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Pharmaceutical Manufacturing and Packing Sourcer

Material Concerns

When selecting materials for drug product container closure systems, there are a whole range of possible options to choose from. These can include glass, metal, plastic and rubber, and understanding the potential of each is crucial. There are a number of key factors associated with material selection; these include the physical performance, the nature of supply and the chemical compatibility of the material must all be considered, and this article will examine the intricacies of each area in turn.

PHYSICAL PERFORMANCE


It is very important to consider the physical performance of the material before anything else – if the device does not perform physically, then there is no product.

Taking plastics as an example, there are a wide range of plastics to choose from: over 90 generic plastic types with over 100 sub-generic modified types. These can come from a huge range of suppliers. The advantages of plastics lie in the fact that they can have a combination of properties that are not available in other materials. This diverse range of properties includes the following:

• Transparency – comparable with glass
• Good chemical resistance
• Good barrier properties – gas/liquid permeation resistance
• Can be sterilised
• Good colourability – many colours, no painting required

Not only does the physical performance make plastics useful, but also their low unit costs, and a number can be reprocessed, to list just a few benefits. Another factor that needs to be considered is the ability of the material to be manufactured/moulded with the correct tolerances. Take, for example, metered dose inhalers; these have multiple parts that have to be manufactured to very tight tolerances in order to enable the patient to receive the correct dose of their medication. The nature of the material is also significant – certain materials have a propensity to shed particulates, and in the last 12 months, there have been numerous product recalls due to potential particulate matter hazards.

As with plastics, there are a huge range of different types and suppliers for rubbers, each offering a diverse range of properties. In general, rubbers are more complex and typically have more processing steps and additives than plastics. The base elastomer may have fillers, pigments or a curing system added, among others. It will then go through processing to form, for instance, a sheet from which gaskets can be cut out.

Glass could potentially be viewed as an ideal material in certain circumstances: it is transparent, has excellent barrier properties and is easily sterilised. However, there have been a number of medical products recalled due to glass delamination, which is when small (visible/sub-visible) particles of glass end up in the product. This typically happens with product formulations that have a basic pH (>7.0); contain citrate buffers; have a high ionic strength (>100mm NaCl); or are stored in a certain vial type (tubing) or vial size (>5mL).

Metals are generally the lowest risk materials in terms of both physical properties and chemical compatibility. But low risk does not mean no risk; care should be taken if metals are treated in some way before use. Even washing and the presence of surfactants need to be observed carefully.

CHEMICAL COMPATIBILITY


There are two main areas when considering chemical compatibility of materials for medical products. Firstly, does the active pharmaceutical ingredient (API) interact directly with the material, for instance through sorption: either adsorption or absorption? This can affect the efficacy of the product by reducing the level of API available for the patient. While receiving the incorrect dose can be a minor problem, in certain circumstances it can be potentially life- threatening. This is highlighted by a recent product recall of an epinephrine auto-injector that failed to deliver the correct dose. Products like these are used to treat life-threatening anaphylaxis; in this case, no chemical interaction took place but a physical malfunction of the device.

Secondly, can a chemical species migrate from the material used in the container closure system and leach into the product, potentially affecting patient safety? This area of study is commonly referred to as extractables and leachables and they are a key area for regulators, as they can affect the safety and efficacy of medical products. It is important to understand the difference between these two elements.

Extractables are chemical species that can be released from a pharmaceutical packaging/delivery system, packaging component, or packaging material of construction under laboratory conditions, including extraction solvent, technique, stoichiometry, temperature and duration. Extractables themselves, and/or substances derived from extractables, have the potential to leach into a drug product formulation under normal conditions of storage and use.

Leachables, on the other hand, can migrate from a packaging/delivery system, packaging component or packaging material of construction into an associated drug product formulation under normal conditions of use, or during accelerated stability studies. Leachables are typically a subset of extractables or are derived from extractables. In summary, extractables depict the possible impact of a product on its user, whereas leachables represent the actual impact.

Regulators are only concerned with leachables, as these are the chemical species that the patient would be exposed to. However, leachables take time to form, so it can be very important to test for extractables, as these reduce the risk of a material not being suitable for its intended use. If – when testing for extractables – a species of toxicological concern is found, it may be prudent to select a different material early in a medical product’s development.

Extractable testing is very much about understanding possible risk to the patient and potentially changing materials before time delays occur prior to a product launch. It should also be mentioned that extractables may not appear as leachables and therefore would have no impact on patient safety. For leachables, there are two main areas of concern regarding patient safety. These are either direct toxicity to the patient from the leachable, or the leachable affecting the efficacy of the drug product. Additionally, the administration route can play a big part in regulators’ apprehension over leachables (see Table 1, page 20).

In terms of limits for leachables, these are typically lower than other impurities, for example from the API, and are dependent on the dose given and the number of doses available in any device. The reason for the allowed level of leachables being lower is that the material of construction for the container closure system offers no direct benefit to the patient, and a different material that produces a lower level of leachables could be chosen.

NATURE OF SUPPLY

Having selected a material based on the aspect of its physical performance, the next step is its supply. Factors that need to be considered include, but are not limited to:

• Location of supply
• Length of supply
• Supplier’s quality system
• Information from supplier

While it does not matter what information is provided or what testing a supplier has done, the selection of materials can be de-risked if sufficient information is available. When choosing materials for a container closure system, for instance, if one supplier provides a wealth of information about a material and a different supplier does not, then it is likely that the first material will be chosen as more of the risks can be understood.

There is only one thing that is certain with materials, which is that change will happen at some point during the product’s life. How this change is managed can be very important.

When any change happens, the faster this is communicated through the supply chain the better – and this change control should be part of a supplier quality agreement. When major changes happen, such as the discontinuance of supply, again, the sooner this can be communicated and actions put in place the better; in this case, it can be very useful to have a minimum length of guaranteed supply. Ideally, this should be a minimum of 36- months’ rolling availability, which can be made up in multiple ways and consist of a mixture of notice period with last call option, raw material shelf life and finished component shelf life.

FORMING FACTORS

The primary consideration when selecting materials for medical products has to be the physical performance of the material. If the material does not perform physically there will be no product. Other aspects like supply of materials, chemical compatibility, communication and change management are of equal importance and need to be contemplated too.

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Dr Andrew Feilden is the Chemistry Operations Director at Smithers Rapra and Smithers Pira and leads the chemistry groups at the Shawbury and Leatherhead facilities in the UK. He has been working in the field of extractables and leachables for over 15 years and has presented at numerous conferences. Andrew is a Scientific Advisor to the International Pharmaceutical Aerosol Consortium on Regulation and Science container closure group, and has been the co-chair of the Extractables and Leachables Safety Information Exchange material group.
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