Ophthalmic drug products (ODP) are specialized dosage forms designed to be applied onto the external surface of the eye (topical), administered inside (intraocular), or adjacent (periocular) to the eye or used in conjunction with an ophthalmic device. Common ophthalmic dosage forms include liquids (eye drops, ophthalmic solutions, suspensions), semi-solids (gels and ointments), and solids (contact lenses coated with drug substances, ocular inserts).
Global regulators consider ophthalmic solutions and suspensions (OSS) to be high risk in terms of adverse outcomes arising from their packaging. For example, Table 1 of the FDA’s 1999 Container Closure Guidance assigns OSS a high level of concern for packaging interactions, based on the high likelihood that a packaging-dosage from interaction could occur and a high degree of concern associated with the route of administration. A somewhat lower risk is established for OSS in USP <1664>, based on a lower likelihood of drug–packaging interaction. Given this classification, Table 2 of the FDA Guidance notes that USP Biological Reactivity Testing and possibly extraction/toxicological evaluation is necessary to establish that OSS packaging has an acceptably small adverse effect on patient health. Similarly, the Immediate Packaging Guidelines of the European Medicines Agency (EMEA) establish that packaging systems (and their materials of construction) for OSS must be tested by rigorous means (including compendial compliance, extraction studies, interaction (leachables migration) studies and toxicological information) to establish their safe use. Lastly, rigorous testing for the selection and qualification of packaging materials and systems, applicable to OSS, is described in various mandatory USP chapters including <660> (glass), <661.1> and <661.2> (polymers), and <381> (elastomers).
Although ophthalmic semi-solids and solids are not specifically mentioned in the regulations, they presumably have a lower assigned risk, due to a lesser likelihood of a drug–packaging interaction.
In addition to the high risk associated with OSS and their packaging, OSS and their packaging have certain unique features which complicate their chemical and biological safety assessment. For example, the most typical packaging format for OSS is plastic (low- and high-density polyethylene; LDPE, HDPE) bottles. A shortcoming of PE materials as primary packaging is that they are relatively poor barriers to chemical migration. Thus, packaged OSS are likely exposed to foreign impurities derived from sources outside of the primary packaging, including printing or labels on the bottle, secondary, tertiary, and auxiliary packaging (overpouches, cartons, shrink-wrap) and the storage/distribution environment (for example, shipping pallets). As such impurities are rarely surfaced in extraction studies and are generally discovered as unexpected substances in leachables profiling, their resolution is more difficult and urgent.
Despite these challenges, ophthalmic solutions and suspensions have several advantages that reduce the risk of unsafe leachables: a low daily dose volume, a different toxicity profile, and a different approach to reporting thresholds. Considering the first advantage, the daily dose volume for ophthalmic solutions and suspensions is typically less than 1 mL. When the daily dose volume is this low, a “safe” leachables concentration in OSS will generally be higher than such a concentration in other, higher daily dose volume products (for example, a large volume parenteral).
Considering the second advantage, the PQRI PODP recommendations note that ocular drugs are designed to achieve a high local exposure and corresponding low systemic exposure. Thus, local topical (ocular) effects are considered a primary area of concern for toxicity potential for ODPs and systemic effects including general and developmental and reproductive toxicity are less relevant to ODP (versus other product types). Therefore, safety thresholds for local effects (i.e., sensitization and irritation/toxicity) will be a primary consideration when qualifying leachables and extractables of ODPs. However, genotoxicity potential is also considered a relevant endpoint for this product type.
This circumstance is significant as the safety threshold for sensitization/irritation is generally higher than that for systemic effects such as mutagenicity and carcinogenicity (e.g., 5 µg/day versus 1.5 µg/day per the PODP recommendations).
Lastly, while an SCT can be derived for many drug product dosage forms, a database of toxicity endpoints relevant to ODPs (i.e., sensitization, ocular irritation), which would be the basis of establishing an SCT, does not exist at this time. Thus, the SCT of 1.5 µg/day adopted for parenteral products cannot be applied directly to ODP.
At first glance, this circumstance would seem to be a disadvantage, as the SCT answers the question “how low do you go” in extractables and leachables screening. Having no SCT means the only viable answer is “go as low as your methods can go,” which presents the possibility that ODPs would have to be screened for leachables at levels so low that many unidentifiable leachables could be surfaced. However, in February 2011, at the PQRI workshop on Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products, FDA’s Office of New Drug Quality Assessment (within the Center for Drug Evaluation and Research [CDER]) gave a presentation that covered leachables for ophthalmic solutions, suspensions, and emulsions in LDPE container closure systems. The presentation, which discussed principles of applying a science-based approach to study design, format of reporting leachable results, and thresholds for leachables, recommended thresholds for reporting, identification, and qualification of 1, 10, and 20 ppm (mg/L or µg/g), respectively. Although the content of this presentation is in the public domain, these thresholds do not appear in official FDA guidelines. Thus, they are described in the PODP recommendations as a reference to provide insight into a possible approach or starting point, but not as a practice that must be followed.
This is an advantage for ODPs as these identification and qualification thresholds are generally higher than one would calculate using, for example, parenteral thresholds such as the SCT.
Performing successful and practical extractables and leachables assessments for ophthalmic drug products requires excellence in study design, skill in study execution, especially in analytical testing, and a profound understanding of materials, extractables and leachables, gained through extensive experience. With our vast experience, Nelson Labs Europe has a broad expertise in designing and implementing chemical testing programs which leverage state-of-the-art analytical techniques, highly trained and competent analytical scientists, and knowledgeable study directors. Nelson Labs Europe has a long history of successfully partnering with opthamlic drug packaging and product manufacturers to effectively and efficiently secure regulatory approval for their products.
