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Extractable and Leachable Impurities Regulation

The loss of quality of the medication due to the presence of extractables and leachables added to the risk that these impurities can pose to the patient has led to the development of wide-ranging regulation on this type of impurity.

EU Regulation

The EMA’s “Guideline on Plastic Immediate Packaging Materials”[1] approaches the assessment of extractable and leachable impurities addressing both the pharmaceutical form (distinguishing solid and non-solid forms) as well as the route of administration (parenteral, inhaled, ophthalmic, oral and topical).

In accordance with this guideline, in all cases it is necessary to provide general information on the materials, including the specifications established on the basis of the European Pharmacopoeia (or of a Member State). In the event that this does not exist, internal specifications must be set considering the general methods described in the Pharmacopoeia[2].

The extraction studies are considered necessary in the case of material in contact with non-solid active substances for oral and topical use if the material is neither described in the European Pharmacopoeia nor in the pharmacopoeia of a member state, nor has it been approved for the packaging of food[3],[4]. In the case of non-solid medications designed for inhalation, or parenteral and ophthalmic routes, the extraction studies are always necessary, even when they have been approved for use on food packaging.

When the extraction studies reveal the presence of one or more extractable, it will also be necessary to carry out migration studies with the aim of proving that, for the planned use, the substances will not migrate in quantities such that will alter the efficacy and the stability of the active substance or the medication, or present a toxicological risk. According to this guide, the migration studies may only be omitted if, based on the extraction study results, the calculated maximum quantity of the leachable substance that could be present in the product returns safe toxicological levels.

Extractable and leachable impurities regulation

It will also be necessary to include further testing (leachable study) when risk assessment of the extraction or migration data reveal a potential risk of extractables in final product.

Finally, in the case of plastic materials and additives used in inhaled and ophthalmic medications, it is necessary to provide a complete toxicological report on the extractables and leachables identified, even when they are approved for use in food packaging.

 

Other regulatory bodies

According to the FDA Code of Federal Regulations (CFR), the surfaces that come into contact with components, process materials or pharmaceuticals must not be reactive, additive or absorbent in a manner that alters the safety, identity, strength, quality, or purity of the pharmaceutical product (21CFR211.65)[5]. Polymers have an elevated product interaction potential, there is even a dedicated section in the FDA Regulation on polymers (21CFR177) and another on “rubber articles intended for repeated use” (21CFR177.2600). Included and reviewed in this section are elastomers, silicones, resins and vulcanisation materials, among others.

Also, the USP (US Pharmacopoeia Convention), in its chapter 1663[6] addresses the assessment of extractable compounds associated with pharmaceutical product packaging / release systems, while chapter 1664[7] addresses the assessment of leachables associated with the same systems. In both chapters general information on the framework for the design, justification and execution of an extractables and leachables assessment for packaging and administration systems for pharmaceutical products is presented, defining practical and technical aspects, although the specific extraction conditions are not established, analytical procedures and the obligatory specifications for specific packaging systems. Furthermore, in chapter 1665 the framework for conducting an extractables and leachables toxicological safety assessment is developed.

Moreover, the PQRI (Product Quality Research Institute) established a working group on regulatory orientation in the analysis of extractables and leachables, also recognised by the FDA, which produced a guide for Orally Inhaled and Nasal Drug Products, (OINDP), also applicable to parenteral and injectable products[8]. Safety thresholds were established for leachable contaminants with proposed values of 0.15 µg/day as the Safety Concern Threshold (SCT) and 5 µg/day as the Qualification threshold (QT). The SCT is the threshold under which a leachable will have such a low dosage as to present and insignificant concern with respect to the carcinogenic and non-carcinogenic toxic effects. The QT interval is the threshold under which a particular non-carcinogenic leachable will not have to be considered for safety qualification, unless the leachable presents indications of concern through the structure-activity relation (SAR).

For inhaled medications, the guide produced jointly by the ITGF (Inhalation Technology Focus Group) and the IPAC-RS[9](International Pharmaceutical Aerosol Consortium on Regulation and Science) establishes that on the basis of the concentration of the leachable in the pharmaceutical product, the total daily ingestion (TDI) of the leachable to which a patient will be exposed according to the maximum daily dose of the medication can be calculated.

 

Furthermore, the BPOG10 (Biophorum Operations Group good practice guide) published in March 2017 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.

 

At Azierta, science and health consultancy we have accredited toxicologists, expert in the identification, and assessment of extractables and leachables impurities, capable of determining the inherent risk of each impurity. If you would like to know more about us, visit: Toxicological Consultancy Services.

 

 

[1] “European Medicines Evaluation Agency (EMEA) 2005. CHMP/CVMP. Guideline on Plastic Immediate Packaging Materials.,” n.d.

[2] “European Pharmacopoeia (Ph. Eur.) 9th Edition. Accessed Online at Https://Www.edqm.eu/En/European-Pharmacopoeia-9th-Edition,” n.d.

[3] “COMMISSION DIRECTIVE 2002/72/EC of 6 August 2002 Relating to Plastic Materials and Articles Intended to Come into Contact with Foodstuffs,” n.d.

[4] “European Medicines Evaluation Agency (EMEA) 2005. CHMP/CVMP. Guideline on Plastic Immediate Packaging Materials.”

[5] Food and Drug Administration (FDA)., “Title 21-Food and Drugs; Part 211- Current Good Manufacturing Practice for Finished Pharmaceuticals. Subpart D-Equipment. Sec. 211.65 Equipment Construction (21CFR211.65).,” n.d.

[6] USP Pharmacopeia. 1663, “Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems,” n.d.

[7] USP Pharmacopeia. 1664, “Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems.,” n.d.

[8] 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., “The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP),” n.d.

[9] IPAC RS, “Recommended Baseline Requirements for Materials Used in Orally Inhaled and Nasal Drug Products (OINDP),” n.d.

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