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TechnicalReport No. 65
TechnologyTfansfer

ParadigmChangein
ManufacturingOperations'"

PTTA
Parcnteral Drug Acsoclatlon
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Technical
Transfur
PDATechnology Team
RepoÉ

Authors
Mirko Gabrlele, EMPHA, Patheon Italia Spa, Jamie Rogers, Biogen Idec
(Team Leader) Victor Sanchez, Pharma-Bio Serv S.L.
Derek Blaettler, F. Hoffinan-LaRoche, Ltd. Melissa Seymour, Biogen Idec
Amnon Elyath, Genzyme Corporation Yi Xie, Ph.D., Eli Lilly and Company
Stephan Krause, Ph.D., Medlmmune Wayland Rushing Ph.D., Analytical Bio-Chemistry
Andrea Morelli, Kedrion Biopharma Laboratories, Inc.
Chittoor Narahari, GlaxoSmithKline Dave Wohlpart, Ph.D., Merck & Co.

The content and views expressedin this technical report are the result of a consensusachievedby the authoring task
force and are not necessarilyviews of the otgarúzattonsthey represent.
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Transfer
Technology
No.65
ReBort
Technical

ISBN:
978-0-939459-68-l
Inc.
DrugAssociation,
O 2014Parenteral
Allrightsreserved.

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in Manufacturing
Ghange
Paradigm (PGM0")
Operations
PDA launched the project activitiesrelated to the PCMO program in December 2008to help imple-
menr the scientificapplicationof the ICH Q8, Q9 and Q10 series.The PDA Board of Directors aP-
proved this program in cooperation with the RegulatoryAffairs and Qualiry Advisory Board, and the
Biotechnology Advisory Board and ScienceAdvisory Board of PDA.

Although there are a number of acceptablepathwaysto addressthis concept,the PCMO program fol-
lows and coversthe drugproduct lifecycle,empioying the strategictheme of processrobustnesswith-
in the framework of the manufacturing operations.This project focuseson PharmaceuticalQualiry
Systemsas an enabler of Qualiry Risk Management and Knowledge Management.

Using the Parenteral Drug Association's(PDA) membership expertise, the goal of the Paradigm
'best
Change in Manufacturing Operations Project is to drive the establishment of practice' docu-
ments and /or training events in order to assistpharmaceutical manufacturers of Investigational
Medicinal Products (IMPs) and commercial products in implementing the ICH guidelines on Phar-
maceuticalDevelopment (ICH Q8, Ql1), Qualiry Risk Management(ICH Q9) and Pharmaceutical
Qualiry Systems(ICH Q10).

The PCMO program facfitates communication among the e4pertsfrom industry university and regula-
tors as well as experts from the respectiveICH Expert Working Groups and Implementation Working
Group. pCMO task force members also contribute to PDA conferencesand workshops on the subject.

PCMO follows the product lifecycleconcept and has the following strategic intent:
. Enable an innovative environment for continual improvement of products and systems
. Integratescienceand technologyinto manufacturingpractice
. Enhance manufacturing processrobustness,risk based decision making and knowledge manage-
ment
. Fostercommunication among industry and regulatory authorities

TheProductLifeGycle

Knowledge

O
Management

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Tableof Gontents

1 . 0 | N T R 0 D U C T.|.0. .N. . . . . . . . ........1 4.1.4.1 Transfer fromNon-GMP

. . . . . . .1.... to GMPFacilities ......,........ 18
1 . 1P u r p o s e
4.1.4.2 NewFacility Construction ................. 18
1 . 2S c o p e . , . . . . . . .1. . . . .
4 . 1 , 5F a c i l iFt yi tR e p 0 r t s . . . . . . . . . . . . . . . . . 1. 8
2.0Gt0ssARy 0t rERMs ............ .............2 4.1.5.1Environmental Variables .................... 1I
4 . 1 . 5V. 2i r aSl e g r e g a t i o n . . . . . . . . . .1. 9....
4.1.5.3 Support Laboratory ............ 19
3.0TECHNoToGY TRANSFER PBoJEGT ...................3 4.1.6 Transfer of D0cuments............................ 20
3.1Technology Transfer Project 0bjectives .....,..... 3 4.1.7 Technology Transfer Pr0t0c01.................. 20
3.2Types ofTechnology Transfer ......................... 3 4.2Stage 2: Process Readiness .........21
3.3TTP0versight. .................4 4.2.1Process Changes ....21
3.4 Multidisciplinary Technology 4 . 2 . 2T r a i n i n g ...................22
Transfer Project Team ...............,.....4 4.2.3Development DataonProcess
3.4.1Administrative andRegulatory Functions... 6 M a n a g e m.e. .n. t. . , , . . ,,..............22
3.4. 1.I Project C0mmittee............................... 6 4.3 Stage 3:TTPlmplementation
3.4.1.2 Project Manager. ................. 6 and0ualification..... .......23
3.4.1B . 3u d g eMt a n a g e r . . . . . . . . . . . . . . . , . . 7 4.3.1Manufacturability Reviews .....23
3,4.1.4 Legal Office Representative........ .........7 4.3.2Transfer ofAnalytical TestMethods .......24
3.4.1.5 Project Facilitator .................7 4 . 3 . 3M o n i t o r i n g ..............25
3 . 4 . 10 . 6A L e a d e r ............7 4.3.3 1 .M i c r o b M i a ol n i t o r i. n. .g. . . . . . . . . . . . .2. 5. . . . . . . .
3.4.20perational Functions ...,........................... 7 4.3.3.2In-Process Monitoring .......25
3.4.2.1 Sending UnitandReceiving Unit.........7 4 . 3 . 4C l e a n iVn ag l i d a t i o n ................26
3.4.2.2 Team Leaders ,.....8 4.3.5Process Validation ..................26
3.4.2.3 R8DRepresentative ............8 4.3,5.1 Components of Process Validation ....27
3.4.2.4 Combined Roles....... ............ 8 4.3.5.2 Process Validation Studies ................ 27
3.4.3Technology Transfer Unit.......................... 8 4.3.5.3 Required Documents ............. ............ 28
3.4.40rganizational Model ................................ I 4.3.6Campaign Summary Rep0rts.................. 28
3 . 4 . 5C o m m u n i c a t i o n s . . . . . . . . . . . . . . . . . . . . . . . 9 4.3.1Continued Monitoring .............28
3 . 4 . 6D o c u m eMnat n a g e m e . .n. .t. . . . . . . . . . .1. .0. . . . . . . 4 . 3 . 8A p p l i c a toi ofcnG M P s . . . . . . . . . . . . . . .2. .8. . . . . . . . . . . .
3.4.6. 1 Common Technology Transfer 4.4Stage 4: Licensing andManufacturing.......... 29
D o c u m e n t s . . . . . . . . . . . . .. . . . . . . 1 . .0. . 4 . 4 . 1P r o c e S s sc a lU e p........... .........29
3.4.6.2 Regulatory Documents ...................... 11 4.4.2Monitoring of Production Batches .......... 29
4.5Stage 5:Project Closure ................30
4.0TECHN0T0GY TRANSFER PR0CESS............. ....12
4 . 1S t a g1e:P l a n n i.n. .g. . . . . . . . . . 2 APPLICATION
. . . . . . . . . . . . . 15.0 OFOUATITY RISKMANAGEMENT
4 . 1 . 1P r o j eR c ta t i o n a l e . ....12 T0 TECHN0t0GY TRANSFER ............................31
4 . 1. 2 P r o j eS c tc o p e . . . . . . . . . 1 2 5 . 10 v e r v i e w .......31
4.1.2.1 Technology to beTransferred............. 13 5.2 0RM in Technology Transfer.......................... 3l
4.1.2.2 Scale-up of Production Level ............. 14 5.3Stages of 0RMinTechnology Transfer..........32
4.1.2.3Control Phi10s0phy............................. 14 5 . 3 . 1O R MP l a n n i n g .........32
4.1.3Control Strategy .....15 5.3.20RMlmplementation (Execution and
4 . 1 . 3M . 1a c h i n e . . . . . . . .1. 6 ... Control Stage)..... ....32
4 . 1 . 3M . 2e t h o d s . . . . . . . .1. .6. . 5.3.3Project Closure 0RM ..............32
4 . 1 . 3M . 3a t e r i a l . . . . . . . . .1. 6... 5.4Risks ofTechnology Transfer ......................... 33
4.1.3M . 4a n p 0 w e r . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 5.50RMConcepts andApproaches Used in
4 . 1. 3 . 5M e a s u r e m. .e.n. .t. . . . . .....,....17 Technology Transfer .......33
4.1.3M N
. 6o t h e r a t u r e . . . . . . . . . . . . 1
. .7. . . . . 5 . 6O R M P l a n n i n g . . . . . . . .........35
4.1.3.1 Feasibility Reviews.. ..........11 5.6.1Selection ofa 0RMAppr0ach.................35
4.1.4Facility Design/Layout Considerations ...18 5.6.2Creation ofa 0RMp|an...........................35
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5.6.3ldentification of 0RMPers0nne|.............. 36 6.1.1General AMTStrategy ...........43

5 . 7R i s A k ssessment.....,...... . . . . . . . . . . . . . . . 3 6 6.1 .2 Design of Comparative AMT Test Studies ...43
5.7.1Types of Risk Assessment...................... 37 6.1.3 Selecting AMT Performance
5 . 7 . 1R . 1i s A
k ssessme 1.n. .t . . . . . . . . . . . . . . 3. .7. . . . . . . . . Characteristics .......44
e .n. t. . . . . . . . . . . . . . .3. .7. . . . . . . . . 6 . 1 . 4A M TD o c u m e .n.t.s. . . . . . . . . .
5 . 7. 1. 2Ri s kA s s e s s m 2 .......44
5 . 71. 3R i s A 6.2
e .n. t. . . . . . . . . . . . . . .3. .8. . . . . . . . .
k s s e s s m3 Case Study 2: Manufacturing
.......,...38 Process Transfer ...........45
5.7.2Risk Assessment Tools
6.2.10verview of Manufacturing Process
5.1.2.1 RiskRanking andPrioritization........... 38
Transfer ..................45
5.7.2.2Assessment of Regulatory Gaps........ 39 to
6.2.2Case Description: Development
5.7.2.3 Assessment ofRUReadiness ........... 39 Commercialization TTP........................... 45
5.8RiskMitigation ..............40 6.2.3Intracompany TTP ............,.....46
5.8.1Experiments to Confirm KeyProcess 6 . 2 . 4C o n c l u s i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 7
Parameter Ranges ..................40 6.3 Case Study3: Manufacturing Process Transfer:
5.8.1.1 Demonstration Runs ..........40 0RMApplication to Start-Up Evaluation........ 47
5.8.2Cycles of RiskAssessment, DataCollection, 6.3.1UseofOuality-by-Design Principles ........41
RiskMitigation, andC10sure................... 41
7.0REFERENCES.... ....57
6.0GASE STUDIES .,,.,42
Study1: Analytical
6.1 Case Transfer.....42
Method 8.0ADDITIONAI
READING .......58

FIGURES INDEX
ANDTABTES

Figure3.4-l Typical functions withina TTP.............5 Table

6.1.3-l Examples of Method Typesand
Table3.4-l TechnologyTransfer0rganizational AMT Performance Characteristics....,
44
C o m p o n e. n
. .t.s. . . . . . . . . . , . . . . .6. , . . Table
6.1.4-l Typical AMTProtocol Sections..........
44
Table Responsibilities
3.4.2.1-1 oftheSUandRU.......7 Figure 6.2.3-l Process/ProductComparabi Iity
Framework ........,.... ...........47
Figure3.4.5-1Common Flowof lnformation and
Communication Withina Technology Figure 6.3.1-10verall Process Mapping...................
48
Transfer Team andProject ..........,,...,. 10 Table 6.3.1-1 Example ofVariable Definitions..........
49
Figure4.1.3-lExample of lshikawa Diagram ........... 15 Table 6.3.1-2 Example of 0ualityAttributes
Definition ...........49
Table5.4-1 ORMApproaches at Each Stage
G a to
e fT T P . . . . . . . . . . . . . . . . . . . . . . . .Table
3 4 6.3.1-3 Severity DefinitionandRating ...........50
Table6.1-l Suggested AMTResponsibility Matrix...42Table 6.3.1-4 Occurance DefinitionandRating........
50
Table6.1.2-l General AMTDesign Parameters Table6.3.1-5 DetectionDefinitionandRating .........
50
andConsiderations ............43 Table6.3.1-6 R i s A
k nalysis........... ..........51
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Pharmaceutical technology tansfer consistsof planned and controlled actions that are basedon well-
defined acceptance criteria to convey a manufacturing process, analytical method, packaging com-
ponent, or any other step or process along the pharmaceutical drug üfecycle from an originator site,
known as a sending unit (SU), to a new site, the receiving unit (RU).

I .1Purpose
The purposeof this technicalreport is to provideguidanceandbestpracticesfor conductingtechnology
transferaaivitiesin the pharmaceuticalindustry.

1.2Scope
The report provides an overview of the knowledge and skills used during a successful technology
transfer project (TTp) along with references to consult, if necessary.The repoft indudes practical
examplesof tecJrnology transfer actiüties. Rather than discussa particular technology transfer topic,
this report aims to provide a guide to safeTTP management.

This report does not addresslogistics and bridging stocks, which are comprehensively discussedin
TechnícalReponN o, 52: Guidancefor Good Diswibution kacüc es ( GDPI Q),

The technology transfer organizational elements outlined in this technical report might not be appro-
priate for all companies. Established practices or the availabiliry of personnel will dictate how firms
conduct technology transfer activities.

ReportNo.65
Technical @2014Parenteral lnc.
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of
2.0 Glossary

(FMEA)
Analysis
ModeEffects
Failure
A tool for analyzing processesor systems to
evaluate all operating steps in order to identify
and assessthe risk associatedwith any potential
failures (2).
(BOM)
Billof Materials
Planning
A complete list of the raw material (chemicals,
media, powders, resin, etc.) and consumables/
components (filters, bags,tubing, containers,etc.)
that are required to manufacture the product.
(PFD)
FlowDiagram
Process
A document, typically prepared by R&D, that
describesthe intended manufacruring process.
The PFD includes all relevant information for
the operation of the manufacturing process,
organizedby unit operation. The PFD servesas
the source document for the initial development
of the master production records and is locked
down once development has determined that
the processcan be controlled.
Unit(RU)
Receiving
Term for the internal or external recipient or site
where the technology is being transferred to.
Unit(SU)
Sending
Term for the internal or external source or origi-
nator site of the technology to be transferred.
(WBS)
WorkBreakdown
Structure
A hierarchical and incremental decomposition of
a project into phases,deliverables,and workpack-
ages;commonly a tree strucfi.rre that shows a sub-
division of effort required to achievean objective.
MaterialSafetyDataSheet(MSDS)
Lformation provided v¡ith chemicalsand other ma-
terials intended to prordde workers and emergenry
personnelwith proceduresfor handling or working
with that substancein a safemanner. Indudes infor-
mation such asphysical data (meltingpoint, boiling
point, flash point, etc.), toxiciry health effects,first
aid, reactivitf storage, diqposal, protectirrc equip-
ment, and spill-handlingprocedures.

@2014Parenteral
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No.65
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Project
Transfer
3.0 Technology

A technology transferprocedure is more of a project than a process,asdescribedby the Project Manage-

ment Body of Knowledge (PMBOK*) Guide. The guide describesa project asa defined sum of non-repet-
itive actiüties that are designedto achievea goal, are performed in a defined time range, employ defined
resources,and are managedby a team. A process,by contrast,is the stepsa given project follows (-l).

A TTP rypically provides governancefor technology transfer by grouping similar activities together
and moving them through eachstep.In this report, the technology being transferredis related directly
or indirectly to a drug (small and large molecule) that is being developedor manufactured, and the
manufacruring process,analytical testing, andl or other aspectsof its processingand packaging are
transferredeither within the innovator organization or to a contract manufacfurer/packager/testing
faciliry.Preservationof the product's qualiry and performance is a critical aspectof the TTP.

Technology transfer can be applied to analyticalmethods and partial production steps(e.9.,interme-

diatesmanufacturing, a filling or packaging step, or a cleaningprocedure). Technology transfer Pro-
cedurescan alsobe applied to manage the transferof individual analyticalmethods or processphases
(e.g.,filling, packaging, or manufacturing of specificintermediates),

The transfer of individual processstepsmust be supportedby stability data,validation of transport of

intermediates,and a gap analysisof premisesand equipment. The result of this type of technology
transfer is generally an increasein manufacturing flexibilicy and capacity.

Project0bjectives
Transfer
3.1 Technology
The objectives of TTP rypically are to:
. Complete processperformance qualification to demonstraterepeatabiliry of manufacturing
. Demonstrate the similarity of the product produced at the end of the TTP at the RU and SU
. Obtain licensing approval to manufacture and market the product
. Demonstrate robust manufacturing over a sufficiently large number of lots, including Process,
product, operations, and testing
. Comply with in-processintermediates and final product analyticalspecifications;processspecifications
(e.g., pH and temperature); expectedyield; regulatory and qualiry requirements; and environment,
health, and saferyrequirements
A successfulTTP doesnof guaranteezero furure rejects.Rather,it provides assurancethat the process
and the product knowledge is fully understood and properly transferredfrom the SU to the RU.

Transfer
3.2 Typesof Technology
TTPs can be classifiedinto severalgroups. For example, for the transfer of a drug manufacturing
process,rypes of approachesinclude:
. Developmentto Gommercialization(lntracompany):During the drug lifecycle,the product and
the processprogressthrough different phases,such as discovery,development, validation, registra-
tion, and commercialization. Tiansition berween eachphaserequires a TTP for scale-upand activi-
ties management. The goal is to bring a processin a deveiopment phaseto a robust and reproduc-
ible commercial processable to consistentlyguaranteethe market supply.
. Gommercial to Gommercial (lntercompany): Establishedprocessescan be transferredfrom one
commercial site to another commercial site for businesscontinuiry or strategic reasons.
Development-to-commercialization,or intracompany, TTPs are usually easy to manage due to the
existing relationship berween the SU and RU. Since they are part of the same comPany,procedures,
mindset, and governance are similar.

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Commercial-to-commercialtransfer generallypresentssome advantages:

. Both sites have experience in regulatory authoriry inspections.
. Qnality systems are in place.
. Personnelare trained and experienced.
. The product (e.g.,intermediate or final) is well characterized.
. Product and processspeci"fications
are well established.
. The processis statisticallyunder control.

The main disadvantageof commercial-to-commercial transfer is that the development resideswith

the SU and is usually not part of the information shareddue to intellecrualproperry concerns.A deep
involvement of the R&D group, therefore, is required independently from the fact that the process
under transfer is a well-established,commercial process.A significant,initial milestone of a commer-
cial-to-commercial TTP should be the establishment of governance suitable for both the SU and RU.

3.3 TTPOversight
Managing TTPs, especiallytheir organization and communication, is a challenge for any company.
Teams must be created and motivated and project activitiesmust be executedand monitored while
the members still accomplishtheir routine work. In addition, interaction ben¡¡eendifferent sites(of
ten located in different countries) and external parties can be difficult.

Basedon the potential complexiry of the TTP, usually three groups are involved in successfultechnol-
ogy transfer governance:
. Technology transfer unit/department
. Multidisciplinary technology transferproject team
. Project committee

3,4 Multidisciplinary
Technology
Transfer
Project
Team
Each pharmaceutical TTP requires the involvement of a well-trained, multidisciplinary team at both
the SU and RU. The team needssuch soft skills asleadership,effectivecommunication, and pharma-
ceutical market accessprinciples. The team also needsthe following technical proficienciesto drive
the team toward a positive outcome:
. Qualiry assurance(QA) . Finance . Regulatory affairs
. Qualiry control (QC) . Maintenance . Legal issues
. Manufacturing . Environment,health, and safery . Project management
. Engineering . Researchand development

The multidisciplinary technology transfer project team should be responsiblefor filing the relevant
documentation for the transfer, including that exchangedberween the SU and the RU. The ream pre-
pares the following key documents:
. Project plan (includes project management documents, and tools, work breakdown structure,
responsibility assignmentmatrix, and Gantt chart)
. Technology transfer protocol
. Technology transfer report

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The team is responsible for the transfer and implementation of the technology in a regulated context,
such as a manufacturing facücy, according to predefined acceptancecriteria, such asprocess,interme-
diates, and finished product specifications.

Establishing nvo distinct teams and related team leaders is not uncommon. Assignment of a more
active role to the RU (e.9., management of its own team) should help lessenthe impact of any resis-
tance to the TTP.

The essential functions to be induded in TTPs are shown in Figure 3,4-l¡ although more may be
required depending on the complexity of the project.

Figure3.f-l Typical withina TTP

Functions

Depending on the size and organizational scyleof the firm, the roles outlined above and the respon-
sibilities listed in Table 3.4-l should be accounted for by, but not necessarily assignedto, individual
personnel. Sections 3.4.L andl.4.zprovide further detail regarding the administrative and regulatory
functions and the operational functions, respectively.

Technical
Report
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Transfer
Table3,4-l Technology Components
0rganizational

3.4.1Administrative
andRegulatory
Functions
.1 ProjectGommittee
3.4.1
Within the SU and RU a dedicatedproject committee should be appointed and chargedwith moni-
toring the TTP. The members of the project committee must representthe interestsof upper man-
agementduring the project.

The committee should provide advice and consultation and should act asthe perfiormancemonitoring
unit. The committee members should be well informed about the project and have authority to act in
the caseof events that could disrupt the TTP's critical path. A strong reporting procedure also needs
to be in place.

Monthly meetings can be set up as part of project governance.In these meetings, the project commit-
tee members should review prior meeting minutes,managementfiles,budgets,operating expense,and
capital expenserecords.

3.4.1.2
Project
Manager
The project manager should have technical,relational,and managerialskills to fulfill the varied responsi-
bilities of this position, describedin Table 3.4-1 above.The use of rypical tools of project managemenr
describedin the PMBOK@ to plan and monitor the project activitiesis strongly recoÍlmended (l). These
tools can identify actiüties that could prolong the project unlessthey areproperly controlled and monitored.

At an organizationallevel,the project managershould be able to mitigate any differencesin approach

bet'weenR&D scientistsand production/qualiry people evenif R&D scientistswere alreadyinvolved
in the scale-upand commercialization of the process.The various technology transfer personnelin-
volved should advise the team leaders and mediate berween manufacturing and R&D views. Report-
ing responsibilities are up to the project manager, as well. The technology transfer unit and project
committee should be routinely updated on the sranrsof the project.

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Budget
3.4.1.3 Manager
A budget manager should monitor the budget and investment expenseforecasts.

3.4.1.4legal OfficeRepresentative
A legal office representativeis required for any intercompany transfersregulated by legal contracts.

ProiectFacilitator
3.4.1.5
A project facilitator should serve as a liaison with regulatory authorities and other parties involved in
the process,(e.g.,applicableengineering societiesin foreign countries).

3.4.1.6
0A Leader
The person who is responsiblefor QA should overseeprocessdocumentation and change control,
qualiry risk management (QRM), and validation documentation.

Functions
3.4.2Operational
Unit(RU)
3.4.2.1SendingUnit(SU)andReceiving
Regarrdless of üe context, technology transfer alwaysinvolves an SU and an RU. The SU and RU are gener-
ally defined asthe originator and the receiver of the technology, respectivelyHowever, the composition of
the units is varied and can be groups wiüin a company,a specificsite, or any other organizationbasedon
companyneeds.The reqponsibilitiesof the SU and RU are outlined in Table 3,4,2,L-L.

oftheSUandRU
Table3.4.2.1-1Responsibilities

The SU and RU leadersprovide regular updatesto the project manager about the progressof the activi-
ties,spendingon the TTB potential technicalor financial concerns,and proposed correctiveactions.

The R(J's functional routine is often disrupted by events unrelated to the TTP but are nonetheless
necessaryas part of their normal functions within their company. Assignment of a more active role
to the RU (e.g.,management of its own team) should help iessenthe occurrence and effectsof any
internal or external resistanceto the TTP. "Resistanceevents"can include:
. Routine daily activities that don't include TTP activities Lack of experience with technology
transfer and project management tools Different priorit2ation of projects within the RU

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In general, the RU needs to review the technology transfer information provided by the SU to analyze
possiblegaps in training or experienceof laboratory personnel. The RU then works with SU to de-
scribepossibletraining needsor additional information/questions regarding the process.

TeamLeaders
3.4.2.2
Each team in the RU and SU should be coordinatedby a team leader who is the "ownei' of the TTP
and is responsiblefor implementing the technology at the RU or SU (e.g.,manufacturing in the case
of transfer of an industrial process).

The SU and RU technology team leadersshould regularly update the project manager on the progress
of the activities,budget use, potential technical or economic issues,and proposed corrective actions.

R8DRepresentat¡ve
3.4.2,3
R&D needs to be included whenever it is the SU or whenever preliminary tests of the technology at
laboratory/pilot scaleare foreseen.

Roles
3.4.2.4Gombined
Delegation of roles or combining different roles into a single function is a common practice for ef-
fective technology transfer. For example, the budget manager task could be assignedto the project
manager or a team might not need a project facilitator.

Transfer
3.4.3Technology Unit
Companies conducting technology transfer should evaluate the need for a dedicated technology
transfer unit. This could be a dedicateddepartment or a group composed of personnel from the ap-
propriate functional areas.Many companies evenrually establish a technology transfer unit within a
department at least.If a company choosesnot to createa technology transfer unit or department, the
company'sengineering and R&D departmentscan dedicateselectstaff members to a TTP.

Technology transfer units are responsiblefor the execution of the technology transfer projects and
define the technology transfer policies for the company; they should have process and engineering
competencies at a minimum, with the addition of R&D expertise as needed. Technology transfer
units should leveragethe expertiseof their staff in support of the SU,the RU, the team leader,and the
project manager,identifying best practicesand gaps to be resolved.

Basedon experienceand the results of the transfer,the technology transfer unit determines whether
the technology transfer was successfulor not and identifiescorrective actions as appropriate.

Model
3.4.4 0rganizational
An organizational or governancemodel that identifiesthe people or groups responsiblefor eachtask
must be developed and identiff which matters are subject to risk-baseddecisions.The risk determina-
tion of the subjects will provide the group with the necessaryawarenessof risk. A policy for enter-
prise risk management should be in place at this stage.

Regardlessof the context of the TTq technoiogy transfer always involves an SU an RU, and the key
activitiesidentified during the operationalphase.From thesepieces,a well-defined organizationalset-
up can be established.This set-upis implemented only after the project progressesto the operational
phase,which is detailed further in Section 4.3: TTP Implementation and Qualification.

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Use of a light matrix organrzatronalmodel can minimize the impact of the transfer activities on the
routine activities of the units involved in the transfer. Other approaches (e.g., hierarchical reports
within a unit and within the transfer set-up or set-up roles engagedhierarchically in the transfer activi-
ties) may be appropriate, depending on the context and importance of the project.

The following project relationshipsneed to be determined:

. Project team internal dynamics
. Dynamics ber'weenproject team and external partners
. Organizationaldynamics that could affect the operational context

3.4.5Gommunications
Ifuowledge management and transfer are key requirements of the TTP for preserving product quality
and processperformance after technology transfer. Becauseof the large amount of multidisciplinary
information collected, evaluated, and elaborated during the TTB a systematic approach to acquiring,
analyzing,storing, and disseminating information related to the technology should be considered and
customized on the basisof the team and the project. In addition, communication should be carefully
regulated and conducted in accordancewith company policies.

During a TTB communication should be carefully regulated and conducted in accordancewith com-
panypolicies. The successof a TTP is related to the communicarion skills of and relationshipsbet'ween
the technology transfer team members (describedbelow). Open communication berween team mem-
bers, effective and timely communication, and direct communication becween subject matter experts
are key aspectsto be considered and reinforced routinely by the project leader and sponsor.

Communication bet'ween the teams should be both vertical (SU with SU leader and RU with RU
leader) and horizontal (SU with RU and RU leader, and RU leader and RU with SU). Technology trans-
fer unit staff should communicate directly with the project aswell aswith the SU, RU and respective
leaders.The project committee should interact primarily with the project manager, budget manager,
and project facilitator. The project manager should act asa liaison berween those responsiblefor man-
agement functions (project committee, project facilitatoq and budget manager) and those oversee-
ing the technical functions (technology transfer team, team leaders, and technology transfer unit or
department). The project manager and budget manager should remain in close communication with
each other, other managers (e.g.,project facilitator), and those responsiblefor technical components
of the TTP (SU leader,RU leader,and technology unit or department).

To maintain proper communication channels and avoid miscommunication, direct communication

berween team members and the project or budget managers should be avoided. The unit leaders
should act as the primary liaison berween team members and management (i.e., project facilitator,
budget manager,and project manager).

Figure 3.4.5-L depictsthis flow of communication.

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3.4.6 Document
Management
The SU should provide all relevant documents to the RU.

3.4.6.1 Technology
Gommon Transfer
Documents
Documents related to the transfer of the processcould include:
. Batch records
. Planning bill of materials
. Item specificationsandjustifications
. Summary of stabiliry
. Lists of potential impurities and degradantsand rypical levels

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. Starting materials and material safery data sheets

. Assay-relateddocuments
. Drug master file for activepharmaceuticalingredients (APIs) and excipients
. Qualification of bioburden tests
. Solubilicy profi.les
. Processflow diagram that provides a rationale for the selectionof the synthesis,route, form,
technology, equipment, clinical tests, and product composition
. Vendor qualification (for transfers to contract manufacturing organízations [CMOs])
. Tiaining protocols
. Processvalidation report and master plan
. Cleaning validation protocols and reports
. Project implementation plan
. Risk assessments
performed for the processor testing

All documents generatedduring the project should be collectedand fi"ledby the RU together with the
technicaldocuments that are relevant to the project (e.g.,know-how documentation). All documents
related to the transfer should be collated in a comprehensive package and taken into account during
approval inspections. The document package should be acknowledged by the RU which generates
its own processand validation documents (4). Nldocuments associatedwith the technology transfer
should be archived at the RU. Internal RU procedures for documentation handling and filing are nec-
essaryand routinely inspected by QA at the site.

Documents
Regulatory
3.4.6.2
The project team must consider the TTP's regulatory requirements and the potential impact of any
step in the processon regulatory filings or authorizations.Some technology transfer documents can
be filed for regulatory authorlzation and may be inspectedduring regulatory agencyaudits. For these
reasons,document management has a very important role in each TTP step.

Report
Technical No.65 O 2014Parenteral Inc.
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4.0 Technology Process

Transfer

A structured approach to the TTP is used to organízecommon activities into distinct stagesand make
the project's clear and logical progressionevident to the team. Such an approachalsoprovidesdefined
points for review by senior leadership (stagegateway reviews). Stagesare logical groupings of associ-
ated activities and tasks, and stagegates are predefined review points for the governanceteam. The
stagescan reflect common project management approachesbut are tailored for technology transfer.

The stagesare demonstrated on the chevron below and discussedin more detail in the following
chapters.

4,1 Stage1: Planning

lmÉlemé,ntátion
* ütralificatis¡1,

During this preliminary stage, the SU and RU collaborate to develop a TTP plan that will govern the
entire project. Critical inputs to the TTP include a regulatory strategy and a gap analysis(a compari-
son of the process,equipment, and faciliry berween SU and RU; a risk assessmentof the changes;and
planned risk mitigation actions).

During the planning stage,requirements and constraints,goals and objectives,and key performance
indicators(includingthe successcriteria) mustbe determined and agreedupon. The technology trans-
fer team should design a plan that takesinto account cost (including materials and people), schedule
(including supply of the product being transferred),scope,technology,and qualiry.

Oulputs of this stageinclude a finaüzedproject plan detailing activities,resources,and schedule,and a

risk assessmentfor the project. A gateway review by senior leadership is used to make visible the plans
and risks and provides approval to move to the next stage.

Rationale
4.1.1Project
Technology transfer is generally aimed at introducing innovation (e.g., a new commercial product
or new productions in existing plants) for the company,which, in rurn, engagesin TTPs for business
opporrunities.

The project rationale and project relationships(analytical/management/social) must be developed

before the project starts.The rationale definesthe project plan and the relationshipsdefine the "social
intelligence." Both are fundamental to the successof a TTP.

4.1.2Project
Scope
Applications of technology transfer must be GMP based and rely on well-documented knowledge.
Specificacceptancecriteria (objectives),batch sizes,and intended production capaciry must be de-
fined in advance.The scopeof the TTP must be clearly statedand agreedupon by the TTP team.

The knowledge (technology) to be transferredfrom rhe SU to the RU should include:

. Product critical qualiry attributes (CQAs) . Specifications(e.g.,for drug substance;drug
. Impurity profile product; starting materials;raw materials;and
auxiliary materials,such as filtration devices)

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. Critical and noncritical processparametersand ' Stabiliry data

ranges and proven acceptableranges . product qualiry and performance history
. Evaluationresultsfor processand assayrobusuress review and statistical analysis(if available)
. Manufacruring procedures . Saferyprecautions,material data saferysheets,
. proceduresfor process-relatedactivities and specialmaterial handling procedures
' Team member skills
. Equipment management and maintenance
procedures(if applicable) . Technicaland instrumental resourcesand

. Technical description of the process and procedures

flows for raw and aufiary materials,waste, ' Timelines

personnel,startingmaterials,intermediates, . Finance/costs
drug substance,and drug product
. Processflow charts with material balancing
. Validation documents, including process
validation, cleaning validation, and equipment
validation (if applicable)

As theseactivitiesoccur, it is alsonecessaryto transferprocessknowledge, equipment, and material to

the recipient faciliry in a timely and accurate manner. This will ensure that product qualiry regulatory
and businessneedsare met.

4.1.2.1 to beTransferred
Technology
To aid in the assessmentand development of a transfer strategy, a detailed description of the technol-
ogy to be transferred (including the synthetic route, starting materials, intermediates, reagents, and
catalysts)needs to be prepared by the SIJ.

Depending on the stage of development, the information to be collected on the technology being
transferredmay differ. The requirementsfor transferring a Phase3 processfrom one CMO to another
will differ significandy,for example,from the assessmentperformed when moving from an R&D en-
vironment into a manufaccuring scale(scale-up)environment.

The description may include the following:

. Flow chart of the processwith a description of each step
. The amounts of materials/reagentsand stoichiometry required
. Order of addition of reagents
. Specificconditions required (e.g.,temperature, humidity, times, and pressures)
. Yields of each reaction step
. Compound attributes (e.g., pH in solution, bulk physical properties, particle size and size
distribution, moisture content and hygroscopic nature, partitioning coefficient, solubiliry profile,
and degradationprofiles)
. Historical process information
. Designation of registered starting material
- Depending on the stage of transfer, the registered starting material might be important. Steps
prior ro this material do not need to be performed under CGMPs, although the conceptsdiscussed
in this document could still be applied.

ReportNo. 65
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. Designation of CQAs
. Allowable variations in schemeand permitted rangesbasedon historical information or qualiry-by-
design information

A review of existing technical and management standardsshould be performed to assesstheir suit-

abiliry and determine whether new standardsare required.

of Production
4.1.2.2Scale-up level
When a process is transferred from a development faciliry to a manufacturing faciliry the level of
production is probably scaledup along with the processtransfer. In such cases,either equipment
modification or installation of new equipment is probably required to accommodate the increased
manufacturing scale.

Therefore, the scale-upphilosophy chosenwill influence the equipment used in production. Once a
scale-upphilosophy has been identified for eachunit operation, it should be documented in the tech-
nology transferplan or in the individual technology transfer study protocol/report.

Along with a formal development of scale-upand controi philosophies,the technology transfer team
should define requirements for:
. Data gaüering: the appropriate requirements are specifiedfor the data historian
. Criticaliry of instruments: may be basedon the criticaliry of the correspondingprocessparameter
. Tolerancesfor instruments: may be basedon control requirements (e.g.,pH)
. Alarming requirements:may be basedon the criticaliry classificationof the processparameters

After a formal assessmentof equipment, instruments, and control needs, the technology transfer
team can incorporate the scale-upor designphilosophy requirements into a set of user-requirement
specifications(URSs).In practice, the URSs are general documents containing environment, health
and safety,GMB and other requirements. The URS will form the basis for the design/fabrication/
procurement of the equipment. Simultaneousiy,functional and design specificationsmay be defined
for any equipment used in the process.

For example, a production bioreactor or fermentor might be scaledup. While the vesselvolume is
scaledup, some factors, such as the volumetric oxygen masstransfer coefficient (kl-a) or power input
per unit volume of bioreactor, might be able to remain constant. If the kl-a is to be kept constant
acrossscales,then the fermentor's gassupply capabilirymay need to be upgraded. If power input is to
remain constant,the fermentor's agitation systemmay need to be upgraded. In either case,a different
type of reactor modification may be required basedon the scale-upphilosophy chosen(5).

4.1.2.3Gontrol
Philosophy
Like a scale-upphilosophy, a control philosophy needsbe identified for each of the major piecesof
equipment that will be used in the process.

In a fermentor, for example,the dissolvedoxygen(DO) control used may be processspecifi.cand may

need to be calibratedand optimizedfor the specificoperation. Control of DO may be affectedby cas-
cade control whereby a changein the agitator speedis the first changein responseto a DO change.
This agitator control loop is a "slave" to the "master" DO control loop. An alternative to cascade
control is a simple increasein air or oxygen spargerate. A similar discussionmay also be given for
the trans-membranepressurecontrol of tangentialflow filtration unit operations employed in many
bioprocesses.

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lnc, Technical
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4.1.3 Gontrol
Strategy
As defined by ICH Q10, control strategy is:
Aplnnned setof controk, dnivedfrom a,trrentproductandprocessunderstandingthatensures process
prformance and product qu.dhty,The controlscan includeparametersand attributes relnted to drug
substanceand drugproduct mntqials and components, facility and equipmentopnaüng condiüons,
ín-processcontrols,finishedproductspecifcations,
andthe assocíatedmethods andfrequ*tcy of moní-
toríng and convol (a).

Control srategy provides critical governance throughout the product lifecycle. The control strategy
continues evolving as the product moves through development, technical transfer, commercial pro-
duction, and discontinuation. Although the strategy varies at the different stages,the core purpose
of the control strategy remains the same: to ensure process performance and product quality. The
principles of QRM can be applied to identify the control strategy.

From a control strategy management perspective,the application of risk analysisand human/techni-

calleconomic resourcesmanagement tools should alsobe taken into consideration.

A general analysis of production feasibiliry, using risk management principles, should be conducted
prior to beginning ransfer activities. The feasibiüty reviews are used to create and update the process
risk assessment(described in the following sections) and identifr potential manufacruring challenges.
Th.y also provide recommendations for processmodifications needed to addressmanufacturing con-
straints and/or desiredutilization strategies(e.g.,yield or processtime targets).

Fishbone (Ishikawa) analysisis commonly used in risk assessmentto identify th. risks by laying out
causesand effects(Figure 4.1.3-L),

Cause Effect

Figure4.1.3-l Example (Fishbone)

of lshikawa Diagram

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The principles of fishbone analysiscan be appliedto identi$' the control strategy.The effectwould be
adverseeffectson product qualiry which are defined by CQAs. The causescan be laid out according
to six main components (the six M's in an Ishikawa,or fishbone,diagram) (7,8):
1. Machine (equipment) 4. Manpower

2. Methods (documentation) 5. Measurement

3. Material 6. Mother nature (environment)

The six Ms are describedin detail below.

4.1.3.1Machine
The technicaltransferteam needsto identi$r the key setsof equipment used to control the CPPs.The
operating ranges of the key equipment at the RU need to be checked, and their capabiliry to achieve
the critical processparameter (CPP) range needsto be evaluated Any gapsrevealedduring the evalu-
ation are documented aspart of the risk assessment.

Equipment operational qualification should be performed as a prerequisite of processvaüdation at

the RU. Preventive maintenance programs should be establishedat the RU and the SU's project man-
agementprogram can be referencedfor consistency.

If the technology is transferred from a developmentsite to a commercial site, the scalabiliryof the equip-
ment needsto be evaluated.The CPPsdevelopedat laboratory or pilot scalemay be scaledependent.

The CPP rangesat the receiving commercial scaieshould be corrected to account for the scale-upfac-
tors. For example,if the agitation rpm of a crystallizeris chosenas a CPP basedon the development-
scalemodels, the appropriate range of rpm at the commercial scaleneeds to be established.This
should be basedon a comparison of factors,such asmixing and shearstressbetween the crystallizers,
at the pilot scaleand at the commercial scale.

4.1.3.2
Methods
The technical documents from the SU need to be examined; practices and instructions described
should be consistentwith each other and with the regulatory registration.

Inconsistenciesor gaps among these documents and difficulties in their execution should be high-
lighted in the initial risk assessmentsummary report and should be corrected or assessed in terms
of risks prior to commercial production at the RU. Inconsistenciescould lead to confusion in opera-
tion, failure to ensure product qualiry, or noncompliance with the registration after the technology is
transferred to the RU.

If the SU is a development site, a development history report (DHR) (where the product conrrol sffat-
egy identified during the product development stageis documented) should be availablefor review as
a part of the technology transfer.The RU should createthe processflow diagram (PFD), SOPs,etc.
according to the DHR.

The SU should review the key technical documents to ensure that the information in the DHR is
captured appropriately.

4.1.3.3
Material
The SU needsto provide the raw material specifications.If an API processwith multiple intermediate
products is transferred,all intermediate product specificationsneed to be provided by the SU.

16 O 2014Parenteral
DrugAssociation,
Inc. Technical
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The SU needs to ensure that the specificationslisted in the iocal documents are consistentwith the
registeredspecifications.The RU is responsiblefor quali$ring the raw material suppliers (unlessthe
agreement befween the f'¡ro units states otherwise).

If the processis transferred from a development site to a commercial site, the suppliers' sustainable
capaciryneeds to be examined during the supplier qualification. The storage conditions of the raw
materials (including the intermediate products) should be specified,and associatedhold times (or ex-
piry datesor reevaluationperiods) should be availableto the RU. The constraintsof ransporting raw
materialsacrossdifferent regions or countries should be considered.Delaysin obtaining thesemateri-
alsasa result of customs clearanceproceduresmay occur, and the storageconditions might therefore
changetemporarily. The impact of delaysand temporary storagecondition changeson intermediate
product qualiry should be assessed.

4.1.3.4
Manpower
The RU should clearly define the roles and responsibilicyof each technology transfer team member
and ensure adequate operation and supporting staffing for commercial production at its faciliry. A
training or personnel qualification should be establishedat the RU. Proof of training completion for
eachperson is neededprior to processvalidation.

4.f.3.5Measurement
Analytical methods should be validated prior to the processvalidation at the RU, regardlessof wheth-
er rhe methods havebeen validated at the SU.The anaiyticalmethods to be validated include those for
both routine samples,such asintermediate products and buffers, and for nonroutine samples,such as
samplesfor process-relatedimpurities. The sampling plan, inciuding samplelocation, size,frequency,
method, and handling, shouldbe clearly defined.The instruments used to measurein-processParam-
erersshould be qualified. The measurementuncertainty for CPPsneedsto be calculatedat the RU.

This information is used to set the operation targetsto ensurethat the true CPP values are within the
predefinedlimits when instrument measurementuncertainty is considered.

MotherNature
4.1.3.6
Whether the RU is prone to natural disastersand how well it is designed to minimize their impact
should be evaluated. This may have been done when the RU's faciliry was built. If the RU and SU
have a dramatic climate difference,temperature and moisture controi would need additional consid-
eration, particularly for raw material storageand transportation.

Reviews
4.1.3.1Feasibility
Regardlessof the knowledge and different types of TTP (e.g.,inter- or intracompany transfer of a manu-
facturing processfrom a multi-purpose department to a dedicateddepartment), the feasibility analyses
and the six Ms describedabovein this sectionhaveto be accountedfor by both SU and RU teams.

The preliminary feasibiliry srudy should consist of at least a gap analysisthat compares the SU's man-
ufacruring plant/department to the RU's manufacturing plant/department. It should identiff Poten-
tial differencesthat could make the process/product fail the set specificationsand identi$ corrective
acrions.The results of this analysisshould be recorded in a controlled document and be approvedby
the SU and RU aswell as the project manager.This document should officially state the suitabilicyof
the RI"lto reproduce the processto be transferred.

Report
Technical No.65 O 2014Parenteral Inc.
DrugAssociation, 17
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Gonsiderations
Design/Layout
4.1.4Facility
It is very common to design and develop the manufacturing technology in a non-GMP faciliry, which
allows for flexibiüty and is more cost effectivethan performing theseactivitiesunder GMP conditions.
As a result, the processmay be transferredfrom a non-GMP to a GMP faciliry.

4.1.4.1
Transfer to GMPFacilities
fromNon-GMP
Per regulatory guidelines, all GMP facilities must maintain certain standardsfor faciliry layout, design,
and controls (e.g.,temperature, air pressure,and humidity) itt addition to the basic elementsof facil-
iry design (e.g.,animal and pest control and environmental monitoring) (9).

The processdevelopment work may havebeen performed using non-GMP utilities (e.g.,plant steam
instead of processsteam or plant air instead of clean air). When such a processis transferred from
the development faciliry to a GMP faciliry the technology transfer team should examine the use of
appropriate utilities at appropriate stagesin the process.The RU might have general policies guiding
the use of GMP and non-GMP utilities for various activities (e.9., use of plant steam for steaming
non-product contact small parts as part of cleaning).Any dedicated/specialequipment used for the
processmay be outside the scopeof the faciliry guidelines,so the technology transfer team may need
to determine the appropriate rype of utilities to be used for those piecesof equipment.

4.1.4.2
NewtacilityGonstruction
If the transfer activity involves the construction of a new faciliry, the RU should generate a user require-
ment-like document that describesüe faciliry characteristicsneededto meet the process/product qpeci-
fications,which in turn drive the engineeringdevelopmentof the facility The transfer of the processcan
sometimesbe conductedusing the transferreddocumentsto define the requirements.It is well understood
that this approachcould lead to mistakesdue to incomplete evaluation of all variables;therefore, a com-
mon solution is to define the requirementsstartingfrom the transferredinformation, proceedwith a deep
gap analysis,and then determine whether the documentsare sufficient to support those requirements.

4.1.5Facility
FitReports
Faciliry fit reports (FFRs)are a key deliverablein steps2 and 3 to aid in the transfer of the late-phase
developmentand commercial processesto the commercial faciliry.These reports translatethe process
description detailsinto an operational map of how the processis to be executedat the site.

Processranges,buffer volumes, column volumes, tank assignments,and step durations are examplesof
the type of information included in thesereports. Thesereports are rypically authored by the RU process
subjectmatter experts(e.g.,commercial technical support personnel) and reüewed and approvedby SU
processsubjectmaffer experts(e.g.,manufacturing, facili¡is5,supply chain, and qualiry personnel).

Thesereportsgovern the transferof processdetailsinto manufacruringbatcirrecordsand solution prepara-

tion recordsand serveasa guide for the flow of the processthrough the facility FFRsmayinclude surrüna-
ries of processrisks,raw material saferyrisks,and action items resulting from fit-to-plant exercises.

Other information rypically found in the FFR includes:

. Detailed processdescriptionsby unit operations and associatedprocessflow diagrams that reflect
the commercial scaleof operations and fit considerations
. Processsampleplan with in-processcontrol limits, where appropriate
. Comprehensivelist of raw materials and components used in the process

18 @2014Parenteral
DrugAssociation,
Inc. Technical
ReportNo.65
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. Gap/risk analyses related to process fit, including new capital equipment or modifications of capital
equipment required, equipment/faciliry capability gaps, clean-in-place/steam-in-place flow path
utilization, new materials or manufacruring supplies needed, andlor automation gaps

Environmental
4.1.5.1 Variables
Environmental variables are normally controlled within set tolerances at given facilities. However,
an assessmentshould cover the potential that, even though both facilities operate within given toler-
ances,facility differencesmay have an impact on the product or the analytical teststo be performed.
The assessmentshould be based on the availableprocessinformation or analytical tests perfiormed
and their susceptibiliryto environmental factors.

The following are examples of some environmental conditions that, even if properly controlled with-
in set tolerances,may have an impact on product production or testing:
. Humidity and Temperatuto! Humidiry and temperature are controlled in most facilities,but they
should be assessed to determine whether potential differencescould affect product production or
testing. This testing may involve evaluating trends over a year in addition to the allowed range.
. Light: The source and rype of lighting should be evaluated.Particular attention should be given
to possiblesourcesof natural light due to their impact on photosensitivecompounds when these
sourcesare compared to the lighting of the RU.
. Pfessufei Pressuredoesnot usually need to be controiled,but it may haveundesirableconsequences
for final dosageforms that are liquids, ointments, or creamsthat are filled in flexible containers.A
light-densirypolyethylene bottle filled at a plant at 3,000m altitude could be aestheticallyaffected,
for example,when marketed at sealevel and vice versa.

4.1.5.2ViralSegregation
Transfer of processesfor biotechnology-derivedproducts expressedin animal cells (e.g.,monoclonal
antibodies from Chinese hamster ovary ICHOI cells) requires consideration of the impact of viral
segregation on faciliry design llayout. CHO cells are known to endogenously expressretrovirus-like
particles.Although dedicatedstepsfor virus clearance(i.e.,inactivation and removal) arebuilt into the
purification scheme,these stepsmay not occur until midway through the purification process.In such
cases,an efficrt should be made to segregate"virus-treated" processstreamsfrom non-virus-treated
processstreams,especiallyif open processingis used. The technology transfer team should consider
initiating specificclearancestepsprior to exposingthe treated and nontreated Processstreamsif phys-
ical segregationor completely closedprocessingis not feasible.

laboratory
4.1.5.3Support
Finally, using an on-site support laboratory (which can be non-GMP) to help with troubleshooting
and routine support for the production faciliry can also be considered. Performing scale-independent
technology transfer studies in an on-site development laboratory will help share knowledge berween
production and support personnel.

An example of such support work is evaluation or generation of worst-casesoil for use in faciliry
cleaningvalidation srudies.If the philosophy used for cleaningvalidation is to use worst-caseProcess
soilsto demonstrate the efficacy of clean-in-placecycles,this material can be generatedfrom the on-
site support laboratory. Generation of this material in the support laboratory early during technology
transfer (insteadof generating this material at scalein the production facility) allows sufficient time
for experimentation / development of cleaning cycles.

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of Documents
4.1.6Transfer
Technology transfer presents challenges relating to the documentation provided by the SU and its
implementation by the RU, especiallyin the transfer from R&D to manufacturing due to the nature
of the project step.

Specificallyin thesecasesbut applicableto all technology transferprojects,the documents transferred

by the R&D unit should include at least the following:
. Product CQAs . Validation documents (at least aseptic process
. Impuriry profile and pathogen clearancevalidation reports)
'
. specifications (at least for drug subsranceT Analytical method SoPs
product and packaging components) . Process development documents (e.9., k y
. critical and noncritical processparametersalong technical reports and Process development
history reports)
with rangesand prorr.r, ranges
"...p,"LI. ' Previous regulatory filing
. Manufacturing instructions
. proceduresfor process-relatedactivities ' Manufacturing processflow and instructions

. Raw and auxiliary materials ' Analytical methods and procedures

' Development rePort
. cleaning procedures
. Available stabiliry data

The following information might also need to be provided to the new product producer:
. Clearanceof processimpurities . Reprocessingor rework data
. Virus clearance . Stability of raw materials, APIs, or cell lines
. Hold times of the process steps . Polymer materials that have direct contact with
. Mix times of the solutions and the product the product (compatibiliry/leakage)

. chromatography, filter, and membrane lifetimes ' Annual product review for ffending
. Container closure sfudy descriptions

4.1.7Technology
Transfer
Protocol
A road map must be designed from the very beginning of the project to ensure comprehensive proj-
ect management. The SU and RU should jointly develop a TTP plan that will govern the entire proj-
ect. Critical inputs to the technology transfer plan include a regulatory strategy and a gap analysis
(describedin Section 5.7). Outputs of this stageinclude afinalvedproject plan describingthe activi-
ties,resources,schedule,and project risk assessment.

The TTP plan should drive the overall processand define the strategic approachby describing:
. The manufacturing processbeing transferred
- Sampling and testing steps
. Roles and responsibilities of the SU and the RU
. RIJ's equipment and facilities
- If the transfer is from one manufacruring faciliry to another, a description of both sites that
includes gaps and/or differences
. Documentation requirements

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. Project schedule,including roles and responsibilitiesof personnel (a Gantt chart is helpful here)
. Technology transfer tools, including templates
. Backup plans for critical tasks to avoid delaying or stopping the project due to unforeseen events
. Status monitoring
. Correlations to previous and subsequent tasks

The technology transfer protocol must establishthe context for the TTB including internal and exter-
nal contexrual factors and which risk-management tools to use. The external context might include
competitive, financial, regulatory, legal, environmental, and cultural aspects.The internal context
can involve company policies and procedures,systems,operational objectives,personnel training and
knowledge, available resources, and culture.

All personnel with management roles in the transfer, inciuding the rwo team leaders, should agree to
and sign the project plan. The exception is the project committee, which functions primarily as a con-
sultant. A gateway review by senior leadership is used to make visible the plans and risks and provides
approval to move to the next stage.

4.2 Stage2: Process

Readiness
Licensing,S,
Manufácturin$

The goal of this stageis to achievereadinessof the process,equipment, automation, facility, oPera-
tions, and assaysto successfullyexecute processperformance qualification (PPQ) lots. Shakedown
activitiesculminate in the production of engineering lots that provide confirmation that all systems
are suffi,cientlyready to perform PPQ lots. Training at the RU is a key goal of this stage.A gateway
review is used to highlight the rationale for proceeding to the next stage and should include a discus-
sion of the potential risks to the successfulexecution of PPQ lots.

At the end of the assessmentand planning phasesand before the start of the TTP implementation,
the technology transfer team sets up a stage/gateway step, The purpose of this step is to confirm
that the processis ready,that all critical aspectsof the project havebeen deeply analyzed,and that the
potential associatedrisks have been identified and properly mitigated.

The formahzatíonof the assessmentand appropriate training of personnei impacted by the transfer
are critical. Thus, the proper procedureshave to be in placein the RU and in the SU.

Changes
4.2.1Process
The RU should manage the transfer via its change control procedure, and a general risk management
analysisshould be performed to evaluatethe impact of the processon the affecteddepartments.

The RU should then translate the R8(D information and procedures(e.g.,specificactivitiesand batch
records)and adapt the processflow to fit the designateddepartment through creation of specificpro-
cedures.Analysis of raw and auxiliary materials should be performed to identify and qualiff suitable
suppliersand materials.A risk management approach should also be applied to classiS and evaluate
the impact of processchangesaimed at optimizing the processitself.

In the course of scale-up,processparametersand equipment may be subjectedto change.Procedures

should be in place at the RU to efficiently manage any changeswhile maintaining traceability.The

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procedures must take into account any documents submitted to regulatory authorities and the pos-
sibility of the need for amendments.Affected processesand equipment include:
. Filtration areas
. Media
. OPeratingPressuresand flow rates
. Processhold times
. Cleaning solutions/procedures and rinse volumes
. Devices(e.g.,changing from housing to a fi.lter-pressfor depth filtration)
. Disposableversusstainlesssteelcontainers

Processdevelopment reports should detaii the rationale to support any changes.The application of
good documentation practices and design of experiment (DoE) techniques during processdevelop-
ment are fundamental to support these changesand the application of GMPs during clinical manufac-
turing. Insertion of new stepsinto, or modification of, the processflow should be carefully evaluated
from qualiry and regulatory points of view. In the event of a substantialprocess modification, the
transfer should be put on hold and feasibilirystudiesshould be perfiormedagain.

4.2.2Training
Basedon an evaluation of the RU's experience,the SU should provide hands-on training for specific
stepsin the processasneeded. This training may be performed either at the SU or the RU facility. The
type and amount of training varies depending on the complexiry of the steps and the e4perienceof
the RU personnel in performing the specificsteps.

Training should be divided into rwo steps:

1. The RU technology transfer team members managing the TTP (e.g., RU leader, manufacruring
department head, plant maintenancehead, and engineers)and other key personnel (e.g.,head of
shift for manufacruring or maintenance departments)should be trained in the processat the SU
(i.e., on-the-job training, training the trainer).
2. Trained personnel should draft the process-relatedprocedures for the RU and for training the op-
erating personnel.

4.2.3Development
Dataon Process
Management
Development data are the data capruredduring the R&D phaseof creating a new product. This may
consist of data from qualiry by design, the CQAs, the specifications,and the assuranceof product
and processconsistency.The development data are the backbone of the process;the data relay how
the processperforms; whether it can perform consistently; and whether it ensuresthe puriry, qualiry,
safery,and effi.cacyof the drug product or drug substance.

Development data are derived from analyticalmethods,testing of the product during rhe R&D phase,
and scale-upof the process.Processmanagementduring the development phaseis critical in light of
compressedtime-to-market expectations.As a result, development strategies and milestone dates for
chemistry, manufacturing, and control activities need to support requirements for product develop-
ment and should be describedin developmentplans. During processdevelopment,ir is important to
understand the production environment, the equipment, the parameters that need to be developed,
and the operations to be used.

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The developmentphasedata are critical becausethey veriff that the saferyand efficacy of the product
align with the specification and ensure consistencyfrom development to manufacturing. The data
from the development phase are part of the TTP from R&D through production as the ranges are
refined throughout the process.

Critical processparameters should be defined during development. These parameters establishcri-

teria that are consistent with process stabiliry. The key is to characteúze the range that will result
in producing a product that meets certain CQAs or proven acceptabieranges while keeping other
parametersconstant, as defined in ICH Q8(R2). Many organizationsalso establishnormal operating
ranges that are tighter and can identiff the need for investigation (2),

To assessrisks and establishcritical processparameters, a top-down approach, such as a fault tree

analysis,can be used to identifr critical subprocesseswithin the overall process.The subprocesses
identified can then be assessed through a failure mode and effectsanalysis(FMEA)-basedapproachto
identifi root causesand critical manufacruring steps.

and0ualification
4.3 Stage3: TTPlmplementation
:LiCensing,&
Ma,n,ufactuiin$:

During TTP implementation, equipment is installedand qualified,preliminary laboratory or manufaccur-

ing trials are conducted,and the PPQ lots are manufacruredto satisfythe requirements for demonstrating
reliable manufacturirg.A gateway review is used to critically evaluatethe performance of the PPQ lots,
induding stabiüty data when applicableand any risks posedto the successfullicensure of the f".ility.

As discussedpreviously,the designof the plant and processis crucial to the successof the technology
transfer and should be monitored closely by the appropriate transfer team members. Moreover, the
transferredknow-how should be the basisfor scale-upevaluationsor establishedprocesstransfer and
to organízethe new plant and processto meet product specificationsand processrequirements.R&D
scientistsshould be involved in such activities.

Reviews
4.3.1Manufacturability
Upon completion of each cycle of processdevelopment,detailed faciliry and processfit assessments
and manufacturing information reviews are conducted prior to creation of manufacturing batch re-
cords. These represent a key deliverable for this step in the TTP.

Manufacrurabiliry reviews are an end-to-endproduct review of the proposed late-phasedevelopment

and commercial processesto be manufacrured at the commercial site. These reviews are facilitated
by the RU and conductedj"i"ü by the SU and RU processsubject mafter experts (SMEs;e.9., com-
mercial technical support and processdevelopmentpersonnel)in collaboration with unit SMEs (e.g.,
facilities and engineering personnel).

Key outcomes of the manufacturabiliry review at the early stagesof the TTP are facility and equip-
ment gaps and recommendations for processchanges.Preliminary reviews may be needed for more
complex processesto identifi' equipment and facility modifications requiring long lead times.

Another key output of manufacrurabiüty reviews is the plan of record. This document describes
srage-appropriate assumptions approved by both the RU and SU. It also lists the process targets
planned by the SU and the facility modifications and scheduleplanned by the RU. For example, this

No.65
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document lists the commercial titer to be targeted for the production bioreactor, the number and size
of chromatography columns, and the cycle time for the bioreactor.

TestMethods
of Analytical
4.3.2Transfer
Analytical test methods are well defined and are usedfor QC of raw materials,intermediates,APIs, or
final drug products. The analytical control methods should be transferredbefore the manufacturing
processto ensureproper testing of the products.

The SU should prepare the following information for evaluation to conduct a risk assessmentof the
analytical test methods:
. Detailed description of the test method procedure
. Method validation report
. Prior method transfer data
. Historical method performance information
. Detailed description of instrumentation used
. Examplesof generateddata (e.g.,spectraand chromatographic plots)

The RU should review this information and evaluate it for possible gaps (e.g., lack of experience in
method type or differencesin instrumentation to be used).Any gapsidentified should be assessed for
risk of failure by both the SU and the RU.

After the initial assessments

of the methods, a pre-approvedprotocol will be preparedto describethe
experiments to be performed. There are a number of ways in which the transfer may be performed.

Examplesof the typesof approachesdescribedin USP<1224> areshown below,but other transferdesigns

may be acceptable.The approachusedshould be justified and evaluatedduring the risk assessment
(lO).

' GomparativeTesting: The RU and SU both analyze apredetermined set of samplesand perform a
comparative analysisof the results generated.
. Govalidation Between Two or More Laboratories: The SU includes rhe RU in the validarion ream
for the validation exerciseto obtain data on reproducibiliry.
' Revalidation:The RU can perfiorm a revalidationor partial validation of the method.
' Transfer Waiver: During the assessment, the given method doesnot require official transfer.
The USP chapter contains examplesof this situation, such as compendial methods, which do not
need to be transferred becween the SU and RU. However, the RU would need to perform method
verification testing as defined in USP <1225> (11),
Other snrdy designsfor method transfersare provided in PDATechnicalReportNo. 57:AnnlyticalMethod
ValiÁnüonand.Transfufor BiotecltnologtProducts.Ultimately the approach chosen should be based on üe
resultsof the risk assessmentfor the methods and this choice shouldbe justified in writing (Iz).

As part of the assessmentof the transfer,the actual teststo be performed for the transfer need to be
evaluated.The testsperformed may depend on the experienceof the laboratory anygaps determined
during the assessment,and the nature of the method to be transferred.

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4.3.3Monitoring
4.3.3.1
Microbial
Monitoring
Depending on the transfer phase and the rype of product being transferred, an assessmentwill need
to be performed of the applicabiliry of microbial control and monitoring. The rype and extent of
microbial control and monitoring (e.g., steriliry endotoxins,bioburden, or container/closure integ-
riry testing) will depend on the manufacturing process assessmentand the probabiliry of microbial
contamination along with the final product's abiliry to support microbial growth.

If microbial monitoring methods are required, these methods should be transferred from the SU to
the RU by on-site validation of the methods. Assessmentsshould be performed of the RU faciliry's
abiliry to support microbial testing or appropriately outsource the work to a third party. For imple-
mentation of compendial microbial monitoring methods, the USP contains descriptionsof the neces-
sary stepsto perform the required verifications/validations.

4.3.3,2
In-Process
Monitoring
The assessmentof the manufacturing processshould include the need for in-processanalytical testing.
Most stepsare iikely to be well defined and controlled, whereasother stepsmay require monitoring to en-
sure completion of reaction or maintenanceof specificprocesstolerances(e.g.,moisture content, extent
of reaction, and pH). In-processmethods may be continuous monitoringof a key arribute (e.g.,pH), or
may be performed at single time intervals (e.g.,moisture content or extent of reaction). The need and
type of in-processmethod shouldbe basedon the resultsof the overall assessmentof the process.

For the selectedin-processanalytical methods, the level of information to be provided and the re-
quirements for transfer will vary. The assessmentshould determine the difficulry of the method as
applied and the criticaliry of the method. Methods determined to be more complex and critical may
require additional information and evaluation during the transfer process.The information should in-
clude a sufficiently detailed description for performance of the method. Additional information may
be required for more complex methods (e.9.,chromatographic analysis).

hr-processanalytical methods do not require the rigorous level of transfer that is required for QC analytical
methods,but the principles usedfor QC methods may be applied to the in-processmethods. It may be useful
to rank eachof the methods to determine the extent of transfer required using the following criteria:
. Analytical Complexity: Including requirements for a specific academic or scientific background,
extensiveinstrument expertise or an extensiveset of method particularities impacting the results
of the analysis(pH is classifiedas a simple method, whereasan HPLC assayis classifiedas complex)
. Product Specific or Product Independent:For example,pH monitoring is a product-independent
method whose result is not affected by the chemical, whereas the extent of reaction assaysis
product specific
. RU Exper¡cnce: The RU's history of using the analyticalmethods required

The necessiryto monitor the manufacruring process can be also faced with a process analytical tech-
nology approachthat is basedon accuraterisk analysisand processknowledge.

According to the current guidance, process analytical technology is "a system for designing, analyz-
ing, and controlling manufacturing through timely measurements (i.e., during processing) of critical
quality and performance attributes of raw and in-process materials and processeswith the goal of
ensuringfinal product quality" (13), Processanalyticaltechnology,when proven, can provide a com-
parable and valid alternative to traditional in-processanalyses.

Technical No.65
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Validation
4.3.4 Gleaning
An important part of the TTP implementation is the cleaning of the equipment train and facility used for
the manufacturing process.The objective of cleaningvalidation is to confirm the reliability of the clean-
ing procedure so that routine analytical monitoring may be reduced. During the manufacturing process,
pharmaceuticalproducts and APIs can be contaminatedby other pharmaceuticalproducts or APIs if the
fr.ility processesmultiple products. Virus segregationshould also be considered in relevant casesfor API
manufacture (e.g.,mammalian cells).Adequate cleaningproceduresare essentialto minimize the risk of
contamination and cross-contamination,operator exposure,and environmental effects.Once the deaning
hasbeen validated,a risk assessmentmay be performed to determine whether the level of routine moni-
toringhas been reduced.This risk assessment must include the risk of cross-contamination.

Analytical methods should be challenged in combination with the sampling methods to demonstrate
both the levelsof recovery from the equipment sudace and the reproducibility of the results.Analytical
testing of swab or rinse samplesshould be validated before the cleaning validation srudy is carried out.

The unit transferring a process should provide information on cleaning procedures that have mini-
mjzed cross-contamination,including:
. Solubility information on active ingredients, excipients, and vehicles
. Minimum therapeutic dosesof activeingredients
. Therapeutic category and toxicological assessment
. Existing validated cleaning procedures
. Cleaning validation reports (chemical and microbiological)
. Cleaning agentsused (efficacyand evidencethat they do not interfere with analyticaltesting for
residual active ingredients)
. Recovery studies to validate the sampling methodology

Limits should be established for product residues,including a rationale that takes into account rel-
evant characteristicsof the starting material (e.g.,potency,toxiciry solubiliry,corrosiveness,and tem-
perature sensitiviry),manufacturing equipment design and configuration, cleaning agent used and
its residue,and rinsing processes.A risk assessmentmay be performed of these limits as well, and its
results should be shared with the RU.

The quality unit at the RU should have validated cleaning and maintenance procedures for buildings,
equipment,services,and support systemsthat affectthe product, process,or method being transferred.

Basedon information on product residue limits identified by the SU the RU should determine irs own
practical, achievable,and verifiable cleaningvalidation limits basedon the materials involved, their prop-
erties,and their therapeuric dose.A risk assessmentcanbe performed to help establishtheselimits.

4.3.5Process
Validation
Processvalidation is the collection and evaiuationof data from the processdesignstagethrough com-
mercial production. These data provide scientificevidencethat a processis capableof consistentlyde-
livering high-qualiry product. Processvalidation is part of the technology transfer ro a new building,
a new company, a new partner, etc. Successfulprocessvalidation dependson the development of a
reproducible and reliable processduring processdevelopment.Processvalidation is a major objective
of a TTP (+,1+).Successfulprocessvalidation allows for regulatory approval submission and subse-
quent commercial manufacruring.

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Processvalidation should be performed under a pre-approvedprotocol detailing acceptancecriteria,

and the results should be summarízed in a final report.

Strategic planning for process validation begins during step 2, and the team is formally launched
after this processis successfully completed. Successfullycompleting deliverables for step 2 allows the
initiation of actual processvalidation campaign runs, and the results of these runs are summarized
for submissionreadiness.The deliverablesin step 4 include elementsneededfor processperformance
qualification and continued processverification. A full explanationof detailsregardingprocessvalida-
tion can be found in PDA TechnicalReportNo. ó0 - Process Validation:A LifecycleApproach(4).

4.3.5.1 Validation
of Process
Gomponents
It is crucial that TTPs take into account all aspectsof the processvalidation lifecycle.Key items that
need to be identified during processvalidation are:
. Processparameters
. Critical processparameters
. In-processcontrols
. Critical in-process controls
. Processranges/boundaries

Further prerequisitesfor a successfulprocessvalidation include:

. Risk assessments
at stagesI,2, and 3
. Processparameter reports summarizing the rationale for parameter categorization and ranges
. Qualification and validation of manufacturing equipment and automation, including associated
utilitiesi facilities
. Effective manufacturing procedures
. Qualification and validation of analyticalmethods and instruments

For legacy products, reviews of historical data can be used aiong with control charts, processcapabiliry,
and the six-sigmamethodologies. For more complex operations, a design of experiments may be used.

4.3.5.2 Validation
Process Studies
Full-scalemanufacruring consistencystudiesshould be performed for each step in the processor each
unit operation. The srudies should demonstrate that processparameters can be maintained within
pre-establishedset-points and limits and that outputs from each process step are consistent with ex-
pectations.These studies should be perfiormedprospectively,and the number of lots to be validated
should be documented.

Validation of the equipment should be carried out by the RU with the cooperation of the SU with
specialattention to the review of qualification protocols. Installation qualification (lQ) requirements
should be determined by a mechanical completion analysisfor confirmation and verification of all
of the required equipment parts. This is especiallyimportant for newly built departments/plants.
Verification of the correct assemblageof the system (commissioning) should be followed by IQ, op-
erational qualification (OQ), and performance qualification (PQ).

Report
Technical No.65 lnc.
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Documents
Required
4.3.5.3
The minimum required information and/or documents required for processvalidation are:
. Definition of the critical product attributes based on known or expected clinical effects of the
measuredproduct attributes (determined in risk assessment1).
. Classification of controlled parameters (process "inputs") as minor, major, or critical. Process
development and process characterization srudiesbased on risk assessmentZ and 3 provide the
rationale for the categonzation of parameters. These also set parameter ranges for the process
validation studies.
- Critical control points: stepsat which control can be applied and that can reduce or eliminate a
risk to an acceptablelevel
- In-processcontrol: checks during production that monitor the process and allow adjustment
within normal operating parametersthat result in maximum yield or businessefficiency
- Critical in-processcontrol: checksduring production that monitor the processand allow adjust-
ments within specifiedlimits, This could include environmental controls aswell.
. A processflow diagram that describesthe detailsof processstepsfor each unit operation.
. Processparameter reports that summanze rhe rationale for the categonzanonand rangesfor the process
parameters,induding critical processparameters,in-processcontrols, and critical in-processconffols.
. Review of potential process hazards regarding chemical, biological, physical, and environmental
impacts. The environment, health, and saferygroups should work with the manufacruring group
to remove or minimize the risks identified.

Both parties shouldjointly write the processvalidation report and the processvalidation master plan.
The processvalidation report should be approvedby the quality unit, summaríze specifictestsper-
formed and their results along with pre-definedacceptancecriteria, and addressdeviations encoun-
tered during the srudy. A processvalidation master plan report should summarize the results and
draw conclusionsas to whether the overall processis validated (+,1+),

4.3.6Gampaign Reports
Summary
The campaign summary reports capfure lessonslearned from manufacturing batchesand are useful
baselinereports for referenceduring subsequentanalysisfor regulatory filing or processhistory.

4.3.7Gontinued
Monitoring
Once the strategy is developed,regular meetingsshould be scheduledto managethe project timeline,
identiff all activities and responsibleparties, and maintain processvisibiliry. Agendas and meeting
minutes should be maintained for all meetings.These meetings ensurethat documents are reviewed
and approved within agreed timelines and provide routine updates to involved parties, including QA,
manufacturing, and development units.

4.3.8Application
of cGMPs
The easewith which a TTP progressesdependson the stageof development and the level of applica-
tion of cGMPs. Processtransfer aiming at the production of batcheswith increasingcGMP expecra-
tions must meet the requirement of improving some stepsof the processitself.

In the European union, cGMPs dedicatea specificannexto investigationalmedicinal products manu-

facruring (l-1,).

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In this instance,change control proceduresshould take into account this potential need for increased
GMP expectations.Products manufacrured at later stagesof development (Phases2 or 3 of clinical
studies)should have a nearly complete level of cGMP application.

As such, the transfer from clinical manufacruring stageto full commercial scaleshould be managed as
a transfer berween commercial sites. The organization of TTP activities and macro-activities are still
valid for this processand will need to be considered.

4.4 Stage4: Licensing

andManufacturing

The license document is completed and submitted to regulatory agencies,and routine commercial
manufacfuring is initiated. An after-action review is an important activiry during this stage as a means
to drive continuous improvement of the technology transferbusinessprocess.The risk ranking in the
previous stagecan be revisedbased on the resultsof the risk mitigation actions implemented. A final
gateway review occurs to decommission the technology transfer team.

4.4.1Process
ScaleUp
Technology transfer berween development and commercial production generally involves a scale-up
acdviry and requires attention to the processand product requirements.For this reason,the prelimi-
nary assessmentand gap analysisstep needsto take into considerationthis critical differencebetween
the SLI and the RU. Involvement of the R&D department is usualiy greater than in the transfer of an
establishedcommercial process.Strong regulatory and qualiry compliance assessmentsare done im-
mediately after the TTP generation, to evaluatethe potentiai impact on the regulatory submission.

Change management is considered even more critical due to the nature of the project for the unavoid-
able changesthat the process required during scale-up.Appropriate procedures for tracking these
changesshould be in place, and the report issuedat the end of the project has to summarize reasons
for changes,and the scientificrationale for decisionstaken during the project. After a scale-upProcess
is finalized and validated, the monitoring step assumesa key role to properly evaluatethe reproduc-
ibiliry and the consistencyof the changesadoptedduring the project. Annual or biannual verification
steps are suggested to measure trends in results and highlight any activities that need to be imple-
mented.

4.4.2Monitoring Batches
of Production
Follow-up involves the strict monitoring of the production batches by the SU and the RU for an es-
tablishedperiod of time or number of batches.This occurs during the licensure and manufacturing
stagein the businessprocess.

After the follow-up period, the technology transfer personnel should prepare the technology transfer
report that describeswhether the RU is able to reproduce the technology according to the expected
qualiry specifications.Approval of the report should state omcially the acceptanceof full responsibil-
iry for the transferred technology by the RU. A pre-determined number of batches produced at the
RU should also undergo a stabiliry srudy.

Statisticalcomparison bet'weenhistorical data at the SU and start-up/follow-up data at the RU is rec-

ommended to highllght any differing data trends or distributions.

Technical No.65
Report DrugAssociation,
@2014Parenteral Inc. 29
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4.5 Stage5: ProjectGlosure

After licensure, the technology transfer closure is formalize in a dedicated document (i.e., a technol-
ogy transfer report). Main tasks, milestones and changes to the original plan along the project are
summarized. Lessons learnt are described and deeply analyzed to provide strong background for
further improvements. Moreover a verification plan needsto be set up in this phase of the project for
the continuous monitoring of the technology transferred.

This stage begins when the goals and objectives of the TTP are fulfilled. Benefits, whether tangible
or intangible, must be identified and communicated during this stage, allowing the organization to
improve furure projects by preventing problems and creating contingency plans. This closing stage
involves a confirmation of the appropriatenessand risk tolerance of the organízation'srisk manage-
ment policies.

In fact, based on the assessmentdone in the planning phase of the project, potential risks are identi
fied and a mitigation plan is set up and implemented afterwards.As a part of the project closurestep,
effectivenessof actionsis verified. The same approachused in risk definition (such as QRM tools; see
Section 5.0) can be used to recalculate the risk prioriry number (RPN) at the end of the mitigation
action.

The technology transfer is considered officially completed and closed if the corrective actions are
successful.

A summary report should be generatedcontaining information related to the non-GMP (such as de-
velopment and laboratory trials) and GMP manufacturing activities, including:
. Processoverview
. In-processand drug substancereleaseand characterizationdata
. Equipment list
. Critical/major deviations
. Lessonslearned
. Technology transfer metrics
. Results of all of the deliverablesin the technology strategy document
. Verification schedulefor the process

The operations groups should sign both the technology transfer protocol and report. Signing of the
report by the RU establishesthe acceptanceof responsibility for execution of the transferred technol-
ogy and the conclusion of the follow-up period. Implementation of agreed-upon corrective actions
should be considered part of the follow-up period and overseenby both the SU and RU.

@2014ParenteralDrug
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5.1 0verview
During the TTB internal (mainly related to the RU) and external (mainly related to the SU and exter-
nal suppliers)variablesplace it at risk. The TTP team must identifr and mitigate the impact of these
variables.ICH Q8, Q9, Q10, and Qt I provide examplesof tools and principles to achievethis objec-
tive. The approach used to design spacein pharmaceutical development, in which the relationship
between the processinputs (material attributes and processparameters) and the CQAs are assessed
and described,can be applied during TTP management (z,a,la,n).

As applied to technology transfer, QRM should cover the risks involved in the processbeing trans-
ferred from the SU to the RU as they relate to the maintenance of product quality (meeting the de-
fined specificationsor qualiry attributes) or the performance qualiry of an analyticalmethod (depend-
ing on the stageof quaüfication or validation).

This technical report only addressesaspectsof QRM that are specific to technology transfer activities.
PDA haspublished severalreports on QRM to which readersshould refer for further discussion,analysis,
and practical applicationsof QRM. The main tenetsare detailedin PDA TechnicalReport No. 54 -lnrple-
mentnttonof Qua\ty RiskManagmtmtfor Phnrmnceuücaland BiotecltnologManufacntring Operaü0rc(7).

Transfer
5.2 ORMin Technology
QRM principles are broadly acceptedin industry and are enablersof the pharmaceutical qualiry sys-
tem. The primary purpose of QRM in biopharmaceuticalmanufacturing is to identifr and evaluate
modes of product or processfailures for the purpose of ensuring product qualiry and patient safery.
The benefitsof QRM in TTPs include leveraginginformation from the designand qualification stages
to provide information back to processvaiidation activitiesaspart of continuous processverification.

Applied to technology transfer, QRM may be used to evaluaterisks associatedwith each step of the
project aswell as the impact of the new product/process and reiated raw materials on existingprod-
ucts andlor faciliry and processcontrols.

The purpose of QRM applied to a TTP is to review the proposed transfer of the manufaccuringpro-
cessto ensurethat potential risks to the patient regarding the qualiry safery and efficacy of the drug
product havebeen identified and are adequatelycontrolled.

Specifically,this QRM should ensure that:

. The sourcesof variability that have the potential to impact CQAs have been identified
. The appropriate risk mitigation strategiesand controls have been integrated into the processto
minimize and control potential change-relatedhazards that could result in the production of
batchesthat do not meet predeterminedspecifications/CQAs
. All critical unit operations and associatedqualiry and critical parametersthat must be controlled to
ensure final drug product qualiry are identified

The expectationsof such a multidisciplinary QRM review of the proposed commercial/development

processare:
. Ensuring that sourcesof variabiücythat could impact final drug product CQAs havebeen identified
. Ensuring üat appropriate risk mitigation strategies and controls have been integrated into the
processto minimize andcontrol potential qualiry hazards to the patient
. Identifring critical unit operations and associated critical parameters that have a high risk of
affecting CQAs

Technical No.65
Report O 2014Parenteral Inc.
DrugAssociation, 31
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QRM should addressat least:

. Processingoperations and parameters(including batch record instructions)
. Impact of new equipment, facilities,and supporting utilities (e.g.,clean air, WFI, cleanrooms)
. Potential for contamination from internal sources
. Potential for contamination from external sources
. Thainingof management,engineeringstaff operators,and QA/QC personnelon the transferredprocess

QRM must be focusedon key areassuch as:

. Identiffing critical unit operations and CPPsthat could be impacted by the transfer
. Identifring potential for contamination from internal and external sources
. Ensuring that batch record instructions are adequate to document operations and control human
variables

5.3 Stagesof ORMin Technology

Transfer
The stagesof QRM in technology transfer are asfollows.

5.3.1ORMPlanning
The technology transfer team must establish the context for the TTP. This will include the identi-
fication of internal and external factors as well as which QRM tools to use. External context may
involve competitive, financial, regulatory,legal, environmental, and cultural aspects.Internal context
may involve company policies and procedures,systems,operational objectives,personnel training
and knowledge, available resources, and culrure. A governance model, including responsibility and
accountabiliry assignments,must be developedin this step and include the matters that are subject to
risk-baseddecisions.The risk determination of the subjectswill provide the group with the necessary
awarenessof risk. A policy for enterprise risk management should be in place at this stage.Require-
ments and constraints,goals and objectives,and key performanceindicators (including the successcri-
teria) must be determined and agreedupon. The technology transfer team should be skilled in basic
project management to design a plan that takesinto account cost (including material and personnel
resources);scheduled(including supply of the product being transferred; scope; technology associ-
ated with the project; and the quality, safery,and efficacyof the product.

(Execution
5.3.2ORMlmplementation andGontrol
Stage)
It is not expectedthat many risk managementactivitieswill be performed during the execution stage.
A rigorous planning stage reducesthe need for decision-makingduring the execution process.Pro-
cesseswhere contingency plans (e.g.,use of alternatesuppliersor contract manufacturers)havebeen
developed from the beginning may help to manage new unforeseen risks. The same risk assessment
tools and control mechanismsmust be used to manage those new risks. It is important to monitor
risks and factors affecting risks to ensurethat the initial context determination is still valid.

5.3.3ProjectGlosure
0RM
This stagebegins when the goalsand objectivesare fulfilled. Benefits,whether tangible or intangible,
must be identified and communicated by the project leaderto the project committee during this stage
to allow the organwationto improve future projects and avoid recurrence of problems or create con-
tingency plans. This closing stageis a confirmation of the appropriatenessand risk tolerance of the
or garization's risk management p olicies.

32 O 2014Parenteral
DrugAssociation,
Inc. Technical
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QRM perficrmed correctly during the development phase may mitigate inherent hazards and reduce
the criticaliry of this step. This is true provided that the risk assessmentsare thorough and define the
impact and uncertaincy of each step of the developmentphase,process,and specifications.

5.4 Risksof Technology

Transfer
Often, poor attention to its objectives (e.g., process specificationsthat are too tight or too broad)
destinesa TTP to failure. Technology tansfer can affect drugs and patients. Consequently, in all tech-
nology transfer activities that a project team designs and executes, the team needs to keep in mind
the scope of the technology being managed and the potential impact of technology transfer failure.

Some cofiunon risks that are often overlooked and can negatively affect the TTP are:
. Objective that is not clear (or clearly defined)
. Objective that is not properly communicated andlor shared
. Objective that cannot be operationally translated
. No assessmentof the effectsof changesto the objective
. Lack of change conrol

Among the risks to be considered prior to embarking on a TTB regardlessof its scope, are the cost
of the project and potential return on investment to determine an acceptablecost/benefit ratio based
on internal RU and SU targets or criteria.

andApproaches
5.5 ORMGoncepts Transfer
Usedin Technology
QRM tools used in accordance with ICH Q9 can facilitate the deliverables for each step in the TTP
outlined in this section. The ICH Q9 briefing book also provides general templates to use for QRM.
Table 5,4-L oudines the application of QRM conceptsand approachesat each step.

Technical
ReportNo. 65 O 2014Parenteral Inc.
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5.6 ORMPlanning
As a company begins to apply a QRM approach, the first step will consist of providing training to
personnelinvolvedin GMP operations to familiarize them with ICH Q9 and the principles laid out in
the document. As a result of the above approach,technology transfer team members, trained in the
QRM approach, will act according QRM principles and tools throughout the life of the TTP.

It is highly recommended, asa secondstep,to setpolicies and proceduresdetermining the use of various
qualitative and quantitative tools and their application. To selectwhere first to apply QRM, companies
may consider implementation of QRM for a particular product or family of products. If this method is
chosen,specialattention must be paid to avoid the creation of different layers of compliance.

Finally, companies must include their decision for using QRM in the technology transfer strategy
document at the project start.

of a ORMApproach
5.6.1Selection
The selection of a risk management approach should be applied along the TTP. This approach will
facilitate decision-m"kittg at different points throughout the TTP while ensuring that all activities are
performed in a manner that protects patient safery.

To realve the utmost benefit from QRM, companiesmust adapt their culture, systems,and proce-
dures. They must shift from a risk-averseto a risk-aware culrure by creating procedures and tools that
enable individuals to apply benefits from QRM to the TTP.

It may be helpful to refer, for project management purposes,to the elements of the risk management
processasdefinedin PDA TechnicalReport 54,ISO 31000(projectconsiderations),and ICH Q9 (process/
product considerations) (2,16,1E-20),

of a ORMplan
5.6.2Greation
Firms should develop a plan to implement and maxtmize the use of QRM throughout all operational
systemsand company areas.This plan should be documented in the site master file and/or the master
validation plan.

A roadmap must be designedfrom the very beginning of the project to ensure comprehensiveProj-
ect management, including the risk assessmentstepsbelow. The roadmap for QRM implementation
should be establishedas a holistic approachrather than a project-specificapproach.It may be helpful
for the technology transfer team to refer,from a project management persPective,to the elementsof
the QRM processas defined in the literature (2,rc,n-zo).

Successfulapplication of QRM in technology transfer requiresestablishmentof a QRM plan early in the

TTP and formalization of the plan (where applicable)in the technology transferprotocol. The QRM plan
should describethe TQM tools to be used,the rationale for their selection,the risk ranking/filtering crite-
ria to be used, and any underlying assumptions.This document servesthe followingpurPoses:
. Aligns cross-functional participants regarding the basis of the transfer team's decision-making
. Informs senior management on project analysis,risks identified, and mitigation plan,
. Ensures consistency over time as ongoing development or vaiidation information suPPorting the
and influence future decisions andl or activities
transfer is used to update risk assessments
. Identifiesparticipants and their responsibütiesin risk assessment
. Defines the responsibilitiesof the applicablemanagementteams or functional leadersthat aPProve

ReportNo.65
Technical @ 2014Parenteral Inc.
DrugAssociation, 35
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risk reduction activities and authorize acceptance of unmitigated related risks. The technology
transferteam must also define the criteria for selectionof managementteams with oversightof the
transfer as well as key stakeholdersaccountablefor the overall successof the project. These teams
and individuals provide appropriate sponsorship of the project and secure resources for QRM
activities (in addition to other transfer related activities), and they must be informed of or approve
critical risk acceptancedecisionsacrossthe entire project. These teams and stakeholdersshould be
identified in a master transfer plan.

The QRM plan should define criteria for identifiiing critical risk factors andhazards so that senior
managementis informed of critical issuesand their statusand remains informed.

Risk assessmentteams, as part of the technology transfer teams, should refer to the master technol-
ogy transfer plan to ensure that the proper stakeholdersare used for the risk assessment.The QRM
plan should also define criteria for identi$ring critical risk factors andhazardsso that senior manage-
ment is informed of critical issuesand their status.

It is recommended to define project triggers and milestones for the TTP based on general QRM
concepts. It is also advisable to evaluate the transfer environment using the volatiliry uncertainry
complexiry, and ambiguiry (VUCA) model. The VUCA elements present the context in which orga-
nizations view their current and furure state. The VUCA tool can be used in strategic leadership en-
vironment to present boundaries for planning and policy management. QRM tools will be preferen-
tially used from a project perspective.The roadmap defined at the project level must include triggers
for all stages:planning, processreadiness,qualification, and licensureand manufacturing.

of ORMPersonnel
5.6.3 ldentification
Stemming from the previous concepts,it is reasonableto include the determination of the risks and
risk tolerancefor the project in the goal of the TTP team that is composed of the transferring and re-
ceiving operations, qualiry and enabling functional groups (e.g.,finance, engineering, and logistics).
Risk tolerance is defined by cwo considerations:the project and the process/product.

At a minimum, the team should include representativesfrom the process development, manufactur-
ing, analytical development, QA, and QC units. Specialemphasismust be placed on including infor-
mation that could indicate an impact on product safery identiry stabiliry puriry, and qualiry. By using a
cross-functionalteam, issuesimpacting stabiliry,specifications,and the use of analyticalmethods can
more easilybe identified and addressed.Failure to take these issuesinto account can lead to transfer
delaysor even failure as there may be unknown factors related to the change that could impact stabil-
icy or drive a processcloser to specificationlimits compared to its performance at the originating site.

Therefore the technology transfer team, acting asthe risk assessmentteam during each step of the TTP,
should refer to the master transferplan to ensurethe proper stakeholdersare used for the risk assessment.

A variety of stakeholders outside the project team include local, regional, and international regula-
tory authorities. Patient safery,through managing the risk to quality, should be of prime importance
(z). Risk is evaluatedby the diverserisk assessmentsby the stakeholdersinvolved becauseeachstake-
holder may perceive different potential risks, assigneach a different probability of occurrence, and
attribute different severitiesto each.

5.1 RiskAssessment
Basedon the overall project knowledge and the initial tasksagreed on and completed, the same sys-
tematic processfor the assessment,control, communication, and review of risks describedin ICH

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can
Q9 to identify and rank project variablesand inputs with a potential impact on the project goals
be used by the technology transfer team. Moreover, due to the quantitative oulPut of the risk assess-
ment, in which the risk is not only describedbut also ranked, a well-defined decisional critical path
can be properly identified. The financial and time requirements for each task can be assessedon the
basisof a scientificallysound approach, allowing for project management that is in compliance with
regulatory authority expectations.

The deliverer of the TTP should provide criteria and information regarding hazards and critical steps
associatedwith the product, process,or method to be transferred,which will serve as a basis for a
QRM exercise.

Risk assessmenr is completed by comparing each processstep againstthe CQAs to determine which
onesrequire further charactenzatsonorassessmentof historical data (if available).The application of
a risk processconsideringprocessdevelopment allows for scientific understanding to identi$r poten-
tial parametersthat may affect the processCQAs. This can reduce the number of processstepsto be
further characterized andprovide a baselinefor establishingindependent parameters during scale-up
or transfer.

Identification and scoring of risk factors and their associatedhazardsbasedon predetermined severity
and occurrencecriteria should result in a comprehensivelist of activitiesto be completed to facilitate
the successfulcompletion of the transfer. The product of these rwo criteria provides a risk-based
means of prioritizinghazards and risk-reduction activities. These activities could include additional
characterizatiorlor validation studies,faciliry modifications, or acquisition of new equipment or ex-
perrise.Input from the technical subteamsand other SMEs should establisha detailed understanding
of the effcrt and time required to complete the identified items.

5.1.l Typesof RiskAssessment

The RU and SU can decide on the particular parametersfor choosing the type of risk assessment.In-
deed,the teams could decide to use all of them to assessrisks.The following are three possibletypes
of risk assessments:

I
5J .1.1RiskAssessment
A risk assessmentcan be performed to include the identification, documentation, and risk assessment
of the product attributes and of the CQAs and their target ranges.Individual qualiry affributes are as-
sessedto determine their impact on product saferyand efficacyaswell asperformance characteristics
that affect safety and efficacy (e.g., stabiüty,pharmacokinetics and clearancealong with immunoge-
nicity). This assessmenrhelps determine the ranges,the basisfor these ranges,and the potential im-
pacr. This assessmentalso provides referencesto the data for each product attribute (if available).This
risk assessmenris alivingdocument that needsto be revised throughout the lifecycle of the product to
take into consideration and properly evaluate all of the changesthat are happetitg.

2
RiskAssessment
5.1.1.2
A second fype of risk assessmentuses a system of risk ranking and filtering in which the individual
processparameters and noncompendial raw materials are evaluated for their potential impact on
product quality and process consistency.Resultsfrom these risk assessmentscan be a guide to the
level of processcharacterizationneededto understandthe impact of eachprocessparameter on qual-
iry attributes and process consistency.The intent of this assessmentis to provide a risk rating from a
product quality andlor processperformance perspective.

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5J.1.3RiskAssessment
3
A third rype of risk assessmentis an inductive risk analysisdesigned to identift potential modes of
processfailure associatedwith operationsparametersthat may affectproduct qualiry and/or process
consistency.This assessmentshould include risk identification and prioritization and a mitigation
plan. It may also reduce the amount of additional data neededto complete the TTP.

Tools
5.7.2RiskAssessment
Some risk management tools mentioned in ICH Q9 arc (16):
. Basicrisk management facilitation methods (flowcharts,check sheets,etc.)
. FMEA
. FMECA
. Fault tree analysis
. Hazard analysisand critical control points (HACCP)
. F{AZ)P
. PHA
. Risk ranking and filtering
. Supporting statisticaltools

QRM tools are useful in prioritizing transfer team activities in rwo ways: 1) they provide the means to
quantitativelyrank (prioritize) and filter risk factors and risk-reduction activitiesacrossthe entire proj-
ect, and 2) they provide a means for documenting risk-ranking criteria and rationales for prioritization
Application of QRM tools can assistin identi8ring, quantiSring, and prioritizngrisks associatedwith
the TTP. However, the ourput from using these tools is only asgood as the information entered, so it
is crucial to ensurethat the risk assessmentis performed by a broad cross-functionalgroup.

PDA TechnicalReport.No. 44: Quality RisleManagementfor AsepücProcesses and TechnicalReport54: Im-

plementaüonof Quality Risk Management for Pharmaceuticaland BiotechnologManufacturing Operations
provide guidanceon how to apply risk assessmenttools to pharmaceuticalprocesses(7,21).The ISPE
BaselineEngineering Guide Volumes 1 (Active PharmaceuticalIngredients)and 7 (Risk-BasedManu-
facrure of PharmaceuticalProducts) are other potential resources(zz,zs).

5.1.2.1
RiskRanking
andPrioritization
Following completion of the site selectionprocess,the product to be transferred and the recipient facil-
ity may be evaluatedusing a risk ranking and fi"ltering(RRF) tool. The RRF tool is used to determine
potential risk factors and hazards acrossall aspectsof the transfer, such as adequacy of the recipient
faciliry quality system, introduction of new raw materials, or processchangesimpacting product stabil-
iry. This method provides a highly selectivelist of risk factors and associatedcorrective or preventive
measuresthat reflect the priorities, constraints,and availableresourcesof the transfer team.

RRF rypically includes application of risk-basedscoring criteria. Using resource, financial, or time-
basedscoring criteria will enablethe transfer team to prioritize risk factors using multiple filters. This
method provides a highly selectivelist of risk factors and associatedcorrective or preventive measures
that reflect the priorities, constraints,and availableresourcesof the transfer team.

Scoring transfer-related risks in aggregate can be helpful given the broad range of hazards evaluated
acrossmultiple disciplines and the difficulty of evaluating multiple risk assessments(conducted for

38 @2014Parenteral
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each individual problem or event) separately.In addition, performing this risk ranking exerciseusing a
high-level, cross-functional transfer team (asopposed to technical subteams)ensuresthat prioritization
decisionsare made at appropriate levelsin the orgarization and with representation from multiple im-
pacted stakeholder groups. The risk ranking can be revised based on the results of the risk mitigation
actions implemented. An illustration of this processis outlined in Table 6.3.I-62 Risk Analysis.

For example,the ransfer team may identif,i severalunacceptablehazardsand many lesscriticalhaz-

ards but lacks the resourcesto sufficiently addressall risk factors within a given time frame. By ap-
plying both risk-basedand resource-basedfrlters, the team can quickly narrow down the list of risk-
reduction activities and focus on only those high-prioriry risks that the team has available resources
to address.

Performance of this ranking exerciseby the transfer team is critical to ensure that resource-basedpri-
oritization decisions are made with full consideration of transfer team priorities, resource availabiliry,
and budgetary constraints. Generally, the transfer team is better suited to make these decisions than
technical teams with less cross-functional representation and a potentially narrow view of general
or garizatíon al concerns.

The complexity of the RRF activity should reflect the complexity of the processbeing transferred.For
example,TTPs rypically require participation from multiple units or require long-term dedication of
specificresources.Filtering criteria may be set up to reflect resourceavailabiliry so that high-prioriry
cross-functionalprojects are preferentially selectedbasedon the availabiliry of limited personnel or
other resources.

Assessment
5.1.2.2 of Begulatory
Gaps
An analysisshould be performed to identi$r gaps berween applicable SU environmental, health, and
saferyregulations and those that govern the RU. It may be useful to create a list of all of the chemical/
material inputs, oulputs, by-products, and wastesused and/or generatedby the processto aid in the
analysis.Risk assessmentsshould be performed on differencesto determine their potential impacts
on the TTP. The üfferences in regulations berween regional governments could potentially impact
how materials are handled, stored, and disposed.Areas that could have an overall impact on how the
materials are handled or processeddue to varying regulatory requirements and to QA, technical, and
environmental, health, and saferyconsiderationsare:
. Occupational exposure ümits
. Compound hazard categories
. Fire/explosion regulations
. Personalprotective equipment requirements
. Regionalbands or limitations on compound classes
. Waste disposal requirements
. Environmental assessmentrequirements

of RUReadiness
5.1.2.3Assessment
The SU and RU need to evaluatethe RU's readinessto perform the chemistry as part of the risk as-
sessment.This may involve evaluation of the RU's experience in performing the ryPes of processes
describedby the SU. It may be useful to rank each of the reaction stepsfrom easyto complex.

ReportNo. 65
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5.8 RiskMitigation
To accomplisha successfultechnology transfer,QRM must be both efficient and effective.Efficiencies
in prioritizing technology transfer team activities, identifring resource requirements, and establishing
meaningful timelines can be reaiized through the tools used for risk analysis.

5.8.1Experiments KeyProcess
to Gonfirm Parameter
Ranges
The purposes of the experiments during the TTP are to confirm key processparameters and fill in the gaps
The operiments arenot designedto redevelopor optimize the process.
identifiedin the risk assessment.

Qualiñed laboratory-scaleor pilot-scalemodels should be established,preferably at the RU. Depend-

ing on the agreementbetween the SU and the RU the qualified models may be maintained at the SU
if they are not establishedat the RU.

Experimental design and protocol are based on the establishedscale-down models and the ranges of
the key processparameters provided by the SU. Design-oiexperiment methods need to be used in the
experimental design. These methods call for the use of raw materials from approved vendors that will
supply the commercial operations in the scale-downmodel experiments.The acceptancecriteria should
be clearly defined in the protocol. The experimentalresultsare documented in the sununary report, and
conclusionsshould be drawn asto whether the key processparameter ranges are confirmed.

Demonstration
5.8.1.1 Runs
After the key processparameter ranges are confirmed at the laboratory or pilot scale,additional ex-
periments may be run at the commercial scale(dependingon the complexiry of the process)prior to
processvalidation, such as demonstration or engineeringruns. Products generatedfrom the demon-
stration runs must not be used commercially.

For well-defined platform or relatively simple processes,demonstration runs may not be necessary.
For complicatedprocesses,demonstration runs are suitableto demonstrate the scalabiliryof the pro-
cessat the RU. Demonstration runs also help discoverpotential gaps in equipment, instrumentation,
automation, utiliry CIP, etc.

A PFD based on the development history report should be ready prior to the demonstration runs.
The PFD should capture the processand equipment flow, generalprocesschemistry,CPPs,raw mate-
rial specifications,forward processingcriteria (or intermediate specifications),sampling plan, etc. A
protocol for the demonstration runs should be prepared to document, at a minimum, the purpose,
scope, roles and responsibilities,test plan, and acceptancecriteria. Batch production records must
be available to document the appropriate operating conditions and any special instructions for the
demonstration runs.

Intentional deviationsin operating parametersfrom the target set point may be used to test process
robustnessduring the demonstration runs.

Depending on how well controlled the CPPsare at the commercial scale,the CPP rangesmay need to
be adjustedafter the demonstration runs. The demonstration run resultsand gaps found, corrections
made during the runs, and recommendationsare documented in a summary report.

Additional demonstration runs may be required if the recommended acrionsmust be taken prior to
Processvalidation. Demonstration runs can be costly.Cost and benefits need to be consideredcare-
fully in conjunction with the risk assessmenr.

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DataGollection,
5.8.2 Cyclesof RiskAssessment,
andGlosure
RiskMitigation,
To bridge the gapsidentified during the initiai risk assessmentand mitigate the risks, data can be collected
througlr experimentation at different scalesand/or data mining of the SU'sdatabase.

Data evaluation is a processto assesswhether the risk-mitigation results are acceptableand whether the
technology transfer is successful.Data evaluation is not a one-time exerciseand should be incorporated
into milestone (or srage gate) reviews. Examples of stage gates are the laboratory-scale data review
prior to the pilot plant testing; the pilot scaledata review prior to the production scaletesting; the data
review of the demonstration runs prior to processvalidation; and post-processvalidation data review.

Two questions need to be answered at each data review:

. Are the data sufficient to support the mitigation plans developed based on the risk-assessment
results?
. Flave the critical successfactors been produced as demonstrated by the data?

The personnel involved in the data evaluation should include the technology ransfer project leader
(or project manager); experienced scientists and engineers from the SU and RU; and representatives
of QA, QC laboratories,operations, and senior management.The data review resultsshould be docu-
mented, and conclusions need to be drawn regarding whether each milestone has been successfully
achieved. Any action items from the data review team should be addressedby the project leader/
manager.

Additional risk assessmentmay be needed after more knowledge is acquired through data reviews.
When new high risks are identified, whether these risks are acceptablemust be determined. If they
are nor acceptable,new risk mitigation measures must be developed and additional data should be
collected. This risk assessmentldatacollection ldatareview cycle continues until all risks are reduced
to an acceptablelevel.

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6.0 GaseStudies

In the following pages, three casesare provided to show the application of the principles, concepts,
and tools of QRM to the TTP.

The first casestudy focuseson the analyticaltransfer of a method, whereasthe secondand third case
studies focus on manufacruring activities.

6.1 GaseStudy1:Analytical
Method
Transfer
Although an AMT may occur at any point in the method and product lifecycle, analytical methods
are often co-transferredwith the manufacruring processduring product development and/or after
commercial licensure.

The stagesof an AMT include a preliminary evaluation and preparation of the new laboratory to re-
ceivethe test method, development of an approvedmethod transferprotocol, and applicationof suit-
able statisticaltools to analyzethe results.The outcome is documented in a method transfer report.

For all AMTs, the responsibilitiesof the SU's and RU's laboratories should be established.The qual-
íty andlor service agreement(s)should clarify all conditions and responsibilities.In addition to the
preparation and sharing of samples,critical reagents,and standardsto be used during the AMT stud-
ies,some continuous post-AMT testing (monitoring) shouldbe considered(+,lz). Table 6.1-1lists the
suggestedresponsibilitiesfor each laboratory and provides some examplesof how tasksand respon-
sibilitiescould be sharedby both laboratoriesduring AMT

Table6.1-l Suggested
AMTResponsibility
Matrix

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AMTStrategy
6.1.1General
The strategy used for an individual method to be transferred and/or to support a product transfer
can vary depending on the exact circumstances.Options for strategiesare illustrated in USP <1224>
Transfer of Analytical Procedures(10). Acomparative study model is further describedbelow.

AMTTestStudies
of Gomparative
6.1.2Design
The AMT protocol should indude a study designspecifyingmethod parametersto compare, samplesto
test,justified acceptancecriteria,and the statisticalmethodology to evaluatethe results(seeThble 6.L.2'L).

Design
Table6.1.2-1 GeneralAMT andConsiderations
Parameters

HowmanyrepresentátiVe Twoorthreebatches activeprotein

theexpected
bracketing ioncentration,ranges
-
batches?Matrixapproách could,be materials
Theselected
used. should ofroutine
berepresentative samples,
(number sample Retain
ofdifferent samples,reference attheextremes
samples
standards, of acceptance
typesand/or
batches stability
to be limits, and/or
samples, spiked should
samples be used, on
depending
evaluated) thesituation.
Forimpurity maybespiked
tests,samples sothatthelevelof ,
ordegraded
theimpurity above
is belowand/or the limit(A0L)(:and/or
quality
acceptable
limit).
specification lf with
samples a impurity
measurable levelarenotavail-
to prepare
able,it mightbenecessary spiked to evaluate
samples théaccuraóy
and,precision amounts
ofmeasurable levels
ofimpurity/degradation their
during
AMTstudies,
therange
intheformulation,
lf therearedifferences offormulationdifferences
should betested. Therationale AMTsamples
of representative
fortheselection
should bedocumented intheAMTprotocol.
' ! , , . . . .

How.many Fer., , Thenumber

replicateS of replicates
depends andintermediate
ontherepeatability preci.
Sámpte '
andlaboratory-?, sionperformance ofthemethod to betransfenedandthedesired confidence:
level(slfs¡meeting product TheAMVreport
specifications. andotherrelated
of independent
{Num,berr runi}
' . . , . datasources (forexample, testresults)
routine should bereviewe6. ' , i,,
HowmanyIntermediate At leasttwocriticalfactors shouldbeselectedbased onpriorknowledge ofwhich
precision factors facto(s)mayhavethegreatest
variability expected onvariations
impact intestresults. :
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AMTPerformance
6.1.3Selecting Characteristics
The intended purpose of the method should be used to justify the rationale of the study design and
acceptancecriteria for each method transfer.Table 6.L.3-Lprovides an example of performance char-
acteristicsto be compared between laboratoriesfor different types of methods. Other performance
characteristicscoveredduring the validation studiesmay alsobe considered.

Table6.1.3.1 Examples
of Method andAMTPerformance
Types Characteristics

6.1.4AMTDocuments
AMT processesare documented through AMT protocols and AMT reports. The AMT protocol typi-
cally consistsof the sectionslistedin Table 6.L.4-L.

T able 6 .1 .4 -l T y p i c a l AMT P ro to c ol S ecti ons

The AMT report describesthe results of implementation of the protocol, compares these results to
the acceptancecriteria, and draws a conclusion regardingthe acceptabilityof the transfer.

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6.2 Gase Process

2: Manufacturing
Study Transfer
Process
of Manufacturing
6.2.1Overview Transfer
The installation of the manufacruring process for a recombinant protein-based vaccine occurred
through cwo different TTPs. The initial technology ransfer from the R6<Dunit to the manufacturing
unit (development to commercialization TTP) resulted in the manufacturing of lots that were used in
Phase3 clinical trials and for launch supply.After this initial TTB a second TTP was conducted (intra-
company TTP) to a scaled-uppurification facilicy,which was required to meet the projected market
supply requirements.

The manufacturingprocessconsistsof yeast-based fermentation,purification, and reassemblyof the recom-

binant protein virus-like-partides (l/LPs); adsorption to an adjuvant; and sterile formulation and filling. Key
challengesduring processdevelopment included protein expressionin a defined media fermentation
and control of VLP aggregation and stabiliry. These challengeswere overcome via the TTP to pro-
duce a small-scaleprocesssuitable for early-phaseclinical testing.

Development
6.2.2 GaseDescription: TTP
to Commercialization
The TTP was initiated with a faciliry fit analysis to compare the unique aspects of the processing
equipment in the existing fermentation facility to the processas defined in RS{D.This led to targeted
developmentwork to better fit the processinto the intended manufacturing facücy. For example,the
relative scale of the fermentation seed processwas modified and tested to fit into the fixed equip-
ment in the existing faciliry. In addition, some facility changeswere required to meet the needs of
the process.A new purification faciliry was required, and close collaboration becweenthe R&D and
manufacruring units led to an agile design that met the processingneeds.Finally, the formulation and
fi[ing processwas transferred to an existing faciliry.

A risk assessment was performed to characterizethe processparametersand attributes.The product's

CQAs were identified, and the processexpertsdetermined the associatedCPPsthat were responsible
for controlling the CQAs.

Other attributes that were important for process consistency (key product attributes and operating
parameters)were also identified to further define the manufacturing process.The ranges associated
with these attributes and parameters were determined experimentally. However, in most cases,the
limits were known "success"values rather than those at the boundary of failure due to the complex-
iry of the process and product. The ranges were approved by the R&D unit and the manufacruring
orgarization (operations, qualiry and technical operations) and were the basis for processvalidation.
The rangesfor CQAs and CPPswere maintained for all components, exceptthat some were changed
due to processscaleand planned processchanges.

A well-defined businessprocessexistedin the enterprise and was used to organízeand manage the
TTP for the product. The featuresof the businessProcessincluded:
. Formation of a technology transfer team that was responsible for executing the technology
transferplan. Members of this team included representativesof R&D, operations,quaüry technical
operations, and regulatory units.
. Appointment of a technology transfer leader who was responsiblefor organizing and managing the
team and reporting progress to a governing authoriry.
. A governanceteam of cross-funaional leadersüat oversawthe technology transfer plan and served as
a decision-making body when issueswere encountered. The team chartered the project and team and

ReportNo.65
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oversawthe project using a "stagesand gates" approach.Stagesare logical groups of associatedactiüties

and tasksthat arepart of a TTP Stagegatesarereview points that aredefined in advanceby the governance
team and focus on project stafus,key milestones for the next stage,and, importantly, the risks and risk
mitigation plans for the project. For example, production of process validation lots was considered a
distinct stage, and a stage gate review was conducted by senior leadership to ensure readinessfor the
processvalidation seriesand communication of the potential risftsto the processvalidation lots.
. A project management system used to ensure sound project definition and execution control.
During the initiation and planning stage, a project plan was produced and was reviewed by the
governanceteam. The plan resulted in approvedschedulemilestonesthat the technology transfer
team was expectedto meet. This stagealsoincluded definition of key assumptionsand project risks
that governed the project plan.
. An execution stageconsistingof processreadinessin the manufacfuring facilities (for example,IQ/
OQ and engineering lots), completion of processvalidation lots, and licensure of the facilities.
The processvalidation lots were used in Phase3 clinical trials, which conclusivelydemonstratedthe
successfultransfer of the process technology from the R&D to the manufacturing unit. Approval of
the manufacturing facilities occurred concomitantly with product regulatory approval.

6.2.3Intracompany
TTP
To limit the capital expenditures before obtaining critical clinical perficrmance data, a small-scalepu-
rification facilicywas used asthe initial manufacturing facilicyto produce processvalidation lots used
in the Phase3 clinical srudies and to manufacrure drug substancefor product launch. However, the
expectedmarket demand exceededthe capaciry of the launch faciliry. Consequently, a scaled-uppuri-
fication facility was constructed.

The processfor the new faciliry was scaledup, which required targeted processchangesto manage
the larger production scale.For example,fi.lter configurations were changed to reflect limitations in
mechanicalequipment design. In addition, a planned material manufacruring changeby the vendor
was evaluated in R&D to ensure successin the new factory.

A project team was assembledin the manufacturing organization for the startup of the new faciliry
and technology transfer from the initial purification faciliry.This team had a similar structure to that
describedabove, although it was based at the manufacruring site. A governance team oversawproject
execution and was responsiblefor rapid decision-makingand resolution of issuesescalatedby the
project leader.A communication plan was defined and implemented to ensurealignment in the orga-
nization concerning proj ect implementation.

Becausethe drug substancewas a recombinant protein that was considereda well-characterizedbio-

logic, a comparability approachwas taken for licensureof the new purification faciliry.This approach
was aligned with the guidance in ICH Q5E Comparabilityof Biotechnological/BiologicalProducts Subject
to Changesin their Manufacturing Process
and provided a framework for evaluating the impact of the
processchangesand scale-upon product safery and quality (zz),

A summary of the businessprocessdeployedfor comparabiliry is shown in Figure 6.2.i-t. Compara-

biüry consistedof demonstration of both processperformance measures(e.g.,key processattributes)
and product quaüry attributes (e.g.,product specifications).The expectedresults for these measures
were defined by statisticalanalysisfrom production lots made in the launch facility. A weighting ap-
proach was used for the analytical measuresto account for the relative importance of test results;
for example,due to its impact on product qualiry the potency test was considereda more important
measurethan the characterizationtest.

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Processand Product characterization

Analytical
lmpurities
Measures Stability

Manufacturing Manufacturing diversity

Analyticalvariablity
Database

Expected Acceptancecriteria {Primary Limit)

Alert Limit (SecondaryLimit)
Results

Meets acceptance
Meets acceptance
Comparable Criteriabut falls
criteria and alert limits
outside alert limits
InYg-sjisation includgtr
. Weighting of parameters
e Data evaluationfrom all lots
¡ Clinicalexperience
. Resultsfrom other parameters

Figure6.2.3-l Process/ProductComparabilityFramework

The processvalidation lots made in the new purification facilicywere tested accordingto the require-
ments in the comparability protocol. All lots made were deemed to be comparable to the small-scale
launch faciliry, which led to the successfullicensure of the faciliry without clinical studies.

6.2.4Gonclusion
A successfulproduction history lasting more than five years after licensure demonstratesthe success
of the technology transfer Processesused for this product.

Transfer:
Process
6.3 GaseStudy3: Manufacturing
Evaluation
to Start-Up
ORMApplication
Principles
6.3.1Useof Ouality-by-Design
The example in this secrion shows how qualiry-by-designprinciples can help the technology transfer
ream plan appropriate activitiesto mitigate risks along the projectpath (Zl).

The objective of this example is the technology transfer of an injectable, small-volume parenteral
solution from the manufacturing site of the originator firm (SU) to the manufacturing site of a CMO
(RU). Supporting information and concepts can be found in PDA TechnicalReportNo.44: QuAlity Risk
ManagementforAsepücProcesses andPDATechnicalReport54:lmplemmtation of Quality RiskManagemmt
(7,21).
for Pharmaceutical.and Biotechnolog ManufactunngOperations

As describedin Figure 6.3.t-trby processingthe deliverablesreceivedby the SU, including informa-

tion on the process and product to be transferred to the new site, the RU can conduct a risk analysis
followed by a mitigation plan using a riskprioriry numbering approach.

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Figure6.3.1-l 0verallProcess
Mapping

As a first acüvicy based on site knowledge, the RU develops a new manufacnrring process scheme that
accountsfor the modifications neededto implement the original manufacturingprocess at the new site.

The RU defines the main variables that could affect product qualicy attributes based on the new pro-
cessscheme (Table 6,3.L-L). The main variable categoriesinclude:
. Processlfac:dty
. Primary packaging components
. APIs and excipients

48 @2014Parenteral
DrugAssociation,
Inc. Technical
ReportNo.65
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Table6.3.1-l Examples
ofVariable
Definitions

The SU transfersthe quaüty attributes of the products to the RU (Table 6.3.L-z),

Table6.3.1-2 Examples
of 0uality Definition
Attributes

The nvo teams merge the newly developed manufacruring process with the qualiry attributes of the
product receivedto assesswhich variablescould affect the product and how they can be controlled.

To take further advantage of the analysis,a risk number can be assignedto each variable based on its
severiry occurrence, and detection.

This activiry, done at the beginning of the project, can detect the most likely potential causesof tech-
nical failures during the TTP and allow planning for mitigating those risks. Following ICH Q9, the risk
can be estimatedbaseda combination of three main factors:
. Severiry (S)
. Occurrence (O)
. Detection (D)

ñeportNo.65
Technical O 2014Parenteral lnc.
DrugAssociation, 49
ffiwM #mWp4rugff
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Severiryconsiders the potential impact on the qualiry attributes of the product and, hence, on patient
health. It can be rated basedon the table below:

andRating
Definition
Table6.3.1-3 Severity

The occurrence factor is defined as the frequency of occurrence of the event. It can be rated as shown
in Table 6.3.L-4.

Table6.3.1-4 Definition
Occurance andRating

The detection factor is defined as the probability of detecting the events if they occur, based on the
control system in place. It can be rated as shown in Table 6,3.1-5.

Table6.3.1-5 Detection
Definition
andRating

Basedon the definitions and ratings of severity,occurrence,and detection, risk rank can be calculated
using the formula R=SxOxD.

A team evaluationis neededto identify acceptancecriteria. For example,in Thble 6.3.L-6,a risk (R) < 9 is
deemedacceptableand no actions are neededto mitigate this risk

Basedon the risk criteria and ranking, a mitigation plan is establishedby the team. After the plan is
implemented, the risks are evaluatedagain to confirm that they have been mitigated.

50 O 2014Parenteral
DrugAssociation,
Inc, Technical
Report
No.65
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@ 2014Parenteral
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58 O 2014Parenteral
DrugAssociation,
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ReportNo.65
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Jeff Broadfo ot, Cdngene(Vice-Chair)
Ruhi Ahmed, Ultragenix PharmaceuticalInc.
Alan Burns, Consultant
Robert Caunce, Hospira
Veronique Davoust, Pfzer
Hongyang Li, Nwartis
Lauren Melton, AltryInm
Elizabeth Meyers,'A--qff+.,_
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Shin-ichiro Mohri, KyoW WHi,#l<irin C0.,Ltd.
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Stephan Roenninger, Lqtg¡¡pi
Junko Sasaki, D ainipp on Suttti Irrl4f lh:,iV.
Anil Sawanr,JohnsonduJght4sú:'
Siegfried Schmitt, earqt)'
Jacqueline Veivia-Pan¡gi,lthA4+
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Jeftey Hartman, Mer1k'
John Finkbohner, MúIryWllf
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Claudio Correa, Roghe
Barbara Jenrges,nhagfl Sa[f"f
Chair: Hal Baseman, Valsource
Chair-Elect:Martin Van Trieste, Amgen
Treasurer: RebeccaDevine, Ph.D., RegulatoryConsultant
Secretary: Michael Sadowski, Baxter Healthcare
Imm. Past Chair: Anders Vinther, Ph.D., Genantech
President: Richard Johnson
Directors
JoyceBloomfield, Merck
Ursula Busse,Ph.D., Nwartis
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''r''i'':-: Jette Christensen,Nwo Nordkk
'",':!.., Veronique Davoust, Pf.zer
't:.,;,¿ Ian Elvins, Lonza AG
John Finkbohner, Ph.D., Medlmmune
: Gabriele Gori, Nov¿rüis
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);-'i;,-.. Stephan Roenninger, Amgen
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Junko Sasaki, D ainipp on Sumitomo Pharmaceutic als
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Hailey Park,PDA M : l:-,

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Emma Ramnarine, 9,9$f,f.*.t Lisa Skeens,Ph.D., Bacter Healthcare
Edwin Rivera-M artineq, ,$$¡!4il!i
:E*¡:!.eyt Chris Smailey, Ph.D., Merck
Glenn Wright, EliLilly

PDA Publication Production and Editing

Joshua Eaton, SeniorkojectManager, Scienüfcü RegulatoryAfairs

Richard V Levy, Ph.D., SeniorVp, Scienüficü RegulatoryAffürs
Walter Morris, Directorof Publishing
Katj a Yount, PublicationD esigner
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Parenteral Drug Aesoclatlon

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