Approach to Technology Transfer Bob Beall

8/10/2019 Approach to Technology Transfer Bob Beall

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Presentation Overview

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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


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2. Technology Transfer Success

Successful technology transfer will depend

on your ability to deploy these patterns ofsuccess within your project organization

The slides that follow describe a roadmapyou can follow to optimize your project

organization of technology transfer


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2. Typical Take-Off Curve

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.

Time

Performance

TechnologyTransfer

Process Go-Live

Secondary

Development(fixing issues)


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2. The Concept of Vertical Take-Off

The goal of any technology transfer should be to achieve the desired level ofperformance 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).

Time

Performance

TechnologyTransfer

Process Go-Live

Secondary Development

(fixing issues)


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2. The Value of Vertical Take-Off

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).

Time

Performance

TechnologyTransfer

Process Go-Live

$Low Yields

Inefficiency

Rework

WasteSlow Speeds

Unplanned downtime

Unclear roles


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3) Process transfers vs. Technology transfers

Process Transfer is the transfer of process information, or capability, associatedwith 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 ofskill transferring, knowledge, technologies, methods of manufacturing, samples of

manufacturing to ensure that scientific and technological developments areaccessible 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.


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3) Technology Transfers vs. Process Transfers

A) Process Transfer examples B) Technology Transferexamples

Bi-Layer tablet compression for FDC

DPI encapsulation

Gamma radiation sterilization for parenteralproducts

Includes:

Change control, Process Flow, URS, FDS,IOQ, PQ, Cleaning validation, PV, Training,

SOPs

OPINA- Two process train transfers every weekend

API manufacturing technology

NDA Product manufacturing

ANDA Product transfer

Includes:

Process transfer plus- Strategic Plan,Validation master plan, Document

matrix, Supply chain planning, Method

transfer, PDA, CPP,

SPIRIVA- One transfer 5 years


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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 5weekends

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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SPIRIVA Technology Transfer

Project Objective Create redundant US production facility for German blockbuster

Special Boundaries-Process not defined, 1 billion x18 g 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.Technology Transfer Documentation One

Process StepAll

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)


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9 Gate Technology Transfer Approach

13

Initial

Assessment 1

ProjectRecommendation

& Proposal

Customer

Review 2

ProjectGo

Develop

Project

Plan3

ProjectPlan

Approved

Process

Mapped with

CPP4

CPP with GapAssessment

Quality DocsCreated 5

QualityDocuments

Complete

Execution 7

ExpansionDocumented

Prepare

for

Validation8

Ready forValidation

MFG

Validation.

batches9

Post-ApprovalAssessment /Post Mortem

Production

Documents

Completed

6

Ready forExecution

Project

Opportunity

Eng. / TransferBatches

Validation /CommercialBatch

Milestones assessed

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5) Application Techniques for Technology Transfers


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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.



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Gate 1. Project Recommendation -Scope of Transfer Process

Specify ...

scope of transfer (process steps)

technology transfer activities and documentation

qualification & regulatory activities

release as additional manufacturer

Product Transfer Master Plan (PTMP)

Establish PTMP

The Master Documentation provides the framework for the transfer process. The Product Transfer Master Plan (PTMP) scope

document defines the boundaries of the transfer.



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Gate 1. Gate 1. Project Recommendation Know what you aretransferring.

P1 Stokes Mixer

Add MCC, API, Dextrose

and Starch, Mix for 5 min

Pony Mixer

Add P1 and P2

Mix for 10 min

Pony Mixer

Add Mag Stearate

Mix for 5 min

Poly Lined Drum

Transfer Blend through #10 screen

Manesty Press

Compress 25 mg tablets

SS Bin

Transfer Blend through

#10 screen

Killian Press

Compress 10 mg tablets

Sending Site Process Receiving Site Process

Study*

P2 Stokes Mixer



P1 Stokes Mixer



Pony Mixer / Blend Cube

Add P1 and P2

Mix for 10 min

Pony Mixer / Blend Cube

Add Mag Stearate

Mix for 5 min

P2 Stokes Mixer



These processes have the same SUPAC classification per CDER

This product transfer will be filed as a CBE 30

Study*



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Gate 1. Project Recommendation Know what you are transferringvs. Company Metrics

CTD Metric Most Favorable Less Favorable Least Favorable Critical #

Comment

P7 Number ofWorldwide

Primary

Packaging

Configurations

Maximum 3(e.g. one size clear blister of one

material, one size opaque blister,

one size HDPE bottle)

Maximum 6

2 blister (7-ct push + 10-ct peel-

push)

2 bottles 60mL + 120mL

Above 6 4

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 considerationduring 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

(Primary or

protective

secondary or

functional

having impact

on product

quality)

Standard HDPE bottle or standard

PVC and/or PVDC blister suitable.

Special moisture barrier packaging

needed (PVDC based materials

inadequate) or if hygroscopic

formulation prone to major failure

after HDPE bottle opened or failure

if bottle not reclosed in-use.

Special light protective packaging

needed (lined bottles or dark glass).

Special design or configuration of

HDPE bottles (e.g. desiccant),

Polypropylene bottle, or

Aluminum blister, bag, overwrap

required.

Special inert atmosphere and

oxygen barrier packaging

required. Novel packaging

materials required not

commonly used for

pharmaceutical products.

Materials not approved for

use in food or drug

packaging in US or EU.

2+

Multiple suppliers available.

Blister foils: Alcan + Constantia

Only single supplier available but

other suppliers can be developed.

Bottle: Gap last

Single source supply with

patent restrictions against

alternate suppliers.

5+

Product Design Attribute (PDA) TABLES



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Handbook for Transfers of Chemical Products V02

18/102 January 17, 2007

Gate 2. Project Go

In order to support the documentation of the decision to execute technical

transfer the Decision' template specifies format and content.

Template

eRoom Folder:

1 Transfer Management

Technology Transfer



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Gate 3. Project PlanThe 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.

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

Preparation of TTP 2Acquisi tion and evaluation of the exist ing documentation on the synthetic

method, including eventual batch recordsP SU yes

Preparation of TTP 2Acquisi tion and evaluation of general documentation about ritical

parameters or of a complete development reportP SU yes

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

Preparation of TTP 2Feasibility analysis in plant on the existing documentation and lay-out

hypothesis of the processP RU yes

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

Preparation of TTP 2Acquisi tion and evaluation of the safety documentation of the process ,

including MSDSP RU yes

Example

eRoom Folder:

1 Transfer Management



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Gate 3. Project Plan

Template

In order to specify the product transfer, the Product Transfer Master Plan (PTMP)

template provides predefined structure, format and content.

eRoom Folder:

2 Tech Transfer



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Gate 3. Project PlanMS 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



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Gate 4. Process Flow

oknot ok

Conduct thePre-Use Flush

for the ClosedSolventTransferSystem

Ensure ventbungholes on

both metalwaste drum and

solvent drumare open

Ensure properbondingandgroundingofequipment.

Sequential orparallel?

ok

not ok

Wheredescribed

open them

Do Ineedtocontact

supervisorfirst?

Attach Inlethose andValve

No.2 ofCSTsystem to the

vessel andrecordthe

weight.

Calculate 95%oftotal required

DehydratedAlcohol,

USP/EP/BP toaddtotheformulation

vessel

Calculatet heamount of

DehydratedAlcohol,

USP/EP/BP toaddto the

vessel via theCSTsystem(underfill?)

Calculate95%minus theUnderfill

is thiscorrect?

confusing tome..

Addthisamount to theformulation

vessel.

Continue agitation throughout solvent transfer

Remove inlethose and ValveNo.2from the

vessel andrecordweight.

Target transferweight ofthe

vessel achieved

1) Map production process with SME / Operators

2) Identify Critical Process Parameters (CPP) and Critical

Quality Attributes (CQA) as they relate to finishedproduct

3) Confirm all CPP / CQA have studies to support

acceptance ranges.

4) Conduct studies to confirm CPP / CQA ranges to fill

gaps

5) Determine best practice / gold standard process6) Create CPP / CQA database (PANDA)

7) Compare CPP / CQA data values to gold standard

and ranges to determine cause of variance.

8) Provide real time data trending to operators to enable

educated process adjustment.



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Formulation SetUpProcessSubStep

CheckRoom

for

Cleanliness

Check

Isolatorfor

Cleanliness

CheckTank

for

Cleanliness

Collect

Equipment

andcheckfor

Cleanliness

PitCheck

Scale

Load

Isolator

Attach

CST

Attach

Isolatorto

tank

Record

Tare

Wt

CQA Specification

Logbookconf

VisualConf

Logbook

conf

VisualConf

Visual,

Mork sheet

Alcohol

rinse.

VisualConf

BOM

Props/

clamp

Challenge

Calibration

Verifycal

Verify

BOM

Integrity

Setup

perSOP

Setup

perSOP

Nobreach

alarms

Printtick

0.5kg

Appearance

Clear,colorlesstopale

yellowfreefromvisable

Contamination 1 1 5 3 1 1 1 1 1

Volume Notlessthan16.7mL/Vial 1 1 1 1 1 1 1 1 1

Assay 98.0%108.0%oflabel 1 3 3 3 3 1 1 1 5

pH 4.06.0 1 1 3 3 1 1 1 1 1

Moisture NMT0.6% 1 3 5 5 1 1 1 2 1

Colorofsolution

NMT0.05AUatA420nm

usingethylalcoholblank 1 1 3 1 1 1 1 1 1

Ethanol 90%110%oflabeledamt 1 1 5 1 3 1 1 1 5

Limitof

Degredation

PaclitaxelProductsNMT

0.1%

7EpipaclitaxelNMT0.3%

TotalDegredProductsNMT

1.0% 1 1 2 4 1 1 1 1 4

ResidualSolvents USP467 1 1 1 1 1 1 1 1 1

Microbe

Testing

NMT0.67EU/mgof

Paclitaxel 3 3 5 3 1 3 1 2 1

ParticulateMatter

NMT6,000parts>10micron

NMT600parts>25micron 1 1 1 1 1 1 1 1 1

Gate 4. CPP / CQA Matrix

Based on ICH Q9 Guidelines



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Gate 5. QC Documents Completed

Specify ...






Establish PTMP

QC Documentation must be set prior to process transfer

Quality Control

Docs complete



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Gate 5. QC Documents Completed

Quality Control

Production

Test

Sending Unit

Test

Receiving Unit

Product

Sending Unit

Product

Receiving Unit1st step:

Qualification of laboratory(Parallel analysis of referencesubstance by SU and RU)

2nd step:Equivalency check of

product(Comparison of transfer batches

with reference batches)

Production Transfer

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)

.

Quality ControlTransfer



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Gate 5. QC Documents CompletedThe 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

fulfillment of the acceptance criteria.

Example

TTLQ P2

(TTRQC relevant part)

eRoom Folder: 3 Quality Control



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Gate 6. Expansion Documents Completed

Specify ...






Prepare

Technology Transfer Docs

Establish PTMP

Quality Control

Docs complete



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January 17, 2007

The technology related part of the transfer is documented in technology transfer

documentation. Technology Transfer - ProductionTechnology Transfer Quality Control

PreparePrepare

Execute

Execute

Specify scope of QC Transfer1)

TT Protocol Quality Control (TTPQC)

Check equivalence of laboratory CL Laboratory Equipment (CLLE)

Check raw material specifications at

CL Raw Material Specifications (CLRMS)

Ship reference substances to RU

CL Shipping (CLS)

Specify qualification of RU laboratory

TT Laboratory QualificationPart 1 (TTLQ-P1)

Train analytical methods at SU3)

CE Certificate Training Quality Control

Execute parallel analysis at RU

TT Laboratory QualificationPart 2 (TTLQ-P2)

Document results of QC Transfer

TT Report Quality Control (TTRQC)

Specify scope of Production Transfer4)

Define Transfer Campaign Size

TT Protocol Production (TTPP)

Check equivalence of process

CL Process Equipment (CLPE)

Specify equivalency check5)

TT Equivalency QualificationPart 1 (TTEQ-P1)

Train manufacturing process at SU

Coach manufacturing process at RU

CE Certificate Training Production (CETP)

Produce transfer campaign at RU

Execute equivalency check

TT Equivalency QualificationPart 2 (TTEQ-P2)

Document results of Production

TT Report Production (TTRP)

Gate 6. Expansion Documents Completed



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Gate 6. Expansion Equivalency Check

Target Value

NormalOperating Range

ProvenAcceptable Range

KnowledgeRange

ParameterScale



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The equivalency check has to be conducted for non critical parameters by min/max

comparison.

For critical parameters QC Charts 1) have to be used to demonstrate equivalency.Production RUProduction SU

Specification

SampleNo

+ 3 3)

Upper Tolerance Limit (UTL) 2)

Lower Tolerance Limit (LTL) 2)

Upper Specification Limit (USL)

Lower Specification Limit (LSL)

MeasuredValue

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 afalse decision is 0,3%

EXAMPLE

Gate 6. Expansion Equivalency Check



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Gate 7. Expansion Completed

Specify ...






Prepare

Technology Transfer Docs

Establish PTMP

Execute

Regulatory Activities

Quality Control

Docs complete

Execute Expansion Document ...

results of technology transfer

results of qualification and regulatory activities


Product Transfer Master Report (PTMR)



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Gate 8. Validation / Stability

1) Never fail validation / stability batches.

Highest variation



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Gate 8. Validation / Stability

1) Never fail validation / stability batches.

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

97.5

98.0

98.5

99.0

99.5

100.0

100.5

101.0

0 2 4 6 8 10 12 14 16 18 20

time [month]

assayT[%]

G76757

G76972

G77267

G77989



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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.


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6) Technology transfer skill sets

Management, Safety, QA, QC, Finance, Change Management, Engineering, Micro, Validations,

Operations, Customer, Contract Management, DRA

RACI


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Questions?

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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


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In Compliance

+

On Schedule

+

In Budget

=

SUCCESS !

ProPharma Group is the Best Choice

to balance all three needs!

Conclusion

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CTD Metric Most Favorable Less Favorable Least FavorableCritical at

Milestone #

Comment

P7 Number of

Worldwide

Primary

Packaging

Configurations

Maximum 3

(e.g. one size clear blister of one

material, one size opaque blister,

one size HDPE bottle)

Maximum 6

2 blister (7-ct push + 10-ct peel-

push)

2 bottles 60mL + 120mL

Above 6 4

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

(Primary or

protectivesecondary or

functional

having impact

on product

quality)

Standard HDPE bottle or standard

PVC and/or PVDC blister suitable.

Special moisture barrier packaging

needed (PVDC based materials

inadequate) or if hygroscopicformulation prone to major failure

after HDPE bottle opened or

failure if bottle not reclosed in-use.

Special light protective packaging

needed (lined bottles or dark

glass). Special design or

configuration of HDPE bottles

(e.g. desiccant), Polypropylene

bottle, or Aluminum blister, bag,

overwrap required.

Special inert atmosphere and

oxygen barrier packaging

required. Novel packagingmaterials required not

commonly used for

pharmaceutical products.

Materials not approved for

use in food or drug

packaging in US or EU.

2+

Multiple suppliers available.

Blisterfoils: Alcan + Constantia

Only single supplier available butother suppliers can be developed.

Bottle: Gaplast

Single source supply withpatent restrictions against

alternate suppliers.

5+

Product Design Attribute (PDA) TABLES


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5) Technology Transfer Skill Sets


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3) Process transfers vs. Technology transfers

Trouble -Typically both process transfers and technology transfer projects get intotrouble 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.

Appendix

A B CDAppendix


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Appendix

9 Technology Transfer Document Flow

Jan 17, 2008Handbook for Transfer of Chemical Products

A B CDpp

9 Technology Transfer Document Flow1)

IChC decision on

Transfer of CPIChC Decision (FID)

Specifytransfer of CP

Specify scope of

Technology Transfer QC

Product TransferMaster Plan (PTMP)

Check equivalencyof laboratory

Check adequacy of raw

material specifi cations RU/SU

Ship reference substances

to RU

Specify qualifi cation

parameters (RU laboratory)

Execute parallel analysis

at RU

Coach analytical methods atRU (optional)

Document results ofTechnology Transfer - QC

Train analytical methods

at SU

Specify scope of Technology

Transfer Production

Define Transfer CampaignSize

Check comparability of

process equipment

Specify equivalencycheck

Produce transfer campaign

at RU

Train manufacturing

process at SU

Execute equivalency check

Coach manufacturing

process at RU

Document results of Techn.

Transfer - Production

Document transfer of CP

Technology TransferProtocol QC (TTPQC)

Checklist LaboratoryEquipment (CLLE)

Checklist Raw MaterialSpecifications (CLRMS)

ChecklistShipping (CLS)

Laboratory QualificationReport Part 1 (TTLQ-P1)

Quali fy CP

Techn. Transfer ProtocolProduction (TTPP)

Execute Regulatory Activities

Checklist Process

Equipment

Equivalency Report

Part 1 (TTEQ-P1)

Training Certificates(CETP)

Training Certificates(CETQC)

Laboratory QualificationReport Part 2 (TTLQ-P2)

Technology TransferReport QC (TTRQC)

Equivalency Report

Part 2 (TTEQ-P2)

Techn. Transfer ReportProduction (TTRP)

Product TransferMaster Report (PTMR)

End

Remarks: CPChemical Product; 1) for more detail s please see Handbook

Production TransferQC Transfer

North to Phase V Product Transfers:


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GATE 4

GATE 3

GATE 2

GATE 1


Project Phases / Responsibilities



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GATE 8

GATE 7

GATE 6

GATE 5





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GATE 9



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3) Technology transfer deliverables


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Handbook for Transfers of Chemical Products V02

48/102 January 17, 2007

Scope of Transfer Process (1)

Establish Product Transfer Master Plan

Prepare Technology Transfer QC

Execute Technology Transfer QC

IChC decision (Start)

Execute Technology Transfer Production

Release as additional Manufacturer (End)

...

Qualify API (by MP)

CRC

ApplicationEstablish Product Transfer Master

Report

Remarks: 1) Start of production of transfer batches; MP Manufacturing Pharma; CRC Change Review Committee; IChC International

Chemicals Committee

Tech Transfer

Execute regulatory activities

Laboratory Qualification 1)

Equivalency of API

Time

Prepare Technology Transfer Production

MP Approval

...

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.

Manage project

conceptual


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