ETO Sterilization - Sterilization of Health Care Products Using Ethylene Oxide - A Guide to Industry Practices & Regulatory Requirements

In the healthcare industry, ensuring the safety and efficacy of medical devices is paramount. Sterilization plays a critical role in achieving this goal by eliminating harmful microorganisms from medical equipment. Among the various sterilization methods available, ethylene oxide (EtO) sterilization is widely used for its effectiveness in sterilizing heat-sensitive devices. ISO 11135 provides guidelines for the sterilization of healthcare products using ethylene oxide. This article aims to explore ISO 11135 and highlight industry practices related to EtO sterilization.

Sterilization processes are subject to stringent regulations and oversight by regulatory bodies worldwide due to their critical role in ensuring the safety and efficacy of medical devices. Regulatory agencies, such as the Central Pollution Control Board (CPCB) India,  Food and Drug Administration (FDA) in the United States, the European Medicines Agency (EMA) in Europe, and the National Medical Products Administration (NMPA) in China, have established frameworks to govern the sterilization of healthcare products. These regulations encompass a wide range of requirements related to sterilization methods, validation protocols, quality management systems, product labeling, and environmental monitoring. Compliance with regulatory requirements is essential for healthcare facilities, sterilization service providers, and medical device manufacturers to obtain regulatory approvals, ensure patient safety, and maintain public trust. Regulatory oversight helps to standardize sterilization practices, minimize risks to patients and healthcare workers, and promote continuous improvement in sterilization technologies and methodologies. By adhering to regulatory standards and guidelines, stakeholders in the healthcare industry demonstrate their commitment to quality, safety, and regulatory compliance in sterilization processes.

ISO 11135 Role and its Objective

ISO 11135 is a crucial international standard that serves as a guide for the sterilization of healthcare products utilizing ethylene oxide (EtO) as the sterilizing agent. This standard outlines the essential principles, processes, and procedures necessary to ensure the safe and effective sterilization of medical devices, thus contributing significantly to patient safety and public health. The key aspects covered by ISO 11135 are:

• Quality Management System (QMS): One of the foundational elements of ISO 11135 is the establishment of requirements for the implementation of a Quality Management System (QMS). This QMS framework is essential for ensuring that sterilization processes are conducted in a systematic and controlled manner, thereby enhancing the reliability and consistency of sterilization outcomes.
• Sterilization Process: ISO 11135 meticulously details the entire sterilization process, encompassing various stages such as pre-treatment, exposure to ethylene oxide, aeration, and post-treatment. Each step is carefully documented and standardized to ensure the efficacy and safety of the sterilization process for different types of medical devices.
• Validation and Control: The standard places significant emphasis on the validation and control of the sterilization process. It outlines specific requirements for conducting validation protocols, implementing robust monitoring mechanisms, and establishing stringent process controls. This systematic approach ensures that the sterilization process consistently meets predefined standards of efficacy and safety.
• Biological Indicators: ISO 11135 specifies the use of biological indicators as a critical tool for monitoring the effectiveness of the sterilization process. These indicators, containing known populations of resistant microorganisms, serve as sensitive indicators of microbial lethality, providing valuable insights into the efficacy of the sterilization cycle.
• Packaging and Labeling: Recognizing the importance of maintaining sterility until use, ISO 11135 provides comprehensive guidelines for the packaging and labeling of sterilized products. These guidelines ensure that sterilized medical devices are adequately protected during storage and transportation, minimizing the risk of contamination or degradation. 
• Environmental Monitoring: Finally, ISO 11135 includes provisions for environmental monitoring to prevent ethylene oxide exposure and ensure workplace safety. By establishing rigorous monitoring protocols and safety measures, the standard helps mitigate potential health risks associated with ethylene oxide sterilization processes, safeguarding the well-being of personnel and the environment.

Role and Importance of Risk Management in ETO process

Risk management plays a critical role in ethylene oxide (EtO) sterilization processes due to the potential hazards associated with this method of sterilization. Ethylene oxide is a highly effective sterilant capable of penetrating a wide range of materials, making it suitable for sterilizing heat-sensitive medical devices. However, EtO is also highly flammable, explosive, and carcinogenic, posing significant risks to both personnel and the environment if not handled properly. Therefore, effective risk management is essential to mitigate these hazards and ensure the safe and reliable operation of EtO sterilization processes.

Ethylene oxide (EtO) sterilization processes present unique risks that require attention and management to ensure the safety of personnel, patients, and the environment. By integrating the principles outlined in ISO 14971 - the international standard for risk management of medical devices - with EtO sterilization practices, organizations can effectively identify, assess, and mitigate risks associated with this sterilization method.

The Key aspects of integrating ISO 14971 with EtO sterilization risk management;

• The consideration of risks associated with the process, sterility assurance level and container closure system
• The residue of ETO gas on the devices and its validation
• Consideration and mitigation of hazards may include but not limited to exposure to ethylene oxide, flammability risks, and potential environmental impacts

Risk assessments for EtO sterilization processes involve evaluating factors such as EtO concentration, exposure duration, ventilation systems, and operational procedures. 

Control measures for EtO sterilization may include; 

• Engineering controls such as ventilation systems, gas monitoring devices, and automated safety interlocks to regulate EtO concentrations and prevent exposure incidents. 
• Administrative controls, including standard operating procedures, training programs, and emergency response protocols, are also implemented to minimize human error and ensure safe working environments.

Industry Practices - ETO Process

In addition to adhering to the requirements of ISO 11135, industry best practices further enhance the effectiveness and safety of ethylene oxide sterilization. Some common industry practices include;

• Equipment Qualification: Healthcare facilities and sterilization service providers conduct qualification studies to ensure that ethylene oxide sterilization equipment meets performance requirements.
• Process Validation: Validation studies are performed to demonstrate the effectiveness and reproducibility of the ethylene oxide sterilization process for specific medical devices.
• Product Compatibility Testing: Prior to sterilization, compatibility testing is conducted to assess the compatibility of medical devices with ethylene oxide and identify any potential risks or adverse effects.
• Monitoring and Documentation: Continuous monitoring of critical process parameters, such as temperature, humidity, and ethylene oxide concentration, is essential to maintaining process control and ensuring product quality. Detailed documentation of sterilization processes and outcomes is also vital for traceability and regulatory compliance.
• Training and Education: Personnel involved in ethylene oxide sterilization undergo comprehensive training to ensure competency in operating sterilization equipment, handling hazardous materials, and adhering to safety protocols.

Regulatory Requirements and Best practices as per ISO 11135

With refrence to the requiremenst during the audit by Indian Regulatory Authority (CDSCO), US FDA, European Notified Bodies (CE Audits) and MDSAP Audits, it is been evidenced that majority of non-cpnformity and CAPA are raised in the field of Sterilization which includes but not limited to; 

• The ETO Process Validation 
• Inclusion of New products in to sterilisation process
• Equipment Qualification and Performance qualification records
• Calibration of measuring equipment and components in ETO Chamber
• Sterility validation records of each lot sterilized 

The basic requirements to comply the ISO 11135 are; 

Requirement	Document Evidence	Explaination	Carried out
Callibration	Reports of Callibration	Calibartion Reports of all measuring and monitoring equipmets installed in the ETO Chamber (i.e Temperature Sensors, Humidity Sensors, Gas Concentartion Sensors gas injectors and Pressure monitors)	External with NABL accredited Laboratory if carried out internal appropriate traceability shall be maintianed
Thermal Mapping	Thermal mapping report	The temperature and relative humidity mapping is carried out annually to validate the ETO chamber which is carried out in three cycles at Empty Load, half Load and Full load.	External  Can be carried out In-House with protocol in lined with ISO 11135
Safety and Precaution	Risk Analysis Report	The Risk analsysis shall include the risks to the product quality assurance and the risks due to the process which affect the environment, employee.	In-house (Proper Instructions, Warnings and Training provided to Operation and Staff)
Qualification (IQ/PQ/OQ)	IQ/PQ/OQ Report	The Equipment Qualification report is generated and kept in record by the organisation with the help of Equipment Manufacturer	External (Carried by Equipment Manufacturer and Organization collectively)
Process Validation	Validation Report	The process validation report shall be prepared in accordance with organization requirement and to establish the cycle time for the device to be sterilized;  The Cycle time is variable and depends on;  Container Closure System Type of Device ETO Gas Exposure time  ETO Gas Concentration	The Process validation carried out In-house as per below;  3 half Cycle (At Full Load) 1 Full Cycle (At Full Load) *The Cycles will be carried out consecutively. *Change in any variable leads to repeat in validation
Bioburden or Sterility Validation of Lot	Microbiology Reports of BI & CI respectively	The BI & CI placed in the chamber shall be tested in real time conditions to affirm whether the sterilization process is effective or not.	In-House & External
ETO Residual Test	ETO residual report as per ISO 10993	The residual report of ETO gas on the device sample to trace the ETO concentration.	External (NABL)
Stability Studies	Stability Study report and Protocol	Provide the Stability report including Realtime and Accelerated.	In-House

By maintaining and preparing these essential documents, healthcare facilities and sterilization service providers can demonstrate compliance with regulatory requirements, ensure the effectiveness and safety of ethylene oxide sterilization processes, and uphold the highest standards of quality in medical device sterilization.

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