	Design for reliability (DfR) is a methodology for ensuring that equipment or other assets are built so that they run consistently without unexpected failure, and that they can be accessed and maintained over time. “Asset health accountability drives the creation and execution of a robust reliability framework,” says John Ganaway, Design for Reliability practitioner at Jacobs. Software may assist in DfR, but in reality it is the stakeholders who must “build and execute a reliability framework,” says Ganaway. 

interviewed Ganaway about DfR and its application in pharmaceutical manufacturing.

Design for Reliability (DfR) aims to ensure reliability, maintainability, ergonomics, accessibility, and availability of assets. The concept blends aspects of statistics, probability, and reliability theory, as well as engineering, analysis, and stakeholder engagement. DfR should be  active throughout an asset’s or product’s lifecycle so that users can evaluate and verify that the equipment has been robustly designed, and so that problems caused by any design issues may be predicted before they can affect performance. 

	DfR practices allow equipment systems to meet reliability requirements, while applying the latest methods for risk management and design assessment. Stage gates for equipment concept and design trigger DfR and the application of each element of the method.

What are the main goals of a DfR program?

Its main goals are institutionalized knowledge improvement, continuous improvement, and the elimination of defects at the design stage. Those using the methodology must be able to transform information into knowledge and to integrate what they have learned. They must also be humble enough to ask all stakeholders for their input to improve overall knowledge, including the craftspeople who support equipment maintenance activities.

Can you share example(s) showing how DfR is used in bio/pharma manufacturing? 

Let’s consider the air-handing system used for a seed lab and associated 20-L room. Its design had to ensure that airflow was adequate in order for the facility to meet biozone requirements. When the design review had reached the 30% point, the equipment included six, fan-powered, high-efficiency particulate air filters (HEPAs). 

	All components within a fan-powered HEPA are accessible from the cleanroom side, eliminating the need to access the fan-powered HEPA from above the ceiling. In this case, the project reliability lead, who understood the holistic maintenance strategy for HEPAs throughout the plant, also projected what might happen if the fan failed. If failure occurred, he noted, unfiltered air could easily enter the seed lab. In this case, the HEPA filter would have to be removed from its sealing frame in order for maintenance technicians to access the fan components (e.g., the damper and controller). 

	HEPA filters are not typically changed at regular intervals. Instead, they are usually recertified at a time interval set by the owner. If the fan-powered HEPA filter were to fail, this failure would result in an expensive process interruption. Not only would the filter have to be recertified before being put back into use, the 20-L room would need to be cleaned three times, and the cumulative time required for all of these activities would exceed allowable downtime and compromise the ISO biozone’s cleanliness requirements. 

	Taking these potential risks into account, the filter’s final design was altered so that there was only one fan-powered HEPA, which prevented the loss of ‘fan power filter fan failure’ mode. Additionally, the fan-powered HEPA’s function was changed so that it is now simply a recirculation fan. 

	During the commissioning of this space, tests were run to understand the impact that loss of one fan-powered HEPA would have overall, and whether it was even needed. In this case, the reliability lead’s knowledge of operations, requirements, and potential risk, led to an improved design, highlighting the importance of involving all stakeholders in the DfR process.

How do new technologies such as AI/predictive maintenance aid in DfR? 

System health indicators (SHIs) are crucial. They are based on such process health indicators (PHIs) as pH, conductivity, pressure, temperature, and flow, and then integrated with asset health indicators (AHIs) (e.g., vibration magnitude with frequencies, oil cleanliness such as ISO codes, temperature using thermography, ultrasound using acoustics, current, voltage, and material thickness). With this data, artificial intelligence (AI), using improved data models, can create a method for enunciating defects. Once users are aware of the defects and the probability of their occurring, they can make better design decisions, eliminating those defects at the design stage.

What do you see as the trend for using DfR? 

The concept is now being integrated into capital planning and execution, which is a very positive trend. As the industry gains more experience with DfR and improves the way it handles and analyses data, information will be freed from individual data silos to create new specifications and standards. Although the pharma industry is still at an early stage in its digitization (compared with the steel, petrochemical, and automotive sectors), as competitive factors continue to impact its profit margins, manufacturers will be more interested in reducing total cost of ownership of their equipment and other assets. Creating standard work within the framework of robust maintenance and reliability programs will demystify that point where capital expenditure and operational expenditure intersect.

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The goal of Design for Reliability (DfR) is to eliminate defects at the design stage; PharmTech interviews Jacobs about DfR for pharma equipment.

Designing Pharma Equipment for Reliability

	Changes in primary packaging for drugs are being driven by industry trends. For example, sales of biologics are growing at double the rate of the pharmaceutical market overall, and these more complex compounds involve high viscosities and concentrations and larger dosages, said Riccardo Prete, product management specialist at Ompi, part of Stevanato Group, in a presentation at Stevanato Group’s seminar on developments in drug delivery devices (1).  These factors affect primary packaging requirements. At the same time, there is a move to shift injectable drug administration from hospital to home. Home administration improves adherence, which in turn results in better outcomes and lower healthcare costs, explained Prete. Drug-device combination products for self-injection, however, require more complex delivery systems, which can present challenges. 

	For example, prefilled syringes, micro-vials, and cartridges for combination products require precise production and handling to control critical dimensions and ensure accurate doses, said Prete. A stringent inspection process is needed during production and assembly, and glass-to-glass and metal-to-glass contact should be avoided (1).  

	For micro-vials, shapes and configuration must be optimized to guarantee full compatibility with different devices and controlled to ensure processability on filling lines. For syringes, auto-injector compatibility depends on tight dimensional control, optimized flange formation, and precise siliconization for optimum glide performance. Cartridges for pen injectors have similar requirements and must offer the appropriate level of mechanical resistance (1).

	The benefits of self-injection, especially for chronic disease management, have spurred strong gains in market share. Today, eight of the top 10 drugs are injectables, and a look at the development pipeline reveals an approaching surge of injectable products, said Robin Hwang, principal at ICP Consulting, in another presentation, citing statistics from PharmaCircle. “There’s a clear trend for user convenience,” he reported, noting auto-injectors dominate for subcutaneous injection for biologics, and on-body injectors are gaining ground for high-dose delivery. Interest in add-on connective devices and/or electromechanical injectors with connectivity also is growing (2). 

	However, Hwang warned, devices reduce margins due to the increased cost of development and add complexity to the manufacturing process, supply chain, and compliance risk. Combination products also require device expertise and partnership management as well as significant levels of customer support, training, and complaint handling. “Training the customer is extremely important-otherwise a $5 device can ruin the future of a $1000 product,” he explained. 

	“So, why do devices?” he asked. “Very simple,” he said, “competition. If there’s no competition, a syringe and vial work just fine. First-in-class drugs have more leeway.” 

	If a combination product is needed to provide a competitive edge and/or preserve market share, leveraging an existing device platform and partnering with a system provider can reduce risk, development time, and cost. Otherwise, Hwang advised, be prepared to spend at least five years and $50 million to develop a new device and cover the costs of clinical development, subassembly and final assembly, and testing (2). 

	Another speaker at the seminar, Valerie Otte, market development manager at Aptar Pharma, discussed the trend for injectable drugs moving to nasal delivery. This conversion is particularly suitable for drug repurposing, which reformulates an existing product for new routes of administration, new indications, or new therapy areas (3). “There are advantages if you can avoid injection,” she noted.

	Stevanato Group, which specializes in glass packaging for pharmaceuticals, and Duoject Medical Systems 

 to collaborate on an emergency-use auto-injector, the companies announced in a Nov. 5, 2019 press release (4). The Maverick auto-injector designed by Duoject is a cartridge-based system with a two-step automatic injection and needle retraction. Although most auto-injectors are designed for use with prefilled syringes, the cartridge-based system has advantages in some uses, according to the press release. The companies expect to refine the design through user discussions and design for manufacturing and design for assembly processes. 

	1. R. Prete, “Primary Packaging - Dedicated Solutions for Drug Delivery Devices,” presentation at New Developments in Drug Delivery Devices (Chicago, IL, Oct. 17, 2019). 

	2. R. Hwang, “Market Requirements and Impact on the Devices Market,” presentation at New Developments in Drug Delivery Devices (Chicago, IL, Oct. 17, 2019).

	3. V. Otte, “New Insights in Nasal Delivery Systems,” presentation at New Developments in Drug Delivery Devices (Chicago, IL, Oct. 17, 2019).

	4. Stevanato Group, “Stevanato Group and Duoject Medical Systems Agree on Exclusive Partnership to Promote and Manufacture the Emergency-use ‘Maverick’ Auto-injector,” Press Release, Nov. 5, 2019.

Trends affecting primary pharmaceutical packaging include the shift to more complex drug-device combination products.

Equipment and Processing Report-11-20-2019

Designing Pharma Equipment for Reliability

Primary Packaging for Combination Products