In search of nightgowns
"We were undergoing our biennial GMP inspection and the FDA inspector wanted to observe second-shift aseptic-filling operations," recalled our GMP Agent-In-Place. "I arranged access for the inspector at 8 PM. The office area was empty and the aseptic-fill-area manager trusted me to guide FDA through the process. To observe the fill, we needed to go into the cleanroom and gown appropriately. We entered the empty, dark clean area without gowning, and it was not until we got to the aseptic-area window that I realized we didn't have the proper clothing on. Both of us were so embarrassed that we never mentioned it again."
More than enough oversight"Our US-manufactured sterile injectable product was distributed only in Japan by a distributor there," noted our GMP Agent-In-Place. "There was a complaint from Japan regarding a malformed stopper. Because this might mean the seal could be compromised, we recalled the six potentially affected batches and informed FDA.
After their evaluation, FDA required a 100% effectiveness check, so we called our distributor and asked if they had, indeed, recalled the product from their customers in Japan. I'm pretty sure FDA didn't understand that these batches were all exported to one customer," theorized our agent.
Whose fault is it?
"During a routine audit of our manufacturing area, we noticed that the stopper washer used to wash and siliconize vial stoppers was operating outside validated parameters," said our GMP Agent-In-Place. "After tracking down the electronic maintenance log, we determined that a recent repair involved replacing the washer control interface. It turned out that the factory default settings for the interface module were not the ones we used, thereby leading to the change in parameters.
"We wash the stoppers to remove particulates and surface contaminants. Changing the wash cycle could, however, add unwanted material to our product and negatively affect our patients. So we tagged out the stopper washer and quarantined the lots made since the repair. Our change-control process allows 'like for like' equipment repairs to be made without a formal validation, so the repair change had slipped through. We re-evaluated our SOP as a result, and ultimately found that the validated wash cycle was sufficiently robust. The changes made did not significantly reduce the required cleaning action. Testing of the product and stoppers showed no change in quality. Whew!"
A single mistake
"Years ago, I was in charge of my company's stability system," reminisced our GMP Agent-In-Place. "Besides the normal stability batches, we put certain exceptional batches on stability. To assure quality, a pharmaceutical development scientist reviewed each deviation to determine whether it should be included in the stability program. The scientist would check the 'stability required' box on the form and sign it.
"During an FDA inspection, the inspector reviewed the one deviation form that we had not picked up for stability," our agent remembered. "When asked for the data, we told the inspector it would take a day to obtain the information. We immediately withdrew one bottle of tablets from retains and tested it, added the data to the computer database, and had a printout for the inspector the next day. The inspector noted the date on the printout. We tried to argue that upon any notice of an error, such as this, our policy was to immediately correct it. We still received a 483."
Let them eat cake
"It's difficult to make people understand GMPs in the best of times," said our GMP Agent-In-Place. "Even long-term employees don't understand the rationale if they don't work in compliance. So our company decided to do some hands-on training. We used baking a cake as an example—a major undertaking involving installing a dozen ovens, buying tools and supplies for hundreds of cakes, and running nearly 1500 people on two sites in different countries through such a program. However, baking allowed us to emphasize the need for proper raw materials, equipment cleaning, equipment calibration (temperature), product testing, product packaging and labeling, and deviation management. It went very well, despite the cost compared with more traditional training."
Pharmaceutical Technology's monthly "Agent-in-Place" column distills true-life cautionary tales from the secret files of Control, a senior compliance officer. If you have a story of clueless operators, oblivious management, inopportune lapses of judgment, or Murphy's Law in action, please send it to Control at [email protected]