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Comparison of Disposable Mixing Systems

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					Comparison of Disposable Mixing Systems
using AGT™ for Preparation of Large Volumes of Media




Jeff Kelly M.Sc.
Packaging Development
• Brief Overview of AGT™

        What is it? / Why use it? / Benefits

• Mixing Systems Evaluated

        Suppliers
        Basic Principles
        Mixing type

• Methods

• Results

• Comparison Overview

• Discussion


                                               Invitrogen Proprietary & Confidential
AGT™


What Is AGT™ ? Advanced Granulation Technology™

Dry form of cell culture media in a granular format that is optimally suited
   to research and industrial-scale production applications.




 Scanning Electron Micrograph
 of AGT™ granules (100X)




         Courtesy of McGill University
         Montreal, Quebec (Canada)




                                                            Invitrogen Proprietary & Confidential
  Manufacture - Fluid bed processing system
1. Granulation
2. Spray powder to build “bridges”
3. Dry granules
                                                                     Exhaust Blower




               Exhaust Filter

            Solution Delivery        Spray Nozzle



                                                Air Preparation Unit




      Air Distribution               Product
      Plate

                                                           Invitrogen Proprietary & Confidential
AGT™ Fluid Bed Granulation




                             Photo Courtesy of Glatt Air Techniques Inc Ramsey, New Jersey
 Fluid Bed
 Fluid Bed
 Processor
 Processor




                                                                                             Invitrogen Proprietary & Confidential
Why use AGT™
   Provides one raw material for the user - AGT™ medium is
   complete.

   Can decrease costs and time involved in raw material
   planning, procurement and testing.

   Medium preparation is also lessened
         granules wet instantly,
         does not require pH/OSMO adjustment.

   Overall operational cost saving
             Single use disposable v SIP / CIP
             No cleaning
             Less training / documentation / equipment maintenance
             Flexibility in designs
             Modular in design / Easily scalable / Integrate innovations



                                                      Invitrogen Proprietary & Confidential
Why use AGT™

   Reduced Number of Containers
              Handling /Logistics / Inventory

                  AGT                              DPM + Add-
                20,000L                           backs 20,000L

   Reduced Number Raw Material Release Tests
    pH           Mycoplasma
    Osmo                          One panel for AGT Four
                 Performance AA   panels for DPM
    Sterility    Profile
    Endo



   Cost – models show significant savings




                                                     Invitrogen Proprietary & Confidential
Mixing Systems Trialed




                         Invitrogen Proprietary & Confidential
Mixing Systems Trialed



       For each supplier overview of:


           Design of System

           Design of product transfer bag




                                        Invitrogen Proprietary & Confidential
ATMI – Newmix™ System
•   Single-use mixing and storing system that has a non-invasive design
•   Newmix™ C-Mix Bag is a closed, drum or cube shaped bag that uses a
    unique design that completely isolates the stir rod from the ingredients
    and the ingredients from the environment.

                                             Powder Transfer bag




                                                            Invitrogen Proprietary & Confidential
AGT ™ Transfer to ATMI System


 Design of product transfer bag

  Bottle shaped bag has a handle for easy, safe and clean transfer of AGT™ powders

  PE tri-clamp connector for easy connection.

  Anti-static film – ease of flow of AGT™




                                                               Invitrogen Proprietary & Confidential
Xcellerex System
    Portable plastic tank with on board motor

    Bag is cube shaped offered in three styles – sterile / non sterile



                            Option for Powder
                            charge port




                                                          Invitrogen Proprietary & Confidential
AGT™ Transfer to Xcellerex System


 Design of product transfer bag

  No powder transfer bag required with the open top non-sterile bags

  The aseptic bags have an integral port system for powder additions

  AGT introduced by flushing powder satellite bag with water




         Opening for
         powder filling




                                                       Invitrogen Proprietary & Confidential
AGT™ Bioprocessing System



     Water Supply


     Satellite Bag
     (AGT Media)



          Mixing Bag   Pump




                              Invitrogen Proprietary & Confidential
AGT ™ Transfer to System

 Design of product transfer bag

  Use Flexboy™ style bag

  Invitrogen modified bag to give a side opening for powder filling




             Opening for
             powder filling




                                                         Invitrogen Proprietary & Confidential
Mixing Systems Trialed



       For each supplier:


            Results

            Design of product transfer bag




                                       Invitrogen Proprietary & Confidential
Methods & Results




                    Invitrogen Proprietary & Confidential
Method

Trial with 100L mixing bag

 1.829kg MDCK PFM as AGT™ was used for final concentration of 18.29g/L

 AGT™ filled into a 15L PTB with clamp closed

 100L WFI grade water filled into mixing bag through MPX connector.

 Mixing paddle started and clamp opened to allow all AGT™ into main mixing bag

 Duplicate sterile 100ml samples were taken at 0, 5, 10, 20, 30, 40, 50, 60 mins

 Sampling was through Invitrogen’s Pall filter / KPC rig system

 Tests
      Visual inspection
      Amino acid analysis




                                                                   Invitrogen Proprietary & Confidential
Results
                                           Amino Acid Analysis

    60




    50



                                                                                                               Contro
    40
                                                                                                               5min
                                                                                                               10min
                                                                                                               20min
%




    30
                                                                                                               30min
                                                                                                               40min
                                                                                                               50min
    20
                                                                                                               60min


    10




    0
         L-Cystine 2Na   L-Tyrosine Disodium Salt          L-Phenylalanine           L-Tryptophan
                                                Minutes




                                                                             Invitrogen Proprietary & Confidential
Methods & Results




                    Invitrogen Proprietary & Confidential
Method

Trial with 200L mixing bag

 2.44kg CHO-CHOII as AGT™ was used for final concentration of 2.44g/L

 AGT™ filled into a closed bag with top and bottom port

 100L WFI grade water filled into mixing bag through open top.

 Mixing impeller started at 70% and all AGT™ added into main mixing bag

  Further WFI grade water filled into mixing bag through open top to total volume of
200L whilst increasing mixing speed to 100%

 10ml samples were taken at 0, 5, 10, 15, 25, 30, 40 mins

 Sampling was directly from the open top of the bag

 Tests
      Visual inspection
      pH
      Conductivity




                                                                  Invitrogen Proprietary & Confidential
Results

                             Test Results

20
18                                                                  Conductivity (mS)

16                                                                  pH

14
12
10
8
6
4
2
0
     0             5   10   15             25   30    40          Target
                                 Minutes




         10 mins                                     20 mins



                                                      Invitrogen Proprietary & Confidential
Methods & Results




                    Invitrogen Proprietary & Confidential
Method
 Trial with 200L mixing bag

  CD CHO as AGT™ was used for final concentration of 2.44g/L

  AGT™ filled into a closed bag with top and bottom port

  500L WFI grade water filled into mixing bag through tubing of satellite bag.

  Mixing on tubing loop using pump set at 1,500L / hour (360rpm)

  Tests
       Visual inspection
       pH
       Amino acid analysis




                                                                 Invitrogen Proprietary & Confidential
Results
                                                 Amino Acid Analysis                                        Minutes

                                                                                                            10        20
160.0%
                                                                                                            30        40

140.0%                                                                                                      50        60

                                                                                                            90        120
120.0%



100.0%



 80.0%



 60.0%



 40.0%



 20.0%



 0.0%
         Folic Acid   L-Tyrosine Disodium Salt       L-Phenylalanine   Riboflavin              Tryptophan




                                                                                    Invitrogen Proprietary & Confidential
Comparison


Feature


Mixing Technology     Stir Rod                 Impeller               Re-circulation

Powder Container      Custom designed with     Unspecified            Use of modified
                      T/C fitting for powder                          Flexboy™ bag
                      filling & emptying

Mixer                 Integral part of bag     Part of bag            Not Applicable

Mixing Bag            Custom designed with     Custom bag with        Custom designed with
                      T/C fitting for powder   powder filling port    ½” MPX tubing
                      transfer bag             and MPX outlet.        connection
                                               Any Powder container
                                               – open top


Closed / Open         Closed                   Closed or Open         Closed

Exit system for re-   Via connectors on base   Via connectors on      Via connectors on base
constituted media     of bag                   base of bag            of bag

Scalable              to 1000L                 to 1000L               to 1000L



                                                                      Invitrogen Proprietary & Confidential
Comparison



 In Use
 Experience

 “Attendance” at        Not required after       Some foaming of            Required to
 system                 powder transfer bag      product – added to         manipulate powder
                        opened                   part fill and then         from bag whilst re-
                                                 topped up to 200L          circulating water
                                                                            through

 Ease of Controls       Easy – PLC control       Easy – PLC control         Easy – standard pump
                        would use pre-set        would use pre-set          would use pre-set
                        program for particular   program for particular     settings for particular
                        media                    media                      media



 Ease of discharge      Very easy – use          Very easy – use            Very easy – use
 After reconstitution   conventional             conventional               conventional
                        connectors               connectors                 connectors




                                                                          Invitrogen Proprietary & Confidential
Comparison



In Use
Experience


Ease of filling       Very Easy                   Not Applicable                Easy
Powder container                                  (open top bag)

Handling and          Easy – in routine use       Easy – used an in-house       Easy – used an in-house
attaching Powder      would have support system   designed inclined support     designed inclined support
container to mixing   to hang bag                 plate for bag                 plate for bag
bag                                               Not Applicable if using
                                                  open top bag.
Emptying AGT into     Very easy – just            Relies on water               Relies on water
mixing bag            remove the clamp            flowing through               flowing through
                                                  powder bag –                  powder bag –
                                                  manipulation needed.          manipulation needed

                                                  Emptying into open top
                                                  bag needs care.
Mixing Complete       100L size – 10mins          200L size – 40 mins           500L size – 40 mins




                                                                              Invitrogen Proprietary & Confidential
                     Conclusion

  Due to the uniqueness of AGT going into solution
very easily little difference in re-constitution time

 All systems achieved homogenity

 Main differences found were:
            Ease of set up
           “Attendance” in use


           Commercially Available Mixing Systems
                             +
                          AGT™
                             =
            A Unique System that is Easy to Use


                                                   Invitrogen Proprietary & Confidential
Discussion




             Invitrogen Proprietary & Confidential

				
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posted:4/13/2011
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