Technology Transfer & Integration Known & Unknowns ... · Prompts FDA Warning Letter to Warner...

Copyright 2012- Yelvigi & Banks 1

Technology Transfer & Integration

Known & Unknowns Impacting Business

Continuity

Sinduspharma/ANVISA/IPS Symposium, Brasilia, Brazil

June 25, 2012

Mike Yelvigi

Sr. Director, CMC Portfolio Management (Retd.)

Pfizer, Inc. New York

&

Michael ‘Mick’ Banks

Vice President, CMC Portfolio Management (Retd.)

Pfizer, Inc. New York

Copyright 2012- Yelvigi & Banks

Current context-Why ?

Review of Technology Transfer & Integration concepts

Types of Technology Transfer & Integration Processes

Risks and Unknown Challenges

Examples of Successful Technology Transfers

The Future

Technology Transfer & Integration AGENDA

2


Current Issues facing Business

Continuity-Headline News !!

Inadequate Tech Transfer of Oral Contraceptive

Prompts FDA Warning Letter to Warner Chilcott

May 2nd, 2012

Doxil Drug Shortage at J&J-impacting cancer patients

FDA imports life saving drugs from Sun Pharma, India to fill shortages

Genzyme plant shut down –viral contamination

Major Pharma delays Phase 3 start of Oncology drug…….


Current Issues facing Business Continuity

Of the ~178 drug shortages in US~50% are due to CMC problems e.g. validation failure, sterility issues, lack of capacity, poor technology transfer…FDA

While QbD is recently introduced concept, we concurrently need to fix manufacturing processes to maintain business continuity

Technology Integration -not well understood across business-processes and regulatory processes !

Overall lost opportunity in billions & ineffective patient care !!!


Technology Transfer & Integration-The Impact

Effort for Technology Transfer and Integration underestimated

Drug shortages at extreme

Major compliance issues

Increased Costs


What is Pharmaceutical Technology

Transfer & Integration - Definition Technology Transfer

Systematic approach of conveying knowledge &

expertise, documentation, equipment & technology,

systems and processes between parties

A technology transfer will be successful if the

receiving unit can routinely reproduce the product,

process and/or method against a predefined set of

specifications, and to up to date standards and

regulations.

Technology Integration:

A systematic approach of harmonization of two or

more functional processes like R&D, Manufacturing,

Quality Systems, IT etc.


Technology Transfer &

Integration-Why is it important ?

Over the last two decades many mergers & acquisitions resulting in:

– Cost Reduction and business simplification

– Consolidation of facilities (R&D/Manufacturing)

– Harmonization of systems

– Increased CRO and CMO participation

– Increased licensing

– Increased Regulatory Scrutiny

– It is imperative that technology transfer meet both regulatory and market place dynamics to be competitive


Industry Consolidation 1980-2003

SKF Allegan Beckman

SKB Beecham

SKB

DPS

Sterling

GSK

Glaxo

Wellcome

GW

Affymax

B-M

Mead

Johnson Westwood

Dupont

BMS

Zimmer

BMS

Zimmer

Squibb

GlaxoSmithKline Bristol-Myers Squibb



Ciba Geigy

C-G Sandoz

Food &

Beverage

Lek

Sygenta

Novartis

BASF

Generics

Novartis Pfizer

Pharmacia

AB

UpJohn

Monsanto

(Ag)

Pharmacia

Wyeth

Pfizer

G.D.

Searle

Monsanto

Monsanto

Sugen

W/L



Marion

Merrell Richardson

Hoechst

Sanofi

Aventis

Centeon

Merrell

Dow

Roussel

Uclaf

Aventis

Behring

Institut

Merieux

Rhône-

Poulenc

Union

Carbide

Ag

Rorer Rhône-

Poulenc

Rorer

Animal

Nutrition

Crop

Sciences

-Bayer

Pasteur

Merieux

Connaught

Connaught

Hoechst

Marion

Roussel

Marion

Merrell

Dow

History Keeps Repeating !!


Marion

Merrell Richardson

Hoechst

Ave

ntis

Centeon

Merrell

Dow

Roussel

Uclaf

Aventis

Behring

Institut

Merieux

Rhône-

Poulenc

Union

Carbide

Ag

Rorer Rhône-

Poulenc

Rorer

Animal

Nutrition

Crop

Sciences

-Bayer

Pasteur

Merieux

Connaught

Connaug

ht

Hoe

chst

Mari

on

Rou

ssel

Marion

Merrell

Dow

Ciba Geigy

C-G Sandoz

Food &

Beverage

Lek

Sygenta

Novartis

BASF

Generics

B-M

Mead

Johnson Westwood

Dupont

BMS

Zimmer BMS

Zimmer

Squibb

SKF Allegan Beckman

SKB Beecham

SKB

DPS

Sterling

GSK

Glazo

Wellcome

GW

Affymax

SKF Allegan Beckman

SKB Beecham

SKB

DPS

Sterling

GSK

Glazo Wellcome

GW Affymax

Pharmacia

AB

UpJohn

Monsanto

(Ag)

Pharmacia

Wyeth

Pfizer

G.D.

Searle

Monsanto

Monsanto

Sugen

Technology Transfers &

Integrations:Wide Scope !


Product Life Cycle & Tech.Transfer

Technology Transfer

Technology Transfer

Pre-Clinical Development

Phase I Phase II Phase III Scale-up through Launch

Post-Approval

New Entity, IND Application

Phase II Phase III Scale-up through Launch


Types of Technology Transfers &

integrations

Internal (Intra-company)

Process Development to Clinical Production

Process Development to QC (Quality Control)

Clinical production to Commercial production

(site to site)

External

Client to CMO (Contract Manufacturing

Organization)

Third party to CMO

CMO to Client or another contractor


Types of Technology Transfers & Integrations

Types of Transfers

– Scale-up

R&D to Process Development

Process Development to Production

– Within site

– Site to Site

Within Region

Within Country

Country to Country

– Company to Company (M&A)

Phase of development

Third Party

Licensing


Facility

Pharmaceutical Technology

Transfer & Integration Scope

DRUG

PRODUCT

Manufacturing

Process

Training

Equipment

Packaging

Systems

Analytical

Methods

Raw Materials

Quality Systems

Drug Substance

Computers


Technology Transfer-Current Status

There is no uniformity in technology transfer process across industry

Technology transfer criteria better understood in other industries -Auto, Diagnostics where it is easier to measure success

Larger companies have their own systems, guidelines and SOPs

No regulatory guidelines in general on technology transfer


Technology Transfer- The Old Way

Phase III Scale-up through Launch

Post-Approval Pre-Clinical

Development Phase I Phase II

R&D Manufacturing

•Unreliable

•Costly

•Wasteful

•Limited Information Exchange


Prod.

Process

Understandin

g

Systematic TTI

approach

People

Expertise SUCCESS

Technology Transfer & Integration:

“An equation For Success”

•Strong

Leadership

•Trust & Respect

•Partnership

•Mutual

recognition of

Expertise &

experience

•Joint ownership

and authority

Guidelines:

ISPE

-WHO

Guideline 2011

Japan guideline

Comprehensive

Business

Process Tools

Training

-

ICH-Q8,

ICHQ9

ICHQ10

QbD

PAT

Modeling

Reproducible

Manufacturing

& Release

Continuous

Supply Chain

Continuous

Improvement

Sustained

Regulatory

compliance

Reduced Cost 19

Copyright 2012- Yelvigi & Banks 20 20

THREE MAJOR BUILDING BLOCKS

Governance

Process

Guiding Principles

Detailed interdependent flowchart of

decisions, documents and physical

deliverables that constitute the

Tech.Transfer process

Structural environment in which

Tech.Transfer process operates

• Dedicated cross-functional -

development team with sub teams

(API, DP) responsible for carrying out

development process

• Single governance team ,

Foundation upon which Master Tech.

Transfer Strategy is built

• Defines Strategy (Master Plan)

• Lays out agreed-upon development

strategies

• Defines roles and responsibilities

1

2

3


Technology Transfer: Ideal Process

Phase III Scale-up through Launch

Post-Approval Pre-Clinical

Development Phase I Phase II

R&D Manufacturing

•Shared Ownership

•Shared technology

•Shared Responsibility

•More reliable

•Much less cost

•Better compliance



Pitfalls

-Corporate level

-R&D Level

-Pharmaceutical Science level


Challenges in Mergers & Acquisitions

Complex process (Business, Regulatory,

Operations, R&D)

Initial focus on financial & timelines

Underestimation of downstream activity

(e.g. Manufacturing transfers-

Integration, R&D process Integration)

Managing third party alliance and

continuity

Many unknowns


Challenges for R&D integration

Huge Merger task- Global centers involved,

personnel, budget (several billon $)

Project goals/deadlines (NDA ,IND, Launch

dates)

Managing Clinical study continuity- supply

complexity

Capacity and skill sets (existing organizational

design constructs)

Expectation is exquisite business continuity !!!!!


Challenges for R&D integration

Different philosophies & organizational construct

Managing R&D Support Systems of two merged

companies:

GMP & Non GMP Documentation systems, IT

systems, LIMS merger, SOP systems

R&D Report Migrations (Thousands of Reports-

need good retrieval system-ease of access)

Change Control systems between two companies

(different global sites)

Managing HR harmonization of personnel

Pharmaceutical Sciences: Some Challenges

Legacy Products-significant technical Challenges, may not

support US FDA Stage 1 process validation requirements

Lack of background information for de-risking the process,

e.g. API , in-process details

Limited process knowledge

Process understanding to minimize Program Risk and to

implement effective control strategy

Complexity of product manufacture, registration time lines

in different global zones



27 27

How to Achieve Effective

Technology integrations:

Senior level Strong leadership

Defined Frame work (clear timelines,

costs, objectives and boundaries)

Comprehensive Plans at all levels

Crisp Communication & Decision

making

Routine follow up on progress and

completion of action

Successful R&D Center Mergers between two

large Pharma companies:

More than 150 projects evaluated from Phase 0-

Phase 3 in less than 1.5 Years

Effective transfers completed for ~80 projects from

Ph1-Ph3 on turn key basis in less than 1.2 Years

Effective merger of vast documentation and Quality

systems (Parallel and Establish mode)-including

merger of IT, Regulatory, cGMP training

Achieved redefined R & D footprint

Secured business continuity-project & regulatory

milestones, clinical trial supplies & time lines

Slim and effective team managements with Roles

and Responsibility defined from top to execution

level Copyright 2012- Yelvigi & Banks 28

How was the R&D Integration successful?

Various Teams from Corporate to individual Project

Team levels

Facility-Equipment Team (Engineering)

People Team (Human Resource Management)

Knowledge Management team (Implicit & Explicit

KM)

Key Transfer Tools-Professional Business Process

Tools , Harmonized Templates across all activities

Members from both organizations

Transparent & Effective communication at all levels

Drug Product Transfer (Lead 1-1.5 Years)

API Transfers (Lead 1-3 Years)



Portfolio: Overall Transition Plan

-

2011 2012

Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

3 months

3 months

3 months

4 months

4 months

Key

Milestones

Waves

Data Exchange in place

Wave 5-15

Wave 4-14

Wave 3-5

Wave 2-20

Wave 1-10

Pre-Data Exchange

Data exchange

available for IT solution

Pending IT solution

by 3/31; if not met,

Wave 2 will resemble

Wave 1

Transfer of

operational roles

& responsibilities


Project Transfer team

Single team per project,

multi-discipline

membership, executes

specific asset activities

and assures coordination

of program across departments

Team

Lead

ARD API

DP

API

DP

Reg

Supply

Sourcing

DP

Clinical

What about Technology Transfer of

Products from R&D to

Manufacturing ?


Technology Transfer of products

from R&D to Manufacturing

R&D Manufacturing

•Shared Ownership

•Shared technology

•Shared Responsibility

•More reliable

•Much less cost

•Better compliance


GUIDING PRINCIPLES & GENERAL STRATEGIES

• A single Development Plan is

jointly developed for each project

• This document will cover the full

development activities for the

project.

• This plan will evolve through the

course of development & transfer

• The plan reviewed and endorsed

by the team.

• Major changes (timeline,

resources, level of risk) to the

baseline plan will be reviewed

with the team.

Guiding Principle

Ownership and Deliverables

Roles & Responsibilities

• Regulatory

• Technology

• Capital Investment

• Manufacture of Supplies in Mfg.

facilities

Strategies and Activities

• Launch

• Teams and timing

• Materials supply

• Site selection & technology

transfer

• Licensing opportunities

• Right First Time


Qualification

An Example of Team Formations:

Design Phase

Pharma Delivery

Team

Core

Line Management

Sub-teams kick-off

-Define Sub-Teams

-Kick Off, as

needed

Dev Plan

Assigne Members

as Line Managers

Initiate Mfg

Site

Decision(1)

Sub-Team

members selected

Provide sourcing

info for Site

Selection

Sub-Teams

R to D

transition

Input to Plan

Submit Plan

Endorse Dev

Plan(2)


NEXT STEPS ARE TO EXECUTE AGAINST

DEVELOPMENT PLAN

Execute Dev Plan

Qualification

Review and endorse

Milestone Docs )

Involved as necessary according team

Engagement Rules

Execute and Update

Dev. plans, if necessary

Ensure cross line alignment,

milestones, endorse

changes to plans, aid issue

resolution

Pharma Delivery

Team

Core Line

Management

Sub-teams

EXECUTE VALIDATION PROTOCOL AND

MANUFACTURE LAUNCH BATCHES


Validation protocol

for commercial

supplies*

Endorse validation

strategy

Involved as

necessary

Validation

Produce

validation

batches

Assume full

manufacturing

responsibility

Post-launch

Transition of Core

and Sub Team

leadership to Prod.

Compile Post-

launch lessons

learned

Review post-

launch lessons

learned

Pharma Delivery

Team

Core

Line Management

Sub-Teams

Mfg.

CTD Filed


How to measure success ?

•Ability of “receiving unit” to manufacture and

release product on a reproducible manner

•Absence of regulatory issues

•Continuous supply chain

•No failures

•Ability to meet cost of goods

TOOLS & TEMPLATES




Product Robustness Index

Product

Robustness

Measures

Descriptions Calculation

Stability Is the following product stability available:

–6 months accelerated product stability data predictive of 24 months expiry/shelf life in the intended commercial packages (bottle/blister)

Yes/No

Dosage Uniformity Definition in process

Goal is to develop a statistical confidence interval to include in the definition

Yes/No

Risk Assessment Has a risk assessment been completed and broadly agreed (by key stakeholders – Technology, R&D, Quality) as per ICH guidelines?

Yes/No

Critical Quality Attributes of Product

Critical Quality Attributes have been identified and assessed at gate, including:

Yes/No


Clinical Supplies Risk Assessment

Project Description /

Business Case

Develop and imbed a

detailed Clinical Supplies

Risk Assessment

processes for program/

protocol clinical supplies

success proactively.

Interface with Clinical and

Dev. Ops colleagues to

align risk assessments across the

R&D organization with regards to

Clinical Supplies to identify and

establish mitigation plans and

improve overall quality.

Project Scope / Objectives

Develop a Clinical Supplies Risk

Assessment Guideline and process to

be utilized during the planning and

upfront initiation of a program phase

or an individual protocol.

Risk assessment Ensure alignment

across various teams (CAPA 1, and

establish communication plan to

ensure all stakeholders are aware of

status, progress, and plan.

areas should include everything from up front

planning in the protocol as well as compliance

issues with the sites.

Project team

XYZ

ABC

DEF(Sponsors)

Project Deliverables

High Level Timeline

Risks /

Assumptions

1.Quality is the

responsibility of all

2.Alignment of

interdepartmental

objectives and initiatives

3.Internal organizational

alignment to support

development of best

model

4.Senior leadership will

need to be vocal advocates to

help drive a successful program.

CLINICAL SUPPLIES RISK ASSESSMENT J F M A M J J A S O N D

Current state review/Stakeholders Defined

Solicit Input on Content from Stakeholders

x

Develop an ongoing Monitoring Plan

Implement/Roll-out to Supply Chain

st Pilot)

Develop a detailed Clinical

Supplies Risk Assessment

Guideline document as an

appendix in CT-02 as well

as tools that will be useful

during the Risk Management

Process

Develop an implementation

plan for communicating and

al roll-out

Develop a monitoring plan for


Site Transfer

Gantt chart example:


Knowledge Transfer Templates

Project Name (if assigned)

Name: CureAll

Project Number (give XX number and any others

that have been used in the past)

XX-abcdefgh / ABC-123 / Sol-abcdef

Instructions for Using The Project Knowledge

Management Template: Column Definitions

Information Category: Most project information can be categorized using the descriptions contained within the PhTx PS Project

Transfer Checklist. This column indexes the descriptions.

Information Category Description: The PhTx PS Project Transfer Checklist descriptions.

Applicable to Project?: Yes/No If no, please enter rationale. For example, project has not reached this stage of development, no

licensing partners or not an on-going project activity. Suggest using "No, R" for the rationale of project has not reached this stage of

development even if the program is in Development.

Report Name: Enter the name of the type of report represented by the document. For example, Dosage Form Nomination or

Analytical Test Report. For technical reports with no formal name, use a generic descriptor such as "technical report".

Technology Transfer & Integration : the Future ?

The Pharmaceutical Industry will continue to

experience mergers, acquisitions, interactions with

many external CRO & CMOs work and internal

changes

Increased use of CMO and CRO ( business

partnership model)

(Continued) Increased emphasis on reducing cost ,

reducing timelines whilst maintaining quality

standards and achieving regulatory compliance


Technology Transfer & Integration : the Future

Increased attention to Tech Transfer &

Integrations by regulators and policy

makers in all geographical areas

Business continuity issues and lost

opportunities will likely to occur


What is needed now and in the future ? Critical focus on technology transfer and integration

exercises to avoid business continuity problems.

Well defined technology transfer and integration

policies

Further development and application of scientific

tools and processes

Further enhancement of roles, responsibilities and

processes for CMO and CRO interactions (business

partnership model)

Refinement and wider application of successful

technology transfer and integration best practices

Training to fill existing gaps and provision of

contemporary processes and templates.



Mike Yelvigi

Center for Pharmaceutical Integration LLC.

[email protected]

&

Michael ‘Mick’ Banks

Banks Consulting Group

[email protected]

mailto:[email protected]

Date post:	06-Aug-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

Technology Transfer & Integration Known & Unknowns ... · Prompts FDA Warning Letter to Warner...

Documents