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Pharmaceutical Manufacturing and Packing Sourcer

Tight Performance

As the pharmaceutical industry evolves with increasingly advanced medicines, sophisticated formulations, continuing strict regulations by the authorities, as well as a focus on full function during the consumption stage of medicines, there is a growing awareness of packaging tightness as a key factor for tablet manufacturers

The increased number of biotech-based medicines has heightened the need of not only watertight, but gas-tight packaging solutions as well. Furthermore, the increasing amount of generic medicines is also driving packaging requirements.Nowadays, not only is the active ingredient itself often patented, but other important additives that enhance the stability of a medicine in a formulation are protected too.The developer of the generic drug in such cases strives to make use of even tighter packaging to overcome stability issues when developing and industrialising their preparation for rapid market introduction, as the original drugs go off-patent.

Factors Affecting Tightness

There are several factors that influence the tightness of primary plastic packaging; this list is by no means exhaustive:

Material Choice
Among standard commercial polymers, high density polymer (HDPE) is one of the tightest for water vapour permeability. For example, when using polypropylene (PP) you would have to add two to three times more wall thickness to reach the same water vapour tightness as when using an HDPE; a 0.3 mm HDPE container will give the same tightness as a 0.5 mm PP container.The equivalent value for a nonstretched polyester (PET) container is 0.8 mm; coupled with the fact that PET has a density that is more than 30 per cent higher than for both HDPE and PP, PET is less resource-effective.

When it comes to gas-tightness however, PET is a lot tighter than PP and HDPE, both of which have about the same gastightness. With 50 times less PET the same gas-tightness can be achieved, and this is one of the main reasons (as well as its clear and shiny appearance) for using stretch blow moulded PET for carbonated beverages, often with high gas overpressure.

The Packaging System
There are many different packaging solutions available in the marketplace as a whole, but several different concepts inside the container and closure product ranges also exist. Basic material and wall thickness, potential material barriers, push-on or thread closures, accuracy, as well as the fit between container and closure are all factors influencing the tightness of primary plastic packaging. Each manufacturer should test and include the tightness properties in the product specification.

Production Process Capabilities of the Packaging Manufacturer
The design, basic quality and technical status of the moulds themselves at the packaging manufacturer’s end constitute good process capability. Most companies use standard injection and injection blow moulding machines,however the general condition and technical status of the machines and auxiliary equipment, with factors such as frequent and up-to-date preventive maintenance, are building the backbone for robust stability in the production process.Unambiguous and comprehensive standard operating procedures are something that normally comes with the quality system certificates. To achieve a robust and stable production process there needs to be a standardised way of running the operation over all shifts. In the end it always comes down to the people operating the production and how well the SOPs are communicated and implemented to achieve a standardised way of working to support the built-in ‘hardware’ process capability.



Container Manufacturing Technology

Using different manufacturing technologies will have an impact on the tightness of the container itself, and the two that currently dominate the market are injection blow moulding (IBM) and extrusion blow moulding (EBM).The IBM process gives better control, more accurate dimensions and a better finish on the neck part of the container compared to the EBM process.The neck appearance and dimension tolerances are key for tightness, as its interaction with the closure is all-important.

Processes and Technology at the Filling Site
The problems affecting the tightness of the packaging system in the filling process are the same as usual for the packaging manufacturer, both in the production process and the manufacturing technology mentioned above.There are often small details in the setup of the filling line that have a large effect on the assembly process. Special attention should be paid to the format of the parts of the assembly line.A thorough analysis of the tolerance windows and the total tolerance chain in both the mounting stage (closure/container, height and centring) of the filling line and of the packaging system itself should be carried out for each individual part to make sure they are aligned and that they fit correctly. Sometimes, in addition to the control system and PLC-system software, the filling line also needs built-in mechanical features that prevent the moving parts going beyond a certain point that could destroy non-visible parts of the closure or reduce tightness.

Supply Chain
For what markets are the products intended to be sold? What type of climate is dominating in those markets: hot and humid or cold and dry? What kind of supply chain setup is present in those markets? Is it a well controlled chain with high turnover and short life cycle or the opposite? This is probably not the most important factor, but could be something to consider when carrying out stability tests on the packaging. Finally, in some countries, pharmacies tend to break the original package and only give the patient a smaller dose for a couple of weeks’ usage. Sometimes a vial with a stopper or even a simple plastic bag is used, which of course are nowhere near as tightly sealed as the original packaging.

Consumption Period
What is the normal prescription pattern/time in relation to the size of the package? Will the end user consume the content of the packaging after a few days or during a longer period,maybe several months or even a year? Upon opening both the content is exposed to both air and humidity, and different packaging systems have different levels of resistance to the impact of the tight seal being broken multiple times.



Where is the Weak Link?


All systems have a weak link that determines their limits.What then is the weak link of the packaging system? It is easy to think that you need to minimise the leakage of both water and air into the container and/or the closure by sealing the container/closure itself tighter.This can be done by adding more materials, either by way of a thicker container wall or through the introduction of various barriers or a type of gasket in the closure mechanism.After various analyses and tests, both internal ones and those carried out by a third party (DTI), the result is clear that the weak link is the actual interaction between the closure mechanism and the container. It is in the section between the closure and the surface of the seal that the highest risk of leakage occurs, regardless of how tight the actual container and/or closure mechanisms are themselves. So, instead of spending resources on more material or enduring a slower manufacturing process because of the introduction of additional material types, first make sure that the packaging system works well in itself with a smart robust design and with as near-perfect a fit as possible between the closure mechanism and the container.

Some Comparative Tests

We have conducted tests of both water vapour and oxygen transmission with three different packaging types, as well as a solid piece of HDPE sheet, corresponding to a standard container wall thickness of 0.8 mm.These include:
  • 35 ml standard bottle (Figure 3A)
  • 35 ml bottle with aluminium liner (Figure 3B)
  • PET (glass) container with EVA sealing, similar to those found in beverage bottles (Figure 4)
The HDPE plastic sheet shows a water vapour transmission close to zero,well in line with the expected theoretical values retrieved from logarithmic graphs in the technical literature.Within the standard packaging system in this test, a 35 ml bottle has half the leakage compared to a solution with an EVA gasket in the closure. The version with the aluminium foil liner which has been heat-sealed onto the container has the best expected result before first opening.After tearing off the liner, a somewhat uneven surface will occur, which will to some extent destroy the tightness of the surface between the container and closure mechanism and is therefore likely to reduce the tightness of the seal during usage.

This second test, showing the oxygen transmission, verifies that the version with a aluminium foil liner is tighter than the standard solution and close to the version with a 2k closure.However, keep in mind that this applies to the liner before the package is first opened. It is expected that the gas-tightness with this version will reduce after the first opening, due to the same reason as for the water vapour transmission: a partly destroyed tightness surface.The PET perform, with EVA/PP closure, gives a much better result in the oxygen test compared with the water test; a fact supported by its use in the drinks industry.The rigid HDPE wall itself only allows for a small gas transmission through the solid sheet,which is also kept in the same range as for the container with aluminium foil.The test is, however, difficult to carry out with a rigid sheet. It needs to be converted through a calculation in order to compare it with the surface of the equivalent container.




Different Solutions

There are different ways to improve the tightness and enhance the micro climate inside a packaging concept, as well as to reduce the negative effects of nontightness. Absorbents can be effective; either as canisters, preferably assembled in the closure, or integrated directly into the closure.There are versions for both moisture and oxygen absorption. It is also possible to make mixes that combine those two aspects and to calculate the expected mass needed to reach the desired absorption level.

Barriers, such as EVA or Ethylene Vinyl Alcohol (EVOH) built into the container, are normally only done with extrusion blow moulding.This creates a very tight container and the material in the barrier can be selected to prevent the type of transmission you want to minimise. However, the weak link of the packaging concept is the container-closure interaction, and with EBM technology it is much more difficult to reach the same accurate dimensions and to finish the neck section of the container, as with the IBM process. In the IBM process a separate barrier cannot be included;however, different additives have been developed and launched in the marketplace that will enhance the base material properties, to avoid the need for a separate barrier. In some cases, such additives might have other negative effects; they will need to be thoroughly analysed and have both migration and stability tests carried out before they can be introduced.

A liner, typically aluminium, can be assembled inside the closure, and heat-sealed onto the container.This method is commonly used in the US, but as mentioned earlier, it will be less effective after the first opening because of the deteriorating surface of the container the liner has been torn off.

Also effective is a two component closure (2k) with a softer material, such as EVA, or a thermoplastic elastomer (TPE) that works as a gasket to give a good surface contact between the container and the closure (see Figure 3C, page 70). If this 2k solution is added to an already tight standard packaging system the tightness will be further improved and can, if put in the right place, act as a second tightening area.The 2k solution may also improve the tightness level of an aluminium linerwelded container after it has been opened.

Conclusion

If a standard solution is required, decide which part of the life cycle is most demanding for the product. Is it on the shelf in the supply chain or during consumption by the end user? Then choose a solution based on this and the other factors which have an impact on the tightness mentioned earlier.Customer-adapted products, with unique tailormade solutions for a specific need, can be a wise solution in many cases, depending on the specific requirements. Make sure you consider more than one factor.Try to find a balance between the various factors in your individual case. It is obvious that the weak link in tightness for a packaging system is the area between the container and the closure. Be sure to use a packaging system that works well, with a smart, robust design and with as near perfect as possible a fit between the closure and the container, before adding to costs by adopting apparently more sophisticated solutions.


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Glenn Svedberg is Managing Director at Nolato Cerbo, a Swedish-based company specialising in developing and manufacturing primary plastic pharmaceutical packaging. Nolato Cerbo is part of the Nolato group and the Nolato Medical business, a global partner within the development and production of polymer products for market-leading medical technology and pharmaceutical customers. Glenn has an MSc in Industrial Engineering and Management. He has worked in manufacturing companies for 20 years, in positions covering purchasing, marketing, business development and factory management. Before joining Nolato Medical in 2007, Glenn worked at Rexam and at Polimoon/Promens, where he was responsible for the Food Nordic division. Email: glenn.svedberg@nolato.se
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