Behaviour and Practices in Cleanrooms and Cleanzones Tim Sandle Microbiology solutions: http://www.pharmamicroresources.com/

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

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

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

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.

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

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’

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’

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

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

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

Part 1: All cleanrooms

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

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

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

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

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

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

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

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

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

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

Part 2: All cleanzones

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

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 

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

Part 3: Aseptic Filling Suite

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

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

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

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

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

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

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