What is an extractable impurity?
Depending on their chemical nature and migratory properties from the container to the medium, these types of organic or inorganic impurities originating from the packaging materials may be classified as extractables or leachables. Therefore, extractables impurities can be defined as compounds released by the material in extreme temperature conditions, exposure times, or in the presence of solvents of different polarity or at different pH values. On the other hand, leachables are compounds that migrate from the material to the pharmaceutical product in normal use and storage conditions. Although extraction studies provide information about leachables that could appear even in less favourable conditions, in some cases, product analysis can reveal impurities that have not been identified in previous extraction studies, resulting from the reaction between the material and the product or the single-use systems used in the manufacturing process.
The containers and administration systems for pharmaceutical and biopharmaceutical products are designed to protect the products from environmental contamination, but, at the same time, they may constitute a contamination source in themselves. Likewise, the single-use systems (SUS) widely used in the pharmaceutical industry for their speed and ease of implementation may pose a risk due to the possible release of compounds and additives into the product.
Figure 1. Array of extractables and leachables identified in extraction studies (theory) and finished product analysis (practice).
The presence of impurities derived from materials that come into contact with the pharmaceutical product leads to a change in its composition that may, in turn, modify its therapeutic action, its organoleptic properties, and/or its stability. Also, these impurities may constitute a risk in themselves, due to their inherent toxicological properties. This underlines the need for exhaustive control of the compounds that may appear in the product derived from the contact materials, above all in pharmaceutical formulations with the greatest risk, such as liquid forms for parenteral, ophthalmic and inhaled administration.
Extractable impurities regulation
The loss of quality of the medication due to the presence of extractables and leachables combined with the risk that these impurities may pose to the patient has led to the development of comprehensive regulations for these types of impurities. It is worth highlighting the following regulatory bodies, extractables and leachables working groups, and panels of experts:
- Groups of experts, such as the PQRI (Product Quality Research Institute), PDA (Parenteral Drug Association), IPAC-RS (International Pharmaceutical Aerosol Consortium on Regulation & Science), ICH (International Conference on Harmonisation) and ELSI (Extractables and Leachables Safety Information Exchange).
- Regulatory agencies that have produced specific documentation such as the EMA’s guidelines on plastic immediate packaging materials1, and the FDA’s guideline on packaging systems for medications2. These guidelines recommend strict and comprehensive control of extractable and leachable impurities, especially in liquid pharmaceutical forms administered via high bioavailability routes, in such a way that the conducting of representative extraction and migration studies of the material must be considered. Additionally, when the result of the extractable impurity analysis indicates that there is a potential risk to health, it will be necessary either to conduct specific migration studies or to control the impurities in the product itself so as to ensure its safety.
Figure 2. Risk found for leachables depending on the probability of product-material interaction and the product’s route of administration2.
According to the chapter on single-use systems in the recently published draft of annex 1 of the GMP (draft 12/2017)3, the compatibility of the materials in contact with products must be guaranteed by assessing the absorption capacity and reactivity of the material. The review of the supplier data will provide information on the potential impurities derived from the single-use systems, permitting the evaluation of whether or not product quality will be compromised by contact with the material. In components considered high risk for leachables, the analysis of impurities in the finished product must be considered.
Furthermore, the BPOG4 (Biophorum Operations Group good practice guide) also provides complete and detailed content for the configuration of the material extraction studies and the assessment of the release risk of single-use polymeric systems used in pharmaceutical and biopharmaceutical manufacturing.
Moreover, the European and American Pharmacopoeias provide specifications for different packaging materials. The American Pharmacopoeia dedicates chapter 1663 to the assessment of extractable compounds associated with pharmaceutical product packaging systems, while in chapter 1664 it addresses the assessment of leachables associated with the same systems. In chapter 1665, the framework for conducting extractable and leachable toxicological safety assessment is outlined, and general information is presented on the design, justification and development of extractable and leachable assessment for pharmaceutical product containers and administration systems, defining practical and technical aspects.
Extraction studies and toxicological risk assessment
As previously mentioned, material extraction studies aim to provide an extensive understanding of the impurities originating from the packaging material and plastic manufacturing systems.
Figure 3. Analysis of the composition of materials via extraction studies
Although the design of extraction studies is not standardised, there are different proposed protocols for the assessment of materials, such as the specifications of food regulations (Regulation (EU) No. 10/2011)5, regulations for polymers that come into contact with food (21 CFR parts 174-186)6, tests described in the European and American Pharmacopoeias, and recommendations provided by groups of experts such as the PQRI or the BPOG.
When it comes to defining the conditions for an extraction study, it is necessary to consider several parameters, such as the types of monomers and polymers that make up the material or the polymerisation process and the additives used. The most commonly used extraction techniques include reflux with organic solvents of different polarity and with solutions at different pH values, Soxhlet treatment, sonication and incubation in controlled temperature conditions, among other methods. Each fraction collected in the extraction study is analysed qualitatively and quantitatively using different spectroscopic and chromatographic techniques with the aim of identifying the products and quantifying them via the use of standards. In this context, the calculation of the Analytical Evaluation Threshold (AET) defines the limit from which extractable and leachable impurities must be identified and their toxicological review considered7,8. To calculate this threshold, a standard toxicological safety standard is used, such as the Safety Concern Threshold (SCT), which is always related to the material or device and the product dose. Therefore, the analytical methods developed for the control of leachables in the pharmaceutical product should be sufficiently sensitive to identify compounds that exceed the toxicological threshold. These analyses are conducted either in migration studies specifically designed to test the materials or in stability studies. In any case, they pose an analytical challenge due to the structural complexity of some impurities and the low levels at which they are generally found.
The preclinical and clinical toxicological evaluation of the products obtained in the extraction study, combined with the risk analysis that associates the toxicity of each extractable with its exposure through the product administration, makes it possible to identify the compounds that present a greater toxicological risk and which, therefore, must be controlled either in the finished products as leachable impurities or via specific migration studies of the material. In any case, risk analysis must be carried out on an individual basis, taking specific parameters into account, such as the characteristics of the material and the product, the dosage and route of administration, and the product’s stability profile.
Figure 4. Workflow in the analysis of extractable and leachable impurities derived from packaging materials and single-use systems.
Ultimately, the toxicological evaluation and the individualised focus, based on the specific risk, will make it possible to determine the suitability of the packaging materials or single-use systems for use with each pharmaceutical product, which will determine to a large extent the quality, safety and efficacy of the medication.
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- EMA (European Medicines Agency). Guideline on Plastic Immediate Packaging Materials. 2005.
- FDA (food and Drug Administration). Container Closure Systems for Packaging Human Drugs and Biologics. 1999.
- Revision of annex 1, on manufacturing of sterile medicinal products, of the Eudralex. Volume 4, 2017.
- Biophorum Operations Group (BPOG) Best Practices Guide for Evaluating Leachables Risk from Polymeric Single-Use Systems Used In Biopharmaceutical Manufacturing. 2017.
- Reglamento (UE) n ° 10/2011 de la Comisión, de 14 de enero de 2011, sobre materiales y objetos plásticos destinados a entrar en contacto con alimentos.
- Code of Federal Regulations (CFR) Citations for Color Additives, Food Ingredients and Packaging.
- Norwood, D., FDA, T. M., Ball, D., PDA, D. P., Blanchard, J., Celado, L., & Vogel, M. (2006). Safety Thresholds and Best Practices For 5 Extractables And Leachables In Orally Inhaled and Nasal Drug Product.
- Paskiet, D., Jenke, D., Ball, D., Houston, C., Norwood, D. L., & Markovic, I. (2013). The Product Quality Research Institute (PQRI) leachables and extractables working group initiatives for parenteral and ophthalmic drug product (PODP). PDA journal of pharmaceutical science and technology, 67(5), 430-447.