Risk analysis in sterile operation

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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

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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

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Sources of contamination

• Primarily:– People (75%)– Air (20%)– Equipment transfer (5%)

• Problem: all are essential for aseptic operations– Water sources should not be present

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People as a contamination source

• Skin flakes• Hair• Saliva• Clothing material• Cosmetics• Touching

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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

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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

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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 ControlThe 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 previously2. 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 controlControl 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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• 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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Structural Slab

HEPA Filter

Inlet duct

False ceiling

Integrity test probe

Gaskets

Seals

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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 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.

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• 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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• 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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• 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: 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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• 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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• 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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• 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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• 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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• 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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• 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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• 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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– 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 Sandlewww.pharmig.blogspot.com

http://www.pharmig.blogspot.com/

Risk analysis in sterile operation

Science

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