Under watchful eyes
"It's a good thing we have some observant employees," our GMP Agent-In-Place sighed. "An employee noticed protein particles when he was bleeding the sterile filter during setup. After a thorough review, the root cause was determined to be an inadequate manual-cleaning process. The filter housing had several valves that needed specific cleaning techniques, which were not performed. As a result, we rejected three batches worth almost €760000 in total."
We never learn"We have four manufacturing sites that make similar biological products worldwide," began our GMP Agent-In-Place. "In 1988, there was a leak that allowed the coolant from the jacket into the final stage of one product. We tested hundreds of batches, and ended recalling all in-date products—nearly 300 batches. As one would expect, we put many corrective actions in place (i.e., pressure testing, inspections) to prevent recurrence. Fast forward to 2006 and a different site, same company. Another leak in the jacket allowed coolant into the product. Four batches were rejected and another marathon testing session was undertaken to verify that on market batches were fine.
"Pretty upsetting, yes? But we're not through. This year, the second manufacturing site had another leak affecting a different product. This time, 140 batches were recalled. Not only can't we learn from other manufacturing sites, we can't learn from our own."
It begins with design
"Class A/B filling suites are carefully designed and built to maintain a maximum amount of sterile product protection," explained our GMP Agent-In-Place. "The equipment that controls the temperature, humidity, air pressure and air filtration are all meticulously sized for this purpose. The rooms are then sealed to prevent incursion of particulates, microbes or other contaminants. During routine production, we had a drip from the ceiling of the Class B portion of the filling suite during a fill. It turned out the designers had designed for 95% of the local weather conditions. But we manufacture 100% of the days and it was one of those extreme days that caused the problem. The weather was 98% humidity. The plenum where the air ducts are routed was at ambient temperature and humidity. The air ducts carried chilled air to supply the filling room. The condensation on the outside of the air ducts puddled, and found a crack to drip into the fill room. In the end, insulating the air duct was sufficient to prevent recurrence. The product correction was easy: reject all filled vials."
Check your trends
"Although handling excursions in environmental monitoring is important," our GMP Agent-In-Place pointed out. "One critical use is to trend the data to catch problems before they erupt in significance. During one trend review, we noted that the bulk sterile product-manufacturing department had increased microbe levels and excursions. We asked whether they had changed their SOP or the way that they cleaned and were told 'No.' When we checked their orders from central stores, we found that they had used 400 mop heads. Reviewing their SOPs and schedules, they actually should have used 1600 single use mop heads. So we asked again what was going on and were told once again that SOPs were being followed. Being the helpful guys that we are, we put Quality on the floor for all three shifts during seven days over a month. The trends reversed, the excursions went down and, better yet, the product bioburden was reduced. In addition, their mop head usage increased dramatically."