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Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING EBOOK 2021 57 over-wrap blanketed with a nitrogen overlay for oxygen-sensitive products as required. Leachable data are unique to each individual drug product and are a key indicator of material compatibility. As pharmaceutical companies de- velop new or generic products, stability testing is required to evaluate and analytically prove leach- able levels meet acceptance criteria for each pro- prietary product. Leachable data are not widely published but is based on the quantity of injectable products in BFS on the market. Today, it can be ascertained that leachable levels could be favorable for many new and existing products. Regulatory approval concerns. Regulators have rec- ognized that human operators are the most signifi- cant source of adventitious contamination in a fill- ing environment. In BFS production, operators are typically absent during filling; the main source of microbial contamination is effectively eliminated (10). Advanced aseptic BFS technology modulates the air pressure flow within a nozzle shroud via high efficiency particulate air filtration or other sterilized air source, meeting ISO 4.8/5 requirements during filling, thus providing product safety and regulatory compliance (6). Drug formulation. BFS plastic containers require for- mulation development with a focus on high permea- bility of water vapor and gases, sorption potential, and the possibility of an API's poor resistance to heat (11). Each product is evaluated, and proper mitigating steps are used. BFS products are typically placed in aluminum-foil pouches to reduce product moisture loss and sustain product integrity over the shelf life of the vial (11). Cooling techniques are used for process- ing heat-sensitive products and range from product flow line temperature controls to vial chilling imme- diately following the filling process. Sterilization. The active components in biologics, proteins, and other complex solutions may degrade when exposed to high temperatures for a long pe- riod, making conventional terminal sterilization unsuitable. Filter sterilization followed by direct BFS packaging may be a safe and effective option for these products (7). When neither sterile nor terminal filtration is feasible, as for certain large- molecule products, aseptic transfer of the product to the BFS machine may be an alternative (6). Supply chain. BFS devices use a single primary packaging material, pharmaceutical-grade resin, which is readily available and can be safely stock- piled for years. Stainless steel is also needed to make the needles, which also holds true for a tra- ditional PFS device. The BFS supply chain, with its single primary packaging material, is far less complex than that for a traditional vial-filling op- eration. The glass, stopper, and plunger lead times have extended dramatically under the current pan- demic environment, and the pre-handling efforts associated with manufacturing are also eliminated by using the BFS manufacturing option. Environmental impact. Companies that have im- plemented BFS technologies report environmental benefits including energy savings, an environmen- tally friendly sterile process, and a smaller carbon footprint. The process also avoids the energy ex- penditures of glass manufacturing and the result- ing industrial waste (12–13). The BFS supply chain, with its single primary packaging material, is far less complex than that for a traditional vial-filling operation.