training technology transfer training

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Topic: Understanding and Implementing a Technology Transfer Process

Presenter: Steven Laurenz

08/05/17 2

Introduction

The purpose of today’s presentation is to review how governance systems in combination with technology transfer tools and templates can be used to transfer knowledge from R&D to a manufacturing site.

• The focus will be on drug products

AGENDA

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• The importance of technology transfer• The use of a technical review system to

update and review technology knowledge obtained during drug product development

• The use of a Product Strategy Review system to review important business aspects in preparation for transfer

• Tools and Templates used for technology transfer

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What is Technology Transfer?

The systematic procedure that is followed in order to pass the

documented knowledge and experience gained during

development and/or commercialization to an appropriate, and

authorized party.

It embodies both the transfer of documentation

and the demonstrated ability of a receiving unit to effectively

perform the critical elements of the transferred technology, to

the satisfaction of all parties and any/all regulatory bodies.

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Why Technology Transfer?Motivations

• Delivering a product of the highest quality is paramount to success of not only the transfer but to the performance of the product and our business – Critical for a successful commercial launch– Timely Development – Cost of failure– Quality of Final Product– Reduce regulatory risk – Efficient Use of Resources

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Importance of Technology Transfer

• Reduce time for transfer• Reduce lost batches on transfer • Lower level of required inventories• Rapid and efficient launch of

transferred projects • Reduced contractual conflicts with third

parties• Improved compliance upon transfer• Reduced level of internal effort to

complete transfer: improved efficiency

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Expected Benefits of a Structured Process for Technology Transfer

• Improve quality and success rate of technology transfers• Improve efficiency• Reduce technology transfer cycle-time and cost

• Improve compliance

• Rapid attainment of post-transfer standards and efficiencies

• Greater predictability of transfer costs, resources, and timelines

• Rapid attainment of post-transfer manufacturing standards

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What Needs to be Transferred

• Technical knowledge

To Operations personnelTo Regulatory personnelTo Quality personnel

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• System transfer from R&D site to Manufacturing site

Manufacturing batch records

Sampling plans

Analytical methods

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• Active Pharmaceutical Ingredient (API)• Drug Product• Analytical Methods• Local and international• Internal or Third Party• Implementation of Process Optimization

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• Knowledge in order to select and prepare the site of manufacture

Capital investment strategyRaw material sourcing planCleaning validation strategyLaunch strategy

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Gated System

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The Need for Gated Systems

• The CMC development process is a complicated system that can take several years to complete

• Critical deliverables need to be accomplished at specific times

• Deliverables have a tremendous impact on timing. Mistakes could add 6 months or more onto timeline and have large business implications

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Research and Development

Operations

CMC Development Team

Technical Review

Project Strategy Review

Quality and Compliance

Quality Review

CMC Development Review Structure

CMC Technical Review

A Technical Governing Program

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• CMC Technical Reviews are a series of reviews scheduled at critical milestones in the CMC development process

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Purpose

• The appropriate work has been completed for the stage of development

• Technical decisions made during development are acceptable to customers/receiving site Potential risks and/or issues are identified and appropriate action plans are available to address them

• Members of R&D, Operations, Regulatory, and Quality management are in agreement with moving ahead with development

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Schedule

Early Development

Full Development & Commercialization Post-Launch

Full Dev. Decision (End of Phase 2a)

LaunchFiling

CMC Technical Reviews

CR Guideline

FIM

TR0

Plans for first in m

an

TR1

Pre-C

omm

ercial Developm

ent

TR2

Pilot S

cale Experience

TR3

AP

I com. S

ynthetic route

TR4

Drug prodcut scale-up

TR5

Registration batches

TR6

AP

I val./DP

demo lot

TR7D

P V

alidationTR8

Manufacturing history

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Deliverables

• Each review has key deliverables that represent the milestones for that stage of CMC development

• The CMC team reports on the progress of those deliverables and maintains the focus

• It is important that risk around the deliverables be addressed so decisions can be made on moving forward to the next stage

• Each Stage has an associated responsibility matrix outlining the role for each functional area

TR1

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•Route of synthesis for First in Human (FIH) material and tox lot(s)•Update on solid form selection and/or salt selection•Polymorph update/plans•Results of forced degradation studies•Expected impurities/degradants•Comparison of impurity profiles for tox lot and FIH lot•Available stability data•Specifications•Plans through Phase IIa

•Development•Clinical supplies•Regulatory submissions

API Drug Product

•Results of excipient compatibility studies•Stability data for preliminary formulations•Description of formulation for FIH•Available stability data for FIH formulation•Dissolution data for FIH formulation•Specifications for FIH formulation•Plans through Phase IIa

•Development•Clinical supplies•Regulatory submissions

Intellectual property overview

TR2

• Acceptable salt selected

• Acceptable polymorph selected

• Scaleable route to API identified

• Crystallization process identified

• Adequate stability data available

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API

• Target dosage form and dosage strength range identified

• Development site identified• Proposed process/equipment

identified for development• Stability data available for

Phase I formulation• Excipient compatibility

studies completed• Potential Critical Process

Parametners (CPP's), IP's, Critical Quality Attributes (CQA's) identified for proposed process/equip

Drug Product

TR3

• Synthetic process proven (pilot scale) and clinical delivery plan

• API impurity profile controlled in Pilot Plant (PP) vs lab data

• API physical properties controlled in PP vs lab data

• Polymorph screen completed

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API

• Formulation (qualitative composition), manufacturing process and potential CPP's, IP's, CQA's identified at pilot scale

• Dosage strength (range) identified• Commercial package evaluation

studies completed

• Stability data available for prototype commercial. formula (pilot, 3-6 mo.)

• Test method for cleaning samples available for verification of equipment cleaning

Drug Product

TR4

• Commercial synthetic route identified• Final finishing steps for API defined

(crystallization, milling drying, etc)• Special processing, equipment,

containment identified• Scale and equipment selected for

registration runs• Tentative Int. specs and analytical

methods• Starting material / End of Phase 2

(EOP2) meeting strategy• Test methods and specs appropriate for

stage of development• Identification of critical parameters and

PJ strategy

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API

• Commercial process/formulation defined (final strength/shape/color)

• Primary package(s) defined

• Proposed product test methods and tentative specs (including dissolution)

• Test method validation complete• Regulatory filing strategy confirmed,

including equipment, scale, stability• Stability data available in proposed

commercial package (pref. 6 mo.)• CPP and CQA revised/updated based on

scale up• End of Phase 2 strategy defined• Studies of the effect of API properties on

the DP complete

Drug Product

TR5

• Registration runs completed• Commercial synthetic process defined• Appropriate validation of analytical methods

completed• Development report completed

• Commercial site, equipment, and capital identified for validation

• Process validation strategy defined• Analytical methods transfer strategy defined• Cleaning validation strategy • Manufacturing checklist initiated • Commercial timeline defined• Commercial volumes /estimated Cost of

Goods (COGs)• Vendor selection

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API

• Summary of registration run manufacturing experience

• Process range justification

• CPP's and CQA's identified • Launch scale plan (covered in detail by

PSR)

Drug Product

TR6

• Process justification critical parameters updated or PJ completion

• Process validation completed

• Analytical method transfer

• Manufacturing checklist completed

• Evaluation of PAI readiness

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• Test method transfer to QA labs

• Critical process parameters confirmed at commercial scale

• Potential manufacturing issues identified and addressed

• Specifications and manufacturing ranges revised for filing

• Rework/reprocess procedures available

• Life cycle management plan• Validation strategy defined• Validation protocol complete

API Drug Product

Demonstration or Verification Lot

• Ensure that product processes, analytical methods and documentation are properly transferred from development to commercial operations

• Identify and resolve issues with manufacturing, testing and packaging (if performed) and revise manufacturing instructions, sampling procedures, specifications, test methods or other production systems prior to the regulatory filing.

• Determine readiness for Process validation and confirm acceptability of validation testing criteria.

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TR7

• Launch build status

• Post validation monitoring plan

• Technology transfer strategy update or completion

• Inspection update• Review and update life cycle

management plan and IP

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• Overview of validation results, including a discussion of process capability

• Commercial launch plan• Technology transfer complete• Post-validation monitoring plan • Life cycle management plan • PAI and FDA review status• Safety information updated based on

clinical trial experiences

API Drug Product

TR8

• Review and update life cycle management plan and IP

• Manufacturing history, lab, and stability data reviewed

• Supplemental filings

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• Post-validation monitoring commitment results

• Review of compliance/CAPA history• Phase IV or other post-approval

commitments completed• Manufacturing history – process

capability• Test method history – adequacy of test

methods

• Stability history• Update CPP's based on manufacturing

history

• Life cycle management plan updated

• Supplemental filings

API Drug Product

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Approval of Reviews

• R&D Drug Substance/Drug Product: Senior

management• Operations

Drug Substance/Drug Product: Senior management

Supply Chain: Senior management

• CMC Regulatory: Senior management

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Approval of Reviews

• Approval indicates the following: Status of the deliverables is represented

accurately in the package and is acceptable

Meeting minutes accurately reflect issues discussed at the review meeting

Action plans for addressing individual issues are acceptable

Any identified risks have been sufficiently addressed to allow development to proceed

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CMC Development Review Structure

Research and Development

Operations

CMC Development Team

Technical Review


Quality and Compliance

Quality Review


Need to ensure that the business infrastructure is prepared for the new

manufacturing process.

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• A governance system is also needed to ensure that the designed manufacturing process fits into the overall business objectives

• Cross functional senior management review body

• Short decision driven meetings - not updates

• Strategic focus

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Objectives

• Ensure business and project management excellence• Focus on project risks and mitigation strategies• Ensure that project teams are resourced for success• Resolve issues and remove barriers• Improve commercialization process• Promote project understanding and cross-functional

communication and alignment

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Integrated View of PSR

Early Development

Full Development & Commercialization Post-Launch

Full Dev. Decision (End of Phase 2a)

LaunchFiling

CMC Technical Reviews

Project Strategy Reviews

CR Guideline

FIM

TR0 TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8

PSR1

Sourcing strategy

PSR2

TT

and Val. strategy

PSR3

Launch strategy

PSR4

Com

mercial readiness

PSR5

Post lauch review

/LCM

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Typical Topics for Review, Agreement, and Decisions

• Project Risk Management Plan Key risks in development, transfer, and launch (e.g.,

as identified by CR and QR)• Site selection• Sourcing strategy• Capital investments• Validation strategy• COGs strategy• Technology transfer• Launch plan• Product life cycle Management plan

Purpose of each PSR

• PSR1:Gain alignment and approval for the Sourcing Strategies and selection of commercial sites for API, Drug Product, and Packaging. Preliminary plans for API and DP Registration

• PSR2:Gain alignment and approval for the Integrated Technology Transfer ,capital investments required, and preliminary plans for API Process Validation and DP Demonstration Lots.

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Purpose of each PSR

• PSR3: Gain alignment on the organization’s readiness (including R&D and Commercial sites) for the first Regulatory Submission and to gain approval for the API and DP launch strategies.

• PSR4: Gain alignment on the organization’s readiness for commercial launch.

• PSR5: Assess post-launch manufacturing experience in commercial site(s) and to gain alignment on the life-cycle strategy for the product.

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PSR Templates

Review Name Key Review topics

PSR1: Sourcing Strategy • API Site Selection, and Sourcing Strategy

• DP Site Selection and Sourcing Strategy

• Packaging Site Selection• Capital• Preliminary API Registration Run Plan• Preliminary DP Registration Run Plan• Significant Issues From TR2

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PSR Templates

PSR2: Tech Transfer & Validation Strategy

• Integrated Tech Transfer Plan• Capital Investment Plan• Preliminary API Validation Strategy• Preliminary DP Demo Lot Strategy• Changes to Project Strategies since

PSR1• Significant Issues From TR3

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PSR Templates

PSR3: Launch Strategy • CMC Filing Readiness• API Launch Strategy• DP Launch Strategy incl. DP Validation

Plans• Changes to Project Strategies since

PSR2• Significant Issues From previous CRs

(TR4, TR5 & TR6)

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PSR Templates

PSR4: Commercial Readiness

• Launch and Commercialization Readiness

• Product Life Cycle Management Strategy

• Technology Transfer Metrics Summary

• Changes to Project Strategies since PSR3

• Significant Issues From TR7

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PSR Templates

PSR5: Post-Launch Review & Life-Cycle Strategy

• Assessment of post-launch performance to date

• Tech Transfer Metrics Summary• Product life-cycle management

strategy• Changes to Strategies Since

PSR4• Significant Issues From CR8

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Project Strategy Review (PSR) Logistics

Follow-upActions

CommunicateDecision and

Distribute Minutes

(within 3 days)

Project Strategy ReviewMeeting or Teleconference

Review Decision Package

One Week prior

Review BodyPreparation

Presentation10 – 20 minutes

Discussion 10 – 20 minutes

Decision Making(ClosedSession)

10 – 20 minutes

Debriefing(Decision Communication,

Action Logging)

10 minutes

Tools & Templates

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Technology Transfer

• DefinitionThe systematic procedure that is followed in order to pass the knowledge and experience gained during development and/or commercialization to an appropriate, responsible, and authorized party

Tools and Templates

• Drug Product Process/Equipment/Excipients of Choice

• Preliminary API Process Description• Preliminary DP Process Description• Site Capabilities Master Template• Technology Transfer Gap Analysis• Technology Transfer Acceptance/Success Criteria• Integrated Technology Transfer Plan

• Technology Transfer Owners Manual

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Tools and Templates

Tool/Template Purpose

Drug Product Process/Equipment/Excipients of Choice

• Guidance documents for project teams on preferred processes, equipments, and excipients for drug products

Preliminary API Process Description

• To communicate high-level API Process information for site and equipment selection, sourcing, gap analysis, and capital planning.

Preliminary DP Process Description

• To communicate high-level Drug Product Process information for site and equipment selection, sourcing, gap analysis, and capital planning.

Site Capabilities Master Template

• To provide description of commercial site capabilities to support the proposed process

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Tools and Templates

Technology Transfer Gap Analysis

• To identify gaps between manufacturing process requirements (DS, DP, Testing, Packaging)

• Current capabilities at the sites that have been selected for a particular project and to describe plans to close the gaps

Technology Transfer Acceptance/Success Criteria

• List of potential Acceptance/Success Criteria Categories for Technology Transfer.

• Acceptance criteria should be pre-determined and mutually agreed upon by the sending and receiving units.

• Finalized after development is complete and prior to process validation.

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Integrated Technology Transfer Plan

• An integrated project management overview of all the technology transfers (e.g. intermediate and final steps for Drug Substance, Drug Product, Packaging, and Analytical Methods)

• Serves as a formal tool for managing coordination and alignment among the different technology transfers and with other pharmaceutical development activities.

• Initially created after site selection, gap analysis, and determination of initial acceptance criteria.

• Updated as development is completed and the receiving sites are prepared for technology transfer. The plan is finalized prior to process validation.

Technology Transfer Owners Manual

To identify the information and documents necessary as part of transferring the process and methods for a product to the receiving manufacturing site

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Process, Equipment,

Excipients of Choice

Review Preliminary Process and Define Acceptance Criteria

Conduct Gap Analysis

Select Mfg Sites(PSR2)

Develop Preliminary Process Description

(TR2)

PreliminaryProcess

Description

Site Capabilities

Develop Technology Transfer Master Plan

(TR3/4) (PSR3/4)

Execute Development and Tech Transfer Plan

(Process Optimization & Justification and Site

Preparation)(TR5) (PSR5/6)

Validate Process & Confirm Acceptance

Criteria(TR6) (PSR7)

Gap List(Process &

Facility Modifications)

Initial Acceptance

Criteria

Initial Technology

Transfer Master Plan

Supply Chain

Workbook & Decision

Tree

Updated Technology

Transfer Master Plan

DS PV, Demo Lot and TMT Protocols

Technology Transfer Owners Manual

Site Capabilities

Master Template

Tools and Templates

How do we measure success

Technology Transfer Metrics

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• Schedule adherence for technology transfer readiness

• Validation (process, analytical, cleaning validation)•Number of lots to complete•System robustness

• Regulatory inspection (adherence to regulatory requirements, no observations)

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• New product introduction metrics (planned vs. what is observed at commercial site)

• Post-transfer process robustness metrics (how well is the commercial process performing)

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Summary

• Technology transfer involves using gated systems and appropriate tools and templates

Gated systems Technical reviews ensure development milestones are

met at critical time points Project Strategy reviews ensure the proposed

manufacturing process fits into the overall business needs of the organization

Tools and templates ensure technical knowledge is captured efficiently for the organization

Metrics provides a method to measure technical transfer success to continually optimize the process

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Summary

• Each company will have a different technology transfer structure but the principles will be the same.

Success of any program will ultimately depend on the close cooperation of the different functional areas and will require the development of collaborative cross-functional teams

training technology transfer training

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