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Jennifer Markarian is manufacturing editor of BioPharm International.
A device manufacturing process must be carefully designed in the early stages of development to ensure success in commercial manufacturing.
Designing and then manufacturing a drug–device combination product is a complex process that must take into consideration variables in manufacturing the drug delivery device, such as an inhaler or an autoinjector, as well as interactions between the drug and the device. Phillips-Medisize, a Molex company, has both clinical and commercial manufacturing facilities for drug–device combination products, and the company is expanding its Global Innovation and Development site in Struer, Denmark by adding a dedicated unit for manufacturing development. Pharmaceutical Technology spoke with the company’s experts: Justin Westendorf, product development manager; Bryan Moris, director of Global Pre-Production Quality; and Chris Conger, director of Connected Health Device Technology, about some of the best practices in manufacturing drug–device combination products.
PharmTech: What are some of the best practices in moving from clinical manufacturing to commercial manufacturing of a drug–device combination product?
Westendorf (Phillips-Medisize): During the design development process, there must be a good partnership and engagement between the device development team, formulation development team, clinical team, and the regulatory team. When scaling from building 500 units to 10,000 units to 10 million units, the device design can often undergo significant evolutionary changes. All stakeholders need to be aligned on which areas are allowed to change (such as assembly features) and which areas have to be locked down early (such as drug contacting features), as well as when features must be locked down to protect the integrity of the data being generated throughout the device development lifecycle.
It’s important to point out that there are perspective differences between a commercial manufacturing team and a product development team. When building products in commercial manufacturing, devices are built with the expectation that if the components and assemblies are produced to specification, then the performance requirements of the device will be met for the intended use population. In product development, however, the need for product may come before the design or manufacturing processes are well established or controlled. There are more nuances associated with ensuring the design and the drug formulation will successfully work together in these early builds.
For instance, there may not be time or value in performing process validation for early builds when the design is still evolving. This situation requires a flexible but compliant quality management system to work with stakeholders on a risk-based approach to controlling early device builds. In addition, how users will use the product must be assessed. This means getting device samples into users’ hands to study how they interact with them in the context of specific environments. If it’s determined that there are points of confusion that could lead to use errors and harm, regardless of drug performance, the design team will need to make adjustments to the design. By the time a product gets to commercial manufacturing, all of these types of questions have been answered by a robust design development process.
PharmTech: What are some of the concerns for choosing materials for the device in a drug–device product? Do you need to evaluate potential interactions between the device and the user or between the drug and device?
Westendorf (Phillips-Medisize): Physical interaction with a user is one concern. It’s important to understand the intended use and use environment and make sure you’ve identified how the user will interact with the product. You should consider which product components may interact with the user’s hands, skin, mouth, nasal passages and other areas of the body. Materials need to be assessed for the potential risks they may pose to the user.
Drug interaction also must be considered—especially for inhalers, where you have very small, often organic, charged molecules that are flowing through a pathway that’s typically plastic and may also be charged. These types of interactions can have an impact on how—and how much—of the drug exits the device. It’s also important to understand the chemical interactions to make sure nothing from the components could leach into the drug or change its chemistry.
Manufacturing is also a consideration. Every component will be manufactured via some means (e.g., machining, injection molding) and likely be assembled using some technology (e.g., adhesive, laser welding). A key variable in material selection is the compatibility between the material, the desired manufacturing method, and assembly to other components in the device.
Early in the design development process, you identify candidate materials. But then you must use tools and evaluation techniques to gain confidence in those candidate materials. It’s here you may realize you need to make a material change, perhaps because structural performance is lacking or clinical performance is falling short, or it could be you’re simply having a hard time making a device component with that material.
‘Material selection’ isn’t an event that happens, but rather a maturing of the design and better understanding of the materials and how they interact with the drug and the patient and how suitable they are for the intended manufacturing processes. This understanding improves as you progress through later stages of the development and verification testing process to reach a point where you’ve demonstrated the component materials meet performance and manufacturing requirements.
PharmTech: What are some best practices for quality assurance (QA)/quality control (QC) of drug-delivery device manufacturing? What are some of the factors that need to be tested that are unique to a drug delivery device?
Moris (Phillips-Medisize): When it comes to drug delivery devices or combination products, it’s really about control—control of the product and control of the components going into it. A high level of control is required, but that can mean many different things. It could refer to additional levels of training or processes and procedures that are well-vetted to ensure control over the drug itself, whether it needs to be filled into a container or in containers that are already prefilled.
A high degree of control is paramount when going from clinical manufacturing to commercial manufacturing. Designing processes and having conversations up-front based on best practices for controlling the device and the drug, from both a clinical and volume manufacturing standpoint, are important. For example, if you’re working with different dosages, you want to ensure a unique vial labeling or color-coding system exists to help minimize the potential for a mix up.
You also need to ensure a fool-proof shift from labor-intense, detailed, and manual clinical processes to automated commercial processes. The process must be carefully designed from the beginning, so that when it does ramp up and a product goes to many global commercial sites, you’re set up for success. Because, ultimately, you’re designing a product for commercialization.
The fact is, there will be variations in the production of the device—from device development to the manufacturing process to final refinements in commercial manufacturing. That’s why it’s important to uncover, on the front end, where variation can occur and how that variation might impact drug delivery performance. Then it’s crucial to take that a step further by characterizing how the variation that’s expected in commercial manufacturing will impact drug delivery performance. Skipping this characterization step can negatively impact the investment around, and commercial success of, the device.
PharmTech: What are some of the risks for a drug delivery device that should be considered in manufacturing?
Westendorf (Phillips-Medisize): The biggest risk to commercial manufacturing is the investment and effort—or lack thereof—made in design development and the manufacturing development that should occur in parallel to development. If you spend time focusing on de-risking the technology piece, but not much time finding sources of manufacturing variation and de-risking them during design development, you’re passing residual risk into the commercial environment, where a combination of variations in manufacturing processes is unavoidable.
There can be an investment impact, especially pertaining to schedule and price. When collaborating with customers to construct a design development proposal, it’s therefore important to understand their approach to risk-based decisions and what they consider important. Some are more willing than others to accept a certain amount of residual risk and deal with those potential repercussions in commercial manufacturing, in favor of speedier outcomes. So, it comes down to collaboration and building a strategy together to determine how much time and effort will be spent identifying user, technology, and manufacturing risks. Both parties will need to decide on either a ‘fast’ approach, in which the customer agrees to accept transferring more risk, or a more thorough approach that draws risk down further during design and development, even if that takes more time.
PharmTech: What are some considerations for designing and manufacturing a drug delivery device that is connected to the Internet?
Conger (Phillips-Medisize): For connected drug delivery devices, you introduce design and manufacturing techniques beyond what are needed for a typical mechanical device. Two additional considerations require significant attention in the design process: validation of the software that goes into the device and managing the cybersecurity of the device.
Validation is typically done against the ISO standard, IEC 62304 (1), which encompasses the process of managing software development through the entire lifecycle, from the beginning of development through the end of the market life of the device. Our development and management processes conform to this standard, which tells us how to develop the device, how to document the development, and how to test it and validate the device so that it meets all requirements.
Device cybersecurity requires as much attention as validation. Once a device is connected, the potential for malicious remote device intervention remains a threat. For this reason, FDA has issued detailed guidance on how to approach device security, which includes taking a risk-based approach to both the software and hardware of the device (2). Risk assessments should be conducted to determine what could go wrong or where vulnerabilities exist, and then correlated to how serious the consequence is of each identified risk. If it’s determined to be a serious risk, the mitigation you must enact to prevent the risk becomes significant. On the other hand, if the potential risk is not very high, the effort to mitigate is much less significant.
1. ISO, IEC 62304:2006, Medical device software—Software life cycle processes (May 2006).
2. FDA, “Cybersecurity,” www.fda.gov/medical-devices/digital-health/
Jennifer Markarian is manufacturing editor, Pharmaceutical Technology.
Vol. 44, No. 9
When referring to this article, please cite it as J. Markarian, “Manufacturing Drug–Device Combination Products,” Pharmaceutical Technology 44 (9) 2020.