Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	Additive manufacturing (AM), also known as 3D printing, is a set of manufacturing methods in which parts are built by adding layer on top of layer of material (e.g., metal, polymer) using a design from a software file. One of the most significant advantages of AM is design freedom-without the constraints of traditional metal or polymer manufacturing methods, parts can be designed for improved functionality or potentially be made smaller and lighter weight. In many cases, multiple parts that previously had to be assembled can be consolidated and manufactured as one part, no assembly required.

	GE Healthcare is exploring the possibilities of AM for biopharmaceutical processing equipment, said Christel Fenge, head of Bioprocess R&D at GE Healthcare who is responsible for additive manufacturing activities at the company’s facility in Uppsala, Sweden, in a presentation at INTERPHEX 2019. “Additive manufacturing simplifies the supply chain,” explained Fenge (1). “Typically, manufacturing requires an extensive supplier base for parts that all need to be managed, documented, and inspected.” In one example, a metal connecting port for large filter housings that was traditionally assembled with 11 parts was reduced to one part using AM, resulting in a 75% reduction in lead time to produce. The redesigned, more compact part with no welding also allowed an 80% weight reduction. The metal 3D printed part did require a post-processing polishing step to make it fit for product contact. 

	Some of the first uses of AM in a wide range of industries were for rapid prototyping. Although AM has progressed beyond simple prototyping and into validated, repeatable manufacturing processes, protoyping continues to be valuable application. “Rapid prototyping can shorten the development cycle from months to weeks,” said Fenge. “Technical transfer to production is also simplified. Conventionally, it can take six months to a year to validate and scale up a manufacturing process, but with AM this time is reduced.”

	Redesigned parts can have a more optimized flow path over what is available on the market today with traditional manufacturing, added Fenge. “Although adding complexity would normally add risk of failure and additional time and cost, AM provides complexity for free,” she said.

	In another example of a project at GE Healthcare, a prototype of a gas mixer was 3D printed using a new design that made the part more compact and improved gas mixing. The number of parts was reduced from 23 to one, and 12 fittings (each of which adds a risk of leakage) were eliminated, said Fenge. 

	AM also allows cost-efficient development and manufacture of products that do not sell in large numbers. GE Healthcare launched a small-scale chromatography column (HiScale 10/40) typically used for viral validation studies during process development (e.g., of monoclonal antibody manufacturing processes) in early 2019 that uses AM to make polymeric, non-product contact components of the column. With traditional manufacturing, the column required seven different tools to generate the relevant components, but the new design requires no tools at all, said Fenge.

	AM offers the potential for more portable manufacturing. “We could potentially use it in-country to manufacture spare parts for a Flex Factory, for example, and reduce inventory complexity and lead time,” concluded Fenge.

	Material supplier 3M has developed the ability to 3D-print fluoropolymer parts made from polytetrafluoroethylene (PTFE). PTFE has very high chemical resistance and temperature stability, but PTFE designs are constrained in conventional manufacturing because it is not melt-processable. With a stereolithography (SLA) or vat-polymerization additive manufacturing method, however, complex part geometries can be created. 3M is now offering AM of PTFE as a service using open-source SLA-based AM and a tailored 3M material formulation developed specifically for the technology. 

	“We’re seeing early adoption for mixers, dispensers, nozzles, and components for chemical processing equipment, as well as custom and complex fixtures, clips/brackets, and sample racks and holders for manufacturing and laboratory equipment used in harsh environments. Parts can be produced on-demand and tailored to the application with custom shapes and sizes,” says Tim Schniepp, business development manager for Additive Manufacturing in 3M's Advanced Materials Division. These applications take advantage of the performance of PTFE in designs where the required geometry was previously either very difficult or not feasible to machine. The technology is currently limited to small parts (approximately 120 x 80 x 80 mm).    

	The company has found that the post-processing needed for PTFE is complex. “Parts are dried and sintered to remove the aqueous solution and binding agents, but results in pure PTFE parts; the process leverages our fluoropolymer processing knowledge and it takes approximately a week,” says Schniepp. The complex post-processing method was a driver for 3M to offer part production as a service rather than simply supplying the material. 

	“Ideally, our vision is to work collaboratively with our customers from the early design concept stages through to part manufacturing to take full advantage of the technology,” says Schniepp. “In reality, customers come to us at all stages of the development cycle, including with fairly mature designs.”

	3M developed a set of design guidelines for PTFE AM and helps companies optimize their designs, but 3M does not provide full design services at this time; customers are responsible for the performance of the final manufactured parts. The guidelines “provide direction for a number of key parameters, including overall part size, wall thickness, print orientation, and much more,” says Schniepp. 

	While the company is actively providing parts to customers now, Schniepp says the technology is in the “scale up” phase, and 3M is establishing its additive manufacturing facilities with the proper controls and requirements in place to be able to meet GMP requirements once the necessary testing is completed. 

	The group is actively working on gathering the data needed to show the reproducibility of the printing process. “Our mechanical and physical property characterization data has shown very good consistency (and very good isotropy as well), but additional quality control testing is in-work to further demonstrate repeatability in a statistically valid manner,” says Schniepp. He notes that the company is applying its lean Six Sigma manufacturing methodologies to the 3D printing business. “[The level of reproducibility] is a good question and one on which we’re definitely focused-the answer is crucial for adoption in critical part applications.”

	1.    C. Fenge, “Accelerating Additive Manufacturing,” Presentation at INTERPHEX (NYC, 2019).

Articles

The freedom of design found in additive manufacturing offers the potential for improved processing equipment, both in prototypes and commercial equipment.

Producing Bio/Pharma Equipment Using 3D Printing

	Twin-screw extruders (TSE) are used in multiple pharmaceutical manufacturing processes, including the extrusion of drug-loaded implants and hot-melt extrusion (HME) of amorphous solid-dispersions for improving bioavailability of oral solid-dosage formulations. The Leistritz Pharmaceutical-Nutraceutical Extrusion Seminar (June 12–13, 2019) offered demonstrations of operating equipment and presentations on best practices from extrusion experts. Philippe David, general manager at Sciences Computers Consultants, spoke about using computer simulation to model the extruder, which enables initial evaluation without using samples. Simulation is being used in HME development today, notes David, pointing to a research paper to be published in the August 2019 issue of the 

European Journal of Pharmaceutics and Biopharmaceutics 

titled “Holistic QbD Approach for Hot-Melt Extrusion Process Design Space Evaluation: Linking Materials Science, Experimentation and Process Modeling” (1).  

spoke with David about the benefits and limitations of simulation in pharmaceutical extrusion. 

What are the benefits of using numerical simulation in pharmaceutical twin-screw extrusion?

Simulation is a powerful tool to schedule the best trials to perform. Even at an early stage of the processability evaluation (without any real samples), it is worth trying to see what could happen in term of the quality-by-design (QbD) operational domain. The bad news is that, in general, the physics of the HME process is by far too complex to be fully modelled. The good news is that even with raw or approximate data, it is worth running virtual trials to evaluate the trends. These trends obviously need to be confirmed by real tests [with material], but the required quantity of material needed has dramatically been reduced. 

What do pharma developers need to understand about TSE simulation?

Mechanistic [extrusion experts] understand the relation between torque, flow rate, RPM, residence time, shear rate, etc. These relations are generic and valid in the polymer world as well as in the pharma world. Pharmaceutical process people are specialists in degradability, solubility, etc. These two cultures need to share and fill the gap to design the mechanical-to-pharma bridge and understand the root causes. 

How does your software for pharma extrusion differ from your original software for polymer extrusion?

Ludovic software, designed as a general-purpose TSE simulation, is valid for plastic as well as pharma, but the Ludovic Pharma Edition (introduced in 2018) incorporates pharma-specific considerations. These include material characteristics defined as a function of temperature (rather than a constant value), a specific design of experiment adjusted to the QbD style, and several temperature-related outputs meaningful for pharma. 

Eur. J. Pharmaceutics and Biopharmaceutics 

online DOI:10.1016/j.ejpb.2019.05.021 (Aug. 2019).

A presentation at the Leistritz Pharmaceutical-Nutraceutical Extrusion Seminar explained how simulation tools benefit the development process.

Simulating the Pharma Twin-Screw Extrusion Process

	Hovione Technology, a Hovione Ventures company, announced in an April 15, 2019 press release that it has secured global rights to develop and commercialize a new, affordable, multi-use blister-based dry powder inhaler (DPI) patented by inventor Dr. Klaus-Dieter Beller, which will be marketed as the Papillon DPI (1). The blister-based inhaler is suitable for both chronic and acute treatments and can accommodate a single- or double-blister configuration. The patient loads a blister to take the daily dose and reuses the inhaler for a defined period of time, typically 30 or 60 days. 

	The simplicity of the device, which is made from a single part, significantly reduces development cost and risk compared to more complex devices, explain Hovione Technology’s CEO Peter Villax and João Ventura, director of Technology Development and Licensing. “Because it is manufactured from a single mold, manufacturing and depreciation costs are much lower,” they add. 

	Villax and Ventura say that simpler DPI designs, which are less costly to manufacture, fulfill the need for readily accessible and affordable treatments, particularly in less developed markets. “Innovators have traditionally used device complexity to increase development and cost barriers for generic competition. [In addition,] smart and connected devices may have a role in the medium-term to further improve treatment effectiveness and adherence, especially in developed markets,” notes Ventura. “But inhaler devices do not fundamentally need to be complex; inhaled drugs can be delivered as effectively from devices made of very few parts and assembly steps.” Ventura says that making simpler inhaler devices is also a “greener” solution that consumes less resources. 

	In addition to being simple to manufacture, devices need to be simple for patients to use correctly. “Inhalers need to work in the hands of the patient. No matter how brilliant our inventions are, at the end of the day they need to bring benefit and value to the patients,” says Villax. He explains that human factors engineering is central for new DPI developments. This systematic design process can capture preferences towards design attributes that improve patient engagement with the device. 

	Creating a simple DPI is not a simple task. It is a difficult “marriage between device physics and formulation properties,” says Villax. “An inhaled combination [drug] is a complex product, because you have to consider not just the drug product, not just the device, but also how they interact with each other. For example: a powder inhaler turns an inspiratory effort into a force that disperses and aerosolizes a powder and entrains the particles into the lung. How efficiently this dispersion and entrainment occur is a key feature of the inhaler, but it depends just as much on the particles themselves and on how well they fly.” 

	Hovione Technology’s co-promotional agreement with API manufacturer Hovione allows the companies to integrate DPI device development with inhalation API formulation development and manufacturing. According to Hovione Technology, Papillon is available for feasibility studies and integrated development with formulation by pharmaceutical partners.

	1. Hovione Technology, “Hovione Technology Announces Papillon DPI,” Press Release, April 15, 2019.

	When referring to this article, please cite it as J. Markarian, “Hovione Technology Develops Blister-Based Inhaler,” 

A simple, one-part DPI aims to make inhalation drug treatment more accessible and affordable.

Hovione Technology Develops Blister-Based Inhaler

Can “smart” drug-delivery devices improve patient compliance? Innovators at 3M think so. Improving adherence and reducing use errors in noncompliant patients have been associated with improved health outcomes, and smart inhalers have the potential to help accomplish this objective, says Stewart Griffiths, a product commercialization manager for 3M Drug Delivery Systems Division. “As a society, we’re growing more accustomed to getting the information we want faster than ever before and in a way that is tailored to our individual preferences,” he notes. “Everything is personalized and on demand. We are starting to see this becoming true with regard to how drugs are delivered to patients and the instant feedback they expect.” 

spoke with Griffiths about the company’s 3M Intelligent Control Inhaler, which is currently in development, and about some of the manufacturing and regulatory considerations for connected combination drug-device products. 

Can you briefly describe how the 3M Intelligent Control Inhaler functions?

Most pressurized metered dose inhalers (pMDIs) on the market require you to coordinate your inspiratory flow when you press down on the canister to release the medicine. If you breathe in and your lungs are nearly full by the time you press, you’ve pressed too late. Conversely, you may press too early in the inspiratory cycle. When you mistime it, less medicine than intended is absorbed.

	The 3M Intelligent Control Inhaler was designed such that it could utilize the familiar MDI dosage form and add value by aiding patient coordination. It uses breath actuation to help correct the coordination problem, so you just breathe in and the drug is automatically delivered when you are inhaling and before your lungs are full. In addition, the display can visually prompt patients on how to use it correctly. This inhaler has been designed to be reusable. The main electronics component is reusable with up to 12 monthly refills of the medicine.

What are some of the benefits of connecting inhalers to a smart device? 

It stands to reason that you can get better patient engagement through ease of use, which can lead to improved compliance. My interpretation of compliance is twofold. The first element is adherence. Is a patient taking his/her medicine at the right time, in the right amount, as prescribed? On a daily basis? Morning and evening? The correct number of puffs each time, as necessary? Are they doing that routinely? 

	The second element is technique. With inhalation therapy, the delivery of the medicine can be greatly affected by how a patient uses a device. We see many delivery issues with press-and-breathe inhalers, soft mist inhalers, and dry powder inhalers. With some dry powder inhalers, a patient needs to use a lot of inspiratory force to deliver the drug, which is difficult for some patients with respiratory diseases to attain.

	Technology can help in both areas. An inhaler that is connected with a smart device can send reminders to a patient to help with adherence, for example. It also has the potential to help improve technique by providing feedback to a patient. The 3M Intelligent Control Inhaler was designed with the potential to do this. We wanted to have the ability to tell patients when they’re not breathing in for long enough or when they’ve not shaken the medicine if it needs to be shaken. Technology gives us the ability to coach and guide patients in the real world, without having to be in a doctor’s office.

How do you incorporate human factors engineering into a device design? 

From my perspective, it is important to get the device into the hands of patients as early as possible-for example, through formative human factors studies in the early prototype stage. These studies allow the scientist in the lab to use input from real patients to design new inhalers that are easy to use, fit comfortably in hand, and are easy to actuate, for example. Only when you put it into the hands of patients will you discover that it may be fundamentally flawed. Those formative human factors studies act as inputs that can inform the design of the device. When patients can easily operate a device, it means the patient receives the correct dose and is more likely to comply with the therapy.

	One of the key outputs of a human factors program is the instructions for how to use the device. The findings will drive what goes into those instructions. They will also inform how the packaging is designed, to ensure that it is easy for patients to open.

What are the regulatory and data security concerns with connected devices and how are they being addressed? 

Protecting patient privacy must be a top priority. There are tremendous opportunities ahead for collecting, sharing, and analyzing data generated by digital delivery devices; however, we need to instill trust in patients from the very beginning. To do that, we need to make sure patients understand how and why we’re using their data, and we need to clearly demonstrate how they will benefit from the use of their data. Today, it is critically important to determine the data strategy before going into design and development. 3M has addressed this by making security part of the up-front development process.

	Finally, regulations around drugs and devices are now becoming intertwined with electronics and software. 3M’s goal is to be ahead of the curve and follow the regulations as they evolve. The speed of electronics and software evolution is at a much faster pace than traditional pharmaceuticals by nature. The industry needs to evolve to incorporate electronics but continue in a safe way.  

What are some of the manufacturing challenges for incorporating electronics into inhalers? Are there special regulatory/quality testing considerations for connected devices?

From a manufacturing point of view, the arrival of connected devices requires a shift from purely plastic components to the incorporation of electronic components. This not only requires updates to the manufacturing lines themselves, but to the testing facilities. If historically you’ve worked only with plastic materials, tests are purely physical in nature. Electronics module testing is very different. For instance, if your connected inhaler utilizes Bluetooth technology, electromagnetic compatibility testing is required to prevent the device from interfering with other connected devices. Regulatory standards also change, once a device is categorized as connected.

	Finally, with technology constantly changing, the use of electronics allows for rapid improvements and the ability to address real patient issues. For instance, improved battery technology can allow a device to be used for a longer period of time. At the same time, it is important to keep in mind that the pace of the pharmaceutical industry is very different than the pace of the technology industry. This can create major challenges on everything from the design to the manufacture of a device.


	Vol. 43, No. 6
	June 2019
	Pages: 27–28

	When referring to this article, please cite it as J. Markarian, “Considering Connected Inhalation Drug Delivery,” 

A connected MDI may encourage compliance and aid proper technique.

Considering Connected Inhalation Drug Delivery

The trend to self-administered, home-based, subcutaneous drug delivery is creating a need for drug-device combination products that are easy to use correctly and designed with patients in mind. Patients may be familiar with prefilled, handheld autoinjectors or pens. Another type of device, not as familiar today but perhaps soon to see broader use, is the wearable autoinjector, which is attached to the skin to inject a larger volume dose over a matter of minutes, compared to seconds for the smaller dose of a handheld injector. The increasing use of biologics that must be delivered in larger-volume doses is creating a growing need for these larger-volume, wearable autoinjectors, which may also be called patch injectors, large-volume body injectors, on-body delivery systems, or wearable bolus injectors (WBIs). 

	Choosing a wearable injector rather than a handheld injector depends on the injectable volume and injection frequency, says Ian Thompson, vice-president of business development at Ypsomed Delivery Systems. “We believe the key applications for patch injectors will be in the 3–10 mL space for monthly or quarterly autoimmune or immuno-oncology therapies,” he notes. Ypsomed is developing YpsoDose as a prefilled, ready-to-use, patch injector for antibody-based drugs in the range of 3–10 mL (see 

). Functional devices for testing are available, and the company is engaging in feasibility trials with pharma companies, says Thompson.   
	

	Using platform technologies that can be easily customized for multiple therapies is important for manufacturing cost-efficiency, which is particularly important for drugs that target smaller patient populations and thus have low annual quantities, notes Thompson. Ypsomed produces devices for multiple products and customers from the same tooling and equipment. In addition, the electromechanical drive system is programmable for different viscosities or fill volumes. This drive system ensures consistent flow rates, which allow reproducible injection times, and the electronic circuitry is already in place to provide connectivity. The devices are designed to hold standard, 10-mL glass cartridges that are filled in a ready-to-fill tub format.

	Sorrel Medical is developing single-use, prefilled wearable injectors in configurations ranging from 1–20 mL. “The 3-mL device configuration has been fully verified and validated and is available for performing feasibility testing by our pharmaceutical partners,” says Andrei Yosef, CEO of Sorrel Medical. “The 20-mL device has working prototypes available. The other configurations are in the earlier stages and can be developed to commercialization with a partner.” Yosef notes that all the devices are based on the same pumping mechanism, with slight modifications to the outer shelling to accommodate different sized primary containers. Using a platform solution lowers risk in development and commercialization, adds Yosef.

	Subcuject is developing a platform for prefilled WBIs to deliver 1–10 mL of drug using an osmotic pump, which is a fully mechanical drive, without electronics. “Osmosis can create a high drive pressure and it is, therefore, not a problem with high viscosities or high tissue back pressure, which can be a problem with electromechanical devices. The injection flow rate is around 1 mL per minute for viscosities up to more than 50 cP,” explains Jesper Roested, CEO of Subcuject. Eliminating the electronic component also eliminates the limitations of battery life in cold storage conditions and reduces the environmental impact of disposal, he says. The company is currently testing performance of functional device models, and the device is expected to be ready for regulatory development by the beginning of 2020. The WBI is designed to have low cost of goods, and assembly and filling is straightforward, says Roested. It is also designed to promote uncomplicated development at pharma companies by using a standard glass cartridge with a plunger of standard material. 

The enFuse On-Body Infusor from Enable Injections, shown in 

, is being developed as a device platform for volumes from 5–50 mL, says Matt Huddleston, Enable Injections executive vice-president and chief technology officer. A unique aspect of the technology is the use of a constant-pressure design using an elastomeric pump, rather than a constant-flow design using an electromechanical pump. “This design allows the enFuse to automatically adapt to the injection site back pressure, and it is hypothesized to potentially alleviate infusion site leakage and pain,” notes Huddleston. The company received a US patent in March 2018 for its expandable elastomeric bladder and infusion cannula system, and additional patent applications are pending in the United States and other countries. Apellis Pharmaceuticals is conducting human clinical trials using enFuse technology to deliver its immunotherapies, and biopharmaceutical company UCB entered a development agreement with Enable Injections in November 2018 (1). 

	West’s SmartDose technology platform (see 

) is an on-body infusor that uses a Daikyo Crystal Zenith cartridge and a Flurotec-coated piston containment system. A combination product from Amgen for a single, monthly dose of Repatha (evolocumab) using West’s SmartDose technology was approved by FDA in July 2016 (2). In January 2019, scPharmaceuticals announced that it had completed preliminary feasibility studies of its Furoscix (furosemide) with the SmartDose Drug Delivery System and was moving forward with development in anticipation of filing a new drug application in 2020 (3). West also announced a collaboration with fill/finish provider Swissfillon, to provide bio/pharma customers with clinical fill/finish capability with the SmartDose technology (4).

	Most wearable injectors are designed to use conventional primary containers. A new development program from SCHOTT is aimed at bringing design freedom to the container, which the company says can give manufacturers the ability to improve the design of wearables. Customized designs could reduce the container size to make the device more discreet, for example, or add dimensional features (e.g., a ring, bar, or notch) to the container to improve alignment and allow easier assembly or improve the connection force between the container and device, explains Tom van Ginneken, global product manager at SCHOTT. Such containers would use standardized tub-and-nest transport packaging for the filling step. 

	The move to self-administration at home rather than in a clinic makes communicating information to patients crucial. Devices designed for self-injection can incorporate “smart” sensors and mechanisms to communicate information from the device to the user. Furthermore, wearable injectors can be connected through the Internet, typically using near-field connectivity (NFC) or Bluetooth, to communicate information through a smart phone or other connected device to a patient or to others, such as their medical team.

	On Sorrel Medical’s devices, for example, smart sensors “include air and occlusion detection, needle position, ensuring the primary container is in place, and on-body detection, in addition to a series of internal system checks,” says Yosef. In addition, Sorrel’s devices have integrated NFC and Bluetooth connectivity.

	In the enFuse device, a gauge and the button mechanism give active feedback to the patient for delivery progress and end-of-delivery cues, says Huddleston. “Beyond this, an option in development for connectivity will be capable of interfacing with smartphone applications to give information such as the delivery status of the device and the patient,” he adds. “Connectivity could potentially improve patient compliance, verify proper device function, and increase patient safety by identifying possible risks.” Management of confidential patient data, however, is a challenge, and connectivity to a healthcare provider or other party can raise concerns about data privacy. 

	“Both pharmaceutical companies and device manufacturers are aware of the vast potential in having data from connected drug delivery devices, and how it may be utilized to benefit various patient populations,” agrees Yosef. “We believe the question of how that data will be used is one that must be had with each individual pharmaceutical partner based on the molecule, the indication, and the patient population.” 

	Connected devices are being developed for combination products besides wearable injectors. For example, Haselmeier is collaborating with Common Sensing to develop a smart, disposable injector pen platform. Haselmeier’s subcutaneous drug delivery injection systems for self-administration will be combined with Common Sensing’s Gocap injector monitoring technology to record the time and amount of every injector dose, along with other information, such as storage temperature, says the company (5). Initially the monitoring cap will be an add-on, replacement cap, but is intended to eventually be an integrated device, says Paul Jansen, Haselmeier advisory board member. “Initial products are expected to be focused on clinical trial use. In this environment, patients are engaged and motivated to collect data,” notes Jansen.

	Connected devices are ideal tools for disease management, says Sai Shankar, vice-president, Global Digital Healthcare Systems, at Aptar Pharma, which offers both add-on and integrated connected devices for several different delivery routes. “They provide real-time analysis of dose adherence and patterns of dose administration, and they are potentially diagnostic tools to assess patient health and potential exacerbations.” Although the initial cost may be a concern, Shankar believes that the cost of connected devices will come down as increased adoption results in higher volumes. A key challenge for manufacturing connected devices is managing the need for manual assembly of early-stage, low-volume devices as well as the need for automated assembly for higher volumes, he notes. Securing the supply chain for electronic components is crucial, adds Shankar. Selecting known suppliers with medical-grade quality components, dual-sourcing components where feasible, and understanding the total cost of supply are key considerations.

	Finding manufacturing efficiencies such as using automation or standard parts (e.g., electronic chip or Bluetooth module) will be important for bringing down the cost of connected products, agrees Jansen. Another challenge is ensuring the electronics and software are compliant, including testing for data security and understanding and minimizing the risk of software bugs. Managing software updates can also be a challenge. “Pharma companies should be prepared for the unique challenges of being accountable for connected products,” Jansen says. 

					Developers of drug-device combination products should use human factors (HF) studies to ensure that the product can be used effectively and safely and “eliminate or mitigate patient adverse events and medication errors attributable to use-related errors” (1).

					“Human factors engineering (HFE) studies are not a ‘check the box’ activity to meet submission requirements,” says Stefanie Johns, Enable Injections associate director of Regulatory Affairs. “Complete response letters for drug-device combination products are most frequently a result of HFE deficiencies. It is up to the marketing application holder to demonstrate safe and effective use of the drug-device combination product by the intended users within the intended use environments. The HFE deficiencies identified by FDA during review are often related to concerns that specific use errors identified in HFE studies may lead to a potential underdose or overdose of the drug constituent part. Without demonstrating that appropriate mitigations have been put in place to resolve these types of use errors, substantial design changes to the device constituent part may be required to gain product approval.”  

					Failure to adequately integrate the drug and device constituent parts within the overall design and development plan for the drug-device combination product is another problem, says Johns. “The bottom line is that drug and device constituent parts cannot be developed independently or in silos; cross-functional team members from both sides must communicate frequently and transparently.” 

	1. Enable Injections, “Enable Injections Enters into Strategic Partnerships with UCB and Apellis Pharmaceuticals,” Press Release, Nov. 13, 2018.
	2. West, “West’s SmartDose Drug Delivery Technology Platform Selected by Amgen for Pushtronex System,” Press Release, July 11, 2016.
	3. scPharmaceuticals, “scPharmaceuticals Inc. Announces Development Agreement with West Pharmaceutical Services for Next-Generation FUROSCIX On-Body Infusor,” Press Release, Jan. 29, 2019.
	4. West, “West and Swissfillon to Partner on an Integrated Solution for Clinical Filling of SmartDose Drug Delivery Platform,” Press Release, Feb. 6, 2019.
	5. Common Sensing, “Haselmeier and Common Sensing Enter Connected Injectable Medicine Collaboration,” Press Release, May 3, 2018. 


	Vol. 43, No. 6
	June 2019
	Pages: 16–19

	When referring to this article, please cite it as J. Markarian, “Putting Drug Delivery into Patients’ Hands,” 

Wearable and smart devices allow user-friendly subcutaneous drug delivery.

Putting Drug Delivery into Patients’ Hands

	Developing a combination drug-device product brings together two distinct industries-pharmaceutical and medical device-to create an integrated product. “It’s not enough to merge specifications for the drug and the device that, on paper, are in sync; there are different sets of design criteria to factor in together,” notes Kerri-Anne Mallet, Clinical and Regulatory Affairs at Pharmatech Associates. “Beyond the technology aspects, there are cultural differences inherent in medical devices and drug development, akin to the differences between hardware and software development. There is a culture of ‘device people’ and ‘pharma people’.” A survey conducted by Pharmatech Associates and Merck aimed to identify cultural issues that may arise when people with specialized expertise from different industries come together to work on combination products (1). The survey identified “a perception that pharma regulations are more prescriptive, more step-based. In devices, there are other challenges. Test requirements are different and more varied; risk management and design controls play a huge part,” says Mallet. Cross-functional training for teams, understanding common goals, and mentoring are important for developing a collaborative working environment, she concludes. 

spoke with Mallet and with Bikash Chatterjee, Chief Science Officer and president; Lynn Hansen, RAC, director, Regulatory Affairs; and Caitlin Bancroft, Regulatory Affairs; all at Pharmatech Associates, about some of the differences in drug and device development, best practices for combination product development, and issues specific to Internet-connected combination products.

What are some of the key differences between drug development and device development?

Medical device development is generally more structured than drug development. Design history, inputs, outputs, and modifications are tracked and recorded in accordance with design controls. Devices also require human factors studies and usability engineering.

	Medical device development, for devices regulated by FDA, requires that the development process follow a design control framework and, where applicable, testing and development that adheres to the corresponding consensus standards. The regulatory pathway also impacts the corresponding development characterization and evaluation and, if required, clinical strategy. 

	Drug development, by contrast, is driven to a great extent by the phases of the clinical program and the drug format (e.g., small molecule, large molecule, complex molecule). Consequently, there is much greater variability in terms of development activity. Drug development is typically a longer development process than the device’s shorter lifecycle. For instance, a main difference between the two would be the clinical trial phases of the development lifecycle. Drugs demand extensive clinical studies running concurrently with product and process development, whereas the product and process development of a medical device are usually complete prior to clinical studies.

What are some regulatory challenges for combination drug-device products?

There are three primary regulatory challenges that combination products companies face: conforming to the different product-specific regulations, the complex electronic Common Technical Document (eCTD) structure, and how to handle the final product. 

	For any company bringing a combination product to market, the challenge is adjusting to each set of regulations associated with the different constituent parts. Since July 2013, 21 

] 4 has allowed companies to avoid duplicated efforts by clarifying regulatory elements that apply to combination products. Understanding whether your primary mode of action (PMA) is driven more by the device or drug is important to ascertain how best to integrate the core elements of 21 

210, 211, and 820 together per the guidance provided by 21 

	Drug and device manufacturers are always required to follow the quality management system and GMP requirements for the PMA constituent part, but these are supplemented by specific regulations governing other product components. Advanced planning and thorough investigation of the requirements are necessary. A common pitfall on the CMC [chemistry, manufacturing, and controls] side, for example, is not considering the device component as part of an extractables and leachables program.     

	The eCTD requirements for a drug product are daunting. Using eCTD for a combination product introduces a new level of complexity on an already burdensome process. It is difficult to determine where information about non-drug constitute parts should be included in eCTD, and familiar understanding and the use of the Regional Section of the eCTD format can be a challenge. Wise manufacturers address these obstacles by providing the most informative data on the device available in order to avoid observations during review. 

	When dealing with the final product, companies must remember to address basic logistical questions. With everyone pulling together the information on the individual constituents, it is easy to forget about the final product. Remember to consider the following: Who is responsible for the final product? Where is the final product being joined and packaged? Are the components and lifecycle being monitored and by whom? Missing these simple questions puts each individual product at risk. 

Can you comment on some of the pros and cons for ‘connected’ devices, such as inhalers or wearable injectors? 

There is no doubt that digital health is transforming the industry-from smart pills that transmit patient data to smart apps that can be used as part of a post-commercial pharmacovigilance and registry framework, the ability to gain insight via real time data is a boon to drug and clinical design optimization. HIPAA [Health Insurance Portability and Accountability Act] considerations, data integrity assurance, and cybersecurity are ‘must haves’ to ensure the ensuing analyses and conclusions are valid, safe, and sustainable.

What are some best practices for manufacturing connected devices? 

Architecting the information management framework is essential before developing the technology. This order will ensure that the design control approach and, most importantly, the appropriate consensus standards, are applied to the connected device’s development. Manufacturing considerations at the design level, such as assembly, via DFM [design for manufacturability], and tolerance analyses to ensure specifications do not consume all of the allowable variation will greatly reduce the likelihood of issues at the commercial scale.

	1.     K. Mallet and D. Oppenheimer, “The Outsider’s Perception and Experience Within the Pharma and Device Industries,” Poster at the 2018 ISPE Annual Meeting and Expo (Philadelphia, PA, 2018).  

Regulatory, cultural, and technical differences between drug and device development can pose challenges to pharmaceutical combination product development.