Top Nonsterile Manufacturing Processes
What are nonsterile processes?
Nonsterile processes are methods or procedures undertaken in an environment where bioburden is controlled to safety levels based on product attributes, route of administration, and target patient population. Non-sterile processes contrast with sterile processes, in which the bioburden is essentially eliminated. The non-sterile products listed below are ranked for 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). This article covers differences between nonsterile and sterile product manufacturing facilities and products, top nonsterile pharmaceutical products, packaging component requirements for nonsterile products, and microbial examination of nonsterile products.
List of common nonsterile pharmaceutical products:
- 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
Why is environmental monitoring for nonsterile processes important for your medical device or product?
Unlike sterile products, microbial examination of nonsterile 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. Nonsterile processing methods for nonsterile pharmaceutical products may be advantageous depending on your medical product’s end use. Nonsterile product manufacture and microbial content management are distinctly different for non-sterile vs. sterile processes. 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, nonsterile 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 manufacturing processing that prevents excessive contamination of the product. Microbial growth in excipients, components, and drug substances is monitored in-depth and is some of the greatest microbial challenges for non-sterile products. Examples of standard non-sterile products are listed below.
How are manufacturing environments monitored for non-sterile products?
Monitoring manufacturing environments for microbes is a qualitative tool to minimize contamination risk in nonsterile pharmaceutical products. 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 nonsterile environments. Often the levels of transient contamination depend on the level of human activity and gowning requirements of the manufacturing facility. Indeed, most microbial contaminants in clean environments are from humans. In nonsterile products, manufacturers expect controlled bioburden levels that will not provide 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 for microbial examination of nonsterile products include microbial sampling, staff evaluations for the appropriate execution of gowning and standard operating procedures, raw material assessments, and evaluations of cleaning protocol effectiveness.
Top 12 Nonsterile Processes For Medical Devices & Products
#1: Decontamination of product contact surfaces, materials, and containers
Regular cleaning and sanitation of large manufacturing equipment, surfaces, parts, vessels, housings, accessories, lines, or any other items are critical to keeping microbial levels low during product manufacturing is critical to keeping microbial levels low. The validation of transfer line cleaning for items such as tubes, pipes, chutes, or assembly lines keeps microbes out of manufacturing processes. Most decontamination processes for microbial examination of nonsterile products utilize steam. Steam is also common for sterile product decontamination processes.
#2: Bioburden and pyrogen reduction treatments for raw materials and active ingredients
Regular audits of raw material sources and creating methods for quantifying pyrogenic burden in raw materials or equipment are essential to keeping endotoxins out of aseptic processes. Most of these bioburden reduction treatments utilize dry heat or steam.
#3: Product transfer processes and systems for handling and movement of materials
It is important to verify that product materials passing through items such as tubes, pipes, chutes, or assembly lines are not contaminated during their movement. Further, when restricted access barrier systems (RABS) are used, all material transfers must be performed safely through special doors, seals, or locks to keep microbes out of the RAB manufacturing space.
#4: Operation of filling and finishing equipment
To prevent microbial contamination, all elements of the filling process (from stopper inserts to the product itself) must be sterile during the filling process. It is also essential for filling equipment like stopper inserters and cappers to be functioning properly and within ISO-certified clean rooms. Packaging component requirements for nonsterile products differ slightly from those of sterile products. Specifically, the sterility limits for the packaging component requirements for nonsterile products are less than those for sterile products. Thus, nonsterile products can be filled in cleanrooms with lower ISO certifications.
#5: Facility monitoring systems, distributed control systems, data collection, electronic record generation, and data storage systems
Environmental monitoring for all levels of product manufacture (from raw materials to storage) is critical to aseptic process success. Environmental monitoring covers monitoring systems, automation, facility monitoring, programmable logic controllers (PLCs), laboratory information management system (LIMS), and other aspects of manufacturing process design for aseptic processing. The environmental monitoring needs for packaging component requirements for nonsterile products are less than for sterile products. Thus, environmental assessments may be performed less frequently.
#6: Warehouse, cold storage, handling
Some products require cold storage, temperature control, light control, or humidity control. It is important to monitor product warehouse and shipping conditions after products leave the facility. Further, products must be packaged and handled such that there is no risk of microbial or toxin ingress during travel.
#7: Cleaning and disinfectant processes
Regular testing is important to ensure all disinfectants are fully functional and within expiry. Further, regular testing ensures that cleaning protocols effectively keep clean rooms as microbe-free as possible.
#8: effectiveness of cleanroom filters and air handling systems
It is important to use higher-level ISO-classified environments in high-risk operations. High-efficiency particulate air (HEPA) filters must be working appropriately and often replaced to keep the microbial levels of air and surfaces free of microbes. Maintenance of HEPA filters and the heating, ventilation, and air conditioning systems is important for microbial monitoring and control in clean rooms. It is important to monitor cleanroom airflow to determine the errant path microbes may take. Through knowing cleanroom airflow, cleaning and sanitation precautions for equipment within that airflow system can be added, and sensitive manufacturing processes can be avoided in those areas.
#9: Protective equipment sterilization and processes for operational personnel
Any cleanroom technicians will need to wear protective equipment to operate within a cleanroom. Gowns and gloves that are used to prevent human microbial contamination must be sterile for appropriate cleanroom protection. The procedure that an operator uses when gowning and when an operator gowns affect how well gowns prevent microbial exposure.
#10: Cleaning and sanitization of RABS and cleanroom equipment, walls, floors, and surfaces
RABS must have protocols for regular surface, wall, and equipment cleaning and disinfection to limit the number of microbes in the space. RABS, unlike isolators, have no automated bio-decontamination cycle using H2O2 vapor or another sanitation vapor. RABS and isolators exist within clean rooms. Regular cleaning and sanitation of cleanroom equipment, walls, floors, and other surfaces is critical to keeping microbial levels low during product manufacturing and is performed using steam and chemical sanitation processes.
#11: Substituting disposable components or utensils for cleaning or manufacturing processes
Where appropriate, processes with high contamination risk for nonsterile products may wish to adapt disposable components or utensils for manufacturing or cleaning processes.
#12: Operation and cleaning of all packaging equipment
Regular cleaning and sanitation of components for packaging (materials, equipment, etc.) are critical to keeping microbial levels low during product manufacturing. Packaging equipment protects aseptically manufactured products from further microbial contamination. Thus, all packaging equipment must be operating effectively and under aseptic conditions during product wrapping, filling, labeling, capping, or sealing.
Summary
Overall, dietary supplements, cosmetics, some pharmaceutical preparations, and my medical devices are manufactured using non-sterile processes. Nonsterile processes monitor microbial levels within the manufacturing facility but do not have excessively stringent requirements like aseptic processes (which aim to eliminate any microbial ingress). This article details the top 12 nonsterile processes to be aware of and validate to ensure your medical and cosmetic products remain within their microbial limits. MycoScience is a contract manufacturing organization that specializes in nonsterile and aseptic syringe and vial filling for parenteral products. Consider choosing MycoScience for your fill-finish parenteral or cosmetic product needs.
MycoScience is a contract manufacturing organization specializing in sterile syringe and vial filling for parenteral products. MycoScience also offers testing services, including Preservative Efficacy Testing, Cytotoxicity Testing, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, EO Residual Testing, Bacterial Endotoxin Testing, Package Integrity Testing, Sterilization Validations & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
United States Pharmacopeial Convention. <1115> Bioburden Control of Non-Sterile Drug Substances and Products. Rockville, MD, USA. 2021. (USPC <1115>).
United States Pharmacopeial Convention. <1211> Sterility Assurance. Rockville, MD, USA. 2021. (USPC <1211>).
United States Pharmacopeial Convention. <2023> Microbiological Attributes Of Nonsterile Nutritional And Dietary Supplements. Rockville, MD, USA. 2021. (USPC <2023>).
