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Approach to Technology Transfer
Presentation Overview
1) Introduction                                     1 min
2) Vertical Take off                                 5 min
3) Process Transfers vs. Technology Transfers       10 min
4) Technology Transfer Deliverables                  5 min
5) Application Techniques for Technology Transfer   35 min
6) Technology Transfer Skill Sets                   10 min
7) Question Answer Session                          10 min




   Confidential                                              2
1.0 Introduction - Robert Beall


                             Hometown: Syracuse, NY
                             Home:      Columbus, OH
                             Family:    Denise (Wife), Günther (Son)
                                        Maren (Daughter),Calvin (Son), Olive(dog)
                             Hobbies:   Sailing, Travel, Olympic Weightlifting
                             Education: RIT BS - Engineering
                                        BI PMI – Ingelheim, Germany



Boehringer – Ingelheim Transfer Experience
1997-2000 BIRI -Columbus, OH Solids Transfer Engineer for Optimization in North America (OPINA)
2000-2007 BIRI Product transfers (Mobic, Spiriva, Micardis Plus) from (BIPKG) to USA (BIRI) .
2007–2010 BIPKG International transfer between Germany and India for WW distribution.
2010–2011 BVL Life-Cycle product transfer of parenteral manufacturing to new facility.



       Confidential                                                                       3
                                                                                              3
2. Technology Transfer Success

 • Successful technology transfer will depend
   on your ability to deploy these patterns of
   success within your project organization
 • The slides that follow describe a roadmap
   you can follow to optimize your project
   organization of technology transfer
2. Typical Take-Off Curve
Performance



               Process Go-Live




                                              Secondary
             Technology                       Development
                                              (fixing issues)
              Transfer


                                                                                 Time
   •    Typically, a newly transferred process experiences less than optimal performance at
        the start. Like an out-of-tune biplane, the “take-off” is bumpy, experiencing ups and
        downs at the start as the receiving team/site works out the kinks of the new process
        and its technology. Performance ramps slowly over time, eventually achieving the
        desired level of performance.
2. The Concept of Vertical Take-Off
Performance



               Process Go-Live




                                                            Secondary Development
               Technology                                   (fixing issues)
                Transfer


                                                                                    Time
    •   The goal of any technology transfer should be to achieve the desired level of
        performance quickly and smoothly. Like a jet, the new process “takes-off” at the
        receiving site and delivers the desired heights of performance right from the start
        (vertical take-off).
2. The Value of Vertical Take-Off
Performance



               Process Go-Live
                                                                   Inefficiency

                                                                Rework
                                                                                       $
                                                                               Low Yields
                                                             Waste         Slow Speeds

                                                           Unplanned downtime

               Technology                                Unclear roles
                Transfer


                                                                                   Time
     •   There is a cost associated with most Technology Transfers that tends to stay hidden.
         The slow, bumpy ramp-up to desired performance represents cash to the business in
         the form of wastes, lower product yields , lost sales opportunities and slower return on
         investment (ROI).
3) Process transfers vs. Technology transfers
Process Transfer is the transfer of process information, or capability, associated
with process from a donor side (knowledge center) to a receptor side. The process is
learned and realized by both sides and complies all the regulatory requirements in
terms of Efficacy, Quality and Safety.


Technology Transfer, also called Transfer of Technology (TOT) is the process of
skill transferring, knowledge, technologies, methods of manufacturing, samples of
manufacturing to ensure that scientific and technological developments are
accessible to a wider range of users who can then further develop and exploit the
technology into new products, processes, applications, materials or services. It is
closely related to (and may arguably be considered a subset of) knowledge transfer.




    Confidential                                                                8
3) Technology Transfers vs. Process Transfers
A) Process Transfer examples                   B) Technology Transfer examples
Bi-Layer tablet compression for FDC            API manufacturing technology
DPI encapsulation                              NDA Product manufacturing
Gamma radiation sterilization for parenteral   ANDA Product transfer
products


Includes:                                      Includes:
Change control, Process Flow, URS, FDS,        Process transfer plus- Strategic Plan,
IOQ, PQ, Cleaning validation, PV, Training,    Validation master plan, Document
SOP’s                                          matrix, Supply chain planning, Method
                                               transfer, PDA, CPP,

OPINA                                          SPIRIVA
- Two process train transfers every weekend    - One transfer 5 years




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3) Technology Transfers vs. Process Transfers
OPINA Process Transfer
Project Objective – Consolidate North American pharmaceutical processing in 1 plant
Special Boundaries- No stockpiling of inventory
Solution – Transfer two process trains and ancillary equipment every weekend for 5
            weekends
Method – Dedicated transfer team developed plan for 6 months prior to execution.
        - Process transfer was like for like.
        - All non production transfer activities (training, utility installation, method
          transfers, RM transfers, qualification documents completed prior to transfer.
        - Minute by minute (micro) plan developed with video tape test runs.
        - Easiest transfer first.
        - Post mortem review of each process to fine tune for next transfer.




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3) Technology Transfers vs. Process Transfers
SPIRIVA Technology Transfer
Project Objective – Create redundant US production facility for German blockbuster
Special Boundaries-Process not defined, 1 billion x18 µg capsule fill.
Solution – Mirror German implementation with 6 month lag.
Method – Dedicated team, Clear roles and responsibilities.




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4) Technology Transfer Deliverables
In order to specify or to document the results of the technology transfer in a flexible
manner, a TTP or TTR could cover the technology transfer of one or all process steps 1).
Required documents detailing the technology transfer are listed in the Appendix of the
TTP or TTR.
                                                            One             All
Technology Transfer Documentation                       Process Step   Process Steps
Prepare Technology Transfer
Technology Transfer Protocol – Quality Control                           () 1)
Laboratory Qualification Report - Part 1 (TTLQ-Part1)        
Checklist 'Laboratory Equipment‘ (CLLE)                                     
Checklist 'Raw Material Specifications‘ (CLRMS)                             
Checklist 'Shipping‘ (CLS)                                                  
Technology Transfer Protocol – Production (TTPP)                         () 1)
Equivalency Report – Part 1 (TTEQ-Part1)                     
Checklist ‘Process Equipment‘ (CLPE)                                        
Execute Technology Transfer
Technology Transfer Report – Quality Control                             () 1)
Laboratory Qualification Report - Part 2 (TTLQ-Part2)        
Technology Transfer Report – Production (TTRP)                           () 1)
Equivalency Report – Part 2 (TTEQ-Part2)                     
5) Application Techniques for Technology Transfers
        9 Gate Technology Transfer Approach
                                                                      Develop                    Process
                 Initial                    Customer
 Project
               Assessment        1           Review        2          Project        3          Mapped with
                                                                                                   CPP
                                                                                                                   4
                                                                       Plan
Opportunity                 Project                      Project                   Project
                                                                                                              CPP with Gap
                        Recommendation                     Go                       Plan
                                                                                                               Assessment
                           & Proposal                                             Approved


                               Quality
                             Documents          Eng. / Transfer
                              Complete                                                         Validation /
                                                Batches                                        Commercial
              Quality Docs
                Created         5                                                              Batch
                                                                     Prepare                    MFG
                                           Execution       7            for
                                                                    Validation
                                                                                    8         Validation.
                                                                                               batches
                                                                                                                  9
              Production
              Documents         6                       Expansion                Ready for                    Post-Approval
              Completed
                                                       Documented                Validation                   Assessment /
                               Ready for                                                                       Post Mortem
                               Execution



          Milestones assessed




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5) Application Techniques for Technology Transfers
Gate 1. Project Charter -Scope of Transfer Process
 Project Recommendation includes the following components:
 1) Safety assessment
 2) Quality assessment
 3) Financial assessment
 4) Overall Timeline
 5) Framework for Technical Transfer Plan
 6) Defines project boundaries – What is in scope, what is out of scope
 7) Risks and Opportunities identified.
5) Application Techniques for Technology Transfers
Gate 1. Project Recommendation -Scope of Transfer Process
 The Master Documentation provides the framework for the transfer process. The Product Transfer Master Plan (PTMP) scope
 document defines the boundaries of the transfer.


                       Specify ...                                                                 Establish PTMP
                 
                       • scope of transfer (process steps)
                       • technology transfer activities and documentation
                       • qualification & regulatory activities
                       • release as additional manufacturer
                         Product Transfer Master Plan’ (PTMP)
5) Application Techniques for Technology Transfers
Gate 1. Gate 1. Project Recommendation –Know what you are
transferring.

  Sending Site Process                                                               Receiving Site Process
   P1 Stokes Mixer                        P2 Stokes Mixer                   P1 Stokes Mixer                  P2 Stokes Mixer
 Add MCC, API, Dextrose                 Add MCC, API, Dextrose          Add MCC, API, Dextrose            Add MCC, API, Dextrose
 and Starch, Mix for 5 min             and Starch, Mix for 5 min        and Starch, Mix for 5 min         and Starch, Mix for 5 min

                               Pony Mixer                                                Pony Mixer / Blend Cube
                               Add P1 and P2                                                    Add P1 and P2
                              – Mix for 10 min                                                  – Mix for 10 min

                               Pony Mixer                                                     Pony Mixer / Blend Cube
                             Add Mag Stearate                      Study*                           Add Mag Stearate
                              – Mix for 5 min                                                        – Mix for 5 min

                                    Poly Lined Drum                                                             SS Bin
                             Transfer Blend through #10 screen                                           Transfer Blend through
                                                                                                              #10 screen


                                     Manesty Press                                                            Killian Press
                                  Compress 25 mg tablets                    Study*                       Compress 10 mg tablets


 • These processes have the same SUPAC classification per CDER
 • This product transfer will be filed as a CBE – 30
5) Application Techniques for Technology Transfers
Gate 1. Project Recommendation –Know what you are transferring
vs. Company Metrics
     Product Design Attribute (PDA) TABLES
                                                                                                                                                 Comment
CTD       Metric                Most Favorable                        Less Favorable                     Least Favorable            Critical #

P7     Number of        Maximum 3                               Maximum 6                           Above 6                             4
       Worldwide        (e.g. – one size clear blister of one
       Primary          material, one size opaque blister, 2 blister (7-ct push + 10-ct peel-
       Packaging        one size HDPE bottle)              push)
       Configurations                                      2 bottles 60mL + 120mL
                        The number of worldwide primary packaging configurations reported here is determined for each drug
                        product dosage form and strength.
                        Blister packaging configurations are determined by counting the different combinations of forming and
                        lidding materials being developed with consideration of the sealing area and perforations. Although the
                        number of tablets per blister is not considered when determining the number of worldwide primary
                        packaging configurations being developed, this aspect must be evaluated and taken into consideration
                        during capacity, transfer and launch planning by Operations.
                        Bottle packaging configurations are determined by counting the different combinations of bottles and
                        closures, with consideration of size, product count and materials.
P7     Packaging        Standard HDPE bottle or standard        Special moisture barrier packaging Special inert atmosphere and        2+
       (Primary or      PVC and/or PVDC blister suitable. needed (PVDC based materials                oxygen barrier packaging
       protective                                               inadequate) or if hygroscopic         required. Novel packaging
       secondary or                                             formulation prone to major failure    materials required not
       functional                                               after HDPE bottle opened or failure commonly used for
       having impact                                            if bottle not reclosed in-use.        pharmaceutical products.
       on product                                               Special light protective packaging    Materials not approved for
       quality)                                                 needed (lined bottles or dark glass). use in food or drug
                                                                Special design or configuration of    packaging in US or EU.
                                                                HDPE bottles (e.g. desiccant),
                                                                Polypropylene bottle, or
                                                                Aluminum blister, bag, overwrap
                                                                required.
                        Multiple suppliers available.           Only single supplier available but    Single source supply with        5+
                                                                other suppliers can be developed.     patent restrictions against
                        Blister foils: Alcan + Constantia       Bottle: Gap last                      alternate suppliers.
5) Application Techniques for Technology Transfers
Gate 2. Project Go
In order to support the documentation of the decision to execute technical
transfer the – Decision' template specifies format and content.

                                    Technology Transfer                            Template




                                                                         eRoom Folder:
                                                                         1 Transfer Management



       18/102                                                                                    January 17, 2007
                       Handbook for Transfers of Chemical Products V02
5) Application Techniques for Technology Transfers
Gate 3. Project Plan
The checklist 'Activities' (CLA) contains a proposal regarding activities which are in
principle relevant for a transfer. Relevant activities can be marked and copied to the
project plan.
  Transfer of Chemical Product - Checklist 'Activites'
          Process Step   GL                                     Activity                                  Start Date   End Date   Resp.   Rel.
                                                                                                                                                 Example

  Set-up Transfer         2   Set up transfer project                                                                              PL     yes


  Set-up Transfer         2   Set up eRoom                                                                                         PL     yes


  Set-up Transfer         2   Denominate transfer team                                                                             PL     yes


  Set-up Transfer         2   Prepare kick-off meeting                                                                             PL     yes


  Preparation of TTP      2   Idemtification of documents                                                                         PM RU   yes


  Preparation of TTP      2   Preparation of documents                                                                            PM SU   yes


  Preparation of TTP      2   Preparation of TTP - Quality Control                                                                QC SU   yes

                              Acquisition and evaluation of the existing documentation on the synthetic
  Preparation of TTP      2                                                                                                       P SU    yes
                              method, including eventual batch records
                              Acquisition and evaluation of general documentation about ritical
  Preparation of TTP      2                                                                                                       P SU    yes
                              parameters or of a complete development report

  Preparation of TTP      2   Check production needs and their compatibility with the actual planning                             P SU    yes


  Preparation of TTP      2
                              Feasibility analysis in plant on the existing documentation and lay-out
                              hypothesis of the process
                                                                                                                                  P RU    eRoom Folder:
                                                                                                                                           yes


  Preparation of TTP      2   Cost analysis on production hypothesis                                                              PM RU
                                                                                                                                          1 Transfer Management
                                                                                                                                           yes

                              Acquisition and evaluation of the safety documentation of the process,
  Preparation of TTP      2                                                                                                       P RU    yes
                              including MSDS
5) Application Techniques for Technology Transfers
Gate 3. Project Plan
 In order to specify the product transfer, the ‘Product Transfer Master Plan’ (PTMP)
 template provides predefined structure, format and content.


                                                                              Template




                                                                         eRoom Folder:
                                                                         2 Tech Transfer
5) Application Techniques for Technology Transfers
Gate 3. Project Plan
MS Project serves as standard tool for the project planning of the product transfer. In
order to accelerate the preparation of the project plan, tasks from the activity list could
be pasted in.
                                                                                 Example




                                                                         eRoom Folder:
                                                                         1 Project Management
5) Application Techniques for Technology Transfers
                                                                                               Conduct the
                                                                                              Pre-Use Flush
                                                                                              for the Closed
                                                                                                  Solvent
                                                                                                 Transfer




Gate 4. Process Flow
                                                                                                  System


                                                                                                                                                                                    Sequential or
                                                                                                                                                                                      parallel?




   1)    Map production process with SME / Operators
   2)    Identify Critical Process Parameters (CPP) and Critical                                Ensure vent
                                                                                               bungholes on
                                                                                                 both metal
                                                                                              waste drum and
                                                                                                                                                                 Ensure proper
                                                                                                                                                                  bonding and
                                                                                                                                                                  grounding of
                                                                                                                                                                   equipment.
                                                                                                                                                                                             Where
                                                                                                                                                                                            described

                                                                                               solvent drum


         Quality Attributes (CQA) as they relate to finished                                      are open




         product                                                                   not ok                      ok                                      ok
                                                                                                                                                                                       not ok


   3)    Confirm all CPP / CQA have studies to support
         acceptance ranges.
                                                                                  open them




                                                                   Do I need to



   4)    Conduct studies to confirm CPP / CQA ranges to fill
                                                                     contact
                                                                    supervisor
                                                                      first?
                                                                                                                                Attach Inlet
                                                                                                                              hose and Valve
                                                                                                                               No.2 of CST
                                                                                                                               system to the


         gaps                                                                                                                   vessel and
                                                                                                                                 record the
                                                                                                                                   weight.




   5)    Determine best practice / gold standard process
   6)    Create CPP / CQA database (PANDA)
   7)    Compare CPP / CQA data values to “gold standard”
                                                                                                                                                Calculate the
                                                                                                                    Calculate 95%
                                                                                                                                                 amount of
                                                                                                                    of total required
                                                                                                                                                Dehydrated
                                                                                                                      Dehydrated
                                                                                                                                                  Alcohol,
                                                                                                                         Alcohol,
                                                                                                                                               USP/EP/BP to
                                                                                                                    USP/EP/BP to
                                                                                                                                                 add to the
                                                                                                                        add to the


         and ranges to determine cause of variance.
                                                                                                                                               vessel via the           is this
                                                                                                                       formulation
                                                                                                                                                CST system             correct?
                                                                                                                          vessel
                                                                                                                                                 (underfill?)        confusing to
                                                                                                                                                                         me..




   8)    Provide real time data trending to operators to enable                                                                   Calculate 95%



         educated process adjustment.
                                                                                                                                    minus the
                                                                                                                                     Underfill




                                                                                                                                      Add this
                                                                                                                                   amount to the
                                                                                                                                                            Continue agitation throughout solvent transfer
                                                                                                                                    formulation
                                                                                                                                      vessel.




                                                                                                                                  Target transfer
                                                                                                                                   weight of the
                                                                                                                                  vessel achieved




                                                                                                                                   Remove inlet
                                                                                                                                  hose and Valve
                                                                                                                                   No.2 from the
                                                                                                                                    vessel and
                                                                                                                                  record weight.




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5) Application Techniques for Technology Transfers
Gate 4. CPP / CQA Matrix
                             Formulation                                                              Set Up Process Sub‐Step
                                                                                                  Collect 
                                                            Check Room  Check         Check Tank  Equipment                                     Attach  Record 
                                                            for         Isolator for for          and check for  Pit Check  Load  Attach  Isolator to Tare 
                                                            Cleanliness Cleanliness Cleanliness Cleanliness         Scale     Isolator CST       tank Wt
                                                                                     Visual,      Visual Conf                                 Set up 
                                                                        Logbook  Mork sheet BOM ‐               Challenge  Verify             per SOP‐
                                                            Logbook confconf         Alcohol      Props /       Calibration  BOM      Set up  No breach  Print tick
           CQA                Specification                 Visual Conf Visual Confrinse.         clamp         Verify cal Integrity per SOP alarms      0.5 kg 
                              Clear, colorless to pale
                              yellow free from visable 
           Appearance         Contamination                             1          1            5             3            1        1        1          1        1
           Volume             Not less than 16.7 mL/Vial                1          1            1             1            1        1        1          1        1
           Assay              98.0% ‐ 108.0% of label                   1          3            3             3            3        1        1          1        5
           pH                 4.0 ‐ 6.0                                 1          1            3             3            1        1        1          1        1
           Moisture           NMT 0.6%                                  1          3            5             5            1        1        1          2        1
                              NMT 0.05 AU at A420 nm 
           Color of solution using ethyl alcohol blank                  1          1            3             1            1        1        1          1        1
           Ethanol            90% ‐ 110% of labeled amt                 1          1            5             1            3        1        1          1        5
                              Paclitaxel Products NMT 
                              0.1%
                              7 Epipaclitaxel NMT 0.3%
           Limit of           Total Degred Products NMT 
           Degredation        1.0%                                      1          1            2             4            1        1        1          1        4
           Residual Solvents USP 467                                    1          1            1             1            1        1        1          1        1
                              NMT 0.67 EU/mg of 
           Microbe Testing Paclitaxel                                   3          3            5             3            1        3        1          2        1
                              NMT 6,000 parts > 10 micron
           Particulate Matter NMT 600 parts > 25 micron                 1          1            1             1            1        1        1          1        1


  Based on ICH Q9 Guidelines


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5) Application Techniques for Technology Transfers
Gate 5. QC Documents Completed
 QC Documentation must be set prior to process transfer


                       Specify ...                                          Establish PTMP
                 
                       • scope of transfer (process steps)
                       • technology transfer activities and documentation
                       • qualification & regulatory activities
                       • release as additional manufacturer
                          Product Transfer Master Plan’ (PTMP)



    Quality Control
    Docs complete
5) Application Techniques for Technology Transfers
Gate 5. QC Documents Completed
The technology transfer products starts with the qualification of the laboratory (QC
Transfer) and continues with the transfer of the manufacturing process (Production
Transfer). The equivalency check of the chemical product has to be performed by the
QC of the Sending Unit 1).
               Production


             Product
           Receiving Unit
                                                          1st step:
2nd step:                                                 Qualification of laboratory
Equivalency check of                                      (Parallel analysis of reference
 product                                                  substance by SU and RU)
(Comparison of transfer batches
with reference batches)

                                                                              Production Transfer
              Product
                                                                              Quality Control
            Sending Unit
                                                                              Transfer


                                                              Quality Control
                                     Test            Test
                                  Sending Unit   Receiving Unit
5) Application Techniques for Technology Transfers
Gate 5. QC Documents Completed
The ‘Part 2’ of the ‘Technology Laboratory Qualification Report (TTLQ)’ template
supports to record the analytical results obtained in the parallel analysis by the RU, to
document the comparison of the results and the conclusions with regard to the
                                                                                 Example
fulfillment of the acceptance criteria.




                                                        TTLQ –P2
                                                    (TTRQC relevant part)




                                             eRoom Folder: 3 Quality Control
5) Application Techniques for Technology Transfers
Gate 6. Expansion Documents Completed


               Specify ...                                          Establish PTMP
          
               • scope of transfer (process steps)
               • technology transfer activities and documentation
               • qualification & regulatory activities
               • release as additional manufacturer
                 Product Transfer Master Plan’ (PTMP)



  Quality Control               Prepare
  Docs complete         Technology Transfer Docs
5) Application Techniques for Technology Transfers
Gate 6. Expansion Documents Completed
 The technology related part of the transfer is documented in technology transfer
 documentation.
  Technology Transfer – Quality Control              Technology Transfer - Production
                                 1)                                                               4)
   Specify scope of QC Transfer    Prepare                 Specify scope of Production Transfer
                                                                                             Prepare
        TT Protocol – Quality Control (TTPQC)              Define Transfer Campaign Size
   Check equivalence of laboratory                              TT Protocol – Production (TTPP)
        CL ‘Laboratory Equipment (CLLE)                   Check equivalence of process
   Check raw material specifications at                        CL ‘Process Equipment (CLPE)
        CL ‘Raw Material Specifications’ (CLRMS)                                     5)
                                                            Specify equivalency check
   Ship reference substances to RU                             TT ‘Equivalency Qualification–Part 1’ (TTEQ-P1)
        CL ‘Shipping’ (CLS)

  Specify qualification of RU laboratory
        TT ‘Laboratory Qualification–Part 1’ (TTLQ-P1)    Train manufacturing process at SU
                                                                                             Execute
                                                             Coach manufacturing process at RU
                                  3)
   Train analytical methods at SU Execute                      CE ‘Certificate Training – Production’ (CETP)
       CE ‘Certificate Training – Quality Control’       Produce transfer campaign at RU
   Execute parallel analysis at RU                         Execute equivalency check
        TT ‘Laboratory Qualification–Part 2’ (TTLQ-P2)
                                                                TT ‘Equivalency Qualification–Part 2’ (TTEQ-P2)
   Document results of QC Transfer                         Document results of Production
        TT Report – Quality Control (TTRQC)
                                                                TT Report –Production (TTRP)




                                                                                                             January 17, 2007
5) Application Techniques for Technology Transfers
Gate 6. Expansion Equivalency Check


                      Knowledge
                          Range


                         Proven
                      Acceptable Range


                          Normal
                       Operating Range



                        Target Value
   Parameter
   Scale
5) Application Techniques for Technology Transfers
Gate 6. Expansion Equivalency Check
 The equivalency check has to be conducted for non critical parameters by min/max
 comparison.                                                                  EXAMPLE
 Production SU              Charts 1) have to Limit (USL) demonstrate
 For critical parameters QC Upper Specification be usedProduction RU equivalency.
                                                       to

                                                          Upper Tolerance Limit (UTL) 2)
          Measured
           Value




                                                                                                                                                        Specification
                                                                                                                                           + 3 3)




                                                                                                                                                                   Sample
                                                          Lower Tolerance Limit (LTL) 2)
                                                                                                                                                                     No
                                                        Lower Specification Limit (LSL)
Remarks: 1) – upper or upper/lower limited control chart 2) Synonym: Upper/ Lower Control Limit; 3) 99,7% of the data should lie within the tolerance limits, the probability of a
false decision is 0,3%                                                                                                                                                    30


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5) Application Techniques for Technology Transfers
Gate 7. Expansion Completed
               Specify ...                                               Establish PTMP
          
               • scope of transfer (process steps)
               • technology transfer activities and documentation
               • qualification & regulatory activities
               • release as additional manufacturer
                 Product Transfer Master Plan’ (PTMP)



  Quality Control               Prepare               Execute
  Docs complete         Technology Transfer Docs Regulatory Activities


                               Execute Expansion
              Document ...
               • results of technology transfer
               • results of qualification and regulatory activities
               • release as additional manufacturer
                 Product Transfer Master Report’ (PTMR)
5) Application Techniques for Technology Transfers
Gate 8. Validation / Stability
 1) Never fail validation / stability batches.




                        Highest variation
5) Application Techniques for Technology Transfers
Gate 8. Validation / Stability
 1) Never fail validation / stability batches.

                                            Degradation T @ 25°C/60% r.H.

                    101.0



                    100.5                                                        G76757
                                                                                 G76972
                                                                                 G77267
                    100.0                                                        G77989




                     99.5
      assay T [%]




                     99.0



                     98.5



                     98.0



                     97.5
                            0   2   4   6     8        10         12        14    16      18   20
                                                   time [month]
5) Application Techniques for Technology Transfers
 Gate 9 Post Approval Assessment / Post Mortem
 1.   Review deliverables vs. plan
 2.   Review budget vs. plan
 3.   Review timeline vs. Base Plan
 4.   Revise templates accordingly.
6) Technology transfer skill sets
Management, Safety, QA, QC, Finance, Change Management, Engineering, Micro, Validations,
Operations, Customer, Contract Management, DRA



RACI




                                                                                           35
Questions?




Confidential                36
Reference Sources
•   *Sources:
•   “Project Management Best-Practice Report”, APQC, 2004
•   “A Guide to the Project Management Book of Knowledge®”, U.S. Department of Defense, 2003
•   “European Technology Transfer Guide to Best Practice”, Teurpin, 2001
•   “Benchmarking Best-Practices in Technology Transfer”, Colorado Institute for Technology Transfer
    and Implementation, 1993
Conclusion
                         In Compliance
                                +
                          On Schedule
                                +
                            In Budget
                                =
                          SUCCESS !

               ProPharma Group is the Best Choice
                   to balance all three needs!




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Product Design Attribute (PDA) TABLES
                                                                                                                                                               Comment
                                                                                                                                                 Critical at
         CTD           Metric                Most Favorable                          Less Favorable                   Least Favorable
                                                                                                                                                 Milestone #

P7                  Number of        Maximum 3                               Maximum 6                            Above 6                            4
                    Worldwide        (e.g. – one size clear blister of one
                    Primary          material, one size opaque blister, 2 blister (7-ct push + 10-ct peel-
                    Packaging        one size HDPE bottle)              push)
                    Configurations                                      2 bottles 60mL + 120mL
                                     The number of worldwide primary packaging configurations reported here is determined for each drug
                                     product dosage form and strength.
                                     Blister packaging configurations are determined by counting the different combinations of forming and
                                     lidding materials being developed with consideration of the sealing area and perforations. Although the
                                     number of tablets per blister is not considered when determining the number of worldwide primary
                                     packaging configurations being developed, this aspect must be evaluated and taken into consideration
                                     during capacity, transfer and launch planning by Operations.
                                     Bottle packaging configurations are determined by counting the different combinations of bottles and
                                     closures, with consideration of size, product count and materials.
P7                  Packaging        Standard HDPE bottle or standard        Special moisture barrier packaging Special inert atmosphere and         2+
                    (Primary or      PVC and/or PVDC blister suitable. needed (PVDC based materials                 oxygen barrier packaging
                    protective                                               inadequate) or if hygroscopic          required. Novel packaging
                    secondary or                                             formulation prone to major failure     materials required not
                    functional                                               after HDPE bottle opened or            commonly used for
                    having impact                                            failure if bottle not reclosed in-use. pharmaceutical products.
                    on product                                               Special light protective packaging     Materials not approved for
                    quality)                                                 needed (lined bottles or dark          use in food or drug
                                                                             glass). Special design or              packaging in US or EU.
                                                                             configuration of HDPE bottles
                                                                             (e.g. desiccant), Polypropylene
                                                                             bottle, or Aluminum blister, bag,
                                                                             overwrap required.

                                     Multiple suppliers available.           Only single supplier available but   Single source supply with          5+
                                                                             other suppliers can be developed.    patent restrictions against
                                     Blisterfoils: Alcan + Constantia        Bottle: Gaplast                      alternate suppliers.




 Confidential                                                                                                                                                       39
Confidential   40
5) Technology Transfer Skill Sets




  Confidential                      41
3) Process transfers vs. Technology transfers
Trouble -
Typically both process transfers and technology transfer projects get into
trouble because:

1) Process was not “Right the first time” before the transfer.
2) Process technology was not up to date technology before transfer.
3) Resolve compliance issues during transfer.

Result – Extended timelines, cost overrun.




   Confidential                                                              42
Appendix A B CD
     Appendix
     9 Technology Transfer – Document Flow1)


9 Technology Transfer –
        IChC Decision (FID)


         Product Transfer
        Master Plan’ (PTMP)
                                                                     IChC decision on
                                                                       Transfer of CP


                                                                           Specify
                                                                        transfer of CP




    Document Flow
       Technology Transfer
      Protocol –QC (TTPQC)
                            QC Transfer
                                                Specify scope of
                                            Technology Transfer –QC                    Transfer –P
                                                                                                          Production Transfer
                                                                                    Specify scope of Technology
                                                                                                   roduction
                                                                                                                      Techn. Transfer Protocol
       Checklist Laboratory                    Check equivalency                                                        –Production (TTPP  )
        Equipment (CLLE)                    of laboratory
                                                                                      Define Transfer Campaign
                                                                                                 Size
      Checklist Raw Material               Check adequacy of raw
      Specifications (CLRMS)             material specifications RU/SU

            Checklist                      Ship reference substances                     Check comparability of          Checklist Process
          Shipping (CLS)                              to RU                               process equipment              Equipment


     Laboratory Qualification                 Specify qualification
     Report –Part 1 (TTLQ-P1)              parameters (RU laboratory)
                                                                                          Specify equivalency          Equivalency Report –
                                                                                                 check                   Part 1 (TTEQ-P1)
                                            Train analytical methods
                                                      at SU
        Training Certificates
              (CETQC)
                                          Coach analytical methods at                     Train manufacturing
                                                RU (optional)                                process at SU
                                                                                                                        Training Certificates
     Laboratory Qualification               Execute parallel analysis                                                          (CETP)
     Report –Part 2 (TTLQ-P2)                        at RU                               Coach manufacturing
                                                                                            process at RU
        Technology Transfer                   Document results of
       Report –QC (TTRQC)                   Technology Transfer - QC
                                                                                      Produce transfer campaign
                                                                                                at RU


                                                                                                                       Equivalency Report –
                                                                                      Execute equivalency check          Part 2 (TTEQ-P2)


                                                                                      Document results of Techn.       Techn. Transfer Report
                                                                                        Transfer - Production           –P roduction (TTRP )



                                                                         Qualify CP


                                                               Execute Regulatory Activities


        Product Transfer
      Master Report’ (PTMR)                                      Document transfer of CP
                                                                                              End

     Remarks: CP –Chemical Product; 1) for more details please see Handbook

     Handbook for Transfer of Chemical Products                                                                                  J 17, 2008
                                                                                                                                  an
North to Phase V Product Transfers:
Project Phases / Responsibilities




                               GATE 1


                               GATE 2

                               GATE 3

                               GATE 4



                                        44
North to Phase V Product Transfers:
Project Phases / Responsibilities




                                GATE 5

                                GATE 6




                                GATE 7


                                GATE 8


                                         45
North to Phase V Product Transfers:
Project Phases / Responsibilities




                                  GATE 9




                                           46
3) Technology transfer deliverables




  Confidential                        47
Scope of Transfer Process (1)
The ‘Tech Transfer starts with a decision to transfer continues with the transfer of
(documented) knowledge, the demonstration of ability of the receiving unit to
manufacture the product to the satisfaction of all involved parties and ends with
successfully regulatory variations and the release as additional manufacturer.
                                                                                             Release as additional Manufacturer (End)
 Tech Transfer
                                                             CRC                 Establish Product Transfer Master
                                                            Application             Report
                                                                             Execute regulatory activities ...
    conceptual
                                                                             Qualify API (by MP)

                                  Execute Technology Transfer – Production
                                                                        Equivalency of API                       MP Approval

                        Execute Technology Transfer – QC Laboratory Qualification 1)

                         Prepare Technology Transfer – Production

                         Prepare Technology Transfer – QC

        Establish Product Transfer Master Plan

   Manage project                                                                                              ...
     IChC decision (Start)                                                                                                    Time
Remarks: 1) Start of production of transfer batches; MP – Manufacturing Pharma; CRC – Change Review Committee; IChC – International
 48/102                                                                                                             January 17, 2007
Chemicals Committee           Handbook for Transfers of Chemical Products V02
Confidential   49

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Approach to Technology Transfer

  • 2. Presentation Overview 1) Introduction 1 min 2) Vertical Take off 5 min 3) Process Transfers vs. Technology Transfers 10 min 4) Technology Transfer Deliverables 5 min 5) Application Techniques for Technology Transfer 35 min 6) Technology Transfer Skill Sets 10 min 7) Question Answer Session 10 min Confidential 2
  • 3. 1.0 Introduction - Robert Beall Hometown: Syracuse, NY Home: Columbus, OH Family: Denise (Wife), Günther (Son) Maren (Daughter),Calvin (Son), Olive(dog) Hobbies: Sailing, Travel, Olympic Weightlifting Education: RIT BS - Engineering BI PMI – Ingelheim, Germany Boehringer – Ingelheim Transfer Experience 1997-2000 BIRI -Columbus, OH Solids Transfer Engineer for Optimization in North America (OPINA) 2000-2007 BIRI Product transfers (Mobic, Spiriva, Micardis Plus) from (BIPKG) to USA (BIRI) . 2007–2010 BIPKG International transfer between Germany and India for WW distribution. 2010–2011 BVL Life-Cycle product transfer of parenteral manufacturing to new facility. Confidential 3 3
  • 4. 2. Technology Transfer Success • Successful technology transfer will depend on your ability to deploy these patterns of success within your project organization • The slides that follow describe a roadmap you can follow to optimize your project organization of technology transfer
  • 5. 2. Typical Take-Off Curve Performance Process Go-Live Secondary Technology Development (fixing issues) Transfer Time • Typically, a newly transferred process experiences less than optimal performance at the start. Like an out-of-tune biplane, the “take-off” is bumpy, experiencing ups and downs at the start as the receiving team/site works out the kinks of the new process and its technology. Performance ramps slowly over time, eventually achieving the desired level of performance.
  • 6. 2. The Concept of Vertical Take-Off Performance Process Go-Live Secondary Development Technology (fixing issues) Transfer Time • The goal of any technology transfer should be to achieve the desired level of performance quickly and smoothly. Like a jet, the new process “takes-off” at the receiving site and delivers the desired heights of performance right from the start (vertical take-off).
  • 7. 2. The Value of Vertical Take-Off Performance Process Go-Live Inefficiency Rework $ Low Yields Waste Slow Speeds Unplanned downtime Technology Unclear roles Transfer Time • There is a cost associated with most Technology Transfers that tends to stay hidden. The slow, bumpy ramp-up to desired performance represents cash to the business in the form of wastes, lower product yields , lost sales opportunities and slower return on investment (ROI).
  • 8. 3) Process transfers vs. Technology transfers Process Transfer is the transfer of process information, or capability, associated with process from a donor side (knowledge center) to a receptor side. The process is learned and realized by both sides and complies all the regulatory requirements in terms of Efficacy, Quality and Safety. Technology Transfer, also called Transfer of Technology (TOT) is the process of skill transferring, knowledge, technologies, methods of manufacturing, samples of manufacturing to ensure that scientific and technological developments are accessible to a wider range of users who can then further develop and exploit the technology into new products, processes, applications, materials or services. It is closely related to (and may arguably be considered a subset of) knowledge transfer. Confidential 8
  • 9. 3) Technology Transfers vs. Process Transfers A) Process Transfer examples B) Technology Transfer examples Bi-Layer tablet compression for FDC API manufacturing technology DPI encapsulation NDA Product manufacturing Gamma radiation sterilization for parenteral ANDA Product transfer products Includes: Includes: Change control, Process Flow, URS, FDS, Process transfer plus- Strategic Plan, IOQ, PQ, Cleaning validation, PV, Training, Validation master plan, Document SOP’s matrix, Supply chain planning, Method transfer, PDA, CPP, OPINA SPIRIVA - Two process train transfers every weekend - One transfer 5 years Confidential 9
  • 10. 3) Technology Transfers vs. Process Transfers OPINA Process Transfer Project Objective – Consolidate North American pharmaceutical processing in 1 plant Special Boundaries- No stockpiling of inventory Solution – Transfer two process trains and ancillary equipment every weekend for 5 weekends Method – Dedicated transfer team developed plan for 6 months prior to execution. - Process transfer was like for like. - All non production transfer activities (training, utility installation, method transfers, RM transfers, qualification documents completed prior to transfer. - Minute by minute (micro) plan developed with video tape test runs. - Easiest transfer first. - Post mortem review of each process to fine tune for next transfer. Confidential 10
  • 11. 3) Technology Transfers vs. Process Transfers SPIRIVA Technology Transfer Project Objective – Create redundant US production facility for German blockbuster Special Boundaries-Process not defined, 1 billion x18 µg capsule fill. Solution – Mirror German implementation with 6 month lag. Method – Dedicated team, Clear roles and responsibilities. Confidential 11
  • 12. 4) Technology Transfer Deliverables In order to specify or to document the results of the technology transfer in a flexible manner, a TTP or TTR could cover the technology transfer of one or all process steps 1). Required documents detailing the technology transfer are listed in the Appendix of the TTP or TTR. One All Technology Transfer Documentation Process Step Process Steps Prepare Technology Transfer Technology Transfer Protocol – Quality Control  () 1) Laboratory Qualification Report - Part 1 (TTLQ-Part1)  Checklist 'Laboratory Equipment‘ (CLLE)  Checklist 'Raw Material Specifications‘ (CLRMS)  Checklist 'Shipping‘ (CLS)  Technology Transfer Protocol – Production (TTPP)  () 1) Equivalency Report – Part 1 (TTEQ-Part1)  Checklist ‘Process Equipment‘ (CLPE)  Execute Technology Transfer Technology Transfer Report – Quality Control  () 1) Laboratory Qualification Report - Part 2 (TTLQ-Part2)  Technology Transfer Report – Production (TTRP)  () 1) Equivalency Report – Part 2 (TTEQ-Part2) 
  • 13. 5) Application Techniques for Technology Transfers 9 Gate Technology Transfer Approach Develop Process Initial Customer Project Assessment 1 Review 2 Project 3 Mapped with CPP 4 Plan Opportunity Project Project Project CPP with Gap Recommendation Go Plan Assessment & Proposal Approved Quality Documents Eng. / Transfer Complete Validation / Batches Commercial Quality Docs Created 5 Batch Prepare MFG Execution 7 for Validation 8 Validation. batches 9 Production Documents 6 Expansion Ready for Post-Approval Completed Documented Validation Assessment / Ready for Post Mortem Execution Milestones assessed Confidential 13
  • 14. 5) Application Techniques for Technology Transfers Gate 1. Project Charter -Scope of Transfer Process Project Recommendation includes the following components: 1) Safety assessment 2) Quality assessment 3) Financial assessment 4) Overall Timeline 5) Framework for Technical Transfer Plan 6) Defines project boundaries – What is in scope, what is out of scope 7) Risks and Opportunities identified.
  • 15. 5) Application Techniques for Technology Transfers Gate 1. Project Recommendation -Scope of Transfer Process The Master Documentation provides the framework for the transfer process. The Product Transfer Master Plan (PTMP) scope document defines the boundaries of the transfer. Specify ... Establish PTMP  • scope of transfer (process steps) • technology transfer activities and documentation • qualification & regulatory activities • release as additional manufacturer   Product Transfer Master Plan’ (PTMP)
  • 16. 5) Application Techniques for Technology Transfers Gate 1. Gate 1. Project Recommendation –Know what you are transferring. Sending Site Process Receiving Site Process P1 Stokes Mixer P2 Stokes Mixer P1 Stokes Mixer P2 Stokes Mixer Add MCC, API, Dextrose Add MCC, API, Dextrose Add MCC, API, Dextrose Add MCC, API, Dextrose and Starch, Mix for 5 min and Starch, Mix for 5 min and Starch, Mix for 5 min and Starch, Mix for 5 min Pony Mixer Pony Mixer / Blend Cube Add P1 and P2 Add P1 and P2 – Mix for 10 min – Mix for 10 min Pony Mixer Pony Mixer / Blend Cube Add Mag Stearate Study* Add Mag Stearate – Mix for 5 min – Mix for 5 min Poly Lined Drum SS Bin Transfer Blend through #10 screen Transfer Blend through #10 screen Manesty Press Killian Press Compress 25 mg tablets Study* Compress 10 mg tablets • These processes have the same SUPAC classification per CDER • This product transfer will be filed as a CBE – 30
  • 17. 5) Application Techniques for Technology Transfers Gate 1. Project Recommendation –Know what you are transferring vs. Company Metrics Product Design Attribute (PDA) TABLES Comment CTD Metric Most Favorable Less Favorable Least Favorable Critical # P7 Number of Maximum 3 Maximum 6 Above 6 4 Worldwide (e.g. – one size clear blister of one Primary material, one size opaque blister, 2 blister (7-ct push + 10-ct peel- Packaging one size HDPE bottle) push) Configurations 2 bottles 60mL + 120mL The number of worldwide primary packaging configurations reported here is determined for each drug product dosage form and strength. Blister packaging configurations are determined by counting the different combinations of forming and lidding materials being developed with consideration of the sealing area and perforations. Although the number of tablets per blister is not considered when determining the number of worldwide primary packaging configurations being developed, this aspect must be evaluated and taken into consideration during capacity, transfer and launch planning by Operations. Bottle packaging configurations are determined by counting the different combinations of bottles and closures, with consideration of size, product count and materials. P7 Packaging Standard HDPE bottle or standard Special moisture barrier packaging Special inert atmosphere and 2+ (Primary or PVC and/or PVDC blister suitable. needed (PVDC based materials oxygen barrier packaging protective inadequate) or if hygroscopic required. Novel packaging secondary or formulation prone to major failure materials required not functional after HDPE bottle opened or failure commonly used for having impact if bottle not reclosed in-use. pharmaceutical products. on product Special light protective packaging Materials not approved for quality) needed (lined bottles or dark glass). use in food or drug Special design or configuration of packaging in US or EU. HDPE bottles (e.g. desiccant), Polypropylene bottle, or Aluminum blister, bag, overwrap required. Multiple suppliers available. Only single supplier available but Single source supply with 5+ other suppliers can be developed. patent restrictions against Blister foils: Alcan + Constantia Bottle: Gap last alternate suppliers.
  • 18. 5) Application Techniques for Technology Transfers Gate 2. Project Go In order to support the documentation of the decision to execute technical transfer the – Decision' template specifies format and content. Technology Transfer Template eRoom Folder: 1 Transfer Management 18/102 January 17, 2007 Handbook for Transfers of Chemical Products V02
  • 19. 5) Application Techniques for Technology Transfers Gate 3. Project Plan The checklist 'Activities' (CLA) contains a proposal regarding activities which are in principle relevant for a transfer. Relevant activities can be marked and copied to the project plan. Transfer of Chemical Product - Checklist 'Activites' Process Step GL Activity Start Date End Date Resp. Rel. Example Set-up Transfer 2 Set up transfer project PL yes Set-up Transfer 2 Set up eRoom PL yes Set-up Transfer 2 Denominate transfer team PL yes Set-up Transfer 2 Prepare kick-off meeting PL yes Preparation of TTP 2 Idemtification of documents PM RU yes Preparation of TTP 2 Preparation of documents PM SU yes Preparation of TTP 2 Preparation of TTP - Quality Control QC SU yes Acquisition and evaluation of the existing documentation on the synthetic Preparation of TTP 2 P SU yes method, including eventual batch records Acquisition and evaluation of general documentation about ritical Preparation of TTP 2 P SU yes parameters or of a complete development report Preparation of TTP 2 Check production needs and their compatibility with the actual planning P SU yes Preparation of TTP 2 Feasibility analysis in plant on the existing documentation and lay-out hypothesis of the process P RU eRoom Folder: yes Preparation of TTP 2 Cost analysis on production hypothesis PM RU 1 Transfer Management yes Acquisition and evaluation of the safety documentation of the process, Preparation of TTP 2 P RU yes including MSDS
  • 20. 5) Application Techniques for Technology Transfers Gate 3. Project Plan In order to specify the product transfer, the ‘Product Transfer Master Plan’ (PTMP) template provides predefined structure, format and content. Template eRoom Folder: 2 Tech Transfer
  • 21. 5) Application Techniques for Technology Transfers Gate 3. Project Plan MS Project serves as standard tool for the project planning of the product transfer. In order to accelerate the preparation of the project plan, tasks from the activity list could be pasted in. Example eRoom Folder: 1 Project Management
  • 22. 5) Application Techniques for Technology Transfers Conduct the Pre-Use Flush for the Closed Solvent Transfer Gate 4. Process Flow System Sequential or parallel? 1) Map production process with SME / Operators 2) Identify Critical Process Parameters (CPP) and Critical Ensure vent bungholes on both metal waste drum and Ensure proper bonding and grounding of equipment. Where described solvent drum Quality Attributes (CQA) as they relate to finished are open product not ok ok ok not ok 3) Confirm all CPP / CQA have studies to support acceptance ranges. open them Do I need to 4) Conduct studies to confirm CPP / CQA ranges to fill contact supervisor first? Attach Inlet hose and Valve No.2 of CST system to the gaps vessel and record the weight. 5) Determine best practice / gold standard process 6) Create CPP / CQA database (PANDA) 7) Compare CPP / CQA data values to “gold standard” Calculate the Calculate 95% amount of of total required Dehydrated Dehydrated Alcohol, Alcohol, USP/EP/BP to USP/EP/BP to add to the add to the and ranges to determine cause of variance. vessel via the is this formulation CST system correct? vessel (underfill?) confusing to me.. 8) Provide real time data trending to operators to enable Calculate 95% educated process adjustment. minus the Underfill Add this amount to the Continue agitation throughout solvent transfer formulation vessel. Target transfer weight of the vessel achieved Remove inlet hose and Valve No.2 from the vessel and record weight. Confidential 22
  • 23. 5) Application Techniques for Technology Transfers Gate 4. CPP / CQA Matrix Formulation Set Up Process Sub‐Step Collect  Check Room  Check  Check Tank  Equipment  Attach  Record  for  Isolator for for  and check for  Pit Check  Load  Attach  Isolator to Tare  Cleanliness Cleanliness Cleanliness Cleanliness Scale Isolator CST  tank Wt Visual, Visual Conf Set up  Logbook  Mork sheet BOM ‐ Challenge  Verify  per SOP‐ Logbook confconf Alcohol  Props /  Calibration  BOM Set up  No breach  Print tick CQA Specification Visual Conf Visual Confrinse. clamp Verify cal Integrity per SOP alarms 0.5 kg  Clear, colorless to pale yellow free from visable  Appearance Contamination 1 1 5 3 1 1 1 1 1 Volume  Not less than 16.7 mL/Vial 1 1 1 1 1 1 1 1 1 Assay 98.0% ‐ 108.0% of label 1 3 3 3 3 1 1 1 5 pH 4.0 ‐ 6.0 1 1 3 3 1 1 1 1 1 Moisture NMT 0.6% 1 3 5 5 1 1 1 2 1 NMT 0.05 AU at A420 nm  Color of solution using ethyl alcohol blank 1 1 3 1 1 1 1 1 1 Ethanol 90% ‐ 110% of labeled amt 1 1 5 1 3 1 1 1 5 Paclitaxel Products NMT  0.1% 7 Epipaclitaxel NMT 0.3% Limit of  Total Degred Products NMT  Degredation 1.0% 1 1 2 4 1 1 1 1 4 Residual Solvents USP 467 1 1 1 1 1 1 1 1 1 NMT 0.67 EU/mg of  Microbe Testing Paclitaxel 3 3 5 3 1 3 1 2 1 NMT 6,000 parts > 10 micron Particulate Matter NMT 600 parts > 25 micron 1 1 1 1 1 1 1 1 1 Based on ICH Q9 Guidelines Confidential 23
  • 24. 5) Application Techniques for Technology Transfers Gate 5. QC Documents Completed QC Documentation must be set prior to process transfer Specify ... Establish PTMP  • scope of transfer (process steps) • technology transfer activities and documentation • qualification & regulatory activities • release as additional manufacturer   Product Transfer Master Plan’ (PTMP) Quality Control Docs complete
  • 25. 5) Application Techniques for Technology Transfers Gate 5. QC Documents Completed The technology transfer products starts with the qualification of the laboratory (QC Transfer) and continues with the transfer of the manufacturing process (Production Transfer). The equivalency check of the chemical product has to be performed by the QC of the Sending Unit 1). Production Product Receiving Unit 1st step: 2nd step: Qualification of laboratory Equivalency check of (Parallel analysis of reference product substance by SU and RU) (Comparison of transfer batches with reference batches) Production Transfer Product Quality Control Sending Unit Transfer Quality Control Test Test Sending Unit Receiving Unit
  • 26. 5) Application Techniques for Technology Transfers Gate 5. QC Documents Completed The ‘Part 2’ of the ‘Technology Laboratory Qualification Report (TTLQ)’ template supports to record the analytical results obtained in the parallel analysis by the RU, to document the comparison of the results and the conclusions with regard to the Example fulfillment of the acceptance criteria. TTLQ –P2 (TTRQC relevant part) eRoom Folder: 3 Quality Control
  • 27. 5) Application Techniques for Technology Transfers Gate 6. Expansion Documents Completed Specify ... Establish PTMP  • scope of transfer (process steps) • technology transfer activities and documentation • qualification & regulatory activities • release as additional manufacturer   Product Transfer Master Plan’ (PTMP) Quality Control Prepare Docs complete Technology Transfer Docs
  • 28. 5) Application Techniques for Technology Transfers Gate 6. Expansion Documents Completed The technology related part of the transfer is documented in technology transfer documentation. Technology Transfer – Quality Control Technology Transfer - Production 1) 4)  Specify scope of QC Transfer Prepare  Specify scope of Production Transfer Prepare   TT Protocol – Quality Control (TTPQC) Define Transfer Campaign Size  Check equivalence of laboratory   TT Protocol – Production (TTPP)   CL ‘Laboratory Equipment (CLLE)  Check equivalence of process  Check raw material specifications at   CL ‘Process Equipment (CLPE)   CL ‘Raw Material Specifications’ (CLRMS) 5)  Specify equivalency check  Ship reference substances to RU   TT ‘Equivalency Qualification–Part 1’ (TTEQ-P1)   CL ‘Shipping’ (CLS)  Specify qualification of RU laboratory   TT ‘Laboratory Qualification–Part 1’ (TTLQ-P1)  Train manufacturing process at SU Execute Coach manufacturing process at RU 3)  Train analytical methods at SU Execute   CE ‘Certificate Training – Production’ (CETP)    CE ‘Certificate Training – Quality Control’  Produce transfer campaign at RU  Execute parallel analysis at RU  Execute equivalency check   TT ‘Laboratory Qualification–Part 2’ (TTLQ-P2)   TT ‘Equivalency Qualification–Part 2’ (TTEQ-P2)  Document results of QC Transfer  Document results of Production   TT Report – Quality Control (TTRQC)   TT Report –Production (TTRP) January 17, 2007
  • 29. 5) Application Techniques for Technology Transfers Gate 6. Expansion Equivalency Check Knowledge Range Proven Acceptable Range Normal Operating Range Target Value Parameter Scale
  • 30. 5) Application Techniques for Technology Transfers Gate 6. Expansion Equivalency Check The equivalency check has to be conducted for non critical parameters by min/max comparison. EXAMPLE Production SU Charts 1) have to Limit (USL) demonstrate For critical parameters QC Upper Specification be usedProduction RU equivalency. to Upper Tolerance Limit (UTL) 2) Measured Value Specification + 3 3) Sample Lower Tolerance Limit (LTL) 2) No Lower Specification Limit (LSL) Remarks: 1) – upper or upper/lower limited control chart 2) Synonym: Upper/ Lower Control Limit; 3) 99,7% of the data should lie within the tolerance limits, the probability of a false decision is 0,3% 30 Confidential 30/102
  • 31. 5) Application Techniques for Technology Transfers Gate 7. Expansion Completed Specify ... Establish PTMP  • scope of transfer (process steps) • technology transfer activities and documentation • qualification & regulatory activities • release as additional manufacturer   Product Transfer Master Plan’ (PTMP) Quality Control Prepare Execute Docs complete Technology Transfer Docs Regulatory Activities Execute Expansion  Document ... • results of technology transfer • results of qualification and regulatory activities • release as additional manufacturer   Product Transfer Master Report’ (PTMR)
  • 32. 5) Application Techniques for Technology Transfers Gate 8. Validation / Stability 1) Never fail validation / stability batches. Highest variation
  • 33. 5) Application Techniques for Technology Transfers Gate 8. Validation / Stability 1) Never fail validation / stability batches. Degradation T @ 25°C/60% r.H. 101.0 100.5 G76757 G76972 G77267 100.0 G77989 99.5 assay T [%] 99.0 98.5 98.0 97.5 0 2 4 6 8 10 12 14 16 18 20 time [month]
  • 34. 5) Application Techniques for Technology Transfers Gate 9 Post Approval Assessment / Post Mortem 1. Review deliverables vs. plan 2. Review budget vs. plan 3. Review timeline vs. Base Plan 4. Revise templates accordingly.
  • 35. 6) Technology transfer skill sets Management, Safety, QA, QC, Finance, Change Management, Engineering, Micro, Validations, Operations, Customer, Contract Management, DRA RACI 35
  • 37. Reference Sources • *Sources: • “Project Management Best-Practice Report”, APQC, 2004 • “A Guide to the Project Management Book of Knowledge®”, U.S. Department of Defense, 2003 • “European Technology Transfer Guide to Best Practice”, Teurpin, 2001 • “Benchmarking Best-Practices in Technology Transfer”, Colorado Institute for Technology Transfer and Implementation, 1993
  • 38. Conclusion In Compliance + On Schedule + In Budget = SUCCESS ! ProPharma Group is the Best Choice to balance all three needs! Confidential 38
  • 39. Product Design Attribute (PDA) TABLES Comment Critical at CTD Metric Most Favorable Less Favorable Least Favorable Milestone # P7 Number of Maximum 3 Maximum 6 Above 6 4 Worldwide (e.g. – one size clear blister of one Primary material, one size opaque blister, 2 blister (7-ct push + 10-ct peel- Packaging one size HDPE bottle) push) Configurations 2 bottles 60mL + 120mL The number of worldwide primary packaging configurations reported here is determined for each drug product dosage form and strength. Blister packaging configurations are determined by counting the different combinations of forming and lidding materials being developed with consideration of the sealing area and perforations. Although the number of tablets per blister is not considered when determining the number of worldwide primary packaging configurations being developed, this aspect must be evaluated and taken into consideration during capacity, transfer and launch planning by Operations. Bottle packaging configurations are determined by counting the different combinations of bottles and closures, with consideration of size, product count and materials. P7 Packaging Standard HDPE bottle or standard Special moisture barrier packaging Special inert atmosphere and 2+ (Primary or PVC and/or PVDC blister suitable. needed (PVDC based materials oxygen barrier packaging protective inadequate) or if hygroscopic required. Novel packaging secondary or formulation prone to major failure materials required not functional after HDPE bottle opened or commonly used for having impact failure if bottle not reclosed in-use. pharmaceutical products. on product Special light protective packaging Materials not approved for quality) needed (lined bottles or dark use in food or drug glass). Special design or packaging in US or EU. configuration of HDPE bottles (e.g. desiccant), Polypropylene bottle, or Aluminum blister, bag, overwrap required. Multiple suppliers available. Only single supplier available but Single source supply with 5+ other suppliers can be developed. patent restrictions against Blisterfoils: Alcan + Constantia Bottle: Gaplast alternate suppliers. Confidential 39
  • 41. 5) Technology Transfer Skill Sets Confidential 41
  • 42. 3) Process transfers vs. Technology transfers Trouble - Typically both process transfers and technology transfer projects get into trouble because: 1) Process was not “Right the first time” before the transfer. 2) Process technology was not up to date technology before transfer. 3) Resolve compliance issues during transfer. Result – Extended timelines, cost overrun. Confidential 42
  • 43. Appendix A B CD Appendix 9 Technology Transfer – Document Flow1) 9 Technology Transfer – IChC Decision (FID) Product Transfer Master Plan’ (PTMP) IChC decision on Transfer of CP Specify transfer of CP Document Flow Technology Transfer Protocol –QC (TTPQC) QC Transfer Specify scope of Technology Transfer –QC Transfer –P Production Transfer Specify scope of Technology roduction Techn. Transfer Protocol Checklist Laboratory Check equivalency –Production (TTPP ) Equipment (CLLE) of laboratory Define Transfer Campaign Size Checklist Raw Material Check adequacy of raw Specifications (CLRMS) material specifications RU/SU Checklist Ship reference substances Check comparability of Checklist Process Shipping (CLS) to RU process equipment Equipment Laboratory Qualification Specify qualification Report –Part 1 (TTLQ-P1) parameters (RU laboratory) Specify equivalency Equivalency Report – check Part 1 (TTEQ-P1) Train analytical methods at SU Training Certificates (CETQC) Coach analytical methods at Train manufacturing RU (optional) process at SU Training Certificates Laboratory Qualification Execute parallel analysis (CETP) Report –Part 2 (TTLQ-P2) at RU Coach manufacturing process at RU Technology Transfer Document results of Report –QC (TTRQC) Technology Transfer - QC Produce transfer campaign at RU Equivalency Report – Execute equivalency check Part 2 (TTEQ-P2) Document results of Techn. Techn. Transfer Report Transfer - Production –P roduction (TTRP ) Qualify CP Execute Regulatory Activities Product Transfer Master Report’ (PTMR) Document transfer of CP End Remarks: CP –Chemical Product; 1) for more details please see Handbook Handbook for Transfer of Chemical Products J 17, 2008 an
  • 44. North to Phase V Product Transfers: Project Phases / Responsibilities GATE 1 GATE 2 GATE 3 GATE 4 44
  • 45. North to Phase V Product Transfers: Project Phases / Responsibilities GATE 5 GATE 6 GATE 7 GATE 8 45
  • 46. North to Phase V Product Transfers: Project Phases / Responsibilities GATE 9 46
  • 47. 3) Technology transfer deliverables Confidential 47
  • 48. Scope of Transfer Process (1) The ‘Tech Transfer starts with a decision to transfer continues with the transfer of (documented) knowledge, the demonstration of ability of the receiving unit to manufacture the product to the satisfaction of all involved parties and ends with successfully regulatory variations and the release as additional manufacturer. Release as additional Manufacturer (End) Tech Transfer CRC Establish Product Transfer Master Application Report Execute regulatory activities ... conceptual Qualify API (by MP) Execute Technology Transfer – Production Equivalency of API MP Approval Execute Technology Transfer – QC Laboratory Qualification 1) Prepare Technology Transfer – Production Prepare Technology Transfer – QC Establish Product Transfer Master Plan Manage project ... IChC decision (Start) Time Remarks: 1) Start of production of transfer batches; MP – Manufacturing Pharma; CRC – Change Review Committee; IChC – International 48/102 January 17, 2007 Chemicals Committee Handbook for Transfers of Chemical Products V02