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www.biopharminternational.com July 2021 BioPharm International eBook 37 tion challenges, Forsyth notes. "You worry more about bioburden in a bio- logical plant than in a small-mole- cule facility, but generally if you have an effective cleaning validation pro- gram, you're fine," he says. However, setting cleaning limits can be tricky because traditional meth- ods fail to consider some of the most signif icant differences between bio- pharma and small-molecule facilities. "The most notable difference between the two types of plants is that biophar- maceutical facilities start processes using equipment with large surface area but generate small batches, both of which require the use of lower cleaning limits, so if you use the entire equip- ment train, your limits may, at f irst, appear to make no sense," Forsyth says. Single-use systems and equipment have eliminated some of those problems, but they persist for hybrid plants still using stainless steel equipment. Another question is how batches are finished and whether pre-cleaning equipment preparation processes are consistent from one batch to another. If they are not, varying amounts of product may be left on equipment sur- faces after each run. "Some types of equipment will empty completely, but others won't," Forsyth says. He recalls one of his f irst experi- ences working on cleaning validation in a pharmaceutical development lab. " We were concerned about pouring active ingredients down the drain, so we wound up scraping equipment and then vacuuming it before clean- ing. By the time we started cleaning that equipment, it was almost visually clean," he says, noting that this type of approach reduces the risk of cleaning failures and compliance problems. At some companies, varying amounts of material may be left on the equipment when cleaning officially begins. OTHER CDMO CHALLENGES CDMOs that focus on clinical trial drug manufacturing face unique chal- lenges in setting cleaning limits. "For clinical operations, you are not mak- ing a lot of batches of the same thing, so you don't make enough batches of any single product to validate the c lea n ing met hods using sta nda rd approaches," says Forsy th. "In this case, it is usually best to work with a more genera l model, establish a worst case, and then evaluate each new product coming in. However, this approach increases the effort and jus- tif ication required to maintain the model, and a lot of CDMOs don't do this very well," says Forsyth. Speci f ic approaches a re needed to prevent cross-contamination in multiproduct facilities, Forsyth says. "Best practices ca l l for ca lculating the amount of residue that can safely be carried over for every product. For a mu ltiproduct facilit y that makes 10 products, that means calculating the limit of one product versus those of the other nine, tak ing the low- est number and then using that, and then following the same procedure for the rest of the products," he says. STATISTICS AND INSTRUMENTATION ASTM standards have been focusing on use of statistics, which are important after a cleaning program has been vali- dated and needs to be maintained, says Forsyth. Maintenance requires trend- ing data. "The basic statistics needed for trending are fairly straightforward, and more advanced statistics can also be applied, but it has been difficult to motivate some companies to do that in the current environment," he says. More work is also being done to use analytical methods to reduce the subjectivity of visual inspection, but Forsyth hasn't seen any consistently effective methods coming into gen- eral use. The best way to remove sub- jectivit y from inspections has been to qualif y those who must perform those inspections, a step that most regulatory agencies now require. "I advise clients to set visual limits for residues and have staffers who might be assigned to perform visual inspections go through specialized tra ining to recogniz e clea rly what various levels of residues look like on equipment, compared w ith images of surfaces with residues that meet safe carryover limits. It's important to have exercises in place that will allow people to visually recognize clean- liness levels to avoid patient safet y risks," Forsyth says. Cleaning is not a popular activity, Cokely noted in his presentation, but it is essential. Taking cleaning and sanitization validation programs for granted only puts facilities and peo- ple at risk and increases the likeli- hood of costly noncompliance. REFERENCES 1. FDA, Form 483, Emergent Biosolutions, FDA.gov, April 20, 2021. 2. ISPE, "Regulatory Requirements and Expectations for Cleaning and Disinfection of Controlled Manufacturing Areas," Webcast, April 9, 2021. 3. ASTM, E3106-18e1, Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation (2018). BP Biopharmaceutical Analysis Cleaning Validation Entegris ........................................................... 9 Sartorius Biologics ....................................... 21 Yokogawa Electric Corporation ................. Opposite Cover, 3 Ad Index COMPANY PAGE