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Pharmaceutical Manufacturing and Packing Sourcer

Fit for Purpose


Package integrity is key in delivering safe and effective drugs to patients, but what are the best strategies to follow to ensure quality packaging design?

Conducting stability studies is a fundamental element in demonstrating to regulators that a drug’s formulation is safe and effective over the indicated shelf-life listed on the package. Too often, pharma companies develop stability studies that do not pay enough attention to package performance, not realising that a stability test failure may have nothing to do with the drug itself, but can rather be attributed to its packaging.

Therefore, it is imperative that the performance of a drug’s packaging is scrutinised at the same time that the drug itself is evaluated. This alignment of testing procedures makes sound commercial sense because it enables the integrity of the package to be determined very early in the stability timeline, enabling failures to be more quickly identified and corrected, and thereby minimising potential delays to the launch programme.

In formulating a strategy to reduce the risk of test failures, pharma companies need to consider three guiding principles relevant to barrier films: suitable design, correct thermoforming and sufficient examination. Following these principles will provide a better understanding of the barrier required to pass stability and help avoid over-packaging and potential delay.

Does Your Packaging Design Shape Up?


Optimising the barrier of the blister package requires pharmaceutical engineers to prepare and plan upfront, taking into account the drug’s sensitivity, materials selection and the type of machinery available. Not all machines are capable of processing every material optimally – especially barrier materials – so the compatibility of machines and materials must be discussed with suppliers at the outset.

Packaging engineers should also pay close attention to design and tooling as these can improve barrier performance dramatically. Successful tooling design can be assured by following these recommendations:
  • All thermoforming moulds should be designed as dedicated moulds with features recommended for high-barrier materials. These will provide more uniform thickness distribution than universal moulds, resulting in improved barrier performance
  • Dedicated cavity dimensions should be designed for each pill size and shape. When standard cavities are used for multiple sizes or shapes, a large cavity design will increase the surface area of the cavity and in turn increase moisture permeation when used for smaller pills
  • The theoretical barrier of the package should be calculated (see ‘Weight Gain Test’ section). This data can be used to assess different barrier materials and/or various cavity designs, helping packaging engineers to select appropriate materials. The theoretical data is important in the examination stage to determine the actual barrier of the formed package

To optimise permeation rates, packaging engineers should also take into account the following design considerations:

  • Cavity dimensions must allow for proper clearance between the dosage and the lid stock to enable efficient product feeding and proper sealing of the lid stock to the blister
  • For cavities deeper than 6mm, or with a deep draw ratio greater than 3:1, pre-forming with plug assist is recommended
  • A draft angle of 7° to 9° must be utilised in the cavity. Higher draft angles will produce less thinning of the forming material, while also allowing blisters to release more easily from the mould when running at high speeds

Is Your Thermoform Process Correct?

Packaging engineers also need to think about thermoforming conditions to ensure that the package delivers the expected barrier performance and is not vulnerable to compromise. High-quality blister results can be guaranteed by adopting a rigorous approach to some of the key elements in the thermoforming and sealing process. Engineers must use the proper forming temperature for materials, and these vary according to material type, thickness and manufacturer; thermoformer; speed; timing; and mould temperature.

Working closely with material and machinery suppliers and properly examining the thermoformed blister card is the best way to establish good forming conditions.

What you want to achieve are fully formed cavities. A good indication of fully formed parts are visible imprints of air evacuation ports in a cavity (air evacuation ports are design features around the bottom of the cavities and in reinforcing elements used to release trapped air). It is essential to avoid cooling the laminate before forming and to ensure there is sufficient force to form the parts. For cavities deeper than 6mm or with a deep draw ratio greater than 3:1, use plug assist in combination with air pressure to improve thickness distribution and barrier performance.

Selecting and using the right lid stocks for the sealing conditions is also critical. If sealing against the PVC side of the laminate, use standard PVC films sealing station setup. Good sealing is a key aspect of attaining package integrity, and it is important that lid stock suppliers are consulted over sealing recommendations as sealing conditions will vary with pack layout, foil type and manufacturer, line speed and machine type. Choosing the right sealant is dependent on the polymer that is in contact with the foil coating – if the contact layer is consistent, no change in conditions is required. For example, PVC mono film, PVdC coated PVC, and Aclar film laminated to PVC can be sealed using the same foil and conditions as long as the foil is sealed to the PVC side in all cases.

Suitable Testing Methods

In addition to using the correct design and thermoforming techniques, pharma companies should also be using a variety of methods to inspect their blister packages to ensure that the performance matches the theoretical barrier expectations. A range of suitable tests are available, the most important of which – albeit the most time-consuming – is the weight gain test.

Leak Detection
Test One of the most common methods used to test blister packages for leakage is the methylene blue test, in which the package is placed into a vacuum chamber partially filled with a mixture of water and dye. The packages are submerged in the liquid and held in place while a vacuum is applied at a specified level for a specific period of time. The chamber is vented to atmospheric pressure and each card is inspected for evidence of blue dye in the cavities and/or seal areas. A statistical sampling method is used to verify that the process is producing acceptable blister cards.

One limitation of this method is that the actual samples tested cannot be used for subsequent weight gain testing. As a result, another option to consider is a new testing technique based on over-pressurising or under-pressurising the blister cavity. This approach can reveal whether or not the blister package has open channels and, because it is non-destructive, all the samples can be re-evaluated in the stability test. However, be aware that, even if no leaks or open channels are found during leak detection testing, micro channels or stress cracks in the lid stock may still be present and go undetected. As a result, additional tests are needed to verify seal integrity, as well as to ensure proper thickness distribution of the film.

Polarised Film Test
This test examines the blister for stress in the sealing flange area. The blister must be made of transparent film and be backed with a reflective background, such as foil lid stock or a second piece of polarised film. Hold the blister card under the polarised film at a 45° angle to the film and, if there is stress in the sealed area, this will show as a colour differential.

For example, for Aclar laminates, the colour will change from brown to blue and then to more brilliant colours as the stress increases. For PVdC materials, shades of grey will indicate stress.

High Intensity Light Test
This simple test will check for cracks in the foil and should be undertaken every time a stability assessment is run. Take the sealed blister card to a dark room and shine a flashlight through one side of the card, looking for any light coming through the foil and plastic. If blister packages are made from opaque film, produce a few packages with clear material and conduct the test to ensure there are no pinholes in the seal (see Figure 2).

Magna-Mike Test

 This test measures the thickness distribution of the blister cavity by holding the gauge’s magnetic probe to one surface of the test material and placing a small steel target ball on the opposite surface. A Hall-effect sensor measures the distance between the probe tip and target ball and provides accurate results – although, due to the nature of this test, only certain points of the blister can be measured, rather than the entire blister cavity.

Microtome Test
In this test, a laser microtome is used to cut an epoxy mould of the blister cavity for microscopic examination. It measures a continuous line around the perimeter of the cavity and assumes that if the cavity is round, it will have the same thickness distribution throughout. This approach is more time-consuming and expensive than the Magna-Mike test and is not appropriate for machine setup or trial. For capsules, two cuts are required: one running lengthwise, and one running the width of the cavity. Although this test will not measure the thickness distribution of the entire blister cavity, it does measure more points than the Magna-Mike test, thereby giving the packaging engineer a greater understanding of the blister’s barrier thickness.

Weight Gain Test

The single most important test for a blister pack is the weight gain test with desiccant. This test, which takes about 40 days, is similar to USP <671> – a test that gauges the moisture permeability for multiple unit containers used for capsules and tablets. By conducting weight gain testing on packages filled with desiccant, the permeation of the package can be studied independently from the drug dosage.

First, the sample size must be statistically significant. Typically, 6 to 10 blister cards with desiccants in each cavity is sufficient for each International Committee for Harmonisation (ICH) condition (the ICH has set up four conditions for stability studies: 40°C/75 per cent RH; 30°C/65 per cent RH; 30°C/75 per cent RH; and 25°C/60 per cent RH). Each blister pack is placed into a properly marked package holder and weighed to determine its initial weight (day zero).

Next, the samples are placed into the humidity chamber with the desirable ICH conditions. Samples should ideally be weighed every day for 10 days (at least every other day). More frequent weighing early in the study allows for more rapid assessment of the performance of the cards under test. After 10 days, the test frequency can be reduced to one weighing per week. The first 10 days are particularly important when measuring low barrier materials such as 40g PVdC at high ICH conditions, as desiccant tablets will become saturated quickly and plotted data will not be linear.

Weight gain results are reported as weight gain (WGdayX) in g/package and plotted on a graph. When interpreting the results, the packaging engineer should check the graph for linearity. Non-linearity may indicate a problem with the samples, saturated desiccant tablets or the data collection method. Similarly, packaging engineers should also check the variation between samples to determine whether or not their design, package and process are robust.

Assuming the weight gain results are linear, the next step is to use this data to calculate the moisture permeation rate per day for each cavity. These weight gain results are then compared to the theoretical results determined during the design phase using a barrier prediction method such as finite element analysis.

The results of the weight gain test compared to the theoretical barrier prediction method used should not show a difference greater than 10 to 20 per cent. If the final numbers are within this percentage, the packaging engineer will have documentation that his package successfully passed stability at the end of the 40 day weight gain study.

If the comparison results are greater than 20 per cent, the packaging engineer can stop the stability study early, recognising that the package has failed.

As a result, the weight gain test provides the information needed to determine what packaging changes are required and then a new stability test can begin, saving cost and avoiding potential lengthy launch delays. If, after several months, the stability test is not producing favourable or expected results, the engineer will have sufficient data to determine whether the package is indeed the reason for failure or, if not, to explore other causes.

Furthermore, the weight gain test provides a wealth of information which is of significant value to research and development. To help determine the best barrier protection for a particular drug, the packaging engineer can reference the catalogue of weight gain data for different cavity shapes and materials and have a better understanding of design limitations or the forming process. The test is also beneficial for package transfer activities, because it allows companies to evaluate other site standards, helping to ensure packaging performance consistency across multiple sites.

Conclusion


If approached in a meticulous way, the three principles outlined above – suitable design, correct thermoforming and sufficient examination – will optimise blister package quality and predictability. While a stability study with dosage focuses on testing the drug for efficacy and safety, weight gain tests with desiccants succeed in separating the performance of the drug from that of the package by testing the package directly without drug influence. The data obtained will assist in the rapid identification of package integrity issues, and in doing so will help ensure that drugs are more likely to be brought to market without delay and in a condition that assures patient benefit.

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Zuzana Sabova-Kepic is the Manager of Honeywell’s Barrier Packaging Analytic Lab in Morristown, US, and is the Lead Technical Specialist for Honeywell’s Health Care and Packaging business. Zuzana provides technical support for Honeywell Aclar films, working with pharmaceutical companies on packaging design, pre-stability and registration stability studies, and new product launches. She helped develop Honeywell modelling systems for barrier calculations, weight gain analysis, and value calculators. Zuzana holds a BSc in Chemical Engineering and an MSc in Analytical and Physical Chemistry from Slovak Technical University in Bratislava, Slovakia. 

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Zuzana Sabova-Kepic
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