Preventing Product Transfer
To prevent contamination from other products, most CMOs, especially the larger European ones, such as Girindus (www.girindus.com), Miltenyi Biotec (www.miltenyibiotec.com), Lonza (www.lonza.com), and Sandoz, use, where practical, closed systems that rely on automating as much of the process as possible and using fixed piping to prevent contamination from getting into the joints between systems and pipes.
Additionally, during a GMP campaign, CMOs that have a number of different production suites available only have one biotherapeutic at a time in each dedicated area.
At Medipolis, a microbial fermentation CMO in Finland that manufactures products mainly for Phase I and II trials, only one product will be in the 930-L fermenter area until this part of the production is finished.
However, since not all of the processes can be automated, the staff plays a key role in making sure products are kept apart. One important way to prevent contamination is to ensure staff turnover is low within the facility and that there is continuous GMP-training program in place. The quality of your processes relies on your people being experienced in what they are doing, comments Dr. Nachtmann.
Many companies also restrict the flow of personnel in and out of each area to prevent potential contamination from the different therapies in production. In our facilities we have a central corridor and an external corridor that runs around the suites, Dr. Ellison says, so that you cannot go from one to another without going out via the external corridor and then back through the change area into the central corridor again.
Some CMOs also prevent their personnel from having access to different production areas. According to Astrid Brammer, Ph.D., senior manger of business development at Strathmann Biotec (www.biotec-ag.de), a German microbial fermentation specialist that manufactures products for Phase I to III clinical trials and for commercial supply, Strathmanns facility has an airlock system with keypad codes so that staff from the fermentation area cannot enter the chromatography suite because they do not have the authorization codes to do so.
During production in multiproduct CMOs, even clothing comes under suspicion of harboring contaminants. We have dedicated color-coded gowns for the different production suites (for example, fermentation, purification, and so on) because even though gowns are washed regularly, there is still a chance that they could carry something unwanted from one suite to another so we make sure they are kept separate, Sirkka Aho, CTO of Medipolis explains.
During product changeover in a multiproduct facility, such as Boehringer Ingelheim (www.boehringer-ingelheim.com), one of Europes largest CMOs producing Phase IIII biopharmaceuticals and commercial therapies from microbial and mammalian cells, a rigorous cleaning process is carried out using chemicals including phosphoric acid and sodium hydroxide. Systems are either cleaned in place, or in the smaller CMOs staff can move them out of the production suites for cleaning.
After cleaning, equipment is rinsed and swabbed to test it for residues and analyzed for total organic carbon and nucleic acids, as well as microbial contaminants such as bioburden and endotoxins.
To check that the residue amounts present are not above the defined acceptance levels after the cross-over phase, cleaning validation and recovery studies are of key importance. We are mindful of contamination and even do cleaning and recovery studies on the systems we use for small-scale pilot work in order to collect information before we continue into GMP manufacturing. We also use dedicated equipment wherever possible because we view any contamination risk seriously, says Monika Henninger, Ph.D., head of customer relations and client projects at Boehringer Ingelheim.
Liselotte Larsson, Ph.D, marketing manager of Novozymes Biopharma (www.novozymes.com), a niche CMO based in Sweden that specializes in microbial fermentation to provide therapies for Phase I and II trials as well as some commercial products says, The main difference for a multiproduct manufacturing facility is that not only do you have more rigorous cleaning procedures but you have to document and prove that everything is clean too.
Where practical, we are now using disposable equipment in our processes as this means we have less cleaning and cleaning validation to do. There is a growing trend in many multiproduct CMOs toward the use of disposables.
In addition to using disposables, we also prevent cross contamination by using dedicated materials like hoses, membranes, filters, and chromatographic resins for each product, says Aho.