The global market for combination products is swiftly accelerating, primarily due to the increasing prevalence of chronic diseases and a steadily rising number of the geriatric population, plus the infusion of advanced technologies. However, the very nature of a “combination product” that includes an array of drug/device/biological components creates a wide variety of challenges, many of which fall in the regulatory category, as the primary and ancillary functions dictate whether the product or device should be regulated as medicinal or medical.
Advancement in this field is highly involved and complex. From the various entities and stakeholders involved in the development and distribution of combination products to the different regulatory pathways required for each component, manufacturers navigate intricacies that become more convoluted as today’s regulatory framework continues to evolve.
Two world-renowned experts on the topic include Asmita Khanolker, Senior Director, Cambridge Pharma SMC, and Alie Jahangir, Ph.D., Senior Principal Engineer, Quality Engineering (QE) Combination Products, Product Quality Management (PQM) Jansen, Pharmaceutical Companies of Johnson & Johnson, both of whom are set to keynote Medical Design & Manufacturing (MD&M) East. Slated for December 7 through 9 at the Jacob Javits Convention Center, the east coast’s most extensive design and manufacturing event is strategically designed to connect the industry and deliver technical and forward-looking insights impacting medical device engineers.
As we’re gearing up for the event next week, I spoke with Asmita and Alie about the dynamic world of combination products and what attendees can look forward to learning in their December 8 keynote session titled “Creating a New Mind Set for Combination Product Development.”
Combination products open the door to technological advancement. Could you speak about these opportunities?
Khanolker: It is a very exciting time for combination products with a number of novel therapies in the pipeline; in many cases, it is groundbreaking for advancing science and medicine, but these also pose many challenges. Recent trends in formulations involving long-acting injectables with high viscosities and intravenous to subcutaneous biotherapeutics requiring high dosage/large volume delivery are pushing the limit of traditional drug-delivery platforms. There is a need for a novel enabling autoinjector technology that can withstand high pressures while also providing patient benefits.
The ArQ-Bios technology from Oval Medical Technologies, an SMC Ltd. company, features a modular approach. The power pack, primary drug container, and patient interface can be substituted with minimal impact making it a truly flexible customizable design for various drug formulation viscosities and volumes. Patient benefits include quiet, gentle activation of the device even when the drug is pressurized at 300 bar and 360 degrees viewing window through delivery. The modular approach helps optimize each of the requirements separately; customized internally to the challenging technical needs of the application and external customization to patient touchpoints towards eliminating user errors and successful self-administration; thus providing an enabling subcutaneous delivery technology for challenging formulations and better solutions to patients that did not exist before.
Given the complexity of these systems, there are many challenges during the production process. Could you speak to these challenges?
Khanolker: The novel complex formulations are not an exact fit to deliver with existing standard device technologies, and the device needs to be designed to deliver the specific formulation appropriately. This is challenging as there are iterative cycles across all the manufacturing processes during formulation development as the drug delivery and dosage is optimized for the therapy outcome.
SMC Group Ltd. provides an integrated manufacturing pathway from early research to launch. The integrated approach combines concurrent development, manufacturing, and testing involvement and removes the fragmented approach and can reduce time to clinic. Starting from molding and assembly, PDC molding flexibility and design for manufacturing (DFM) inputs are key manufacturing considerations. PDC molding allows customized designs to be tailored to the needs of each drug. Tolerance control on device assembly stack ensures repeatability and enhances device performance reliability. Adaptive manufacturing, including customizable fill-finish processes and flexible lines capable of GMP manufacturing, provide an integrated approach to the successful development through the commercial launch of novel therapies.
What tools can designers and manufacturers implement to overcome said challenges?
Khanolker: Modern digital and mathematical transformation techniques such as predictive modeling and simulation provide avenues for optimizing design. It can predict the delivery time of challenging formulations and predict shear dependent behavior of formulations. The simulations can look at likely variations of injection times across millions of simulated devices constructed by random selection of different input variables.
Oval’s methodology involves a thorough understanding of the needs of the patient population and formulation characterization to define the device requirements very early in the customization process. We have developed an injection characterization system that can analyze the drug formulation, vital for non-Newtonian suspensions and two-phase systems. This system can truly measure the viscosity in an autoinjector context, including an indication of the homogeneity of the fluid, and reveals the influence of a range of variables on the fluid, and a numerical model is generated. The outcome of this approach is a thorough understanding of the formulation being delivered in the context of the delivery mechanism and sensitivity of the drug to environmental influences. Coupled with early user research and formative studies, the path to device design is based on a thorough understanding of the needs.
What are quality considerations critical for combination products?
Jahangir: One of the key aspects of successful market approval for any combination product is to ensure that proper regulatory requirements and quality system management are followed. Since each constituent part of the combination product will retain its regulatory status (e.g., drug, biologic, or device) even after they are combined, the main question for many manufacturers is, which regulatory requirements should be applied to the final combination product as a whole?
Pursuant to the FDA’s Final Guidance on GMPs (2017), a combination product manufacturer may meet the requirements of both drug cGMPs (21 CFR parts 210 and 211) and device Quality System (QS) regulation (21 CFR part 820) by designing and implementing a cGMP operating system that demonstrates the most efficient compliance. However, to reduce the burden on manufacturers of combination products, FDA proposed a “streamlined” approach under 21 CFR 4.4(b) to demonstrate compliance with any specified provisions of cGMP requirements and eliminate cGMP requirements that are common between drug and device regulations. Therefore, depending on whether the manufacturer of combination products is either a pharmaceutical or medical device company, section 4.4. indicates that:
- A pharmaceutical company with a QMS compliant to 21 CFR 210/211 (drug cGMPs) in place shall only implement certain sections of 21 CFR 820 (Device cGMPs).
- A medical device company with a QMS compliant to 21 CFR 820 shall only implement certain sections of 21 CFR 210/211.
In summary, due to the regulatory complexity of combination products, the management must be actively engaged to oversee, develop, and implement an effective quality system for the final product. Specifically, this engagement should start from the early stage of product development when both device and drug teams initiate the process of creating or reviewing policies and procedures to ensure operation under an appropriate GMP system that each set of regulatory requirements is met or exceeded and done so with integrity.
You both are presenting the keynote address at MD&M East. What can attendees look forward to learning?
Jahangir: Our keynote address and related roundtable will cover some critical innovation, quality, and manufacturing aspects of combination products and provide practical guidance to leverage this unique knowledge and tools to develop safe, effective, and functional combination products at lower cost in a more efficient manner. Specifically, we will be discussing the application of computational modelling and simulation (CM&S) in designing and validating specific drug delivery devices aligned with ASME’s new Verification and Validation Guidances.
What excites you most about engaging with your community in person this December?
Jahangir: While virtual technologies/tools have allowed people to continue collaboration and communication globally during the pandemic, they still struggle to mimic the richness of face-to-face gathering. I am, therefore, excited to deliver my talk and a round table discussion on the subject of computational modeling and simulation of drug-delivery devices to a live audience at the MD&M East event in NYC. Once again, I am particularly looking forward to having the opportunity to network in person and forge new relationships with colleagues from different industries. I thank the organizers of MD&M for this great opportunity and would look ask everyone to join me in the above-mentioned sessions!
To tune into the keynote session and more forward-looking educational content, register for MD&M East here today.