	Printed pharmaceutical packaging materials perform a myriad of functions. Many suppliers are broadening capabilities, too.


	Rondo-Pak recently merged with Contemporary Graphics Solutions and now provides a product range that extends from marketing materials to leaflets and cartons. Digital printing and in-house carton production allow Rondo-Pak to deliver ready-to-pack cartons in days. Capable of producing runs ranging from five or 10 production samples to several hundred thousand, the ready-to-pack cartons are particularly well-suited for clinical trials and human-factor testing. “It’s a way to provide the same packaging the commercial product will use before the commercial line is installed,” says Victor Dixon, president and chief operating officer of Rondo-Pak.

	In addition, Rondo-Pak designs leaflets to match cartons for optimum performance on the packaging line. In one case, the optimized carton/leaflet combination improved line efficiency so much, “it eliminated overtime on the weekends,” reports Dixon. “Rondo-Pak line technicians and packaging engineers perform line optimization studies to identify ways to boost efficiency, which might involve a different gauge of paperboard, a different fold on the insert, or a different orientation of the insert.”


	To eliminate the need to load inserts on the packaging line, CCL Healthcare supplies cartons with the inserts glued in place inside. Added flaps provide space for multiple languages. 

	A more interactive carton, Memo Solution, integrates an electronic-ink-based display and sensors to create a “smart box.” Part of Palladio Group’s PhutureMed program, which won a Silver Award in the 2016 edition of the DuPont Awards for Packaging Innovation, the Memo Solution carton registers the time a dose is taken, monitors ambient temperature, and provides a warning if conditions exceed specified parameters. Another PhutureMed carton, Phill Solution, is printed with conductive inks. Each time a pill is removed from the blister, and the foil seal is broken, a message is sent to the patient’s smart device. This record of doses also can be shared with a caregiver, doctor, or insurance provider (1).

	A magnet holds together a dual-carton physician sample kit from Rondo-Pak. The design consists of two, four-sided cartons to create a six-sided unit (see 

). One carton features a partition to hold an item; its mate includes a dispensing spout.

	As regulatory requirements grow so does insert size. One of the largest currently available, the 294 Panel RTA by Mini Graphics, unfolds to present 818 square inches of text.


	Labels that do more than one job include the Hanger Info Label from August Faller Group, the winner of a WorldStar Award 2016 from the World Packaging Organization (see 

	Designed for use on infusions, the label includes a multi-page brochure, which provides space for instructions in multiple languages and can be removed to be read and firmly reattached many times so information stays with the container. In use, a portion of the tear-resistant label is peeled away. A special adhesive firmly secures the resulting loop to the bottle. Removable sections peel off for application to patient records to document administration. This eliminates the need for manual data entry and associated errors (2).

	Another award-winning hanger label, the Pharma-Tac Plus label from Schreiner MediPharm, includes several pages for product information and two detachable documentation parts, which can be post-printed with the batch number. In fact, Schreiner MediPharm recently established a process center for this type of late-stage customization (3). Developed jointly with Octapharma, the Pharma-Tac Plus label won first place in the “multi-process” category of an international competition organized by the North American Tag and Label Manufacturers Institute (4).

	A label with a detachable section helps reduce the risk of patients receiving the wrong medication at clinical sites. The peel-off section of the Peel-ID Safe Storage Label from Catalent Pharma Solutions is printed with the patient kit identifier and applied to the kit so it’s easy to locate in storage. The printed identifier facilitates inventory management, retrieval, and dispensing and minimizes risks associated with illegible handwriting or transposed numbers (5).

	1.   Palladio Group, “DuPont Packaging Award Winner – PhutureMed,” Press Release, June 3, 2016.

	2.   August Faller GmbH, “WorldStar Award 2016: August Faller Impresses Expert Jury with ‘Hanger Info Label,’” Press Release, May 2016.

	3.   Schreiner Medipharm, “Schreiner MediPharm Introduces Late Stage Customization for Functional Labels, Press Release, Aug. 5, 2016.

	4.   Schreiner Medipharm, “Pharma-Tac Plus Label from Schreiner MediPharm Wins First Place in North American Tag and Label Manufacturers Institute International Competition,” Press Release, Oct. 27, 2015.

	5.   Catalent Pharma Solutions, “Catalent Introduces Peel-ID™ Safe Storage Label to Improve Storage and Retrieval of Patient Kits, Press Release, May 19, 2016. 

Articles

Packaging

Award-winning drug packaging innovations include interactive cartons and multifunctional labels.

Innovations in Cartons, Labels, and Inserts

	The biopharmaceutical industry relies on hygienic diaphragm valves for its demanding process applications due to a unique need for cleaning and draining and for pressure and temperature capabilities. Over the past 40 years, the basic design of such valves has remained the same: body, diaphragm, topworks, and four fasteners (see 

). Properly installing and maintaining these valves requires experienced personnel and stringent maintenance practices to assure consistent and reliable valve performance. 

	Facilities can cut costs and decrease downtime through preventative maintenance, which involves a schedule and process for maintaining equipment; preventative maintenance is particularly important when it comes to valves. Although it can take hundreds of hours a year to properly maintain hygienic diaphragm valves, resulting in thousands of dollars of maintenance cost and lost hours of production, the primary function of a maintenance program is maximized production up-time, reduced planned and unplanned man-hours of labor, and early detection of diaphragm failure. Many plants fail to have a maintenance schedule for their hygienic diaphragm valves and may even wait until a piece of equipment fails before performing any maintenance at all--resulting in a costly and lengthy plant shutdown.

	Failure of the diaphragm, which will occur if it is not replaced on a routine basis, will most likely contaminate the process somewhere along the process lines. In many cases, the three major types of failures include valve leakage (fluid leaks between diaphragm and valve body to atmosphere), complete diaphragm rupture (diaphragm tears allowing process fluids to escape through the valve bonnet), and diaphragm tears (diaphragm tears allowing process fluids to escape through the valve bonnet).

	The result of these failures can be loss of product. In addition to the product that leaks out, a leak can put the entire batch at risk because of possible contamination entering the system. A diaphragm rupture can introduce contamination from the non-sterilized internals of the valve topworks, allowing the product to come into contact with greases and other contaminating liquids. Diaphragm tears can cause contamination from fluids that get entrapped in the diaphragm tears. Diaphragm tears can be especially insidious; because the pressure boundary of the diaphragm is not breached, the in-line instrumentation does not detect a system problem. Many times, all of the process fluids produced from the time of detection of the problem may be recalled or put on hold for testing.

	Valve leakage can also result in lost production time and an additional need for maintenance and time to clean up the equipment and repair the leaking valve. Additionally, valve leakage can cause potential safety risk, including employee exposure to dangerous process fluids, steam leaks, clean-in-place fluids, and dangerous organisms.

	Preventative maintenance can help maintain these seals and decrease the risk of leakage. Ultimately, detecting failures before they occur can result in improved sterility and minimized risk of contamination, and therefore, reduced maintenance hours and commissioning. Additionally, going through the process of preventative maintenance reduces the need for managers to unnecessarily replace valves or react to potential problems that can occur, resulting in greater efficiency, reliability, and ease of use.

	The keys to proper valve maintenance are knowing the steps involved in maintaining valves and implementing a preventative maintenance plan that works for a particular facility and application.

	How to maintain hygienic diaphragm valves

	Hygienic valves act as both the static seal (shell seal) and a dynamic seal (weir shutoff). They are often exposed to harsh chemicals, high temperatures, and high pressures, resulting in high amounts of wear and tear and an increased need for routine maintenance. Proper valve maintenance requires several steps by the maintenance team to ensure that the valve will function to its full potential.

 One of the most important parts of maintenance is proper assembly during the diaphragm change-out process. If the valve is not assembled properly, it can leave room for batch contamination, poor valve performance, and short lifecycle. Proper diaphragm installation per manufacturer’s instructions is essential. If installed improperly, excessive force during operation can result in diaphragm damage. Fluids can then pass through the closed valve or, in the worst case, cause catastrophic failure that results in process fluid contamination and leaks. Torquing and retorquing are also important steps in the  assembly process that can often lead to seal failure, by either making the seal too tight or too loose for proper performance.

 Another aspect of valve maintenance is knowing when a replacement diaphragm is needed. To make sure valves do not fail, some companies change out their diaphragms on a regular basis (e.g., every six months), regardless of whether or not it is needed. Facilities that use diaphragms with a shorter life expectancy, such as rubber-type diaphragms, may be more likely to perform require more regular changes. However, consistently replacing diaphragms with no signs of failure can cost plants unnecessary expenses and time. Knowing the signs of valve failure is also essential to maintaining a facility’s valves. Physical signs that a valve or diaphragm needs to be replaced are excessive wear, corrosion, or fluid leakage.

	Because of the wide range of applications and conditions within the pharmaceutical processing industry, preventative maintenance programs should be built up over time and should be specific to the application. Programs can vary widely from one plant to another.

	There are many factors to consider when facilitating a preventative maintenance program. The biopharmaceutical industry is fairly unique in that valves are used in many different applications with different exposures to temperatures and harsh fluids. Different applications for valves can include steam-in-place (SIP) or high-temperature sterilization; cleaning in place (CIP) where caustics and acids act as detergents; cold processing where purification is usually below ambient conditions (2-8 °C typically); and purification processes, such as chromatography and filtration. Many of these processes run in sequence or through the same pipes, which means the valves are exposed to a wide range of application temperatures and conditions.  

	Other factors that affect valve performance and maintenance include the amount of exposure time to liquids and steams, the type of diaphragm (one-piece vs. two piece diaphragm), and the thermal cycle (the swings between minimum and maximum temperature). Diaphragms and other soft parts, such as gaskets and o-rings, often face fluctuations between steam sterilization and cold-processing temperatures in the biopharmaceutical industry. A typical valve undergoes hundreds of thermal cycles in its maintenance lifecycle, which can affect the valve seal and ultimately the product. As thermal cycles increase, the valve diaphragm is continually being compressed and relaxed, resulting in thinning of the diaphragm. These dimensional changes create less seal contact and will eventually result in valve leakage to the atmosphere.  Although some leaks can be addressed with re-torquing, most end-user procedures do not allow valves to be re-torqued after the process has been released to production.

	Thermal cycle performance has been a significant topic for the biopharm industry for some time.  The American Society of Mechanical Engineers Bioprocessing Equipment Committee, which drives many of the industry best practices, has developed a test procedure that will help the end user determine the potential performance of a given seal/diaphragm in these varying conditions. This “Appendix J” test (1) allows seal/diaphragm manufacturers to rate the performance of their elastomers based on a standard test protocol.  This testing is currently non-mandatory and is in its infancy of adoption by the end users in the industry.  Eventually these Appendix J ratings will provide end users a consistent basis to assess expected life expectancy with regards to thermal cycle performance.

	Many of the forward-thinking pharmaceutical companies are now partnering with valve manufacturers to assess maintenance frequencies.  With proper application data, including temperature, pressure, process fluid data, and exposure times, valve manufacturers can help develop a maintenance program that aligns with the risk profile of the end user. In this way, the end user can save unnecessary maintenance costs and production down time, ultimately reducing their total cost of ownership of the process system.

	In recent years, the design of the hygienic diaphragm valve has been optimized to increase productivity, ultimately advancing maintenance practices in biopharmaceutical facilities. New valve technology, for example, can reduce average diaphragm replacement time from 23 minutes to three minutes and total maintenance time from hundreds of man hours to just a few hours, hence reducing maintenance cost by more than 90% (2). Preventative maintenance practices and more innovative technology, such as valves that do not require tools or retorquing, are preventing the potential of human error and making processes safer and more efficient. Improved designs can help meet the biopharmaceutical industry’s growing demand for increased productivity, extended maintenance intervals, and reduced operating costs, in conjunction with an effective preventative maintenance program.

		ASME, ASME Bioprocessing Equipment (New York, NY, 2014).	


	Paul McClune is global product manager, ITT Engineered Valves, www.engvalves.com.

:
	When referring to this article, please cite it as P. McClune, " Maintaining Hygienic Diaphragm Valves," 

Troubleshooting

A process-specific preventative maintenance program improves productivity and reliability.

Maintaining Hygienic Diaphragm Valves

	With the growing prevalence of “smart,” connected machines and automated data collection, there is no shortage of process data. Analyzing this “big data” and using it to make decisions, however, can be a challenge. 

 spoke with Bert Baeck, CEO at TrendMiner, which provides data mining for process industries, about some of the challenges and best practices for using the process data that is collected in the process historian.

What are some of the challenges with getting information from the process historian?

 Pharma is similar to other kinds of industrial processes in that the information in the process historian includes time-series data (e.g., temperature, flow, pressure, concentration, calculated aggregates, or derivative data/profiles). Context information-such as product or recipe names, process phases, and batch identification-adds value for the process engineer, but it is not always stored in the historian. If you have the right software, you can find specific batches, filter on products or phases, or overlay profiles for good and bad batches (complete or phase by phase). Typically, information such as laboratory measures (i.e., quality data) is still stored in an isolated laboratory information management system (LIMS); however, it’s good practice to integrate these data. 

	A technical constraint is that historians are not ‘read’ optimized. They are ‘write’ optimized, which means they store and compress new data. Therefore, extracting data from historians is generally slow. For example, searching through 10 years of historical data would overload the system and/or would take hours or days to compute. 

	Process engineers and other subject matter experts must be able to search time-series data over a specific timeline and visualize all related plant events quickly and efficiently. This includes the time-series data generated by the process control systems, laboratory systems, and other plant systems and the usual annotations and observations made by operators and engineers. Typically, if a certain search takes too long, users will abandon the search and this is harmful for diagnosing problems and even more for preventing abnormal situations. The challenge typically presented by historian time-series data is an inability to provide an intelligent mechanism to search through this data to solve day-to-day business questions (e.g., Have I seen similar behavior before? Have I seen similar batch patterns?) or to make annotations (e.g., process context/metadata) effectively. By combining both structured time-series process data from the historian and data captured by operators and engineers, users can predict more precisely what is occurring or what will occur in the future with continuous and batch industrial processes.

	TrendMiner’s approach uses an on-premises, packaged virtual server deployment that integrates to the local copy of the plant historian database archives and uses ‘pattern search-based discovery and predictive-style process analytics.’ It is also cloud-ready with a more scalable architecture, and it targets the average user, without a big data or modeling background and no need for a data scientist. Searches provide intelligent ways to navigate through the historical data, solving day-to-day operational or asset-related questions, as well as diagnostic capabilities for explanatory power. Because the past is the best predictor for the future, it provides predictive capabilities.  Pattern recognition and machine learning technology turns human intelligence into machine intelligence. Saved or learned patterns (e.g., abnormal situation signature, golden batch) can be used to alert that a certain event is likely to happen.

Can you share some best practices or guidelines for setting up process data collection systems to optimize the ability to get information back?

		Store data with the timestamp of interest. For instance, LIMS data should be logged with the sample time as the primary date time, not the analysis time.

		Think about which context information is useful and save it as digital tags. Have a plan for how this information should be saved to keep it consistent throughout the plant.

		Think carefully about the data compression. Save the data at a rate that contains the most information for the user. For example, one point for every 10 minutes will probably not be enough for a thorough analysis.

		Think about asset structure. How will you break down your process data structure? Which system should be the master for this asset structure?

		Make sure there is a way to save certain calculations or patterns of certain profiles (e.g., golden batch profiles, model deviations).

		Utilize capture capabilities that support manually created event frames or bookmarks by users or automatically generated by third-party applications. These annotations are visible within the context of specific trends.

		Monitoring capabilities integrated with predictive analytics and early warning detection can offer a live view to operators in determining if recent process changes match expected process behavior. This gives the opportunity to proactively adjust settings when this is not the case. 

Production Trends

Manufacturing data collected in the process historian can be analyzed to better understand the process and use past behavior to predict future results.

Equipment and Processing Report-09-21-2016

Innovations in Cartons, Labels, and Inserts

Maintaining Hygienic Diaphragm Valves

Making Use of Process Data