On 26 May 2017, the European Commission (EC) introduced the In Vitro Diagnostic Regulation (IVDR 2017/746), which replaces the current In Vitro Diagnostic Directive (IVDD 98/79/EC) and introduces major changes for IVD manufacturers throughout the European Union (EU).
The IVDR: The Fantastic 4 (Systems) or 1 System for All?
The IVDR clearly lays out that manufacturers must demonstrate performance, safety and possible risks/controls of products prior to availability within the European marketplace. With this requirement comes the reinforcement of four systems as described in the regulation:
- Quality Management System (QMS)
- Post-Market Surveillance (PMS)
- Risk Management
- Vigilance System
Quality Management Systems & IVDR: Device Representatives
The IVDR has brought forward a new drive to establish “a robust, transparent, predictable and sustainable regulatory framework for in vitro diagnostic medical devices which ensures a high level of safety and health whilst supporting innovation.” Truthfully, this change gives many different requirements for IVD manufacturers to comply with, but in terms of Quality Management, one of the most significant requirements is that of manufacturers to create and maintain a robust, adaptive, continuously improving and informative QMS for their products.
In reality, Article 10 (8) illustrates that an adequate process should be implemented that ensures that production meets IVDR conformity. A manufacturer’s QMS should include aspects such as:
- Design changes
- Process verification/validation
- Production process controls
- Regulatory compliance
- Risk management
- Performance evaluation
- Post-Market Surveillance…and much more!
As Section 2 of Annex IX mentions, a QMS assessment—beginning May 2022—will be part of a Notified Body assessment when submitting to place a device on the EU market. While many of these requirements are not new within industry (ISO 13485:2016, for example), the IVDR does give emphasis to Document, Implement and Maintain Quality Systems.
Specifically, Annex II Section 3.2, states that clear information should be available on the production and design processes for devices and that manufacturer’s QMS must reflect changes both externally and internally with regular updates to continually review and improve.
Responsible for aligning the QMS and the strategy for regulatory compliance, the PRRC will play a significant role in product release to market, technical documentation, PMS obligations and reporting to Competent Authorities and Performance Evaluations. Is it a coincidence that these are all mentioned within the IVDR?Curiously, Article 15 informs manufacturers that they must have an individual responsible for regulatory compliance (PRRC). This puts forward essential responsibility for regulatory compliance with criteria set for both qualification and experience in quality management and IVD manufacturing. Technically, this is not a requirement specific for QMS; however, the PRRC is a crucial position in an IVD organization.
Post-Market Surveillance (PMS) & Performance Evaluation: Proactive, not just Reactive
Article 56 and Annex XIII in the IVDR discuss the requirement that QMS must have a Post-Market Performance Follow-Up (PMPF) plan, which is well-defined. PMPF plans will vary at a high degree due to the type of device being reviewed and the classification of the device. Therefore, a PMPF plan must be sufficiently descriptive, but have a degree of variation based on the device.
However, plans can stand alone or, for example, if a manufacturer has a family of products that are similar, a standardised plan could be appropriate. Incorporation into the QMS as either a procedure or a template to be completed as part of a device’s Technical File could be used. Note that if introduced as a procedure (relating to transparency), the scope of the procedure must be clear and should be identified within the PMPF plan.
Article 78 states that post-market activities are to be “incorporated” into PMS systems and should be planned, established, implemented, documented, maintained and updated in a proportionate manner based on risk and type of device. Article 79 and Annex III address what is to be included in the PMS plan and its links in other aspects of the regulation such as Risk Management, Scientific Validity, Clinical Performance, Analytical Performance (Performance Evaluation), Corrective and Preventive Actions (CAPA) and Safety Monitoring.
Overall, these IVDR requirements are shifting the industry and require a more proactive approach to IVD development and ensures that claims are accurate and devices are safe.
Risk and Vigilance Systems: Controlling Risk, Reporting Incidents and Always Watching!
Risk assessment plays a major role throughout device development, which the IVDR strengthens through its Articles and Annexes. From a QMS perspective, the key is ensuring that risk management is so well-embedded throughout development that it flows as part of the process throughout the product lifecycle (integration is based on product classification of the device and not just a one-time activity).
This means that a one-size fits all approach is not appropriate as controls would be scaled inappropriately for all devices. Manufacturers, when embedding risk into QMS, should confirm that the risk for each device, or family of devices, are scaled appropriately—but are also well documented.
Breaking risk down into specific requirements, the IVDR discusses this in-depth in Section 3 of Annex I. Quite similar to ISO 14971:2012to Risk Management expectations, it has included identification of risks, including foreseeable misuse, mitigation of risks with preference for design reduction to eliminate the risk as far as possible (Design Control) and communication of any residual risks to the user (such as IFU). It also describes the benefit/risk ratio, meaning that the risk should be controlled to have benefits that outweigh any remaining risk. It should be noted that the benefit/risk ratio during PMS activities should also be assessed to ensure that the ratio is still acceptable.
Interestingly, General Safety and Performance Requirements (GSPR) of products must be taken into account within QMS; these requirements must be identified—where applicable and appropriate—and, they should guide the process from one device to the next, but also respond to common requirements.
Overall, manufacturers (new or established) must review products to identify how they wish risk to be evaluated, group products (family or generic but with large catchment); this should be documented and transparent in order to comply with IVDR requirements.
Communication is also mentioned significantly throughout the IVDR in the context of Vigilance; this is of major importance. The IVDR is clear in stating that the Vigilance process must show a company’s due diligence for reporting serious incidents and field safety corrective actions with deadlines, responsibilities and reconciliation management. These requirements could potentially be difficult within QMS with usage of distributors, importers, subsidiaries etc. The manufacturer’s QMS must demonstrate that it is responsible for their products’ vigilance activity and show due diligence with regards to communications/responses with internal and external Economic Operators.
The IVDR is most certainly changing the industry, pushing manufacturers to focus on the creation and maintenance of a robust QMS. For Sponsors, this is a means to ensure processes deliver a safe and reliable product that meets patient needs consistently and effectively while also demonstrating compliance to one’s Notified Body.
How Can NAMSA Help?
NAMSA is a leading contract research organization (CRO) and the world’s only Medical Research Organization (MRO) that assists In Vitro Diagnostics (IVD) manufacturers translate great ideas into great medical products.
From point-of-care diagnostics to instrument platforms to companion and complimentary devices, NAMSA provides global expertise for the full product development continuum. Through our regulatory consulting, laboratory testing and clinical research services, we consistently deliver proven time savings and cost efficiencies to clients around the world, resulting in hundreds of successful IVD regulatory submissions.
Warren R. Jameson, PhD
Over 15 years experience in IVD research, development, manufacturing, regulatory affairs and quality management. Served in Research and Development as well as Quality and Regulations Manager ensuring compliance with legislation, managing quality documentation, risk assessment, risk management and audits. Expert in reviewing technical files and guiding IVD sponsors for IVDR compliance. Creating technical documentation such as Performance Evaluation Plans (PEP) and Reports (PER) for IVD devices to be used as part of technical file submissions for IVDR compliance and to carry out performance evaluation. Significant experience in gap analysis reviews of analytical performance and clinical performance data and determination of the data is to the latest guidelines for performance, acceptable to IVDR standards and advise on solutions. Clinical performance creation including review of clinical performance protocol, studies and literature to determine the needs of devices and any gaps for IVDR compliance or US submissions. Scientific Validity report creation with search and review of scientific literature for analyte link to pathological or physiological conditions as stated in the IVDR for legacy and novel devices.