Controlling facility contamination. Presented by Eoin Hanley 1 July, 2016

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1 Controlling facility contamination Presented by Eoin Hanley 1 July, 2016

correct disinfectants for microbial control Maintain appropriate levels of cleanliness Important for

2 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 Slide 2 PharmOut 2015

3 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 Slide 3 PharmOut 2015

4 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 Slide 4 PharmOut 2015

5 Sources of microorganisms People Raw materials Equipment Facility Clothing Processes People are the greatest source of contamination to the manufacture of sterile product Slide 5 PharmOut 2015

6 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 Slide 6 PharmOut 2015

7 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 Slide 7 PharmOut 2015

8 Cleaning practices Cleaning effectiveness must be demonstrated Qualification of: Facility Systems Equipment (& utilities) Cleaning Validation Plans, protocols and reports for FSE Gowning/Dress codes Slide 8 PharmOut 2015

Cleaning Practices Appropriate materials,

9 Cleaning Practices Appropriate materials, movement of materials, product, process, waste and personnel Effective training program with clear responsibilities Understanding of crosscontamination risks Cleaning and disinfectant procedures, programs and schedules Slide 9 PharmOut 2015

adequate cleaning prior to disinfection Disinfectant

10 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 Slide 10 PharmOut 2015

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

11 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. Slide 11 PharmOut 2015

Disinfectants: Remove or eliminate microorganisms Germicide-varying activity &

12 Detergents and Disinfectants Detergents: Cleaning agents Removal of soils The more soil removed, the better the disinfectant effectiveness Detergent Disinfectants: Remove or eliminate microorganisms Germicide-varying activity & effectiveness Some are also sporicidal but usually called a steriliant Slide 12 PharmOut 2015

Detergents Chemical used to clean a surface by

electrostatic forces) Reduce the surface tension

microorganisms from the surface and then be

13 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 Slide 13 PharmOut 2015

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

14 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/nonionic/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 Slide 14 PharmOut 2015

Several terms depending on use: Disinfectant Biocide Normally applied to

15 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 Biocide Normally applied to inanimate objects Sanitiser Antiseptic Reduction of micro on living tissue Slide 15 PharmOut 2015

Disinfectant Efficacy and Performance #, type and location of

density and a pure population Unlikely to kill all but survival

Different types (cell membrane composition) have different

16 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. Slide 16 PharmOut 2015

17 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) Slide 17 PharmOut 2015

Disinfectant Efficacy and Performance Interfering Substances:

may not be inactivated Act as a barrier (dirt, oil, blood,

the label claim for effectiveness (i.e. still effective in the

18 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?) Slide 18 PharmOut 2015

activity, modes of action and differing efficacies

19 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 Slide 19 PharmOut 2015

20 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) Slide 20 PharmOut 2015

Personnel health & safety Sporicidal properties Different formats Cost Performance

21 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 Slide 21 PharmOut 2015

22 Hand sanitisation and antiseptics Hand sanitisers (removal of bacteria). Alcohol and nonalcohol 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 Slide 22 PharmOut 2015

Skin microflora Need to distinguish between

Can be grouped into: Resident: permanent

Staphylococcus species) Transient: picked up from

Coli, as well as yeasts, moulds and viruses)

23 Skin microflora Need to distinguish between different microorganisms found on skin. Can be grouped into: Resident: permanent inhabitants (i.e. Staphylococcus species) Transient: picked up from surfaces or from aerosols (can be pathogenic i.e. E. Coli, as well as yeasts, moulds and viruses) Impossible to completely remove all microflora Use of sterile disposable gloves Slide 23 PharmOut 2015

Common sanitisers/antiseptics Alcohols (aqueous & gels) Quaternary ammonium compounds (disinfectants and surfactants) Bisbiguanides (cationic nature-binds strongly to skin and tissues.

24 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. Slide 24 PharmOut 2015

25 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 1 st use and 3 log reduction on each hand within 5 mins after the 10 th use. Slide 25 PharmOut 2015

Hand washing techniques Must be carried out correctly

important Soap first, then the sanitiser/antiseptic (pump

instructions Awareness of activities/actions Training is

26 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 Training is key! Frequent re-sanitisation & hand washing crucial Slide 26 PharmOut 2015

Hand washing techniques According to approved procedures for hand

removed Short and tidy nails (must not puncture gloves) No nail

applied with vigorous washing for a defined period Rinsing not to

27 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. Slide 27 PharmOut 2015

bacteria from hands into the air Modern hand dryers actually spread more germs than paper towels Airborne germ counts

28 Hand dryers vs paper towels? VS 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 dispensers Slide 28 PharmOut 2015

dryers, bacteria persisted in the air well beyond the 15 second drying time, with 48% of microbes still

29 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 Slide 29 PharmOut 2015

30 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 Hand drying with single-use towels has the least risk of airborne microbial contamination Slide 30 PharmOut 2015

of water Distance of dryer from sink Size of the sink

31 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 Slide 31 PharmOut 2015

dependant on: Cleanroom size Cleanroom grading/classification Materials of construction/surfaces

32 Cleaning a cleanroom Cleanrooms: transfer of materials and movement of personnel are sources of contamination Correct design of cleanrooms and AHUs to prevent crosscontamination 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 32 PharmOut 2015

(but they must not be source of contamination) Can clean and disinfect at the same time Wipes usually

33 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 Slide 33 PharmOut 2015

Cleaning a cleanroom Mops need to be abrasive

and ceilings Multi layer wipes/foam heads, or

Need to be careful of damage/ snagging etc

fit a handle system Single use or cleaned

34 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 Slide 34 PharmOut 2015

35 Cleaning a cleanroom Mop heads with pieces or telescopic handle Lightweight 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 Slide 35 PharmOut 2015

required Other equipment may include: Cleanroom vacuum

36 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 Slide 36 PharmOut 2015

to rinse contamination off the mop head Outer

37 Three bucket system Inner bucket used to collect waste solution under wringer Middle bucket used to rinse contamination off the mop head Outer bucket holds cleaning agent Slide 37 PharmOut 2015

38 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 Slide 38 PharmOut 2015

39 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. Slide 39 PharmOut 2015

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

40 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 Slide 40 PharmOut 2015

Cleaning Techniques Solutions and equipment prepared/controlled

applied evenly over the whole surface Cleanrooms must be

technique with overlapping (10%) unidirectional strokes If

41 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 Slide 41 PharmOut 2015

42 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 Slide 42 PharmOut 2015

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

43 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, stepovers, transfer hatches etc) Slide 43 PharmOut 2015

44 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 Slide 44 PharmOut 2015

or 3 full wheel rotations Not possible to

45 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 Slide 45 PharmOut 2015

46 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) Slide 46 PharmOut 2015

Environmental monitoring Demonstrates effectiveness of cleaning &

and surface sampling Contact plates more efficient than swabs Agar with

recovered organisms to grow Dual incubation step to pick up a range of

47 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 Slide 47 PharmOut 2015

Bactericidal, fungicidal, and or sporicidal activity Suspension Tests (quantitative testing with interferences) Surface Tests

48 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) Slide 48 PharmOut 2015

Various Standards Basic Suspension tests:

(bactericidal) Surface/carrier tests: EN

49 Various Standards Basic Suspension tests: EN 1275 (fungicidal) EN 1040 (bactericidal) Quantitative Suspension tests: EN 1650 (fungicidal) EN 1276 (bactericidal) Surface/carrier tests: EN EN AOAC 991,47 Global Standards Slide 49 PharmOut 2015

50 Thank you for your time. Questions? Eoin Hanley Technical Manager Slide 50 PharmOut 2015

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