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Lecture 1 Part 2

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Lecture 1 Part 2 Powered By Docstoc
					    Process Stages
                  Typical Process Steps
       1.   Dispensing and Weighing
       2.   Compounding
       3.   Sterile Filtration
       4.   Container Preparation
       5.   Stopper Preparation
       6.   Filling and Stoppering
       7.   Capping and Crimping
       8.   Inspection
       9.   Packing
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    Process Stages

            Process Flow for an Aseptically
     Typical
     Processed Vial Formulation




2
                                                 Typical Process Block Flow Diagram for an Aseptically Processed Vial Formulation




         Vials            Water           Nitrogen             Bulk Drug                                     Caps
                                                                                            Stoppers
                      for Injection                            Substance

      Vials Shrink      WFI               Nitrogen                                                            Caps
       Wrapped       Generation           Storage                                            Stoppers       (Gamma
         Pallets      System                Tank                                                           Irradiated)
                                                                                                                                                         Background Area Classification
                                                                                                                                                         Required By Process Step
                                                   Warehouse
     Warehouse
                                                           Cold Store                                                                                           External


                                                               Store at 20C                    Store         Store
      Warehouse
                                                                  to 80C                                                                                         Unclassified



                                                                                                                                                                Pharmaceutical Grade



                                                                                                                                                                Laminar Flow Zone


                                                                                                                                                                Grade D
                                                                                                                                                                (Pharmaceutical with
                                                                                                                                                                local monitoring)

                                                                                                                                                                Grade C
                                                                                                                                                                (ISO8 Class 100,000)


                                                                                                                                                                Grade B
                                                                Transfer to                                                                                     (ISO7 Class 10,000)
                                                               Compoundin                    Airlock        Airlock
                                                                 g Room
                                                                                                                                                                Grade A
                                                                                                                                                                (ISO5 Class 100)


                                                       Compounding
                                                       Room                                                                                                     Open Processing


                                                                Pool into
                                                                 Tank                                                                                           Closed Processing



                                                                                                                                                                ISL
                                                                                                                                                                Isolator (Class 100)



                                                                QC Tests




                                                               Filter thru 2
                                                                x 0.22µm
                                                                   filters




                                                                                             Unpack
                                                                                                            Caps
                                                                                            Stoppers



                                                                                                                                                        Inspection
                                                                             Formulation
                                                                                Room
                                                                                            Stopper
                                                                                           Processor
                                                                                                                                                                                          Cold
                                                                                                                                                                                          Store
                                                                                                                                                                                         (2-80C)

                                                                                            Transfer
                                        Filter                                              Container
                                      (0.22µm)
                                                                                                                                                                                       Inspection


                                                                                           Transfer
                                                                                           Container
                                                 Filling                                                        Capping   Inkjet/Tray                   Warehouse
                                                 Room                                                           Room      Off Room            Cold
                                                                                                                                              Store
                                                               Head Tank
                                                                                              Load                                           (2-80C)
                                                                 at Fill
                                                                Station                      Stopper       Cap Seal
     Unpack Vials                                                                                                            Ink Cartridge
                                                                                              Feed        Feed Station
                                                                                             Station
                                                                                                                                                                                Cold Store
                                                                                                                                                                                (20C to 80C)

                                       Depyrogenate                                                        Seal Vial           Print Vial    Tray Off     Stretchwrap              Warehouse
      Load Vials     Wash Vial             Vial
                                                                 Fill Vial                 Stopper Vial                                                                            (Quarantine
                                                                                                           with Cap               Cap         Vials          Pallet
                                                                                                                                                                                        )

    Component Prep Room

                                                                                                                                                                                        Release
3                                                                                                                                                                                        from
                                                                                                                                                                                       Quarantine




                                                                                                                                                                                       Dispatch
    Process Stages
    1. Dispensing and Weighing
       Centralised Dispensing:
           Solid Actives and Excipients
           Small Quantities of Liquid Actives and Excipients
       Key Considerations:
           Area Classification
           Cross Contamination Potential
           Toxic Compounds
       Decentralised Dispensing: Water and Solvents
           Key Consideration – Design of Compounding Room(s)
            where dispensing performed
4
    Process Stages
    2. Compounding (Formulation)
              Room where product components (Active, Excipients, Solvents etc) are
               brought together to produce the formulation that will subsequently be filled.
        E.g.
              Pooling of premixed product
              Simple Liquid Mixing
              Dissolution of solid active
              Emulsification

       Key Consideration
              Utility Requirements
              Proximity to Filling Point
              Area Classification
              Cross Contamination
              Flow of people, clean and dirty equipment, raw materials, product, waste
5
    Process Stages
    3. Sterile Filtration
       Product is sterile filtered through 0.2m filter(s) to
        provide a defined reduction in the microbiological
        concentration prior to filling. Post filtration the product
        is deemed sterile.

           Key Considerations
                Sterilisation of filter in place
                Post sterilisation pre-production integrity testing
                Post production integrity testing (in situ)
                Elimination of Aseptic connections
                Filter Location
6
    Exercise 2
Compounding and Filtration
 Product being
  compounded/ formulated,
  filtered and filled into
  mobile 300l vessels.
 What design features
  should be considered to
  mimimise issues such as
  manual handling/
  contamination for:
        A: Filling Area
        B: Vessel

7
    Exercise - Answer
    Filling Area:
     Manual handling considerations
           Access to isolation valves
           Lifting method of filter housings
       Contamination:
         All feed lines sloped with no dead legs
         Minimise joints minimises contamination.
         Internal finishes polished for ease of CIP/ SIP

8
    Exercise - Answer
    Mobile Vessel:
     Manual handling considerations
           Weight of full vessel and method of transport
           Access to sight glass/ isolation valves
       Contamination:
         All feed lines sloped with no dead legs
         Minimise joints minimises contamination.
         Internal finish polished for ease of CIP/SIP.

9
     Process Stages
4. Container Preparation – Cleaning and Sterilisation
   of Empty product Containers
        Cleaning
            Washing and rinsing of containers using suitable grade of water to
             remove extraneous particles and chemicals
               Initial rinses can be carried out using Purified water
               Final rinse must use WFI (Water for injection)
               Containers blown dry using sterile air

        Equipment
            Rotary Washer
            Linear Washer

10
     Vial Washing Machine - Rotary Washer

       Bosch
       RRN 2020 Rotary Washer




      Bausch & Ströbel
      FAW 1120 Rotary Washer


11
     Process Stages – Vial Washer
         IMA/Libra - Hydra - Linear Washer
                   WORKING PROCESS




12
     Process Stages
     Container Preparation
          Sterilisation
             Dry heat Depyrogenation of clean containers to deactiviate
              bioburden (viable contamination) and degrade endotoxins
              (non-viable pyrogenic contamination)
             Heat-up, sterilisation and cooling zones
             Combination of residence time and setpoint temperature
              (250oC – 350oC) in sterilisation zone to achieve required
              degree of depyrogenation
             Typically 6 log reduction of bioburden required


13
     Process Stages
        Equipment
            Dry Heat Oven
            Continuous Depyrogenation tunnel
               Tunnel Pressure Profiles
                                 HOT ZONE
                                            COOLING ZONE




                                                           Sterile area


14
     Depyrogenation Tunnel




15
     Depyrogenation Tunnel
                       Tunnel Air Flow




16
     Process Stages
     5. Stopper Preparation
     Stoppers must be sterile as they are in direct contact with the
        product at some time during storage, handling or use
            Washing and rinsing to remove extraneous particulates and chemicals
            Detergent washing sometimes used for endotoxin load reduction
            Stopper may be siliconised for ease of insertion of stoppers into vials
            Stoppers must receive a final rinse of WFI
            Stoppers must be sterilised (typically using clean steam)
            Stoppers must be dried using sterile air
            Stoppers must maintain sterility during transfer to filler
        Equipment
            Rotating Drum Stopper Processor
            Fluidised Bed Stopper Processor
17
     Stopper Processor
                Fedegari (Modified Autoclave)
                The stoppers are simply and quickly
                loaded through hatches in the drum

                       The loaded drum is slid into the
                       chamber on its carriage.


                                  As the door is hinged
                                  shut the magnetically
                                  coupled drive
                                  engages
18
      Stopper Processor
  Huber Stopper Processing Cycle


1. Washing/         2. CIP                 3. Direct          4. SIP-System           5. Rinsing/
Detergent           System                 Impact Cleaning    (Patented)          Siliconisation
Addition            (Patented)             (Patented)




   6. Subaqual-      7. Sterilisation to
   Siliconisation    DIN 58.950                   8. Drying            9. Unloading
 19
     Stopper ProcessorOperation
                                      WSSD processor (Getinge)
                                            Wash, Siliconize, Sterilize, Dry
                                             processing, in the sequence below

                                                 Docking of transfer container
                                                 Wetting of closures
                                                 Washing (optionally with detergent)
                                                 Rinsing
                                                 Siliconization
                                                 Sterilization
                                                 Drying
                                                 Pressurization for transfer & storage
                                                 De-docking of transfer container

     Any combination of Wash, Siliconize, Sterilize, Dry may be
     performed
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     Process Stages
     Contact Parts Preparation
        Equipment parts which come into contact with either the product
         or container closure components must be cleaned and sterilised
         before each batch, e.g. product filling vessel, filling pumps,
         stopper feed tracks
        Washing and rinsing with detergent to remove product residues
        Initial rinses with purified water
        Final rinse(s) with WFI
        Sterilised using steam in pass through autoclave
        Equipment
            Parts Washer
            Ultrasonic Bath
            Autoclave
21
     Process Stages - Autoclave




22
     Process Stages - Sterilisation
      Sterility Assurance Level (SAL)
         The probability of any given unit being non-sterile after
          exposure to a validated sterilisation process.
         Autoclaves generally obtain an SAL of 10-6 (i.e. assurance
          of less than one chance in a million that viable micro-
          organisms are present in the sterilised article)
         To calculate the SAL for an autoclave, you need to know:-
          A: Starting bio-burden
          B: Log Reduction Valve (LRV) must be known.
         The LRV is the number of logarithmic reductions in initial
          count brought about by the autoclave (sterilisation method)


23
     Process Stages - Sterilisation

        LRV = t/D
         Where:
         t = Sterilising Time, mins
         D = Length of time to reduce the number of viable organisms by 1
         log reduction (or 90%) at a specified temperature


        SAL= (Initial Bioburden Count)- (LRV)

24
     Process Stages
     6. Filling / Stoppering
            Sterile filtered product is dosed into the washed and sterilised
             depyrogenated containers and then containers are stoppered
            Critical Process Step – Exposure time minimised to further
             reduce contamination risk
        Key Considerations
            Grade A / Class 100 / ISO 5 Conditions required
            Fill accuracy of equipment
            Product container contact surfaces should be of a suitable
             material and finish to prevent contamination
            Design of critical area should support an optimal laminar flow
             pattern
            Ease of changeover between batches and batch sizes
25
     Filling and Stoppering Machine


      Bosch
      MLF 3002 IN



      Bausch & Ströbel
      FVF 5060


26
     Time Pressure Fill (TPF) Technology
    Most Common System Supplied
          Today
    Tank feeds manifold feeds
          pinch valve feeds filling
          needle




27
     Piston Pumps Technology
 Until   recently the most common system supplied
 Tank feeds   manifold feeds pump feeds filling
           needle
 Unfavorable    for shear sensitive products as small
           gap between piston and cylinder




28
     Rolling Diaphragm Pump Technology
        Used for Many Shear Sensitive Bio-Pharmaceuticals Protein
              Products (Considered ‘Gentler’ on Proteins)




29
     Rolling Diaphragm Pump Technology




30
     Filling Methods – Peristaltic Pumps
        Gentle Transfer Action
         Suitable for Protein
        Usually in Hazardous Product
         Application (No Metallic
         Contact)
        Quick Change-Over (Product
         Contact Tubing Disposed)




31
     Stoppering
      Application of Stoppers Usually by Means
        of Pick & Place Device
      Vibratory Bowl Used to   Sort Stoppers
      Track-Feed Stoppers to Pick &   Place
        Device
     Key Considerations
      Grade A / Class 100   / ISO 5 Condition
        Required
      Stopper / Closure Contact Surfaces
        should be a a Suitable Material and Finish
        to Prevent Contamination
      Movement & Stoppers and Vibratory Bowl
        make this an Area of Risk

32
     Process Stages
     7. Capping and Crimping
      Secures the Inserted Stopper into the
       Vial Neck Helping to Ensure Long-
       Term Integrity and Sterility of the Vial
        Caps can be Plastic or Aluminium
     Key Considerations
        Capping Machines are Contaminant
         producers as They Release Particles
         During Crimping
        Capper and Filler Usually in Different
         Rooms to Avoid Contamination             Bosch
33
     Process Stages
     8. Inspection
      Filled Containers of Paranteral Product Should be
       Inspected Individually for Extraneous Contamination or
       Other Defects such as:
        Foreign Matter

        Fill Volume

        Container Integrity

        Product Clarity / Colour

      Inspection can be Manual, Semi-Automatic or Fully
       Automatic
34
     Process Stages

        Inspection:
            Vial Integrity Tester
             (Wilco)



            Seidenader Vial Inspection
             System




35
     Process Stages
     9. Packing
          Protection for transport to
           warehouse/ pharmacy/
           hospital
          May include carton,
           booklet, leaflet.
          Many forms for Sterile
           Products including vials
           and syringes



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