Extractables and leachables testing (E&L)

Extractables are by definition compounds that can be extracted from a material when in the presence of solvents with variable polarity in extreme conditions. Generally speaking, manufacturers are aware of which types of compounds can be extracted and in ideal cases, provides clients with a list of extractible substances found in a given product. Similarly, leachable substances are compounds capable of migrating from one material to another given the right conditions. Information about extractible substances can be turn out to be useful during tests on specific leachables. However, the correlation between extractables and leachables must be made carefully because leachables are not always found during analyses of extractables. Given that a formulation of a drug can chemically alter known extractables, it is possible to detect leachables that had not shown up during the analysis of extractables. Moreover, matrix effects of the sample, differences in the analytical system, changes in the test method, etc. limit the possibility of drawing direct correlations.

Evaluating a material, its ageing over time, compatibility between different materials (containing polymers, metals or glass) coming into contact with contents (cosmetic or pharmaceutical products, food, medical devices…) constitutes a primary concern for industrialists from the food, cosmetics, pharmaceuticals and Medical Device industries. The impact of a chemical migration (container, packaging, detergent, utensil, implant, equipment…) coming into contact with the product itself (Medical Device, bulk, powder, pills, liquid, the human body…) can be a problem : contamination, non-conformity, complaints, user harm…

The logical question that arises from all this is what are these compounds or substances, and consequently, what are the risks to the patient/client? This are the questions that studies of extractables and leachables must answer. As an example, the FDA published a Guidance for Industry : Container Closure Systems for Packaging Human Drugs and Biologics in 1999 in which it is specified that :

“Packaging must be made of materials that do not release undesirable or hazardous substances to the patient treated with the product.

Accordingly, files should contain extraction tests on the packaging to determine which chemical components or materials are likely to migrate into the product. A toxicity study of these components will need to be conducted.”

In 2005 this text was amended by a European guideline issued by the EMA: Guideline on plastic immediate packaging material which specifies that the purpose of extraction tests is to identify and quantify additives (antioxidants, plasticizers, catalysts, etc.) that can be extracted by contents in contact with its packaging, whether the product is liquid or solid.

Following this in 2006, the Product Quality Research Institute (PQRI) carried out extensive research into inhaled products or products administered nasally.

This research led to certain recommendations : Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Product

These recommendations are now part of FDA standards and referenced across the world in the pharmaceutical industry.

This research mostly covered packaging materials (blister packs, bottles, prefilled syringes, dosing valve, inhalers…) but also elements coming into contact with the product during the manufacturing process (filtration systems, transfer pipes, single use materials…)

The regulated substances can have an effect either on the patient (ex. Carcinogenicity : N-nitrosamines, polyaromatic hydrocarbons…) or on the physicochemical stability of the drug itself.

Given that a specific formulation can have an effect on the type and quantity of leachables, it is the manufacturers’ responsibility to prove that the level of leachable substances does not exceed toxicological constraints. Current guides such as the FDA’s “Container Closure Systems for Packaging Human Drugs and Biologics” and the EMA’s “Guideline on Plastic Immediate Packaging Materials” directives clearly indicate that it is preferred to perform leachable testing on the final formulation.

As part of studies into E&Ls we will mostly be referencing :

• GC-MS, HPLC or UHPLC/MS/MS for detecting, identifying and quantifying organic compounds present in solvents, anti-UV additives, antioxidants, dyes, inks, detergent residues, sterilization residues, polymer residues, … that have been extracted and/or released from the material by a standardized simulant
• UV-Vis spectrophotometry for dosing Chromium VI leached out of metallic alloys
• ICP-AES and ICP-MS particularly adapted for pollutants, inorganic and metallic additives such as heavy metals, mineral or metallic fillers, dyes…
• SEM-EDX microscopy is a quick and reliable tool for diagnosing the state of the surface of a material after an ageing process, the observation of particulates or deposits…

In this context, FILAB has managed to implement extraction and leaching techniques described in standards and guidelines (USP 1663, USP 1664, EN 1186, EN 1388-2, ISO 10993-12…) and in accordance with relevant national or European standards. Moreover, FILAB develops protocols specific to clients’ challenges with the aim of simulating real conditions of contact between a container and its contents to be able to analytically determine their chemical compatibility and to evaluate their level of chemical inertia. Testing chemical inertia consists of demonstrating a containers ability to resist the invasive effects of its contents which are susceptible of extracting and/or leaching chemical compounds. 

With extensive experience in implementing these techniques and in developing specific analytical techniques, FILAB can assist you in the context of a study into E&Ls and studies of ageing materials.

For more information, feel free to contact one of our experts via email at : contact@filab.fr