Transcript Basic Principles of GMP Sterile Pharmaceutical Products Annex 6. TRS 902, 2002 Module 14 | Slide 1 of 62 January 2006

Basic Principles of GMP
Sterile Pharmaceutical Products
Annex 6. TRS 902, 2002
Module 14 |
Slide 1 of 62
January 2006
Sterile Production
Objectives
 To review basic GMP requirements in the manufacture of sterile
pharmaceutical products
 To review air classifications for activities related to the
manufacture of sterile products
 To review the different types of sterilization methods
 To review quality assurance aspects in the manufacture and
control of sterile products
 To consider current issues applicable in your country
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Sterile Production
GMP Requirements for Sterile Products
 Additional rather than replacement
 Specific points relating to minimizing risks of contamination
 microbiological
 particulate matter
 pyrogen
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Sterile Production
General Considerations




Production in clean areas
Appropriate standard of cleanliness
Filtered air supplied
Airlocks for entry
 personnel and/or equipment
 materials
 Separate areas for operations
 component preparation (containers and closures)
 product preparation
1.1 – 1-2
 filling, sterilization, etc.
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Sterile Production
Premises
 Design
 avoid unnecessary entry of supervisors and control personnel
 operations observed from outside
 In clean areas, all exposed surfaces
 smooth, impervious, unbroken
 minimize shedding and accumulation of particles,
microorganisms
 permit cleaning and disinfection
 no uncleanable recesses, ledges, shelves, cupboards,
equipment
 sliding doors undesirable
9.1 – 9.6
 false ceilings sealed
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Sterile Production
Premises (continued)
 In clean areas, all exposed surfaces (2)
 proper installation of pipes and ducts, no recesses,
no unsealed openings
 sinks and drains avoided, and excluded in Grade A and B
areas
– where installed, design, location, maintenance
– effective cleanable traps
– air breaks preventing backflow
– floor channels open and easily cleanable
9.6.
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Sterile Production
Premises (continued)
 Changing rooms
 designed as airlocks
 effective flushing with filtered air
 separate rooms for entry and exit desirable
 hand washing facilities
 interlocking system for doors
 visual and/or audible warning system
 Use filtered air supply to maintain pressure cascade
 Pressure differential approximately 10 to 15 Pascals
 Zone of greatest risk – immediate environment
9.7 – 9.9
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Sterile Production
Premises (continued)
 Pathogenic, highly toxic, radioactive materials
 Pressure cascade may be different
 Decontamination procedures – air, equipment, garments
 Qualification including airflow patterns
 no risk to the product
 Warning system to indicate failure in air supply
 Pressure indicators – results regularly recorded
 Restricted access – e.g. use of barriers
9.9 – 9.12
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Sterile Production
Equipment
 Conveyer belts
 Effective sterilization of equipment
 Maintenance and repairs from outside the clean area
 if taken apart, resterilized before use
 use clean instruments and tools
 Planned maintenance, validation and monitoring
 equipment, air filtration systems, sterilizers, water
treatment systems
10.1 – 10.5
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Sterile Production
Equipment (continued)
 Water treatment plants and distribution system
 design, construction, maintenance
 operation and design capacity
 testing programme
 Water for Injection (WFI)
 produced, stored, distributed – prevention of growth of
microorganisms
 constant circulation at temperature above 70, or not more
than 4 degrees Celsius
10.6
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Sterile Production
Environmental Monitoring - I
Microbiological
 Air samples
 Surface swabs
 Personnel swabs
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Sterile Production
Environmental Monitoring – II
Physical
 Particulate matter
 Differential pressures
 Air changes, airflow patterns
 Clean up time/recovery
 Filter integrity
 Temperature and relative humidity
 Airflow velocity
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Sterile Production
Sanitation
 Frequent, thorough cleaning of areas necessary
 Written programme
 Regular monitoring to detect resistant strains of microorganisms
 Chemical disinfection
 Monitoring of disinfectants and detergents
 Dilutions
 clean containers, stored for defined periods of time
 Sterilized before use, when used in Grade A or B areas
3.1 – 3.2
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Sterile Production
Sanitation (continued)
 Monitoring of clean areas
 Monitoring of personnel and surfaces after critical operations
 Frequent monitoring in areas where aseptic operations are
carried out
 settle plates, volumetric air samples, surface sampling
(swabs and contact plates)
 sampling methods should not contaminate the area
 Results considered when batch release is done
3.3
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Sterile Production
Sanitation (continued)
 Limits of detection established
 Alert and action, and monitoring trends of air quality
Table 1. Limits for microbial contamination (information only)
Grade
Module 14 |
3.4
Air sample
Settle plates
Contact plates
Glove print
(CFU/m3)
(90mm diameter)
(55mm diameter)
(5 fingers)
(CFU/4hours)
(CFU/plate)
(CFU/glove)
A
<3
<3
<3
<3
B
10
5
5
5
C
100
50
25
-
D
200
100
50
-
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Sterile Production
Personnel
 Minimum number of personnel in clean areas
 especially during aseptic processing
 Inspections and controls from outside
 Training to all including cleaning and maintenance staff
 initial and regular
 manufacturing, hygiene, microbiology
 Special cases
 supervision in case of outside staff
8.1 – 8.3
 decontamination procedures (e.g. staff who worked with
animal tissue materials)
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Sterile Production
Personnel (continued)
 High standards of hygiene and cleanliness
 Periodic health checks
 No shedding of particles
 No introduction of microbiological hazards
 No outdoor clothing
 Changing and washing procedure
 No watches, jewellery and cosmetics
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8.4 – 8.6
Sterile Production
Personnel (continued)
 Clothing of appropriate quality:
 Grade D
– hair, beard, moustache covered
– protective clothing and shoes
 Grade C
– hair, beard, moustache covered
– single or 2-piece suit (covering wrists, high neck), shoes
– no fibres to be shed
 Grade A and B
8.7
 headgear, beard and moustache covered, masks, gloves
 not shedding fibres, and retain particles shed by
operators
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Sterile Production
Personnel (continued)
 Outdoor clothing not in change rooms leading to Grade B and C
rooms
 Change at every working session, or once a day (if supportive
data)
 Change gloves and masks at every working session
 Disinfect gloves during operations
 Washing of garments – separate laundry facility
 No damage, and according to validated procedures
8.8 – 8.9
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Sterile Production
Group session 1
 You are asked to visit a factory producing the following
product lines:
 injections in ampoules and vials, including insulin, vaccines
and heat-stable pharmaceuticals
 sterile eye ointment
 Describe the type of facility you would expect to find
 List the typical rooms, their purpose and air classification
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Sterile Production
Possible Issues
 Poor design of the building
 Poor design of the systems, e.g. water, HVAC
 Flow of personnel
 Flow of material
 No validation or qualification
 Old facilities not complying with current requirements
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Sterile Production
Possible Issues (continued)
 Particulate levels/microorganisms
 Differential pressures
 Air changes
 Temperature/humidity
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Sterile Production
Two categories of manufacturing operations
 Terminally sterilized
 prepared, filled and sterilized
 Aseptic preparation
 some or all stages
1.3
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Sterile Production
Manufacture of sterile preparations
 Classification of clean areas
 Manufacturing operation in an appropriate environment
cleanliness level
 Minimize risks – particulate and microbiological contamination –
product and material
 Meet classification "at rest"
 (That is "completed installation, equipment installed and
operating, but no operating personnel present")
4.1
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Sterile Production
Manufacture of sterile preparations
 For sterile pharmaceutical preparations:
 Grade A
 local zone, high risk operations, e.g. filling, aseptic
connections
 usually UDAF systems used
 Grade B
 background environment to Grade A (in case of aseptic
preparation and filling)
 Grade C and Grade D
4.1
 Clean areas for less critical operations
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Sterile Production
Air Classification System
Grade
At rest
In operation
maximum permitted number of particles/m3
0.5 - 5.0 µm
> 5 µm
0.5 - 5.0 µm
>5µ
A
3 500
0
3 500
0
B
3 500
0
350 000
2 000
C
350 000
2 000
3 500 000
20 000
D
3 500 000
20 000
not defined
not defined
3.1
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Sterile Production
Manufacture of sterile preparations
 To reach Grade B, C and D, the number of air changes should be
appropriate to the size of the area, number of personnel,
equipment present
 Minimum of 20 air changes per hour
 Clean-up time about 15 – 20 minutes
 Good airflow pattern in the area
 HEPA filtered air
 Suitable methods to determine particulate matter and micro
 e.g. EU, ISO, Japan, USA
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4.1 – 4.2.
Sterile Production
Manufacture of sterile preparations
 Control particulate during operation
 Monitoring during operation
 Alert and action limits for particulate and micro
 Action taken when exceeded
 Area grades should be proven (e.g. validation runs, media fills,
environment, time limits - based on microbiological
contamination/bioburden found)
4.3 – 4.5
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Sterile Production
Airborne particulate classification
WHO GMP
US 209E
US Customary
ISO/TC (209)
EEC GMP
Grade A
M 3.5
Class 100
ISO 5
Grade A
Grade B
M 3.5
Class 100
ISO 5
Grade B
Grade C
M 5.5
Class 10 000
ISO 7
Grade C
Grade D
M 6.5
Class 100 000
ISO 8
Grade D
4.1
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Sterile Production
Processing
 Minimize contamination - all stages including before sterilization
and during processing
 No unsuitable materials, e.g. live microbiological organisms
 Minimize activities
 staff movement controlled and methodical
 avoid shedding of particles
 Temperature and humidity comfortable
 Containers and materials in the area
4.15 – 4.16, 4.20 – 4.21
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Sterile Production
Processing
 Validation – should not compromise the processes
 Aseptic process validation: sterile media fill (“broth fills”)
 simulate actual operation – intimate as closely as possible
 simulate worst expected condition
 use appropriate medium/media
 sufficient number of units, e.g. equal to batch size (small
batches)
– acceptable limit
– investigations
 revalidation: periodic and after change
 New processing procedures validated
 revalidation after significant changes
4.17, 4.18, 4.28
 and regular intervals
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Sterile Production
Processing
 Water sources, water treatment systems and treated water
 Monitored regularly
 chemicals
 biological contamination
 endotoxin
 Water specification
 Records of results and action taken
4.19
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Sterile Production
Processing
 Components, bulk product containers and equipment
 fibre generation
 no recontamination after final cleaning
 stage properly identified
 sterilized when used in aseptic areas
 Used in clean areas, passed through double-ended sterilizers
or use triple wrapping
 Gas used to purge solution or blanket a product – passed
through a sterilizing filter
4.22 – 4.23
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Sterile Production
Processing
 Bioburden monitored
 products: before sterilization
 working limits established
 solutions to be filtered before filling (especially LVP)
 pressure release outlets – hydrophobic microbiological air
filters
 Starting materials – microbiological contamination should be
minimal
 Monitored as per specification
4.26, 5.3
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Sterile Production
Processing
 Time intervals: components, bulk containers, equipment
 Washing and drying and sterilization; and sterilization and use
 as short as possible
 time limit validated
 Time intervals: product
 Start of preparation of solution and sterilization (filtration)
 as short as possible
 maximum time set for each product
4.23 - 4.24
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Sterile Production
Group session 2
 Considering the same factory as in the previous group session,
discuss the process of sterilization
 List all the items that will need to be sterilized (and indicate the
choice of sterilization process)
 What are the key features you should find in each sterilization
situation?
 Discuss the relevance, need, and the extent of qualification and
validation required
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Sterile Production
Possible Issues
 Autoclave - no pressure gauge
 Autoclave - no temperature recorder
 Autoclave - superheated steam
 Clean room - pressure differentials
 Exposure for settle plates
 Interlocks turned off
 Rusty Laminar airflow cabinets
 HEPA filters not checked regularly
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Sterile Production
Sterilization
 Methods of sterilization
 moist or dry heat
 irradiation (ionizing radiation)
 sterilizing gaseous agents (e.g. ethylene oxide)
 filtration with subsequent aseptic filling
 Whenever possible: terminal sterilization by heat in their final
container - method of choice
5.1 – 5. 2
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Sterile Production
Sterilization
 Validation
 all sterilization processes
 special attention when non-pharmacopoeial methods are
used
 non-aqueous or oily solutions
 Before the method is adopted – its suitability and efficacy
demonstrated with desired conditions
 all parts of the load
 each type of load
 physical measurements and biological indicators (where
appropriate)
 verified at least annually and after change
 records maintained
5.4 – 5.5
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Sterile Production
Sterilization
 For effective sterilization
 Whole of the material subjected to the treatment
 Biological indicators
 Additional method of monitoring
 Storage and use, quality checked through positive control
 Risk of contamination
5.6 - 5.7
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Sterile Production
Sterilization
 Differentiation between sterilized and not-yet-sterilized products
 Each basket/tray or other carrier, properly labelled
 name of material
 batch number
 sterilization status
 Use of autoclave tape
 Sterilization records for each run – approved as part of the batch
release procedure
5.8 - 5.9
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Sterile Production
Terminal Sterilization
 Sterilization by heat
 Sterilization by moist heat
 Sterilization by dry heat
 Sterilization by radiation
 Sterilization by gases and fumigants
6
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Sterile Production
Terminal Sterilization
Sterilization by heat
 Recording of each cycle, e.g. time and temperature chart
 temperature: validated coolest part
 check from second independent probe
 additional chemical or biological indicators
 Heating phase: sufficient time for the whole load
 determined for each load
 Cooling phase: after sterilization cycle
 precautions to prevent contamination
6.2 – 6.3
 sterilized cooling fluid/gas
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Sterile Production
Terminal Sterilization
Sterilization by moist heat (heating in an autoclave)
 Water-wettable materials only, and aqueous formulations
 Temperature, time and pressure monitored
 Temperature recorder independent of the controller
 Independent temperature indicator
 Drain – temperature recorded from this position
 Regular leak test when vacuum is part of the cycle
 Material allows for removal of air and penetration of steam
 All parts of the load in contact with steam
 Quality of the steam – no contamination
6.4 – 6.6
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Sterile Production
Terminal Sterilization
Sterilization by dry heat
 For non-aqueous liquids, dry powders
 Air circulation in the chamber
 Positive pressure in chamber to prevent entry of non-sterile air
 HEPA filtered air supplied
 When removing pyrogens, challenge tests
 validation (using endotoxins)
6.7
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Sterile Production
Terminal Sterilization
Sterilization by radiation
 Suitable for heat-sensitive materials and products
 confirm suitability of method for material
 ultraviolet irradiation not acceptable
 Contracting service – ensure validation status, responsibilities
 Measurement of dose during procedure
 Dosimeters independent of dose rate
 quantitative measurement
 number, location and calibration time-limit
 Biological indicators only as additional control
 Radiation sensitive colour discs
6.8 – 6.10
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Sterile Production
Terminal Sterilization
Sterilization by radiation (2)
 Information forms part of the batch record
 Validation to cover effects of variation in density of
packages
 Handling procedures to prevent misidentification of
irradiated and non-irradiated materials
 Each package to have a radiation-sensitive indicator
 Total radiation dose administered within a predetermined
period of time
6.10 – 6.13
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Sterile Production
Terminal Sterilization
Sterilization by gases and fumigants
 Only when no other method is suitable
 E.g. ethylene oxide, hydrogen peroxide vapour
 Validation: also prove the gas has no damaging effect on product
 Time and conditions for degassing (specified limits) - residue
 Direct contact with microbial cells essential
 nature and quantity of packaging materials
 Humidity and temperature equilibrium
6.14 – 6.20
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Sterile Production
Terminal Sterilization
 Monitoring of each cycle with biological indicators
 time, pressure
 temperature, humidity
 gas concentration
Sterilization by gases and fumigants (2)
 Post-sterilization storage – controlled manner
 ventilated conditions
 defined limit of residual gas
 validated process
 Safety and toxicity issues
6.21
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Sterile Production
Terminally sterilized products
Grade
Preparation
Remark
D
Components and product
Ensure low microbial and
particulate count
C
Product at unusual risk of
microbial contamination
C
Filling before sterilization
E.g. product actively
supports microbial
growth, or
is held for a long period
of time before
sterilization, or
is not prepared mainly in
closed containers
-
4.6 – 4.7
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Sterile Production
Terminally sterilized products
Grade
Preparation
A in
C background
C
Filling before sterilization if
product at unusual risk of
contamination from
environment
Preparation and filling
Remark
E.g. slow filling
operation, or
Wide neck containers, or
Exposure for a few
seconds before sealing
Ointments, creams,
suspensions, emulsions
4.8 – 4.9
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Sterile Production
Aseptic processing and sterilization by filtration
Aseptic processing
 Objective is to maintain the sterility of a product, assembled
from sterile components
 Operating conditions so as to prevent microbial contamination
 What do you think are the aspects that require careful attention?
7.1 – 7.2
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Sterile Production
Aseptic processing and sterilization by filtration
Aseptic processing (2)
 Careful attention to:
 Environment
 Personnel
 Critical surfaces
 Container/closure sterilization
 Transfer procedures
 Maximum holding period before filling
7.3
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Sterile Production
Aseptic preparation
Grade
Preparation
D
C
A
(in B
background)
Components after washing
Preparation of solutions to be
sterile filtered later in the
process
Preparation and filling of
sterile ointments, creams,
suspensions, emulsions
Remark
When the product is
exposed and filtered
4.10, 4.11, 4.14
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Sterile Production
Aseptic preparation
Grade
Module 14 |
Preparation
Remark
A
(in B
background)
Sterile starting materials and
components
(Unless subjected to
sterilization or filtration
through a microorganism
retaining filter later in the
process)
A
(in B
background)
A
(in B
background)
A
(in B
background)
A
(in B
background)
Preparation of solutions (if
not to be sterile filtered later)
Slide 55 of 62
Handling and filling of
aseptically prepared
products,
Handling of exposed sterile
equipment
Transfer of partially closed
containers, before complete
stoppering
January 2006
4.10 – 4.13
E.g. in freeze drying
(Grade B environment if
in sealed transfer trays)
Sterile Production
Sterilization by Filtration
 Through a sterile filter of 0,22 µm or less, into previously
sterilized containers
 remove bacteria and moulds
 not all viruses or mycoplasmas
 Consider complementing with some degree of heat treatment
 Double filter layer or second filtration advisable, just before filling
- no fibre shedding or asbestos filters
 Filter integrity testing immediately after use
 also before use if possible
7.4 – 7.7
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Sterile Production
Sterilization by Filtration (2)
 Validation to include
 time taken to filter a known volume
 pressure difference to be used across the filter
 Significant differences to be noted and investigated, recorded in
batch records
 Integrity of gas and air vent filters checked after use, other filters
at appropriate intervals
7.7
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Sterile Production
Sterilization by Filtration (3)
 Same filter not used for more than one working day, unless
validated
 No filter interaction with product, e.g.
 removal of ingredients
 releasing substances into product
7.8 – 7.9
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Sterile Production
Quality Control
 Samples for sterility testing should be representative
 From parts of the batch, most at risk
 aseptic filling - at beginning and end of batch filling, and after
interruptions
 heat sterilized – coolest part of the load
 Sterility of the batch ensured through validation
 validated sterilization cycle
 media fill
 Sterility test procedure as per pharmacopoeia, and validated for
each product
 Batch processing records, sterility testing records, environmental
records should be reviewed
2.1 -2.2
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Sterile Production
Quality Control
 Endotoxin testing for injectable products
 water for injection, intermediate and finished product
 Always for large volume infusion solutions
 Pharmacopoeia method, validated for each product
 Failure of the test – investigation
 Corrective action
2.3
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Sterile Production
Finishing of products





Containers closed by means of validated methods
Samples checked for integrity
Maintenance of vacuum (where applicable) checked
Parenteral products inspected individually
Visual inspection under suitable and controlled conditions
 illumination and background
 eyesight checks of operators
 allowed frequent breaks
 Other methods
 validated, and equipment performance checked at intervals
 results recorded
11.1 – 11.3
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Sterile Production
Group session 3
 Considering the same factory as in the previous group sessions,
devise a plan for monitoring of the facility
 List the parameters to be tested, tests to be used, acceptance
criteria and frequency of testing
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January 2006