	Many points during the packaging process pose a risk to product quality and safety. Package design and production risks include material/product interactions, incorrect labeling, incomplete product information, translation mistakes, out-of-specification containers and components, and supply-chain disruptions. Packaging line risks may involve handling that damages the product; stray, damaged, or contaminated product; inaccurate count or fill level; missing components; incorrect components; and poor seal integrity.

	“In pharmaceutical packaging processes, there is a risk of creating critical defects,” Shannon Walker, vice-president of Quality H&PC Packaging Americas at Essentra Packaging, told 

. He added, “In some cases, this may lead to a regulatory breach and, more importantly, a patient injury. For example, print defects in product mixes, critical dosages, or usage instructions may change the meaning of statements, creating critical consequences for the patient.” He reports that commonly overlooked risks in product interactions are associated with processing aids and equipment lubricants. If transfer through the packaging material occurs, the medication could be rendered ineffective or even unsafe.

	So how can risks be mitigated? Walker says, “ISO 9001 provides basic regulatory guidelines, while PS 9000 is a standard for primary, secondary, and complex packaging materials intended for medicinal purposes. PS 9000 provides complete GMP guidelines and risk assessment requirements to mitigate potential risks” (1, 2). Another tool is the FDA’s 

Guidance for Industry, Safety Considerations for Product Design to Minimize Medication Errors

	Software also can play a role in managing risk. Packaging components can be either attribute-driven (e.g., bottle closure torque) or variable-driven (e.g., container wall thickness), notes Walt Murray, CEO of ARC Experts and a member of the Quality and Compliance Consulting services team at MasterControl, who stresses the importance of understanding the difference between the two.

	“Either type of data can be analyzed for patterns which present potential risk conditions,” says Murray. “A risk-based analysis should be performed during each of the six interrelated phases of the design control process (requirements and planning, development, verification, transfer, validation and commercial release). A design review should be conducted at the end of each phase. Change control, on the other hand, can be initiated wherever necessary.”

	Murray also notes that human factors present the greatest risks. These risks can be minimized or eliminated by automating the label and packaging processes with software. “Everyone needs to understand where the risks lie when a process is not automated. Automation controls the risks associated with human application. This is explicitly spelled out in the new quality standards.”

	Controlling risk must extend across the supply chain. Essentra Packaging, a supplier of cartons, labels, leaflets, and blister foils, has established a validated Risk Management System to protect all stakeholders associated with its products and services. Walker says, “Essentra provides a significant, continuous amount of cGMP training to employees.” In addition, “Essentra advocates for paying attention to detail at all levels of the organization.” This philosophy has helped prevent at least one recall. In this case, an experienced press operator, setting up for a run of cartons, noticed the most recent artwork change was for a medication intended for daytime use only. From his previous work with this client, the operator knew the image on the carton matched the capsule intended for nighttime use. So the operator stopped the setup and requested confirmation. It turned out the artwork was incorrect. The operator’s alertness made it possible to correct the artwork before thousands of cartons were produced. Expenses associated with scrapping cartons with the wrong artwork or recalling mispackaged product were averted, and the product’s good name was preserved. 

	Essentra holds third-party-verified ISO 9001 and PS 9000 certifications for its quality systems and performs business reviews on new projects to ensure quality requirements will be met. Walker reports, “We work to ensure equipment and processes are validated against predefined protocols, to ensure their output is as intended before operations begin. Essentra also has a separate and independent quality assurance organization. This includes offline electronic comparison systems (print verifications), 100% vision inspection on some equipment (print verifications), and 100% identity scanning of materials (to prevent product admixture).”

	Essentra’s Risk Management System is complemented by a comprehensive Disaster Recovery Plan, which includes strategies and tactics for rapid communication, the ability to qualify multiple production sites, and plans that cover specialty products, which may include qualification of external service providers. As a result, if a department or site should experience a slowdown or stoppage, production continues.

		The Chartered Quality Institute, PS 9000:2011 

Articles

Packaging

Reducing Risks in Pharma Packaging

	A good understanding of the properties of the plastic materials used to make single-use biopharmaceutical manufacturing system components is crucial. Polymers can vary in their barrier properties, whether physical properties change at extreme high or low temperatures, in their ability to hold up under sterilization conditions, and in extractables and leachables. Polymers used for single-use bio/pharmaceutical systems can include polyethylene (PE), polypropylene (PP), polycarbonate (PC), and-more recently-fluoropolymers. 

 spoke with Eric Isberg, director of Life Sciences at Entegris, which recently introduced its Aramus single-use bag assembly made from a gamma-stable fluoropolymer, about considerations for single-use materials.   

 Are there temperature limitations for single-use materials?

 Most single-use bag assemblies are limited to a temperature range of -20 to 40 °C. The limitation is mostly due to the bag film itself. Below this range, the materials become brittle and fail, and above it the materials soften and can melt. Rapid changes in temperature, temperature cycling, or temperatures below -70 °C can cause delamination of the film layers and film failure due to cracking.

	The Aramus single-use bag assembly is designed and tested from -85 to 40 °C. However, the film and bag boat fitment are made from a single layer of fluoropolymer material that is suitable for use down to -200 °C and as high as 200 °C.

 What are the concerns with single-use materials affecting cell growth?

 All additives-whether they are by-products or purposely added chemicals like antioxidants, UV stabilizers, or processing agents-are potential leachables that can have a negative effect on processes and products.  For example, certain purposely added chemicals have been shown to negatively affect cell growth. Our fluoropolymers have none of these by-products or additives that can leach out into the process.

 What are the concerns with particulates coming from the materials? 

 Both foreign particles, as well as particles native to the bag assembly materials, which are generated during manufacturing, are potential process contaminates. Aramus single-use bag assemblies are manufactured in an ISO Class 5 environment, greatly reducing the potential for particulate contamination. The advantage of manufacturing in an ISO Class 5 environment is a reduction in foreign particles from both the manufacturing environment and the manufacturing process itself. Utilizing sufficient laminar air flow across the parts during manufacture can sweep away any airborne particles that are generated. Also, controlling the dryness of the air, combined with other static-elimination methods, can keep airborne particles from sticking to surfaces, including the surface of the single-use components being assembled. Lastly, reducing the number of penetrations on the interior of the bag reduces the chance of particles being introduced. Fluoropolymers are not inherently better than other plastics in terms of native particle generation during manufacture. It is a matter of how those particles are reduced using these steps as well as other proprietary methods, including post-processing procedures.

Production Trends

Gamma-stable fluoropolymers are an alternative material for single-use bags and assemblies in biopharmaceutical manufacturing.

Considering Single-Use Materials

	Pinch valves were introduced to pharmaceutical processing more than 35 years ago to facilitate the use of electronic valves in place of mechanical valves and pistons for dispensing sterile injectable fluids. Pinch valves introduced the concept of timeâpressure filling and allowed a disposable sterile fluid path to be maintained for dispensing parenteral drugs into containers.

	Unfortunately, a number of technical problems accompanied timeâpressure filling and its dispense accuracy could not achieve what the industry demanded. More recently, many of these problems have been solved using the concept of timeâdispense filling. One issue has remained, however. When the electric pinch valve heats up, the dispense volume changes. Preheating the pinch valve can solve this problem.


	Electric pinch valves warm as the electric charge opens and closes the valve. As the valve continues to warm, the time it takes to open and close changes, so that a different amount of fluid passes through the valve each time it opens and closes. If the change is too great, the dispense volume can drift out of specification. 

	A common method used to minimize valve warm-up is to reduce the voltage to the valve coil after it has been energized. With this approach, a cold cube is used to diminish the maximum valve temperature. Unfortunately, this approach does not prevent warm-up entirely, nor eliminates the change in dispense volume. 

	A close examination of the valve during its warm-up phase reveals three factors:

		As the valve starts to dispense fluid, the dispense volume changes while the valve warms up.

		After a period of time, the temperature of the valve reaches equilibrium and dispense volume remains stable.

		The equilibrium temperature is a function of the valve's duty cycle time (defined as the time required for the the valve to open and then close, once).

	To further explore the problem, an approach was taken to preheat the pinch valve before dispensing fluid. A test was conducted to determine the optimum temperature to heat the valve. A valve was cycled on and off, and its temperature was monitored while it warmed to equilibrium. Additional tests were conducted at different duty cycles and similar temperature data were collected. A summary of the results is shown in 

. Higher duty cycles correspond to higher equilibrium temperatures.

	To further evaluate this data and search for a way to predict the equilibrium temperature, duty cycle is plotted against the equilibrium temperature, as shown in 

. The data result in virtually a straight line, enabling the user to select the best temperature at which to preheat the pinch valve.


	Dispense volume testing was conducted on a timeâdispense filling machine to study the impact of valve preheating at the optimum temperature.  Using a 1-cc target dispense volume, data from 1000 replicates were gathered during the first 45 minutes of filling. Without valve preheating, prior to equilibrium, dispense weights typically ranged from 0.992 to 1.008 mg, a range of 16 mg or +/- 0.8%. With valve preheating, prior to equilibrium, dispense weights typically ranged from 0.096 to 1.005 mg, a range of 9 mg or less than +/- 0.5%. Results showed that preheating can significantly improve accuracy.  


	Denis Keyes and John Randall are partners at Acertacorp LLC, 

. The data shown here are part of a current US patent submission.

Troubleshooting

Preheating pinch valves prevents drift in the volume of liquid dispensed.

Equipment and Processing Report-07-20-2016

Reducing Risks in Pharma Packaging

Considering Single-Use Materials

Optimizing Accuracy in Pinch Valves for Sterile Injectables