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12 BioPharm International eBook September 2019 www.biopharminternational.com Regulatory Sourcebook Good Manufacturing Practices many, if not most of the cGMP problems that regulators do cite. "T he cGMPs draf ted in 1977 had called for adequate educa- tion, training, and experience. But when have we ever defined what 'adequate' means for people who work in cGMP, for the inspectors at FDA, for the reviewers at FDA? We have this fundamental flaw in the system," Hussain says. "So how can we expect people who are not qualified for their jobs to do any- thing better? Our attention needs to be focused on being objective," he adds. Hussain sees professional development as the key to develop- ing the type of managers needed to instill a "culture of quality" within the industry. Inadequate management train- ing and development may also have implications for the indus- try's use of technology, says con- su lt a nt Ga r y R itc h ie. He u ses d ig ita l records as a n exa mple. Like paper-based records, digital records are subject to the predicate rule; they must be retained for a set period of time after the drug expires. But digital records offer an immediate transparency that paper does not. "In some cases, companies are afraid to be stuck with electronic records that actu- ally show how management made decisions when they processed something. You cannot erase the record," he notes. "The reality is that people are still working on paper in the 21st cent u r y d ig ita l world, because it is more flexible," says Ritchie. "FDA has suggested that, in the future, it may not allow hybrid (i.e., paper-on-glass) systems, but until the science of manufactur- ing evolves, change won't take place," he says. "FDA wants to hold up as an example those com- panies that have moved to digital records, but there are still so many more facilities that use paper and whose practices remain stuck in the 1900s." PROCESS VALIDATION PRACTICES Another area where cGMPs could be shored up, observers say, is in process validation and delineating the expectation of statistically valid sampling and statistical process control. "That was the stated princi- ple behind FDA's process validation guidance in 2011," says Hussain. As he notes, only a handful of Big Pharma companies appear to be using modern process validation principles correctly. "The rest are struggling, and haven't even begun to use the concept for new, let alone legacy, products," he says. One problem pointed out by FDA compliance officer Grace McNally in a 2011 presentation is a failure to use the best statistical methods and validation principles. As she noted, "At times, compendial standards take on the character of statistical procedures … but, in all cases, state- ments about whether the compen- dial standard is met apply only to the units being tested"(8). Optimal production calls for meaningful in- process tests and for a statistically significant number of tests based on batch size of final dosage forms, Ciurczak says; companies may be following traditional practices, yet failing to meet the requirements set by cGMPs. "Let's say that a com- pany tests 20 tablets out of two million. Even someone without a math background knows that's not statistically significant," Ciurczak says. He uses military standards as a contrasting example. "If you are manufacturing more than a half million units, the US Department of Defense says that you must run 25,000 tests. If a pharma company had to run 25,000 HPLC [high- performance liquid chromatogra- phy] tests, it would cost way too much and it wouldn't show what was happening in the other 1.75 million." Finally, there are the tests themselves, and whether they make sense given today's manufacturing realities. "Friability and disintegra- tion tests are not meaningful, and they are simply not timely any- more," says Ciurczak. "They may have been timely when you had a single-punch machine that was put- ting out 100 tablets an hour. They are not timely when you have a 36- or 40-punch machine that is put- ting out 100,000 or 200,000 tablets an hour," he says. GETTING PAST THE THREE-BATCH RULE FDA's 2011 process validation guid- ance was supposed to mean the end of the "three batch" rule for product release but that concept is still alive and well at many com- panies, and sampling is still being handled in a rather primitive way at some facilities, says Ciurczak. The problem with adherence to this practice is the fact that "any time you take selective samples, Industry observers pinpoint the need for more clarity with GMPs in the key areas of training and employee personal development; statistics and sampling; and process validation.