Organizational Imperatives For Combination Product Development

By Fran DeGrazio, executive editor, Drug Delivery Leader

In the U.S. and globally, there have been many challenges over the last decade related to developing and commercializing drug device combination products. Examples of these include adopting new regulations as agencies release them, staying on top of industry best practices, and ensuring employees can adjust to the changing regulatory climate in their day-to-day work. What must the industry do to address these challenges, especially since industry insiders and observers view combination products as the future standard in bringing new products to market?

Frankly, at the heart of the matter lies the ability for a pharmaceutical organization to effectively manage change and to stay agile. There are multiple benefits pharma companies can realize if these approaches to addressing challenges are enabled within the organization.

Adapt to Regulatory Complexity

First is the benefit of more effectively meeting regulatory compliance. Let’s start with some facts. The FDA issued Current Good Manufacturing Practice Requirements (CGMP) for Combination Products (21 CFR Part 4) in 2013. The FDA then followed this document with guidance on CGMP requirements for combination products published in 2017. Most recently, in February 2024, the FDA incorporated by reference the quality management system requirements of ISO 13485 into CFR 820 and Part 4. The FDA announced this revision as the Quality Management System Regulation (QMSR) for devices and for combination products. These are just a few of the guidance documents and references in the industry. Of course, then add these to the European Medical Device Regulations (MDRs) and other regional and country-specific regulations, and you can see how quickly confusion can grow and the complexities of real-life applications multiply. Yes, change management and organizational agility are keys to getting that confusion and complexity under control.

Foster Cross-Functional Communication

The next benefit is the ability to make gains in efficiency and alignment throughout the organization. Organizations typically structure themselves around functional silos (i.e., vertical depth). If combination product development teaches us anything it is that, although organizations need deep functional expertise, the most important aspect in execution is broad, cross-functional ability (i.e., horizontal alignment). Drug formulation, packaging, and delivery device areas, along with other critical functions, should operate more collaboratively and transparently in a development process that begins to integrate functions in the earliest stages. Doing so means making conscious, purposeful decisions about the process at key inflection points along the way and not just allowing for current drug and device processes to somehow meld over time – or hope that they do. Not only are the regulators looking to see this kind of process integration happen early and intentionally, but cross-functional collaboration, communication, and education provide the opportunity for scientists and engineers to speak the same language and, therefore, avoid potential downstream problems that may otherwise appear in non-integrated, silo-structured operations.

As an illustration, a drug formulator, typically a scientist, could be using a Quality by Design (QbD) approach in development. In this approach, the focus is on defining the Target Product Profile (TPP) and Critical Quality Attributes (CQAs) of the drug product. In a non-integrated development process, that formulator may not be aware of related factors downstream, closer to the patient.

Although safety and effectiveness are always priorities for all involved, the reality is that downstream concerns related to delivery (including decisions made by device engineers) must also be considered in order to get the product to the end patient in a way that allows that patient to successfully gain the benefit of the drug product being formulated.

For example, too great a viscosity level in the drug being developed can have a direct, negative impact on the delivery to the patient. If a device engineer were to work with the drug development team early to identify and understand such risks, the company could work to mitigate any potential negative impacts, even in formulation development stages. An integrated process that brings together scientists and engineers earlier and more purposefully can significantly increase the effectiveness of risk mitigation strategies.

For the horizontal organization to work, there is nothing more important than the ability to communicate and to speak the same language across functional areas. A good example of this is the difference between terminology, such as that used in executing via Quality by Design in drug development versus the language of Design Controls used for execution in the development of medical devices. Although the terminology is different, these two scientific approaches are, upon execution of them, quite similar. People working in the various combination products areas should understand and be able to speak both these languages. Furthermore, digitally sharing data and information can help, the design of communication-supporting information systems must have cross-functional subject matter expert involvement for companies to glean the full value from speaking the same language.

Manage Challenges with Oversight and Education

Of course, these kinds of organizational changes can also lead to challenges. An example is the need for clarity in decision-making. As more functions are involved and in more stages of an integrated process, decision-making can become blurred. For instance, who is responsible for identifying and qualifying the delivery system for the drug and, within that decision process, determining the individual packaging component? Individual componentry and related development processes can have a direct impact on the entire working of a combination product. A simple example of this is the understanding of the siliconization process for a plunger used in a prefilled syringe system that may be in an autoinjector for self-administration. In this case, a poor understanding or lack of control in this critical process parameter (CPP) for the plunger can lead to negative results for the patient using the autoinjector.

To enact effective change in moving toward integrated, cross-functional product development without creating added, unwanted challenges, management oversight is critical. Such oversight not only encourages and fosters this change, but it also helps all involved to identify and learn from the practical difficulties of execution. Moreover, a management focus on education and understanding of how the new guidance and regulations impact every function expands the knowledge of those involved in delivering the combination product.

For efficiency and compliance reasons, it is imperative, frankly, that the pharmaceutical industry assure that a repeatable, risked-based combination product process becomes the standard to deliver efficiency and meet conformity challenges going forward.