In vitro diagnostics (IVDs) are vital for detecting diseases, conditions, and infections through tests performed outside the human body. The development and maintenance of a robust Quality Management System (QMS) for IVDs are essential to ensure product quality, regulatory compliance, and patient safety. This Blog provides a comprehensive overview of the critical components involved in establishing and sustaining an effective QMS for IVD devices, with a focus on regulatory requirements, core processes, and best practices. It highlights the regulatory framework under the In Vitro Diagnostic Regulation (IVDR) in the EU, including the categorization of devices and the emphasis on maintaining and improving the QMS. The paper explores the role of ISO 13485 in supporting QMS implementation and outlines key components such as document control, risk management, supplier management, corrective and preventive actions, and training. It also covers the importance of risk management and post-market surveillance, especially for WHO-prequalified IVDs. The introduction of Unique Device Identification (UDI) under IVDR is discussed, emphasizing the need for procedural adjustments and data management. By adhering to these guidelines and fostering a culture of quality, organizations can ensure their IVD devices are safe, effective, and compliant with regulatory standards, ultimately contributing to improved patient outcomes and enhanced product performance.
Introduction
In vitro diagnostics (IVDs) are tests that can detect disease, conditions, and infections. In vitro simply means ‘in glass’, meaning these tests are typically conducted in test tubes and similar equipment, as opposed to in vivo tests, which are conducted in the body itself. In vitro tests may be done in laboratories, health care facilities, or even at home. The tests themselves can be performed on a variety of instruments, ranging from small, handheld tests to complex laboratory instruments. They allow doctors to diagnose patients effectively and work to provide appropriate treatments.
Definition:Â In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.
Regulatory Authority:  IVDs are devices as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act, and may also be biological products subject to section 351 of the Public Health Service Act. Like other medical devices, IVDs are subject to premarket and post-market controls. IVDs are generally also subject to categorization under the Clinical Laboratory Improvement Amendments (CLIA ’88) of 1988.
Regulatory Requirements for IVDs in EU
Under the IVDR, IVDs are categorized based on the risks they pose to patients, healthcare professionals, and public health. The regulation classifies devices into Classes A, B, C, and D, with increasing levels of scrutiny and requirements corresponding to the risk class. Manufacturers must adhere to rigorous standards for design, manufacturing, clinical performance evaluation, and post-market surveillance.
QMS Maintenance
“Although the core requirements for effectively creating, documenting, and following a QMS remain largely consistent with previous directives or standards, the IVDR specifically emphasizes the importance of maintaining the system, keeping it up to date, and continually improving it.”
A quality management system QMS is a structured system that documents processes and responsibilities for planning and executing quality objectives and policies. The implementation and maintenance of a QMS are required when placing medical devices and in vitro diagnostic medical devices (IVDs) in the EU market according to the MDR (EU Medical Device Regulation 2017/745) and IVDR (EU IVD Regulation 2017/746) respectively.
ISO 13485 is a stand-alone quality management system (QMS) standard that is internationally recognized and accepted as part of the quality management standard series. ISO 13485 is built on the concepts from ISO 9001, but it offers a more defined and focused framework for medical device manufacturing.
The purpose of ISO 13485 is to ensure the consistent design, development, production, installation, and delivery through to disposal of safe medical devices for their intended purpose. It was written to support medical device manufacturers in designing a QMS that establishes and maintains the effectiveness of their processes.
How to Ensure Your QMS Compliance?
Establishing a QMS tailored to IVDR requirements is critical for compliance. It involves defining organizational roles and responsibilities, documenting procedures, implementing risk management processes, and ensuring traceability throughout the device lifecycle.
Key components of an effective QMS include:
Document Control: Maintain accurate records of procedures, work instructions, and technical documentation to demonstrate conformity with IVDR requirements.
Risk Management: Implement a systematic approach to identify, assess, and mitigate risks associated with the design, manufacture, and use of IVD devices.
Supplier Management: Ensure that suppliers and subcontractors adhere to applicable regulatory requirements and provide necessary documentation to support the quality and safety of components and materials.
Corrective and Preventive Actions (CAPA): Establish procedures for investigating non-conformities, implementing corrective actions, and preventing recurrence to continuously improve product quality and safety.
Training and Competence: Provide ongoing training to personnel involved in the design, manufacture, testing, and distribution of IVD devices to ensure they possess the necessary skills and knowledge to perform their roles effectively.
Risk Management
Risk management plays a pivotal role in ensuring the safety and performance of IVD devices throughout their lifecycle. Manufacturers must conduct comprehensive risk assessments to identify potential hazards, evaluate the severity and probability of harm, and implement measures to mitigate risks to an acceptable level.
Key elements of Risk Management under the IVDR include
Hazard Identification: Identify and characterize potential hazards associated with the device, including biological, chemical, and physical hazards, as well as use errors and software failures.
Risk Assessment: Evaluate the severity of harm that could result from each identified hazard, considering factors such as the intended use of the device, the characteristics of the target population, and the probability of exposure.
Risk Control: Implement measures to eliminate or reduce identified risks to an acceptable level, such as design modifications, protective measures, or warnings and precautions.
Risk Communication: Clearly communicate residual risks to users, healthcare professionals, and regulatory authorities through labeling, instructions for use, and other relevant documentation.
Post-market Surveillance for Prequalified In Vitro Diagnostics
Manufacturers of WHO-prequalified in vitro diagnostics (IVDs) must follow WHO guidelines for post-marketing surveillance as part of their on-going commitment to WHO prequalification. In order to be able to do this they must be familiar with relevant international standards, including ISO 9001:2015 Quality management systems — Requirements, ISO 13485:2016 Medical devices — Quality management systems — Requirements for regulatory purposes and ISO 14971:2019 Medical devices — Application of risk management.
Key responsibilities
Manufacturers of WHO-prequalified products must carry out the following post-market surveillance obligations: These consist of:
- Encouraging users/customers to report any feedback including all adverse events and/or product problems experienced during use of a prequalified product, as soon as they become aware of these using a standardized form such as the WHO customer feedback form included in WHO’s guidance document for post-market surveillance of IVDs.
- Ensuring their economic operators are aware of their post-market surveillance obligations and timelines.
- Notifying the relevant regulators of specific complaints as defined in national guidelines.
- Notifying WHO of specific complaints relating to a WHO-prequalified product that have affected (or could have affected) the performance of the assay, the quality of the assay, the safety of the individual being tested/of users of the assay/of any person associated with the assay. Specifically:
- Manufacturers should report events/observations that represent a serious public health threat immediately and not later than 48 hours to WHO (e-mail: [email protected]).
- Other serious events/observations including death, or serious deterioration in health that has occurred for the patient, end-user or other individual, should be reported as soon as possible but no later than 10 days by manufacturers to WHO (e-mail: [email protected]).
- Other serious events/observations including death, or serious deterioration in health that might have occurred for the patient, end-user or other individual, should be reported as soon as possible but not later than 30 days by manufacturers to WHO (e-mail: [email protected]).
- Any complaints that require a field safety correction action, such as withdrawal of the relevant IVD from sale or distribution, physical return of the IVD to the manufacturer, IVD exchange, destruction of the IVD, IVD modification/s or additional advice provision to customers to ensure that the IVD continues to function as intended should be reported as soon as possible.
- All feedback (including serious, moderate and mild complaints, as well as technical service calls, etc.) should be reported to WHO annually, including the effectiveness of Field Safety Corrective Action Reports (FCSAs), as a periodic summary report.
Unique Device Identification (UDI)
The IVDR introduces a new requirement for Unique Device Identification (UDI) in the EU. While similar to the UDI rules in the US, the IVDR has several differences that will require manufacturers with existing UDI systems to make adjustments. As UDI adoption becomes more widespread, manufacturers need to develop processes to manage variations across different regions and risk classifications.
From a Quality Management System (QMS) perspective, it’s essential to establish procedures and policies for managing UDI codes. This includes overseeing the issuance of UDI numbers, ensuring the quality of automatic identification and data capture symbols (like barcodes) on labels, handling data management, and maintaining records. Although issuing agencies provide the initial UDI number ranges and standards, manufacturers must ensure that UDI numbers are assigned correctly, not reused, and properly documented throughout the device’s lifecycle.
With the need to align extensive product data with databases such as EUDAMED (European Database on Medical Devices) and GUDID (Global Unique Device Identifier Database in the US), manufacturers must implement governance for data creation, submission, and maintenance. Identifying data owners and creating a single source of truth for data used across the organization is crucial, and these responsibilities should be clearly documented.
Moreover, the UDI and related data need to be incorporated into the change management process to ensure that any changes affecting identification are reflected in the UDI and that data updates are synchronized with the required databases. The UDI must also be included in post-market activities, including managing complaints, reporting medical device issues, and field actions.
Conclusion
Developing and maintaining a Quality Management System for In Vitro Diagnostic devices is a complex but essential task. By adhering to regulatory requirements, implementing core QMS processes, and fostering a culture of quality, organizations can ensure that their IVD devices are safe, effective, and of high quality. A well-managed QMS not only supports regulatory compliance but also enhances product performance and customer satisfaction, ultimately contributing to better patient outcomes.