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Controlling facility contamination
Presented by Eoin Hanley1 July, 2016
Slide 2 © PharmOut 2015
Cleaning & Disinfection
Control of contamination:• Equipment cleaning (validated processes)• Cleaning of cleanrooms• Disinfection of cleanrooms
• Need clearly defined cleaning methods, use of detergents and correct disinfectants for microbial control
• Maintain appropriate levels of cleanliness• Important for sterile medicinal products that are not
terminally sterilised• Technical and operational controls
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Microbiology: The basics
• Wide variety of microorganisms that could potentially contaminate product
• Microorganisms need to be controlled, killed and/or excluded in the process of making sterile product
• 4 main types of microorganisms:
Bacteria Fungi Yeast Virus
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Types of Contamination
Contamination can enter cleanrooms or be generated within them
Viable and non-viable
Contamination can enter on solids, in fluids, on materials, personnel and air
Contamination can be generated by processes and movement of personnel
Large particles can settle on surfaces and small ones can be blown around
Facilities must be operated according to GMP ensuring the correct product quality
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Sources of microorganisms
People Raw materials Equipment
Facility Clothing Processes
People are the greatest source of contamination to the manufacture of sterile product
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What is a cleanroom?
Controlled environments
Classified or graded (ISO 14644) based on concentration of airborne particles.
HVAC systems with suitable air filtration/dilution
For sterile medicinal products, other physical and microbiological parameters must be met and maintained
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What is a cleanroom?
Physical parameters include cleanable surfaces, controlled temperature & humidity
Microbiological alert & action levels (i.e. EU and US FDA for aseptic processing)
Control of personnel
Sanitisation and disinfection procedures must be validated
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Cleaning practices
• Qualification of: • Facility• Systems • Equipment (& utilities)
• Cleaning Validation Plans, protocols and • reports for FSE
• Gowning/Dress codes
Cleaning effectiveness must be demonstrated
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Cleaning Practices
Appropriate materials, movement of materials, product, process, waste and personnel
Effective training program with clear responsibilities
Understanding of cross-contamination risks
Cleaning and disinfectant procedures, programs and schedules
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Cleaning Practices
• Removal of residues and soils from surfaces
• Visually clean• Defined methods for cleaning• Surfaces require adequate
cleaning prior to disinfection• Disinfectant effectiveness can
be inactivated by organic residues
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Cleaning Practices
Cleaning will remove some microorganisms
Some cleaning agents also contain disinfection agents
Cleaning ≠ Disinfection, but can remove microbes
EU and US standards for disinfectant validation
Must reduce a microbial population to a certain log reduction (disinfectant validation)
Have a technical agreement with company who supplies the disinfectant and be able to track the lots.
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Detergents and Disinfectants
Disinfectants:• Remove or eliminate microorganisms• Germicide-varying activity & effectiveness• Some are also sporicidal but usually called a steriliant
Detergents:• Cleaning agents• Removal of soils• The more soil removed, the better the disinfectant
effectiveness
Detergent
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Detergents
• Chemical used to clean a surface by removing unwanted soil (capillary effects or electrostatic forces)
• Reduce the surface tension to allow removal
• Synthetic surfactants• Surfactant = Surface Active Agent• Hydrophilic and hydrophobic
aspects• Can also disassociate microorganisms
from the surface and then be removed by a water rinse or destroyed by a disinfectant
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Selecting the correct Detergent
Two key considerations:• Chemical composition
• Typically neutral and non-ionic and low/non-foaming• Compatibility with the disinfectant
• Detergent must not leave a residue that neutralises the active ingredient in a disinfectant
• Common detergents include soaps, anionic/cationic/non-ionic/alkali/acidic/amphoteric detergents
• Other chemicals added to improve performance i.e. act against hard water/scaling, dispersal of fats etc.
Should be ARTG listed
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Disinfection
• A disinfectant is a chemical agent which reduces number of microorganisms present by removing them or destroying them.
• Several terms depending on use:
Disinfectant
Antiseptic
Sanitiser
BiocideNormally applied to inanimate objects
Reduction of micro on living tissue
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Disinfectant Efficacy and Performance
• #, type and location of microorganisms:• More effective against low numbers/low
cell density and a pure population• Unlikely to kill all but survival and
multiplication dependant on conditions they are left in
• Different types (cell membrane composition) have different resistances
• Easier to kill if in suspension. Biofilms difficult.
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Disinfectant Efficacy and Performance
Temperature and pH:
• Will have optimal temperature and pH• Temperature influences rate of reaction but for cleanroom
use, made for use at ambient conditions• pH influences ionic binding• If outside ranges, will not be as effective
Water:
• Some do not work well in hard water. • Normally not an issue for cleaning of high grade
cleanrooms (WFI)
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Disinfectant Efficacy and Performance
• Interfering Substances:• On surfaces and/or equipment• Require increased contact time or may not be
inactivated• Act as a barrier (dirt, oil, blood, protein etc)• Materials of construction & surface finish
Check the label claim for effectiveness (i.e. still effective in the presence of small amounts of organic matter?)
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Types of Disinfectants
Thousands of disinfectants available (also refer to ARTG)• Different spectra of activity, modes of action and differing
efficacies• Phenols• Alcohols• Aldehydes• Oxidisers
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Selecting the correct Disinfectant
• Important decision for cleanroom managers & microbiologist• Compatible with detergents• Must have a wide spectrum of activity• Must have a fast action• Should not be neutralised by residual matter• Environmental conditions (temperature, pH)
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Selecting the correct disinfectant
• Non-reactive/non-corrosive (i.e. may require rinse/wipe steps with sterile water)
• compatibility with the cleanroom surfaces • Personnel health & safety• Sporicidal properties• Different formats• Cost
Performance should be periodically reviewed based on results of microbial monitoring
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Hand sanitisation and antiseptics
Hand sanitisers (removal of bacteria). Alcohol and non-alcohol types.
Hand antiseptics (bind to the skin giving a longer activity and destroy bacteria)
~80% of microorganisms are transferred by hands
Effectiveness of the sanitising agent and the integrity of the skin
Cannot have harsh chemicals on skin…but personnel also wear specific clothing/gloves for added protection
Cleaning of hands also prevents cross-contamination
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Skin microflora
Resident:
• permanent inhabitants (i.e. Staphylococcusspecies)
Transient:
• picked up from surfaces or from aerosols (can be pathogenic i.e. E. Coli, as well as yeasts, moulds and viruses)
Need to distinguish between different microorganisms found on skin. Can be grouped into:
• Impossible to completely remove all microflora• Use of sterile disposable gloves
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Common sanitisers/antiseptics
Alcohols (aqueous & gels)
Quaternary ammonium compounds (disinfectants and surfactants)
Bisbiguanides (cationic nature-binds strongly to skin and tissues. Wide range of effectiveness)
Poidone Iodide (surgical hand scrubs)
• All must be stored, controlled & used correctly. • Should not be transferred into secondary containers,
diluted or mixed.
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Testing for efficacy
International Standards i.e. EN1500, ASTM E1174
Tests require a number of subjects/groups
Test organism ( S. marcescens or E. Coli) applied to their hands
Sanitising agent then applied (or a reference solution)
2 log reduction on each hand within 5 mins after the 1st use and 3 log reduction on each hand within 5 mins after the 10th use.
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Hand washing techniques
• Must be carried out correctly• Physical rubbing and then agent applied• Time taken is important• Soap first, then the sanitiser/antiseptic
(pump dispensers/automatic)• Follow the manufacturer instructions• Awareness of activities/actions
Trainingis
key!
Frequent re-sanitisation & hand washing crucial
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Hand washing techniques
• According to approved procedures for hand hygiene, glove application and contamination control
• Jewellery/watches removed• Short and tidy nails (must not puncture gloves)• No nail varnish/make-up• Wash according to a set procedure• Sanitiser can then be applied with vigorous
washing for a defined period• Rinsing not to re-contaminate the hands• Dry hands/arms• Gloving and apply alcohol. Leave to dry.
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Hand dryers vs paper towels?
• Recent study at University of Leeds (Jan 2015)• Compared different hand drying methods and their
potential to spread bacteria from hands into the air• Modern hand dryers actually spread more germs than
paper towels• Airborne germ counts were nearly 30% higher around
hand dryers compared with paper towel dispensershttp://www.cleanroomtechnology.com/news/article_page/Hand_dryers_in_washrooms_spread_bacteria_and_diseases/105011
VS
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Hand dryers vs paper towels?
Key findings:• Bacterial counts in the air close to jet
air driers were 4.5 times higher than around warm air dryers and 27 times higher compared with using paper towels
• Next to the dryers, bacteria persisted in the air well beyond the 15 second drying time, with 48% of microbes still airborne after five minutes.
• Lactobacilli were still detected in the air 15 minutes after hand drying
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Hand dryers vs paper towels?
Key findings:• Drying with warm air and jet air driers resulted in
widespread droplet release; contamination was found on all areas of the body demonstrating potential for spread and inhalation to other washroom users
• Airborne bacteria were dispersed 1m away within the first five minutes of sampling and bacteria were found up to 2m away
http://www.cleanroomtechnology.com/news/article_page/Hand_dryers_in_washrooms_spread_bacteria_and_diseases/105011
Hand drying with single-use towels has the least risk of airborne microbial contamination
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Other factors to consider
• Air filters on dryers• Location of sanitiser dispensers• IR beams for activation• Pressure of water• Distance of dryer from sink• Size of the sink• Glove dispensers• Automatic shoe covers
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Cleaning a cleanroom
• Cleanrooms: transfer of materials and movement of personnel are sources of contamination
• Correct design of cleanrooms and AHUs to prevent cross-contamination
• Cleaning program dependant on:• Cleanroom size• Cleanroom grading/classification• Materials of construction/surfaces• Equipment in the room• Movement of materials and personnel• Product characteristics• Cleaning methods
Slide 33 © PharmOut 2015
Cleaning a cleanroom
• Various materials and equipment used• Hand wipes, mop wipes, tacky rollers, • multiple bucket systems etc• Physical removal of contamination • Dry and also wet for distribution of cleaning agent (but
they must not be source of contamination)• Can clean and disinfect at the same time• Wipes usually polyester/cellulose/cotton/multilayer and
non-shedding• Can be sterilised but needs control
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Cleaning a cleanroom
• Mops need to be abrasive but robust• Cleaning of floors, walls, doors and
ceilings• Multi layer wipes/foam heads, or
microfiber heads with electrostatic charge
• Need to be careful of damage/ snagging etc
• Various shapes and sizes for ease of use to fit a handle system
• Single use or cleaned• Tacky rollers also useful in low grade
areas
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Cleaning a cleanroom
Mop heads with pieces or telescopic
handleLightweight but
rotate and easy to move
Full surface contact during the cleaning
process
Aluminium shaft and a PVC head
Must be easy to clean and sterilise
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Cleaning a cleanroom
• Multiple bucket system with a ringer• Three bucket system the best but more storage room
required
• Other equipment may include:• Cleanroom vacuum cleaners • Steam cleaners • VHP cleaning systems
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Three bucket system
Outer bucket holds cleaning agent
Middle bucket used to rinse contamination off
the mop head
Inner bucket used to collect waste solution
under wringer
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Cleaning a cleanroom
Broad spectrum against bacteria, fungus, spores and virus
Easy to apply and safe for personnel
Prepared and effective immediately
Non-corrosive, evaporates quickly, no residues
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Cleaning a cleanroom
Effectiveness dependencies already discussed
Expectation to rotate between two or more different agents on a routine basis
Irradiated solutions in high grade areas or filtration.
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Cleaning Techniques
• Robust procedures as part of a sanitisation program:• Reduction of airborne and viable contamination to
specified limits (separate activities)• Cleaning/disinfection/rinsing stages and techniques,
frequencies, rotation, surfaces, area classification/grade
• Environmental Monitoring program to demonstrate effectiveness
• Periodic training/re-training• Periodicity appropriate using validated methods
Shutdown, commissioning and start-up
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Cleaning Techniques
• Solutions and equipment prepared/controlled according to validated SOPs
• Application of agents must be applied evenly over the whole surface
• Cleanrooms must be designed without crevasses, ledges, recesses etc
• “Pull and lift” technique with overlapping (10%) unidirectional strokes
• If using hand wipes wipe is re-folded to expose clean fabric
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Cleaning Techniques
• Define how often each rooms is cleaned and the surfaces.• Horizontal surfaces will require more frequent cleaning and• the higher the grade and the greater the activity, the
more often it will be cleaned• Use the correct gowning & PPE
• Clean the cleanest areas first-from room of highest grade towards CNC
• Start in area furthest away from the exit door• Start with high surfaces and work downwards: clean
ceilings before walls, and walls before floors
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Cleaning Techniques
• Clean walls with downwards overlapping strokes and avoid the mop head touching the floor
• Log of cleaning & disinfection activities to be maintained• Care when transferring cleaning materials and waste
between rooms using correct transfer hatches and appropriate cleaning of packaging
• Take care around HVAC grilles and vents• Also attention to stationary and non-stationary
equipment as well as doors, handles, windows, step-overs, transfer hatches etc)
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Other considerations
Various regulations on authorisation of cleaning agents
Must be safe for use or use the correct PPE
MSDS available
Stability, storage and handling instruction
Risks, exposure, health assessments, surveillance
Correct disposal
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Peel off mats
80% of cleanroom contamination by feet or wheels• 27% prevented
by peel-off mats
Effective decontamination needs at least 6 footfalls or 3 full wheel rotations
Not possible to decontaminate
wheel traffic using a peel-off mat
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Peel off mats
• Switching from peel-off mats to Dycem proven to reduce airborne particles by 75%• 99.9% prevented by Dycem
• Tests demonstrate that 200,000 particles released during peeling (and a lot of waste)
http://www.dycem-cc.com
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Environmental monitoring
• Demonstrates effectiveness of cleaning & disinfection program
• Sample surfaces and equipment• Swabs, contact plates and surface sampling• Contact plates more efficient than swabs• Agar with neutralising agent to eliminate disinfectant
residues and to allow any recovered organisms to grow• Dual incubation step to pick up a range of environmental
microorganisms• Review results and look for trends
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Validation of Disinfectants
• Demonstrate its efficacy-documented evidence• EU and US FDA requirement (there are differences)• Performance testing: can reduce the microbial
bioburden either in suspension or from cleanroom surfaces to an acceptable level
• Bactericidal, fungicidal, and or sporicidal activity• Suspension Tests (quantitative testing with
interferences)• Surface Tests (effective concentrations)• Field trials (effectiveness in cleanroom)• Other tests for hand sanitisers (EN 1500)
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Various Standards
• Basic Suspension tests:• EN 1275 (fungicidal)• EN 1040 (bactericidal)
• Quantitative Suspension tests:• EN 1650 (fungicidal)• EN 1276 (bactericidal)
• Surface/carrier tests:• EN 13713• EN 13697• AOAC 991,47
GlobalStandards
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Thank you for your time.Questions?
Eoin Hanley
eoin.hanley@pharmout.net
Technical Manager
www.pharmout.net