The direct and sometimes long-term contact of packaging, storage containers, transport hoses, filter materials etc. of plastics with pharmaceuticals involves the risk of the transition of chemical ingredients from the respective contact materials. This applies not only to pharmaceutical compositions, but also food or medical products of daily use. Often this is done only at trace levels and thus remains undetected. The OFI has for decades engaged in the review of pharmaceutical packaging, medical devices and food contact materials of plastic.
In the course of the increased use of plastic in recent decades it has been observed that it can just come in polymers through interactions with pharmaceuticals or food to critical changes such filling substances. Since such products go directly to the end consumer, these changes threaten directly the product safety and thus represent a non-negligible factor in the health of the population.
The complexity of these issues is demonstrated by a brief overview giving compilation of possible ingredients. Alone for the primary package are several thousands of additives and excipients in the production of plastics worldwide. In addition, in the pharmaceutical manufacturing various storage containers, transport hoses, filter materials, etc. used, whereby more questionable ingredients can pass into the preparation.
Typical ingredients of materials on polymer, silicone and cellulose-based, organic ingredients such as oligomers, monomers, antioxidants, stabilizers, plasticizers, lubricants (paraffins, stearates, etc.), nucleating agents, spinning aids for fibrous materials (fatty acids, silicone oil, etc.), binders (acrylates, formaldehyde resins), adhesives, residual solvents, mold release agents or cleaning agents , Other typical ingredients are inorganic substances and particles. These often come inks that may contain solvents or can pass from which, for example, photoinitiators or degradation products
However, packaging materials also subject to a number of chemical, physical and biological factors. All of these factors can lead to chemical and cause mechanical changes, both affecting the protective function of the packaging, as also carry the risk of emerging contaminants, degradation products and reaction products.
Diagnostic Tests often inadequate
In total, there are thus in plastic packaging numerous compounds at trace levels that are not listed in the specification of the polymer! However, the European standardized test methods are often inadequate because not the actual product safety is assessed, but only generalized model-like parameter (simulants). The common audit practice for the suitability of packaging aimed primarily from a material compliance check is in the tested substances known. In the pharmacopoeia of these are, for example, EP 3.1 Materials for the production of containers, EP 3.2 containers (glass, plastic, rubber stoppers) and USP 661, 381, 87
far-reaching investigations into biocompatibility are provided for medical products.: EN ISO 10993 biocompatibility of medical devices. And for food limit checks are already carried out for listed ingredients for migration with simulant solvent: VO 10/2011 / EU “PIM” migration test with simulant solvent and ÖNORM EN 13130 Specific migration as limit testing
Many of these tests. depend on the existence of a recipe. The risk assessment of unspecified plastics like looking for a needle in a haystack. In order to estimate an actual hazard potential, it is necessary to detect possible, all substances that migrate from the plastic into the contents. Only on the basis of such a broad screening the risk can be minimized a toxic hazard potential to be overlooked.
extractables study in pharmaceutical packaging
In the field of pharmaceutical packaging is the subject in the context of so-called leachables and extractables investigated. In the first part, the extractables study, all substances are detected, which can be removed from the packaging material in the worst case. In the second part, the leachables study, those substances are detected that migrate under real conditions from the packaging material into the preparation. The primary regulatory requirements this can be found at European level in the EMA Guideline on Plastic Immediate Packaging Materials. In America, to the USP 1663/1664 (Assessment of extractables / leachables Associated with Drug Product Pharmaceutical Packaging / Delivery Systems) in preparation.
In the extractables studies, the plastics are typically extractions with solvents 2-3 different polarity subject, such as water, ethanol and dichloromethane. In addition, different extraction methods are employed, such as Soxhlet extraction plus ultrasound to detect possible changes by the extraction itself. Typically, it is in this case for example, for the hydrolysis of carboxylic acid esters, whereupon the corresponding acid must be taken into account. Other spreading tete extraction methods are reflux, high pressure liquid extraction or microwave.
and solvent extraction method are chosen such that they result in a worst-case image of the actual application area in terms of chemical parameters. Finally, those substances are to be determined, which are possible Leachabels. For example, it is very unlikely that extremely lipophilic substances migrating into a purely aqueous solution.
The quantitative results of extractable study also observed over the time course in order to ensure an exhaustive extraction. Conversely to ensure that not too long extraction already secondary processes occur through, for example hydrolysis of an additive.
leachable study at an elevated storage temperature
Before leachable study a simulation study is usually performed with the real product that under stressful conditions, ie For example, elevated temperature, is stored. This results in a further containment is obtained on a subset of the possible to the probable Leachabels leachables.
It was only then be carried out over the period of storage stability studies of pharmaceutical product which leachables studies. These studies primarily examined specifically on the set of probable leachables. The investigation into the entire storage period is necessary because the behavior of polymers can change during the life cycle. As part of a storage period of 24 months and more age polymers and can, for example additives and other substances release easily than immediately after their preparation. Be reaction products of residual monomers can also, among other things form substances that are recognizable only after a long time.
Even, for example, increasing the storage temperature of 40 to 60 ° C causes a great extent the development of byproducts, such as from is the storage of a polypropylene can be seen that as additives caprolactam, bisphenol-A and benzophenone Diephenylphthalat contains:. 95% ethanol, 40 ° C, 10 d, 95% ethanol, 60 ° C, 10d
The analysis of the extracts typically takes place by means of chromatographic methods, HPLC and GC, where usually a combination of detectors is used. A 100% coverage of all substances is not possible per se, as each substance is visible only with a limited number of detectors. By using multiple detectors, this risk is minimized. So, typically, by HPLC both UV / VIS and MS / MS used, and can at the GC FID and MS.
As a direct analytical method and the headspace GC-MS are used in the plastic is heated in a closed system and those substances are measured, which migrate from the material in the gas phase.
Also possible heavy metals must not be forgotten, here is mainly the ICP-MS or ICP-OES proven. In part may also be necessary to analyze in elementary ions which are carried out by ion chromatography.
carrying out risk analyzes
In order to estimate the actual hazard potential, risk analyzes on the individual study periods carried out , These include the likelihood of migration and toxicological potential. This is usually dependent on concentration (Paracelsus: “the dose makes the poison”), so fundamentally a limit for leachables must be set. Because one can find traces of leachables always. That’s just a matter of detection limit. Of crucial importance therefore is the knowledge of the amount of collected contents per unit of time, ie for example, the application schema of drugs. Considered separately in assessing high-risk substances, such as carcinogens. Here is a very low limit of detection crucial to detect even the smallest amounts and prevent damage to the patient.
The OFI has detailed experience in the field of polymers and the implementation of Extractables and leachables studies and offers This application-oriented for all areas of the plastics industry. By integrating trace analysis, material expertise and toxicological evaluation can the manufacturers of plastic products and users from the fields of pharmacy, medical products and the food industry an instrument offered to increase product safety significantly and development times of pharmaceutical products and shortening of plastic products.
OFI Technologie & amp; Innovation GmbH
1110 Wien Austria
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