Ophthalmic drug products (ODP) are special dosage forms to be applied to the outer surface of the eye (topically), to be applied inside (intraocular) or adjacent to the eye (periocular), or designed to be used 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 view ophthalmic solutions and suspensions (OSS) as a high risk of adverse consequences from their packaging. For example, in Table 1999 of the FDA 1 Container Closure Guidelines, a high level of concern for packaging interactions is given to OSS based on the high likelihood of an interacting packaging dosage occurring and the high degree of concern associated with the administration route. There is a slightly lower risk for OSS at USP <1664> due to the low probability of drug packaging interaction. Given this classification, Table 2 of the FDA Guidelines notes that the USP Bioreactivity Testing and possibly extraction / toxicological evaluation are required to ensure that OSS packaging has an acceptably small negative impact on patient health.
Similarly, the European Medicines Agency's (EMEA) Emergency Packaging Guidelines determine that packaging systems (and building materials) for OSS must be tested in rigorous means (mandatory compliance, extraction studies, interaction (leaking migration) studies and toxicological information). ensure their safe use. Finally, rigorous testing for the selection and qualification of packaging materials and systems applicable to OSS, <660> (glass), <661.1> and <661.2> (polymers) and <381> (elastomers). interaction (leaky migration) studies and toxicological information) to ensure their safe use.
Although ophthalmic semisolids and solids are not specifically specified in the regulations, they are likely to be at a lower risk due to the lower probability of drug packaging interactions.
In addition to the high risk associated with OSS and its packaging, OSS and its packaging have some unique properties that make chemical and biological safety assessments difficult. For example, the most typical packaging format for OSS is plastic (low and high density polyethylene; LDPE, HDPE) bottles. The lack of PE materials as primary packaging are relatively weak barriers to chemical migration.
Despite these challenges, ophthalmic solutions and suspensions have several advantages that reduce the risk of unsafe leakage: low daily dose volume, a different toxicity profile, and a different approach to reporting thresholds. Given 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, the "safe" leachable concentration in OSS will generally be higher than this concentration in other, higher daily dose volume products (eg large volume parenteral).
Considering the second advantage, the PQRI PODP recommendations note that ocular drugs are designed to achieve high local exposure and a corresponding low systemic exposure. Therefore, local topical (ocular) effects are considered to be an area of primary concern for the toxicity potential for ODPs, and systemic effects, including general and developmental and reproductive toxicity, are less relevant to ODP (than other types of products). Therefore, safety thresholds for local effects (eg, sensitization and irritation / toxicity) will be a key consideration in characterizing the extractables of leachate and ODPs. However, genotoxicity potential is also considered as a relevant endpoint for this product type.
This is important as the safety threshold for susceptibility / irritation is generally higher than systemic effects such as mutagenicity and carcinogenicity (eg 1.5 µg / day versus 5 µg / day per PODP recommendations).
Finally, while a SCT can be obtained for many drug product dosage forms, a toxicity endpoint database (ie, sensitivity, ocular irritation) related to ODPs that are the basis for generating a SCT is currently not available. Therefore, the 1.5 µg / day SCT considered for parenteral products cannot be directly applied to ODP.
At first glance, this seems like a disadvantage, because SCT answers the question of "how low will you go" for removable and leaky scans. The only valid answer to not having the SCT means that it is "as low as your methods can go", offering the possibility that ODPs will be screened for leaks so low that many unidentified leaks can arise. However, in February 2011, at the PQRI Parenteral and Ophthalmic Drug Product Thresholds and Best Practices workshop, the FDA's New Drug Quality Assessment Office (within the Drug Evaluation and Research Center [CDER]) delivered a presentation covering ophthalmic leaks in LDPE container closure systems. , suspensions and emulsions. Presentation that discusses the principles of applying a science-based approach to study design, the format for reporting leachable results and leachable thresholds, 1, 10 and 20 ppm (mg / L or µg / g) respectively, the recommended thresholds for reporting, identification and qualification. Although the content of this presentation is publicly available, these thresholds do not appear in official FDA guidelines. For this reason, PODP recommendations are defined as a reference to provide information on a possible approach or starting point, but they are not defined as a practice that should be followed.
This is an advantage for ODPs as identification and proficiency thresholds are generally higher than would be calculated using parenteral thresholds such as SCT.
Conducting successful and practical extractable and leachable evaluations for ophthalmic drug products requires excellence in study design, ability to conduct studies particularly in analytical testing, and a deep understanding of materials, extractables, and leachables gained through extensive experience. EUROLABhas broad expertise in designing and implementing chemical testing programs that utilize state-of-the-art analytical techniques, highly trained and competent analytical scientists, and knowledgeable study directors. EUROLABhas a long history of successfully partnering with optical pharmaceutical packaging and product manufacturers to effectively and efficiently secure regulatory approval for their products.
EUROLAB, with its highly expert team and internationally accredited laboratories, Ophthalmic Drug Product Tests It performs all test, analysis, measurement, evaluation and report generation services completely and reliably.
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