	When confronted with a treatment regimen involving an inhaler, many people feel intimidated. Proper use generally takes some training and practice. Until the patient feels comfortable with the device, compliance may be low, and treatment won’t be as effective as it could be.

	“Smart” inhalers, which are equipped with sensors and other technology, can improve compliance. At the most basic level, smart units track the number of times the medicine is dispensed so the clinician can record the data at the patient’s next visit. Newer technology enables remote transmission of usage data to healthcare providers and may include software that provides feedback to patients and analytics to providers.

	One product on the market, the cloud-based CareTRx solution from Gecko Health Innovations, now part of Teva Pharmaceutical Industries, combines remote monitoring and real-time adherence tools in a Bluetooth-equipped, battery-operated device that fits on metered-dose inhalers (MDIs). Pressure sensors boost actuation accuracy. Another facet of the solution, the CareTRx Population Monitoring Dashboard, monitors behavior, reviews trends, aggregates data, and connects patients and caregivers (1).

	Another option, the Smartinhaler platform from Adherium, a New Zealand company with a US office in San Mateo, CA, recently won the "Most Innovative Hi-Tech Hardware Product" in New Zealand’s Hi-Tech Awards competition. The judges noted in a press release (2), “Adherium has developed a deceptively simple asthma drug-delivery system, which elegantly embeds multiple sensor technologies into a small device, and combines it with smart applications and cloud data services to help people with asthma and other chronic obstructive pulmonary diseases (COPDs). It gives healthcare providers and pharmaceutical companies access to a rich database of medication use that can be used for continuous improvement and application to achieve better health outcomes. The Adherium platform has enormous potential, not only with asthma and COPD medication, but also many other medication regimes.” Compatible with MDIs, dry powder inhalers, and nebulizers, the platform relies on sensors, touchscreens, audiovisual medication reminders, cloud data storage, and wireless technology (2). Clinical evidence shows the technology substantially improves outcomes (3).

	Technology for quantitative measurement of inhaler use

	Emerging smart inhaler technology being developed by HealthFactors and Koronis Biomedical Technologies (KBT) will be able to inform clinicians and respiratory therapists about how a patient uses the inhaler and how drug absorption is impacted. With that data, clinicians, therapists, and parents or caregivers can decide if the patient needs assistance to perfect the dosing technique.

	Until now, identifying patients that need extra support has been based primarily on self-reporting. Kyle Dolbow, CEO at HealthFactors, notes, “Even the best patients may not be able to self-assess their technique and the impact of that technique consistently or correctly. Quantitative information about successful inhalation usage can address that challenge … [and] can be used to intervene and guide … training efforts and adjust treatment protocols. The technology that we’re bringing to market will also help enable newer healthcare models like telemedicine and chronic care management.”

	Key to the technology are algorithms based on measuring the flow waveform parameters of each inhalation. The algorithms support training in dosing technique and assessment of each dose. Work continues to correlate inhalation profiles with delivery of medication to the desired areas in the lungs. 

	Dan Spors, chief commercial officer at HealthFactors, reports, “Our Phase I pilot results showed positive outcomes for participants. More specifically, there was a statistically significant increase in the amount of medication that was aerosolized with each of five inhaler trials for 34 adult patients who were newly diagnosed with asthma or COPD, and who were unfamiliar with inhaler use. In addition, the device received positive feedback from five respiratory therapists and pulmonary function specialists who were involved with the trial.”

	HealthFactors and KBT are working with leading research institutions and physicians in respiratory care to develop a clinical scale that can be used to go beyond adherence monitoring to therapeutic and diagnostic elements. Spors says, “Correct inhalation technique is critical for the successful use of inhaled medications. This new smart inhaler technology is envisioned to be part of an overall commercial platform whereby patients are first assessed and interactively trained on proper technique in a clinical setting for a prescribed inhaler. The patient continues to receive this technique feedback and reinforcement at home through the smart inhaler.”

	“The technologies being developed will allow pharmaceutical companies to differentiate their products … by integrating clinically validated treatment management tools,” adds Dolbow. “Now that our initial collaborators are in place, we are actively looking to add one or two pharmaceutical partners in 2017 for this opportunity,” he concludes.

	1. Gecko Health Innovations, “Asthma and COPD Management Made Simple,” www.caretrx.com, accessed June 16, 2017.

	2. Adherium, “Adherium Wins 'Most Innovative Hi-Tech Hardware Product Award' at the 2017 NZ High Tech Awards,” Press Release, May 15, 2017.

	3. Adherium, “Proven Results for Increasing Adherence and Improving Health,” http://smartinhaler.com/outcomes, accessed June 16, 2017. 

Articles

Feature

Sensors and communication capability support proper usage, improve compliance, and may enable telemedicine. 

Smart Inhalers Improve Patient Compliance

	As is the case with many industries, thermal and catalytic oxidizers are widely applied air-pollution control devices used throughout the pharmaceutical industry for the destruction of hydrocarbons. Many pharmaceutical processes, however, also generate emissions that contain halogenated hydrocarbons such as chlorine. Because of their stability and persistence in nature, most regulatory agencies require further treatment or removal for these halocarbons at the plant level.

	When treated by thermal oxidation, halogenated compounds present additional challenges. In particular, they form corrosive compounds in the oxidizer and in treated exhaust air. For example, methylene chloride can easily be converted to carbon dioxide and water vapor in a thermal oxidizer, at rates of 99% and greater, but the reaction results in the formation of acid gas. This condition presents a few important considerations in oxidizer design.

	Regenerative thermal oxidation (RTO) has become a common solution to treat volatile organic compounds (VOC) and hazardous air pollutants (HAP) present in the emissions of many pharma production processes. RTOs are flexible control devices, able to handle a wide variety of VOCs and HAPs in a wide range of concentrations. The key feature of an RTO is its ability to recover nearly all the energy required to heat up and combust the pollutants-up to 97% efficiency. In air streams with low pollutant concentrations, this feature results in a very low auxiliary fuel requirement in comparison with other types of thermal or catalytic oxidizers.

	This high level of heat recovery results in an RTO outlet temperature only slightly higher than the inlet; although the combustion chamber temperature where the pollutant conversion occurs is approximately 1550 degrees Fahrenheit or higher, the outlet temperature is typically only approximately 70 degrees above the inlet temperature. This condition, when combined with water vapor and acid gases in the outlet exhaust, can result in aggressive corrosion of carbon steel in improperly designed RTO support structures. Further, if the acid dewpoint is reached in the oxidizer, any formed acids could condense and cause further corrosion.

	Strategies to protect RTOs against corrosion in these applications include:

Upgrade materials of construction in key RTO subsections. 

Heat exchanger support areas, air diverter valves, and connection ducts are all crucial to ongoing RTO operation and therefore should be constructed of corrosion-resistant alloys.

 The outer RTO shell, while not required to be upgraded to alloy construction, could see acid gas vapors, and corrosion resistant coating over carbon steel should be considered.

By artificially raising the inlet temperature to the RTO, usually with a stand-alone heat source or recirculation of clean RTO exhaust gas to the inlet, the process air stream stays above the acid gas dew point.

All RTOs come with a process exhaust fan used to advance the polluted air through the oxidizer and out the clean air stack. Although an induced draft fan arrangement sees higher temperatures than a forced draft option, the system remains under negative pressure, and any leaks that may develop in ductwork or expansion joints over time would have air drawn through them into the system, as opposed to acid gas leaking out.

	Material selection for RTO construction in these applications is crucial. Designers should review specific defenses, such as avoiding pitting and crevice corrosion from chlorides and minimizing chloride stress-corrosion cracking. Several commercially available alloys are specific solutions to these challenges and have proven themselves over decades of operation.

	Pharmaceutical process emissions are not typical industrial applications, but strategies exist to address them successfully. The key is to address potential fail points in the typical industrial design, particularly in the materials of construction. Time spent wisely at the design stage will ensure uptime and long life of the emission control equipment downstream.

	Jim Stone is senior sales manager for Anguil Environmental Systems, which specializes in exhaust air purification; 

Regenerative thermal oxidation (RTO) has become a common solution to treat volatile organic compounds (VOC) and hazardous air pollutants (HAP) present in the emissions of many pharma production processes. Regenerative thermal oxidation devices used to treat halocarbons should be designed to prevent corrosion. Anguil Environmental Systems explains best practices for addressing potential fail points in the materials of construction when designing process emission handling systems. 


Treating Halogenated Hydrocarbon Emissions from Pharmaceutical Production

	Cyber attacks on major companies in June 2017, including US-based pharma company Merck & Co. (1), have highlighted the importance of cybersecurity for every part of a company, including manufacturing. Interconnected operations and manufacturing execution systems, while beneficial, do create more connections that could be compromised, noted Mark Cristiano, Network and Security Services business development manager at Rockwell Automation (2).

	A “defense in depth” security approach, as recommended in the International Electrotechnical Commission (IEC) 62443 standard series, uses multiple layers of protection including policies and procedures as well as protection of networks and devices using tools such as anomaly-detection software and authentication software (3).

	“No single security product, technology, or methodology can be expected to contain cyber threats on its own. Rather, a holistic security approach should be the priority, following industrial automation and control system (IACS) security standards, including IEC 62443 and [National Institute of Standards and Technology] NIST 800-82” (4), says Gregory Wilcox, Global Technology business development manager at Rockwell Automation.

	Information technology (IT) and operations technology (OT) engineers should work together to build layers of defense, using diverse technologies, at multiple levels of the IACS, says Wilcox. “Neither side can effectively defend against cyber threats on their own. Protecting operations should include limiting physical access, hardening devices and computers, persistent monitoring through traffic inspection (i.e., detect), and segmenting (i.e., zoning) the IACS network via industrial firewalls (i.e., conduits) and virtual local area networks.”

	Assessing risk and understanding your company’s vulnerabilities, including having an updated inventory of systems, networks, and dataflows is a first step, notes Martin Kunz, product and business development manager, Plant Security Services, at Siemens. Raising awareness of cybersecurity throughout the company is also key. “Criminals look for targets, and many attacks start with a human error that lets something in,” says Kunz. He notes that training programs that give examples of possible scenarios are simple yet effective in raising awareness and empowering personnel. Controlling access, using security technology, and being prepared to respond to an incident are other important aspects of cybersecurity.  Security is not a one-time action, notes Kunz; monitoring is a continuous measure. Siemens now has three Cyber Security Operation Centers (in the United States, Portugal, and China), which are part of the company’s Plant Security Services for continuous surveillance of industrial facilities. If this monitoring detects cyber threats, experts issue a warning and coordinate countermeasures. These services are suited for process control systems used in the pharma industry, such as Siemens Simatic PCS7 or similar environments, says Kunz.

	“Threat awareness is everyone’s job,” says management and technology consulting and engineering services firm Booz Allen Hamilton (5), which suggests that security should be part of everyone’s work practices. The firm suggests that another key component is using privileged account management to make “superuser” or administrator accounts more secure.

	“The requirement to enable remote access and data sharing between OT and IT networks is now paramount,” adds Shmulik Aran, business leader for Honeywell's Security Operations Center. “While in the past, ‘security through obscurity’ was the norm, these days, pharma cyber security teams and manufacturing engineers … must cover the basics first. A secure remote access platform is essential.”

	Having an automated inventory of network assets is crucial for managing all connected devices and determining whether they are secure. “Pharma engineers should be aware of the existence, status, and compliance of every network connected device,” says Aran. “Malicious actors need only a single-entry point into the OT network to attain their goals. Employees shouldn’t be viewed as ‘weak links;’ instead, they should be actively trained and considered as a valued line of defense.”

		H. Shaban and E. Nakashima, “Pharmaceutical giant rocked by ransomware attack,” (June 27, 2017), 

www.washingtonpost.com/news/the-switch/wp/2017/06/27/pharmaceutical-giant-rocked-by-ransomware-attack

		M. Cristiano, “Addressing Security Risks in Connected Operations,” 

www.pharmtech.com/addressing-security-risks-connected-operations

Industrial communication networks–Network and system security

Framework for Improving Critical Infrastructure Cybersecurity 

		Booz Allen Hamilton, “Business Insights: 5 Facts about Cyber Security for Pharmaceutical Companies,” 

www.boozallen.com/content/dam/boozallen_site/ccg/pdf/thought_p/5-facts-about-cyber-and-pharma.pdf

Everyone from IT departments through to manufacturing line personnel should be aware of cybersecurity threats and how to prevent attacks. 

Equipment and Processing Report-08-16-2017

Smart Inhalers Improve Patient Compliance

Treating Halogenated Hydrocarbon Emissions from Pharmaceutical Production

Managing Manufacturing Cybersecurity