Site Master Plan

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 40-60 tons/ hr @ 0 bar • Chilling 20-30 MW • Cooling 40-60 MW • Compressed Air 4,000-6,000 Nm3 / hr • Divide all into modules – min 3 equal sized units • Power 20-30 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 floor @ 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. 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. Technology Transfer Definition

28. 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 ? 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 • 211.160 Subpart I, Laboratory Controls, General Requirements • 211.186 Subpart J, Records & Reports, Master Production and Control Reports • 211.110 Subpart F, Production and Process Controls, Sampling and Testing of in-process materials and drug products. • 211.100 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 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 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. Steering Committee • TT Team Leader • TT Team • TT Team Members • TT Sub Team Leader • TT Sub Team(s) • TT Sub Team Members Roadmap - Tech Transfer Governance What defines Governance ? • TD&T • Technology Transfer Agreement • Quality Agreement • Quality Policy • Site Specific SOP(s) Project Governance & Administrative roles & responsibilities

37. Strategic Decision Making Project & Technical Decision Making Empowered Technology Transfer Teams

38. 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 • Approve plans & reports TT Team Leader: • Construction & maintenance of overall TT plan • Primary liaison

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

44. 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. DO 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 One-Team culture

47. 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 Vehicles for Team Success

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