Outsourcing When is a sterile fill-finish required?
Drug products that are delivered via the parenteral, ophthalmic, inhaled, or otic (administered via the ear) route present an increased risk of infection or harm because they bypass many of the body’s natural defences. To ensure patient safety, the FDA requires that drug products delivered via these routes be supplied as sterile products. This designation includes many complex drug products, including ophthalmic suspensions, sterile injectables, reconstituted lyophilised powders for injection, and aqueous-based aerosols for inhalation. ■ Terminal sterilisation: A process that involves filling and sealing product containers under high-quality environmental conditions, then subjecting the product in its final container to a process such as heat or irradiation.
■ Aseptic sterile fill-finish: A process in which the drug product, container, and closure are first subjected to sterilisation methods separately, as appropriate, and then brought together (aseptic manufacturing). As there is no process to sterilise the product in its final container, it is critical that containers be filled and sealed in an extremely controlled environment. This represents one of the hardest challenges in pharmaceutical manufacturing.
The FDA has made it clear in multiple guidances that aseptic manufacturing and sterile fill-finish should only be employed when terminal sterilisation is not feasible, because aseptic processing involves more variables and therefore carries more risk. However, as formulations become more complex, a growing number of drug products and containers cannot be terminally sterilised due to degradation or loss of performance when exposed to heat or radiation. When terminal sterilisation is not possible, manufacturers of parenteral, ophthalmic, inhaled, and otic drug products must turn to aseptic manufacturing and sterile fill-finish. When the term “sterile fill-finish” is used, often the first drug products that come to mind are sterile injectables (e.g., liquids filled in vials or syringes). While liquid solutions, suspensions, and emulsions are common candidates for sterile fill-finish operations, powder fills and lyophilisation (for example., freeze-drying to preserve and obtain greater stability) are also performed under aseptic conditions. Regardless of the form factor, each individual component comprising a drug product must be sterilised prior to aseptic fill-finish. This includes active pharmaceutical ingredients (APIs), water for injection (WFI), and any other excipients that are part of a
formulation. Equipment and container systems must also be sterilised. Source:
Lubrizolcdmo.com
“An example of one such device is the Finia Fill and Finish system by Terumo, which is an automated and flexible platform offering electronic data capture.”
Dalip Sethi
It is also essential that the doses aliquoted – or divided – from a single batch have volume and cell number consistency. “Cells are suspended particles and require gentle mixing to maintain a uniform suspension during the mixing and aliquoting procedure. This challenge can be overcome by automated systems that can provide gentle mixing,” says Sethi.
Reducing the number of manual steps in the fill/finish process should reduce effort per batch, and automated systems that capture electronic data may increase efficiency through parallel batch processing. “An example of one such device is the Finia Fill and Finish system by Terumo, which is an automated and flexible platform offering electronic data capture,” Sethi highlights.
Automation, coupled with functionally closed systems, is a way to ensure the cellular product is viable, consistent between product bags, and traceable from a GMP perspective. Sethi says additional benefits of automation are that labour and facility costs can be driven down and reliable processes can be maintained, with electronic records of each action performed – a big advantage if regulators come knocking. There is no doubt the production of large volumes of Covid-19 vaccines complicated the sterilisation process. CDMOs had to scale up the alternative sterilisation techniques to keep up with demand, because heat sterilisation damaged the vaccines. Development in the market to meet the demands of Covid-19 moved things forward as CDMOs diverted resources to be able to respond to the need for immediate vaccines.
But with more cell and gene therapy products expected to arrive, more companies will have to adapt their aseptic sterilisation capabilities or partner with third parties already proficient in this area. Given the benefits listed above by Sethi and Heathman, automation is likely to become a large part of the process as companies strive to become more efficient, both for the sake of patients and their profitability. ●
Living products like cell and gene therapies cannot be sterilised at the end of manufacturing without the risk of killing the live components.
22 World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net
Lightspring/
www.shutterstock.com
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