Aseptic vs. Non-Sterile Processes For Medical Devices & Products
What are aseptic processes?
Aseptic processes are methods or procedures that are undertaken in a sterile environment. The aseptic sterile environment is maintained through specialized equipment that prevents microbial material from technicians, raw materials, or machinery from contaminating medical devices or products.
The terms aseptic and sterile are not synonymous. While both sterile and aseptic products will prevent microbial contamination following use, the processes by which microbial contamination is prevented are different. Sterile is either a complete absence of viable microorganisms or the death of microbes that have the potential to reproduce. Thus, sterile products are often chemically or heat sterilized after being placed in their final packaging. This chemical or heat sterilization process ensures that any microorganisms inside the products (obtained during manufacturing and packaging) are no longer viable. This chemical or heat sterilization process after final product packaging is known as terminal sterilization. However, an aseptic process prevents contamination by the exclusion of microorganisms. For microorganisms to be excluded, an aseptic healthcare product’s manufacturing and packaging processes happen with sterilized materials in a controlled environment designed to prevent microbial contamination of the product. Though the definitions for aseptic and sterile are not the same, sterile is used interchangeably with aseptic. Indeed, many products labeled as sterile are manufactured by aseptic processing rather than terminal sterilization.
What are examples of medical products manufactured in aseptic environments?
- Pharmaceutical sterile products
- Bulk sterile drug substances
- Sterile intermediates
- Excipients
- Medical devices
- Biologics
Note that the USP guidelines referenced for microbiological evaluation should be applied only to ISO-classified clean environments, restricted-access barrier systems (RABS), and isolators used for aseptic processing. Other clean environments are not required to meet the levels of contamination control required for aseptically produced sterile products.
What are examples of common medical products manufactured in non-sterile environments?
- Metered-dose and dry powder inhalants
- Nasal sprays
- Optics
- Vaginal suppositories
- Topicals
- Rectal suppositories
- Oral liquids (aqueous)
- Liquid-filled capsules
- Oral tablets and powder-filled capsules
The non-sterile products listed above are ranked for the potential risk of microbiological contamination (from high to low). The same list applies to medical devices for use in the same body areas (nasopharynx, vagina, skin, rectum, and mouth).
What are the differences between aseptic and non-sterile processes, and which is best for your medical device or medical product?
Aseptic processing requires the exclusion of microorganisms from the manufacturing methods. Microorganisms must be prevented from entering open containers or product materials during processing. Thus, product bioburden and the bioburden of the manufacturing environment impact the risk of unacceptable microbial contamination. Since products made from aseptic processing will not undergo terminal sterilization, it is critical to keep aseptic processing environments free of microbes to alleviate the risk of patient infection following product use. In advanced aseptic processing, operators wearing cleanroom garments are not needed or permitted for aseptic processing.
Unlike sterile products, microbial content in non-sterile products is controlled to the level needed for patient safety within the parameters of product use. Excessive sterility or aseptic processing controls add complexity and cost without safety benefits. Eliminating unnecessary sterility or aseptic processing controls saves money for both manufacturers and patients. Non-sterile processing methods may be advantageous to use depending upon your medical product’s end-use. The manufacture of non-sterile products is distinctly different from sterile products. Similarly, the management of the microbiological content in sterile vs. non-sterile products is different. Sterile products are injected or applied topically to sensitive tissues with a high risk of infection, little to no microbial flora, and no barriers to infection.
In contrast, non-sterile products are administered to regions of the human body that have a high density of natural microbial flora as well as physical and immunological barriers to infection. Even though the microbial requirements for sterile products are stricter, non-sterile products must still go through special manufacturing processing to prevent excessive contamination. Microbial growth in excipients, components, and drug substances are monitored in-depth and are some of the greatest causes for concern for non-sterile products.
How is environmental monitoring for aseptic or non-sterile processes different?
Microbial contamination is inevitable in environments with human operators. Even the most cautious clean-room environment design and fastidious operation will not eliminate the shedding of microorganisms if human operators are present. As a result, zero contamination at aseptic locations during every aseptic process is unrealistic. There are no perfect means to verify that an aseptic processing environment and the product-contact surfaces within that environment are sterile all the time. Technically, monitoring results can neither prove nor disprove sterility. However, manufacturers should review environmental monitoring results frequently to operate the facility in a validated state of control.
Due to monitoring limitations, manufactures cannot rely on monitoring, statistics, or aseptic processing simulations to assure a sterility level for aseptic processes. Sterility assurance is best created by focusing on human-borne contamination and designing the facility to mitigate risk from this contamination. Microbial contamination risk is greatly mitigated by reducing or eliminating human interventions through proper equipment design and by providing sufficient air exchanges per hour for the personnel population within the facility. Effective movement of personnel and materials, the proper control of temperature and humidity, and periodic sanitization are other risk mitigation factors. The list below of USP 1116 gives the suggested contamination recovery rates in various aseptic environments.
Environmental monitoring of aseptic processes involves:
- Establishing mandatory trainings for operators on proper cleanroom garb and practices for aseptic processes.
- Creating an evaluation program for microbial contamination (control parameters, sampling plan, and sampling sites).
- Creating protocols for culture conditions and quantification of the microbes following sampling.
When it comes to non-sterile processes, monitoring manufacturing environments for microbes is a qualitative tool to minimize contamination risk. A successful environmental monitoring program confirms the effectiveness of microbiological controls and detects unforeseen contamination issues early, saving time and money. Microbial methods and practices for aseptic facilities may be used but are not intended for non-sterile environments. Often the levels of transient contamination depend on the level of human activity and gowning requirements of the manufacturing facility. This is because most microbial contaminants in clean environments are from humans. In non-sterile products, manufacturers expect controlled bioburden levels that will not result in a risk to the end-user. Thus, manufacturers need to establish acceptable levels of microorganisms within each product and perform regular production plant hygiene assessments to keep up the effectiveness of the facility’s microbial environmental controls. Hygiene assessments include microbial sampling, staff evaluation for appropriate gowning and standard operating procedures, raw material assessments, and evaluations of cleaning protocol effectiveness.
Summary
Overall, medical products and medical devices are manufactured using aseptic and non-sterile processes. Non-sterile processes still monitor microbial levels within the manufacturing facility but do not have stringent requirements like aseptic processes (which aim to eliminate any microbial ingress). Environmental monitoring for aseptic processes evaluates whether ISO-certified clean environments (such as restricted-access barrier systems (RABS) and isolators used for aseptic processing) are suitable for preventing microbial contamination of medical products during manufacturing, packaging, or testing. Environmental monitoring of non-sterile processes makes sure that all clean rooms and equipment meet microbial levels in alignment with the safety limits for the medical product. Examples of common non-sterile products are oral and aerosolized drugs. All in all, make sure you choose a contract testing organization that can support you with appropriate and consistent environmental monitoring for aseptic and non-aseptic processes for your medical product or medical device.
MycoScience is a contract manufacturing organization specializing in sterile syringe and vial filling. MycoScience also offers Preservative Efficacy Testing, Sterilization Validations, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, Cytotoxicity Testing, Bacterial Endotoxin Testing, EO Residual Testing, Package Integrity Testing & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
References
United States Pharmacopeial Convention. <1115> Bioburden Control of Non-Sterile Drug Substances and Products. Rockville, MD, USA. 2021. (USPC <1115>).
United States Pharmacopeial Convention. <1116> Microbiological Control & Monitoring of Aseptic Processing Environments. Rockville, MD, USA. 2021. (USPC <1116>).
United States Pharmacopeial Convention. <1211> Sterility Assurance. Rockville, MD, USA. 2021. (USPC <1211>).
