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Pharmaceutical Manufacturing and Packing Sourcer

Pack up your Troubles

Julian Rae at Reading Scientific Services Ltd explains how extractables and leachables pose a threat to the strict anti-contamination requirements of packaged pharmaceutical products

The successful production and distribution of modern pharmaceuticals owes much to the development of safe and secure packaging systems. Good packaging serves many functions, primarily that of preserving and protecting the pharmaceutical contained inside, but also of controlling or delivering dosage, facilitating distribution, informing patients and pharmacists, and providing the means of distinguishing between one drug and another.

In its primary role, packaging represents a continuation of the clean, sterile, pristine environment in which the drugs were produced, at least up until the point the product is opened. The pack and process together represent a system of ultimate control, which patients, pharmacists and doctors rely on to deliver a pharmaceutical product free from contamination and external influence. So it has to be acknowledged that the very systems that are designed to preserve and protect pharmaceutical products can also, very occasionally, be the cause of problems that affect quality, compromise stability and even put patient safety at risk.

The underlying assumption that most people would make about packaging and process equipment is that they don’t interact or interfere with the products that the equipment contains or those products with which they come into contact. However, as experience proves, and as the regulators all recognise, packaging and components of production machinery are not so inert. Chemicals can leach out of glass or plastic containers and find their way into products, just as they can leach out of plastic stoppers and rubber seals, or from plastic pipes, fittings and components on a process line. It is worth pausing at this point to make an arbitrary distinction between extractables and leachables. Extractables are thought of as chemicals that can be ‘forced’ out of the packaging under stress, whereas leachables might pass into the drug product during normal conditions of storage and use. Both possibilities need to be tested for, and hopefully, discounted.

Where problems do occur, sometimes the root issue is an incompatibility between the product and the packaging or process component. Or it might turn out that there is an inherent fault with the chemical composition of the plastic, or a failure of a laminate that would otherwise cover a particular surface. Then again, there might be a basic error in specification, or an oversight by a contractor, which means the wrong type of fitting, tubing or sealant is used. Of course, if the pharmaceutical product is found to have been compromised by contamination of this kind, getting to the root cause may require significant analytical investigation. We will return to investigative topics below.

However, since prevention is always better than cure, we turn first to the testing methods that are intended to ensure that problems don’t arise in the first place. Such testing is advisable at the earliest stages of drug development. No company that has spent millions developing a new drug would wish to have the launch of a new product delayed because it can’t provide regulators with evidence that a relatively inexpensive closure system is appropriate and safe.


The relevant pharmacopoeia set out a whole battery of tests that are designed to assess the suitability of packaging materials and closures, both from the perspective of keeping the product in, and keeping contaminants out. As noted above, the contaminants could include chemicals that are inherent in the composition of the packaging material (for example plastic monomers), or that are used in their production (for example metal catalysts), or that are entirely external to the packaging (for example moisture from the air). In some cases it is also appropriate to test the transmissibility of light, since light could also be considered as a contaminant, and is certainly capable of affecting the stability of some pharmaceuticals.

Of course, the testing required differs depending on the material in question and the manner in which it was made. Polypropylene, for example, is not a uniformly consistent material. It may contain up to 25 per cent ethylene, or 25 per cent polyethylene, and a variety of additives used as antioxidants, lubricants or antiblocking agents, as well as titanium dioxide used as an opacifying agent if needed. The precise combinations of these ingredients will depend on the process used by the manufacturer. It is necessary to know which additives have been used in the manufacture of the plastic in order to decide which tests to apply. It is also important to be aware of the material’s potential uses. Containers to be used for liquids are subject to different tests from those to be used for solids. Similarly, plastic components used for products of high risk, such as those intended for inhalation, parenteral preparation and opthalmics, must pass a stricter testing regime than a blister pack.

In addition, it is important to know what active pharmaceutical ingredient (API) is contained within the packaging so that any contaminants can be assessed as having been derived from the packaging rather than degradation of the API (accepting that there might be interaction between the API and a packaging leachable).

The issue of interaction between API and leachable may be especially important when dealing with biopharmaceuticals. One can easily imagine a trace element leaching from a plastic into a traditional pharmaceutical product at harmless (non-toxic) levels, whereas the same degree of leaching would be sufficient to entirely denature a protein in a biopharmaceutical formulation. Similarly, many biopharmaceuticals are sensitive to silicone oil, which is commonly used to lubricate elastomeric stoppers prior to fitting.

The clear message is that thorough testing is vital as early as possible in the drug development process to ensure that the specific combination of packaging and product work well together. As the development progresses, any change in one must be considered for its impact on the other. If the packaging specification alters, this might compromise the product. If the drug formulation is amended, it might elicit problems with the packaging.


The compendial methods do not provide all the answers when assessing the suitability of a particular packaging system for use with a particular drug. A competent laboratory (and a concerned client) will want to develop and validate bespoke methods that will provide product or packaging specific results that can be used in support of submissions for approval of a new drug system or medical device.

It is worth noting at this point that it is not safe to assume that a material used with a given pharmaceutical in one packaging form will necessarily be approved for use with the same drug in a different packaging form. Take the example of an injectable drug supplied in a glass vial with a bromobutyl stopper. Should the manufacturer wish to repackage the same drug in a pre-filled syringe system featuring a syringe plunger made from the same bromobutyl material, one cannot assume that the test results from the stopper case can be transferred to the plunger case. This would be true even if the dosage quantities and surface area exposure (for stopper and plunger) remained the same.


Clearly, from the client’s perspective, an absence of extractables and leachables is the ideal outcome of any testing. From the chemist’s perspective, the ideal outcome is an accurate result, and it is probably fair to say that a failure, or out-of-specification result, represents the most challenging and interesting case. Investigating any out-of-specification result always begins with a repeat of the initial experiment to ensure that the results are valid, and not some artefact of a mistake in the testing procedure or a malfunction of detection equipment. Should the test itself prove to have been faulty, ideally the laboratory will be able to locate where the problem arose so that it can address any issue in its own quality management system. However, should the results continue to show that there is a genuine problem, the race is on to discover the identity of the contaminant and its source.

Modern chemists have a wide range of sophisticated analytical instruments at their disposal for detecting trace levels of contamination. Technologies such as liquid chromatography mass spectrometry (LC-MS) and gas chromatography mass spectrometry (GC-MS) are hugely powerful in isolating and identifying trace amounts of non-volatile and volatile contaminants respectively. Fourier Transform Infra-red Spectrophotometry may also be used, and inductively coupled plasma mass spectrometry and atomic absorption spectrometry will be used for identifying metal elements.

On the other hand, modern supply chains are also extremely complex, and will involve excipients and APIs coming into contact with myriad containers and surfaces during storage and distribution, as well as during processing and packing. In investigating the possibility that chemicals have leached out of packaging, one cannot discount the possibility that they could have leached out of other materials too at any point along the supply chain.

For the laboratory charged with the investigation of ‘what went wrong?’, it is important to have a thorough understanding of the production process and its potential vulnerabilities as well as the specifics of the packaging. Many hours of fruitless sampling and testing can be avoided if the client can provide these details, though it still needs the laboratory to understand what it is being told! On the flipside, it greatly helps the client if the laboratory can present and interpret its results in a meaningful way, rather than merely presenting a stack of numbers. Communication is key to reaching a rapid conclusion about where a fault lies, and in implementing a quick resolution.


The success and safety of modern packaging systems is attested to by the sheer size of the pharmaceutical industry. Without the proven quality of packaging, the industry would simply not exist. That said, it is important to accept that problems with extractables and leachables can arise, and where they do, they can compromise the stability or quality of pharmaceuticals.

Hence, it makes commercial and ethical sense to thoroughly test the packaging and product together as early as possible in the drug development process to be sure that they are suited, and to repeat these tests before sanctioning any change in product formulation or packaging specification. Should a problem arise, rapid, investigative analysis is essential, and it helps to use a laboratory with a good understanding of pharmaceutical and packaging production processes, as well as the skills and expertise of experienced chemists.

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Julian Rae is Technical Specialist (Pharmaceutical) at Reading Scientific Services Ltd, and has worked in the pharmaceutical contract research industry for 27 years. His roles have included microbiology, mutagenicity, analytical chemistry, pharmacopoeial testing, HPLC method development and validation, radiochem analysis for metabolism studies and investigative analysis involving LC-MS analysis.
Julian Rae
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