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Pharmaceutical Manufacturing and Packing Sourcer

The Extractable Question

The parallels and differences in regulations for extractables and leachables testing between the food, medical device and pharmaceutical industries can pave the way for drug packagers to achieve a superior safety profile. Ask anyone about extractables and leachables (E&Ls) and you are sure to get different responses: excitement about the analytical challenge from the chemist; uncertainty about the best means to fulfil regulatory requirements from the quality manager; and concerns about toxicology from everyone else. For those new to E&Ls, I should start by explaining the terminology in the pharmaceutical industry. Extractables are described as those species that can migrate from the contact surface – in terms of pharmaceutical packaging, as well as manufacturing equipment such as tubing, filters and gaskets – and may migrate into the pharmaceutical product. Leachables are those species that actually migrate into the drug substance and are present in the final dosage form. There are numerous articles, best practice guides, regulatory guidelines and standards within the pharmaceutical industry. However, to get a good understanding of E&Ls, it can be useful to look at how other industry groups are addressing the same subject. This article explains how other industries (specifically the medical device and food sector) answer the question ‘are my E&Ls safe?’, and the rationales, tools and testing strategies used to find the answer.

E&Ls are a growing concern in all industrial sectors. In the food industry, E&Ls, albeit by other names, have long been studied. In fact, the prescriptive regulations in this industry have been heavily relied upon in other industrial sectors, including pharmaceuticals. Like the pharmaceutical industry, the food industry has also seen increased focus on E&Ls due to the growth of single-use packaging systems and recycled materials (both paper and plastic) that could be the source of unknown contaminants. The regulators of the food industry have moved to address these issues by assessing the risk of contamination and determining the best means to remove, manage and control those risks. In the pharmaceutical sector there has been increasing regulatory focus on E&Ls generally driven by the adoption of plastic packaging materials (over glass), packaging incorporating the drug delivery systems (for example, prefilled syringes and inhalers) that use multiple valves and contact parts, and products containing more ‘aggressive’ solvents; all of which increase the likelihood of a product/packaging interaction. The medical device industry considers E&Ls in a somewhat different light; here, the increased focus is driven by new combinations of medical devices with pharmaceutical products that bring with them a joint responsibility of the manufacturer to comply with both the medical device and medicinal product regulations.

Pharmaceutical Regulations

The medicinal product regulation in the EU details the requirements of pharmaceutical manufacturers; in the US it is Title 21 of the Code of Federal Regulations (CFR) (1,2). Neither of these regulations uses the terminology of E&Ls or how such assessments should be performed. Generally, both regulators specify that the drug contact materials should be appropriate for the intended use, not adversely affect the drug product and also state that the toxicological effects must be assessed. Thankfully, both the EU and US regulators have issued guidance documents on this topic (3,4). Both the EU and US regulators (and therefore the associated best practice and guidance documents) take a risk-based approach. Two factors are considered. The fi rst is the likelihood of an interaction between the contact material and the drug formulation. For example, those drugs in an organic solvent or oil base would be expected to be at a greater risk from E&Ls than those that are in an aqueous, powder or tablet form because of the increased extraction potential. The second factor is the degree of concern associated with the route of administration. Oral and topical drugs are considered to be of the lowest risk, whereas ophthalmic, parenteral and inhalation drugs are considered to have greater risk because these latter drug formulations (and therefore the E&Ls in the formulation) may be delivered to the already damaged organs.

Interestingly, guidance in the EU specifically states that food compliance can be used for oral drug formulations. With regards to testing, all regulatory and industry groups follow a typical pattern as shown in Figure 2, although the acceptance criteria and scope of such a study should be considered prior to the study, and then justified based on the specific use of the drug product and the packaging or contact material. A number of industry groups have reacted to their obligations by issuing guidance on how their E&L assessments may be performed. Most notable is the best practice guidance issued by the Product Quality Research Institute (PQRI) for orally inhaled and nasal drug products, released in 2006, that details testing practices and a rationale for establishing a reporting threshold (5).

Food Contact Regulations Compared to Pharmaceutical Regulations

Food contact regulations, when compared with pharmaceutical regulations, are extremely detailed and well established for E&Ls, although in this industry the terms migrant and migration are typically used. Detailed food contact regulations originate from the late 1950s and early 1960s in both the EU and US, whereas in the pharmaceutical industry, extractables were not widely discussed until the mid-1990s. Although a detailed discussion of the evolution of these regulations is outside the scope of this article, both EU and US food regulations have evolved to become very prescriptive. Unlike pharmaceutical products, which are consumed by a relatively small percentage of the population (and are therefore a relatively low consumer of packaging material), almost everyone is exposed to migrants from food packaging, and this fact, in some part, may explain why food contact regulations evolved more quickly.

It is interesting to apply the risk assessment approach used by the pharmaceutical guidelines to a food contact scenario, even though with pharmaceutical and medical devices the patients may be more at risk from the effects of extractable substances due to illness or trauma than the general population. In a food contact scenario, the degree of concern relating to the route of administration may be low. However, unlike pharmaceuticals, where typically only a small volume of drug product is consumed (for example, milligrams to grams per day for tablets, or grams per day or grams per year for parenterals), food and drink is consumed in considerably higher quantities (kilograms/day) and therefore is of high risk. The most significant difference is that in the food industry, examination of migrating species in the actual food stuff, akin to a ‘leachables’ study, are rarely performed, even though some food stuffs, such as those containing oils and fats, would be expected to have a high likelihood of interacting with packaging material. Instead, testing is typically performed in suitable ‘food simulants’. In the EU, a number of simulants are specifically used, such as three per cent acetic acid, X per cent ethanol solution (where X is the amount of ethanol in the fluid of interest), sorbent or vegetable oil.

The EU and US do, however, differ in their approach to regulating migrating species in the food contact industry. In the US the regulators have chosen to specify the materials that can be used in the product, setting detailed parameters of the contact materials based on both their formulation and physiochemical properties (6). The test programmes performed for US food contact regulations may therefore not correlate directly to the type of foodstuffs involved and the material it is intended to come into contact with. Indeed, there is often a misuse of the US food contact regulations because of this. In the pharmaceutical industry ‘FDA compliant’ materials are often referred to; however, this can be misleading to those new to the field because a material cannot, based on its formulation alone, be ‘compliant’ with any specific pharmaceutical regulation. Such a statement is often merely a claim that it meets the requirements of the food contact regulations.

In the EU, a slightly different approach is taken to the regulation of food contact materials. There are general requirements specifically for food contact materials, which state that materials should not transfer their constituents to food in quantities which could endanger human health or bring about an unacceptable change in the organoleptic characteristics (6). For plastics, there are additional requirements that include lists of authorised monomers and additives, an overall migration limit of 60mg/dm2 (determined by a non-volatile residue analysis following extraction of the contact material into an appropriate solvent), and specific migration limits (for certain individual chemical species present in the contact materials) (7). As such, the testing needed for compliance with the EU plastics regulations is very much focused on the formulation and expected use. The general requirements do, however, infer that all materials (such as degradation products, contaminants and oligomers) should also be assessed; a similar approach to the E&L studies performed for pharmaceutical products. Such substances have been labelled as non-intentionally added substances (NIAS) and are of much discussion in this industry at the moment.

In the EU and in part, the US, mathematical modelling can be used to predict the likely migration of particular substances. Such modelling is based on Fick’s Law (see Figure 4), a model that uses the diffusion coefficient ‘D’ to describe a particular migrating substance passing through a particular polymer at a specified temperature. Although such modelling would be unlikely to be suitable for regulatory submission in the pharmaceutical industry, such a tool may allow the analytical chemist to pick the most appropriate analytical range to be used for an extractable analysis.

Medical Device versus Pharmaceutical Regulations

Medical device regulations do not consider E&Ls in the same way as either the food or pharmaceutical regulations. This may well be because of the vast number of different types of medical device. Some devices have obvious needs for an E&L-type assessment, and there are some that clearly do not. Medical devices (and the regulations that govern them) cover a vast number of products such as breathing tubes, electronic support equipment, surgical gloves, catheters, implants and eye glass lenses. All these components would be expected to have extractables, but because of the use of the device an assessment is not always needed. All risk assessments for medical devices are therefore based on the use and ‘class’ that the product falls within. In Europe there are four medical device classes: I, IIa, IIb, and III as outlined in the amended 93/42/ EEC directive. Class I devices, such as non-invasive devices, are those generally regarded as low risk (to the patient and the user of the equipment, including nurses, doctors and so on) and Class III are those considered to be high risk, such as devices that are in contact with the circulatory or central nervous system. Devices are therefore assessed on a case-by-case basis and it would be expected that any device, or component thereof, that comes into contact with the patient, or fluids infused to the patient would require an assessment of E&L. E&L species that migrate from medical devices are generally considered as contaminants or residues from a particular device and are therefore a function, albeit unwanted, of the device. A traditional pharmaceutical extractable and leachable study is generally not considered appropriate for medical devices. Instead, bioreactivity tests following the series of standards under ISO 10993 are generally performed and accepted for submissions in the US and EU. ISO 10993 testing is not sufficient in its own right, and obviously a compliant design history file and product information is required to ensure that the materials of construction do not contain substances that require special attention, such as those which are carcinogenic, mutagenic or toxic to reproduction. A single product that combines a medical device with a pharmaceutical agent will need to comply with applicable sections of both the Medical Device Directive and the Medicinal Products Directive. An example would be a single-use medical device incorporating a substance intended to give a pharmacological action, such as a prefilled syringe.


There are many parallels between food contact regulations and pharmaceutical regulations, including similar extraction conditions and risk assessment process. However, the food industry differs in that the regulators have, to some degree, taken on the burden of the risk assessment and laid down prescriptive regulations. NIAS are increasingly becoming of interest to the food contact regulators and such substances would require studies similar to that of a pharmaceutical extractables study. This may therefore lead to some interesting developments in this area.

The food regulators in Europe have already published and commissioned a number of studies on substances that migrate from packaging materials. The results of these studies will be of interest to all parties involved in extractables and leachables. A list of reports commissioned by the UK Food Standards Agency can be found on their website (8). In the medical device industry, although the testing philosophy is somewhat different, the same principles of a risk assessment are required taking into account factors such as likelihood of patent exposure and the form of the product.

For all industrial sectors the importance of understanding the supply chain is critical, especially so for products manufactured from polymeric materials that may have a number of tiers in their supply chain. Regardless of the industry, a risk assessment of migrating or extractable substances that the patient or consumer will be exposed to is essential. The nature of the assessment is based on regulatory guidance, exposure route, frequency of exposure, and likelihood of an interaction. It should be noted that many material suppliers will be supplying into different regulatory environments, and therefore some complementary data may be available to support or assess regulatory compliance in the pharmaceutical sector. In all cases it is the responsibility of whoever markets the product to ensure that it is safe for the intended use and meets all regulatory obligations.

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Michael Creese is a Principal Consultant at Smithers Rapra, where he has been supporting a variety of customers for extractables and leachables testing for pharmaceutical process equipment and packaging. Michael provides advice to all regulated industries for extractables and leachables testing and general polymer support, and helps the company remain at the forefront of rubber, plastics and polymer testing and consultancy.
Michael Creese
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