FDA 483 Observations in 503B Outsourcing Facilities

In this issue, we will begin looking at example FDA 483 observations in 503B outsourcing facilities. As of September 3, 2021, there were 72 Registered Outsourcing Facilities on the FDA website. Of these, 14 have not been inspected, 4 have not received a 483, 51 have been issued 483's, and 5 have been issued warning letters. Keep in mind that 503B Outsourcing Facilities are required to follow cGMPs, but many of the observations are the same as in 503A compounding pharmacies; we can learn from all of them.

We will look at example 483 observations in the following general categories:

1. Personnel
2. Facility
3. Equipment
4. Environmental Monitoring
5. Cleaning, Disinfecting and Deactivation
6. Compounded Product Quality
7. Unapproved and Unvalidated Components
8. Administrative and Regulatory

This week, we will begin with:

Personnel

• Your technician failed the gowning qualification. No investigation was conducted, and the isolates were not sent out for identification.
• Your firm's pharmacists and PIC's failed to supervise/monitor required activities during each day of production.
• Two technicians were not exhibiting slow and controlled movements within the ISO-5 Hood during filling and stoppering of XXX for injection.
• Your technicians were observed quickly tapping their fingertips to each media plate, rather than rolling their fingers to capture the gloved hands utilized during aseptic production. One technician was observed with wet gloves from previously spraying them prior to sampling.
• Your firm failed to follow your SOP where the technician was observed exhibiting poor technique while quickly and incompletely inverting the sterile syringes (clear plastic) during the visual inspection process for XXX Injection.
• Operators were observed moving sterile vials and equipment within the ISO-5 LAH during manufacturing, and the top of the head and parts of the shoulders of these operators entered the hood.
• The operator's lower legs were exposed with non-sterile scrubs, socks, and footwear during the cleaning operation.
• We observed the use of sterile wipes rendered nonsterile, having been left open on top of the LAFH for an unknown period prior to production. These wipes were subsequently used to clean the inside of the ISO-5 zone and to clean equipment introduced into the ISO-5 zone throughout production.
• Procedures for the disinfection and introduction of the diluent and component i.v. bags into the cleanroom production area does not ensure the firm's established dwell time is achieved.
• Operators producing i.v. bags using the Repeater Pump retrieve paper labels from the support cart in the ISO-7 area which are introduced into the ISO-5 workbench without changing or sanitizing their gloves, and then label the filled i.v. bags within the ISO-5 workbench.
• Sterile connection manipulations made by operators working in the ISO-5 workbenches were observed using twist and push motions with both hands while hanging new components and sterile connecting and disconnecting the i.v. bag, blocking the first pass air with the upper hand. Viable as well as non-viable particulate monitoring of the ISO-5 workbenches is not always sampled within the critical manipulations zone per written procedure.
• Personnel fingertip monitoring is not always sampled as appropriate and/or according to written procedure. The operator sprayed and wiped the ISO-5 workbench in the critical manipulation area with sterile disinfectant immediately after which the EM monitoring operator performed the surface sampling on that workbench in the freshly-cleaned area.
• The pharmacy technician performing the aseptic addition of XXX to XXX via the Repeater Pump observed a black residue on the entry ports of approximately XX and used these bags following spraying with sterile XXX and wiping the ports.
• You do not mimic the worst-case manufacturing operations which occur during aseptic processing operations to qualify your aseptic operators through your media fill operations.
• In your facility, I observed aseptic operators in the cleanroom suites wearing a goggle type in the ISO-5 LAF hood which contained numerous holes (about 50) for direct venting, while performing aseptic filling.