1. Behaviour and Practices in Cleanrooms and Cleanzones
Tim Sandle
Microbiology solutions:

2. Contents Part 1: all grades of cleanrooms
Part 2: all grades cleanzones
Part 3: Aseptic Filling Suite
in addition to Parts 1 and 2

3. A bench-mark...
Expected standard
GMP, audit and
inspection failure
Standards in cleanroom/zone behaviour and practices will be assessed via specific micro audits

4. Definitions:
Cleanroom
a room designed, maintained and controlled to prevent particulate and microbiological contamination of drug products

5. Definitions:
Cleanzone
an area with a defined particulate and microbiological cleanliness standard, usually consisting of Laminar Air Flow protection.
A cleanzone is designed to maintain asepsis or sterility of the critical activity, product, test, or material contained within it.

6. Definitions:
Critical activity
an activity that involves close proximity or manipulation of exposed product, raw materials or sterile equipment and components
Laminar Air Flow (LAF)
Uni-Directional Air Flow (UDAF) at a velocity sufficient to uniformly sweep particulates away from the Cleanzone

7. Sterile Drug Products Produced by Aseptic Processing [FDA]
where the drug product, container, and closure are subject to sterilisation processes separately, as appropriate, and then brought together
‘Any manual or mechanical manipulation of the sterilised drug, components, containers and closures prior to, or during, aseptic assembly poses a risk of contamination and thus necessitates careful control’

8. Sterile Drug Products Produced by Aseptic Processing [FDA]
‘Poor cGMP conditions…can ultimately pose a life threatening health risk to a patient’
‘Even successfully qualified systems can be compromised by:
poor personnel activities
poor operational activities
poor maintenance activities’

9. Sterile Drug Products Produced by Aseptic Processing [FDA]
‘It is essential that operators involved in aseptic manipulations adhere to the basic principles of aseptic technique at all times…’
Appropriate training should include:
cleanroom behaviour
aseptic technique
microbiology
gowning
patient safety hazard posed by a non-sterile product
Personnel training should be updated regularly
Supervisors should routinely evaluate operators

10. Scope of SOP... All graded cleanzones (Grade A)
Microbiology sterility isolator (Grade A)
All graded cleanrooms (Grades B - D)
Standards of behaviour and aseptic technique must be transferable to all relevant situations
this will be observed by an auditor/inspector
if in doubt guidance must be sought

11. SOP responsibilities Everyone entering cleanrooms/zones must:
be trained and competent, or
must be ‘closely’ supervised
Everyone has a responsibility to:
be familiar/compliant with expected standards
report substandard behaviour (e.g. gowning)
report damaged room fabric, equipment, gowns
Any persons who pose an unacceptable risk to the product, process or facility must be excluded immediately and retrained

12. Part 1: All cleanrooms

13. All cleanrooms: Behaviour
Good practice:
gowns/PPE changed if damaged, wet or used for long durations
check yours and others regularly
target max duration = 4 hours
Time 
Efficiency 
Avoid rapid movements
creates particles
disturbs air flows
Avoid aerosol production
 personnel =  contamination

14. All cleanrooms: Behaviour
Aseptic technique must always be used wherever applicable
Fresh sterilised gloves must be worn immediately before a critical activity and regularly sanitised
but do not use disinfectant spray near product, components, raw materials or env. mon. equipment

15. All cleanrooms: Behaviour
Minimise spread of contamination during critical activities:
avoid touching your person or other people
avoid touching human contact sites such as:
pens bin handles
keyboards paperwork
keypads desks
doors plugs/switches
chairs any unclean equipment
telephones containers (disinfectant cans?!)
if you do make contact - sanitise gloves

16. All cleanrooms: Behaviour
Sterile/sanitised implements must be used for handling product. If sterile their sterility must be maintained throughout the activity
Minimise particles when opening autoclave bags
50ml syringe
Tubing
Lid
Container

17. All cleanrooms: Surfaces
Items dropped on the floor
floors are relatively dirty areas
items must NOT be picked up during a critical activity unless under exceptional circumstances
if really needed the item must be thoroughly sanitised and the operators gloves changed if they are completing the activity

18. All cleanrooms: Surfaces
Touching floors must be avoided at all times
if having to kneel, sit or lie on the floor, either
disinfect the floor before and after
place a sanitised/sterile sheet on the floor first
Aseptic items must not be placed on the floor, or any other unsterile/unsanitised surface
place on a suitable surface, or
place on a sterile, or disinfectant wipe

19. All cleanrooms: Practices
Items entering cleanrooms
avoid material that cannot be effectively sanitised
avoid material that sheds excessive particles

20. All cleanrooms: Practices
Work areas must be kept clean, neat and tidy to reduce cross-contamination/mix-ups

21. All cleanrooms: Practices
Items within cleanrooms must not obstruct HVAC/LAF vents
Standing water must be cleaned up

22. All cleanrooms: Practices
Status labelling
e.g. cleaned, sanitised, disinfected or sterilised
soiled disposable equipment must be discarded
soiled reusable equipment must be removed

23. Part 2: All cleanzones

24. Cleanzones: Behaviour
To avoid contamination and disruption of air flow:
Control movements within, and adjacent to, cleanzones
Talking must be avoided within, or adjacent to, cleanzones
Interventions must be performed slowly and deliberately
Covers, curtains and doors surrounding cleanzones must be opened with minimal distance/force
Aseptic technique must always be used regardless of any other protection present

25. Cleanzones: Behaviour
‘First Air’ principle:
items being protected by air flow must receive clean ‘first air’ - so all operator manipulations must be done downstream of air flow
Aseptic manipulations and operator gloves must be restricted to within the protected zone during a critical activity
Vertical LAF 
Horizontal LAF 

26. Cleanzones: Behaviour
Operation of cleanzone:
Workareas must be clean, neat and tidy.
Items present within the cleanzone must be minimised and located so as not to disrupt or reduce air flow protection
Cleanzone airflows must be allowed to operate for at least 10 mins prior to use
Cleanzone work areas must be cleaned prior to use

27. Part 3: Aseptic Filling Suite

28. Aseptic Filling Suite: Behaviour
Gloves must be sanitised at regular intervals, but especially when related to a critical activity:
Before leaving the final change/SW5
Entering the filling room/critical zone
Before opening cleanzone screens/doors
Before handling container/closure bags
Before handling a sterilised implement/surface
After touching any part of ones self or others
After touching a human contact site
After touching microbiological media

29. Aseptic Filling Suite: Behaviour
Use of disinfectant sprays
avoid excessive particles
spray away from env.mon. equipment including particle counters (use Safe Zones in filling rms)
Use a jet spray for sanitising gloves
deliver a pool into the palm of the hand
spread across all surfaces
allow to dry before commencing

30. Aseptic Filling Suite: Behaviour
Filling rooms
must not be used as short cuts, even when not in use
must not be used to store items not required for filling activity in progress
must have personnel numbers minimised
Long 24” outer gloves are mandatory at all times
Goggles to be worn during critical activities

31. Aseptic Filling Suite: Behaviour
‘Buddy system’ recommended for some aseptic activities, e.g. Huber unloading
Grade A
‘CLEAN’
operator
Grade B
‘DIRTY’
operator
N.B. The clean operator must NOT touch anything that is not sterile
Single wrap
Double wrap

32. Aseptic Filling Suite: Behaviour
When working in cleanzones the operator must hold gloved hands:
at working height
at/above waste height
under protective air flow
avoiding touching anything unsterile
Aseptic technique must be demonstrated at all times, regardless of any other protection

33. NEW: microbiological audits
Facilities, utilities and equipment
Liquid, moisture Storage
Fabric HVAC/UDAF
Interlocks/airlocks Documentation
Specific activities
Gowning Aseptic Technique
Working in UDAFs Cleaning/disinfection
Aseptic Filling
General items
Cleanroom behaviour
Process flows/Personnel Housekeeping
For all areas covered by this SOP
For Correction & PREVENTION

34. Summary
Increase in activity/personnel = increased chance of contaminating product/facility
Behaviour and practices required at BPL are industry practice and regulatory expectations
You may well be observed by an inspector and will need to demonstrate good standards
Standards of behaviour and aseptic technique should be a transferable skill applied to different situations. If in doubt - ask.
From NOW you must comply with this SOP