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1
Risk Analysis In Aseptic
Operations
Tim Sandle
www.pharmig.blogspot.com
2
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
3
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
4
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?
5
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
6
Contamination
• The particles allowed in
a cleanroom, which can
pass through a HEPA,
are very small.
Average human hair is about 100
microns
7
Sources of contamination
• Primarily:
– People (75%)
– Air (20%)
– Equipment transfer (5%)
• Problem: all are essential for aseptic
operations
– Water sources should not be present
8
People as a contamination source
• Skin flakes
• Hair
• Saliva
• Clothing material
• Cosmetics
• Touching
9
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
10
Air as a contamination source
• Clean rural areas air = 108
particles of 0.5µm
and greater per m3
(including many
microorganisms)
– So air is a contamination problem
– However air flow is also the answer to many
contamination problems
11
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
12
Contamination Control
The principles of contamination control are based on risk considerations:
1. Find the sources of microorganisms
2. What can we do to eliminate these sources?
3. 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
13
Contamination Control
• What needs to be considered?
– Design
– Control of people
– Air filtration
– Air dilution
– Air direction
– Air movement
14
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
15
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
16
Air & Contamination Control
• There are four principle applying to control of
air-borne microorganisms in clean rooms.
– Filtration
– Dilution
– Directional Air Flow
– Air Movement
17
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
.
18
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
19
Air & Contamination Control:
Filtration
Structural Slab
HEPA Filter
Inlet duct
False ceiling
Integrity test probe
Gaskets
Seals
20
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 air-changes per
hour. The minimum is 20 air changes per hour – the air
in a clean room is replaced at least every 3 minutes.
21
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
22
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).
23
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
24
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
25
Air & Contamination Control:
Directional Airflow
26
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
27
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
28
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?
29
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
30
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.
31
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
32
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.
33
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
34
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)
35
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
36
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?
37
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
38
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
39
HACCP
• Hazard Analysis and Critical Control Point
(HACCP)
– To identify and review hazards
– Originated in food industry, adopted by WHO
– 7 step approach
40
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
41
FMEA
• Failure Mode and Effects Analysis
– Severity
– Occurrence
– Detect
42
FMEA
• Scale: 1 to 10
– severity score x occurrence score x detect score
– Assign a numerical risk
43
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
44
Thank You
Tim Sandle
www.pharmig.blogspot.com

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Risk analysis in sterile operation

  • 1. 1 Risk Analysis In Aseptic Operations Tim Sandle www.pharmig.blogspot.com
  • 2. 2 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
  • 3. 3 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
  • 4. 4 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?
  • 5. 5 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
  • 6. 6 Contamination • The particles allowed in a cleanroom, which can pass through a HEPA, are very small. Average human hair is about 100 microns
  • 7. 7 Sources of contamination • Primarily: – People (75%) – Air (20%) – Equipment transfer (5%) • Problem: all are essential for aseptic operations – Water sources should not be present
  • 8. 8 People as a contamination source • Skin flakes • Hair • Saliva • Clothing material • Cosmetics • Touching
  • 9. 9 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
  • 10. 10 Air as a contamination source • Clean rural areas air = 108 particles of 0.5µm and greater per m3 (including many microorganisms) – So air is a contamination problem – However air flow is also the answer to many contamination problems
  • 11. 11 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
  • 12. 12 Contamination Control The principles of contamination control are based on risk considerations: 1. Find the sources of microorganisms 2. What can we do to eliminate these sources? 3. 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
  • 13. 13 Contamination Control • What needs to be considered? – Design – Control of people – Air filtration – Air dilution – Air direction – Air movement
  • 14. 14 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
  • 15. 15 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
  • 16. 16 Air & Contamination Control • There are four principle applying to control of air-borne microorganisms in clean rooms. – Filtration – Dilution – Directional Air Flow – Air Movement
  • 17. 17 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 .
  • 18. 18 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
  • 19. 19 Air & Contamination Control: Filtration Structural Slab HEPA Filter Inlet duct False ceiling Integrity test probe Gaskets Seals
  • 20. 20 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 air-changes per hour. The minimum is 20 air changes per hour – the air in a clean room is replaced at least every 3 minutes.
  • 21. 21 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
  • 22. 22 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).
  • 23. 23 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
  • 24. 24 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
  • 25. 25 Air & Contamination Control: Directional Airflow
  • 26. 26 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
  • 27. 27 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
  • 28. 28 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?
  • 29. 29 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
  • 30. 30 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.
  • 31. 31 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
  • 32. 32 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.
  • 33. 33 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
  • 34. 34 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)
  • 35. 35 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
  • 36. 36 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?
  • 37. 37 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
  • 38. 38 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
  • 39. 39 HACCP • Hazard Analysis and Critical Control Point (HACCP) – To identify and review hazards – Originated in food industry, adopted by WHO – 7 step approach
  • 40. 40 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
  • 41. 41 FMEA • Failure Mode and Effects Analysis – Severity – Occurrence – Detect
  • 42. 42 FMEA • Scale: 1 to 10 – severity score x occurrence score x detect score – Assign a numerical risk
  • 43. 43 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

Editor's Notes

  1. To identify sources of contamination, construct a risk diagram / diagrams. This will show sources and routes of contamination. Examples include: