Risk Management in Pharmaceutical Microbiology

FMEA schematic:


FMEA score: 3 x 1 x 1 = 3

Risk Evaluation: There is no problem considered from the room environment. Entry to the room is controlled; the sanitization cycle has been challenged with a level of microorganisms far greater than would ever be found in the environment (spores of Geobacillus stearothermophilus); all items entering the Isolator are sanitized (using a chlorine dioxide based sporicidal disinfectant) and the Isolator itself is an effective positive pressure barrier to the outside (at >15 Pascal). As detailed earlier, environmental monitoring is performed inside the Isolator during testing [10]. This monitoring, which has an action level of 1 cfu, is designed to detect any potential contamination inside the Isolator environment.

Examination: Potential of Sanitization Cycle Failure

FMEA schematic:

FMEA score: 4 x 1 x 1 = 4

Risk Evaluation: The severity of an ineffective sanitization cycle is a potential sterility test failure. However the sterilizer parameters are checked for every transfer and main Isolator cycle and post-sanitization environmental monitoring is performed on the main Isolator. This has a long history of producing no growth of viable microorganisms.

The Isolators are loaded with a set amount of equipment and consumables. This is described in authorized procedures and the maximum load has been determined through BI studies. One potential area of weakness for the sanitization of the main Isolator are valves for the removal of waste during the membrane filtration sterility test. These are autoclaved prior to each sanitization and during the first hour of the cycle they are opened both inside and outside to allow the sanitization agent to penetrate. A further preventative measure is taken post-sterility testing where the valve which has been used is rinsed through with disinfectant.

Examination: Frequency of Isolator Sanitizations

FMEA schematic:

FMEA score: 4 x 2 x 1 = 8

Risk Evaluation: Each transfer isolator was sanitized, each run using a validated cycle and the Sanitization physical parameters were checked each run (evaporation rate and pressure chart recorder). The main isolator is sanitized every three months (this has been set by monitoring trends in biocontamination over time). Environmental monitoring is performed during each sterility test and examined monthly for trends. Testing showed that, if contamination occurred in the main isolator it did not recur when repeat monitoring is performed. It is reasoned that this is because the level of post-test disinfection is sufficient; that the air-changes in the isolator are such that most contamination will be removed every hour. Furthermore, the main isolator was continuously monitored to show that it remained at positive pressure to the outside. Every six months a range of physical tests were performed: pressure decay, HEPA filter integrity and particle classification.

Examination: Pressure Leaks to Gloves

FMEA schematic:

FMEA score: 4 x 2 x 3 = 24

Risk Evaluation: This FMEA has been given an occurrence of 2 because weekly checks on the gloves do show, on occasions, holes in gloves. A detection of 3 has been given due to reasons outlined below.

The weakest spot on the Isolator is considered to be the glove ports [11] therefore the gloves have been subject to a separate FMEA. Although these are tested after each test using finger plates and are visually inspected by the testing technician pre-test and weekly, such visual checks are unable to detect pin-pricks leading to slow leakage. Pressure monitoring would show a significant leak from torn gloves but is not subtle enough to detect tiny holes [12]. In order to improve detection the organization undertook to purchase a glove-leak tester. This reduced the FMEA score by improving the detection rate from 3 to 1.

The probability of contamination is further reduced by the use of aseptic technique by the testing technician at all times. Tests are performed to the same level of aseptic technique that would be provided to performing a sterility test in a clean room. Furthermore all technicians are trained in aseptic technique prior to testing final product for batch release. In addition technicians wear a pair of sterile gloves underneath the Isolator gloves and procedures are in place for an aseptic change of gloves. Spare gloves are held in the Isolator for this purpose.

Despite the pre-glove leak testing system FMEA rating of 24—as a possible risk—the exceedingly favorable history of environmental monitoring gives assurance that there is little contamination in the Isolator and no adverse trends. Therefore the gloves are a potential weak spot but this has not been observed in practice. A further weakness is associated with the glove change procedure, which could also be explored as an area for improvement.

Other leaks associated with the Isolator also pose a risk and could be similarly examined through FMEA.

Summary of Other FMEA Exercises
Several other exercises were conducted for this case study, including those for:

•    Compromise of Isolator Integrity
•    Connection of Transfer Isolator to Main Isolator and Transfer-in / out of Material