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Supplementary Training Modules on Good Manufacturing Practice. Sterile Pharmaceutical Products. Annex 6. TRS 902, 2002. Sterile Production. Objectives To review basic GMP requirements in the manufacture of sterile pharmaceutical products

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supplementary training modules on good manufacturing practice
Supplementary Training Modules on Good Manufacturing Practice

Sterile Pharmaceutical Products

Annex 6. TRS 902, 2002

sterile production
Sterile Production


  • 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
sterile production3
Sterile Production

GMP Requirements for Sterile Products

  • Additional rather than replacement
  • Specific points relating to minimizing risks of contamination
    • microbiological
    • particulate matter
    • pyrogen
sterile production4
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, filling, sterilization, etc.

1.1 – 1-2

sterile production5
Sterile Production


  • 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

sterile production6
Sterile Production


  • 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


sterile production7
Sterile Production


  • 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

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Sterile Production


  • 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


  • 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


  • 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


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Sterile Production

Environmental Monitoring - I


  • Air samples
  • Surface swabs
  • Personnel swabs
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Sterile Production

Environmental Monitoring - II


  • Particulate matter
  • Differential pressures
  • Air changes, airflow patterns
  • Clean-up time/recovery
  • Filter integrity
  • Temperature and relative humidity
  • Airflow velocity
sterile production13
Sterile Production


  • 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


  • 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


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Sterile Production


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

Table 1. Limits for microbial contamination (Information only)


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Sterile Production


  • 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

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Sterile Production


  • 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

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Sterile Production


  • 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


sterile production19
Sterile Production


  • 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


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


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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
    • Clean areas for less critical operations


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Sterile Production

Air Classification System


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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

4.1 – 4.2.

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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


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Sterile Production


  • 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

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Sterile Production


  • 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

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Sterile Production


  • Water sources, water treatment systems and treated water
  • Monitored regularly
    • Chemicals
    • Biological contamination
    • Endotoxin
  • Water specification
  • Records of results and action taken


sterile production33
Sterile Production


  • 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


  • 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


  • 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.
sterile production37
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
sterile production38
Sterile Production


  • 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


  • 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

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Sterile Production


  • 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


  • 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


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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
    • Sterilized cooling fluid/gas

6.2 – 6.3

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Sterile Production

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

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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)


sterile production46
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
  • Monitoring of each cycle with biological indicators
    • time, pressure
    • temperature, humidity and gas concentration

6.14 – 6.20

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Sterile Production

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


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Sterile Production

Terminally sterilized products

4.6 – 4.7

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Sterile Production

Terminally sterilized products

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


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Sterile Production

Aseptic preparation

4.10, 4.11, 4.14

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Sterile Production

Aseptic preparation

4.10 – 4.13

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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


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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


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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.