Oral Liquids and Topical Drug Products

The liquid (or non-solid) oral and topical drug products represent – without any doubt – the broadest variety of different dosage forms, such as creams, emulsions, lotions, aerosols, gels, ointments, pastes, syrups, solutions, suspensions, extracts... Because these drug products are presented in a liquid phase, there is a significant potential for leaching of compounds from the packaging component into the dosage form. High viscosity drug products – with a high organic content (e.g. glycerine in ointments) – may show a high affinity for container closure interaction. However, the same high viscosity will limit the rate of migration into these dosage forms.

Table 1 of the FDA-Guidance “Container Closure systems for packaging Human Drugs and Biologics” classifies the “Transdermal ointments and patches” as a high concern, associated with the route of administration, while "Topical solutions suspensions, topical and lingual aerosols, oral solutions and suspensions" are here being classified as of low concern. In terms of likelihood of packaging component-dosage form interaction, both categories of dosage forms are considered as having a high risk. The General “Safety” Considerations in the FDA-guidance state that liquid oral and topical drug products will categorize under “case 3s”, which requires – for acute dosing regimens – typically an appropriate reference to the indirect food additive regulations for aqueous based solvents or relevant USP compendial tests (e.g. USP<661>). However, for a chronic drug regimen, it should be proven that the patient's exposure to leachables can be expected to be no greater than the exposure through foods. In addition, for non-aqueous based solvents and for aqueous based solvents containing co-solvents, it is generally required to have additional suitability information. Section III F.1 of the FDA Guidance states that “ ... if the dosage form contains co-solvents(..), then additional extractable information (such as extractable studies) may be needed to address safety issues.”

In Paragraph 4, "Extraction Studies", the EMEA Guideline stipulates that for non-solid substances or dosage forms for oral and topical use, extraction studies are considered to be necessary for plastic material used for container closure systems if the material is neither described in – or tested according to – the compendial tests of the European Pharmacopoeia (or any other member state Pharmacopoeia), nor approved for food packaging. In addition Paragraph 5, “Interaction Studies”, states that “..the risk of interaction with the container closure system requires comprehensive and suitable studies specific for each active substance/formulation. Interaction studies may include migration studies to monitor the leaching of substances from the plastic material into the formulation/active substance..”

Migration studies should prove that – when extraction studies have resulted in one or more extractables – no leachables are introduced into the active substance/medicinal product as to alter its efficacy, stability or overall toxicological risk. In certain cases, migration studies may be omitted when, based upon the outcome of extractable studies, the calculated maximum amount of individual leachable compounds lead to levels that are toxicologically safe. In this approach, extractable studies should lead to analytical results that are amenable to a toxicological evaluation, which implies to use validated methods in an extractable study.

Nelson Labs Europe offers its expertise in qualifying container closure systems for all liquid oral and topical applications, starting from the typical compendial EP and USP testing up to a high level of Extractables / Leachables studies.

If you would be interested to find out more about our services and testing programmes, please feel free to contact us at InfoEurope@nelsonlabs.com or call us at ++32 (0)16 400.484. 

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Nelson Labs Europe | Oral and Topical Formulations