Critical Support Components
Scale-up efforts that focus strictly on unit operations and engineering algorithms may still miss critical support activities, without which processes cannot move forward.
Analysis, including process analytic technology (PAT) and more traditional QA/QC and process monitoring, play an integral role in scale-up. The larger the process the greater the investment and hence more tightly processors must control product characteristics. “We see more delays and constraints from product comparability characterization than for process-related events,” says Friedrich Nachtmann, Ph.D., head of biotech cooperations at Sandoz (www.sandoz.com).
Sandoz maintains a broad portfolio of products that it manufactures for customers as well as its own medicines. Most are produced through microbial fermentation, although the company also maintains a cell culture facility for mAbs. “There is more excitement with microbials, however, because product variability is higher in that production system than with cultured cells,” Dr. Nachtmann adds.
To eliminate the risk of product quality drifting from batch to batch or during scale-up, Sandoz is investing significantly in “up-front analytical characterization,” according to Dr. Nachtmann. Most of this work is performed offline in parallel with process development. Sandoz also has a PAT program in place for achieving continuous process improvement of established processes. However, Dr. Nachtmann distinguishes PAT-related monitoring from real characterization of product purity.
Data is another easy-to-overlook issue in scale-up. According to Pete Latham, president of Biopharm Services (www.biopharmservices.com), pharmaceutical/ biotech manufacturers spend 13% of their time looking for data and fail to find it between 10% and 20% of the time. Data problems plague the pharmaceutical value chain from discovery through manufacturing, where lost data means duplication of effort. Biopharm Services recently received a grant from the U.K. government to study how data is managed and used during process development and scale-up.
Numerous electronic data-management tools already exist for handling manufacturing operations. However, current practice is not as unified as one would imagine from reading data-management vendor literature. In the real world, end-users rely on electronic laboratory notebooks, off-the-shelf data programs like Excel and word processors, and old-fashioned paper records. “This creates islands of data,” says Latham. “In fact there is no comprehensive system for managing and leveraging that data consistently enough to serve the tech transfer needs of bioprocess scale-up.”
Biopharm Services is working on a new data architecture wrapped around ISA-88, the international standard for flexibility in production, which Latham hopes will make manufacturing data more amenable to scale-up situations. “ISA-88 is a methodology for collecting and putting data into a format that is scale independent.” The standard employs a modular design approach that speeds and facilitates building process definitions and reuse of previously defined processes and scale-up logic.
From this data, one may apply transition algorithms that translate process details to fit any type of equipment or facility. Ultimately, the goal is data-management software that facilitates scale-up and technology transfer. “One way to look at this is to take general process data and translate it into a master recipe,” adds Latham.
Don’t software packages already do this? “Yes, ERP software and lab notebooks, in particular, facilitate scale-up and technology transfer, but users lack sufficient faith in ELNs, which means that most people keep paper records side-by-side with electronic records. Biomanufacturers desperately need an impetus to abandon the existing paradigm,” concludes Latham.
The other problem with a universal data system is the unique value system for pharmaceutical and biotech drugs. A one-size-fits-all mentality simply doesn’t apply to bioprocess scale-up, nor are suited to “hard” process industries like semiconductors particularly amenable to biotech. “We can’t just put the process into a bigger pot and get the same result,” adds Latham.
For these recurring questions of scale, Biopharm Services BPS is involved with the U.K.’s Innovative Manufacturing Research Centre for Bioprocessing at University College, London, which has been building scale-down models for some time.