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PharmTech.com Bio/Pharma Outsourcing Innovation eBook February 2024 Pharmaceutical Technology ® 7 Development for injection into the vitreous humor of the eye, offer- ing a direct and targeted approach for treating var- ious ocular conditions, such as glaucoma and acute macular degeneration (AMD). One key consideration in the development of IVT products compared to other parenteral preparations is the injection volume and the associated fill vol- ume in the primary packaging container. The vitre- ous humor is a confined space within the eye, and precise control over the injected volume, currently between 10 µL to a maximum of 100 µL, is essential to not majorly disturb basic physiolog y, including intraocular pressure. However, (accurate) filling of small volumes into primary packaging containers, such as pre-f i l led syringes is cha l lenging wit hin most ster i le faci l it ies a nd cont rac t m a nu fac t u r- ing organizations (CMOs), and fill volumes of IV T products typically significantly exceed the intended dosing volume. This implies that IVT products are of ten significantly overfilled, and the selection of pre-f i l led sy r inge presentat ions in luer-lock con- f ig u rat ion ra nges f rom 0.5 to even 1 m L . Con se- quently, the end-user, in many cases a healthcare professional, needs to manipulate syringes for IVT use by expelling air or volume, a practice k nown as "down-dosing", introducing the risk of variabil- it y i n ad m i n i stered volu me depend i ng on g rad- uation marks and the proficiency of the end-user. In add it ion, t h is dow n-dosi ng process resu lts i n significant product waste negatively impacting the overall cost of goods (COGs). The absence of an air bubble in the syringe is particularly desirable from a user perspective: down-dosing becomes consid- erably less challenging in absence of an air bubble. Any (even minimal) air bubble increases the risk of stopper movement during air transport because of pressure differences, which could potentially com- promise the sterile barrier. However, accurate fill- ing of small volumes with minimum product loss in addition to reducing dif f iculties during visual inspection of sma l l-volume products, and f i l ling w it hout an air bubble, requires specia l manufac- turing knowledge and expertise. Meeting stringent regulatory requirements is par- amount in the development and manufacturing of IVT products. Regulatory requierments, as defined by FDA, the European Medicines Agency, and pharmaco- peial standards such as the United States Pharmacopeia, European Pharmacopoeia set strict—and for IVT prod- ucts more stringent—compendial requirements and standards, compared to products from other routes of administration to ensure quality, safety, and effi- cacy of the products. As two examples, the amount of particulate contamination, and endotoxin levels are critical parameters demanding meticulous attention, measurement, and observation. IVT products must adhere to compendial require- ments including visible and sub-visible particle con- trol. In particular, the limits for sub-visible particu- late contamination are tighter (in the United States Pharmacopeia) compared to those for other parenteral preparations. Particulate contamination might be a result of extrinsic contamination originating from container or stopper manufacturing, the environ- ment of the filling process, or originating from the actual formulation (intrinsic par ticles as a result from degradation products due to sub-optimal for- mu lat ion). For I V T products, ready-to-use (RT U) product conf ig urations have gained prominence because of increased f lexibility of handling diverse product configurations at the manufacturing lines, and short turnover times. In addition, the demand for user-friendly, pre-assembled products has increased, reducing the risk of microbial contamination and er- rors during preparation. This shift in configuration aligns with the broader trend in the pharmaceutical industr y toward improving ease of use and mini- mizing the risk of medication errors. However, the particulate control of RTU material, which is not yet a standard, is challenging, and the selection of the primary packaging container during development, and its rigorous characterization, is key to circum- vent associated challenges and losses during visual inspection during manufacturing. Endotoxins, bacterial byproducts that can cause inf lammation and tissue damage, pose a particular challenge for IV T products. Strict limits on endo- toxin levels are established for the final product to prevent adverse effects, cumulating from individ- ual contributions from manufacturing equipment/ consumables including the RTU primary packaging container. A pivotal emphasis should be placed on establishing acceptable limits for endotoxins within these container closure systems. The critical consid- eration lies in establishing a coherent relationship be- tween these specifications and the final drug product Meeting stringent regulatory requirements is paramount in the development and manufacturing of IVT products.