Look Up!

Lessons from three pharma quality investigations. Let’s call them the tub, the tubes, and the sledgehammer

Lessons from three pharma quality investigations. Let’s call them the tub, the tubes, and the sledgehammer

Ceilings are often ignored in cleanrooms. Best case, they are cleaned once a quarter. In fact, if it wasn’t for the location of critical HEPA filters, ceilings would garner little attention at all.

When walking through your cleanroom, try to look at the stars knowing the ceiling is in the way and that’s what you need to inspect.

Here are three quick stories to give you another reason to thoroughly walk through your cleanrooms.

The Tub . . .

In 2013, my employer, a large contract manufacturer of sterile parenterals, announced they were closing. Almost all manufacturing stopped immediately. We needed to make dozens of batches of one last critical product on the FDA drug shortage list to fulfill a customer contract.

Due to all the site issues that led to this decision, we implemented extra controls to ensure product was safe. One of those controls included testing rinse water from every Clean-Out-of-Place (COP) equipment cleaning cycle. The COP washer was responsible for cleaning equipment with direct product contact. Soon after this testing started, we recovered an increasing variety of gram-negative and gram-positive Rods.

We swabbed all over the COP washer clean room to find the contamination source. We sampled the usual dirty suspects—corners, crevices, underneath the washer, etc. The swabs were surprisingly clean.

However, we found the root cause thanks to the keen eye of my supervisor. She looked up during her walk-through. She noticed a slightly discolored ceiling tile above the COP washer. Upon further inspection, we found leaking exhaust piping in the mechanical space. The leaks dripped through the ceiling directly into the COP washer tub while the cycle was running!

Through all the corrective action fall-out from this event, I was responsible for removing the ceiling tile from the cleanroom. I did it too quickly. I wanted to avoid the “extra work” of swabbing and matching identifications to what we recovered from the rinse sample. It was obvious this was the root cause. Were ID’s necessary?

Absolutely.

For a site with a history of mold recovery, ID’s would have been critical to tracking and trending impact to the rest of our facility’s EM results.

. . . The Tubes . . .

One event that contributed to this site closing happened a few years earlier. An operator was waiting for parts to arrive so they could assemble the filling line. During the wait, the operator casually looked around the room. Through the haze of their frequently irradiated clean-room goggles, the operator noticed some spots on the HEPA filter grates. What were those spots? Cleaning agent residue? Mold? They discussed these observations with their supervisor.

In these rooms, product transferred from formulation vessels to filling lines through pressurized, flexible, tubes. The tubes were disconnected after filling cycles. They were often still pressurized, causing residual product to spray into the room, unnoticed by the operators. The HEPA grate spots were the buildup of product residue from years of these disconnections.

The site made a variety of products in these rooms. Most were clear, but some were bright red, blue, yellow, or even cloudy white. The inspection team could only see the colored product residue. However, it’s inevitable clear products splashed like this too. The possibility of cross contamination between products necessitated a temporary shut-down to replace every HEPA filter in the entire building. Processes were also updated to prevent product splashing in the future*.

On behalf of patients receiving these drugs, thank you operator for looking up!

. . . And the Sledgehammer . . .

I previously wrote about a Pseudomonas Contamination Event . I inspected centrifuges that were used for lots contaminated with Pseudomonas. I didn’t mention the sledgehammer because it didn’t contribute to the root cause. However, it left recognizable marks on the cleanrooms.

Centrifuges are very active pieces of machinery for a manufacturing process. Constant vibration can loosen pieces leading to spills. Their lids need to be screwed on tight! A specialized tool to tighten and loosen industrial grade centrifuge lids didn’t exist. The site used a simple, cleanable sledgehammer. After screwing on the lid, the operators would bang a specific spot to fully tighten it.

My attention went to the sledgehammer when it was used to open the centrifuges. To the operator, it was the same process, but in reverse. However, the disassembly process was messy; the equipment was still covered in product residue. This residue was essentially a micro broth paradise. With every BANG and SLAM, residue splashed around the room. Operators and cleaning crew were great cleaning the floors and walls, but the ceiling looked like a monotone Jackson Pollock.

It was disgusting! Can you imagine what regulators would think if they walked in and looked up? Who wants micro broth hanging over their manufacturing equipment? We immediately upped our cleaning frequency. Unfortunately, we didn’t have an affordable work-around for the sledgehammers.

*Interesting side note here: Recently, I talked to one of the quality managers responsible for fleshing out the corrective actions for this event. She moved to a manufacturer of a popular OTC product. This product has a very distinctive color. Do you know what that site did to prevent this issue? They painted all the walls, floors, and ceilings the color of that product.