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Pharmaceutical Manufacturing and Packing Sourcer

Clean Sweep

The purpose of packaging is to protect the product it contains. In the world of pharmaceutical devices, to protect also means to ensure patient safety. To this will often be added other more ‘practical’ functions, such as traceability, consumer information, and assistance in gripping and opening. Ultimately, all these packaging functions combined provide complete, ongoing protection and mean added value for the device’s manufacturer.

Despite the significant role of the packaging, however, this is not the factor that will determine the choice of sterilisation. What counts is not the container but the content, of course. Consider the case of a medical device: it is primarily designed to perform a function, and the materials of which it is composed will be best suited to this purpose. After that, the sterilisation method considered to be non-destructive or degrading will be retained. It is only after this process that the packaging material will be chosen, taking into account not only its ability to provide the mechanical functions listed above, but its ability to withstand sterilisation without alteration as well.

Take breast prosthesis in a glycol modified polyethylene terephthalate (PETG) blister for example: the material should be compatible with the prosthesis, making it efficient and cheap. This can technically pass ethylene oxide (EtO) sterilisation, but given its implantable nature in the long term, this mode is not considered optimal. Plasma sterilisation is not considered adequate either, given the volumes to be treated, and sterilisation by radiation is suitable for the PETG blister but not for the prosthesis (due to deterioration). Therefore the only other option is steam sterilisation, which although supported by the prosthesis is not suitable for the blister. So in this case, the vote must go to a polycarbonate blister. Ultimately, the nature (and price) of the packaging used will have to change and adapt to the adopted sterilisation method.

The Purpose of Packaging

As mentioned, in addition to protecting its contents, packaging also serves multiple other functions.

Protection

Packaging must not only protect the device from traditional risks such as falls and various shocks, but it must also preserve the sterile condition of the device. This second requirement – specific to the world of ‘clean’ industries in general, and health in particular – imposes some constraints. These are particularly well defined in ISO 11607-1 and 11607-2. However, knowledge of the regulations will not be enough to make good packaging. Working in cleanrooms involves a combination of compatible primary and secondary packaging which meet a number of characteristics: transparency to view the product; ease of gripping a clipped product in a blister; mastery of the lids sealing process; qualifications of equipment and facilities; and product validation. There are many tests – such as the burst test, peel test, dye penetration test, or stressviewer – that allow the end user to ensure that their packaging repeatedly meets these requirements.

Maintaining Sterile Conditions

Once closed, the packaging – often blister-sealed with lids – should allow sterilising agents to penetrate to the heart of the contents, and then let any toxic residues escape after the sterilisation cycle, which ensures a total barrier against further contamination from the outside.

This technological feat is made possible thanks to the existence of materials with enhanced barriers, such as Tyvek. Implementation has to meet some strict rules and standards that packaging professionals in cleanrooms must know. Sealing the blister and its cover is the key phase of this long process to combine two different materials, and requires the use of machines particularly suited to work in cleanrooms. Once this last operation is finished, the product may be subjected to sterilisation.

Sterilisation Techniques

As already mentioned in the earlier example of a PETG blister, choosing the correct sterilisation method is crucial. Each available technique, and its compatibility with materials, is outlined in detail below.

1. Steam Sterilisation

This is a traditional method and wellknown for its simplicity, effectiveness, low cost and speed of implementation. It is usually considered to be the best solution from the point of view of the environment, health and safety. It is predominantly used in hospitals and laboratories, as it is suitable for the sterilisation of reusable medical devices and ancillaries. Standard sterilisation treatment with steam is 121°C for 15 minutes. Faster sterilisation, or socalled ‘flash’, can be operated at 134°C, or longer at 115°C.

Temperature resistance is the key factor that determines the compatibility of products that can be sterilised with this technique. Using temperature levels between 115°C and 134°C immediately excludes paper; polyolefins such as polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) and ethylvinyl acetate (EVA); polyacetal (POM); and polystyrene (PS). Some polyacetals, such as PVC and PP, can be used if they have been specifically modified by their suppliers (3). Compatible plastics include acrylonitrile-butadiene-styrene (ABS), polycarbonate, polyamides, silicones, polytetrafluoroethylene (PTFE) and rubber.

2. Plasma Sterilisation

Low-temperature plasma gas (hydrogen peroxide, H2O2) sterilisation is a commonly used method for small devices or in small quantities. Plasma is the fourth state of matter; its gases are highly ionised and composed of ions, electrons and neutral particles that produce a visible glow. The advantage of low-temperature plasma gas is that it has the ability to effectively remove traces of residual hydrogen peroxide (used here as a sterilising agent) on materials and devices.

A vacuum is created within the sterilisation chamber. H2O2 sterilant is then injected into the chamber to penetrate and interact with the devices to be sterilised. A strong electric field is applied to create the plasma phase. Here, gas plasma peroxide decomposes into a ‘cloud’ of particles which are ‘energised’ and produce visible light. This is the phase during which the microorganisms are killed. The main objective of the plasma is to remove any residual traces of H2O2 which, when the electric field is turned off, is recombined to form water (H2O) and oxygen (O2).

The main features of this sterilisation method are:

Speed

  • Cycle times of 28-120 minutes, depending on the system
  • Cycles can be adapted to the type of medical devices intended to be sterilised (with or without lumens)
  • Products are released immediately at the end of the cycle

Safety

  • Sterilisation guarantee: sterility assurance level (SAL) = 10-6 for terminal sterilisation
  • Non-toxic process: no direct contact with the sterilising agent and therefore no toxic residues

H2O2 gas plasma sterilisation, at low temperatures, is a method that offers a good level of compatibility with many materials (see Table 1). This is due to the ‘soft’ nature of these cycles (low temperature, below 50°C and no humidity).

3. Sterilisation using Ionising Radiation

Radio-sterilisation uses gamma radiation (photons emitted by a cobalt-60 source) and beta rays (generated by an electron accelerator) with an energy of less than or equal to 10 MeV. In these conditions, the radiation is unlikely to result in the formation of radioactivity within the material; it will only trigger the chemical process of formation of free radicals.

Although each installation could be subjected to a different type of treatment (per parcel or pallet, for example), they will all have similar processing chains based on the same pattern: a conveyor system through a protective concrete enclosure which is located in the radiation source (electron accelerator or cobalt-60 source). Differentiated storage areas are located at the entrance and exit of the conveyor system.

Gamma facilities consist of a radioactive source of cobalt-60 (or, less commonly, cesium-137), confined in a concrete bunker with two metre thick walls to protect the outside environment from the photons emitted by the source. An overhead conveyor carrying containers (also called the swing) ensures that the product being treated circulates around the source, as well as transferring it between the inside and outside of the bunker. Best performing facilities can handle a full pallet in one run without de-palletising.

Beta rays are generated by an electron accelerator, also located within a bunker for protection. The accelerated electrons form a beam that sweeps the products moving beneath a conveyor roller or plate. They have a scan width of up to one metre, which is equivalent to the width of a layer of packages from a pallet.

Both types of beta and gamma radiation employ the same mode of sterilisation with an equivalent radiation dose. Radio sterilisation occurs via free radical formation. It cuts, alters and distorts the DNA molecule, causing the destruction of organisms such as bacteria, yeasts, moulds, fungi and viruses. A similar result can also occur in any exposed material; free radicals may be formed, creating side-effects.

The effects of ionising radiation are a balance between ruptures and molecular rearrangements, such as cross-linking or cyclisation. There is no general rule of behaviour, but trends can be identified by considering the structure of the polymer and the irradiation conditions, the dose being the main influencing factor in this case.

In the polymers structure, the most sensitive chemical bonds will be affected first. This corresponds mainly to polymers containing halogen (for example, fluorine or chlorine), such as PVC or PTFE, and polymers that have quaternary carbon atoms (substituted with four different groups), such as butyl rubber or PP.

Secondly, most polymers will withstand sterilisation doses of about 25 kGy to 75 kGy, however they will deteriorate beyond this, as is the case with PP, PVC and cellulose. PTFE and butyl rubber will degrade at low doses, and POM from 25 kGy.

Apart from a few exceptions not used for packaging, most polymers are compatible with sterilisation by ionising radiation (see Table 2). The main risk of change is yellowing, which results from the formation of double bonds due to cut channels: sufficient to emit light, but not enough to affect the mechanical properties. The risk of yellowing means that the radiation dose must be high.

Generally, this is reversible; it largely reduces within a few weeks after treatment. In addition, suppliers of medical packaging materials have already worked around this problem and modified the basic material, and any additives, to minimise yellowing.

4. Sterilisation using EtO

This technique uses a sterilising gas, which is also characterised by high diffusivity and permeability associated with conditions favouring these two factors. The products are placed in contact with the EtO in an autoclave with a capacity of several tens of m3, under controlled conditions of temperature, humidity, pressure and duration of exposure.

EtO is often used to treat radiation- or steamsensitive products. This industrial technique is used, as with ionising radiation sterilisation, on a large scale in the field of pharmaceuticals and medical devices. Compared to steam and plasma sterilisation, ionising radiation and EtO are more suitable for industrial volumes, as well as implantable medical devices and pharmaceutical devices for single use.

Sterilisation is effected by alkylation of the ends of enzymes chains and channels chains of DNA and RNA. Functions -OH, -COOH, -SH and -NH react with the EtO radical -CH2-CH2-OH, altering microbial metabolism. The chemical structures of plastics (except cellulosic polymers) are not rich in functions that react by alkylation with EtO. These are the molecules and biological macromolecules that are most sensitive to EtO. Therefore, secondary reactions with plastics are quite limited.

Particular attention should be paid to PS and its derivative styreneacrylonitrile. In both cases, a loss of mechanical properties by 30 per cent can be observed. This does not restrict their use; the decision to use EtO for these materials will depend on the role assigned to parts made with them.

Instead of the composition, it is the physical conditions (temperature, pressure and humidity) of the process that can influence the choice of materials, including plastics. The preparation stages and contact with EtO are usually conducted at a temperature of between 40°C and 50°C, under relative humidity of 50 to 60 per cent for six to eight hours. Particular attention, through the use of a validation test, must be given to plastics whose maximum operating temperatures are around 70°C to 80°C, such as polyolefins or hydrophilic coatings, which may otherwise swell.

The ability of the material to adsorb EtO and allow its migration through the whole product is also a factor to be considered. To this, we must refer to Table 3 and confirm the treatment conditions by trials.

Conclusion

The specific characteristics of each of these sterilisation techniques mean that they are more compatible with some types of packaging than others. Many medical packaging suppliers have already adapted their packaging materials by integrating the characteristics and proposed concepts of their selected sterilisation process.

For steam sterilisation, for example, typically operated in hospitals, special flexible packaging is available for packing on site. For other techniques, there is no insurmountable incompatibility, or packaging suppliers will often offer a solution. Then, as required by standards, it is simply the sterilisation validation of the device in its packaging which will confirm the right choice.

References

1. Rouif S, Modifications physicochimiques des polymères par ionisation, Techniques de l’Ingenieur: Traité des Plastiques et Composites AM3039, 2008

2. Rogers W, Sterilisation of polymer healthcare products, Rapra Technology Limited, 2005

3. The Effect Of Sterilization Methods On Plastics And Elastomers, Plastics Design Library, PDL Handbook Series, 1994

4. Icre P, La stérilisation des produits médicaux par les rayonnements ionisants, Maison d’Edition et de Promotion GAL, 2010


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Delphine Blondard is the Group Quality and Environment Manager at Top Clean Packaging Group. She is a graduate of Biology Organism at Clermont-Ferrand, France and of Quality System and Environmental Management, Industrial Risk and Safety at Vichy, France. After beginning her career in the quality service of Clermont-Ferrand Hospital, Delphine integrated the Cartolux-Thiers team to build their quality system. She now leads the global quality department for all group sites and develops a complete range of services for clients.

Sophie Rouif has an Engineer Diploma from the Chemistry Engineering School of Montpellier, France, and a PhD in Polymers and Composites at the University of Lyon, France. After one year in a textile company as Research and Development Engineer, Sophie joined Ionisos in 2000 and is in charge of the development of activities in relation to materials, including resistance of materials during sterilisation by radiation and chemistry with radiation.

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