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52 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING EBOOK 2021 P h a r mTe c h . c o m uum, can also be performed more easily if the air bubble is smaller. Any air in the container must be expelled before an injection can be adminis- tered, resulting in loss of the drug substance. If the drug has a high viscosity, any existing small air bubbles cannot be removed and so would be injected into the eye. Implementation of the stoppering process on a filling line can be highly complex when using very small stoppers to close 0.5 mL pre-filled syringes. In addition, the behavior of stoppers developed for the ophthalmic market (i.e., silicone oil-free) means that the DP manufacturing requires an even higher level of expertise from the contract development and manufacturing organization to guarantee that the stoppers are correctly trans- ported and positioned, and that they are not dam- aged during the process. Batch size difficulties PharmTech: Does batch size contribute to difficul- ties with fill/finish processes? Kehl (swissfillon): The major fill/finishers may ex- pect to see line losses of approximately 200 mL sometimes as high as five liters depending on the set-up in the pipping system. For very large batch sizes, there is likely to be at least 1–2% wastage in the system, and this level of loss may be accept- able. However, if 200 mL out of a two-liter batch is lost in setting up the machine, 10% of the drug is wasted. We have experience of working with customers who have as little as 1.2 L of their drug substance at project initiation and even further down during clinical manufacturing. In older fa- cilities, with stainless-steel equipment rather than single-use disposable equipment, working with such small batch sizes is impossible. Preparation to set up the machine is critical to minimize losses, and there are systems on the market that aid in emptying the filter in the di- rection of the fill line. The considerable pressure to reduce losses of the drug substance must be balanced against the cost of such equipment, and it is important to discuss options with customers. There is increasing demand for small batch fill- ing, and more companies are investing in suitable filling lines, but this is an area where the experi- ence and expertise of outsourcing partners can be beneficial in reducing losses of enormously valuable drugs. High value and difficult-to-fill products PharmTech: What complications might arise when approaching fill/finish of high value and difficult- to-fill products, and how can these complications be overcome? Kehl (swissf illon): The main challenge is opti- mizing systems to reduce losses of the drug sub- stance. An important part of this is close col- laboration with primary packing manufacturers, to understand how the primary packaging and drug substance handling can be integrated into the process. Operations "There is increasing demand for small batch filling, and more companies are investing in suitable filling lines, but this is an area where outsourcing partners can be beneficial …" —Daniel Kehl, swissfillon