Inhaled combination products (ICP) have emerged as a significant advancement in the treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and other pulmonary conditions. Inhalation offers a targeted route of drug delivery directly to the lungs, minimizing systemic side effects and maximizing therapeutic benefits. As the prevalence of respiratory diseases continues to rise, the development of ICPs plays a pivotal role in addressing both clinical and patient-centered needs. 

However, these products present unique challenges from a Chemistry, Manufacturing, and Controls (CMC) standpoint. The combination of different active pharmaceutical ingredients (APIs), each with distinct physical and chemical properties, along with the need for precise, efficient drug delivery to the lungs, requires careful CMC planning and execution. 

In this blog, we will discuss what a combination product is, why there is a particular advantage for inhaled products, and regulatory factors that apply to CMC activities.  

What is a combination product?

A combination product is a medical product that contains: 

1. Both a drug and a device 
2. Two or more drugs 

The nature of the combination dictates the CMC requirements since each component (drug, device, biologic) has its own regulatory requirements. Therefore, developers must ensure that the drug or biologic meets the appropriate guidelines under FDA or EMA while ensuring that the device component adheres to ISO standards for safety and performance.  

A closer look at ICPs and their advantages

The most common types of devices used for ICPs include pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), and nebulizers (see Table 1). The formulation and development requirements are often tailored for each type of device, making device selection and/or manufacturing a key aspect of the overall product development process.  

Table 1: Examples of Common ICPs 

pMDI	DPI	Nebulizer

 

Combination products are beneficial for respiratory treatments as they offer the potential to improve the efficacy and safety of therapies. Some of the essential benefits of ICPs include: 

• Enhanced efficacy: ICPs can provide better control of respiratory conditions, such as in asthma and COPD symptoms, as compared to single-drug inhalers because the combination of drugs in the product work synergistically to target different aspects of the disease. 

• Reduced side effects: ICPs can offer reduced side effects compared to individual drugs because a lower dose of each drug is often sufficient when they are combined. 

• Improved convenience and patient compliance: ICPs can offer improved convenience for patients by requiring only one device, rather than two or more separate inhalers – ultimately resulting in better patient compliance. 

The goal of ICPs is to improve the quality of life for patients suffering from chronic respiratory diseases. By offering better symptom control, reducing exacerbations, and simplifying treatment regimens, these products help patients lead more active, comfortable, and fulfilling lives. 

What regulatory division governs ICPs?

ICPs are subject to rigorous regulatory scrutiny due to their complexity. Developers must ensure that their CMC documentation is comprehensive, covering both the APIs and the device. Combination products are regulated by multiple divisions within the FDA, including: 

• Drug/Device combination products are subject to the requirements of both the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Devices and Radiological Health (CDRH). 

• Drug/Biologic/Device combination products are subject to the requirements of all three FDA centers: CDER, Center for Biologics Evaluation and Research (CBER), and CDRH. 

The regulatory classification of the product depends on its primary mode of action (e.g., as a drug or a device, although ICPs are often classified as drug-led, drug/device combination products). The PMOA (primary mode of action) dictates the regulatory pathway and the level of scrutiny required for each component of the product. 

An evolving regulatory landscape

As ICPs become more sophisticated and integral to respiratory disease management, the regulatory CMC landscape continues to evolve to ensure these products meet the highest standards of safety, efficacy, and quality. From ensuring API compatibility and advanced analytical methods to navigating device-drug interactions and post-market surveillance, developers must stay abreast of changing regulatory requirements across different regions. 

For example, we are seeing a trend from the FDA asking for additional clarity from sponsors regarding how their drug is topically delivered to the lungs, e.g. in situ dissolution profile, permeability, and clearance rate. The FDA has also pushed for sponsor companies to try to prove an “in-vivo/in-vitro correlation” for their ICPs – combining some or all of the below: 

• “Clinically relevant” in-vitro testing 

• “Anatomically correct” induction ports for inertial impactor testing 

• Realistic/representative inspiratory flow profiles, e.g. “disease state” airflow 

• Particle dissolution in representative lung fluid 

• Particle permeability in bronchial/alveolar tissue 

Helping your CMC plan breathe easy

The complexity of ICP development makes it essential for developers to plan early, engage with regulatory agencies, and rigorously validate their manufacturing and testing processes. By focusing on these key CMC considerations, developers can bring safe, effective, and patient-friendly combination products to market, improving treatment outcomes for millions of individuals suffering from respiratory diseases. 

Premier Consulting’s experts can help you understand these regulatory considerations and strategically guide your ICP development to streamline your path to approval. Contact us to speak directly to our team. 

Author: 

Randall White, Director, Regulatory Affairs – CMC