	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).  

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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

	Machine vision inspection is more powerful than ever. Automated, camera-based systems increase speed and accuracy and eliminate human error, and artificial intelligence allows machines to continually improve inspection performance.

	Camera-based systems from Acquire Automation simplify vial counting and check caps. The CountQ vision inspection system automates the counting of vials in trays, eliminating the need for counting manually or with a stencil as well as the duplicate counts generally required by standard operating procedures. The system consists of a linescan camera plus software, adjustable lights, and label printer. Advanced product counting tools enable it to adapt to targets with varying visual characteristics. Standard features include an easy-to-use HMI, report and audit logs, security levels that control access, two-touch changeover, and configurable run modes that increase the system’s flexibility (1). 

	The CapQ system from Acquire Automation performs a 360-degree inspection of caps up to 38 mm in diameter and 330 mm in heightto check presence, color, height, and skew. It also confirms the integrity of the tamper-evident band and verifies fill level. The stainless steel, NEMA 4X/IP65 inspection unit fits over the conveyor, simplifying integration on existing packaging lines. Advanced software using artificial intelligence enables the system to ignore water droplets and plastic fragment shedding that can skew measurement results and cause false rejects. The system produces reports and audit data for production and inventory records and provides data for continuous improvement programs. Options include a height-adjustable main system enclosure, automatic camera and light adjustments during changeover, and a high-speed reject system (2). 

	For print inspection, Optel Group offers the HD PrintSafe digital inkjet with built-in 100% web inspection. The serialization-ready system checks artwork, alphanumerics, barcodes, and variable data and can grade print quality. Options include dual and multi-color printing, wide screen for large webs, and additional inspection capability for products inside blisters or trays (3). 

	Other serialization-ready equipment also integrates machine vision including the TQS Fast Track line from Wipotec OCS. The TQS-LI-Bottle machine, for example, prints, inspects, and labels bottles at a rate of 150/min. Changeover to a new size between 30 and120 mm in diameter and 30 and 200 mm in height takes five minutes (4).

	Machine vision also is used to ensure the quality of the package itself. “…Reducing packaging defects, such as cracks and bruises or even scratches in the glass, as well as particle generation is of high importance,” explains Christoph Döppes, project director New Production Concept Vials, Global Operations at SCHOTT Pharmaceutical Systems, which has partnered with SINCAD, a French engineering company and expert in modular vision control systems. 

	High-quality glass containers depend on high-quality glass tubing. Döppesreports, “As it is our aim to reach ‘zero defect’ in both tubing and pharma packaging, we moved from statistical quality control to 100% inspection of each FIOLAX tube during the production process. The process known as perfeXion leads to a glass tube that has been completely evaluated.” The Automated Inspection System (AIS) inspects all key surfaces of vials and cartridges and can detect defects invisible to the human eye. Advanced software creates a 3D image of the container based on visual data gathered from multiple cameras with different light settings. “We can therefore analyze the container surface in a more comprehensive way,” explains Feldhaus

Next-generation camera systems, equipped with artificial intelligence, will be able to learn from images of defective products and use that knowledge to independently recognize containers with defects. 

	Another packaging supplier, family-owned Colbert Packaging, which is celebrating its 60

anniversary in 2019, also has upgraded its quality assurance (QA) capabilities and now provides 100% vision inspection capabilities at all three of its manufacturing facilities. Its Leary Array with LearyVIEW Print QA system, recently installed at its Elkhart, IN, plant detects and rejects folding cartons with quality defects including missing copy, blemishes, streaks, oil spots, or other imperfections. “The new Leary QA system has a camera that scans the entire carton against the approved customer-supplied proof for visual quality defects,” said Nick Stober, Colbert’s Elkhart production manager. Eye C inspection software supports 100% inline inspection at speeds of 400 m/min (1300 ft/min) (5).

	1. Acquire Automation, “Acquire Automation’s New CountQ Vision Inspection System Counts and Verifies Trayed Containers and Records Results,” Press Release, March 15, 2019. 

	2. Acquire Automation, “New Acquire Automation CapQ Vision Inspection System Employs Artificial Intelligence to Increase the Accuracy of Bottle Cap Inspections,” Press Release, Oct. 26, 2018. 

	3. Optel Group, “HD PrintSafe,” Brochure, 2018. 

New machine vision systems are designed for inspecting primary and secondary packaging for defects.

Equipment and Processing Report-08-21-2019

What Pharma Needs to Understand About Combination Product Development

New Machine Vision Technology