Safety Assessment of Materials by Extractables & Leachables (E&L) - Studies

Extractables and Leachables (E&L) studies are performed to assess the safety of pharmaceutical packaging and medical devices. By using advanced trace analysis to detect, quantify and identify contaminants, we offer you the highest quality and efficiency.


Patient safety through medical devices tested at OFI

As a testing and research institute, OFI has detailed experience in the field of polymers and the performance of extractables and leachables studies and offers these for all application-related areas of the plastics industry. Through the integration of trace analysis, material know-how and toxicological evaluation, OFI can offer a range of instruments that can significantly increase product safety and shorten development times for pharmaceutical and plastic products for the industry.


New regulations for more security

The latest developments clearly show that chemical characterization for the safety assessment of materials is becoming increasingly important not only for medical devices (ISO 10993-1ff). The pharmacopoeias (especially the USP) are also upgrading strongly. The current version of USP 41 of the US Pharmacopoeia, for example, lays down essential principles for the safety assessment of pharmaceutical packaging. Extractables & Leachables (E&L) are evaluated as central criteria.

  • E&L for pharmaceutical packaging: GMP, EMA and US-Guidelines USP (USP 1663 and 1664), as well as the relevant international guidelines.
  • E&L for medical devices: ISO 10993-1, -17,- 18, MPG


Extractables & Leachables (E&L)

Many material conformity tests depend on the existence of a recipe. The risk assessment of unspecified plastics, on the other hand, resembles the search for a needle in a haystack!

In order to be able to estimate an actual hazard potential, it is necessary to record as many substances as possible that migrate from the plastic into the product. Only on the basis of such a broad screening can the risk of overlooking a toxic hazard potential be minimized.

The first part, the Extractables Study, covers all substances that are released from the packaging material in the worst case. In the second part, the Leachables Study, those substances are recorded that migrate from the packaging material into the preparation under real conditions.

In the extractables studies, plastics are typically subjected to extractions with 2-3 solvents of different polarity, such as water, ethanol and dichloromethane. In addition, different extraction methods are used, e.g. Soxhlet plus ultrasonic extraction, in order to detect any changes caused by the extraction itself. Typically, this results in the hydrolysis of carboxylic acid esters, for which the corresponding acid must also be taken into account. Other common extraction methods are reflux, high-pressure liquid extraction or microwave.

Solvents and extraction methods are chosen in such a way that they result in a worst-case scenario of the actual field of application with regard to the chemical parameters. Finally, those substances are to be identified that could be possible leachables. For example, it is very unlikely that extremely lipophilic substances migrate into a purely aqueous solution.

In the risk assessment - possibly combined with a simulation study with the real product - the possible leachables are limited to the probable leachables.

If questionable leachables can be deduced, the leachables studies are carried out over the storage period of the stability studies of the pharmaceutical product. The investigation over the entire storage period is necessary, since the behavior of polymers can change in the course of the life cycle. Within a storage period of 24 months and more, polymers can age and release additives and other substances more easily than immediately after their production. Likewise, reaction products of residual monomers and other substances can form, which only become recognizable after a longer period of time.


Chromatography gives answers

The analysis of extracts is typically performed by chromatographic methods, HPLC and GC, usually using a combination of detectors. A 100% detection of all substances is not possible per se, as each substance is only visible with a limited number of detectors. This risk is minimized by using several detectors. Typically, both UV/VIS and MS are used with HPLC, and FID and MS with GC.

The Headspace-GC-MS can also be used as a direct analysis method, in which the plastic is heated in a closed system and the substances migrating from the material into the gas phase are measured.

More important than ever is the structural determination of the detected compounds in order to be able to assess a possible toxic hazard potential. High resolution mass spectrometry is primarily used for this purpose. Nevertheless, the question often arises in practice as to which of the possible structural proposals is correct. And often a classification is only possible if the recipe is announced by the manufacturer and the degradation reactions of the additives can be linked with the proven extractables.

Also for possible heavy metals, the ICP-MS or ICP-OES has proved its worth. In some cases, the analysis for elementary ions by ion chromatography may also be necessary.


"The dose makes the poison"

In order to be able to estimate the actual hazard potential, risk analyses are carried out for the individual study sections. These include the probability of migration and the toxicological potential. This is usually dependent on the concentration, so that a limit value for the leachables must be set fundamentally. Because you can always find leachables in traces. This is only a question of the detection limit. Therefore, it is of decisive importance to know the quantity of product absorbed per time unit, e.g. the application scheme of drugs. High risk substances, such as carcinogens, should be considered separately in the evaluation. A detection limit as low as possible is decisive here in order to detect even the smallest quantities and to minimize health risks for the patient.


Our range of services

  • Preparation of a study designs
  • Research and assessment of formulations: LMSVG, Ph.Eur. or US-FDA 21CFR178
  • Determination of limit values/ Thresholds
  • Calculation of AET values
  • Qualitative and quantitative extraction studies
  • Migration and simulation studies
  • Risk assessment based on chemical and toxicological criteria
  • Bridging Studies
  • Leachables Studies