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Flashcards in Sterile Manufacturing Deck (46):

Types of contamination

Viable matter: bacteria, fungus, yeasts, viruses
Non-viable matter: particles, dust etc.


Sources of contamination

Human: hands, hair, skin, nose, mouth etc.
Non-human: environment, equipment, surfaces, components etc.


Methods of removing or preventing viable contamination

Sterilisation- cannot sterilise everything e.g. heat labile
Disinfection- disinfectants are harsh chemicals, release of particles
Preservation- multi-dose containers


Sterile manufacturing

Controlled environment- ideally free from all sources of contamination
Terminally sterilised products
Aseptically dispensed/manufactured products


GMP requirements

Qualified personnel with appropriate training
Adequate premises
Suitable production equipment, designed for easy cleaning and sterilisation
Adequate precautions to minimise the bio-burden prior to sterilisation
Validated procedures for all critical production steps
Environmental monitoring and in process testing procedures


Terminal sterilisation

Terminal sterilisation using heat or radiation methods on the final product should always be the method of choice
Even though the product will be sterilised the manufacturing process should attempt to reduce the bio-burden before the sterilisation takes place
Not all products can be terminally sterilised by heat or radiation, in this instance only aseptic manufacturing is available for producing a safe product


Environmental control

Historically- hospital control of infectious diseases (containment)
Currently- environment attempts to actively reduce contamination levels caused by the environment, equipment and personnel


Effects of contamination

Viable matter- infection, sepsis etc.
Non-viable- pathological effects, spoilage of products (quality control issues) etc.


Contamination- skin

Viable: the outer skin layer sheds every 24 hours, these particles having a median size of 20 micrometres, with some less than 10 micrometres
These cells also carry the natural bacterial flora of the body (males worse than females)
Studies have shown that impervious clothing prevents dispersion of these cells e.g. a ten fold reduction in viable particulate counts led to a halving of the sepsis rate in implant operations


Contamination- non-viable

Particles may disperse from personnel within the manufacturing facilities
These may be from skin cells, normal clothing or containment clothing itself
Containment clothing accounts for only 1% of the total particulate load recorded in sterile manufacturing facilities
A further source is the respiratory tract of the operator, sneezing or talking generating substantial amounts of particulates



Special manufacturing facilities with control over the levels of contamination (both viable and non-viable)
A room in which the concentration of airborne particles is controlled by specific limits


Cleanroom history

1950-60s: rooms with well filtered air systems developed for building inertial guidance systems
1961: Scandia laboratories (USA)- use of directed air flow to reduce particle counts
Scandia team developed first standards for cleanroom air cleanliness in 1963


Cleanroom applications

Biotechnology- antibiotic production, genetic engineering
Pharmacy- sterile pharmaceuticals, sterile disposable
Medical devices- heart valves, cardiac by-pass systems
Hospital- immunodeficiency therapy, isolation of contagious patients, operating rooms


Classification of cleanrooms

Classified by the cleanliness of the air
The number of particles equal to or greater than 0.5 micrometres is measured in one cubic foot of air, an this count is used to classify the room
Classification level dependent upon room's activity and use, an empty room will have a low particulate load


Classification levels of cleanrooms

1. As built- empty of all equipment
2. With equipment but no personnel
3. Fully operational


Section titles for BS-5295

Part 0- General introduction, terms and definitions for cleanrooms and clean air devices
Part 1- Specification for cleanroom and clean air devices
Part 2- Method for specifying the design, construction and commissioning of cleanrooms and clean air devices
Part 3- Guide to operational procedures and disciplines applicable to cleanrooms and clean air devices
Part 4- Specification for monitoring clean rooms and clean air devices to prove continued compliance


Classification equation

Depends on: maximum permitted concentration of particles, ISO classification number and considered particle size


Industrial requirements for cleanrooms

Ranges from 1 to 100,000
100: Manufacturing of aseptically produced parenterals, isolation of immunosuppressed patients, and implant/transplant surgical operations
10,000: Assembly of precision timing devices, servo-controlled valves, production of terminally sterilized pharmaceuticals


Guides to good pharmaceutical manufacturing process

1977 UK orange guide suggested a class 1 room for aseptically produced products and a class 2 room for terminal sterilised products
1992 EC guide to good manufacturing practice for medicinal products superseded local GMP guides


Organism monitoring

Air sampling- slit air samplers
Settle plates- agar exposed to atmospheric air
Contact plates- agar plates wipe on surface of units
Finger dabs- glove testing


EEC guidelines

Conditions should be maintained in the zone immediately surrounding the product, and throughout the background when unmanned and should be recovered after a short clean up period
Terminally sterilised products should be manufactured in a grade C environment, parenteral products should be manufactured in a grade A zone within a grade C environment
Aseptic parenterals should be prepared in grade A zone within grade B environment


Types of cleanroom air flow

Conventional cleanrooms: turbulently ventilated cleanrooms/non-unidirectional air flow cleanrooms
Unidirectional flow cleanrooms: laminar flow cleanroom/ultra cleanrooms


Conventional cleanrooms

Similar to general ventilation systems used in offices i.e. air supplied by an air conditioning plant through ceiling diffusers
Increased air supply compared to normal ventilation systems
HEPA filters
Rooms are pressurised to keep dirty air out
Rooms constructed of materials which do not generate particles, and are easy to clean
Class 1,000 or 10,000


Unidirectional cleanrooms

Flow of air in one direction, either vertical or horizontal at uniform speed of 0.3-0.45m/s throughout entire air space
Problems when equipment and personnel convert supplied laminar air flow into turbulent air flow, which can generate particle vortexes
Cleanliness directly proportional to air velocity (10-100 times air supplied to normal rooms)


Mixed ventilation cleanrooms

Conventional ventilated cleanroom with the critical work zones isolated within a unidirectional flow system i.e. a laminar flow bench or isolator
Advantages in terms of cost, highly expensive unidirectional air flow units only required in the critical work areas


Types of clean room areas

Mixed flow


Technological advances

Isolators- positive vs negative
Originally used in nuclear industry
Protect product and operator from each other
High risk products- cytotoxics, BSE, gene therapy etc.


HEPA filtration

HEPA filters used until 1980s for removal of particles that would contaminate the processes being carried out in cleanrooms
For the production of integrated circuits, a higher quality of filtration has been required- ultra low penetration air filtration


Particulate air filtration

The arrangement and spacing of the filters together with the velocity of air passing through, affects both the concentration of airborne particulate material, and the formation of turbulent zones and pathways within the room
Remove particles and direct airflow (unidirectional flow)
For class 100 HEPA filters should be used for all air ventilation from ceiling, using unidirectional flow
For class 10 or lower, ULPA filters should be used in unidirectional format


Construction of HEPA filters

Aim to generate a large surface area of filter paper in a frame from which there are no leakages of unfiltered air
HEPA filters based on traditional construction with aluminium foil separator
Rated by efficiency to remove 99.97% of 0.3 micrometre particles at an air flow rate of 1.5-2.2cm/s


Particle removal

Pre-filtration of HEPA and ULPA filters allows removal or coarse/large particles
Pre-filters will prolong the survival of the expensive HEPA and ULPA filters
HEPA and ULPA filters made from glass fibres in range 0.1-10 micrometres


Mechanisms of particle removal

Diffusion- small particles
Impaction- large particles
Interception- medium particles


Filter efficiency factors

Particle density
Velocity and mean free path of particle
Thickness of filter medium
Velocity, pressure and temperature of transporting gas (air)
Sizing and distribution of fibres within the filter medium


Filter efficiency testing

Hot DOP test- detection of thermally generated particles of DOP of average size 0.3 micrometres
Sodium flame test- detection of aerosolized sodium chloride particles of mass median size 0.6 micrometres
Frame/seal tests- must be carried out after installation within working system


Cleanroom validation and maintenance

Check that design specifications have been met
Check at specific intervals that area continues to operate within the limits required


Cleanroom clothing

Head cover, mask, body suit (one or two piece), gloves and overshoes or dedicated shoes
Disposable or recyclable
Disposable- higher expense?
Recyclable- washing, drying, re-sterilization and validation- can be more expensive


Properties of clothing to be examined

Pore size, air permeability, particle removal efficiency (usually 0.5 and 5 micrometres)
E.g. Gortex, hospital cotton
Problems with joints/seals, air pumping


Basic rules for working in cleanroom

Know proper gowning technique
Never reuse a garment without rewashing or re-sterilizing
Know disinfection techniques
Once inside, cannot return to air lock and come back without re-gowning and re-sterilizing
All equipment must be designed for easy cleaning
Minimise number of people and personal articles
Clean up immediately
No illness
Use intercom for external communications


Design of cleanrooms for pharmaceutical industry

Not normally a single cleanroom
Suite of connecting rooms, of various grades/classes and accommodate different parts of the manufacturing processes
Aseptic and terminally sterilised products have different room classification requirements


Types of pharmaceutical product

Injectables- oily, aqueous, freeze-dried, powder
Ophthalmic- drops, lotions, ointments


Packaging of pharmaceuticals

Industry/hospital- central intravenous additive services (CIVAS)- supply of drugs in ready to use form rather than manipulating on the ward
Materials- glass, plastic etc.
New developments- blow fill technology, pre-filled/ready to use products


Design objectives

Exclusion of environment
Removal/dilution of contamination from processes
Containment of hazards from product
Protection of operators
Optimum working conditions for operators
Special environments for certain products
Effective monitoring of room conditions
Control and management of the flow of material and operator movement
Overall security of the operation


Design methodology

Analyse production stages
Prepare process flow diagrams
Define activities and environment for each room
Quantify production, process and space requirements
Prepare room association diagrams
Develop layouts and schemes
Prepare designs and specifications


Isolator technology

A containment device which utilises barrier technology for the enclosure of a controlled workspace


Isolator running cost savings

Reduction in quality of air required and amount of sub-division of space for manufacture
Reduction in garment quality and the number of changes required
Reduction in required monitoring of particles and micro-organisms
Reduction in area of critical surfaces requiring cleaning and disinfection
Increased flexibility of operating staff


Isolator environmental concerns

Process risk
Barrier integrity
Manipulation techniques
Transfer techniques
Internal pressurization
Sanitization techniques
Regulatory requirements