Environmental and Human Health Impact
For environmental and occupational health and safety hazards the following section does not address hazards from associated equipment electrical, piping, enclosed spaces, utilities, lasers, facility modifications, and worker ingress and egress.
Heat Sterilization
Heat sterilization can have a significant impact on workers who operate and maintain the sterilization equipment. The high temperatures and pressures involved can pose a risk of injury, and workers must be properly trained and equipped with appropriate personal protective equipment, including eyewear and heat resistant gloves to ensure employee safety. Steam sterilization is the most common and most reliant sterilization technique. Additionally, the high-energy and water consumption of heat sterilization can increase the cost of manufacturing and contribute to global climate change. (5,32,61,62)
The use of heat sterilization can also have environmental impacts, including the emission of greenhouse gases and the production of hazardous waste. The large amounts of water and energy required for heat sterilization can contribute to resource depletion and pollution. For an autoclave >800L the “Total electricity and water consumption per mass sterilized was 1.9 kWh kg–1 and 58 L kg–1, respectively. The linear regression model predicting electricity use was: kWh = 15.7+ 0.14 × mass (in kg; R2 = 0.58, P < 0.01).”(63) One study found that on average an idle autoclave, meaning the jacket and chamber are not heated between periods of use, consumed 11kwh/day where a high use unit consumed more than 200kwh/day.(64) This demonstrates that a huge cost and energy savings could be gained by idling the sterilizers between use periods. In addition to this, by not heating the unit it would reduce the risk of accidental burns to employees. (65)
Gas Sterilization
Gas sterilization is a widely used technique in the pharmaceutical industry to sterilize medical devices, equipment, and other materials. In the United States, the Food and Drug Administration (FDA) regulates the use of gas sterilization in the pharmaceutical industry. Manufacturers of gas sterilization equipment must obtain FDA approval for their products, and users of gas sterilization must comply with FDA regulations for the sterilization of medical devices. Gas sterilization can also have environmental impacts, including the emission of greenhouse gases and the production of hazardous waste. Ethylene oxide is a known carcinogen and must be handled carefully to prevent environmental contamination. Hydrogen peroxide, on the other hand, breaks down into water and oxygen and is less harmful to the environment. Gas sterilization requires careful safety protocols to ensure that workers and the environment are not exposed to harmful levels of gas. Gas detectors must be used to monitor gas levels, and ventilation systems must be in place to prevent gas buildup. Additionally, gas sterilization equipment must be properly maintained to prevent leaks and ensure the safety of workers and the environment. For gas sterilization, a system like an isolator or other system that would self-contain the chemicals for the sterilization cycle and then evacuate the chemicals to prevent worker exposure should be used. Depending on the gas used, additional safety measures may need to be in place for environmental and human health. (5,24,30,51,66–68)
PPE and engineering controls can be used to reduce exposure to gas sterilization methods. PPE will be provided to all employees at the expense of the company and not of the employee. PPE includes training on its use: respirator protection rated for the specific chemical and use, chemical protective clothing including but not limited do a face shield, chemical safety goggles equipped with impact resistant lenses, full body protection clothing. For work where it is feasible to install engineering controls, like high ventilation or a closed process, to protect employees a company will do so. For ventilation systems the air handlers must be designed to ensure that none of the chemical exhausted air is recirculated into the workplace. (69–71) Where it is not feasible a company will provide training and PPE to limit and minimize exposures. Respirators must meet 29 CFR 1910.134. Employers must also have a program for the care, inspection, storage, and integrity of respirators to ensure they are in acceptable condition for use. (69) Employers cannot use scheduling to keep employee limits within the environmental exposure or excursion limits. In addition, employers will have a plan for periodic leak tests and detection, periodic maintenance, and a plan for emergencies, putting procedures in place to protect workers and minimize injuries. For employees exposed to chemicals, an employer will have monitoring records identifying the environmental monitoring, analytical method, as well as employees and PPE used. This record will be retained for NLT 20 years and made available to the employee or former employee as well as any representatives from the Secretary of Labor and Secretary of Health, Education, and Welfare. (69)
Employers must inform employees of the hazards associated with the chemical(s) they may encounter at work. In addition employers must provide continuous education and all information available for exposure hazards, safe use, maintenance procedures, emergency plan, and symptoms (69). Any employees showing signs and symptoms of overexposure will be provided medical surveillance by the company. (27)
ETO has occupational safety and health standards imposed by the United States Department of labor standard 1910.1047. ETO is a known carcinogen and has been tied to reproductive effects and learning disabilities. Within the standard the Occupational Safety Health Administration (OSHA) established permissible exposure limits (PELs) of 1‐ppm airborne ETO TWA for an 8‐hour work shift in a 40‐hour work week. The action level for ETO is 0.5 ppm for an 8‐hour TWA, and the short‐term excursion limit is 5 ppm for a 15‐minute TWA.5 In addition the employer must ensure that employees will not be exposed to the excursion limit of 5ppm over 15 minutes. All monitoring must have a confidence interval (CI) of 95% and for any monitoring the employer must notify the employees of the results withing 15 days. For all areas containing EtO the entrance(s) must be labeled with a sign stating the dangers and risks as well as regulating access to the area for authorized personnel only. 72 ETO is a volatile organic compound (VOC), a hazardous air pollutant (HAP), and a known greenhouse gas that cause climate change by trapping energy in earth atmosphere retaining heat. (73–75)
Nitrogen Dioxide can be an effective method for sterilizing medical devices, it is important to follow strict safety protocols when using this method. NO2 is a toxic gas and can be harmful to humans if not used properly. Proper ventilation and personal protective equipment are essential when working with NO2, and all safety protocols and regulatory requirements must be followed to ensure safe and effective sterilization. In addition to worker safety, environmental safety must also be considered. NO2 affects the environment by reaching with water, oxygen, and other chemicals to form acid rain, make the air hazy, and contributes to nutrient pollution in coastal waters. (67,76,77)
Additionally, NO2 gas sterilization is subject to regulation by several federal and state agencies, including the U.S. Environmental Protection Agency (EPA) and the Occupational Safety and Health Administration (OSHA). Manufacturers and users of NO2 gas sterilization equipment must comply with all applicable regulations to ensure the safety of workers and the environment. For occupation limits known as oxides of nitrogen since nitrogen dioxide in the environment results in some nitric oxide due to oxidization. (69) With this in mind the nitrogen dioxide PEL is 5ppm and STEL 1ppm per 8 hour TWA as determined by 15 minute sampling. (76) Nitric oxide even though it is not the target chemical will need to be monitored, its PEL is 25ppm TWA for a 10 hour workday (69). For worksites that meet or exceed half of the respective PEL’s for oxides of nitrogen there needs to be environmental monitoring of the areas at least every six-months and after any installation, equipment changes, process modification, or other worksite change (69). If the worksite is exceeding the limits, then engineering controls must be added and environmental monitoring data from consecutive 15-day monitoring results show that the controls were effective in bringing the oxides of nitrogen within the acceptable limits. The EPA regulates the use of NO2 under the Clean Air Act, which establishes standards for air quality and emissions of hazardous air pollutants. Facilities that use NO2 must comply with EPA regulations related to emissions of nitrogen oxides (NOx) and other air pollutants. (67)
Chlorine Dioxide has a STEL of 0.3 ppm for 15 minutes of exposure and 0.1 ppm TWA. (78) Chlorine Dioxide is highly reactive and breaks down quickly in water, oxidizing organic materials within it. It is well established that chlorine dioxide is harmful to all forms of life and in the USA is ranked as one of the top 10% of the most hazardous compounds to ecosystems. (79,80)
Hydrogen Peroxide decomposes into water and oxygen and is non-flammable. It is highly oxidizing and can be toxic if ingested, inhaled, or dermal absorption. It has a PEL of 1 ppm for 8-hour TWA. (28,81) Hydrogen peroxide and peracetic acid safety management fall under 1910.119- Process safety management of highly hazardous chemicals. Peracetic Acid has a STEL of 0.4 ppm and doesn’t create harmful disinfection by-products. (82) Peracetic acid decomposes into acetic acid, water, and oxygen and is being considered as an alternative to chlorine dioxide in some industries because of its minimal environmental impact and absence of carcinogenic and mutagenic compounds. (83,84)
Formaldehyde is regulated for workplaces through standard 1910.1048 which covers all occupational exposure. The action level for formaldehyde is 0.5 ppm over an 8-hour TWA and the PEL should not exceed 0.75 ppm for an 8-hour TWA. The STEL is for 2 ppm airborne formaldehyde for 15 minutes. (85) It's worth noting that formalin, the vaporized form of formaldehyde, can be toxic and potentially carcinogenic, so it's important to follow proper safety protocols when using it for sterilization. Additionally, formalin is not suitable for all types of equipment or surfaces. Formaldehyde also breaks down into formic acid, a component of acid rain, and carbon monoxide which is a GHG. (86)
Chemical
Chemical sterilization can have a significant impact on workers who operate and maintain the sterilization equipment. Chemical sterilants are toxic and can cause harm to workers if not properly handled. Exposure to these chemicals can cause respiratory, skin, and eye irritation, as well as more serious health effects, such as cancer. Therefore, workers must be properly trained and equipped with appropriate personal protective equipment to ensure their safety. Chemical sterilization can also have environmental impacts, including the emission of greenhouse gases and the production of hazardous waste. Chemical sterilants can be hazardous and must be handled carefully to prevent environmental contamination. Additionally, the disposal of chemical waste can have negative impacts on the environment if not properly managed. (18,30,32,50)
Chemical sterilization requires careful safety protocols to ensure that workers and the environment are not exposed to harmful levels of chemicals. Chemical detectors must be used to monitor chemical levels, and ventilation systems must be in place to prevent chemical buildup. Additionally, chemical sterilization equipment must be properly maintained to prevent leaks and ensure the safety of workers and the environment. (28,30,87)
Radiation
Gamma, X-ray, and e-beam radiation sterilization are commonly used techniques in the pharmaceutical industry to sterilize medical devices, equipment, and other materials. The ISO 11137-1 standard on radiation sterilization applies to all three modalities of ionizing radiation sterilization, including gamma radiation, electron beam radiation, and X-ray radiation. However, gamma radiation has been used much more extensively for sterilization than the other two modalities, and as a result, the ISO 11137-1 standard has been primarily developed and validated for gamma radiation sterilization. For single use materials in drug manufacturing there is not a direct regulation, but the components must meet 21CFR211.65. (56) This regulation from the FDA states:
“Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” 88
Gamma, X-ray, and e-beam sterilization can generate peroxides, peracids, and other reactive species during the oxidation of proteins (55). Ionizing radiation is regulated by the United States Department of Labor, the Nuclear Regulatory Commission (NRC), the Department of Energy. Radiation sterilization can have a significant impact on workers who operate and maintain the sterilization equipment. Exposure to high levels of radiation can cause acute radiation sickness, which can be fatal. Therefore, workers must be properly trained and equipped with appropriate personal protective equipment to ensure their safety. (89)
For gamma, x-ray, and e-beam sterilization within a facility needs a radiation protection program for the health and safety of its employees. The program should include qualified staff, As Low as Reasonably Achievable (ALARA) doses, a personnel monitoring program, surveys and environmental monitoring, radiological controls (time, distance, and shielding), robust training for employees, a written emergency procedure, reporting programs for dosimetry reports, and internal audit procedures to audit the program annually. Radiation sterilization can also have environmental impacts, like contamination of air, water, surfaces, soil, plants, buildings, and wildlife. Biologic effects of acute radiation include damage to genetic material which can cause reproductive damage, cancer, and cardiovascular disease in humans and in higher or prolonged dosages can lead to death. Radiation also creates emission of greenhouse gases from the energy required to power the equipment. Additionally, the disposal of radioactive waste can have negative impacts on the environment if not properly managed. (90–93)
For the design of a room containing ionizing or radioactive equipment and components the radiation source and surrounding areas should be shielded. The recommendation from the National Council on Radiation Protection and Measurements (NCRP) is 5mGy for restricted controlled areas and for uncontrolled 2mGy. The shielding design will need to consider adjacent rooms including any floors above and below the radiation source. The shielding can be achieved through using lead lined materials for the floors, walls, ceilings, and doors. The thickness of the materials and other materials like concrete will need to be suitable to provide the recommended shielding without creating additional radiation. Additional radiation can occur if inappropriate materials are used for shielding which can split beta particles into x-rays. The type of radiation matters because it will require different shielding materials like aluminum or plastic. A health physicist should be on the shielding design group to evaluate if shielding and radiation protection is appropriate and sufficient. (90)
Interlocking systems can also be used for shielding by cutting off or reducing the emission rate from a radiation source or piece of equipment. Additional controls like radiation caution signs as required by the 29 CFR 1910.1096, warning systems, robust training program, shielding PPE (lead lined aprons, vests, thyroid collar, gloves, and goggles), respirators, and detailed standard operating procedures can also reduce the risk of radiation exposure to employees. The employer must also monitor exposure levels for employees and track radiation doses to ensure the protection of its employees. (90) Contamination but also be considered, monitored, and minimized. Contamination occurs when radioactive materials are on the surface of a material (90). The Department of Energy outlines surface contamination values and at what level the contamination needs to be controlled or removed (91).
X-ray and e-beam use machines to create radiation so they do not pose the same risk as gamma since they can be paused and when not in use the machine(s) can be turned off. (57) In addition per 1910.1096 Radioactive materials have to be secured against being removed and will not be disposed of in a manner that is not approved byy the Nuclear Regulatory Commission or a State. (89)
Microwave
The use of microwave sterilization in the pharmaceutical industry is currently in the experimental stage, and there is not yet a well-established regulatory framework for its use. However, the Food and Drug Administration (FDA) has issued guidance on the use of microwave sterilization for medical devices, which provides some indication of the regulatory considerations that may apply to its use in the pharmaceutical industry. (94)
According to the FDA, manufacturers of microwave sterilization equipment must obtain FDA approval for their products, and users of microwave sterilization must comply with FDA regulations for the sterilization of medical devices. Radiation detectors must be used to monitor radiation levels, and ventilation systems must be in place to prevent radiation buildup. Additionally, microwave sterilization equipment must be properly maintained to prevent leaks and ensure the safety of workers and the environment. In addition, the FDA recommends that users of microwave sterilization equipment perform rigorous testing to demonstrate the effectiveness of the sterilization process, and that they implement strict quality control procedures to ensure the consistency and reliability of the process. Microwave sterilization can have a significant impact on workers who operate and maintain the sterilization equipment. Exposure to microwave radiation can cause burns and other health effects. Therefore, workers must be properly trained and equipped with appropriate personal protective equipment to ensure their safety. Microwave sterilization is affected by water content of materials so extensive validation of the settings would need to be performed to ensure adequate log reduction. Microwave technology does not require large amounts of energy input as compared to other sterilization technologies, for a 500L chamber only 3Kw/h of energy are used. Studies have shown that with 50% and greater water content and 19kw of power for several minutes (depending on load size) that over 99% sterilization is achieved. (95–99)
Ozone
The FDA regulates the use of ozone sterilization for medical devices and equipment. Manufacturers of ozone sterilization equipment must obtain FDA approval for their products, and users of ozone sterilization must comply with FDA regulations for the sterilization of medical devices. The EPA regulates the use of ozone as a sterilant under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). Ozone is considered a pesticide under FIFRA, and its use as a sterilant must be registered with the EPA. Employers who use ozone sterilization must comply with OSHA's standards for hazardous substances, which include requirements for monitoring, ventilation, personal protective equipment, and employee training. (100,101)
Overall, the use of ozone sterilization in the pharmaceutical industry is subject to a complex and evolving regulatory environment, which requires careful attention to compliance and risk management to ensure the safety of workers and the environment. Ozone can be toxic to humans if not used properly, and exposure to high levels of ozone gas can cause respiratory problems and other health effects. Therefore, workers must be properly trained and equipped with appropriate personal protective equipment to ensure their safety. Ozone can have negative environmental impacts, including the emission of greenhouse gases from the energy required to generate ozone gas. Manufacturers and users of ozone sterilization equipment must stay up-to-date on all applicable regulations and follow strict safety protocols to ensure safe and effective sterilization.