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Winning Strategies for Tech Transfer Projects:

Key Issues that Affect Successful Product Manufacture in “New” Facilities

Presented By - Presented By -John M. Hyde, Chairman and Founder

Hyde Engineering + Consulting, Inc.

ISPE Rocky Mountain Chapter Fall Meeting1 October 2015

Presentation Overview

• Drivers for Technology Transfer

• Tech Transfer Process:

• Product/Process Definition

• Process Modeling

• Process Fit Assessment

• Planningg

• Readiness Check & Execution

• Tour of Newly Constructed Indian CMO

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Technology Transfer Drivers

• Scale up/Capacity:• New Product Introduction• Rapid Globalization of Core Products

• Redundant Sourcing of Strategic Products• Quality/Technology:

• Remediation changesR id Ad i f N T h l i• Rapid Adoption of New Technologies

• New Market Entry• Economics

Economics of Outsourcing

Economic considerations:

– Time to Market

–Alternative to large upfront capital expenditures

–Consolidation

Key Drivers: Cost of Goods

Market Demand

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Cost of Goods Reduction

– Reduced Operating Costs

• Lower Labor and Material costs – Economies of Scale

• Expenditure by CMO at favorable terms to Owner• Expenditure by CMO ‐ at favorable terms to Owner

• Contract ‐ limited flexibility for unplanned upside costs

– Reduced Costs of Quality

• Limited exposure to costs of quality – waste

• Reduced direct oversight by Owner Quality Function

Big Caveat:  How does CMO fit seamlessly into Owner Operating and Quality models with minimal Owner Oversight?

Guidelines on Tech Transfer

– ISPE Good Practice Guide – Technology Transfer, 2003:• Planning and Success Criteria

• Analytical Methods

• Active Pharmaceutical Ingredient

• Dosage Forms

– WHO Technical Series Report 961, Annex 7 – Guideline on transfer of technology in pharmaceutical manufacturing, 2011: • Organization and ManagementOrgani ation and Management

• Production Transfer

• Quality Control: Analytical methods

• Premises and Equipment

• Qualification and Validation

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Technology Transfer Process MapHigh Level View

Product Definition

Process ConformanceProcess Conformance

Process Re-Definition

Process Fit Assessment

Technology Transfer Planning

Transfer Readiness Check

Release and Execute

Concurrent Processes:•Regulatory requirements review, planning, execution stream•Analytical Methods review, transfer planning, execution stream•Planning and Logistics management•Quality management•Marketing and Sales as needed

Technology Transfer Process MapProduct Definition

Product Definition

Markets/Countries Where SoldPackage List and BOM

Packages to Be Sold

Purpose:Understand everythingg

Product Formulation by MarketQC Tests and Methods•Release•Stability

Understand everything there is to know about the product and manufacturing process!

Raw Materials•Specifications•Sources•Compendial Requirements•Tests and Methods

Process Definition•Process Flow Diagram•Detailed Process Narrative•CPPs/CQAs by Step•Equipment and Instrumentation•In-Process Tests and Methods•Other (Quality History, CAPA’s, etc.)

Tests and Methods

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Process Conformance (Gap analysis)

Manufacturing and Laboratory Documentation•Batch Records

Technology Transfer Process MapProcess Conformance / GAP Analysis

Purpose:Identify gaps in product

Supporting Studies•Container Closure Integrity•Extractable/Leachable•Stopper Coring, ResealFilt

Process Validation Review

Batch Records•SOPs•Method Validations•Stability Studies

y g p psupporting documentation before it is moved. Avoid surprises and unexpected delays!

Quality by Design (QbD) facilitates this process!

Regulatory Filing Review

•Filters•Etc., Etc.

Regulatory CommitmentsInternal Quality Commitments

• Which Agencies– Manufacture, Sale and Distribution

Technology Transfer Process MapProcess Conformance ‐ Regulatory Issues

• Prior Regulatory Agency Interaction (the Owner and CMO)– Outstanding Observations

– Resolved Observations Dealing Directly With the Product, Process or Facility

– Potential Process Changes that may RequirePotential Process Changes that may Require Additional Regulatory Filing(s)

• Product or Process Specific Regulatory Issues

• Consistency of Manufacturing Process (Annual Reviews, Process Capability Monitoring, etc.) 

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Process Optimization

New Technology Review•Disposable vs. Re-Usable•Separation Technologies

Technology Transfer Process MapProcess Re‐Definition

Purpose:Develop and select best

Process Cycle Time•Single Step vs. Multi-Step•Batch Size Optimization•PAT vs. In-Process Tests•Continuous vs. BatchEt Et

•Separation Technologies•Purification Resins/Filters•Dosage Form (Vials vs. Syringe)

Develop and select best case for product transfer success, quality, cost, compliance. Adjust product and process as needed. Stay ahead of the curve!

•Etc., Etc.Process Development Plan•Address known quality/cost issues•Introduce higher quality or lower cost components•Rationalize multiple formulations•Extend patent protection?

Process Block Flow Diagram

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Process Model ‐ InputsAll process model input required for the various unit operations  is identified on single sheet 

Process Model – Process Calculations

• All detailed process calculations are captured on a single sheet

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Process Model – Output Block Flow Diagram

• The  calculation results are summarized in a Block Flow Diagram format

Process Model – Utility Sizing

Utility Sizing based on Process Model and Production Schedule

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Process Fit Assessment

Develop Product Information Package•Detailed Product Specifications•Process Flow Diagram as Desired

Technology Transfer Process MapProcess Fit Assessment

Purpose:Provide as desired

Submit to potential Receiving Sites

•Develop evaluation criteriaMarket Regulatory conformanceQuality / Management culture fitQuality Systems Robustness

Process Flow Diagram as Desired•API and Drug Component Specs.•Analytical Tests (In-Proc., Release, Stab.)

Provide as desired product and process details to second site.

Review and assess second site proposed process. Know what you’re getting into!

Receiving sites return proposals

Q y yHistory/ReputationReliability/Financial stabilityTechnologies fit to ProcessCapacity, Cost, Etc.Perform Due Diligence inspections

Evaluate and Select Receiving Site

The Right CMO: 

• Communication & Responsiveness

Selection of CMO

– CMO functions as internal manufacturing site

– Decentralized decision making ‐ Operations and Quality

• Culture:

– Management ‘culture’ are strongly aligned and “Fit” to Owner’s culture

Aligned Quality Systems CMO Procedures/Standards– Aligned Quality Systems – CMO Procedures/Standards  harmonized 

• Business Fit:

– Capacity and Costs

– Owner/CMO Integrated planning and logistics systems

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Technology Transfer Planning

Prepare Project Execution Plan

Execute Quality AgreementExecute Business Agreement

Technology Transfer Process MapTechnology Transfer Planning

Purpose:Prepare Project Execution Plan Purpose:Prepare a detailed plan that lists all deliverables, assigns roles and responsibilities, provides timelines and milestones, to provide basis for checking readiness to proceed and progress

Prepare Analytical Laboratory

Prepare Validation Master Plan

Order/Modify/Transfer Equipment Order raw materials and consumables

Prepare Regulatory FilingsFinalize artwork and copy

Prepare Tech Transfer Plan

toward goals. If you fail to plan….!

py

• Equipment Scale – Process & Utilities

D f P S t

Process & Utilities Readiness Check

• Degree of Process Systems Automation– Extent of Reliance on Software 

Algorithm Versus Manual Operations

– Degree of Process Data Collection Capabilities

• Process Containment Capabilities

• Sterilization and Cleaning Practices

• Segregation ‐ Plant and Clean Utilities

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• HVAC Zoning– Air Segregation Between 

Facility Readiness Check

g gFunctional Areas

– Appropriate Pressure Gradients

• Routing– Adequate Corridors for “Supply” 

and “Return” of People and Materials

• Gowningg– Appropriate Gowning Areas and 

Gowns

• Storage of In‐Process Materials– Segregation by Lot and Product

• Documentation

Documentation/Personnel Readiness Check

– Batch records and SOP’s

– Address all Manufacturing, Laboratory and Facility Issues Including GMP, GLP, Safety, etc.

– Specific to Markets Served, e.g. WHO, EMA, FDA, etc.

Training Program• Training Program– Training Program for Manufacturing and Support Staff

– Documented Training Records

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QC ‐ Analytical Methods (collection, management and testing)

Methods Transfer Readiness Check

and testing)

• Instrument and Procedure Validation

• Sample Collection and Tracking Methodologies

• Sample Storage Requirements

• Re‐Testing Policies and Criteria

• Requirements for Out‐Sourced Analysesq y

• Sample Segregation Requirements

• Laboratory Staff Qualifications– Documented Training for Samplers and Analysts!

• Bases of Equipment and Facility Validation Practices

Validation Readiness Check

Facility Validation Practices– Risk Basis– Grouping of Equipment and Facility Systems

– Re‐Qualification

• Process, Sterilization and Cleaning ValidationCleaning Validation– Risk Basis– Quality and Quantity of Lab and Pilot Scale Supporting Data, e.g., “Design Space” Understanding

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• Carryover Risk of Contaminants from Prior Products

Validation Readiness Check (cont.)

– Value of Residue Removal and Fragmentation Studies

– Replacement of Elastomers?

– Dedication of Key Equipment

– Chromatography Resin and UltrafiltrationMembrane Replacement and StorageMembrane Replacement and Storage

– Pre Versus Post Viral Equipment Systems and Manufacturing Suites

– Raw Materials and Finished Goods Handling

• Facility Cleaning and Decontamination

• Management of Change– How are Change Requests Initiated?

Quality Systems Readiness Check

g q– Who Approves of Change Requests– How are Completed Changes Evaluated and Closed?

• Documentation of Change– How is Change Recorded?– Chronological, Departmental, Equipment Systems and Product Cross Referencing

• Evaluation of “Drift”– Real‐Time Manufacturing Data to Assess Un‐Planned Change

– Basis for Re‐Qualification

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Case Study – Indian CMO

• Facility Basics− Total Facility Footprint is ~40,000 Sq. Ft., ~18,000 Sq. Ft. Classified Space

− Process Designed to Manufacture Microbial Based Bio‐Therapeutics

− Process Systems are a Mix of Single‐Use and Re‐Usable Equipment

− Process is Designed to Manufacture Bulk Drug Substances− Manufacturing Areas Include:

− Media Prepp− Seed and Production Fermentation and Harvest− Inclusion Body Dissolution and Refolding− Buffer Prep, Storage and Distribution− Primary Purification− Final Purification and Pegalation− Final Bulk Filling

Case Study – Indian CMO

• Media Preparation– 150L Reusable Vessel for Prep of Fermentation Media, Nutrient Feed, Dextrose and Lysis Buffer ConcentrateNutrient Feed, Dextrose and Lysis Buffer Concentrate

– Reusable Media Transfer Piping

• Fermentation– 20L Seed and 250L Production Reusable Fermenters

– 50L Dextrose 150L Nutrient Reusable Vessels

– Reusable Lysis Buffer Hold Vessely

• Harvest– Ultra Filter

– Disk‐Stack Centrifuge

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Case Study – Indian CMO

• Upstream Purification

– Inclusion Body Dissolution

• 500L Reusable Vessel and Interconnecting Piping

– Ion Exchange Chromatography

• 5 Buffer Concentrate Bags, 1 Product Pool Bag

• 200L Reusable PW Dilution Vessel

• Upstream Purification Buffer Preparation

– 500L Buffer Prep Vessel and Transfer Piping

– Guanidine HCl Based Buffer Concentrates

Case Study – Indian CMO

• Downstream Purification

– Reaction and Refolding

• Two 500L Reusable Vessels and Interconnecting Piping

– Ion Exchange and Affinity Chromatography

• 10 Buffer Concentrate Bags, 1 Product Pool Bag

• 250L Reusable WFI Dilution Vessel

• Two 250L Reusable Pool Vessels

• Diafiltration

– 3 Diafiltration Skids

• 3 Buffer Concentrate and 1 Pool Bag per Skid

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Case Study – Indian CMO

• Buffer Preparation

– 50L, 250L and 1,000L Reusable Vessels

Preparation of Buffer Concentrates– Preparation of Buffer Concentrates

– Reusable Buffer Transfer Piping

• Buffer Hold

– 29 Bag Bins

– Storage of Buffer Concentratesg

• 3x to 10x Solutions Diluted Inline with WFI

– Reusable Buffer Concentrate Transfer Piping to Upstream and Downstream Purification Operations

Keys To Successful Tech Transfer:

• Knowledge Management ‐ QbD

Technology Transfer Summary

Knowledge Management ‐ QbD• Strong Product Understanding

• Strong Process Understanding  ‐ CCP and CQA’s

• Document knowledge

• Project Management

/• Capability and Preparation of CMO/ Receiving Site 

• Planning & Communication

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John M. Hyde

Questions?

yChairman and Founder

Hyde Engineering + Consulting, Inc

Voice: +1.303.641.5468

E‐mail: john hyde@hyde‐ec comE mail: john.hyde@hyde ec.com