Risk Analysis In Aseptic

Operations
Tim Sandle
www.pharmig.blogspot.com
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Introduction
Contamination risks
Microbiological
Particulate
Sources of contamination
Contamination control: how can
contamination risks be minimized?
Detecting risks: the environmental
monitoring program
Risk assessment tools for environmental
monitoring
Summary
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Risk

Risk assessment
Now increasingly common in
the pharmaceutical industry
First developed in food
industry and medical
devices
ICH Q9 / EU GMP Annex 20
Risk
Many forms and different
levels
Some are so low as not to
worry about
Some are so high as to be a
hazard to health

Risk
Risk management
Umbrella term: includes risk
identification, risk assessment, risk
analysis / evaluation and risk review.
Focusing resources on the things that
are important
Pharmaceutical risk management
Ultimate aim is patient safety
What is the risk to the product?
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Contamination
Various definitions
Direct or indirect activity into the product or
environment by a contaminating agent
Contaminating agent: chemical, microbial,
particulate

No such thing as sterile operation,

what we mean is aseptic operation
Need a high level of contamination control
in aseptic filling and sealing
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Contamination
The particles
allowed in a
cleanroom, which
can pass through a
HEPA, are very
small.
Average human hair is about 100
microns

Sources of
contamination
Primarily:
People (75%)
Air (20%)
Equipment transfer (5%)

Problem: all are essential for aseptic

operations
Water sources should not be present

People as a
contamination source

Skin flakes
Hair
Saliva
Clothing material
Cosmetics
Touching

People as a
contamination source
The risk in sterile garments is that
personnel contaminate the outsides
when putting them on
Training in gowning is important and it
must be assessed periodically and
monitored frequently

Air as a contamination
source
Clean rural areas air = 108 particles
of 0.5m and greater per m3
(including many microorganisms)
So air is a contamination problem
However air flow is also the answer to
many contamination problems

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Air as a contamination
source
On one hand:
Microorganisms do not
grow and increase in
numbers in air
Most microorganisms find
it hard to survive in air

On the other hand:

Survival often depends
on being carried on
rafts of physical matter,
such as skin flakes.
Typical airborne
microorganisms are
transient or residential to
human skin
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Contamination Control
The principles of contamination control are based on risk considerations:
1.
2.
3.

Find the sources of microorganisms

What can we do to eliminate these sources?
What can we do to minimize these sources if we cannot eliminate them?

With these:
1. We have looked at the sources previously
2. Eliminate the microorganisms at source:
Inactivation (Sterilization)
Removal by filtration
Disinfection

3. Protect our processes and products from microorganisms:

Enclosed processes
Air-flow protection

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Contamination Control
What needs to be considered?
Design
Control of people
Air filtration
Air dilution
Air direction
Air movement

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Contamination Control:
Design
Design
All facilities are designed to eliminate as many
sources of microorganisms as possible
Aseptic manufacture is conducted in classified
clean-room facilities
Equipment and consumables taken into aseptic
processing area are sterilized
Aseptic areas are cleaned and their surfaces
disinfected with sterilized disinfectants

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People and
contamination control
Control of contamination
from people in aseptic
clean rooms is achieved by
application of two
principles:
We wrap the people
to minimise the
amount of shedding
of microorganisms
We put localised
protection around the
product to minimise
the amount of contact
with the people
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Air & Contamination

Control
There are four principle applying to control
of air-borne microorganisms in clean
rooms.
Filtration
Dilution
Directional Air Flow
Air Movement
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Air & Contamination

Control: Filtration
Filtration removes
microorganisms:
HEPA filters remove up to about
99.997% of particles from air
HEPA Filters are protected from
blockage by pre-filters which
remove up to about 90% of
particles from air
HEPA filters have a certified
efficiency rating which applies
to the medium (need to test the
integrity of the whole assembly
of filter and ductwork)

Therefore if air
contains about 3 x
108 particles per
m3, and you have
one pre-filter and
one HEPA Filter:
Pre-filter leaves about 3 x 107
per m3 as a challenge to the
HEPA filter
The terminal HEPA Filter
leaves about 103 per m3.
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Air & Contamination

Control: Filtration
Most pharmaceutical
air handling system
re-circulate up to 80%
of the air supplied to
clean rooms.
So the initial
challenge to the HEPA
Filters is probably only
about 106 particles
per m3.
In practice no more
than 3 x 102 particles
per m3 are supplied to
pharmaceutical clean
rooms

HEPA filter schematic

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Air & Contamination

Control: Filtration
Structural Slab

Inlet duct

Gaskets

Integrity test
probe

HEPA Filter

Seals

False ceiling

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Air & Contamination

Control: Dilution
Particles build up in enclosed spaces where
there is no ventilation.
Ventilation is the process by which any
particles generated in cleanrooms are carried
away for any remaining in the room to be
diluted with new clean air
The ventilation rate is expressed as airchanges per hour. The minimum is 20 air
changes per hour the air in a clean room is
replaced at least every 3 minutes.
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Air & Contamination

Control: Dilution
Ventilation is measured as air changes per hour
This is not a real measure, it is a calculated
measure based on air velocity measurement
The velocity is measured as units of length
divided by units of time
The velocity is then multiplied by the area = a
figure in units of volume divided by units of time
(how much air is supplied per unit time)
When figure is divided by the volume of the
cleanroom measured in (say) m3 or ft3 you get the
number of air changes per hour

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Air & Contamination

Control: Dilution
Cleanrooms have a clean-up time.
This the time taken for a room to return
to a set level of particles in the air after
it has been used for an activity. This is
required to take place within 20 minutes
of the room last being used.
This is an optional test for cleanrooms,
although one often undertaken for new
facilities (in ISO 14644).
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Air & Contamination

Control: Directional Airflow
Cleanrooms are rooms designed to be full
of clean air
If there is free access to this room from
a surrounding area containing normal
environmental air
The less clean air could move into the
cleanroom
To make sure that the dirty air does
not enter the clean room by ensuring
that there is always a flow of air in an
outward direction
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Air & Contamination

Control: Directional Airflow

To prevent dirty air entering the clean room: by ensuring

a very high rate of air supply to the clean room thus
keeping it at a higher pressure than its surroundings
If there is contact with outside air, any mixing of the
two types of air takes place outside the clean room
because the direction of air flow is from the clean to the
dirty area
Particles and microorganisms cannot swim upstream
against a directional air flow
This directional air flow is measured and monitored
through pressure differentials
Importance of air locks

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Air & Contamination

Control: Directional Airflow

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Air & Contamination

Control: Air Movement
For product or equipment to be contaminated
from air-borne microorganisms, they have to
settle out of the air onto whatever you are
trying to protect.
As long as particles and microorganisms stay
suspended in the air they are not really a
problem it is only when they settle out that
they become an actual cause of contamination
So we need to control air movement

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Air & Contamination

Control: Air Movement
The principle of air movement is applied in two
beneficial ways in clean rooms:
Turbulent air flow

The initial supply velocity is sufficient to keep air in

constant turbulence therefore particles and
microorganisms do not settle out
This is an ideal and there can be dead air beneath
tables etc,

Unidirectional air flow (UDAF)

`The idea of unidirectional air flow is that if air is

supplied at a very high velocity through specially
designed grilles it will flow for quite a distance in
straight lines
Unidirectional air flow blows away all the contamination
and particles that come into its path
Unidirectional air flow is capable of sweeping up
microorganisms that are sitting on surfaces and thereby
cleaning the surfaces up

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Detecting risks: the environmental

monitoring program
If the problem cannot be designed out,
environmental monitoring must take place
The aim is to answer the questions:
how many?
how frequent?
when does contamination occur?
how frequently does contamination occur?
Is the contamination a risk to product or
patient?
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Detecting risks: the

environmental
monitoring program
Importantly:
The point of EM is a measure of the state of control of
the facility, not the microbial quality of the finished
product
The process of EM involves:
Risk assessment
Identification of hazards
Severity, probability & detection
To stop things from going wrong
To investigate when things have gone wrong
To find root causes
To propose CAPA
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Detecting risks: the environmental

monitoring program
Environmental
monitoring must be
undertaken in each
cleanroom in the
dynamic state.
During aseptic filling,
monitoring must be
for the duration of the
activity
Monitoring consists of:
Non-viable particles in
the air;
Viable micro-organisms.

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Detecting risks: the environmental

monitoring program
We need to monitor:
The contamination in air
The contamination that can settle out of
air onto surfaces
The people who shed contamination into
the air

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Detecting risks: the environmental

monitoring program
Particle counting:
2 sizes of particle
are examined (0.5
and 5.0 micron,
based on the EU
GMP) in a cubic
metre of air;
This is carried out
using an optical
(laser) particle
counter.
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Detecting risks: the

environmental monitoring
program

Viable monitoring:

Settle plates: gives an

indication of how many
micro-organisms in the
air might settle onto a
surface;
Active air-samples: these
measure how many
micro-organisms there
are in a cubic metre of
air.
Surface contact plates
(or RODAC) and swabs
Finger plates
Plates of sleeves / gowns
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Detecting risks: the

environmental monitoring
program
The documented environmental monitoring
programme must address the following:
Where should monitoring be done
When should monitoring be done
How should monitoring be done, technique, media
etc
Limits: what can be tolerated (and what cannot)

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Detecting risks: the

environmental monitoring
program

There must be a justifiable decision as

to where monitoring should be done
and when it should be done:
where there is likelihood of contamination
where there are personnel interventions
where the personnel interventions are:
(a) close to exposed sterile product/components
(b) complex
(c) take some time to perform

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Detecting risks: the

environmental monitoring
program
When to monitor ?
Start-up
Duration of the filling activity
Interventions and off-line periodic
activities
Post fill monitoring

The expectation is for a low level

contaminants
Frequency arguably more
important than count
Can EM lead to batch rejection?
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Risk Assessment Tools

To help with this different risk
assessment tools can be used:
Imaginary grid, using ISO 14644
approach
Saturation monitoring reduced
monitoring
Risk assessment (what is going on?)
HACCP
FMEA
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Risk Assessment Tools

Similarities:
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
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HACCP
Hazard Analysis and Critical Control
Point (HACCP)
To identify and review hazards
Originated in food industry, adopted by
WHO
7 step approach

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HACCP
The 7 steps:
Analyze hazards
Multi-disciplinary team

Identify critical control points

Establish critical limits for control points
Establish corrective actions
Establish a record keeping system
Establish procedures to verify that the
system is working
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FMEA
Failure Mode and Effects Analysis
Severity
Occurrence
Detect

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FMEA
Scale: 1 to 10
severity score x occurrence score x
detect score
Assign a numerical risk

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Summary
Air and people are the main sources of
microbiological contamination in
aseptic manufacturing facilities.
We need to consider the risks and then
design cleanrooms and manage people
to minimise the risks so control
contamination
Where we cannot eliminate risks or
where problems can occur we need to
monitor
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Thank You

Tim Sandle
www.pharmig.blogspot.com

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