Extractables and Leachables: An Overview of Emerging Challenges - Pharmaceutical Technology

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Extractables and Leachables: An Overview of Emerging Challenges
Extractables and leachables are a growing concern for pharmaceutical manufacturers and regulatory bodies.


Pharmaceutical Technology
Volume 32, Issue 8

Materials used for container-closure systems

The materials most commonly used as primary-container components for pharmaceutical preparations include glass, metal, plastic and rubber. Out of these four materials, glass has been the primary container of choice for pharmaceutical dosage forms owing to its relative inertness and availability of glass in various compositions for different purposes. The excellent barrier characteristics of glass render it as an ideal packaging material for parenteral/liquid products. Glass

has normally been considered far less reactive than plastic with regard to parenteral/liquid products. It also has much lower levels of leachables and extractables. Glass exhibits numerous advantages over other packaging materials, and the problem of release of alkali and flakes is mainly confined to lime-soda glass.

The stability of numerous drugs can be adversely affected by the release of soluble alkali from the glass containers. As a matter of safety, liquid preparations maybe buffered to eliminate or minimize any adverse effect due to possible change in pH following release of alkali from the glass container. Release of alkali from borosilicate glass is negligible but it is relatively expensive. Sometimes, insoluble flakes have been found to appear in solutions stored in glass containers. Flake formation may occur in non-borosilicate glass immediately after autoclaving, whereas in borosilicate glass, it occurs at temperatures much higher than those used for autoclaving. Pure glass that is made from silicon dioxide alone is known for its inertness, but its high melting point and excessive cost prohibit its use in packaging. Several manufacturers produce glass containers in various formulations that comply with USP Type I requirements. Compendial standardization of Type I glass facilitates ease in any necessary vendor changes even after market approval. [1, 2, 22].

Plastics are the fastest growing segment in packaging and have already captured market shares from all other packaging materials, converting glass bottles to plastic bottles, paper bags to plastic bags, fiberboard boxes to plastic wraps, and steel drums to plastic drums. Plastics are synthetic high-molecular-weight polymers of diverse nature, and a wide range of plastics is currently in use. High strength and thin walls amalgamated with low density and transparency render plastics increasingly popular owing to their capacity to withstand mechanical shocks. This leads to steep decrease in breakage losses during routine handling and transportation when compared to glass. Plastic containers, closures, and films generally use less material, are less costly to fabricate and weigh less, thus reducing cost of transportation and handling.

Some of the plastics that are currently in use include: polythene, polypropylene, polystyrene, polyvinylchloride, polyamide, polycarbonate, polytetrafluoroethylene (PTFE), phenol-formaldehyde, urea-formaldehyde, melamine-formaldehyde and several others. Moreover, availability of numerous plastics of diverse nature provides ease in formulating packages of desired flexibility, rigidity, and other characteristics. As a consequence, plastics packages range from flexible packages such as collapsible tubes, strip packs, blister packs, pouches, and stand-up pouches for injectables, to rigid containers meant for solid, semisolid, and liquid products.

A wide range of additives such as plasticizers, lubricants, anti-static agents, antimicrobial agents, antiblocking agents, colorants, antioxidants, coupling agents, flame retardants, impact modifiers, fragrance enhancer agents, nucleating component materials that have potential extractables include glass, plastic, rubber, labeling and bulk packaging and process equipment. Each material or area has factors that can affect the extent of the extractables (5, 6,8, 10, 11, 17, 18).

Certain approaches can help minimize concerns emanating from extractables. The data generated by extractables screening during initial package selection and compatibility studies can be used to help select an appropriate container closure for a drug product. However, low extractables do not ensure compatibility, and compatibility does not ensure low extractables. Both should be assessed as part of a drug product market introduction (6).

Leachables are chemical species that migrate from packaging or other components under normal conditions or use or during the shelf life of a drug product. Extractables are the most common source of leachable contamination arising from a product formulation's contact with its package materials (5,6,10,11,17).


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