PAT for Biopharma Slow to Take

PAT is in low-level use inbiomanufacturing partly becausethere is little understanding ofits cost, quality and schedulebenefits, says Xcellerex's Galliher.Photo courtesy of Xcellerex.Biotech contract manufacturer Xcellerex, Inc. (Marlborough, Mass.) is at the forefront of PAT in the biopharmaceutical industry. Founder, president and CTO Parrish M. Galliher hosted a session at this year’s IFPAC conference on the bio aspects of PAT. Pharmaceutical Manufacturing's managing editor Paul Thomas followed up with Galliher about the outlook for PAT in biopharma.Click the “Download Now” button below for Galliher’s IFPAC presentation slides.PM: How was the crowd at your IFPAC session? Were they ready for PAT? P.G.: Generally, PAT is received with concern and skepticism by participants because they view PAT as yet another FDA burden rather than an important tool to develop faster, better and cheaper biomanufacturing. My goal as session chairperson was to bring five speakers who had installed PAT applications already, to reduce variability, improve quality, reduce cycle time and to reduce cost.PM: Where is PAT in the biopharmaceutical industry right now?P.G.: PAT is in low-level use in biomanufacturing. It’s used in downstream purification operations, but these are mainly parametric methods that monitor and measure surrogate markers of product quality, not direct product quality measurements. Nevertheless, there are several good PAT applications in use at Eli Lilly, Biogen Idec and Baxter Healthcare, to name a few.PM: What, if anything, is holding PAT in biomanufacturing back?P.G.: PAT is not required yet by the FDA for biopharm applications and the PAT contingent at the FDA is still enrolling the CBER contingent. Until then, we are unlikely to see a guidance from the FDA on PAT for biologics.Until PAT for biomanufacturing is really pushed by the FDA and the benefit of PAT is translated (and clearly understood) into cost, quality and schedule benefits, it will be slow to take in the industry.Sensor technology limitations are the other big issue. There are only a handful of sensors available to us now and they are surrogate indicators. The technology development cycle for these sensors is three to five years to get into the hands of the users.PM: What are the key differences in how PAT is applied to biologics manufacturing (as opposed to conventional pharmaceutical manufacturing)?P.G.: The key differences are:

1. There are approximately 15 quality attributes of a biologic (due to their complex structure and complex biological function), versus five or so for small molecules.
   
   
2. The fluids in which biologics are produced are more complex and contain more ingredients and therefore present more interferences to sensors.
   
   
3. Several steps in the biological manufacturing processes need to be sterilized with heat and many sensors delicate enough to measure biologics cannot withstand these extremes.

PM: What is Xcellerex doing in regards to PAT? Has the industry been receptive?P.G.: Xcellerex takes a broad view and interpretation of PAT to improve manufacturing quality and control. Specifically, we have three broad approaches: We are using disposable manufacturing systems to eliminate product cross contamination. We are housing the manufacturing systems in clean air modules to remove the operator and to keep the manufacturing system cleaner. We are using electronic batch records with on-line compliance watchdog to reduce human error.

1. We have brought environmental monitoring on-line in our production module systems.
   
   
2. We have built a cGMP compliance watchdog on-line in our process control, electronic batch record software.
   
   
3. We are adapting the current parametric on-line sensors to work in our disposable mfg. systems and converting them to optical sensors so that they are non-invasive and do not contaminate the product stream.
   
   
4. We are examining on-line HPLC for improved process control and yield of a biomanufacturing process.