1. Site Master Plan
2) Site Master Plan

2. Site Master Planning Planning Rationale
Serious investment – long project duration – good long term planning essential
Planning, and even investment frequently required before product goes into phase 3
Combination of specific and generic elements – flexibility essential
Assume full scope site including fill/ finish even though later is frequently separate

3. Site Master Planning Assumptions
Product and Process ranges have been agreed
We have completed a build/ buy/ outsource analysis and have noted current world capacity position
Focus on Monoclonals and our process will follow broad Mab guidelines
Our broad philosophies are established in terms of: GMP, Single v’s Multi-product, Expandability etc

4. Site Master Planning Prerequisites Defined product characteristics
Broad product demand parameters e.g. dose, patients population etc
Our market potential and penetration
Broad process parameters
Location philosophy
Scope of investment on our site
Site selection is nor a prerequisite for master planning

5. Site Master Planning Site Scope
Filling process and process utilities are core, usually in single building
Site usually includes process development, QA, QC, warehouse, utilities, personnel facilities and technical management are needed
Fill finish (stages from bulk to dose form) are optional as are packaging and distribution
R&D, high level admin, finance, sales, etc are optional. Decision between ‘flagship facility’ and ‘lean, mean’ functional unit’ is essential early

6. Site Master Planning Flexibility, Expandability, Future Proofing
Key decisions are needed here – must be a cap!
Define how much to install, how much to provide space for, how much to service for?
Philosophy on expandability, modularity, flexibility is needed
Define modularity – can range from slotting in a serviced vessel to stand alone modular segments
These decisions are fundamental, they can determine the success or failure of the facility and must be in the context of 5 years in the future

7. Site Master Planning Determine Site Requirements
Sizing is based on output requirements. These derive from dose x patient population and this applies to all facility levels (pilot, chemical, full scale)
Dose may be in vials, pre-filled syringes or other forms. Main form is lyophilised product in vials.
Separate logistics apply to sizing fill/ finish facility including formulation, bulk preparation, filling, lyophilization

8. Site Master Planning Sizing & Shaping
SMP is a collection of ‘boxes’ of varying size and shape arranged in a functional, orderly and aseptically pleasing configuration
Sizing individual boxes requires analysis of the process requirements, sizing and arranging the equipment and services and configuring the internal workings for optimal personnel and material movement
Arranging the boxes needs an analysis of inter box movements and requirements for adjacency, closeness etc. Expansion philosophy is applied here

9. Site Master Planning Broad Rules
Minimise process transfers – address CIP considerations
Recognise basic contiguity needs e.g. airlocks, gowning areas, autoclaves, sterilizers vs protected core
All material movements should be under cover (link corridors)
HVAC plant rooms should be above classified areas – minimise duct runs
Buffer Prep and clean utilities to be adjacent to process areas
Design from process core outwards and from output requirements backwards

10. Site Master Planning Configuration Philosophy
Various layers are placed around production core – based on proximity requirements
Layers
Adjoining
Adjacent in same building
Adjacent – linked by corridor
Reasonably close – preferably covered access
Remote

11. Site Master Planning Layer 1 – Contiguous/ Adjoining
Airlocks for materials/ components
Secondary change areas
Autoclaves and sterilisers
CIP skids
Process development/ pilot plant
Air handlers and distribution
Process drains
In-process cold storage

12. Site Master Planning Layer 2 – Same Building Clean utilities
Buffer Preparation QA
In-Process Lab
Some personnel facilities on large site

13. Site Master Planning Layer 3 – Adjacent
Warehouse – separate linked building
Cold Store – Central
Primary change for operators
Maintenance workshop
Cafeteria

14. Site Master Planning Layer 4 - Near - Preferably Linked QC labs
Engineering HR
Administration
Security
EHS

15. Site Master Planning Layer 5 – Remote or Distributed
Utilities - general - steam, comp air, potable water, chilling, fire water
Effluent treating
Fire water storage and pumping
Tank farms
Car parks / roads
Gas storage

16. Site Master Planning Configuration Options
Single Building – most economical but not good option for large scale – limits expansion and mixes incompatible operations
Spin link corridor – probably ideal – buildings attached on 2 sides – can extend length and travel distances if expansion space is required
Rectangular loop link – also good – again can limit expansion but reduces some travel distances
Radial – good concept but impractical for implementation

17. Site Master Planning Buffer Make Up
Separate areas for filling and buffer make up
Requires solids handling capability
Generally all buffer solutions are presented aseptically to Formulation/ Filling
Area adjacent to Formulation/ Filling

18. Site Master Planning Other Considerations Chilled Vessels for storage
Intermediate cold storage
Possible separate air handling systems
Separate entry and exit facilities for materials and personnel
Decontamination of exiting clothing and equipment
Later stages require aseptic handing and freezing facilities

19. Site Master Planning Sizing Buffer Make Up
Requires prep and hold vessels
Material handling and dust control
Transfer by aseptic filtration

20. Site Master Planning Sizing Process Utilities
WFI requirements calculated on flows demands and minimum circulation rates
Storage vessels can be 10-20m3 – required balanced calculation between storage and generation
CIP demands determine capacities – high instant flow rates
Clean Steam based on max SIP load – usually empty vessel – made from clean steam
Clean gases based on process demands and some transfers – all filtered

21. Site Master Planning General Utilities
Normally located centrally – CUB concept
Allow for pipe-racks (usually in link corridors)
Includes steam, chilling, cooling, compressed air, power, effluent treatment

22. Site Master Planning Utilities Sizing – Ranges
Steam tons/ 0 bar
Chilling MW
Cooling MW
Compressed Air 4,000-6,000 Nm3 / hr
Divide all into modules – min 3 equal sized units
Power MVA – Supply at H.T.

23. Site Master Planning Building Sizes - Ranges
Sizing based on previous slides – boxes must be sized before being arranged
Multi-floor arrangements more economical within reason
In all cases, top floor for plant with prospect of additional plant space on 1 side
Crude sizes for 100,000L facility approx, 60,000 – 80,000 m2
Bulk Production/ DSP 20,000m2 (3-4 floors)
Fill/ Finish 10,000 – 15,000m2 (3 floors)
Warehouse 10,000 m2 (1 12m)
CUB 5,000 – 10,000 m2 (1 floor)
Development 9,000m2 (3 floors)
Admin 5,000 – 10,000 m2 (3 floors)

24. Site Master Planning Expansion
Clear policy needed – otherwise high ‘fuzz’ potential
Built space essential to avoid future disruption
Adjacent space needed for all functions
Constructability of expansion needs some study even at GMP: stage

25. Technology Transfer
3) Technology Transfer

26. Overview Introduction Critical GMP Drivers Tech Transfer Process
Team Participation
Tech Transfer Completion & Success

27. Technology Transfer Definition
4/21/2017
Technology Transfer Definition
Transfer of all necessary information and support to successfully manufacture and evaluate the transferred product, process or analytical test method, at the selected manufacturing site(s).
A successful transfer is a collaborative effort among cross-functional technology teams representing various site disciplines with communication as a cornerstone to that success.

28. What is Technology Transfer ?
4/21/2017
What is Technology Transfer ?
Product Technology Transfer
Business Considerations
Shipping Considerations
Material Availability
Regulatory Considerations
Strategic Facility considerations
Process/ Method Technology Transfer
Specific Tests or Process Steps
Specifications
Process/ method development & validation
Process related Facility Considerations

29. What is Technology Transfer ?
4/21/2017
What is Technology Transfer ?
Why conduct Technology Transfer?
Systematic approach
Define responsibilities
Ensure process/ method validation
cGMP Drivers
Business Considerations ?
Speed to Market
Lower Cost
Improved Customer Service
Compliance Obligations

30. Critical GMP Drivers
No Specific Reference in 21CFR 210/211

31. Critical GMP Drivers Indirect References in 21CFR 211
Subpart I, Laboratory Controls, General Requirements
Subpart J, Records & Reports, Master Production and Control Reports
Subpart F, Production and Process Controls, Sampling and Testing of in-process materials and drug products.
Subpart F, Production and Process Controls, Written Procedures, Deviations

32. Critical GMP Drivers
Eudralex Vol 4 Chapter 7 – Contract Manufacture and Analysis
7.10 “A contract specifies their respective responsibilities relating to manufacture and control of the product. Technical aspects of the contract should be drawn up by persons suitably knowledgeable in pharmaceutical technology, analysis and Good Manufacturing Practice”

33. Critical GMP Drivers Capture Critical GMP Drivers under Training
Subject Matter Experts (SMEs)
Understand Science & Technology
Documentation
Technical Documentation Package
Document Robustness
Document consistency of control
Platform for Validation

34. Establishing a TT Process
4/21/2017
Establishing a TT Process
Who conducts Technology Transfer ?
Originating – Receiving sites
R&D / Commercial
Intra Company transfer
Site – Site or Internal
Transfer to External Business Partners

35. Technology Transfer Roadmap
4/21/2017
Technology Transfer Roadmap
How is Technology Transfer Conducted?
Governance
Technology Development & Transfer (TD&T)
TT Plan
Strategic Overview
Experimental Outline and Validation Approach
Accountability Table
Technical Documentation Package
TT Report(s)
Technical info & data generated in support of strategic plan

36. Roadmap - Tech Transfer Governance
4/21/2017
Roadmap - Tech Transfer Governance
What defines Governance ?
TD&T
Technology Transfer Agreement
Quality Agreement
Quality Policy
Site Specific SOP(s)
Steering Committee
TT Team Leader
TT Team
TT Team Members
TT Sub Team Leader
TT Sub Team(s)
TT Sub Team Members
Project Governance &
Administrative
roles & responsibilities

37. Empowered Technology Transfer Teams
4/21/2017
Empowered Technology Transfer Teams
Strategic Decision
Making
Project & Technical
Decision Making

38. Technology Transfer & Project Governance
4/21/2017
Technology Transfer & Project Governance
TT Team:
Organise & execute the TT plan
Compile TT report
Ensure all required documentation is in place
Appoint sub-teams as required
Originating Facility:
Provision of analytical expertise to receiving site
Provision of process expertise to receiving site
Provision of all required documentation
Provision of standards, controls & other necessary
materials & information required to support process
transfer
Receiving Facility:
Perform Gap Analysis
Practical work involved in execution local gap closure
Identify, procure & qualify equipment to support
the process
Site Management:
Approve plans & reports
Assign site resources & establish priorities
Steering Committee:
Appropriate technical management from Originating & Receiving sites specific to the project
Appoint TL and defines SOW
Ensure compliance with Quality & Tech Transfer Agreements
TT Team Leader:
Construction & maintenance of overall TT plan
Primary liaison

39. Tech Transfer Execution
4/21/2017
Tech Transfer Execution
Conduct Gap analysis & Identify Gaps between originating and receiving facilities
Process/Method Gaps
Conduct studies & generate data to support process / method
Information Gaps
Gather / Source technical documents to support process / method
Facility Gaps
Process change request through appropriate capital approval committee
Gap Analysis yields Work packages
Work packages comprise Accountability Tables
Action Items / task lists

40. Technology Transfer Execution
4/21/2017
Technology Transfer Execution
Develop TT Plan
Integrates action items from
gap analysis with project timeline
Directs completion of Work Packages
from gap analysis
Integrates validation plans with
technology transfer

41. Technology Transfer Plan
4/21/2017
Technology Transfer Plan
Elements of the TT Plan
Strategic Overview
Technical Descriptions
Experimental Outline
Validation Approach
Success criteria
Gates (accountability table)
Training requirements
Milestones & deliverables (schedule)
TT Structure implements the plan

42. Functional Team Participation – Critical Drivers
Originating and Receiving Responsibilities Defined & Agreed up front.
Key Stake holder participation
Open Communication
Manage and Track Action Item closure on the TT Team to complete Gap Closure Relationship Management (Team)
Excellent Management of Interfaces
Establish relationships
Manage Relationships
Maintain Relationships
Use metrics to track TT progress
On-time milestone tracking
% Documents transferred / generated
% Training Complete
% Gaps closed

43. Tech Transfer Execution
4/21/2017
Tech Transfer Execution
When is Technology Transfer Complete?
1. Phases
Learn
Demonstrate
Validate
2. Gates
Define transition to
next phase (readiness)
Success
criteria
3. Deliverables
Process / Method
validated at receiving site
Technology Transfer
Report Approved

44. Tech Transfer Execution
4/21/2017
Tech Transfer Execution
Phases of Technology Transfer
Phase I – Planning, Learning and Knowledge Capture
Training of SMEs at originating site
Integration with originating/receiving site schedules
Transfer of Technical Documentation to receiving site
Phase II – Demonstration Batch Phase
Transfer Execution at scale at receiving site
Demonstration of robust process/method at receiving site
Phase III – Validation Batch Phase
Validation of process at receiving site
Production of commercial material
Gates are defined by the TT Plan

45. Functional Team Participation – Critical Drivers
Technology Transfer SME Model
Key individuals on “assignment” for training at originating site during learning phase
Gather Data & Source Documentation
Gain Expertise – learn “folklore”
Train Operations (customer)
Escort the process to Receiving site (Demo phase)
Trouble-shoot & support start-up (Validation phase)
Transition into Tech Services/Support (Comm phase)

46. One-Team culture DO DON’T Invest in face to face meetings
Spend time in partner facilities (walk in their shoes)
Assign specific SME partnerships
Agree clear accountability and decision-making
Constantly adapt to schedule opportunities
Adopt formal, planned training programs early
DON’T
Escalate everything-keep the team empowered
Allow ‘us and them’ to develop
Keep critical information from team members

47. Vehicles for Team Success
PEOPLE
Effort, commitment and expertise from teams (and assignees where available)
Willingness to look for and exploit new ways to do things
Resources - effective hiring ramp-up providing staff when needed and allowing training to occur
Flexible working environment
ORGANISATION
Focus on empowered teams with clear goals, accountabilities and timelines
Effective integration and leveraging of external (business partner) staff
A Quality organisation that acts as a partner to get the job done

48. Key Business Processes
Tech Transfer agreement
Formal plan developed with input from donor and acceptor groups
Provides clear governance, boundaries and deliverables
Tech Transfer plan and schedule
Resource loaded, part of overall project schedules
Modified to meet threats and opportunities
Defines Responsibilities
Provides for experimental outline, validation approach & success criteria
Change Control
Ensures process under transfer remain current (~ years)
Impact on equipment shared promptly with design, construction, commissioning and validation

49. Management of Information Flow
Manage information received from Originating Site (technical / project)
Shared Servers – ‘E-Rooms’
Version Control, Transmittal Notices,
Single Point Contacts
Preserve the integrity of the technical information during TT phases
Change Control (Multi-Site / Intra-Site)
Additional challenges during development & scale-up
Data Registers – useful for trouble shooting
Decision Registers & Change Registers – Track Changes during development & scale-up
Gating Reports – captures findings from a TT phase

50. Tech Transfer Process Flow - Documentation
Originating
Site
Pre-requisites
Source Documents
Technical Package
Weeks ~ Months
TIMELINE
Receiving Site
TT Team Review
Detailed Process Description (CPPs)
PFD
Analytical Methods
Initial BOM
Buffer List
Small Scale Familiarization Studies
Training Package
Execution Protocol
Study protocols
REVIEW & APPROVAL
Batch Records
Automation
SOP’s
Final BOM / SAP
Specifications
Sampling Plan
Other
Data Register
Execute Process Training
Gating Check List
GENERATE DRAFTS
Batch Records
Automation
SOP’s
Final BOM / SAP
Specifications
QC Sampling Plan
Training Package
Complete trials
Change Controls
Demo
Phase Gate

51. Tech Transfer Completion
4/21/2017
Tech Transfer Completion
Outcomes / Deliverables
1. Technology Transfer Package
Process / Method descriptions
Supporting Technical documentation
2. Technology Transfer Report
Gaps closed
Training complete
Gating checklists for each phase complete
Process Validated

52. Measure TT Success - Metrics
Measurement of data, value, timeframe, numbers
Number of Deviations
Operator or method errors
Equipment failure
Lots on hold
Number of investigations
Lots requiring rework
Equipment malfunction

53. Measure TT Success - KPIs
Key Performance Indicators (KPIs)
Normalizing a few metrics so that efficiencies or effectiveness can be compared
Number of lots required to complete validation Vs target
Number of revalidations (target = 0)
Number of lots failed in 100 lots
Cycle time against target
Yields against target
Percent reworks (target = 0)

54. QUESTIONS???

55. Take 10 minutes!