In the ever-changing realm of healthcare innovation, the intersection of medical devices and drugs has given rise to a new class of therapeutic solutions known as combination products. These groundbreaking advancements hold the promise of enhanced efficacy and improved patient outcomes by integrating medical devices with pharmaceutical agents. However, navigating the regulatory landscape governing these complex products requires a meticulous understanding of Chemistry, Manufacturing, and Controls (CMC) requirements. From stringent quality control measures to harmonizing the diverse elements of device and drug components, the path to regulatory approval is laden with challenges and opportunities that can shape healthcare’s future.

When submitting a combination product to the U.S. Food and Drug Administration (FDA), the Office of Combination Products (OCP) will determine the FDA center that should be the lead for the product based on its primary mode of action (PMOA). For most products comprised of a drug filled into a device (such as pre-filled syringes or autoinjectors), the drug itself is responsible for the product’s PMOA, so either the Center for Biologics Evaluation and Research (CBER) or Center for Drug Evaluation Research (CDER) will typically be assigned as the lead center. However, combination products whose PMOA is achieved by a device constituent with a drug serving a secondary action (i.e., a drug-eluting stent) are regulated by the Center for Devices and Radiological Health (CDRH) under device requirements.

Early FDA Engagement

When a combination product program is still in its early stages, it is crucial to actively involve the FDA to obtain valuable input about building the development plan. This will also give the agency an opportunity to offer guidance and advice on critical issues that may arise, as well as a beneficial preview of upcoming innovative technologies.

There are inherent differences between drug-led and device-led combination product development timelines for review. The CMC guidance offered by the FDA during an end-of-phase-2 (EOP2) meeting is typically actionable in time for phase 3 trials for a combination product’s drug component. These trials may start six to nine months after the meeting. In contrast, for the device component, the timeline from critical design inputs to phase 3 readiness extends over a much longer period, typically ranging from one to four years. Waiting for an EOP2 meeting before engaging with the FDA on a device-led combination product’s CMC program may be too late to encompass any advice or warnings before scheduled phase 3 studies.

In addition, there are innate limitations of the combination product review processes. CDRH houses the FDA’s team of subject matter experts in device engineering, design, and validation whether the product is drug- or device-led. CDRH’s review is often not initiated until later development stages. Proactively involving CDRH experts during phase 1 is crucial for the company or sponsor; failure to do so increases the risk of facing device-related issues in later development stages, leading to potential regulatory CMC discrepancies and necessitating financially burdensome modifications. Even when engaging CDRH subject matter experts as early as possible, challenges may emerge from variations in requirements or expectations between the review divisions of CDRH, CDER, and CBER about the convergence of a combination product’s drug and device components.

It is therefore advisable for companies to communicate with FDA centers to ensure the progress of device development aligns with that of drug development. This proactive engagement is particularly valuable for CMC aspects, ensuring harmonized progress between drug and device components for a cohesive and efficient combination product development program.

Managing Device Design Changes During Development

Effective CMC change management, especially technical changes to a device, is paramount during combination products’ clinical development. The dynamic nature of development often necessitates adjustments to various components, including formulation, manufacturing processes, and analytical methods. While these changes are sometimes unavoidable, they pose potential risks to product quality, safety, and efficacy if not managed meticulously. Therefore, a rigorous and well-structured approach to handling CMC changes is essential to ensure clinical data integrity, regulatory compliance, and drug development success.

Certain modifications in design may necessitate supplementary human factors studies, additional pharmacokinetics data, or, in the case of specific alterations to autoinjector pens, investigations to establish that a post-change design can effectively deliver the drug to the same tissue plane as the pre-change device. When transitioning a drug product from one device to another—from a prefilled syringe to an autoinjector, perhaps—it is important to contemplate studies assessing potential changes in pain perception upon injection.

Nevertheless, design modifications deemed minor or confined to a specific aspect of a combination product’s user experience—like adjustments to an autoinjector plunger mechanism without any accompanying alterations—may necessitate only pertinent studies related to that specific change, such as human factors assessments. When suggesting device changes to the FDA, companies should provide a thorough risk assessment accompanied by a detailed justification outlining the necessity or exclusion of specific studies.

The meticulous management of device design changes is a cornerstone to successfully developing combination products. As the nuanced interaction between drug and device components evolves during the development journey, addressing potential challenges becomes paramount. Transparent communication with regulatory bodies facilitates not only compliance but also the optimization of the combination product’s performance and safety. By navigating these complexities with diligence and foresight, companies pave the way for innovative and effective therapeutic solutions that meet the highest quality standards and regulatory approval.

Developing Combination Products for Orthopedics

Orthopedic combination products represent a dynamic and innovative approach in musculoskeletal healthcare, addressing both implant integration challenges and postoperative infection prevention. Common orthopedic combination products include implants enriched with growth factors, aimed at promoting tissue regeneration and enhancing bone healing, and antibiotic-loaded bone cements designed to mitigate the risk of infections associated with orthopedic procedures.

CMC plays a central role in ensuring the safety, efficacy, and quality of these complex interventions, as the development process delves into defining the chemical and physical characteristics of each constituent, establishing robust manufacturing processes, and implementing stringent quality controls. A key player of orthopedic combination product development, CMC underscores the commitment to producing products that not only meet rigorous scientific standards but also adhere to the highest levels of manufacturing precision, ensuring their ultimate success in enhancing patient outcomes.

Developing an implant enriched with growth factors involves comprehensive CMC considerations, each crucial for ensuring the success and efficacy of these advanced orthopedic interventions. These considerations include the starting material choice. Selection of the expression system and cell line used in the product involves a comprehensive disclosure of genetic modifications, accompanied by evidence showcasing the stability and consistency of protein expression over time. Some sources might necessitate extra testing considerations, such as targeted pathogen testing for particular diseases.

Further, protein characterization entails a rigorous examination of the engineered protein’s structure, post-translational modifications, and purity through advanced analytical methods. Biological activity considerations involve the demonstration and validation of the protein’s intended therapeutic properties through specific assays. The purification and manufacturing process is scrutinized to achieve high purity levels, with an emphasis on reproducibility and stringent quality controls. Formulation and stability concerns drive stable formulations development, including shelf life evaluation. Integration of the growth factor material with the implant mandates compatibility assessments and addressing potential interactions during manufacturing and storage.

Likewise, creating antibiotic-loaded orthopedic combination products demands meticulous yet distinct CMC considerations, including aspects such as the choice of antibiotic. The antibiotic itself is a critical aspect, requiring a clear identification and justification of the selected antibiotic(s), along with information on their spectrum of activity, concentration, and pharmacokinetic properties. Ensuring drug-device compatibility is paramount, involving validation to confirm the incorporation of antibiotics does not compromise the device matrix’s mechanical properties. The manufacturing process must be robust and reproducible, with controls in place to guarantee uniform antibiotics distribution throughout the matrix. Sterilization methods, particularly considering the heat-sensitive nature of some antibiotics, demand careful selection and validation to eliminate microbial contaminants without jeopardizing antibiotic stability. Additionally, characterizing drug release kinetics is essential, ensuring the antibiotic concentration released aligns within the therapeutic range for an appropriate duration.

These multifaceted CMC considerations underscore the commitment to delivering orthopedic combination products that meet the highest standards of quality and performance. 

---

Nicole Gribbin is associate director for Regulatory Affairs in Pharmaceuticals and Biologics at MCRA, focusing primarily on CMC requirements for U.S. regulatory submissions. After obtaining her bachelor’s degree from Cabrini University and her master’s degree from Drexel University, Nicole has been actively involved in the pharmaceutical industry in various capacities, specializing in CMC and biologics, since 2009. She joined MCRA in 2022. Nicole provides MCRA clients with FDA regulatory strategies and submission support, such as pre-submissions, 510(k)s, INDs, BLAs, and Premarket Approvals.