Combination product QMS requirements for pharma companies entering the EU market

The global market for drug-device combination products is booming; it was valued at $118.13 billion in 2021 and is expected to expand at a compound annual growth rate of 8.8% by 2030. To capture the growing market with minimal business disruption, most pharma companies used to rely on third parties to develop and obtain the regulatory approval for the device in a combination product, a product that combines a medicinal product or substance and a medical device in a single integral unit (e.g., prefilled syringes).

However, pharma companies are now building the capability to manufacture combination products in-house to increase flexibility and reduce dependency on third parties when ensuring the safety and efficacy of the combination product. Therefore, pharma companies have begun to expand their quality management systems (QMS) to allow them to become the legal manufacturer of the medical device components of their combination products.

A QMS is a structured system that includes policies, processes, and procedural documents that a pharmaceutical or medical device manufacturer has in place throughout the product’s life cycle. Implementing a QMS that supports medical devices is an essential step in building the new capabilities and becoming a legal manufacturer of such devices.

This will also enable pharma companies to manufacture personalized treatments that maximize positive health outcomes and system resilience, which is a market that will increase by $70 billion to $390.4 billion by 2030. In this article we discuss the challenges and considerations for companies that are interested in entering the EU market with combination products.

How are combination products regulated?

Combination products are governed by Regulation (EU) 2017/745 (EU MDR) as a medical device or by the Medicinal Products Directive 2001/83/EC (MPD) as a drug, depending on the principal mode of action.

The EU Medical Device Coordination Group (MDCG) recently published guidance document MDCG 2022-5, Guidance on borderline between medical devices and medicinal products under EU MDR, providing additional information for manufacturers when deciding the regulatory status of a combination product.

When a combination product is considered a drug, and thus regulated under the MPD, the medical device in the combination still needs to meet specific requirements of EU MDR. Examples of combination products regulated as medicinal products are prefilled syringes (e.g., vaccine in a prefilled syringe) and single-use inhalers. Having a QMS that complies with both pharma and device regulatory requirements will ensure that the combination product will meet the requirements of both regulations.

Advantages of implementing a medical device QMS

The major benefit of having a medical device QMS is that the device development and related documentation will comply with the applicable regulatory requirements and the company can CE mark the device to demonstrate compliance of the device with EU MDR requirements. The letters “CE” signify that products sold in the European Economic Area (EEA) have been assessed to meet high safety, health, and environmental production requirements.

When a device is developed and CE marked by a third party, the pharma company has less oversight of the process and timelines. By becoming a legal manufacturer of medical devices, the pharma company can CE mark the devices by issuing a Declaration of Conformity per their own project plan and will be less dependent on third parties.

If the device is not CE marked or the device is high-risk, the company has to submit a dossier to a Notified Body to obtain a Notified Body Opinion that will be part of the Marketing Authorization Application (MAA) for the combination to the European Medicines Agency (EMA). The EMA will expect the submission to comply with EU MDR requirements. Having a medical device QMS in place will ensure the documentation will meet the Notified Body’s expectations.

The advantage of CE marking the device, however, is that it eliminates the need for a Notified Body opinion and takes this approval out of the critical path to submission. The only documentation to be submitted as part of the MAA is the Declaration of Conformity issued by the legal manufacturer, in this case the pharma company.

Combination products are often accompanied by an app to enhance the patient’s or healthcare professional’s experience. Depending on the features of the app, it can also qualify as medical device software (SaMD) and will need CE marking to be marketed in the EU. Having a medical device QMS in place will allow a pharma company to develop and CE mark both the device in the combination and the stand-alone app.

Considerations for implementing a medical device QMS in a pharmaceutical environment

Implementing a medical devices QMS in a pharmaceutical environment requires careful consideration and planning to do it right the first time and avoid any delays or additional costs.

Therefore, it is key to perform an end-to-end assessment of the existing processes, capabilities, and systems to identify any gaps, as well as the resources that can be leveraged to build a medical device QMS. Building the medical device QMS as an extension of the pharma QMS has the advantage that existing processes and resources can be leveraged. Obtaining ISO 13485 certification for the QMS from an independent certification body can accelerate and harmonize the MDR auditing process, without showing all the product design and documentation to the NB.

The end-to-end assessment needs to include the in-house capabilities to ensure the company has the right expertise to manage and maintain the QMS. For medical device development and post-market surveillance, the company will require experts with biotechnology, biomedical, engineering, software, and related backgrounds. In other words, a company with combination products in its portfolio will need to ensure the employee portfolio includes all necessary expertise to cover both medicinal products and medical devices, so they can keep the QMS up to date.

How to design a strategy to implement a medical device QMS

The pharma company must start with a multifunctional project team representing the various parts of the business, including the necessary medical device experts. In many cases, companies will leverage third parties to perform the assessment and to develop the implementation plan.

When considering the document hierarchy of a pharma QMS, the high-level procedural documents, such as policy, can usually be leveraged across devices and drugs because they typically do not contain the details of the process and roles and responsibilities at the execution level. Taking the CAPA (corrective and preventive action) and the complaint management processes as examples, the policy elements will be similar across drugs and devices, whereas the execution will involve different expertise and systems.

Some processes will require enhancement to ensure they are robust across drugs and devices. For example, the risk management process may require different expertise and risk analysis methodologies to address the mechanism of the product. Risk analysis of a medicinal product will mostly focus on the molecular and chemical interaction in the human body associated with a side effect. Risk analysis of a medical device will focus on the design and its use by both the user and the patient in relation to an incident, as medical devices often involve more complex systems. However, the high-level process is very similar for both, as the risk management team will assess the product, score the potential risks, and design a solution to minimize the impact on a patient.

While high-level procedural documents and some processes can be leveraged across different types of products, some lower-level processes may be easier to manage separately. For example, the complaint management process will be easier to manage if there are separate procedures or work instructions for medicinal products and medical devices. This is related to the type of complaints received. For pharma, most of the complaints are related to adverse events and side effects. For medical devices, most of the complaints received are typically quality complaints that do not necessarily have an impact on a patient at the time of reporting. Therefore, complaint evaluation will require different expertise and different processes. Medical devices will typically require a technical assessment of the device’s design and operation, while a medicinal product complaint assessment will require medical/clinical expertise. Therefore, it is essential to have the right experts to ensure a proper investigation is conducted.

Differences in the regulatory experts’ roles

A QMS for medical devices overlaps with pharma QMS requirements but with some significant differences. We use one of the requirements — the regulatory expert’s role — as an example to highlight the commonalities and differences.

Both medical device and medicinal product QMSs require a quality management representative who is responsible for the effectiveness of the QMS; these specific roles are also defined in the regulations. Under the EU MDR and MPD, companies are required to appoint at least one Person Responsible for Regulatory Compliance (PRRC) for devices and have a Qualified Person for Pharmacovigilance (QPPV) and at least one Quality Person (QP) at their disposal for drugs. The PRRC, QPPV, and the QP play key roles in managing the quality and safety of the products, but their responsibilities are quite different. In pharma, the QPPV has the responsibility to monitor and review the safety profiles of the medicinal products and the QP is responsible for assuring the safety, quality (batch control), and efficacy of the medicinal product. For medical devices, the PRRC is responsible for the safety, quality, and regulatory compliance of the medical devices, which seems to be a combination of the roles of the QP and the QPPV.

Table 1: An overview of the regulatory obligations of the PRRC, QPPV, and QP per EU MDR and MPD.

Although all three roles are responsible to ensure the safety, quality, and efficacy of the product comply with the relevant regulations, the scope of each role is quite different, as listed in the table above. Therefore, it is essential to have clear job descriptions and processes in place to ensure the roles are duly fulfilled.

Conclusion

Implementing a medical device QMS in a pharma company will bring significant advantages when developing combination products. However, it needs careful consideration and strategic planning. It will require implementing new capabilities with the right expertise on the new/future medical devices, new processes that will enable the experts to execute in line with the requirements, and new IT systems to address medical device requirements. Therefore, stakeholder management will become essential throughout the entire process, from planning to implementation. In addition, a pharma company will need to establish new relationships with different regulatory groups in a territory and with a Notified Body (EU).

This was first published in Outsourced Pharma