Risk Management in Pharmaceutical Microbiology

b) Defining the problem;
c) Setting scales for factors of severity, occurrence and detection (see below);
d) Process mapping;
e) Defining failure modes;
f) Listing the potential effects of each failure mode;
g) Assigning severity ratings to each process step;
h) Listing potential causes of each failure mode;
i) Assigning and occurrence rating for each failure mode;
j) Examining current controls;
k) Examining mechanisms for detection;
l) Calculating the risk;
m) Examining outcomes and proposing actions to minimize risks.

Where the number of risk is very high, the ICH Q9 guideline proposes the use of a risk filter.

Sterility Testing Isolator: The Case Study
The definition of an Isolator is a device [6]:
a) Provided with microbial retentive filtered air (and which does not exchange any other air with the surrounding environment)
b) Has a decontamination cycle (for the Isolator itself and for material entering)
c) Has a means for material transfer and / or connection to another Isolator
d) No human part directly enters the Isolator

All Isolators are at risk from contamination [7]. Although Isolators are superior in many ways to clean rooms, the approach of regulators, such as the FDA, is: “Barrier Isolators cannot prevent contamination caused by GMP deficiencies such as poor aseptic procedures and inadequate training of…operators.” [8]

The main risks which different Isolators (those used for both sterility testing and for aseptic filling) are susceptible include [9]:
•    Leaks;
•    Gloves / operator manipulations;
•    Filters;
•    Other airborne contamination;
•    Transfer of material into and out of the Isolator;
•    The Isolator room;
•    Decontamination cycle;
•    Cleaning / environmental monitoring issues.

Application
The Isolator system is used for the sole purpose of performing final product sterility testing on a range of plasma derived parenteral products according to Ph. Eur. 2.6.1 or USP <71>. The methods used are membrane filtration and direct inoculation. A variety of environmental monitoring methods are performed during and after testing: air-samples (passive settle plates and an active volumetric air-sample); finger plates; contact plates and swabs. A spray bottle of a sporicidal disinfectant remains in the Isolator for spillages and for a post-test clean down.

Monthly monitoring is performed in the Isolator room. A number of daily, weekly and six-monthly physical tests are performed on the Isolator system using pressure charts; cleaning and formal classification as a Grade A clean zone (to ISO 14644-1).

A score from 1 to 5 (most severe) was assigned to each of the following categories describing risk.
i) Severity
ii) Occurrence
iii) Detection

Where:
i) Severity is the consequence of a failure, should it occur;
ii) Occurrence is the likelihood of the failure happening (based on past experience);
iii) Detection is based on the monitoring systems in place and on how likely a failure can be detected.

The following questions were asked of every main part of the isolator system:

i) What is the function of the equipment? How are its performance requirements?
ii) How can it fail to fulfill these functions?
iii) What can cause each failure?
iv) What happens when each failure occurs?
v) How much does each failure matter? What are its consequences?
vi) What can be done to predict or prevent each failure?
vii) What should be done if a suitable proactive task cannot be found?

The scoring system adopted was: a scale from 1 to 5. It followed that the likelihood of high severity would be rated 5; high occurrence rated 5; but a good detection system would be rated 1. The scoring system was based on the Table 1.

 

 

 

 

 

 

 

 

 

 

 

Using these criteria a final FMEA score or “risk priority number” is produced:

x
__
125

The total of 125 is derived from: severity score x occurrence score x detect score, or:

5 x 5 x 5 = 125

Depending upon the score produced it can be decided whether further action is needed. There is no published guidance on what the score that dictates some form of action should be. In this study the company adopted a score of 27 as the cut-off value where action was required. This was based on 27 being the score derived when the mid-score is applied to all three categories [i.e. the numerical value ‘3’ from severity (3) x occurrence (3) x detect (3)] and the supposition that if the mid-rating (or a higher number) was scored for all three categories then as a minimum the system should be examined in greater detail.
 
The FMEA Exercise
To conduct the exercise used the defined scheme on the Isolator system, the Isolator set-up was broken down into a number of critical areas and each area was subsequently assessed. Several of these steps are examined below.

Examination: The Isolator Room

Description of critical area: The Isolator is situated in an unclassified room. There is not requirement to place a sterility testing Isolator in a classified room.