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Pharmaceutical Manufacturing and Packing Sourcer

Making a Material Difference

Packaging and storage containers are not as passive as we often think, and can have a significant impact on the quality of the product they contain. Currently, diagnostic and biochemical products are commonly stored in glass or plastic containers. Glass has long been used to store food, beverages and other liquids without altering their taste, flavour, aroma, smell, scent or colour. It has proven effective as a container largely because it is relatively inert and airtight due to its molecular structure, meaning that products that are sensitive to oxygen and other gases can be safely stored without fear of rapid degradation or contamination.

Despite these strengths, glass is gradually falling out of favour as the packaging and storage material of choice. This is mostly due to its fragility, weight and cost of production. Instead, plastics are gaining popularity as a viable and safe alternative, because they are resistant to breakage, lighter and more durable. Perhaps surprisingly, plastics may also be more environmentally friendly than glass, at least according to a study performed in 2009 that compared the whole lifecycle of polyethylene terephthalate (PET) with glass containers (1). The findings suggested that the lower temperatures required during raw material processing and the significantly lighter weight of plastics considerably reduce the CO2 generated during container production and transport.

The plastics used in packaging are diverse in nature and can be composed of a variety of different resin types. This is important to consider when selecting a packaging material, as each resin has inherent properties that can impact on the purity of the products being stored (2). Biological reagents such as solvents, acids, bases, buffers and proteins tend to be reactive, so choosing the right plastic type for a given product is essential. This is especially true when storing reagents that make up the basis of diagnostic tests for detecting human disease, where false positives and negatives must be kept to a minimum. Such reagents are commonly packaged in containers made of one of three polymers: PET, polyethylene terephthalate glycol modified (PETG) – both of which form an effective O2 and CO2 barrier – or the chemical-resistant high-density polyethylene (HDPE).

Extractables and Leachables


The production of plastics inadvertently introduces a wide range of compounds and elements that can influence biological products, and many more are incorporated deliberately to modify the properties of the material. For example, makers of HDPE products often include antioxidants and heat stabilisers in order to minimise plastic degradation due to heat, oxygen or radiation, while using PET and PETG often involves incorporating anti-hydrolysis agents to protect against premature wear. Further additives include flame retardants, plasticisers, clarifiers, ultraviolet stabilisers, fillers and colourants, as well as those used as processing aids such as mould release agents (3).

Plastic packaging is generally inexpensive, but low-quality containers may contaminate high-value contents, causing greater expense in the longer term. Therefore, part of the measure of quality for plastic packaging is to verify that detrimental substances do not leach into the contents of the container.

To better understand how these factors might affect a container’s contents, an ‘extractables’ analysis is performed to release, detect and quantify them under controlled and harsh conditions. These conditions include an increase in temperature or exposure to a strong solvent. As such, this represents the ‘worst-case scenario’, indicating the maximum amount of contaminating substances that might be released from the packaging into the stored product. The process contributes to a best guess estimate of the impact of ‘leachables’ – the chemicals that could be released from the plastic container over the course of its shelf life under normal process conditions – representing the risk of contamination during normal use. When considering containers of biological reagents, these leachables could affect certain assays and enzymatic reactions by causing proteins to precipitate, inactivating other reagents, influencing pH, or otherwise contaminating critical components of the assay (4).

Metal Contamination


Biological and chemical reagents can be particularly sensitive to metal contamination, especially when enzymes are involved. An example is the enzyme alkaline phosphatase, which is used in many assays such as ligation, radiolabelling of DNA, and as a way of generating a colourimetric readout for a wide range of immunoassays.

Several metals can affect the performance of alkaline phosphatase. Zinc (specifically, Zn2+) is essential for its activity at micromolar concentrations and inhibitory at higher concentrations, while magnesium (Mg2+) enhances the enzyme’s catalytic activity. Many other bivalent cations – such as cadmium (Cd2+), nickel (Ni2+) or manganese (Mn2+) – and trivalent cations – aluminium (Al3+) or iron (Fe3+), for example – inhibit the action of the enzyme very effectively, even at low millimolar concentrations. Thus, there is a fear that trace metal contamination originating from reagents, glassware and plastics could introduce significant variation into experiments, and might even be responsible for the disparities in results generated by different laboratories (5).

Despite the low concentrations of metal contaminants in most plastics, many solvents are capable of extracting them from the plastic resin, resulting in the build-up of a significant concentration within the solution. These metals can originate from a variety of sources, such as residual catalysts from the manufacturing process like the antimony trioxide (Sb2O3) used in the production of PET. Other sources of metal contaminants can come from the agents used to lubricate the manufacturing process (zinc, cadmium or magnesium stearate) or facilitators of the moulding process (aluminium, nickel, iron, cobalt or chromium).

Detecting Metal Extractables


Given the potential effect of metal contamination on biological assays and diagnostic tests, we sought to understand the levels of metal ions found in a wide range of plastic bottles typically used in laboratories around the world. One way of examining the nature and amount of these metal extractables is to digest samples from these plastic containers, and apply high-resolution inductively coupled plasma mass spectrometry to evaluate the metal contents.

We used this method to compare several available HDPE bottle containers. Testing was conducted at a third-party laboratory using three samples, each from six different manufacturers. The results indicated that only one brand contained close to negligible amounts of contaminating metal. Including silicon and phosphorus, the amount of contaminants within the bottles of the other brands were at least a magnitude higher than found in the Nalgene product.

In total, our tests included the quantification of 17 substances that could potentially be present in plastics, of which 11 were below the detection limit in the purest product. Some of the other brands tested had concerning amounts of contaminants, at levels likely to affect biological assays and diagnostic tests. These included calcium – an important regulator of many enzymes – and magnesium, which plays a key role in manipulating biological polyphosphate compounds like adenosine triphosphate, DNA and ribonucleic acid.

Even though the metal amounts found in the bottles during this study represent the worst-case scenario, their presence in these plastics is important – even trace amounts of such contaminants can become problematic, contributing to protein destabilisation and enzyme inactivation. At best, they could increase variation and make it difficult to replicate results. At worst, sensitive diagnostic reagents for detecting diseases could be severely impacted. These could include reagents used for measuring the blood levels of calcium and magnesium, where any external sources of these metal ions could heavily bias results.

Conclusions


Containers for reagents and diagnostic samples play an important role in protecting their contents and preventing contamination. Considering usability and cost, plastic containers have a slight advantage over glass. However, different resins provide different advantages and disadvantages, while specific additives introduced during the production process must be considered carefully as they may have an impact on downstream applications.

In particular, metal contamination is a serious concern when storing reagents that will be used in biological assays, with proteins such as enzymes likely to be particularly at risk. Unfortunately, many of the plastic bottles used in laboratories contain significant amounts of trace metals. These have the potential to leach from the containers during storage, increase variability between experiments, and impact on the accuracy of diagnostic tests.


References

1. Life cycle inventory of three singleserving soft drink containers, Franklin Associates, 2009. Visit: www. container-recycling.org/assets/pdfs/ LCA-SodaContainers2009.pdf
2. Croston L, Considerations for glass to plastic labware conversion, American Laboratory, 2012. Visit: www.americanlaboratory. com/914-Application-Notes/111807- Considerations-for-Glass-to-Plastic- Labware-Conversion/
3. Dimitrakakis E, Janz A, Bilitewski B and Gidarakos E, Determination of heavy metals and halogens in plastics from electric and electronic waste, Waste Manage 29: pp2,700-2,706, 2009
4. Shanker AK, Mode of action and toxicity of trace elements, Trace Elements: Nutritional Benefits, Environmental Contamination, and Health Implications, Prasad MNV (ed), John Wiley & Sons, Inc, 2008
5. Rej R and Bretaudiere JP, Effects of metal ions on the measurement of alkaline phosphatase activity, Clinical Chemistry 26(3): pp423-428, 1980

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Rodolfo Merola is Product Manager, Packaging for Thermo Fisher Scientific, where he is responsible for the Nalgene-branded packaging containers. He has over 15 years of experience in marketing and sales – from raw materials to packaging converted products – having worked in various roles within global marketing and business development, as well as product management. Rodolfo holds a Master’s degree in Business Administration from Alma Graduate University, Bologna, Italy, and a BSc in Pharmaceutical Chemistry from the University of Milano, Italy.

Robert Scott is Applications Scientist, Laboratory Consumables for Thermo Fisher Scientific. With 10 years of experience in various laboratories, including working in a Good Manufacturing Practice environment in the pharma industry, he brings a wide range of skills and knowledge on how laboratory products are typically used. Robert holds an MS in Cell and Developmental Biology and Anatomy from SUNY Upstate Medical University, Syracuse, US, and a BS from Le Moyne College, also in Syracuse.


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Rodolfo Merola
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Robert Scott
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