Food And Drug Gas Production

GAWDA CONSULTANT CORNER FDA & MEDICAL GASES

There have been some recent FDA inspections with violations of cleanliness standards. This article highlights things you can reasonably implement to avoid compliance problems with cleanliness.

Cylinder/Container Cleanliness (21 CFR 211.94)

Current Good Manufacturing Practices specify that the container (cylinder) must be cleaned before use. The intent of this cleaning is to protect the drug quality from contamination. For high-pressure cylinders, this container internal cleaning is accomplished primarily by evacuation of prior contents during the pre-fill process. The FDA Compressed Medical Gases Guideline (1989) states that the vacuum be “equal to 25 or more inches of mercury prior to filling.” For cryogenic containers, the internal cleaning is assured by purging/testing when the container is:

  • Initially placed into service
  • After maintenance to the container when it could have been opened to the atmosphere or returned with a purge gas (typically 25 psi of Nitrogen)
  • When the container is returned from the customer with a product valve open or completely vented
  • When the pre-fill inspection indicates that the container could be contaminated.

Among other things, the pre-fill inspection assures that each container and valve is free from external contamination (bodily fluids, hydrocarbons, mud/dirt, etc.). If bodily fluids are found on a cylinder/container, the personnel handling or cleaning the cylinder must be included in a “Blood-borne Pathogen” protection program.

Other circumstances that have led to non-compliance observations include bird droppings on cryogenic container shoulders and excessive rust buildup on cylinder surface.

Operator Cleanliness (21 CFR 211.28)

Personnel who manufacture drugs “shall practice good sanitation and health habits.” In addition, they are required to wear appropriate clothing, gloves, etc. to protect the medical gas from contamination. Be sure the gloves used to handle medical gas cylinders are “clean.”

Facility Cleanliness (21 CFR 211.50 & 211.56)

The regulations are clear: “Any building used in the manufacture, processing, packing or holding of a drug product shall be maintained in a clean and sanitary condition. Any such building shall be free of infestation by rodents, birds, insects and other vermin (other than laboratory animals). Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.” In addition, you must have procedures to clean the facility and have a record of the cleaning. I recommend the use of a simple checklist to document your inspection and cleaning. If you would like a free copy of the Facility Cleaning And Maintenance Checklist, send a message to Juliet@asteriskllc.com.

Inspectors have been known to crawl under tables, look behind equipment and cylinders and aggressively search for evidence of insects or rodents. Be forewarned—food wrappers and beverage containers around the fill area could draw extra attention as well. Ensure all trash cans are emptied before they are overflowing. One facility was cited for the dumpster (located on the corner of their property) not being emptied in a timely manner. It was felt by the inspector that it would attract insects and rodents that would find their way to the facility.

If any pest control service is used, keep copies of the service report available. Be sure your restrooms are clean, have hot/cold running water and single-use towels. You are not required to maintain the same type of clean-room production environment as a traditional pharmaceutical company, but you should be aware that your inspector is accustomed to being in very clean environments while drugs are being manufactured. His standard for cleanliness and our standards may not be the same. In any event, it is a good practice to keep the cylinder shoulders dusted off periodically, especially to not obscure the lot number. Similarly, even though the exterior of process piping has no effect on the purity of the medical gas, inspectors will expect the piping to be externally clean. Years of leak test solution accumulation and normal dust can make a cylinder fill manifold look unclean. Consider a program to periodically clean the outside of your medical gas manifolds.

Even though we work in a largely industrial environment, appropriate housekeeping and cleanliness is still very possible. A clean facility will also give a good first impression. Contact me if you would like further information about housekeeping and cleanliness compliance or have interesting inspector experiences to share.

Thomas Badstubner

Thomas Badstubner

GAWDA’s FDA & Medical Gases Consultant Thomas L. Badstubner is president of AsteRisk LLC in Blackstone, Massachusetts. Members can reach him at 508-883-0927 and tom@asteriskllc.com.