	At Pharma EXPO and the co-located PACK EXPO International (Nov. 6-9, 2016, McCormick Place, Chicago), exhibitors serving the pharmaceutical industry featured every technology on attendee shopping lists, including serialization, parenteral fill/finish, solid-dose packaging, adherence (i.e., compliance), quality control, anticounterfeiting, tamper evidence, child resistance, and shelf-life protection.


	Parenteral fill/finish systems were well-represented by Ronchi America, NJM Packaging, Capmatic, Marchesini Group, Vanrx Pharmasystems, and others. Monobloc designs, which integrate filling, stoppering, and capping operations on a single base, are widely available. In some cases, monoblocs also include labeling and inspection stations as well as robotic handling. Servo motors and drives maximize repeatability and accuracy, and many systems are flexible enough to handle vials, syringes, or cartridges. A choice of filling and capping technologies maximize flexibility, and optional clean-/sterilize-in-place product paths minimize changeover time.

	Interest appears to be growing in nest filling lines like the Dara Moduline Model NFL isolator-equipped fill-finish system from NJM Packaging. Building the monobloc and isolator simultaneously cuts costs and turnaround time, making it possible to deliver the equipment in as little as eight months (2).


	On the solid-dose side, Romaco North America displayed a strip packaging machine capable of heat-sealing foil laminations or polyvinyl chloride film. Less expensive, smaller, faster, and simpler to maintain than traditional blister packaging machines, the strip packager runs at up to 400 unit-dose packs per minute. Modules pull film, drop the dose in the cavity, confirm the dose is present, perforate the strip horizontally and vertically, and cut it to the specified length.  

For multi-dose bottles, Enercon Industries and ITW Pillar Technologies demonstrated the latest induction sealing technology. An induction seal, applied to the mouth of a container, not only discourages pilfering and provides tamper evidence, but also can extend shelf life and prevent leaks. The new Pillar iFoiler induction cap sealer combines seal assurance, system control, and line connectivity, plus a first-of-its-kind proportional speed control. The flexible unit offers multiple coil configurations and can communicate with the operator in a variety of languages. A PackML machine control code option standardizes collection of data across machines, lines, shifts, plants, and business units and supports analysis of overall equipment effectiveness (3).

	Enercon’s upgraded Super Seal Touch induction cap sealer series offers enhanced features for high-speed lines, large containers, challenging caps, remote control and monitoring, network communication and data collection, and applications needing more flexibility for locating sensors and reject devices. If a container without a seal approaches the sealer, the line stops. An advanced laser light curtain detects high, cocked, or loose caps and can be configured to specified tolerances. “Before we could only detect gross failures; now we can detect more subtle problems,” Ryan Schuelke, vice-president of sales at Enercon, told 


	For liquid and powdered products, stick packaging is an option that simplifies unit-dose dispensing. “We’ve seen rising interest in stick packs in the past couple years, particularly for [dry] nutritional supplements, which are mixed with a liquid,” explained Jonathan Braido, marketing manager at Key International, at Pharma EXPO. Key International, which represents Imar Spain Pack in the US, displayed an eight-lane Imar i6208 vertical form-fill-seal stick-pack machine with a volumetric filling system. Capable of operating at 45 stick packs per minute per lane, the machine can be built with up to 20 lanes. The machine delivers 2-g fills with +/- 3% accuracy and is compatible with liquid or dry dosing systems.

	An optional installation qualification/operational qualification package simplifies startup of the Stick Pack ST600 machine from Viking Masek, which was shown with an integrated takeaway conveyor with stick-pack transfer system, bucket conveyor, and end-load cartoner. Compatible with powder or liquid fills, the unit works with a variety of filling technologies and web widths up to 600 mm. It also offers a choice of straight, zigzag, or round end cuts and standard or offset back seal. Tear notching, micro perforation, and laser scoring also are available (4).

		NJM Packaging, “NJM Packaging Introduces Dara Moduline Model NFL Aseptic Nest Filling Line Inside an Isolator,” Press Release, Sept. 13, 2016.	

		ITW Pillar Technologies, “ITW Pillar Technologies Announces New Induction Cap Sealing System,” Press Release, Aug. 15, 2016.	

		Viking Masek, “Grow Your Business with the New Stick Pack ST600 Packaging Machine,” Press Release, Oct. 26, 2016. 

Articles

Packaging

The co-located Pharma EXPO and PACK EXPO International presented technologies to protect products and people.

Packaging Innovations on Display

	Single-use mixing equipment for GMP bioprocess manufacturing must be capable of effectively mixing buffers (i.e., sinking powders) and media (i.e., floating powders). Effective mixing can be a challenge, especially at high volume. Powder–liquid mixing requires good dispersion and dissolution of particles. To more fully understand the process space for mixing, it is useful to employ tools to measure mixing in both a qualitative and quantitative way. These tools include real-time monitoring probes for pH, conductivity, and particle count, along with means to better observe and record visual trends.

	Real-time monitoring using probes inserted into the vessel can be used to track and record homogeneity throughout the vessel and are often used to measure mixing time, especially in liquid–liquid mixing. For example, addition of a small amount of concentrated salt solution into the larger vessel volume raises the conductivity of the liquid, first in a small area and then throughout the vessel as mixing proceeds. When the conductivity reading becomes stable (i.e., usually within +/-1%), the system is determined to be fully mixed. In a similar manner, when a small amount of concentrated acid or base is added to the system, the reaction to change pH starts in the local area of addition and continues throughout the entire volume as mixing occurs. Once again, when the pH reading is stable, the system is determined to be fully mixed. For powder–liquid mixing, similar measurements can be made, focusing on parameters affected by components in the powder, which are often conductivity or pH, but can also include osmolality or even measurements of the ultraviolet absorption spectrum of proteins (UV280). Conductivity and pH are most useful because in-line, real-time sensors are readily available.

	ParticleTrack (Mettler-Toledo) is a probe-based instrument that uses a measurement technique called focused beam reflectance measurement (FBRM) to track particle size and count in real time. Using a laser beam launched down the probe tube through a set of optics, a light beam is focused into the process where particles flow across the probe window. As the optics rotate, the focused beam scans across the system, and individual particles or particle structures will backscatter the laser light to the detector. These distinct pulses of backscattered light are detected, counted, and used to calculate the distance across each particle, defined as chord length. Statistics from each chord length distribution, such as counts in fine and coarse size classes, can be trended over time. Powder distribution is reflected in reaching homogeneity in particle count, while powder dissolution is shown as particle count moves to a minimum.

	Use of data from multiple probes in multiple locations and a record of visual mixing allow better understanding of the process space and allow design and operational parameters to be adjusted for optimal performance.

	During the design and development of single-use mixing systems at MilliporeSigma, studies were performed to show the effect of key equipment and process variables on mixing time, including impeller size, impeller position, impeller rpm, rate of powder addition, location of powder addition, and liquid volume. Being able to quantify the effects of changing process parameters allows tailoring of the process to the customers’ specific needs, such as minimizing mixing time, foaming, or shear. This article outlines examples of using quantitative and qualitative tools to better understand the mixing process.

	Novel methods for both qualitative and quantitative measurement of powder–liquid mixing, including powder dispersion and dissolution, were employed at MilliporeSigma. Use of acrylic prototype vessels during development provided a powerful tool for characterization of the mixing process because the clear walls allowed qualitative understanding of mixing, not only from the top of the tank, but throughout the entire volume. Measurement devices included real-time monitoring of traditional parameters, such as pH and conductivity. Probe ports were located at minimum working volume, along with probe placement at the top of the vessel, to provide a comprehensive documentation of the mixing process. Beyond traditional measurements, the ParticleTrack tracked changing particle size and count in real time. This instrument was key in not only tracking powder distribution, but also dissolution.

The first step in engineering the Mobius Power MIX systems (MilliporeSigma) was construction of acrylic tanks, with dimensions and equipment (e.g., impellers and motors) as models for the final design. These acrylic tanks provided the first qualitative evidence of the mixing potential for powder–liquid mixing. The generation of a strong vortex is vital to keeping sinking powders off the bottom of the vessel and allow the transport of floating powders off the liquid surface and into the bulk solution. Vortex height was measured at a range of speeds (i.e., impeller RPM) from 20% to 100% of maximum speed and at working volumes from 20% to 100% of the full volume in the 2000-L vessel, as plotted in the vortex map in 

. The vortex map allows an understanding of critical speeds and volumes to optimize powder–liquid mixing. 

 shows the vortex in the clear tank at a range of speeds with an 1800-L working volume. 

 Traditional methods for quantifying a mixing process include measurement of a traceable parameter over time and identification of the time to a stable measurement. For most buffers and media, measurement of conductivity can be used to trace the concentration of powder in solution. To enhance this method, real-time monitoring provides an advantage over sampling, as does monitoring in multiple locations. The mixing of 1X Dulbecco’s Phosphate-Buffered Saline (DPBS) in the Mobius Power MIX 2000 was determined by measuring  conductivity in two key locations, at the top of the liquid volume and at the low volume of 300 L, where ports for sampling and probes are located. The advantage of monitoring at a one-second sample rate was evident in analyzing the traces during the first two minutes of mixing, as shown in 

. The action of the sinking powder was clearly seen as an immediate spike in conductivity near the bottom of the vessel. As mixing progressed, the conductivity measurements at the minimum and maximum volumes converged to show a final homogeneous solution.

 Conductivity measurements alone do not always give the most complete picture of solid-liquid mixing, because this process involves both the distribution and dissolution of particles. Reaching a stable conductivity measurement will indicate complete distribution of the powder, but not complete dissolution. Visual records can be made to describe dissolution, but it is useful to have a quantitative measurement of powder dissolution. Measurement of particles, both size and count, can be accomplished through the use of the ParticleTrack FBRM technology.

	To test the limits of the new mixer for use with sinking powders, a high concentration salt solution was created. A total of 144 kg of sodium chloride (NaCl) was added to 1600 L of deionized water, producing a final solution of 90 g/L (1.5M NaCl). 

 provides a record of the mixing process, where conductivity measurements (

) show a fully distributed powder within 5 min and visual mixing complete at 15 min when it is once again possible to see through to the bottom of the vessel (

). Particle count corresponds to the visual record, reaching a minimum at 15 min, where distribution and dissolution are both complete.

 In another case study, mixing of a floating media powder was examined. A quantitative record of media mixing was created by collecting conductivity, particle count, and pH measurements obtained during mixing of a chemically-defined Chinese hamster ovary (CHO) medium (see 

). In this case, conductivity reached a stable value at 15 min, when most of the floating powder was incorporated into solution. Once again, conductivity alone does not give the best record of mixing. At 25 min, with no visible powder on the surface, particle count peaked at a maximum value, indicating complete powder distribution into the bulk liquid. Dissolution of components in the chemically defined medium did not happen until the pH of the solution was adjusted up to pH 7. Here, the FBRM provided a striking record of particle count decreasing to zero with the increase in pH. The FBRM probe is sensitive enough to recognize air bubbles created during volume increase to 2000 L at 55 min, suggesting that FBRM can be used as an indicator for unwanted foaming. The use of multiple sensors is necessary to fully document the mixing process and quantify the mixing time beyond just visually mixed.

	Both qualitative and quantitative measures of mixing can be used to characterize performance of mixing systems, allowing comparison among designs and confirmation of equipment performance. In addition, these data can be used to more fully understand the process space and allow parameters to be adjusted to achieve optimal performance in areas such as mixing efficiency, limitation of shear, or limitation of foaming. In addition, documentation of the mixing data can create a record for process development and regulatory demands. The ability to quantify the mixing process allows development of better equipment and processes. 

:
	When referring to this article, please cite it as A. Hansen, " Evaluating Mixing in a Single-Use Bioprocessing System," 


	Anne Hansen is a development engineer at MilliporeSigma, 80 Ashby Road, Bedford, MA 01730. Tel. 1.781.533.2436, anne.hansen@emdmillipore.com.

Troubleshooting

Quantitative and qualitative tools allow better understanding of mixing in a single-use bioprocessing system.

Evaluating Mixing in a Single-Use Bioprocessing System

	The cold chain for bio/pharmaceutical drugs involves controlling the temperature throughout the supply chain, and storage chambers are a crucial element. Cold, temperature-controlled chambers-from as small as a freezer to as large as a warehouse-are often used to store raw materials, intermediates, and finished bio/pharmaceutical drugs and are operated under cGMP. The International Society for Pharmaceutical Engineering (ISPE) recently released a Good Practice Guide for mapping and monitoring temperature-controlled chambers. The guide describes industry good manufacturing practices for using data to determine the location and number of monitoring sensors, as well as developing test acceptance criteria and using a risk-based approach to system performance review (1). The new guide is consistent with the ISPE 

Good Practice Guide: Cold Chain Management

 spoke with Paul Daniel, senior regulatory compliance expert at Vaisala, about the types of sensors used for monitoring cold temperature-controlled chambers and best practices for mapping, placing, and maintaining these sensors.

: What types of sensors are used for temperature-controlled chambers?

 Cold temperature monitoring is typically performed with one of four sensors: a thermometer, a thermistor, a resistance temperature detector (RTD), or a thermocouple. Monitoring does not require a high accuracy sensor for most applications, especially for cold temperatures, so most types of sensors can be used.

	Glass thermometers containing alcohol, while simple, reliable, and inexpensive, are being used less frequently because they require human labor for daily checks and data recording, as well as compiling reports. There are many opportunities for error in reading the device, recording the data, and compiling the reports. They do continue to be used in some emerging markets and developing nations, where labor is inexpensive and higher-tech solutions are prohibitively expensive.

	Thermistors, RTDs, and thermocouples determine temperature by measuring an electrical value, such as resistance, which changes with temperature. These devices vary widely in terms of cost, initial accuracy, long-term stability, and range. For most applications in monitoring cold temperatures (8 °C to -80 °C), a device equipped with an RTD or a thermistor would be selected. For very cold applications, such as liquid nitrogen cryogenic applications, generally a thermocouple is used due to the extreme cold (as low as -196 °C), though an RTD can be used at these temperatures as well.

	In general, the advantages of thermocouples include low expense, a linear response to temperature changes (therefore easy to calibrate), a wide range of temperatures that can be measured, durability, and energy efficiency. Disadvantages include relatively low accuracy and low stability. Thermistors are also inexpensive, durable, energy efficient, accurate, and stable, but they have a non-linear response (harder to calibrate) and a narrow range of temperatures. RTDs have a linear response, high accuracy, high stability, and a moderate range of temperatures, but they are expensive, fragile, and energy inefficient (i.e., need external power).

	The measurements from these electronic sensors are typically measured by a device like a chart recorder or a data logger. Chart recorders, due to the labor requirements of changing charts and real possibility of mechanical failure, seem to be disappearing from the field.  The modern method is to collect the data from the electronic sensor and store it in a data logger for later collection and download. The data logger is generally considered to be superior because there is a very low risk of data loss. The downside of the data logger is downloading the data, but an automated system can automatically download over a network connection.

: What are some of the best practices for placing sensors in a temperature-controlled chamber?

Before you can monitor a space, you need to map it to demonstrate that the space is suitable for controlled storage.  You can also use the mapping data to inform the placement of your monitoring sensors. For mapping, sensor placement best practices are well detailed in the new ISPE guide.   ISPE recommends that a sensor should be placed in each corner of the chamber and one in the geometric center, for a total of nine sensors. This practice is good enough for any chamber less than two cubic meters in volume-basically anything smaller than a large free-standing refrigerator or freezer. If the chamber is larger (up to 20 m

), an additional six sensors should be added, one at the center of each wall of the chamber (including the ceiling and floor).

	If the space is even larger, such as a large cold-room or warehouse space, sensors should be distributed in three planes in three dimensions, at a density that it suitable for the space.  Another way to say this is to place sensors in vertical ‘stacks of three’-one at the lowest storage shelf, one at the highest shelf, and one in between-and distribute these stacks of three evenly throughout the space to be monitored. I suggest a starting density as follows: for cold-rooms, the maximum lateral distance between sensors should be no more than five meters; for warehouses this distance may be increased to 15 meters.

	These best practices are a conservative starting point and a theoretical model of sensor placement that must then be modified to account for the realities of the space, such as doors, windows, and heat sources in the environment.

	Vaisala’s new VaiNet enabled sensors use a wireless technology that has five-times better range than Wi-Fi. The sensors communicate on radio frequencies and are battery powered, which means we will be able to do real-time mapping of large spaces with no wires involved.

	Once mapping is completed, select a location for the monitoring sensor(s).  The best practices around sensor placement are varied. Technically, most guidance will tell you to place monitoring sensor(s) in a way that takes into account the performance of the chamber, as documented in the mapping process which previously identified hot and cold trouble spots.  As a result, this is misinterpreted as requirement to monitor the hot and cold spots.

	Placing of the monitoring sensors is a risk-based decision, into which hot and cold spots are simply one element to be considered.  The ISPE guide highlights the factors that should be considered, such as protecting the sensors from damage.  In almost all situations I have seen personally, the placement of monitor sensors follows some simple and pragmatic rules.  Chambers smaller 2 m

than usually have a single sensor placed on the wall out of the way of normal use, but close enough to the door to detect an open door condition.  Larger spaces often get multiple sensors, spaced evenly across the space at a low density, and there often are significant distances between sensors.

: What are some best practices for maintenance?

Sensor maintenance is quite simple.  For Vaisala devices, we recommend an annual calibration against a National Institute of Standards and Technology (NIST)-traceable standard to determine that the sensor accuracy is within expected tolerance. If the sensor has drifted a small amount but is still in tolerance, it may be adjusted for better accuracy and then returned to service. If the sensor has drifted a large amount and is found to be out of tolerance, an out-of-specification (OOS) report (or other deviation report) would need to be filed and an investigation performed to determine if the sensor measurements could have compromised product quality in any way. It is best to prevent an OOS occurrence by selecting a reliable and resilient device from a reputable manufacturer, mounting the device in a protected location, and performing calibrations within the manufacturer-recommended interval.  For instance, with our line of DL Data Loggers, we find that of all the loggers sent in for annual calibration, 97% of them are within tolerance.

	Another way to ensure the health of your instruments is to do spot field checks against a hand-held reference. This practice isn’t a calibration, but it can provide confidence that an instrument is performing properly between the calibrations.

	Other than regular calibrations and periodic battery changes, there is not much to do for preventive maintenance. The most important part is that a written procedure for calibration/maintenance exists, is approved, and is followed, and that the written records of the calibration/maintenance are available for review.

	An automated data-collection system will usually store records electronically and, therefore, has some preventive maintenance requirements, such as periodic review of the audit trail and of the user accounts.

ISPE Good Practice Guide: Controlled Temperature Chamber Mapping and Monitoring

ISPE Good Practice Guide: Cold Chain Management 

Production Trends

Consider best practices for placing, maintaining, and calibrating temperature sensors.

Equipment and Processing Report-12-21-2016

Packaging Innovations on Display

Evaluating Mixing in a Single-Use Bioprocessing System

Monitoring Temperature-Controlled Chambers