Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	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).

Articles

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.

What Pharma Needs to Understand About Combination Product Development

	Bio/pharma companies proceeding with digital transformation aim not only to collect more data but also use it to improve process efficiency and reliability and product quality. Raw material variability, which has been a challenge for many bio/pharma manufacturing processes, is one of the areas that has the potential to be transformed by new ways of collecting and analyzing data. Making a change in this area, however, requires more communication and transparency between raw material suppliers (who have the detailed data about raw material production) and their customers (who have the data about using raw materials in their process). 

	In March 2019, GE Healthcare announced a digital data exchange collaboration program with Amgen, with the aim of increasing understanding of the relationship between raw material variability and process performance during the manufacture of biologic drugs. As a part of this initiative, GE Healthcare and Amgen will be installing a connection for data transfer between GE Healthcare raw material manufacturing sites and Amgen’s process development center in Cambridge, MA (1).

	“Our collaboration with Amgen aims at using data analytics created through sharing of data and insights to improve efficiencies, performance, and quality of our products and processes,” says Olivier Loeillot, general manager of GE Healthcare Life Sciences’ BioProcess business. “The data insight enables GE Healthcare and Amgen to track and monitor variances in raw materials. With access to such specific data, both teams … [can manage] the effect of raw material variability on process performance during biopharmaceutical manufacturing.” 

	Amgen has been developing new tools and programs to address raw material variability. Several years ago, the company created an in-house information system to document and store raw material data, but needed a standard file format to allow data exchange between raw material suppliers and users (2). Amgen’s initial work on this format led to a broader industry collaboration that was published in 2017 as ASTM E3077-17, 

Standard Guide for Raw Material eData Transfer from Material Suppliers to Pharmaceutical & Biopharmaceutical Manufacturers

	The ASTM standard for data transfer is a helpful tool. “The exchange of eData lies at the very foundation of our collaboration, which builds on ease of interoperability, a common data format, and supply chain transparency,” notes Loeillot. 

spoke with Loeillot to learn GE Healthcare’s perspective on the data-exchange program.

What are the key drivers for creating a data exchange program? 

The data exchange capability GE Healthcare will be installing in collaboration with Amgen [aims to push] biomanufacturing further into Industry 4.0, in which cyber-physical systems collect and interpret data in order to optimize operations, enhance productivity, and strengthen performance reliability. Advanced data analytics will enable both GE Healthcare and Amgen to clearly understand, monitor, and control the effect of raw material variability on process performance during biopharmaceutical manufacturing. This way, both GE Healthcare and Amgen may drive product and process improvements, while advancing performance predictability and consistency. This performance improvement is paramount in substantially mitigating the potential of supply interruptions, safeguarding quality and regulatory demands, and increasing the speed to market, so that the biopharmaceuticals reach patients without delay. 

Can you give an example of how raw material variability could affect process performance, and how data exchange will improve the situation?

Variability means any inconsistency or unexpected change in raw material. When issues arise, they can have a significant impact on the entire biomanufacturing supply chain. There are many sources of variability, and in many cases, it is hard to identify the root cause. For example, these sudden variations can be contaminants or changes in the chemical composition of the raw material. 

	While many variables are trivial and have no impact on production, serious raw material variability can lead to inconsistency in the manufacturing performance, quality compliance issues, and ultimately, supply chain problems, which can compromise safety. It is crucial to have solid monitoring, control, and management of the process variability, and this is the main reason we have installed the data exchange program. Scrutinous management of raw material variability brings greater transparency to the supply chain and, in turn, gives customers greater control in achieving a more robust biomanufacturing process. 

For GE Healthcare, utilizing data analytics means that we will be able to better predict the impact of raw material variability on manufacturing outcomes, expand our understanding of root causes of inconsistencies, and reduce the risk of supply chain interruptions. At the same time, our customers will have novel access to several types of data, [providing them with] greater control and insights into their biomanufacturing process.

What were some of the logistical challenges to setting up such a data exchange, and how did you solve them?

This collaboration aims to establish a seamless data-exchange program between a supplier and a customer. [This goal challenges us to shift] from the traditional way of delivering finished products and data to customers to actually tracking and monitoring raw materials in real-time, while also sharing electronic data immediately with our customer.  

	GE Healthcare is transferring data through a complex network of internal and external sources directly to Amgen, our customer. The internal connectivity allows GE Healthcare to centralize data, while external connectivity helps us supply Amgen. More specifically, GE Healthcare is connecting legacy manufacturing equipment,which provides information for Amgen to first understand and then perform product and process optimization.The data shared with Amgen will provide unparalleled transparency into the supply chain.

What are the benefits of an electronic certificate of analysis (eCoA)? 

An eCOA has several advantages over the traditional paper COA. Today, GE Healthcare is developing an eCOA that follows the current ASTM standard format, is easily read by a computer, and is available immediately at the time of product shipment.  An eCOA enables customers to quickly access the data necessary for in-depth analytics and process optimization.

	In short, more seamless and transparent data exchange has the potential to facilitate “near real-time automated detection when a raw material results in process and/or product variation,” noted Cenk Undey, executive director at Amgen (2). Both partners in this program believe that improved data exchange and other digital tools will enhance troubleshooting and process optimization for both drug manufacturers and their suppliers.

	1.    GE Healthcare, “GE Healthcare announces digital collaboration with Amgen to improve biomanufacturing performance reliability,” Press Release, March 11, 2019.

	2.    C. Undey, “Amgen’s Digital Transformation: Linking Raw Material Data from Suppliers to Patients,” 

www.gelifesciences.com/en/us/solutions/bioprocessing/knowledge-center/amgen-linking-raw-material-data-from-suppliers-to-patients

A data exchange program between GE Healthcare and Amgen aims to improve biologics manufacturing through analysis of how raw materials affect the process.