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16 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING EBOOK 2021 P h a r mTe c h . c o m Manufacturing towards ready-to-use containers and sophisticated packaging components, such as on-body devices. When producing small quantities, filling, process design, and quality concepts present pharmaceutical services providers with new challenges. For example: given the small amount of available API, fixed line losses mean sub-optimal yield; packaging configura- tions might be more varied; [and] fill-weigh checks of 100% of containers are needed as in-process sampling might not provide the right level of process control and is also destructive and costly. The filling system for small commercial-batch quantities needs to be ad- justable with quick decontamination, aeration, and product and format changeover, all in accordance with international regulatory requirements. PharmTech: What are some of the considerations for choosing the type of cleanroom equipment for fill/finish? Zimmermann (Vetter): Given the individual ben- efits of isolators and restricted access barrier systems (RABS), the technology best utilized is largely depen- dent upon the manufacturer´s portfolio and business strategy. Isolators are often considered the best solu- tion for a high sterility assurance level. They employ a fully sealed unit entirely 'isolated' from the outside environment and rely on a reproducible, automatic, and extensive biodecontamination process. Usually, an isolator requires a fairly long downtime for product changeovers, which makes it best suited for large-scale runs of single products. RABS, on the other hand, involves barrier and dy- namic airflow separation between the environment and drug product. Thus, the system offers the ad- vantage of faster setup and efficient product change- over. The key, however, is to operate the RABS with the barrier doors closed at all times. As RABS are usually situated in a class B cleanroom, there is an additional layer of protection. This distinction al- lows for a higher utilization and f lexibility when running multiple products. The long-term vision for small-batch manufac- turing is shifting from a human-centered produc- tion towards a fully automatic process with robotic equipment to reduce as much as possible any risk to the product. With the small footprint for such commercial batch sizes, isolator-type technology might be best suited for this use. Both systems offer opportunities and challenges. Ultimately, the chosen type of cleanroom technol- ogy is one that best addresses the individual needs of the divergent product requirements as well as a high level of performance that meets strict regula- tory and customer requirements. Technology developments PharmTech: What are some recent technology devel- opments in aseptic filling? Zimmermann (Vetter): Over the past few decades, the technology for aseptic fill/finish has continued to evolve. Developments in cleanroom technology— both with isolators and RABS—are mainly directed to a higher automation of processes for providing ad- ditional sterility assurance and new technologies with sufficient integrated versatility to anticipate future re- quirements for format, packaging, and filling. "The vision for small-batch manufacturing is shifting to a fully automatic process with robotic equipment to reduce risk to the product." —Joerg Zimmermann,Vetter