How Strategic Analytical Services Accelerate Combination Product Timelines

Jennifer L. Riter, Vice President of Analytical and Development Services, Kindeva

The global market for drug-device combination products presents a significant opportunity, valued at an estimated $139B in 2024 and projected to reach $267.7B by 2032, growing at a compound annual rate of 8.5%.¹ As therapies become more targeted and patient requirements more specific, the demand for specialized delivery systems, including autoinjectors, inhalers and transdermal patches, continues to grow. For drug developers, bringing these innovative products to market requires navigating a demanding path of technical hurdles and stringent regulatory expectations.

Delays in meeting filing or launch targets can cost a company substantial revenue. At the same time, regulatory authorities are requiring more rigorous evidence for products that incorporate devices. According to the U.S. Food and Drug Administration (FDA), combination product submissions must include functional testing, usability evaluations and device performance data in addition to traditional chemistry, manufacturing, and controls (CMC) data.²

The complexities are particularly pronounced for sterile injectables, pressurized metered dose inhalers (pMDIs), nasal sprays and dermal patches. These categories demand that developers not only perfect the formulation but also demonstrate that the delivery mechanism performs safely, effectively, and consistently. In this article, Jenifer Riter, Vice President of Analytical and Development Services at Kindeva, explores the challenges facing drug developers and how an effective, phase-appropriate analytical development program can streamline their drug products’ journey to market.

Navigating the Complexities of Combination Products

A successful development program must prove that a product is not only functionally equivalent but also usable and stable over its shelf life, including how the product will be transported and its storage conditions. Intellectual property also presents a significant hurdle, as many existing combination products are protected by patents covering the device mechanism, specific components, or the manufacturing process.³ This requires developers to innovate by designing around these patents, a process that adds engineering complexity and legal risk to the development timeline.

• Sterile injectables: Developers of sterile injectables face numerous challenges. First, they must ensure the device functions consistently, focusing on key performance attributes such as delivered dose accuracy, break-loose and glide forces, and reliable device activation. Second, they must demonstrate product integrity through container closure integrity (CCI) and the evaluation of extractables and leachables (E&L). Finally, the product must be manufactured under strict aseptic conditions in cGMP-compliant fill finish facilities that adhere to standards such as the European Union’s Annex 1 for sterile processing. Failures in any of these areas can derail entire programs.
• pMDIs: Pulmonary products are among the most challenging. Proving performance requires demonstrating not only chemical stability but also consistent device performance across aerodynamic particle size distribution (APSD), spray pattern and delivered dose uniformity. Small formulation or actuator changes can significantly alter outcomes. Developers also face the industry-wide transition to low global warming potential (low-GWP) next-generation propellants (NGPs), which adds further complexity. To manage these challenges, in-vitro bioequivalence (IVBE) testing has become central to many programs. This pathway remains technically demanding, as it requires highly sensitive analytical studies for factors like particle size and spray pattern that must meet rigorous statistical standards for regulatory acceptance.
• Nasal sprays: Nasal spray development requires more than just a stable formulation. Developers must precisely characterize and control key performance attributes such as plume geometry, droplet size distribution and delivered dose uniformity, as these factors determine deposition in the nasal cavity and subsequent absorption. Device reliability, including leakage or clogging behaviors, must be thoroughly evaluated, and usability testing may be required. Device patents and regional regulatory expectations add further hurdles.
• Dermal patches: Dermal patches must demonstrate consistent performance in key areas, including permeation, adhesion, and stability under real-world and patient centric conditions. This presents several challenges where developers must validate consistent drug release, manage formulation issues like the crystallization of active ingredients within the adhesive matrix and evaluate residual solvents. Adhesive performance must also be verified under conditions that mimic patient use. Specialized analytical and manufacturing capabilities are required to address these complexities, including for emerging formats like microneedle array patches.

The Importance of a Phase-Appropriate Analytical Strategy

A successful development program depends on applying the right analytical rigor at the right time. A phase-appropriate strategy aligns testing with the evolving goals of the product development program, from initial feasibility to post-market support. This approach prevents unnecessary work in early stages while ensuring that data is robust enough for regulatory submission later on.

In early-phase development, the focus is on characterization and feasibility. Analytical methods are used to screen formulations, compatibility, performance (ins some instances with a reference product) and understand the fundamental aspects of the drug and device as a combination product. The goal is to generate sufficient data to make informed decisions and identify potential risks without the full burden of validation.

As a product moves into mid-stage clinical development, the analytical requirements become more stringent. Methods must be qualified or partially validated to ensure they are reliable for generating data intended for regulatory review. Full-scale stability programs are initiated to understand long-term product performance, and a deeper understanding of leachables and performance is required.

For late-stage development and commercialization, a comprehensive and fully validated analytical package is essential. All methods used for lot release and stability testing must meet cGMP standards. The data generated must be robust enough to prove product quality, consistency, and safety to global regulatory agencies. This phase also includes planning for lifecycle management, such as qualifying new raw material suppliers,supporting manufacturing process changes or next generation delivery system (i.e. prefilled syringe to autoinjector). Adopting a phase-appropriate mindset ensures that resources are used efficiently and that the program builds a foundation of strong data at each step, minimizing the risk of costly delays.

How Emerging Analytical Methods Reshape Development

Robust data is essential to demonstrating product performance, satisfying regulators, and gaining market confidence. As products become more complex, the reliance on advanced analytical science has grown, with the most important accelerators being emerging technologies that provide greater reproducibility and regulator-ready evidence earlier in development.

To ensure success and achieve faster approval, developers are increasingly leveraging advanced analytical methods. For pulmonary products, IVBE methods can simulate dissolution, absorption and aerosolization to predict in vivo behavior, reducing reliance on lengthy clinical trials. Similarly, for nasal drug products, sophisticated plume geometry and droplet sizing analyses use laser technology and high-speed photography to precisely characterize the spray. This deterministic data is crucial because the spray pattern and particle size directly govern deposition.

This shift toward predictive, deterministic testing is also clear in sterile injectables, particularly for CCI. Older, probabilistic approaches like dye ingress are limited because they can often only confirm a failure, offering little quantitative information. In contrast, modern deterministic techniques such as helium leak detection, high-voltage leak detection (HVLD), vacuum decay and laser-based headspace analysis are now preferred. These methods offer superior sensitivity and generate quantitative, reproducible data, providing a much higher degree of sterility assurance.

A similar move toward predictive data is happening in dermal products. Developers are moving beyond simple drug release tests to employ advanced methods like In Vitro Release Testing (IVRT) and In Vitro Permeation Testing (IVPT). These tests precisely measure the rate and extent of drug release and its movement through skin models, providing predictive data that correlates far better with clinical performance.

In E&L analysis, high-resolution accurate mass spectrometry (HRAM-MS) and inductively coupled plasma mass spectrometry (ICP-MS) detect potential leachables and elemental impurities earlier. This allows developers to select appropriate container materials and address risks before submission, preventing costly late-stage reformulations.

Modern stability testing has also advanced. Cycling chambers, shipping simulations and in-use studies generate a more comprehensive picture of product robustness. This reduces the likelihood of late-stage failures and supports smoother regulatory reviews.

Modelling and Simulation as Analytical Tools

Computational modelling has moved into the mainstream of drug development, offering powerful tools like computational fluid dynamics (CFD) that allow developers to predict spray plume behavior, droplet formation and aerosol deposition in pMDIs and nasal sprays. Simulating different device geometries and inhalation profiles can refine designs before physical prototypes are built.

Finite element analysis (FEA) supports injectables by modelling mechanical forces, tolerances, and stress points in syringes or autoinjectors. For microneedle array patches (MAPs), FEA can model the stress and strain on the microneedles during skin insertion. These simulations reduce trial-and-error cycles, save time, and cost, and generate quantitative data that strengthens regulatory submissions.

Functional Performance Testing

Functional testing ensures that devices are reliable and perform consistently for its intended use. For injectables, this includes measuring injection force profiles, verifying dose accuracy, and confirming the reliability of device mechanisms. For pMDIs and nasal sprays, automated actuation systems replicate patient technique and reduce operator variability, producing reproducible data on spray pattern and plume geometry.

When these studies are conducted in cGMP environments with product-filled devices, the results are more representative of real time storage and shipping conditions and carry greater weight with regulators.

Navigating Regulation, Intellectual Property, and Adoption

In addition to scientific hurdles, drug developers must navigate differing regulatory expectations across global markets. Requirements vary between agencies such as the FDA, the European Medicines Agency (EMA), country-specific Notified Bodies and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). Understanding regional expectations is critical to designing studies that will be accepted across jurisdictions.

Intellectual property is another barrier. Device mechanisms are often protected, requiring developers to design around existing patents or work within narrower options. Market dynamics also play a role, as even when new combination products achieve approval, uptake may be limited if patients and clinicians are reluctant to switch devices. This adds commercial risk on top of the technical and regulatory challenges.

Five Strategies to Accelerate Development

1. Develop analytical methods early: Design robust analytical methods, such as assays, impurity tests and performance protocols, to be reliable across the entire product lifecycle. Integrate CCI and E&L strategies from the outset.
2. Optimize device design with computational modelling: Apply CFD to optimize actuator and nozzle design and predict aerosol deposition for pulmonary and nasal products. Use FEA to anticipate device stresses for injectables.
3. Build a comprehensive IVBE case: Integrate dissolution, particle size and device performance studies into a staged program to build a robust and compelling case for equivalence.
4. Test functionality under realistic conditions: For injectables, account for viscosity ranges and user forces. For sprays, use automated actuation to mimic patient technique.
5. Generate robust stability data: Include shipping, cycling and in-use studies that mirror commercial realities, reducing post-launch risks.

Analyzing the Value of an Integrated Partnership

Navigating the technical hurdles of combination product development ultimately hinges on the ability to integrate advanced analytical science into every stage of development. This involves more than simply adopting new technologies. It requires ensuring that analytical strategies are designed and executed effectively.

Working with an integrated contract development and manufacturing organization (CDMO) offers distinct advantages. When analytical development, formulation and manufacturing are managed within a single, unified organization, the risk of knowledge gaps and delays is significantly reduced. This structure ensures seamless technology transfer, as the same teams that develop the analytical methods can validate them for quality control and lot release. It also provides a holistic understanding of the product. If a stability issue arises, a cohesive team can rapidly determine the root cause, whether it originates from the formulation, device components or manufacturing process. This continuity extends to lifecycle management, providing consistent support for post-approval changes and market needs.

By working with a CDMO with these comprehensive analytical capabilities, developers can design smarter programs, anticipate regulatory requirements, and turn analytical obstacles into long-term successes.

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