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					                        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


Module 14 |   Slide 2 of 62   January 2006
                               Sterile Production

                GMP Requirements for Sterile Products

      Additional rather than replacement

      Specific points relating to minimizing risks of contamination
         microbiological
         particulate matter
         pyrogen




Module 14 |   Slide 3 of 62   January 2006
                               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.

Module 14 |   Slide 4 of 62   January 2006
                               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
         false ceilings sealed                               9.1 – 9.6


Module 14 |   Slide 5 of 62   January 2006
                               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.


Module 14 |   Slide 6 of 62   January 2006
                               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


Module 14 |   Slide 7 of 62   January 2006
                               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


Module 14 |   Slide 8 of 62   January 2006
                               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



Module 14 |   Slide 9 of 62   January 2006
                               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



Module 14 |   Slide 10 of 62   January 2006
                                 Sterile Production

                               Environmental Monitoring - I

    Microbiological

     Air samples

     Surface swabs

     Personnel swabs




Module 14 |   Slide 11 of 62    January 2006
                                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


Module 14 |   Slide 12 of 62    January 2006
                               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


Module 14 |   Slide 13 of 62   January 2006
                                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


Module 14 |    Slide 14 of 62   January 2006
                                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)                   3.4



       Grade                   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                 -


Module 14 |   Slide 15 of 62   January 2006
                               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)

Module 14 |   Slide 16 of 62   January 2006
                               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                      8.4 – 8.6




Module 14 |   Slide 17 of 62   January 2006
                               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


Module 14 |   Slide 18 of 62   January 2006
                               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


Module 14 |   Slide 19 of 62   January 2006
                               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




Module 14 |   Slide 20 of 62   January 2006
                               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




Module 14 |   Slide 21 of 62   January 2006
                               Sterile Production

                                Possible Issues (continued)

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




Module 14 |   Slide 22 of 62   January 2006
                               Sterile Production

          Two categories of manufacturing operations



    Terminally sterilized
           prepared, filled and sterilized


    Aseptic preparation
           some or all stages

                                                    1.3


Module 14 |   Slide 23 of 62   January 2006
                               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


Module 14 |   Slide 24 of 62   January 2006
                               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

Module 14 |   Slide 25 of 62   January 2006
                                   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



Module 14 |   Slide 26 of 62      January 2006
                               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.



Module 14 |   Slide 27 of 62   January 2006
                               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



Module 14 |   Slide 28 of 62   January 2006
                                  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



Module 14 |   Slide 29 of 62      January 2006
                               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


Module 14 |   Slide 30 of 62   January 2006
                               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
Module 14 |   Slide 31 of 62   January 2006
                               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



Module 14 |   Slide 32 of 62   January 2006
                               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


Module 14 |   Slide 33 of 62   January 2006
                               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


Module 14 |   Slide 34 of 62   January 2006
                               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


Module 14 |   Slide 35 of 62   January 2006
                               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


Module 14 |   Slide 36 of 62   January 2006
                               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

Module 14 |   Slide 37 of 62   January 2006
                               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


Module 14 |   Slide 38 of 62   January 2006
                               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


Module 14 |   Slide 39 of 62   January 2006
                               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


Module 14 |   Slide 40 of 62   January 2006
                               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


Module 14 |   Slide 41 of 62   January 2006
                               Sterile Production
                                    Terminal Sterilization
    Sterilization by heat

    Sterilization by moist heat

    Sterilization by dry heat

    Sterilization by radiation

    Sterilization by gases and fumigants


                                                             6



Module 14 |   Slide 42 of 62   January 2006
                               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


Module 14 |   Slide 43 of 62   January 2006
                               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


Module 14 |   Slide 44 of 62   January 2006
                               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


Module 14 |   Slide 45 of 62   January 2006
                               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


Module 14 |   Slide 46 of 62   January 2006
                               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


Module 14 |   Slide 47 of 62   January 2006
                               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


Module 14 |   Slide 48 of 62   January 2006
                               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


Module 14 |   Slide 49 of 62   January 2006
                                  Sterile Production

                               Terminally sterilized products
    Grade                                  Preparation                  Remark

              D                 Components and product         Ensure low microbial and
                                                               particulate count

              C                 Product at unusual risk of     E.g. product actively
                                microbial contamination        supports microbial
                                                               growth, or
                                                               is held for a long period
                                                               of time before
                                                               sterilization, or
                                                               is not prepared mainly in
                                                               closed containers
              C                 Filling before sterilization                 -


                                                                     4.6 – 4.7

Module 14 |   Slide 50 of 62     January 2006
                                Sterile Production

                            Terminally sterilized products


          Grade                                Preparation                    Remark

                  A in              Filling before sterilization if   E.g. slow filling
              C background          product at unusual risk of        operation, or
                                    contamination from                Wide neck containers, or
                                    environment                       Exposure for a few
                                                                      seconds before sealing
                      C             Preparation and filling           Ointments, creams,
                                                                      suspensions, emulsions




                                                                          4.8 – 4.9



Module 14 |    Slide 51 of 62   January 2006
                               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


Module 14 |   Slide 52 of 62   January 2006
                               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


Module 14 |   Slide 53 of 62   January 2006
                                Sterile Production

                                 Aseptic preparation

         Grade                                 Preparation                 Remark

                    D             Components after washing
                    C             Preparation of solutions to be
                                  sterile filtered later in the
                                  process
                   A              Preparation and filling of       When the product is
                 (in B            sterile ointments, creams,       exposed and filtered
              background)         suspensions, emulsions




                                                                          4.10, 4.11, 4.14


Module 14 |    Slide 54 of 62   January 2006
                                 Sterile Production

                                    Aseptic preparation
        Grade                                   Preparation                       Remark

                   A              Sterile starting materials and        (Unless subjected to
                 (in B            components                            sterilization or filtration
              background)                                               through a microorganism
                                                                        retaining filter later in the
                                                                        process)
                   A              Preparation of solutions (if
                 (in B            not to be sterile filtered later)
              background)
                   A              Handling and filling of
                 (in B            aseptically prepared
              background)         products,
                   A              Handling of exposed sterile
                 (in B            equipment
              background)
                   A              Transfer of partially closed          E.g. in freeze drying
                 (in B            containers, before complete           (Grade B environment if
              background)         stoppering                            in sealed transfer trays)


Module 14 |     Slide 55 of 62   January 2006             4.10 – 4.13
                               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


Module 14 |   Slide 56 of 62   January 2006
                               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


Module 14 |   Slide 57 of 62   January 2006
                               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


Module 14 |   Slide 58 of 62   January 2006
                               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

Module 14 |   Slide 59 of 62   January 2006
                                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


Module 14 |    Slide 60 of 62   January 2006
                               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


Module 14 |   Slide 61 of 62   January 2006
                               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




Module 14 |   Slide 62 of 62   January 2006

				
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