Overview of Combination Products

Combination products are those products that are made up of two or more distinct components, each of which satisfies an intended medical purpose on its own.

Combination products can be anything from a grouping of devices and drugs, to a combination of devices and software.

In this section, we will look into the different types of combination product, their advantages and disadvantages, and the regulatory environment that governs them.

Definition of Combination Products

Combination products are medical devices composed of both drug and device components that function as an integrated whole to achieve the intended use. Such components may be device components, drugs, biologics, or any other kind of material or substance with medicinal properties. Combination products should not be confused with co-packaged products, which are two separate but related items that are conveniently packaged together to aid in their use.

The United States Food and Drug Administration (FDA) defines ‘combination product’ as a product composed of any combination of drug(s), device(s), biologic(s), or material(s) used for diagnosis, cure, mitigation, treatment or prevention of disease in humans or animals. The parts that make up such a combination product can either be physically intermingled – like a transdermal patch containing both drug and device elements –or separate but interact to achieve the intended purpose – like two separately administered drugs produced by the same drug source material and meant to interact synergistically for treating a condition.

This definition is broad enough to encompass all types and forms of combination products; however there is further distinction based on the method used to regulate them and the personnel responsible for their oversight. Combination products undergoing evaluation by FDA may either require separate review of each component by different centres within FDA (dual filed) or they may receive single review by one center (joint filed). In either case, one set of regulations applies regardless of whether they are dual or joint reviewed. It is simply the submitter’s responsibility to divide information package into appropriate parts so that it undergoes the right level of review before being approved for market entry in United States.

Regulatory Guidance and Requirements

Combination products, as recognized by FDA, are comprised of two or more regulated components such as drugs, biologics and medical devices that are separately regulated by different FDA centres. Combination products are known to offer therapeutic benefits unavailable with stand-alone devices.

The regulatory requirements for combination products depend on the unique characteristics of the product and whether the product requires approval or clearance by the FDA. The agency’s guidance document states that “in some cases, components that meet individual requirements may still be subject to additional review as part of a combination product” (FDA, 2017). Additionally, premarket review is not necessarily required for all combination products and decisions regarding what is necessary will be made on a case-by-case basis.

Ultimately regulatory guidance for combination products depends heavily on the nature of each individual product. While there may be an overarching approach to these types of medical devices from a process and regulatory perspective – e.g., defining roles and responsibilities between different legal entities including an outsourcing facility – the details related to any one specific device can vary significantly from another. Companies engaging in development, manufacture or sale of combination products should understand all relevant requirements and become familiar with current regulations to ensure compliance with governmental standards (FDA, 2017).

Design Considerations

When designing a medical device combination product, there are numerous design considerations to be taken into account. These considerations can range from the materials to be used, to the usability and safety of the device, to the regulatory requirements for medical device combination products.

This article will provide an overview of the design considerations that are typically considered when designing a medical device combination product.

Design and Development

When developing combination products, manufacturers must follow design and development processes that reflect the special considerations for safety and efficacy associated with combination products based on their intended use. Manufacturers should evaluate the risk associated with a specific device (as well as any device components) of a combination product throughout its entire lifecycle, from planning to disposal.

Manufacturers must also ensure that the design of an effective combination product is sufficiently robust to meet its intended uses while minimizing potential risks. The design should factor in all areas such as materials selection, hardware configuration, software development and verification/validation. Additionally, the designs should consider control strategies to ensure safe operation of the product over its lifetime throughout its intended use conditions which includes temperature, pressure, shock/vibration and moisture sensitivity.

Furthermore, risk controls must be integrated into a quality system that addresses specific requirements related to combination products such as document controls (e.g., SOPS), device master records (DMR) and validation testing in accordance with regulatory agencies’ guidelines. Pre-market activities such as Risk Analysis and Mitigation Strategies (RAMS), Functional Requirements Specifications (FRS) and Hazard Analysis and Critical Control Point (HACCP) evaluations are also required when necessary for certain applications to help drive compliance activities associated with combined medical devices prior to first use by end users or patients.

Testing and Validation

Testing and validation are key components in the design of any combination product that involves both medical device and/or drug components. The testing phase helps to ensure safety, effectiveness, reliability, and performance with the overall goal of helping to protect the end user and maximize patient health. Generally, device manufacturers are expected to complete two primary types of testing for combination products: Subsystem Testing to ensure safety and effectiveness at subsystem level, as well as System Integration Testing (SIT) that tests system performance as an overall integrated product.

Subsystem Testing: Subsystem designs must be tested in a systematic manner from components all the way through completed subsystems to verify electrical/mechanical/software functions in physical environments. Key tests should be performed during development activities for mechanical parts, electronic components, software coding, manufacturing processes and individual modules for biological material performance.

System Integration Testing (SIT): With SIT studies whole systems are tested by configuring hardware then simulating pre-defined patient scenarios or conditions that represent real-world use or anticipated use conditions or scenarios determined through Risk Management. Validation is critical here to check if stated requirements have been realized such as user interface verification, functional output confirmation by operators including usability analysis such as how does it work in the hands of physicians / nurses etc., safety validations such as power management for batteries etc., reliability validation & maintainability verifications with respect to service strategies identified such as calibration validations & PM cycle intervals based on cyclic loading etc., risk management related elements such suitable warnings & hazardous notifications plus desired alarms validations etc., also need to be verified while conducting SIT testing.

Labelling and Packaging

When designing the labelling and packaging for a medical device combination product, there are several important considerations. The primary goal should be to ensure that the combination product is easily identified through visual inspection as well as in other situations such as laboratory tests.

The following points should be addressed when designing labelling and packaging for a medical device combination product:

  • Ensure that the intended use of the medical device is clearly indicated on the label.
  • Present detailed instructions for mixing, calibrating, and operating the medical device in its entirety.
  • Illustrate any special precautions or warnings associated with using the medical device so that they can easily be understood by all potential users.
  • Include both visible labelling and tamper evident packaging materials to prevent misapplication or accidental contamination of components in transit or storage.
  • Accurately display expiration dates to identify when components must be replaced over time due to degradation.
  • Define colour codes, pictographs, and fonts in order to distinguish different types of devices and components across a range of conditions (e.g., normal lighting, night time settings).
  • Provide instructions on safe disposal procedures at end of life as a means of containing environmental hazards associated with decomposing materials over an extended period of time.

Manufacturing Considerations

Medical Device Combination Products (MDCPs) bring together two or more devices into a single product. When manufacturing these devices, a number of factors must be accounted for in order to ensure safety, efficacy and quality of the final product.

In this section, we will discuss the factors involved in manufacturing MDCPs.

Quality System Requirements

Medical device combination products are subject to several unique manufacturing considerations for quality system requirements that must be adhered to when pursuing ISO 13485 Quality Management System (QMS) certification. Quality systems in these settings must meet all of the requirements listed in ISO/IEC 13485, “Medical Devices – Quality Management Systems – Requirements for Regulatory Purposes.”

Quality system requirements vary based on the magnitude and complexity of the medical device combination product being manufactured. Generally, manufacturers must have a designated quality management representative responsible for developing, maintaining, and improving the organization’s QMS. Additionally, manufacturers must ensure that records demonstrating conformity with applicable design and production processes are maintained. This includes verification activities such as inspection and testing of components and process validation.

The implementation of preventive actions is also critical in prevention of issues related to medical device combines products: specific procedures should be implemented to identify root causes associated with issues (complaints, non-conformances) in order to establish corrective actions accordingly and prevent future problems from arising. In addition, there should be policies put in place outlining compliance responsibilities of personnel involved in product realization stages as well as risks posed by unforeseen events or abnormal situations during production stages are accounted for (i.e. continual monitoring). Lastly, validated methods and suitable controls should be established to measure product characteristics in-process or finished product against predetermined criteria prior to being released into market.

By adhering to these regulations and taking necessary precautions, manufacturers can effectively ensure their medical device combination products comply with all applicable regulatory regulations set forth by local regulatory offices or health care facilities.

Quality Control and Inspection

Quality control and inspection are critical elements of the manufacturing process for combination products. Quality control is the process of ensuring that all materials, processes, parts and components necessary to manufacture a medical device combination product comply with established specifications and standards. The quality assurance team should continuously assess the effectiveness of the quality management system and verify that all requirements are met throughout production.

Quality Control includes activities such as conducting audits, inspections and tests, evaluating data analysis results and performance trends, monitoring customer complaints and investigating potential product issues during development or production.

Inspections involve assessing design inputs to ensure they meet specifications and validating that processes such as assembly, sterilization or medical labelling are effective. These inspections must be conducted both in-process and upon completion of the product to ensure adherence to established requirements. All documentation should be stored securely in accordance with FDA regulations for traceability purposes in case there is a recall situation or an investigation.

Additionally Careful attention must be paid to third-party testing requirements and approved vendors record management evidence should be maintained in order to successfully receive regulatory approval for commercialization of new products.

Risk Management

The manufacturers of medical device combination products have an increased obligation to ensure that all risks associated with the product design and production, from development to post-production, are identified and managed. Risk management involves assessing the product’s design, use of components, materials, systems and processes for their potential to cause harm or damage to users or other persons in foreseeable scenarios. This requires manufacturers to take a proactive approach through risk analysis whilst ensuring that all technical documentation is kept current and consistent with the actual implementation.

Manufacturers must evaluate product safety hazards posed by medical device combination products by using various methods such as a hazard analysis (HA) process which deploys techniques such as failure mode and effects analyses (FMEA). Furthermore, Product Risk Management (PRM) techniques can be used in order to identify customer requirements, along with comprehensive analysis of customer preferences in relation to risk when purchasing the combination product. Manufacturers need consider factors such as: user interfaces; control logic; quality assurance tests; installation environment; contamination risks; product lifecycle etc. for successful risk management integration.

Additionally, mitigation measures should be put into place including but not limited to recommendations for actions doing risk acceptance/repudiation decisioning along with developing quality system procedures such as comprehensive training programs for supervisors and operators specific applicable regulations/standards impacting validation procedures while ultimately ensuring efficacy of safety mechanisms apart from assessing changes in design intention/requirements throughout production and post-production phases.

Post-Market Considerations

Medical device combination products / products composed of multiple medical device components intended to work together to achieve a medical purpose–are subject to additional post-market considerations in the United States.

Combination product manufacturers must be aware of these considerations to make sure their product meets all applicable regulations and requirements. In this article, we’ll discuss the key post-market considerations that must be taken into account for medical device combination products.

Post-Market Surveillance

Post-market surveillance is an essential element for ensuring the ongoing safety, effectiveness and quality of combination products. It involves collecting and analysing data from the market to assess these parameters and identify any risks associated with a product after it has been approved for marketing. Post-market surveillance activities can include collection of customer feedback, evaluation of product use under real conditions, analysis of adverse events reports and product performance reviews.

Post-market surveillance should be conducted at regular intervals throughout the life cycle of a combination product to ensure continued safety, effectiveness and quality. Companies should consider collecting customer feedback on their products as part of post-market surveillance in order to gain an understanding of how customers perceive their products and identify any potential issues that may need further investigation. In addition, it is important for companies to monitor adverse events related to their products in order to develop strategies for preventing harm from occurring in the future or minimize its effects should it occur. Finally, companies should review the performance of their products on an ongoing basis by comparing actual results with predictions based on pre-market data.

All post-market surveillance activities carried out by medical device combination product manufacturers must be documented clearly so that regulatory authorities are able to access information regarding how a specific product’s safety, effectiveness and quality is being monitored over time. Documentation should include details such as who was responsible for carrying out the activities, when they were performed, what methods were used and what data was collected/analysed as part of the process.

Reporting Adverse Events

Reporting Adverse Events should be part of any post-market considerations for medical device combination products. All manufacturers must report medical device related adverse events to the appropriate regulatory authority, as per regulation 803 of 21 CFR Part 803. Additionally, manufacturers of combination products regulated by both the FDA and the European Commission have unique reporting requirements set out in Chapter V of Directive 2001/83/EC.

There are numerous resources available to educate personnel within a manufacturing organization on how to properly report information regarding adverse events. Additionally, manufacturers should have rigorous processes in place to capture and assess unanticipated adverse events on an ongoing basis so that they can be accurately reported to the relevant regulatory bodies. The goal is to provide timely notice of any risks or safety concerns associated with a particular combined product as soon as possible, so that corrective actions can be taken quickly if necessary.

It’s important for manufacturers of medical device combination products to ensure that all personnel within their organizations are well informed about industry standards and regulations related to reporting adverse events. This includes monitoring manufacturer’s websites and attending relevant seminars or conferences related to post-market considerations and FDA regulations surrounding combination products. Following these procedures helps ensure prompt notification and timely assessment when unanticipated risks do arise with medical device combination products after they have been sold to market.

Post-Market Clinical Follow-up Studies

Post-market clinical follow-up studies are designed to assess the long-term safety and effectiveness of medical devices. These studies are recommended to detect potential risks associated with the use of medical devices in combination products. Study results provide essential information on product performance, including benefits or harms that may not have been detected during premarket evaluation.

Such post market clinical follow-up (PMCF) studies are typically required for class III and implantable combination products and should be performed by experienced clinical investigators, who have expertise and merit in device trials design, conduct, and analysis. Post-market clinical follow-up studies can include retrospective questionnaires, registry reviews or databases analysis – or a prospective randomized trial with extended evaluations. The type of PMCF study chosen for a device is based on its characteristics, such as frequency of usage and interaction with other critical components in the system; overall complexity; demonstrated safety benefits; patient population involved; targeted indications for use; and severity of patient illness or condition treated by the device component / component individually or in combination with other medical treatments.

Ultimately, post market clinical follow-up studies provide vital information to manufacturers so they can evaluate potential risks associated with medical device combination products that could not be detected strong during premarket evaluation. Such records also support manufacturers’ further modifications of product features in responses to post market findings. Additionally, results from PMCFs serve as an important basis on which regulatory bodies make changes to safety standards relevant to combination products containing medical devices so that end users continue derived optimum safety benefits from these combined products for improved healthcare outcomes.

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