By Michael Song, Ph.D.
Injection devices, whether manual or automated, are a must-have for most drug products in today’s competitive pharmaceutical landscape, as the majority of biologic products — with the exception of a number of oncology products — are launched as some form of combination product. The Needlestick Safety and Prevention Act (NSPA) was signed into law nearly 20 years ago, and today it is an industry expectation that all injectable products will have some form of needle stick prevention mechanism. The exception to this is products like insulin pen injectors, where the patient, for the most part, purchases and installs the attachment needles during administration.
Coupling an injector device with a drug product takes careful planning and project-level work to ensure the device can reliably deliver the intended medication dose. One cannot just assume that an off-the-shelf device will work with a particular drug product. Just on the device side, developing a combination product requires careful consideration, selection, development, and testing. In addition, many other factors must also be considered, from manufacturing to controls strategy to packaging and more. To help pharmaceutical companies navigate this landscape and help them to develop combination products in a compliant manner, 21 CFR Part 4 on combination products was introduced early in 2013. Later, in 2015, the FDA issued draft guidance on Current Good Manufacturing Practice Requirements for Combination Products, which was subsequently finalized in 2017 to help further provide clarity to the industry.
With the adoption of 21 CFR Part 4, the term “combination product” was introduced. By definition, a combination product is a product that comprises two or more different types of medical products (i.e., a combination of a drug, device, and/or biological product). This means the device needs to be co-developed along with the drug product — even more so with automated injection devices, where the device often needs to be tuned to the specific drug product characteristics, primary container, and fill volume. A pharmaceutical company developing a combination product is expected to follow medical device design control requirements, such as design history files, risk management documents, design verification and validation, etc. There are many elements that go into the development of the device part of the combination product, starting with drug characterization and primary container selection and continuing with manufacturing, labeling, and logistics.
This is Part 1 of a two-part article discussing important areas to consider when developing devices for combination products — and why they need to be addressed early in development. In this installment, we will look at the areas of primary container, device development, device selection, and design control. Part 2 of this series addresses manufacturability and control strategy, packaging and shipping, biocompatibility, and clinical and commercial needs. Subsequent articles in this ongoing series will dive deeper into these and other related areas of drug delivery device development.
The transition from drug product to combination product typically starts with the transition from vial to either prefilled syringe or cartridge. Because prefilled syringe and cartridge technologies have advanced significantly and component vendors have optimized their products to be compatible with many drug products, the importance of this step is often overlooked, and the more convenient or on-hand primary container is often selected. This should be avoided, as the choice of primary container components and specifications can have considerable impact on subsequent device development complexity and performance.
Primary container selection is multifaceted and requires multiple considerations. You can view the primary container as the bridge between the drug and the device. Its importance cannot be overstated, as it ensures the drug product is protected and can be effectively delivered by the device.
The choice between prefilled syringe and cartridge depends on a number of factors, from technical to supply chain to commercial strategy. For example, if the drug is a single-dose weekly injection and the dosing is at a volume that is not too small, then it may make sense to select a prefilled syringe. If, on the other hand, the drug is a daily injection and the dosing per day is at a relatively small volume, then it may make sense to select a cartridge and use a multi-dose injector. Other factors, such therapeutic area cost sensitivity and target patient population, must also be considered to determine if this selection makes sense.
Selection of the primary container will involve both assessment of the drug’s interaction with the primary container and the primary container material’s impact on drug stability over the product’s shelf life. It also involves ensuring compatibility of the primary container system with the selected device and manufacturing process.
As an example, a critical variable associated with the transition from vial to injectable primary containers (i.e., prefilled syringe or cartridges) — aside from the obvious drug product-silicone interaction — is the drug formulation characteristics and its effect on primary container’s ability to effectively expel the drug product. This is because allowable tolerances in the drug formulation, such as pH, concentration, etc., can have a significant impact on drug product viscosity, which is less critical when using a vial, where there is a lot more flexibility on how the drug product is removed. This also applies to understanding how the drug product formulation viscosity changes with changes in temperature. Changes in viscosity can have a significant impact on device performance and the amount of development work needed to dial in the device.
Pharma companies looking to develop combination devices should be cognizant that development of the device component cannot be an afterthought. A look at the number of FDA 483 warning letters post 21 CFR Part 4 implementation is indicative of the seriousness of the regulator’s stance on proper development of the devices used as parts of combination products.
How to select and develop the appropriate device in a de-risked but accelerated manner would require a good number of articles to go over each consideration appropriately; it should be noted that regulatory agencies expect pharma companies to follow 21 CFR Part 4 and incorporate and understand the requirements specified therein.
With device development, pharmaceutical companies will need to adjust to new required documents and development approaches, including design reviews, and to the importance of formative and summative human factor studies and why the FDA requires them. Pharmaceutical companies will also need to be familiar with device risk management approaches, as well as differences between analytical and device test method development and qualification. In addition, design verification and control strategy are another significant area that pharmaceutical companies need to understand. For example, sample sizes used in device design verification are often different from what pharma is used to, and understanding that this number is based on risk and confidence interval will be new to many.
There is no such thing as off-the-shelf, ready-to-go devices, and pharmaceutical companies need to realize that. Each device selected will need to be co-developed with the drug product. While there are aspects of vendor data that, if done correctly, can be leveraged to help accelerate and reduce the workload of combination product development, the device must ultimately demonstrate usability and reliability in delivering the intended drug product.
Often, once a company starts combination product development, it quickly recognizes that the amount of work that goes into developing the device warrants its own project team (as an arm of the CMC team) and that this team requires specialized technical expertise. While there is flexibility as to how the design control process is set up within each company, the key elements with any design control consist of a stage gate approach whereby device needs and requirements are defined, usually in a target device profile (TDP) that complements the combination product’s target product profile (TPP). From the defined TDP, candidate devices are evaluated, and the one that best fits the TDP and business needs is ultimately selected.
The evaluation and selection of a device for development is normally a pre-design control process that can have a significant impact on the success and on-time completion of the development program. In evaluating candidate devices, it is essential to not just check that the device meets the TDP but also to dive deep and take into consideration various other aspects associated with successful device development, such as robustness of the device design, usability based on the therapeutic area and patient profile, assembly and manufacturing risks, supply chain and post use environmental/sustainability requirements (especially if your device contains electronic elements and battery), and packageability, just to name a few.
An essential element associated with device selection is understanding how the device performs after undergoing shipping conditions. A common failure mode that is often found down the road during design verification is device pre-activation during shipping. As such, it is common practice to perform ASTM D4169 shipping simulation when evaluating devices to ensure the selected device is fit for use and will not produce unexpected results during shipping. I recommend ASTM over ISTA because ASTM is recognized in the FDA guidance document.
In developing a medical device component of a combination product, pharmaceutical companies must implement design control procedures such as creation of design history files, a design and development plan, design input and output documents, a design review process, approaches to design verification and validation, and design transfer to operations. In addition, procedures such as medical device risk management and design change also need to be implemented. Companies also need to consider post-market surveillance and device complaint handling as part of commercial preparedness.
One important thing to realize about the design control process is that all the elements are interlinked. Oftentimes, when new teams undergo design development, they tend to focus on the immediate task at hand or the segment that is applicable at the moment, and they overlook the bigger picture — with negative consequences down the road. For example, when developing the design input and output requirements, teams often overlook the fact that these requirements need to be verified, only to find out when trying to develop test methods to demonstrate compliance with these requirements.
Another pitfall often seen is that teams will reference all potentially applicable standards, such as ISO, USP, JP, EP, ASTM, etc. This should be done with care, as sometimes standards have subtle differences that will needlessly overcomplicate the design verification process. Other pitfalls abound, such as performing tests that either the vendor has already done or are that are out of scope for the product, which we will delve into in more detail in subsequent articles.
To help accelerate and minimize development work, it is common practice to leverage data from vendors. This is a widely accepted practice, but it should be done only if leveraged data is directly applicable. Biocompatibility data is one such example. Some device vendors do perform full biocompatibility testing, and in those cases their data often can be leveraged directly. Caution needs to be taken when a device vendor takes the approach of toxicology or biological safety justification to avoid performing biocompatibility testing. These justifications need to be scrutinized carefully to ensure they are done correctly and do not leave gaps. Taking the justifications at face value may expose the program to regulatory risks where you will not find out deficiencies until after IND or BLA submission.
These are just a few examples of areas of consideration and points to watch out for in device development for combination products. Part 2 of this series looks at manufacturability and control strategy, packaging and shipping, biocompatibility, and clinical and commercial needs.
Disclaimer: Opinions expressed in the article is that of the author and do not necessarily represent that of the author’s employer.
About The Author:
Michael Song, Ph.D., leads the biological device functionality, safety, and digital connectivity group within AstraZeneca’s biologic device development. In his current role, he oversees device functionality and safety, primary container science and technology, biocompatibility, container closure integrity strategy and testing, and digital connectivity development. Prior to his current role, Song was head of the Device, Packaging, and Process Engineering Department at Adello Biologics (part of Amneal Pharmaceuticals). He has held key technical positions at Stryker, Amgen, and Kavlico Corporation and has led the development of both combination products as well as 510(k) medical devices. He received his postdoctoral training at Barrow Neurological Institute / St. Joseph Hospital and Medical Center (part of Dignity Health) and holds a B.S. in electrical engineering from Purdue University and Ph.D. in neuroscience and Toxicology from Iowa State University.