“Alarming” Number of US FDA Recalls Attributed To Equipment Breakdowns
Sanofi Describes Its Proactive Approach To Maintenance
Executive Summary
Agency urges pharmaceutical industry to be proactive on equipment monitoring. Sanofi efforts include an interdisciplinary approach to equipment inspections.
The number of US biopharma product recalls attributed to equipment breakdowns is “alarming and concerning," a Food and Drug Administration official said, urging industry to adopt proactive equipment monitoring programs to prevent such occurrences.
Speaking at the recent Parenteral Drug Association/FDA regulatory conference in Washington, DC, FDA’s Carmelo Rosa said that many of the facilities that inspectors see during inspections “have been built using technologies and processes from the 1950s and 1960s and these technologies are inefficient and not always capable." Rosa is the division director for the Office of Compliance in the Center for Drug Evaluation and Research.
Rosa shared some of the “gross” things that FDA officials see in inspection, showing photographs of worn-out granulators, worn-out granulator rings, missing stainless steel pieces in granulators, and discolored compression machines. He also showed pictures of discolored and corroded stainless steel sieves, peeling tape and plastic sheets fastened to filters in a cleanroom.
Recent enforcement actions involving shoddy equipment maintenance include the FDA's request that drug compounding pharmacy Pacifico recall sterile eye drops. The FDA said these products were being made under insanitary conditions, using equipment that had not been adequately sterilized. (Also see "FDA Warns Consumers Not To Use Sterile Drugs Made By Pacifico National After Firm Refuses Recall Requests " - Pink Sheet, 30 Aug, 2019.) At first the firm refused but then agreed to recall the affected drugs. In another example, the agency issued a warning letter to Aurobindo Pharma Ltd. in July for using rusty equipment to manufacture active pharmaceutical ingredients. (Also see "Aurobindo Faulted In US FDA Warning Letter For Poor Root Cause Investigations" - Pink Sheet, 3 Jul, 2019.)
Rosa said that firms with a “mature” quality culture have fewer equipment problems than an immature one which is constantly reacting to problems instead of preventing them. The FDA official described a mature quality culture as one with an ongoing equipment monitoring program to detect for potential equipment failures. It should include quality risk management principles to measure process improvements and facility upgrades.
One sign of an unhealthy quality culture is when equipment is being repaired more than it is being used.
Rosa reminded the audience that three separate parts of the US GMP regulations require manufacturers to maintain equipment in good working order to prevent possible contamination: 21 CR 211.42 which covers design of facilities, 21 CFR 211.58 which requires manufacturers to ensure that equipment in properly working, and 21 CFR 211.56 which requires facilities to be clean and kept in a sanitary manner.
Sanofi's Interdisciplinary Team Approach
Sanofi has taken a proactive approach to equipment maintenance and cleaning in recognition that contamination can directly impact patients, Cheryl Essex, head of microbiological control, told the PDA/FDA audience. She described how this approach centers on a self-inspection program using a multidisplinary team and also noted particular challenges in biologics facilities.
It can be difficult to spot potential problems with equipment in biologics facilities because surfaces are not exposed. In fill-finish facilities, she said, “more surfaces are exposed, making it easier to inspect.” It is also difficult to maintain equipment in these facilities which have stainless steel tanks and “miles” of piping.
Another obstacle is that no one takes ownership of equipment, and there are a “lot of handoffs,” Essex said, “Engineering knows very little about the equipment before it is handed off to validation technicians on the shop floor that may be aware of these risks.” Also, “not many people look into the equipment, the engineers do the commission work and qualification and the validation people do the validation yet who looks inside of the equipment? This is done on an ad hoc basis by the engineers and the validation folks but where is quality microbiology?’
Essex said that “in most firms,” the firm’s quality microbiology staff do not routinely look inside of the manufacturing equipment, which she called a “gap” in self-auditing.
To address these kinds of issues, the company created a multidisciplinary self-inspection program, which is operating at several sites with plans to eventually roll it out worldwide.
Essex called it a “simple” program that involves a team of four to six people from various departments within the company including representatives from quality microbiology, engineering, and manufacturing. The team goes to a site as a group and are charged with inspecting various pieces of equipment. This includes upstream equipment such as glass flasks and spinners, tanks, vessels and bioreactors. They also look at downstream equipment such as chromatography skids. Lastly they inspect calibration equipment such as flow meters and CIP tanks and vessels.
The inspectors must check a simple yes-or-no box indicating whether the equipment is dry and clean.
Essex encourages the team to take photographs when they inspect. “I can’t stress how important it is to take pictures. If you want to convince the upper management to spend money, take pictures, lots and lots of pictures, this will help, and show it to everybody."