In the EU, the definition of combination products is not as clearly defined as it is in 21 CFR 3.2(e) of the US FDA. However, this definition can also be applied in the EU.
With the entry into force of the EU MDR, the requirements for integral combination products, whose main intended use is not achieved by the medical device part, have increased in particular. Simplified, the approval of these combination products now involves not only the medicinal products authority but also the Notified Body.
Innovations for Integral Combination Products within the EU
All Market Authorization Holders of integral Combination Products which are approved as a pharmaceutical product must comply with new regulatory requirements. By the end of the transitional period of the EU Medical Device Regulation (EU MDR 2017/745) on May 26, 2021, the requirements of Article 117 have to be implemented.
For the medical device component – if the component itself is not an approved medical device – a confirmation of the Notified Body must now be obtained, certifying that the General Safety and Performance Requirements (GSPR) according to EU MDR Annex I are met. As a result of these General Safety and Performance Requirements (GSPRs), Market Authorization Holders are faced with new requirements, as for example Risk Management according to ISO 14971:2019, which is state of the art at this time but not yet a harmonized standard to the EU MDR.
Market Authorization Holders have so far been able to launch integral Combination Products on the European market solely via the pharmaceutical approval process. In the future, however, medical device regulations will also have to be taken into account, and expert knowledge will have to be built up or consulted.
The experts at gempex are the right contact in the field of compliance for medical devices and for medicinal products – with knowledge of the requirements of the authorities, well-founded know-how and years of experience.
Revision of the Product Documentation
Integral combination products that are approved on or after May 26, 2021, or undergo a significant change on or after that date must comply with the new requirements of Article 117 of the EU MDR. This means that the Medicinal Product Dossier must contain a "Medical Device Chapter", organized according to the structure of the General Safety and Performance Requirements and including all required supporting documents.
One elementary component is Risk Management according to ISO 14971:2019, which has not yet been applied in the pharmaceutical industry. The basic approach is very similar to the approach of ICH Q9. Risk is analyzed and controlled throughout the product life cycle. Appropriate measures to avoid or reduce risk are implemented, and likewise monitoring their effectiveness is an integral part of the process. However, there are also some very important additional requirements, such as the very detailed requirements for a Risk Management Plan. In addition, Usability Engineering according to IEC 62366:2017 is added as a new component for the pharmaceutical industry (state of the art, no harmonized standard at this stage). The development of combination products taking into account Usability, which is closely interwoven with Risk Management, represents a further, new challenge.
Revision of the QM Processes
The new requirements, which are both implicitly and explicitly required by EU MDR Article 117, are largely process standards and results of the medical device development process, which must be integrated into quality management system processes. For example, processes should be aligned with the requirements of ISO 14971:2019 and IEC 62366:2017.
But it is not only in the EU that there are requirements for the Quality Management System. According to 21 CFR Part 820 (Quality System Regulation), the US FDA imposes special requirements on processes in the areas of Management Responsibility, Design Controls, Purchasing Controls, Corrective and Preventive Action, Installation and Servicing.
Vigilance Activities for Combination Products
According to EU MDR Article 117, vigilance activities for Combination Products, following the processes of the medical device industry, are not required. They are executed exclusively according to the established processes of the pharmaceutical industry.
In contrast, the US FDA requires vigilance activities according to the processes of all components of the respective Combination Product (Biological, Drug, Device). There is a new guidance for Post Market Safety Reporting since July 2019, which creates the possibility to simplify the "multi-track" reporting process. In this case, the information required in the different reporting processes is integrated into one report. The type of this report/ reporting pathway (Biological, Drug, Device) is based on the component that achieves the intended main effect.
This notification also includes coding according to the new IMDRF codes in the case of a Combination Product with a medical device part. They were developed by the International Medical Device Regulators Forum (IMDRF) to accelerate the international harmonization of vigilance activities. The IMDRF codes are also required in the EU for vigilance notifications involving medical devices.
To ensure the development of Combination Products and the supply of these products to the market in compliance with the requirements, a pharmaceutical manufacturer should do the following, for example:
- Check whether the integral combination product falls under EU MDR Article 117
- Train staff on applicable regulations, such as EU MDR, ISO 14971:2019, IEC 62366:2017, etc.
- Gap analysis of product documentation against EU MDR Annex I
- Gap analysis of the quality management system against applicable requirements, such as US FDA 21 CFR Part 820
- Create a compliance plan that outlines strategy and steps for regulatory compliance
- Installation of a project team by top management to ensure implementation of the compliance plan
- Ensure timely communication & coordination with the Notified Body
Many Years of Practical Experience for Customized Compliance Solutions
Thanks to their many years of experience in both the medical device and pharmaceutical industries, gempex experts provide competent support to Market Authorization Holders in all compliance matters. In doing so, solutions are not offered "off the shelf", but are individually tailored to the needs and efficiently implemented.
gempex provides support throughout the entire product life cycle, such as:
- Performing gap analyses
- Preparation of compliance/project plans
- Execution of internal workshops
- Preparation of compliant product documentation
- Revision of the product risk management system, considering ISO 14971:2019
- Preparation for the assessment by the Notified Body
- Revision of procedures & work instructions or the entire quality management system, taking into account the applicable sections of 21 CFR 820, US FDA Guidelines (e.g. Post Market Safety Reporting), and other applicable regulations
- Staff training
- Performing "Mock-up" audits
- Communication & coordination with the Notified Body
- Secure regulatory knowledge in the medical device and pharmaceutical industry
- Structured and expeditious determination of the required effort
- Experience and routine in incorporating compliance functions
- Precise targeting of product, process and project
- Efficient "on-the-job” training of employees
- Taking over communication and coordination with the Notified Body