The FDA-guidance, “Container Closure Systems for Packaging Human Drugs and Biologics” of 1999 makes a classification of pharmaceutical container closure systems, based upon the Likelihood of Interaction between the dosage form and the packaging, but also based upon the degree of concern associated with the route of administration. Table 1 of this document classifies the risk for ophthalmic solutions and suspensions of both the likelihood of interaction and the degree of concern for the administration as being “high”. Since ophthalmic drug products are applied to the eye, compatibility and safety should also address the container closure system’s potential to form substances which irritate the eye. Therefore, the General “Safety” Considerations in the FDA-guidance states that, in case of ophthalmic products, a comprehensive study – including at least an extraction study and a toxicological evaluation – is appropriate. However, based upon the feed-back from regulatory submissions, it is clear that since 1999, the FDA has gradually increased the level of required documentation for ophthalmic containers. If the requirements for a container closure system would not be clear or conclusive, the FDA encourages discussing the documentation in container/closure requirements with the appropriate CDER chemistry review staff or CBER review staff.

In Europe, the EMEA-Guideline on Plastic Immediate Packaging Materials of 2005, both solid and non-solid products for ophthalmic administration require the same level of immediate packaging requirements as parenterals and inhalables. A first step herein is to demonstrate compliance for the plastic material to the European Pharmacopoeia. However, for non-compendial plastic materials used of ophthalmic administration, extraction studies are required even if they are approved for the use in food packaging. The decision tree in the EMEA-Guideline indicates that for non-solid dosage forms, Interaction studies (which include migration studies to monitor the leaching of substances from the plastic material into the formulation) are considered as a requirement. For solid ophthalmic dosage forms, interaction studies should be performed “when necessary”.

Although label migration is not a specific requirement for ophthalmic pharmaceuticals, it is often a concern for these types of products. In numerous cases, it has been shown that label components (such as adhesive compounds, photo-initiators, curing agents, ink residues) were able to migrate through the polymer container into an ophthalmic drug product, causing unexpected impurities in stability studies and leading to time and resources consuming root cause analyses. Non-solid ophthalmic drug products are often solutions marketed in a LDPE bottle (e.g. droptainer), of which is it known that label migration cannot be excluded. In both the FDA and the EMEA Guidelines, the label is considered as part of the total container closure system and it should be verified that no contamination of the drug product is occurring from these label components.

Nelson Labs Europe works with both the ophthalmic container manufacturers as well as with the pharmaceutical companies working in ophthalmic drug development. The services in testing ophthalmic CCS range from the typical compendial EP and USP testing up to a high level of Extractable/Leachable studies.

Because of our vast experience in this field, Nelson Labs Europe has built a broad expertise in developing testing programs which require a combination of state-of-the-art analytical techniques, such as Headspace GC/MS, PTV-GC/MS, GC/MS, LC/MS, LC/MS/MS, ICP, IC... In addition, Nelson Labs Europe can offer its assistance in the elucidation of structural information for critical compounds, using GC-ToF, LC-ToF, FT-MS or NMR.

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 | Ophthalmics