted to demonstrate that sterile product can be made in the process equipment.
(Thiel and Loffredo, Hospira): When terminal sterilization by autoclaving is not possible, the next default sterilization approach is sterile filtration
followed by aseptic filling, as noted. However, some types of ER injectables are also unable to be filter-sterilized. For
example, poly(lactic-co-glycolic acid) (PLGA) microparticle ER formulations cannot be filter-sterilized because the diameter
of the PLGA microparticles exceeds the pore size of a sterilizing-grade filter (0.2 µg). These microparticle formulations
require specialized manufacturing with sterile compounding and processing.
Stickelmeyer (Lilly): It is correct that terminal sterilization by heat, chemical agents, or radiation is not recommended. Typically, ER formulations
containing polymers may be susceptible to degradation at elevated temperatures due to the low glass-transition temperature
of the polymers, thus making heat sterilization difficult. Ready-to-use suspension formulations may be able to withstand an
autoclave cycle; however, heat treatments of aqueous suspensions may accelerate hydrolysis reactions, flocculation, or Ostwald
ripening and, thus, in many cases are not suitable.
For chemical sterilization by gases, there are concerns about achieving adequate sterility and minimizing residual gas levels.
Ionizing radiation may be feasible for solid particulate formulations (either gamma or electron beam) but may not be appropriate
for biologics or for polymeric formulations because the radiation may affect polymer properties (e.g., cross-linking, degradation)
that impact drug release.
Development of electron-beam sterilization cycles that expose the product to a higher energy—yet shorter processing times—may
minimize the impact on release properties and long-term chemical and physical stability. Lower irradiation doses based on
bioburden level may also provide required sterility assurance while reducing impact on chemical and physical stability.
Sterilizing filtration can be successfully applied to smaller particulate delivery systems but may not be feasible for larger
particulate systems. In these cases, aseptic processing of sterile subsystems can be complex and increase risk.
Tipton (Evonik): The notion that ER injectables cannot be terminally sterilized is not universally true. If both the active and the excipients
used in an ER formulation can withstand ionizing radiation independently—and combined in the dosage form—a terminal sterilization
process can be developed and validated. However, many ER injectables are more complex and cannot handle radiation sterilization.
This may be due to a complex active such as a protein that is susceptible to chain scission, oxidation degradation, disulfide
bond rupture, or changes in conformation. Also, some of the formulation materials may be susceptible to radiation (i.e., they
may undergo chain scission). In some cases, the formulation can be engineered to handle this decrease in polymer molecular
weight. Finally, there may be complex interactions between formulation ingredients that can lead to instability.