technology transfer

04/10/2023 ISPE Indonesia 100412 MVS allrightsreserved

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TECHNOLOGY TRANSFERHow It is Implemented

in Pharmaceutical Industry

Mimi Virlany Syahputri,Ssi.,Apt


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Facing challenges : Patent expiration Lack of blockbuster medicines Regulatory Expectation Economical factor/politics many more

Current Pharmaceutical Industry Situation


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Current Pharmaceutical Industri Situation


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Responses :

Improve R&D Efficiency Merging/Aquiring Expand business activities Re-focus business activities Relocate/build manufacturing site Internal Improvement (i.e lean process) Exploring collaboration among Pharmaceutical

Company



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Collaborate of The International Conference

on Harmonization (ICH) and The United States Food and Drug Administration

Main goals of this initiative are: To promote the use of modern quality systems

approaches Encourage a risk management approach Support adoption of modern technology Harmonize cGMPs

Modernize cGMP for 21st Century


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Pharmaceutical Quality System

ICH Q10 provides a harmonized model for a pharmaceutical quality system throughout the lifecycle of a product and is intended to be used together with regional GMP requirements

Objective :• Achieve Product Realization• Establish and Maintain a State of

Control • Facilitate Continual Improvement

TECHNOLOGY TRANSFER A QUALITY SYSTEM APPROACH


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New Process Validation Guideline

Emphasis to use ICH Q 8, 9 und 10 Process Validation: The collection and evaluation of data,

from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.

Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.

Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.


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Q8 – Product Development

(Product Knowledge)

Q9 - Risk Managemen

t

Q10 – Pharmaceutic

al Quality System

(Technology Transfer)

Product Knowledge – Risk Management - Technology

Transfer


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Process of transferring knowledge about how to produce a specific drug from discovery research to process scale up, to full scale size in manufacturing, to Health

Authority licensing, and commercial launch of the product into the market

place.

Technology Transfer


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The systematic procedure that is followed to pass

the documented knowledge and experience gained during development and/or

commercialization to an appropriate, responsible, and authorized party. Technology transfer embodies

both the transfer of documentation and the demonstrated ability of Receiving Unit to

effectively perform the critical elements of transferred technology, to the satisfaction of all

parties and any, or all, applicable regulatory body.

Technology Transfer


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Success Criteria: Demonstrate with data conformance to success criteria standards as

outlined in the technology transfer plan: Process parameters and control mechanisms. Material suppliers Analytical methods Health, safety and environmental concerns Compliance with all registered commitments

Technology Transfer must also be completed: Safely The process being transferred runs as expected (yield, purity, cycle

time, etc.) On time (product launch). On budget. No “CRISIS” situations

Technology Transfer


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Product development cycle

Additional capacity Relocate business (site to site)

By product of corporate merger and consolidation

Technology Transfer


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Estimated cost to bring new drug to market is $500 to $800

million Requires 10-15 years of time Only 1 of 200 discovered drugs ever get to market Estimated 7 of every 10 products do not return capital

investment to their company

More efficient and effective To develop new products Utilize research findings and translate into commercial innovation Improve application of “upstream” scientific knowledge“ Downstream” activities of new product design

Ineffective technology transfer delays cost $1-$3 million loses per day in sales

Technology Transfer


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Technology Transfer Team (Giving/Receiving Site)

Experienced Cross Department (Core Member, Ad Hoc Member, Support Team) Strong Leader (Process, Quality and Business) Define deliverables

Nominate TT steering committee Realistic Timeline

Define Milestone High level timeline Details timeline (Identified your predecessor) Considers all delay factors

Periodic update meeting TT Team TT Team with Steering Committee

Key Factors


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Steering Committee

TT Team (RS)

TT Product A

TT Product B

TT Team (GS)

TT Team

QA QC

Engineerin

g

Productio

n

Purchasing

HSE


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Site to Site (Different Company)

Legal binding Confidentiality agreement Detail roles and responsibilities

(Giving/Receiving Site) Within Company

Service Level Agreement Detail roles and responsibilities

(Giving/Receiving Site)

Key Factors


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Confidentiality Agreement

Regulates the terms of disclose of confidential information by one person to another.

Material Transfer Agreement On how material is regulated and provided. A Material Transfer Agreement has similarities to a Confidentiality

Agreement. Deed of Assignment

Cease intellectual property from initial owner to assignee. Divested of all ownership of the intellectual property, include

future interest in the intellectual property. The assignee of the intellectual property becomes the owner of

the intellectual property. Financial compensation is paid to the former owner.

Agreement


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License Agreement

Grants a license, or a permission to use, the intellectual property, to the licensee.

The licensee is permitted to exploit the intellectual property. Licensee financially compensates the licensor Generally, the licensor is passive in this legal relationship. The licensor does not necessarily further develop the intellectual

property, nor participates in its marketing, but passively receives the financial compensation for having granted the license.

Strategic alliance or joint venture. Development and exploitation of the intellectual property.

Agreement


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The types of legal agreements to record such strategic

alliances are: (a) Co-Development Agreement

Jointly undertake the further development of the intellectual property.

The licensor seeks to continue to add value to the development of the intellectual property

Licensor is entitled to greater financial remuneration (b) Co-Marketing Agreement

Similarly licensed by the licensor to the alliance partner, but additionally, partner together to jointly market the pharmaceutical products developed from the intellectual property.

Adds value in a occurs by the alliance partners together accessing their respective marketing

Agreement


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The common terms of a confidentiality

agreement are:1. Secrecy : Recipient must maintain its secrecy,

and not disclose it without the discloser’s prior written consent.

2. Use for permitted purpose : identifies the permitted use or purpose to which the recipient can put the confidential information. The permitted purpose or use : will be the only

use to which the recipient can put the confidential information, and the confidentiality agreement



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3. Ending of obligations of confidentiality : will

provide that the obligations of confidentiality come to an end in each of the following events: the confidential information enters the public

domain the recipient receives the confidential information

from another person entitled to disclose it, without any obligation of confidentiality

the recipient can demonstrate it was independently developed by the recipient, by employees who did not have access to the confidential information.



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4. Duration of obligations of confidentiality :

Common used in biotechnology sector, often five to seven years.

5. One way and Two Way agreements A confidentiality agreement may be a one

way agreement or a two way agreement. A one way agreement is where one party

discloses confidential information, and the other party receives confidential information.

A two way agreement is one where each party is a discloser, and each party is a recipient in relation to the other’s disclosure.



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Roles and Responsibilities

Giving Site Provide latest source

documentation Latest specification

(internal/registered spec.)

Provide process expert (transfer knowledge)

Protocol/Report (Analytical Method Transfer)

Receiving Site Execute Protocol

(Analytical Method) Qualified Facility

and Equipment/ Instrument

Set up System Set-up Training

Program


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Documentation

Common language (hire translator if needed!) Define required document Latest version (Registration Document) Robust TT documentation system (e.g. version

control)

Key Factors


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Commercialization

Stage

Validation Stage

Pre-Validation Stage

Strategy Set-Up Stage

Assessment Stage

PhasesEff

ort

<<

<<

<

GxP

>>

>>


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Assessment :

Site Capability (e.g. Facilities, Utilities, License, Safety, Cleaning Validation Port-folio, Warehouse, Resource)

Product Specific (e.g. Equipment, Lab Instrument, Method, Specific Skill, Raw Material, Reference Standard)

System Review (e.g. SAP, LIMS, SCADA)

Predecessors : Information from Giving Site

Assessment Stages


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Massive Exercise Staggered : Site level, product specific, supporting

system Details (with timeline if possible) Team effort (supported by giving site) Duration may vary (project scale) Important information for :

Timeline Strategy

Appropriate Tools : Process Mapping

Make it Right First Time!

Assessment Stages


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Main Issues : Lack/Improper data and information Lost of details Lost in detail/Missing Big Picture

Challenges on getting data : Political issues from giving site Pandora box Poor GDP/no data at all

Assessment Stages


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Plot assessment outcome :

Pre-Validation Validation Commercial Stage (Project Closure)

To understand GMP expectation (Risk based approach) To understand whole process To understand the criticality

Strategy Set-up

When You Don’t Know What You Don’t Know …the Tendency is to

•Do More than is Necessary •Conduct Activities in Series Rather than in Parallel •Worry More than is Necessary •Become Confused by Varying

Opinions


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Include the timeline

High level : Stakeholder/Steering Committee Detail timeline : To track actual project Need to get acknowledgement form both GS and RS Be realistic Updated with version control

Lesson Learned for next project Important information for change over, set-up

bridging stock, avoiding lost on market sale Gant Chart

Strategy Set-up


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To understand rational behind from formulation,

process, material characteristic To transfer the knowledge To challenge the transferred product(s) to an

extreme condition (design space) To record and document initial transfer process Source of product information for long run The activities (depend on product nature) :

Placebo trial Technical Trial Pre-Validation Batches (e.g. FDA submission)



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R&D to Scale Up Manufacturing

•R&D Product Assessment

Pilot

•Scale-up Product Assessment

•Trial Protocol

Scale-Up•Trial Report•Updated Scale-up Product Assessment

Ready for Validation

•Validation Protocol

•Validation Report•Batch Disposition

Validation•Project Closure

Commercialization


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Expectation from R&D Updated document of (minimum).

Product Information Formula Rationalization Material List Product characteristic Self Life (Finished Product) and Bulk Holding Time Storage/Transport Condition Equipment List (include it’s type as per SUPAC) Specification (Registered/To be registered, critical and non

parameter) Testing Method (Include Method Validation) Precaution information (e.g. Sensitive to moisture, brittle if the

hardness below X kN) usually with FMEA assessment. Quality by Design or PAT



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IND Applicatio

nCover sheet

Tablet of Content

Introductory

General Investigation

Plan

Investigation Brochure

Clinical Protocol

Pharmacology and

Toxicology

CMC

Previous Human

Experience

Additional Information

Scale Up

R&D

CMC


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Consolidated under one document (Product Quality

Information, Quality Risk Analysis, Product Information)

Show an understanding of product knowledge Useful for long run (align with ICH Q10) Life cycle document Managing Risk Patient Safety Not for registration purposes, but subject to audit Facilitate Technology Transfer Translate R&D Information to Scale-UP Risk

Assessment (as per scale-up process)



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Not for registration purposes, but subject to audit

New Chemical Entity/New Biological Entity Extensive Information

Scale up/product transfer General Information (specific enough)

Material comparison Process flow (general equipment, process, IPC) Specification

Don’t limit industries’ space for improvement Close collaboration : Regulatory Person and Manufacturing

Site Conquered by Manufacturing Site and or R&D before

submission to Health Authority



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Material Information

Generic Chemical Name Testing Method (Pharmacopoeia or non

Pharmacopoeia) Process Information

Equipment (normally up to SUPAC Class only) Process Flow Discharge information (in total)

Specification Define registration specs. (based on product nature)



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Scale-up Product Assessment

Comparison all aspect between Pilot Scale and Scale-Up

For equipment type comparison : use SUPAC To help TT Team, Regulatory, and Health

Authority on assessing the impact To help on performing risk assessment To define process parameter/approval range To define trial strategy



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Example : Getweelsoon FCT Scale Up Phase

Same Material (API and Excipient) Different Equipment same equipment sub-class Scale up 10 folds Specification remained the same (limit,

registered, criticality) Need to define process parameter



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Critical Parameter

Control

• Speed• Compression

Force

Critical Quality

Parameter (Compression

)

• Hardness• DT

Critical Quality

Attribute

• Dissolution


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Challenge the compression process :

Low Speed – High Compression Force High Speed – Low Compression Force Low Speed – Low Compression Force High Speed – High Compression Force Mid Point

How we estimate Low and High Limit ? Use Equipment Operation Range as per Qualification

Document (50%-75%) Trial

Outcome : set point and proven range/acceptable range



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Benefit :

Understand process and product characteristic To confirmed and define parameter :

Registered - Critical Parameter Non Registered – Critical Parameter Non Registered – Non Critical Parameter Facilitate Change Management, Deviation, further continuous improvement.

Trial report Update Scale Up Product Assessment Base information for Manufacturing Instruction Ready for process validation



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Site to site Transfer

•Product Assessment/ Information

Giving Site

•RS Product Assessment

•Trial Protocol

Pre-Validation•Trial Report•Updated Scale-up Product Assessment

Ready for Validation

•Validation Protocol

•Validation Report

•Batch disposition

Validation•Project Closure

Commercialization Phase


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Internal Company

Same principle with R&D to scale up manufacturing More data (existing/mature product) – APR Easier on transfer knowledge Continuous support

External Company Confidentiality agreement Legal binding Extensive training Short term support

Site to Site Transfer


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Challenges

DON’T HAVE INITIAL DATATHEN HOW?

Product

Informatio

n


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Commercialization

Stage

Validation Stage


Strategy Set-Up Stage

Assessment Stage

ChallengesEff

ort

<<

<<

<

GxP

>>

>>

BIG

EFFO

RT


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Collecting Data (Annual Product Review) Product Release Data Deviation/OOS History Others

Basic Information

Confirmed with :Technical Trial (Placebo/With Actives)

Challenges


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GMP Principle : Write what you must to do and

do what you have written, record what you have done

Not only about record availability reason behind (knowledge based) and process thought

Subject to be audited Don’t based on memory No one can be

retained forever Let system works Minimize micro manage

Documentation


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Technology Transfer Procedure

Roles and Responsibilities General aspects per stage Pre-requisite action per phase/state (Pre

Validation/Validation) Items to be assessed (provide guidance) Interlink to other system/procedures (Project

Change Control/Change Control)

Documentation


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Technology Transfer Procedure

Roles and Responsibilities General aspects per stage Pre-requisite action per phase/state (Pre

Validation/Validation) Items to be assessed (provide guidance) Interlink to other system/procedures (Project

Change Control/Change Control)

Documentation


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New Site :

Project Change Control Existing Site :

Change Control Why Change Control :

Introduction new product may change your : Cleaning Validation portfolio Database Testing capability Facility/Utilities

Documentation


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Product Specific

System Based

Site Level

Change

Product Transfer from

Site A to B

Product Transfer

Tablet A

Tablet B

Facilities HVAC

Documentation


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Documentation

Initiation

•Supporting Document •Justification Risk Assessment

Review &

Approval

•Subject Master Expert Review•Management Review•QA Approval

Execution

•Complete all pre-requisite action

•Review before implementation

Implementation

•Implementation of change

Completion

•Follow up action

If regulatory impacted, implementation date must

align with regulatory approval

- To understand and define prerequisite action list before implementation (ICH Q9) -


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Closure

Team review and check Verified by QA

Product History

Update product assessment document

Documentation

CHANGE CONTROL

PRODUCT RISK ASSESSMENT

UPDATE

IMPROVEMENT INIATIVE


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Closure

Team review and check Verified by QA

Product History

Update product assessment document

Documentation

CHANGE CONTROL

PRODUCT RISK ASSESSMENT

UPDATE

IMPROVEMENT INIATIVE


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Technology Transfer

Systematic Approach on Transfer Knowledge Team Effort Emphasis robust documentation on process Build product knowledge for long run Align with health authority regulation (variation

handling) Establish agreement between sites

SUMMARY


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Thank you for your attention


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ISPE Technology Transfer Guide, 2003 Technology Transfer, A Quality Systems Approach, Frank S. Kohn, PhD.,

FSK ASSOCIATES, INC. Joseph A. DiMasi, PhD, Risks in new drug development: Approval

success rates for investigational drugs Le Trong Vu, P. Eng.,Joint CVG/Therapeutic Products Directorate

International Conventionand Exhibition Toronto, Canada, October 5 -6, 2006

Process Validation: General Principles and Practices, FDA Guidance For Industry, 2011

Philip Mendes, Partner, Innovation Law, Licensing and Technology Transfer in the Pharmaceutical Industry

ICH Q8, Product Development ICH Q9, Quality Risk Management ICH Q10, Pharmaceutical Quality System

REFERENCE

technology transfer

Documents