Supplementary Training Modules on Good Manufacturing Practice - PowerPoint PPT Presentation

Sterile Pharmaceutical Products

Annex 6. TRS 902, 2002

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

GMP Requirements for Sterile Products

• Additional rather than replacement
• Specific points relating to minimizing risks of contamination
• microbiological
• particulate matter
• pyrogen

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, filling, sterilization, etc.

1.1 – 1-2

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
• False ceilings sealed

9.1 – 9.6

Premises

• 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.

Premises

• 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 Pascales
• Zone of greatest risk – immediate environment

9.7 – 9.9

Premises

• 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

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

Equipment

• 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

Environmental Monitoring - I

Microbiological

• Air samples
• Surface swabs
• Personnel swabs

Environmental Monitoring - II

Physical

• Particulate matter
• Differential pressures
• Air changes, airflow patterns
• Clean-up time/recovery
• Filter integrity
• Temperature and relative humidity
• Airflow velocity

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

Sanitation

• 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

Sanitation

• Limits of detection established
• Alert and action, and monitoring trends of air quality

Table 1. Limits for microbial contamination (Information only)

3.4

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
• Decontamination procedures (e.g. staff who worked with animal tissue materials)

8.1 – 8.3

Personnel

• 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

8.4 – 8.6

Personnel

• 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
• Headgear, beard and moustache covered, masks, gloves
• No shedding of fibres, and retain particles shed by operators

8.7

Personnel

• 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

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

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

Possible Issues (continued)

• Particulate levels/microorganisms
• Differential pressures
• Air changes
• Temperature/humidity

Two categories of manufacturing operations:

• Terminally sterilized
• prepared, filled and sterilized
• Aseptic preparation
• some or all stages

1.3

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"
• (i.e. "completed installation, equipment installed and operating, but no operating personnel present").

4.1

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
• Clean areas for less critical operations

4.1

Air Classification System

3.1

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

4.1 – 4.2.

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

Airborne particulate classification

4.1

Processing

• Minimise 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

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
• And regular intervals

4.17, 4.18, 4.28

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

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

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

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

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.

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

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

Sterilization

• Validation
• All sterilization processes
• Special attention when non-pharmacopoeia 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

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

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

Terminal Sterilization

• Sterilization by heat
• Sterilization by moist heat
• Sterilization by dry heat
• Sterilization by radiation
• Sterilization by gases and fumigants

6

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
• Sterilized cooling fluid/gas

6.2 – 6.3

Terminal Sterilization

Sterilization by moist heat (heating in an autoclave)

• Water-wetable 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

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

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

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

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
• Monitoring of each cycle with biological indicators
• time, pressure
• temperature, humidity and gas concentration

6.14 – 6.20

Terminal Sterilization

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

Terminally sterilized products

4.6 – 4.7

Terminally sterilized products

4.8 – 4.9

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

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

Aseptic preparation

4.10, 4.11, 4.14

Aseptic preparation

4.10 – 4.13

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

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

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

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

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

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

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.