Application of FMEA to a Sterility Testing Isolator: A Case Study

Dr. Tim Sandle

www.pharmamicreouresources.com

Introduction

Introduction to risk assessment

What are risks?

Advantages and disadvantages of FMEA

Applying FMEA to review a sterility testing isolator – case study

Risk Assessment

Risk Assessment

Increasingly used tool in the pharmaceutical sector.

An expectation of regulatory authorities.

Important because:

– A proactive tool;

– A reactive tool;

– To explore weaknesses and seek improvements;

– To construct rationales;

– Part of the qualification and validation of processes.

Risk is ever present

THERE IS NO SUCH THING AS

“ZERO” RISK

Need to understand, “quantify” and manage risks in

pharmaceuticals and healthcare.

Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm i.e.

– What might go wrong?

– What is the likelihood (probability) it will go wrong?

– What are the consequences (severity)?

Risks relate to a situation where a recognized hazard may result in harm.

Risk Assessment

Different approaches for risk assessment including:

– HACCP (Hazard Analysis Critical Control Points), which has its origins in the food industry;

– Fault Tree Analysis (FTA) ;

– Modelling software (such as the Monte Carol model);

– FMEA (Failure Mode and Effects Analysis), which originated in the engineering sector.

– Several described in ICH Q9 and EU GMP Annex 20.

Risk Assessment

Important steps:

– Define problem;

– Select tool;

– Hazard identification;

– Risk assessment;

– Risk control;

– Risk review;

– Risk communication.

ICH Q9

Risk Assessment

A more detailed approach involves: – Gathering data through an audit and analysis;

– Constructing diagrams of work flows;

– Pin-pointing areas of greatest risk;

– Examining potential sources of contamination;

– Deciding on the most appropriate sample methods;

– Helping to establish alert and action levels;

– Taking into account changes to the work process / seasonal activities;

– Using some type of scoring system so that the risk can be ranked and the level of risk determined.

FMEA

What is it?

FMEA

FMEA is “Failure mode and effects analysis”

It is an analytical tool which was originated by the US military and is widely used in the engineering industry

Very structured approach (ISO/TS 16949)

FMEA is applied to many areas as a problem solving tool

This talk adopts one possible approach based on the approach of the non-commercial FMEA Information Centre:

http://www.fmeainfocentre.com/introductions.htm

FMEA

FMEA looks for failure modes.

A failure mode is a characterization of the way a product or process fails.

The term may be applied to mechanical failure, structural failure, electrical failure, biological risks and systems failure.

FMEA

Advantages: – Improve product/process reliability and quality – Increase customer satisfaction – Early identification and elimination of potential

product/process failure modes – Prioritize product/process deficiencies – Capture engineering/organization knowledge – Emphasizes problem prevention – Documents risk and actions taken to reduce risk – Provide focus for improved testing and development – Minimizes late changes and associated cost – Catalyst for teamwork and idea exchange between

functions

FMEA

Disadvantages:

– It is subjective;

– It has a long-drawn-out approach;

– The focus is on failure / non-conformance types and not on the chain of events (cause / effect);

– It tends only to focus on major issues;

– Not ideal for environmental monitoring – HACCP is better.

FMEA

FMEA

Dangers:

– Looks at ‘detection’ as a risk mitigation, which influences the determined score

Need to be careful with microbiological data since our methods have poor detectability

With microbiological risks, focus on severity and likelihood

– Application of a ‘score’ is subjective.

FMEA

Determining failure mode

Assessing severity

Assigning probability number

Assigning detection number

Calculating risk priority number

FMEA

FMEA steps: – Setting the scope; – Defining the problem; – Setting scales for factors of severity,

occurrence and detection (see later); – Process mapping; – Defining failure modes; – Listing the potential effects of each failure

mode; – Assigning severity ratings to each process

step;

FMEA

Steps continued: – Listing potential causes of each failure mode;

– Assigning and occurrence rating for each failure mode;

– Examining current controls;

– Examining mechanisms for detection;

– Calculating the risk;

– Examining outcomes and proposing actions to minimise risks.

Ideally it should be team based.

FMEA case study

Sterility Testing Isolator

Isolator Study

Despite a superiority to cleanrooms, all Isolators are at risk from contamination

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”

(The Gold Sheet, Vol. 32, No.10)

Isolator Study

Description: – From a pharmaceutical manufacturer based in the

south-east of England.

– The Isolator was one half-suit Isolator, two transfer Isolators and a steriliser unit.

– Positive pressure, flexible film Isolators with stainless steel frames and wood bases designed for aseptic processes (in this case: sterility testing to Ph. Eur. 2.6.1).

– Air is using HEPA filters and material is transferred into and out of the main Isolator using transfer Isolators connected using Rapid Transfer Ports (RPT).

– Sanitised by hydrogen peroxide vapour.

– The internal environment is classed as Grade A / ISO 5

Isolator Study

Identifying the main risks:

– 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.

Isolator Study

Designing the FMEA scheme

– FMEA schemes vary in their approach, scoring and categorisation.

– All approaches share in common a numerical approach. The approach adopted was to assign a score (from 1 to 5) to each of the following categories:

i) Severity

ii) Occurrence (or probability)

iii) Detection

Isolator Study

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.

A good detection system is one that can detect a failure before it occurs.

Isolator Study

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.

See over….

Isolator Study

Severity 5 Specification limits exceeded. Probable rejection of

test or shutdown of system.

3 Observed trend takes place, but no critical excursions. Requires investigation.

1 No excursion has taken place. No upward trends and no investigation is required.

Occurrence 5 Expected to occur 50% time.

3 Expected to occur ≥10 - ≤50% time.

1 Expected to occur ≤10%.

Detection 5 No way to detect the failure mode.

3 Can be partially detected but detection could be improved.

1 Good detection systems in place.

Isolator Study

Using these criteria a final FMEA score is produced (sometimes called a Risk Priority Number):

x

125

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

5 x 5 x 5 = 125

Isolator Study

A score of 27 was the cut-off value: where action was required.

Based on 27 being the score derived when the mid-score is applied to all three categories

The numerical value '3' from: Severity (3) x Occurrence (3) x Detection (3) 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.

Application of FMEA

Some examples

Examples

3 examples

– Potential for sanitisation cycle failure

– Pressure leaks to gloves

– Connection of transfer Isolator to main Isolator and transfer-in / out of material

Isolator Example 1

Potential for sanitisation

cycle failure

#1

Process step Failure Mode

Significance of failure

Severity of consequence (score)

Performing sanitisation cycles on transfer or main Isolator

An Isolator is not correctly sanitised

Contaminated items enter main Isolator or main Isolator itself is contaminated

4

Isolator Example 1

Potential for sanitisation

cycle failure

#2

Measures to detect failure

Occurrence

(score)

Detection systems

Detection (score)

Evaporation rate / pre- and post-lot testing of acid / sanitisation cycles developed using BIs

1 Steriliser parameters checked after sanitisation and before use / acid potency checked for each lot / post-sanitisation environmental monitoring performed for main Isolator

1

Isolator Example 1

Potential for sanitisation

cycle failure

#3

FMEA score:

4 x 1 x 1 = 4

Isolator Example 2

Pressure

leaks to

gloves

#1

Process step Failure Mode

Significance of failure

Severity of consequence (score)

Use of gloves to transfer material or to perform sterility test (sterile gloves may be worn underneath Isolator gloves)

Contamination from technician into Isolator or weak area of positive pressure to allow contamination in

Contamination present in Isolator / compromise of aseptic technique

4

Isolator Example 2

Pressure

leaks to

gloves

#2

Measures to detect failure

Occurrence

(score)

Detection systems

Detection (score)

Environmental monitoring (post-use finger plates) /

pressure charts

2 Environmental monitoring is performed post-test on gloves / gloves are wiped with disinfectant / gloves are visually examined weekly and changed as appropriate

3

Isolator Example 2

Pressure

leaks to

gloves

#3

FMEA score:

4 x 2 x 3 = 24

Isolator Example 2

However, on review….

FMEA score:

4 x 2 x 1 = 8

Isolator Example 3 The transfer of material in and out of the Isolator is, arguably, the biggest risk:

Non-sterile area between doors

*

*Area of biggest risk

Transfer isolator

Isolator Example 3

Connection of transfer Isolator

to main Isolator

and transfer-in

/ out of

material #1

Process step Failure Mode Significance of failure

Severity of consequence (score)

Connection of transfer Isolator to main Isolator and moving material in and out

Contamination on outside of both Isolators may enter the main Isolator / failure to maintain positive pressure

Contamination enters the Isolator or positive pressure is not maintained

4

Isolator Example 3

Connection of transfer Isolator

to main Isolator

and transfer-in

/ out of

material #2

Measures to detect failure

Occurrence

(score)

Detection systems

Detection (score)

Environmental monitoring / pressure monitoring

1 DPTE seal system / use of disinfectant for connection

1

Isolator Example 3

Connection of transfer Isolator

to main Isolator

and transfer-in

/ out of

material #3

FMEA score:

4 x 1 x 1 = 4

Isolator study

Revisit the ranking

Define residual risk

Perform a short summary

– Scope

– Data from the assessment & control (e.g. no. of identified failure modes)

– Level of accepted risk without actions i.e. residual risk (e.g. risk priority Number < 27)

– Recommended actions, responsibilities and due dates (including approval, if appropriate)

– Person in charge for follow-up of FMEA

Isolator Study

Summary of the entire study:

Isolator FMEA risk assessment

0

5

10

15

20

25

30

RoomCycle

Frequency

Inte

groty

Connection

Sanitisa

tion

Physica

l

Glo

ves

Category

FM

EA

sco

re

Cut off score

Further examples

Sandle, T. ‘The use of a risk assessment in the pharmaceutical industry – the application of FMEA to a sterility testing isolator: a case study’, European Journal of Parenteral and Pharmaceutical Sciences, 8(2): 43-49

FMEA

A risk assessment technique – FMEA can be readily applied to a key operation

This technique did not originate in the pharmaceutical industry.

This indicates how the synergy of different approaches can be achieved.

FMEA

Regular reviews must take place;

FMEA is not suitable for everything e.g. HACCP may be more suitable for suitable for aseptic filling.

It is not able to discover complex failure modes involving multiple failures or subsystems, or to discover expected failure intervals of particular failure modes.

Thank you Dr. Tim Sandle www.pharmamicroresources.com

Any questions?