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Site Master Plan2) Site Master Plan

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Site Master PlanningPlanning 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

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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

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Site Master PlanningPrerequisites 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

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Site Master PlanningSite 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

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Site Master PlanningFlexibility, 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

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Site Master PlanningDetermine 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

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Site Master PlanningSizing & 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

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Site Master PlanningBroad 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

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Site Master PlanningConfiguration 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

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Site Master PlanningLayer 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

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

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Site Master Planning

Layer 3 – Adjacent Warehouse – separate linked

building Cold Store – Central Primary change for operators Maintenance workshop Cafeteria

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Site Master Planning

Layer 4 - Near - Preferably Linked QC labs Engineering HR Administration Security EHS

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Site Master PlanningLayer 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

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Site Master PlanningConfiguration 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

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Site Master PlanningBuffer 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

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Site Master PlanningOther 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

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Site Master Planning

Sizing Buffer Make Up Requires prep and hold vessels Material handling and dust control Transfer by aseptic filtration

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Site Master PlanningSizing 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

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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

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Site Master PlanningUtilities 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.

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Site Master PlanningBuilding 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)

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Site Master PlanningExpansion 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

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Technology Transfer

3) Technology Transfer

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Overview

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

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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.

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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

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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

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Critical GMP Drivers

No Specific Reference in 21CFR 210/211

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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

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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”

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Critical GMP DriversCapture 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

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Establishing a TT ProcessWho conducts Technology Transfer ?

Originating – Receiving sites R&D / Commercial Intra Company transfer

Site – Site or Internal Transfer to External Business Partners

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Technology Transfer RoadmapHow 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

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Roadmap - Tech Transfer GovernanceWhat defines Governance ?

TD&T Technology Transfer Agreement Quality Agreement Quality Policy Site Specific SOP(s)

Project Governance & Administrative

roles & responsibilities

Steering Committee TT Team Leader TT Team TT Team Members TT Sub Team Leader TT Sub Team(s) TT Sub Team Members

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Empowered Technology Transfer Teams

Steering Committee Comm

TT Team

Subteams as As Needed

Membership as Appropriate: - Team Leader - Transferring Site Development - Receiving Site Manufacturing - Development Operations - Quality - Engineering - Regulatory Affairs - Materials & Logistics - others as appropriate

Periodic Status Updates

provided by Team Leader

Further Subteams

As Needed

Senior Management

Project & Technical Decision Making

Strategic DecisionMaking

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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

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 supportthe process

Technology Transfer & Project Governance

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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

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Technology Transfer ExecutionDevelop 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

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Technology Transfer PlanElements 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

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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

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Tech Transfer ExecutionWhen is Technology Transfer Complete?1. Phases

Learn Demonstrate Validate

2. GatesDefine transition to next phase (readiness)

Success criteria

3. DeliverablesProcess / Method

validated at receiving siteTechnology Transfer

Report Approved

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Tech Transfer Execution

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

Phases of Technology Transfer

Gates are defined by the TT Plan

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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)

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One-Team cultureDO 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

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Vehicles for Team SuccessPEOPLE 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

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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

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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

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Tech Transfer Process Flow - Documentation

Receiving SiteTT Team Review

•Detailed Process

Description (CPPs)•PFD

•Analytical Methods•Initial BOM •Buffer List

•Small Scale Familiarization Studies

•Training Package•Execution Protocol

•Study protocols

GENERATE DRAFTS

Batch RecordsAutomation

SOP’sFinal BOM / SAPSpecifications

QC Sampling PlanTraining Package

Complete trialsChange Controls

REVIEW & APPROVALBatch Records

AutomationSOP’s

Final BOM / SAPSpecifications Sampling Plan

OtherData Register

Execute Process Training

Gating Check List

DemoPhase Gate

Originating Site

Pre-requisites

Source DocumentsTechnical Package

TIMELINE

Weeks ~ Months

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Tech Transfer Completion

2. Technology Transfer Report Gaps closed Training complete Gating checklists for each phase complete Process Validated

Outcomes / Deliverables1. Technology Transfer Package Process / Method descriptions Supporting Technical documentation

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Measure TT Success - MetricsMeasurement 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

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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)

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QUESTIONS???

clement.farrar@gmail.com

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Take 10 minutes!