Dr. Tim Sandle

Pharmaceutical Microbiology Resources: www.pharmamicroresources.com

Introduction Introduction to quality risk management

Definitions of risk

What is the aim of environmental monitoring?

Risk management tools and techniques for environmental monitoring Application of HACCP for selecting environmental

monitoring locations

Use of risk filtering to determine frequencies of monitoring

Applying FMEA to assess risks from process equipment – a sterility testing isolator.

Risk In general, risks describe any potential dangers.

We are confronted with risks in our day to day life.

Risks cannot be avoided.

There is no such thing as 'zero risk.’

Risk assessment is not an exact science.

Risks relate to a situation, event or scenario in which a recognised hazard may result in harm.

How to define risk? 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)?

What is risk assessment about? Is the risk acceptable and what controls are available to

mitigate the risk?

Is the risk above an acceptable level?

What can be done to reduce or eliminate risks?

What is the appropriate balance among benefits, risks and resources?

Are new risks introduced as a result of the identified risks being controlled?

Risk assessment Risk assessment involves identifying risk scenarios

either prospectively or retrospectively. Prospective = determining what can go wrong in the

system and all the associated consequences and likelihoods. Can also be used for process improvements.

Retrospective = what has gone wrong .

Risk assessment can be used to assess the process, product or environmental risk and to aid in formulating the appropriate actions to prevent the incident from re-occurring.

This requires risk analysis.

Basics of risk assessment Risks relate to a situation where a recognized hazard

may result in harm. A hazard is any circumstance in the production, control

and distribution of a pharmaceutical product, which can cause an adverse health effect.

Formal risk approaches normally share four basic concepts: Risk assessment,

Risk control,

Risk review,

Risk communication.

Microbiological risks Microbiological contamination in the product, which

might cause patient harm.

From: Equipment

Air e.g. Cleanrooms: Air filtration

Air direction

Air movement (pressures)

People

Water

Central issue is contamination transfer.

Relationship of risk

Level of bioburden

Opportunity for bioburden transfer:

Airborne

Direct transfer

Likelihood of transfer

EM: risk assessment and root causes The process involves:

Risk assessment

Identification of hazards

Severity, probability and detection

To stop things from going wrong

To investigate when things have gone wrong

To find ‘root causes’

To propose CAPA

Biocontamination control Understanding risk and environmental control leads

to a biocontamination control strategy:

Developing plans to minimize microbial contamination for pharmaceutical operations

Understanding manufacturing, quality and contamination control are interconnected

This stratgey is all about risk identification and risk minimisation

Then risk mitigation

Then targeted environmental monitoring

Three case studies Application of HACCP for selecting environmental

monitoring locations

Use of risk filtering to determine frequencies of monitoring

Applying FMEA to assess risks from process equipment – a sterility testing isolator.

Hazard Analysis and Critical Control Points

HACCP “A systematic, proactive, and preventive method for assuring

product quality, reliability, and safety.”

Potential Areas of Use(s)

To identify and manage risks associated with physical, chemical and biological hazards (including microbiological contamination)

Useful when process understanding is sufficiently comprehensive to support identification of critical control points (critical parameters / variables)

Facilitates monitoring of critical points in the manufacturing process

HACCP How to perform?

1. Conduct hazard analysis: identify preventive measures for each step of the process

2. Determine critical control points (CCP’s) 3. Establish target levels and critical limit(s) 4. Establish system to monitor the CCP’s 5. Establish corrective actions to be taken, if CCP is out of

control 6. Establish verification procedures, that HACCP works

effectively 7. Establish documentation of all procedures and keep

records

HACCP

Risk Review

Risk Assessment = H azard A nalysis

Target levels & critical limit(s)

unacceptable

Risk Control: C ritical C ontrol P oints

Determine critical control points (CCP’s)

System to monitor the CCP’s

Identify preventive measures

Verification that process works effectively

Corrective actions, if CCP is out of control

Initiate HACCP

Output / Results: process described by HACCP

R i s

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HACCP Benefit

Teamwork in cross functional groups

Use very similar principles in Qualification & Validation

Critical control points (CCPs) are similar to critical process parameters

Limitations of the model Has to be combined with another tool (e.g. FMEA, statistical

tools)

Not good for complex processes

Assumes you know the processes

Most CCPs should be addressed for risk control activities

May need to use other models for quantifying risk

HACCP uses A route map (where the facility is drawn and the route

indicated).

Identification of hazards (which can be divided into biological, physical, equipment, transport and chemical). This will allow an assessment of existing control measures.

Process flow.

Assessment of environmental monitoring. This will determine if the activity is safe to proceed.

Approaching HACCP Prior to performing the individual risk assessments,

the scope and the process should be evaluated.

Obtain a process flow diagram / area map. Where required the process steps can be broken down into process steps or sub steps to help focus the effort.

Walkthrough the area, detailing the process steps / activities based on personnel flow, material flow, storage, waste disposal and product transfer.

A Historical Review of data (12 months) or previous risk assessments, which should be considered.

Approaching HACCP Define every available contamination hazard from

each process step / activity.

The hazard can be assessed and rated based on the likelihood of occurrence and severity.

To determine if the hazard is high medium or low.

The risk rating will determine if a critical control point is required and the level of monitoring which is required.

Approaching HACCP – CCP’s

Approaching HACCP For each critical control point:

Define what level of risk warrants monitoring i.e. if only high and medium risks require monitoring.

Where monitoring is required based on the risk rating,

The monitoring type should be selected e.g. Settle plate, contact plate etc.

The monitoring type will depend on the hazard.

All critical control points will require critical limits assigned to them.

Define monitoring frequencies.

HACCP example: sampling locations ISO 14644 grid approach for particles should not be

followed

Microbiological sampling sites are best selected with consideration of human activity during manufacturing operations.

From careful observation and mapping of the clean room

The most likely route of contamination (ingress into product):

Airborne

Operators – direct transfer

Materials – direct transfer

Problem statement Issue :

How to set the frequencies for viable monitoring for a non-sterile manufacturing area?

A risk based method Using risk ranking and risk filtering

Consideration of 10 risk factors

Assessing the level of risk for each risk factor for:

Severity and Probability

Considering methods of:

Detection

Risk process The risk assessment process involves:

What are risk factors for microbiological contamination in cleanrooms (risk identification)?

What is the likelihood (probability) that contamination will occur?

What are the consequences (severity) for the product should contamination occur?

Risk process The process allowed:

An evaluation of multiple factors for each risk: Identifying factors (risk identification) relating to cleanroom

design and processing which could pose a microbiological risk to the environment and to the product

Breaking down a basic risk question into as many components as needed to capture factors involved in the risk.

The factors were combined into a single relative risk score. The score can be compared, prioritized and ranked.

Risk process Risk factors were divided into two categories: Severity

The impact upon the product or the environment Categories:

LOW (unlikely to cause product contamination) MEDIUM (low possibility of product contamination) HIGH (high probability of product contamination)

Probability The likelihood that an environment will have a high recovery of

microbial counts Categories:

LOW (contamination events are rare) MEDIUM (contamination events are infrequent) HIGH (contamination events are frequent)

Step 1: Frequencies of monitoring Frequencies of monitoring:

Review historical data:

For trends

Action level excursions

Review resources

Consideration of costs

Step 2: Assigning monitoring frequencies Criticality Viable Factor

Frequency of Monitoring

CV1 Weekly monitoring

CV2 Fortnightly monitoring

CV3 Monthly monitoring

CV4 Three-monthly monitoring

Step 3: Scoring range for risk factors Each factor was scored (0

to 4) for severity and / or probability

A score range was set up for severity and probability

Probability

Low 0 - 5

Medium 6 - 11

High 12 - 16

Relationship between Severity and Probability

Low 0-5

Medium 6-11

High 12-16

Severity

Pro

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ity

Hig

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11-1

5

Lo

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0 -

5

Me

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5-10

Risk Class ONE

Risk Class TWO

Risk Class THREE

Risk Ranking

I

Risk Matrix (1)

Step 4: Identify risk factors The factors selected were considered carefully, using

professional judgement:

What, in relation to room design and processing, poses a microbiological risk to the environment and to the product?

Risk factors A number of risk factors can be

selected Temperature

Ambient Cold Warm

Wet or dry areas Water sources or drains in room Open or closed processing Duration of activity Number of personnel present Cleaning frequencies Distance from final formulation Fixed or mobile equipment Environmental monitoring

history

Risk factors Risk Factor 1: Room

Temperature

Freezer 0

Cold (typically 2-8oC)

1

Ambient (typically 18-25oC)

4

Warm (typically with periods of 30oC, e.g. autoclave preparation area)

3

Risk factors Detection methods need

to be reviewed

Factor

Group

Sub-factors Description and reason Weighting /

score

DETECTION

Room environmental

monitoring

Room environmental

monitoring, examined

over time for trends,.

Low detection

In-process sample test

and room environmental

monitoring

In-process samples,

provide a direct

assessment of the quality

of the material.

In addition, the room

environmental

monitoring as indicated

above.

Medium

detection

In-process sample test,

room environmental

monitoring and a

monitored water (WFI)

outlet

In addition to the room

environmental

monitoring and in-process

tests, the presence of a

Water-for-Injection (WFI)

outlet affords an

additional detection

method. WFI is assessed

as part of a fortnightly

rota.

High detection

Example 1 Clean room: P100

Grade D / ISO class 9

A room used for preparing equipment prior to autoclaving

The room is reviewed and scored It is at ambient (severity = 3) It is a dry area (probability = 1) It has no floor drain (probability = 0) It is not used directly for processing

(severity = 0) The room is used for long periods of

time (severity / probability = 3) It is cleaned at a lower frequency

(probability = 3) The room is more than three steps

removed from final formulation (severity = 1)

The room has a low occupancy (probability = 1)

The equipment is fixed (severity = 1) The environmental monitoring

history is good (probability = 1)

Example 2 – risk class

Low 0-5

Medium 6-11

High 12-16

Severity

Pro

ba

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ity

Hig

h

10-1

4

Lo

w

0 -

4

Me

diu

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5-9

Risk Class ONE

Risk Class TWO

Risk Class THREE

Risk Ranking

I

Risk Matrix (1)

P100

Example 3 - detection

THREE

TWO

ONE

Detection

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lass

ific

ati

on

Hig

h

Lo

w

Med

ium

HIGH priority

MEDIUM priority

LOW priority

Risk Filtering

Risk Matrix (2)

EM EM

+IP EM, IP +

water

P100

Example 4 - frequency

Risk Filtering

Risk Matrix (3)

CV4

CV4

CV4

THREE

CV3

CV3

CV3

TWO

CV2

CV2

CV1

ONE

Detection

Ris

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lass

ific

ati

on

Hig

h

Lo

w

Me

diu

m Room P100

Outcomes Lowest frequency of monitoring:

Freezers Store rooms Cold storage areas Offices

Medium frequency of monitoring:

Wash-up areas

Airlocks

Changing rooms

Areas one step removed from final processing.

Slightly higher frequency: Corridors Store rooms Autoclave rooms Cleaning areas

Highest frequency of monitoring:

Ultra-filtration areas

Final formulation of product

Open processing areas

Filtration rooms

Poor environmental monitoring history

Review Review annually

Has the room use changed?

Have the room parameters changed?

Has the room been redesigned

Has the environmental monitoring trend altered?

Failure Modes and Effects Analysis

FMEA Evaluation of potential failure modes for processes

The likely effect on outcomes and/or product performance

Once failure modes are established, risk reduction can be used to eliminate, reduce or control the potential failures

FMEA relies on process understanding

Summarize the important modes of failure, factors causing these failures and the likely effects of these failures

How to perform? Break down large complex processes into manageable steps

FMEA Potential Areas of Use(s)

Prioritize risks

Monitor the effectiveness of risk control activities

Equipment and facilities

Analyze a manufacturing process to identify high-risk steps or critical parameters

FMEA How to perform?

1. Establish a team

2. Identify the known and potential failure modes: Develop lists of known problems and brainstorm other

potentials… e.g.

Product not meeting specification

Process not meeting yield requirements

Malfunctioning equipment

Software problems

Newly identified failure modes should be added at any time

FMEA How to perform?

3. Characterise the severity, probability and detectability

An equal number of levels is sometimes helpful Some preference to 3, 4, 5, 6 or 10 levels

But: an even number of levels avoids the mid point

Use different scales Linear: 1, 2, 3, 4

Exponential: 1, 2, 4, 8

Logarithmic: 1, 10, 100, 1000

Self made: 1, 3, 7, 10

Multiplying different scales will differentiate the outcome

FMEA How to perform?

4. Define actions

5. Revisit the ranking

6. Define residual risk

7. 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 < 50) Recommended actions, responsibilities and due dates

(including approval, if appropriate) Person in charge for follow-up of FMEA

FMEA: severity • 10 Extreme

• Predicted to cause severe impact to quality (Product out of specifications, no Expert Statement possible)

• 7 High • Predicted to cause significant impact on quality (Failure to meet

specifications, no Stability data, Expert Statement possible)

• 3 Moderate • Predicted to cause minor impact on quality (Failure to meet

specifications, Stability data available)

• 1 Low • Predicted to have no/minor impact on quality of the product

(Quality within specifications)

FMEA: probability • 8 Regular failures

• Expected to happen regularly

• 4 Repeated failures • Expected to happen in a low frequency

• 2 Occasional failures • Expected to happen infrequently

• 1 Unlikely failures • Unlikely to happen

FMEA: detection • 4 Normally not detected

• Failure very likely to be overlooked, hence not detected (no technical solution, no manual control)

• 3 Likely not detected

• Failure may be overseen (manual control, spot checks)

• 2 Regularly detected

• Failure will normally be detected (manual control, routine work with statistical control)

• 1 Always detected • Failure can and will be detected in all cases

(monitoring, technical solution available)

FMEA: case study #1 Sterility testing isolator

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.

FMEA: case study #2 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

FMEA: case study #3 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. Sometimes, a good detection system is described as one that can detect a failure before it occurs.

FMEA: case study #4

FMEA: case study #5 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

FMEA: case study #6 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 (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.

FMEA: case study #7 An example:

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

FMEA: case study #8

FMEA: case study #9 Connection of transfer

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

FMEA: case study #10

FMEA score: 4 x 1 x 1 = 4

Summary Risk assessment Risk management Importance of assessment What is the aim of

environmental monitoring? Types of risk assessment tools

and case studies: HACCP Risk ranking FMEA

Thank you for your attention References: 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, 2003; 8(2): 43-49

Sandle, T. Environmental Monitoring Risk Assessment’, Journal of GXP Compliance, Volume 10, Number 2, 2006, pp54-73

Sandle, T. (2012). Application of Quality Risk Management To Set Viable Environmental Monitoring Frequencies in Biotechnology Processing and Support Areas, PDA Journal of Pharmaceutical Science and Technology, Vol. 66, No. 6, November–December 2012: 560 - 579