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50 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING EBOOK 2021 P h a r mTe c h . c o m Operations allow very small quantities to be filled, while mini- mizing losses of these extremely expensive drugs. Working in close connection with a primary pack- aging manufacturer is the key to success. Oral dosage forms of biologics are the holy grail of drug delivery, for example supplying insulin pills rather than injections, but have yet to be realized commercially. Some companies are also investigating the use of aerosols to allow drugs to be administered in liquid form, or implants for controlled release over time to facilitate de- velopment and manufacture. Although research in this area is ongoing, the next decade will see fill/finish continue to dominate the market for the delivery of biologic drugs. However, there is an increasing trend for fill/finish technology to be used with innovative delivery systems such as pens, wearable devices, or auto injectors to allow self-injection and home care. Main challenges PharmTech: What are the main challenges associ- ated with fill/finish of ophthalmic therapeutics and biologics? Kehl (swissfillon): Ophthalmic drug products (DPs) require a high level of process know-how and state- of-the-art manufacturing technologies to maxi- mize safety, meet stringent regulatory require- ments, and minimize manufacturing costs. The fundamental requirement for ophthalmic drugs, which are injected into the back of the eye, is that the DP is essentially free from subvisible particles and 'f loaters'. Particulates can occur due to contamination or may arise from primary packaging or during the filling process, and there is evidence that silicone oil plays a role in both the denaturation of pro- teins and the initiation of aggregation processes in proteins (2). If required, filling activities for ophthalmic drugs can be performed using a ro- tary piston pump, which precludes the possibil- ity of particulates occurring due to damage to the pump tubing. Even if the subvisible particle requirement is met, f loaters or micro silicone oil droplets can still be present, and these can ac- cumulate in the eye with repeated injections (3). For these reasons, silicone oil-free systems are preferred for ophthalmic applications. In the case of biologics, the drug substance is usually supplied in frozen form at –70 °C. The thawing process, before the compounding and di- lution steps, has to be carefully controlled to avoid foaming as a result of aggregation, and to secure a smooth transfer and manufacturing process. Another important consideration is ensuring highly accurate filling and minimizing overfill of containers. The injection volume of ophthal- mics is usually 50 µL, but containers are routinely overfilled by a factor of three to guarantee the safe expected extractable volume, and two thirds of the drug substance is wasted. A close relation- ship with primar y packaging manufacturers, which leads to high understanding of the packag- ing characteristics to be taken into consideration, can help to minimize overfill and can lead to cost savings for customers. When required for a specific project, vacuum filling can help to remove or reduce residual air in the system. This is important as denaturation of a protein-based product could start at the f luid and air interface, and the container may be exposed to variations in pressure during transport, leading to stopper movement and loss of sterility of the product. Final sterilization, which involves vac-