Testing for Extractables and Leachables from Container Closure Systems
Leachable impurities can migrate from components in container closure systems, packaging systems, storage systems, process equipment and device packaging, that can affect the overall purity and safety of the therapeutic product. In order to identify potential sources of leachables, it is important to conduct controlled extraction studies to identify extractables and the components that generate them. Hence Extractables and Leachables (E&L) testing is crucial to product release.
The FDA defines extractables as “organic and inorganic chemical species that can be released from the surfaces of components used in the manufacture and storage of drug products under laboratory conditions (accelerated or exaggerated temperatures, solvents or surface exposure)” and leachables as “organic and inorganic chemical species that can be released from the surfaces of components used in the manufacture and storage of drug products under conditions of normal use”.
Sources of extractables include manufacturing equipment, packaging components and others such as labels, adhesives and inks. Sources of leachables can be stabilizers, antioxidants, coatings, emulsifiers, vulcanizing agents, lubricants, dyes and colorants. Pharmaceutical packaging, device packaging, container closure systems, drug delivery systems and implantables can be complex combinations of polymer, rubber, glass and other materials and all can contribute to the E&L profile of the product.
- PBL’s Services per USP <1663> and <1664>
- Analytical Techniques available at PBL
- Testing per USP <661>
- USP <661.>
- USP <661.2>
The analytical chemistry team at PBL can perform E&L testing per Good Manufacturing Practices (GMP), USP chapters <1663>, <1664> and <1664.1>, and follow FDA guidelines as well. We can conduct exhaustive extractions, controlled extractions and even simulated extraction studies to discover possible extractables. We can write protocols and perform testing per GMP for E&L and stability studies. Our team will work with the client to design a study that meets the client’s needs for regulatory and development purposes.
- Screening for Volatile and Semi-Volatile Organic Compounds using GC and GC/MS
- Screening for Non-Volatile Inorganic Compounds using HPLC and LC/MS/MS
- Impurity Analysis
- Heavy Metals and Elemental Analysis using ICP-MS according to USP <232>
- Gravimetric Analysis
Systems used to package therapeutics products – often called “Packaging Systems”, are generally constructed and composed from materials that may include glass, metals, plastics and elastomers/homologous polymers with a range of molecular weights and several additives. These systems are usually in contact with the pharmaceutical product at some point during manufacturing, storage or administration and cause a big concern regarding safety. With recent revisions, the USP <661> focuses on Safe Plastic Packaging for Pharmaceutical Products.
New packaging systems that have not gained regulatory approval for use with a to-be-marketed pharmaceutical product would need to be tested according to <661.1> and <661.2>. However, testing of packaging systems used with a currently marketed pharmaceutical product to be applied to a different pharmaceutical product would depend upon the dosage form and conditions of use according to the level of risk. For example, a high risk product using a new nebulizer packaging system would need to be tested in accordance with the revised USP <661> chapter.
Pacific BioLabs offers testing services catering to both USP <661.1> and <661.2> chapters. Our objective is to help you determine the required testing for your materials and the ideal testing matrix so you will be able to plan ahead for your product.
The purpose of this chapter is to determine whether a material has been well-characterized for its intended use and is designed to ensure that the material characteristics match the relevant performance requirements.
This chapter solely applies to individual plastic and raw materials, and contains tests, methods and specifications for cyclic olefins, polyethylene, polypropylene, polyethylene terephthalate, polyethylene terephthalate G, and plasticized polyvinyl chloride.
The characterization is done by identity, biocompatibility (biological reactivity), general physicochemical properties, additives and extractable metals.
- Biological reactivity (Biocompatibility)
- Infrared spectrophotometry
- Extraction (possible solvents: water, toluene, alcohol)
- Acidity or alkalinity
- Metals (ICP- MS), HPLC (as required for the additive composition)
USP chapter <661.2> provides test methods and standards for plastic packaging systems such as bags, bottles, blister packs, inhalers, syringes and vials.
The testing matrix would primarily depend on the composition of the packaging system. According to USP, “This testing generates a chemical safety assessment of a packaging system, based on risk-based testing.” However, if a material is well characterized and has data available, this step can be bypassed.
For <661.2> the focus is on suitability for use with respect to patient safety, and therefore the testing regimen would be inclusive of the establishment of the packaging systems:
- Biocompatibility (biological reactivity)
- Physiochemical properties (water extraction, acidity or alkalinity, absorbency, TOC)
- Metals (ICP- MS)
- HPLC (as required for the additive composition)
- Chemical safety assessment required involving the Extractables/Leachables profiling and the Toxicological risk assessment of the test data.