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Sterile Manufacturing Flashcards

1
Q

Types of contamination

A

Viable matter: bacteria, fungus, yeasts, viruses

Non-viable matter: particles, dust etc.

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2
Q

Sources of contamination

A

Human: hands, hair, skin, nose, mouth etc.

Non-human: environment, equipment, surfaces, components etc.

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3
Q

Methods of removing or preventing viable contamination

A

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

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4
Q

Sterile manufacturing

A

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

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5
Q

GMP requirements

A

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

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6
Q

Terminal sterilisation

A

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

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7
Q

Environmental control

A

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

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8
Q

Effects of contamination

A

Viable matter- infection, sepsis etc.

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

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9
Q

Contamination- skin

A

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

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10
Q

Contamination- non-viable

A

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

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11
Q

Cleanroom

A

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

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12
Q

Cleanroom history

A

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

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13
Q

Cleanroom applications

A

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

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14
Q

Classification of cleanrooms

A

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

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15
Q

Classification levels of cleanrooms

A
  1. As built- empty of all equipment
  2. With equipment but no personnel
  3. Fully operational
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16
Q

Section titles for BS-5295

A

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

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17
Q

Classification equation

A

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

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18
Q

Industrial requirements for cleanrooms

A

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

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19
Q

Guides to good pharmaceutical manufacturing process

A 
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
20
Q

Organism monitoring

A

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

21
Q

EEC guidelines

A

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

22
Q

Types of cleanroom air flow

A

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

23
Q

Conventional cleanrooms

A

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

24
Q

Unidirectional cleanrooms

A

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)

25
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
26
Types of clean room areas
Conventional Unidirectional Mixed flow Isolators
27
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.
28
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
29
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 ```
30
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
31
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
32
Mechanisms of particle removal
Diffusion- small particles Impaction- large particles Interception- medium particles Sieving
33
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
34
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
35
Cleanroom validation and maintenance
Check that design specifications have been met | Check at specific intervals that area continues to operate within the limits required
36
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
37
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
38
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
39
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
40
Types of pharmaceutical product
Injectables- oily, aqueous, freeze-dried, powder | Ophthalmic- drops, lotions, ointments
41
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
42
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
43
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
44
Isolator technology
A containment device which utilises barrier technology for the enclosure of a controlled workspace
45
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
46
Isolator environmental concerns
``` Process risk Barrier integrity Manipulation techniques Transfer techniques Internal pressurization Sanitization techniques Regulatory requirements ```

PH3114 (28 decks)

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