Numerous benefits

The combination product market has witnessed significant growth with the recent scientific and technological advancements.

Any combination of drugs, devices, and biologics are considered combination products. A few examples are inhaler, nasal spray, transdermal system, or a drug or biologic with an administration device like an auto-injector or a prefilled syringe.

There are numerous benefits of combination products, such as reduced drug waste (for example, prefilled syringes provide the right amount of drug dose as compared to the additional 20-30% amount in vials), reduced cost of drugs (where manufacturing cost of drugs are high), avoidance of exposure to toxic products (when delivered through separated vial and needle), and so on.All these benefits are invaluable to patients. Previously, cancer patients had to visit clinics after chemotherapy to take a specific drug; now, it is administrated through an auto-injector at home. Additionally, self-administration has been instrumental as telemedicine is now widely accepted by users.

However, there is always another side of the story; the conveniences of the combination products have risked patient safety.

A cohesive process

Traditionally, pharmaceutical and biotechnology companies’ processes and adherence to regulatory compliance requirements have been drug and biologic-focused, while the administration devices were considered separately.

One of the reasons for not having an established process with these companies is a lack of regulation. For example, the Current Good Manufacturing Practice Guidance (cGMP) for combination products 21 CFR Part 4 had not evolved until 2013.

Companies now realize the need to define an integrated and cohesive process and adhere to compliance of drug or biologic and device design, development, and manufacturing of their combination products. Regulatory authorities like the US Food and Drug Administration (FDA) have provided their observations and warning letters to the pharma and biotech companies alleging that they have not met the proper standards of resources and controls in the production processes

Devise new strategy

While the need for cohesiveness is recognized and regulatory guidelines (for example, 21 CFR Part 4 cGMP for combination products) are in place, it is still difficult to define and implement end-to-end processes in the value chain, starting from combination product design to commercialization.

Before defining and implementing the processes, the challenge is to alleviate workplace isolation and change the mindset of people in the organization. Industry leaders need to guide bio-pharma companies to act like medical device companies and drive comprehensive strategies for combination products. To build an integrated working environment, both the departments must understand each other’s common objectives, processes, sciences, and technologies.

The leadership team must enable cross-training for each group. The drug or biologics development team needs to understand device development factors like design control, human-centric usability design, and the like. The device development team needs to understand drug or biologics development factors such as scale-up, process transfer, and so on.

On the execution side, companies must develop new strategies and processes with deep knowledge of both the worlds of biopharma and medical devices while complying with individual guidelines for a device (such as 21 CFR Part 820), and a drug (such as 21 CFR Part 210 and 211).

• Advancing combination product development:One way to get combination products to market faster is to build an integrated clinical strategy for drugs and devices. If the device design and development team understand the drug or biologic clinical phases, they can plan the scale of device manufacturing to ramp up drug development. While clinical and commercial production requires adhering to cGMP, the prototype does not require it. Integrating science and engineering of the drug or biologic and device is critical for success. For example, the material used for the biologic’s auto-injector may impact drug efficacy; this may delay the overall combination product launch if developers don’t engineer the product cohesively.

The overall risk management of drug or biologics and devices, including the quality target product profile (QTTP), needs to be integrated for all possible scenarios. It is advisable to initiate the device design through CAD models, drawings, parts, attributes, failure modes, effects analysis, and bill of materials (BOM), and regulatory deliverables, including design history file (DHF) and device master record (DMR), and device specifications at the same time and in collaboration with the drug substance development processes. The integration of the product and its lifecycle management requires an integrated system too. The objective is to build and maintain the final combination of product information cohesively during the development and manufacturing cycles.

• Navigating regulatory challenges across countries: Before developing a combination product, creators must determine the product’s regulatory agency and associated compliance requirements. These regulations will vary based on the product’s country of origin. For example, the US has multiple departments within the FDA regarding the regulations for drugs, devices, and combination products, including:

1. The Center for Drug Evaluation and Research (CDER) – for products like inhalers
2. The Center for Devices and Radiological Health (CDRH) – for products like drug-eluting stents
3. The Center for Biologics Evaluation and Research (CBER) – for products like syringes prefilled with cellular therapeutics

Determining which center to register a product with, in the US, depends on the primary mode of action (PMOA), which identifies the single most important therapeutic area being treated by the product. If US developers struggle to determine the PMOA, they can submit a pre-request for designation (Pre-RFD) and a request for designation (RFD) to the FDA’s Office of Combination Products (OCP).

Companies with specific competencies need to review their processes and establish a suitable set of compliance processes to receive approval for marketing, manufacturing practices (cGMP), and post-market safety. Each individual part of the combination product must be compliant with the constituent’s regulatory agency.

• Cognitive platform critical for saftey reporting:There is a critical need to adopt an integrated process for combination product safety surveillance and reporting. A cognitive automation-based platform for combination product safety management—covering end-to-end process automation from complaints intake to processing, process improvement, and finally reporting to regulatory agencies—is a critical step toward PMSR (postmarketing safety reporting). The platform requires the capability to differentiate automatically between reactions to the drug or device, process the complaint through the appropriate module, and produce an integrated safety report.

The way forward

With the technological advancements and the rise of telemedicine, it is imperative to enable and promote a combination product to benefit more patients.

It is time to reconsider and implement a fresh strategy and process for combination product design and manufacturing.

It is time for companies to come together to build a strategy that integrates global (or regional) regulations like Medical Devices Single Audit Plan (MDSAP) and European Medical Device Regulation (MDR) in the combination product context.

In the rising demand for personalized medicine, the combination product development and manufacturing processes need end-to-end agility, to provide better care to patients. Hence, companies need to plan for faster, cost-optimized, and compliant development and manufacturing of their products.