COMBINATION PRODUCTS
Combination products
TECHNOLOGICAL AND REGULATORY COMPLEXITY
Being different from strict medical devices because of the active substance in their composition, combination products benefit from all existing advances in multiple technological fields. Complex and increasingly efficient, their control over the entire life cycle, to guarantee safety and the desired patient benefit, is a challenge. Experience, methodology and a holistic approach are key.
COMPLEX TECHNOLOGIES
TO INTEGRATE
A combination product combines a medical device, often intended for administration to the patient, and an active substance for therapeutic or diagnostic purposes. Combination products are to be distinguished from strict medical devices, which do not contain any active substance, used to treat or medically intervene in patients.
Recent technological innovations in terms of miniaturization, elastomers and synthetic materials, electronics, remote transmission, micromechanics, innovative materials and mathematical algorithms have led to increasingly effective combination products to meet the expectations of patients and prescribers. Combination products integrate multiple technologies that must work in synergy.
This requires advanced Quality by Design approaches as well as in-depth knowledge of the interactions between components and their compatibility with the drug product. These are all dimensions that make them complex and highly technological products.
MULTIPLE APPLICATIONS,
IN CONSTANT EVOLUTION
Combination products are designed to ensure the best possible administration of a substance to guarantee the expected therapeutic or diagnostic efficacy,
in complete patient safety.
In addition, there are many innovations to ensure maximum comfort of use for the patient. They are particularly developed in cases of repeated use of the drug over long periods of time or for pediatric use, for which the child's comfort is an essential element of therapeutic management.
In addition, the design of the combination product plays an important role, particularly in terms of patient compliance.
Thanks to technological innovations, combination products are finding many applications, often for greater patient comfort.
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The applications are multiple: administration of injectable drugs such as injection pens for emergency medication, injection of a single dose of hormone or anticoagulant, inhalation of powdered or micronized drugs for respiratory pathologies, skin patches for hormone treatments, closed-loop autonomous insulin injection and control systems for the treatment of diabetes, and medical devices to which an auxiliary substance is integrated to support the device's own operation.
BREAKTHROUGH INNOVATIONS FOR
THE BENEFIT OF PATIENTS
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The future of combination products lies in the use of disruptive technologies and the integration of innovative materials.
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Combination products have a bright future to combine the two contributions of the device and the drug product. This will require transformation and innovation at the industrial level. In particular, the supply chain will also have to evolve to integrate two radically different industrial flows (batch processes for drugs and a manufacturing industry for devices).
Much of the innovation has been driven by the rise of single-dose medications in pre-filled syringes, which in recent years has propelled a stream of improvements in auto-injectors that are simpler and less painful to use.
As biologics remain primarily injectable drugs, a stream of strong technological advances will continue to be deployed in the future.
The integration of innovative materials that are as inert as possible and miniaturization will be the spearhead of future improvements. In addition, new needs will emerge, such as the administration of large volumes of products in complete aseptic safety, in treatments self-administered by patients at home, thus avoiding hospitalization. The combination products of the future will be based on breakthrough innovations that research laboratories are working on. Examples include needle-free injectors, implanted or ingested devices, integrated monitoring and algorithms, and many other innovative ideas in the pipeline.
A NEED FOR TRANSFORMATION
THAT IS BECOMING UNAVOIDABLE
The regulatory framework for combination products is complex. It anticipates atypical cases ("borderline" products and MDCG guide) and is intended to evolve to respond to innovations and new associated issues.
While the drug on the one hand, and the medical device on the other hand, are clearly described and framed by regulatory guidance, combining the two in a combination product does not seem to be the subject of harmonized definitions and requirements in the reference texts.
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In addition to the challenge of innovation and the complexity of combination products, manufacturers are also faced with a dual and evolving regulatory framework.
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In Europe, the EMA has published a guideline (applicable on 01-Jan-2022) to harmonize quality requirements in line with the new European MDR 2017/745 regulation and to provide support to manufacturers in the preparation of their technical dossiers.
In the United States, the combination product is defined in 21 CFR 3.2 and the FDA OCP service directs to the relevant evaluation service. The regulatory requirements for a combination product are defined in two main texts: 21 CFR part 210 & 211 for drugs and 21 CFR part 820 for medical devices.
The complexity of combination products, the evolving regulatory frameworks and the flow of innovations represent major challenges for manufacturers in terms of technology, skills integration and organization. These are all subjects of transformation expected within companies and their human resources.