Technology Transfer

Risk Management in TT – Siviglia Nov 2018

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 Why Join this training

60 to
$1T $160B
10
Global pharma and biotech Shrink in number of Pharma
Global Rx sales by 2020
R&D spend by 2020 players due to M&A in the last
20 years

TT IS AND WILL BECOME A MORE CRITICAL BUSINESS NEED,

A “BEST TO BEST DEAL” WITH CUSTOMERS, TOP PLAYERS LOOKING FOR CDMO
TOP PLAYERS
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 Why Join this training

• Incredible increase of number of Technology Transfer projects (TTP) in the

pharmaceutical environment, both internal & external and consequent increase of
attention on Technology Transfer (TT) handling by Authorities;

• Project complexity is growing day by day;

• Risks of failure is always high;

• Quality Risk Management (QRM) & Project Management (PM)

skills and knowledge are fundamental for success!

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 My expectations for the two days…

• Meet new people

• Networking

• Share experience on TT

• Benchmarking on TT organization, Approaches

• Understand opportunity for improvements

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What about you?

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Day 1
Thursday, 23 November 2017 9:00 – 17:30
9:00 Welcome & Attendees Introduction
9:00 Technology Transfer – Definition and Main Principles
• Opportunities along product lifecycle
• Regulatory guidance on technology transfer
• Planning and Social Intelligence
• Tool for planning
10:00 Technology Transfer – Definition and Main Principles (continued)
• Tool for Social Intelligence
• Role and responsibility
• General org chart in technology transfer
11:00 Coffee Break
11:30 Technology Transfer Project Management Tools
• Timelines
• Leadership
• Communication
12:30 Lunch Break
13:30 Technology Transfer Documentation
• Technology Transfer Plan
• Technology Transfer Report
• Feasibility batches Protocol and Report
14:30 Technology Transfer Procedures
15:30 Coffee Break
16:30 Analytical Transfer
• General approach (transfer vs validation)
• Analytical Master Plan
17:00 Recap of the Day
17:30 End of Day 1
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 Day 2

Friday, 24 November 2017 9:00 – 16:30

9:00 Recap of the Main Concepts of Day 1
9:30 Introduction into Technical Report TR 65
• Project staging
• Risks in technology transfer
• Risk Management in technology transfer
10:30 Introduction into Technical Report TR 65 (continued)
• Severity/Occurrence/Detection in technology transfer
• FMEA
11:00 Coffee Break
11:30 TR 65 – Case Study 1 ‘Analytical Method Transfer (AMT)’
• Design of Comparative AMT Test Studies
• Selecting AMT Performance Characteristics
• AMT Documents
12:30 Lunch Break
13:30 TR 65 – Case Study 2 ‘Manufacturing Process Transfer’
• Overvew of Manufacturing Process Transfer
• Development to Commercialization Technology Transfer Process
• Intracompany Technology Transfer Process
16:30 End of Course

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Technology Transfer – definition and main principles
 Terminology

Receiving Unit (RU) Technology Transfer (TT)

The involved disciplines at an organization The transfer of product and process
where a designated product, process or knowledge between development and
method is expected to be transferred. manufacturing, and within or between
Risk Management (RM) manufacturing sites to achieve product
realization (ICH Q10).
Risk is combination of severity of harm and
probability of occurrence (ICH Q9). Technology Transfer Project (TTP) is a set of
planned and controlled actions based on
Applicable to Technology Transfer Projects –
well-defined acceptance criteria needed to
harm is event that could delay/stop a project
transfer a technology from a sending unit
Comparability (SU) to a receiving unit (RU).
The demonstration that the quality attributes Sending Unit (SU)
are highly similar and that the existing
The involved disciplines at an organization
knowledge is sufficiently predictive to ensure
from where a designated product, process
that any differences in quality attributes have
or method is expected to be transferred.
no adverse impact upon safety or efficacy of
the drug product (ICH Q5E).

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 Technology Transfer main concepts

A process for conceiving and implementing a new/novel application for an existing

technology (Reisman, 1989)

The technology transfer consists of actions taken ….to realize the quality as designed
during the manufacture (NIHS, 2005)

A logical procedure that controls the transfer of an established process together with its
documentation and professional expertise to a site capable of reproducing the process and
its support functions to a predetermined level of performance
(WHO Guideline on transfer technology, 2008)

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 Technology Transfer main concepts

The Technology Transfer Project (TTP) is defined as a set of planned and controlled
actions, based on well-defined acceptance criteria needed to transfer a technology
from a sending unit (SU) to a receiving unit (RU).
The Technology Transfer implies four main topics:

• Technical knowledge
• Documentation management
• Project management
• Personnel training and skills

PDA – PMCO Program – Technical Report N.65

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 Technology Transfer main concepts

The Technology Transfer Project (TTP) is defined as a set of planned and controlled
actions, based on well-defined acceptance criteria needed to transfer a technology
from a sending unit (SU) to a receiving unit (RU).

Technology = Drug

Technology Transfer Projects must have product quality, product safety and process
performance as primary objectives.

Good Transfer Good, Reproducible, Safe and Good & Safe Product delivered
Practice Effective Manufacturing Practice to the Patient

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 Technology Transfer main concepts

The Technology Transfer Project (TTP) is defined as a set of planned and controlled
actions, based on well-defined acceptance criteria needed to transfer a technology
from a sending unit (SU) to a receiving unit (RU).

Scope of the project must be clearly stated and agreed upon within the team and a
structured plan needs to be developed.

Project is a sum of non-repetitive activities which are:

- addressed to a particular goal
- have to be performed in a defined time range
- employ defined resources
- and are managed by a team.
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 Technology Transfer main concepts

The Technology Transfer Project (TTP) is defined as a set of planned and controlled
actions, based on well-defined acceptance criteria needed to transfer a technology
from a sending unit (SU) to a receiving unit (RU).

Two main Risk Categories in Technology Transfer:

- Project Risks, associated with project management and people handling

- Process Risks, associated with technical issue during process execution

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Technology Transfer – When ?
Technology Transfer – When?

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Technology Transfer – When?

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Technology Transfer main concepts

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 Technology Transfer – When?

Identify Establish Maintain Discontinue

Relationship Commercial Product

Search
Foundation Production Retirement

Technology Relationship Partnership

Assess
Transfer Management Retirement

Knowledge Change
Audit
Development Management

Process
Select
Qualification

Registration
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 Technology Transfer – When?

Different pharmaceutical Technology Transfer Project contexts can be managed; each

with specific peculiarities; assuming the technology to be transferred is the drug
manufacturing process, several possibilities arise:

•Development to clinical phase TTP

•Clinical Phase to Commercialization TTP

•Commercial TTP

•Intra-company site to site TTP

•Inter-company site to site TTP

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Technology Transfer – Standard Project description
 Technology Transfer main concepts
Quality Control

Compliance
Materials
Analytical definition &

(QAC)
Stability activities Regulatory file
(QC)

transfer documentation PV release

Project Plan TT,QC Analytical Process Validation preparation
report Report Project plan Materials
specifacations
Process Validation report
Technology Transfer

NO

Preliminary Define and Tech Run

assessment on Final Assessment TT Plan Protocol TT Report
CCF preparation
(TT)

KO meeting Yes share preparation

SU document on Project preparation preparation
project plan
TT Team TT Team TT Team
TT agreement Additional TT Team and rework TT Team Project Plan Tech Run Process
Info to be Protocol Validation
reworked? Report

Pharmaceutical
Logistics (LOG)

Development
System (PDS)
Equipment
Validation and
Materials Materials order manufacturing Developement
procurement and delivery scheduling activity
Project plan Materials Project plan Activities scheduling If expeted withinTT;PDS Developement
available the TT agreement report
Engineering (ENG)

Regulatory Affairs
Equipment
Validation Master Materials installation &
Plan preparation available Regulatory
validation

(RA)
activities
Project plan Validation Equipment
Master Plan Validation Project plan Regulatory
Report file
Equipment
Validation Protocol
Manufacturing

Process
(MAN)

Process validation
Tech Run MBR Analytical report Tech runs Validation MBR manufacturing
preparation manufacturing preparation stability
Tech Run Tech runs Process Vaidation Process Validation
protocol report protocol report

Materials available

Equipment
Validation (QAV)

Validation Process Development report Cleaning

Media fill Protocol Validation validation
Process

preparation Protocol assessment

If expeted within Project plan MF Report Validation TT Team Equipment Validation Tech run TT Team Process Validation Cleaning
the TT agreement Master plan Protocol Report protocol Report

Validation Master Plan

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 Technology Transfer main concepts

5 main steps!

1. Planning
a. Definition of Project Scope and Rationale and the overall project plan
b. Technology and Knowledge clearly stated
c. Delvierables defined
d. Control philosophy agreed
e. Risks evaluated and mitigation plan defined

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 Technology Transfer main concepts

5 main steps!

2. Process Readiness
a. Control and Achieve the readiness set for the poject
b. Each TT phase and milestones has its own readiness
c. Stage/Gate step along the project exeution
d. Process changes tracking and handling
e. Training and expertise challenge

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 Technology Transfer main concepts

5 main steps!

3. Implementation and Qualification

a. Facility modification
b. Equipment installation and modification
c. Analytical transfer
d. Cleaning and environmental monitoring
e. TT batches
f. Process Validation

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 Technology Transfer main concepts

5 main steps!

4. Licensing & Manufacturing

a. Regulatory submission
b. Monitoring of the manufacturing batches

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 Technology Transfer main concepts

5 main steps!

5. Project Closure
a. Continuous improvement
b. Lesson learned

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Technology Transfer main concepts

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 Technology Transfer main concepts

The technology transfer protocol must establish the context for the TTP, including internal and
external contextual factors and which risk-management tools to use. The external context might
include competitive, financial, regulatory, legal, environmental, and cultural aspects. The internal
context can involve company policies and procedures, systems, operational objectives, personnel
training and knowledge, available resources, and culture.

All personnel with management roles in the transfer, including the two team leaders, should
agree to and sign the project plan. A gate review by senior leadership (or sponsor) is used to
make visible the plans and risks and provides approval to move to the next stage. In same cases
project committee, which has a mainly consultant role, could be useful for the success of the
project.

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 Take Away

- Multidisciplinary Context

- Be always focus on Patient as this is our final «Client»

- Dynamic and challenging environemnt

- Two main Risks categories to be considered

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Technology Transfer – Project Risk ans Social
Intelligence
 Technology Transfer main concepts

The Technology Transfer Project (TTP) is defined as a set of planned and controlled
actions, based on well-defined acceptance criteria needed to transfer a technology
from a sending unit (SU) to a receiving unit (RU).

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 Technology Transfer main concepts

Which are the main Project risks?

1. Project Scope missed or misunderstood

2. Underestimating of new site/process impact on product attribute
3. Lack of product/ process understanding
4. Lack of communication
5. Lack of escalation process
6. Wrong extimation of time/resources/costs
7. Lack of engagement of Team members
8. Lack of performance monitoring during execution

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 Technology Transfer main concepts

Quality and
Technical Internal team
Objectives features External dynamics
and Time Team
dynamics

Costs & Organization

Resources and
Management

Planning Social Intelligence

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 Technology Transfer main concepts

An organizational model that identifies the people or groups responsible for each task must be developed and
identify which matters are subject to risk-based decisions.
Two main organizational model are seen in the pharma environemnt: light matrix and hard functional
Often a light matrix approach is preferred. The hierarchical relationship between a project figure (such as an SU
leader, technology transfer department, or SU staff member) is maintained in a priority way (bold arrow). This
organizational model minimizes the impact of the transfer activities on the routine activities of the units involved in
the transfer

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 Technology Transfer main concepts

In a hard functional approach, a «Business Unit» is created around the technology transfer needs. Main SMEs report
directly to the Technical Lead with a «silos» approach.
Typical of small companies with few TTs per year, it seems to be the best way to provide hard control of well defined
and specific activities in a routine and standardized environment.

Production
SME

Engineer Technical SC SME

ing SME Lead

Quality
SME
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 Technology Transfer main concepts

Each team in the RU and SU should be coordinated by a team leader who is the “owner” of the

technology project and is responsible for implementing the technology at the RU or SU (e.g.,

manufacturing in the case of transfer of an industrial process).

The SU and RU technology team leaders should regularly update the project manager on the progress

of the activities, budget use, potential technical or economic issues, and proposed corrective actions.

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Technology Transfer main concepts

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 Technology Transfer main concepts

The success of a Technology Transfer is largely related

to the communication skills and relationship of the
Technology Transfer team members.
• Open communication between team members
• Effective and timely communication
• Direct communication between subject matter
experts

The Technology Transfer leader facilitates meetings and communication

between teams

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 Technology Transfer main concepts

1) Weekly Technical Call

2) Weekly Project Management Call

3) Monthly Stirring Committee

4) Business Review meetings

Cultural / organizational differences to be considered and assessed!

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 Technology Transfer main concepts

Tentative Duration
# Meeting Attendees Frequency Purpose Tool Deliverables
(min)

SU Leader Alignment between Receiving Units and Sending Units in terms of

1 Intra Company alignment Weekly/Biweekly based on project step 30 Project Dashboard Meeting Minutes
RU Leader evaluation/plans/actions

Discussion between PMs on Project status and execution, performance Project Dashboard
RU Leaders
2 Project Meeting Weekly 30 and communication between teams, main risks to be mitigated to avoid Project Plan Meeting Minutes
SU PM (or equivalent role)
delay or stops Risk Register

RU Leader Technical Documents

Meeting Minutes
SU PM (or equivalent role) Project Plan
3 Technical Meeting Weekly 60 Detailed technical discussion on project tasks or issues Risk Register updated
SMEs from parties based on Risk Register
Project Dashboard updated
agenda Project Dashboard

SU Leader Update the project sponsor on Project status , SU relationship, RUteam

Project Dashboard
4 Internal Sponsor meetings RU Leader Biweekly 30 performance and needs, risks and mitigation plan, issues and related N/A
Risk Register
RUSponsor action on going for resolution

RUSponsor
SU Sponsor Update the SU/RUSponsors on the Project status, Relationship, Team Project Dashboard
5 Project Sponsors Meetings Monthly 30 Minutes
RU Leader performances, risks and needs Risk Register
SU PM (or equivalent role)

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 Technology Transfer main concepts

Technical Skills

Planning

Multitasking and Organization

Flexibility

Troubleshooting

Negotiation

Goal oriented

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 Technology Transfer main concepts

– TTPMs are the “General Manager of the project” for our clients

– Take ownership of project/product opportunities and drive them from early quotation stages to
manufacturing and routine supply:
• Relationship management – Key window for the sending unit into the receiving unit
• Relationship management – Key and entrusted by all the members of the TT team
• Project / Opportunity Cost Evaluation and Budget management
• Contract Negotiation and ongoing MSA maintenance
• Project Management – leading all company functions, Operations, Quality, Finance, Quotation
group, Business development and Account executives.
• Financial Reporting – revenue forecasting

The TTPMs have a strong site technical knowledge linked with business acumen

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 Technology Transfer main concepts

Roles and Responsibilities….Clear Definition in the team, avoiding conflicts and putting in
place a clear efficient way of executing the TT

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 Technology Transfer main concepts

Project Leadership

Equipment Validation
Business Managment

Development System
Technology Transfer

Process & Cleaning

Quality Compliance

Regulatory Affairs
Role

Logistics (LOG)
Quality Control

Pharmaceutical
Engineering &

Manufacturing

Validation
(ENG)
(QAC)

(MAN)

(QAV)

(PDS)
(QC)
(BM)

(RA)
Project Deliverable

(TT)
(or Activity)

Preliminary assessment A/R A/R C C I C C C C I/C

Meet the customer and verify information A/R A/R I I I C/I I I C I/C
Define and share the project plan A/R I/C I I I C/I I I I I
Change Control Form preparation A/R I/C C R/C C I C C C C
Technology Transfer Plan preparation A/R I/C C C I I C/I C/I C I
Tech run protocol preparation A/R I/C C I/C I I C/I C/R I I
Technology Transfer Report preparation A/R I/C I I I I I I I I

Analytical transfer I/C I A/R I/C I I I I I I

Stability Activities I/C I A/R I/C I I I I I/C I

Materials definition & documentation preparation I/C I/C I A/R I I/C I/C I/C I I
PV release I/C I/C I A/R R I/C R I/C I/C I

Materials Procurement I/C I/C I I A I/C I I I

Materials Order and delivery I/C I/C I I A I/C I I I
Equipment validation and manufacturing sheduling I/C I/C I I R A/R I I I

Validation Master Plan I/C I I I I A I/C I I I

Equipment Installation and Validation I/C I I I I/C A I/C I I/C I

Tech run MBR preparation I/C I/C I/C I/C I I A I/C I I

Tech run manufacturing I/C I/C I/C I R/C I A I/C I I
Process Validation MBR preparation I/C I/C I/C I/C I I A C I I
Process Validation manufacturing stability I/C I/C I/C I R/C I A I I I

Regulatory activities I/C I I I I I I I A I

Developm ent activities I/C I/C I I I I I I I/C A/R

Media Fill I/C I/C C/R I R I R A I I

Equipment Validation Protocol Preparation I/C I/C I I I A I I/C I I
Process Validation Protocol I/C I/C C I I I/C C A I I
Cleaning Validation assessment I/C I/C C/R I I I C A I I

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Technology Transfer main concepts

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 Technology Transfer main concepts

• Project Gantt

• Action List

• Decision List

• Risk Register

• Activities completion tracking

Define scope, plan, execute and track

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Technology Transfer main concepts

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Technology Transfer main concepts

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Technology Transfer main concepts

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Technology Transfer main concepts

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 Technology Transfer main concepts

Company Name

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 Technology Transfer main concepts

Company Name

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Technology Transfer – Risk Assessment
 Technology Transfer – Risk Management

Risk Risk reduction

- combination of the probability of - processes for mitigation or avoidance of
occurrence of harm and the severity of that harm quality risk when it exceeds a specified
(acceptable) level.

Quality Risk Management

- Quality risk management is a systematic
Risk acceptance
process for the assessment, control, - formal decision to accept the residual risk
communication and review of risks to the quality or a passive decision in which residual risks are
of the drug product across the product lifecycle. not specified

Risk communication
- sharing of information about risk and risk
management between the decision makers and
others

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ICH & Risk - http://www.ich.org/

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ICH & Risk - http://www.ich.org/

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ICH & Risk - http://www.ich.org/

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 ICH & Risk - http://www.ich.org/

It is commonly understood that risk is defined as the combination of the probability of

occurrence of harm and the severity of that harm.

In relation to pharmaceuticals, although there are a variety of stakeholders, including medical

practitioners as well as government and industry, the protection of the patient by managing the
risk to quality should be considered of prime importance.

It is important to understand that product quality should be maintained throughout the product
lifecycle such that the attributes that are important to the quality of the drug (medicinal) product
remain consistent with those used in the clinical studies.

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 ICH & Risk - http://www.ich.org/

Two primary principles of quality risk management are:

• The evaluation of the risk to quality should be based on scientific knowledge and

ultimately link to the protection of the patient;

• The level of effort, formality, and documentation of the quality risk management process

should be commensurate with the level of risk.

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 ICH & Risk - http://www.ich.org/

Quality risk management activities are usually, but not always, undertaken by interdisciplinary teams. When
teams are formed, they should include experts from the appropriate areas (e.g., quality unit, business
development, engineering, regulatory affairs, production operations, sales and marketing, legal, statistics, and
clinical) in addition to individuals who are knowledgeable about the quality risk management process.

Decision makers should

• take responsibility for coordinating quality risk management across various functions
and departments of their organization and

• ensure that a quality risk management

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 ICH & Risk - http://www.ich.org/

The quality risk management (QRM) is “a systematic process for the assessment, control,
communication and review of risks to the quality of the drug (medicinal) product across the
product lifecycle.”

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 Technology Transfer – Risk Management

Risks of Technology Transfer

 Often, poor attention to its objectives (e.g., too tight or too broad process specifications) destines a TTP
for failure. Technology transfer can affect drugs and patients. Consequently, in all technology transfer
activities that a project team designs and executes, the team needs to keep in mind the scope of the
technology being managed and the potential impact of technology transfer failure.

 Some common risks are:

• Lack of information

• Objective that is not clear (or clearly defined) or not properly communicated and/or shared

• Poor preliminary assessment with lack of changes identification

• No or poor assessment of the effects of changes to the objective

• Lack of project management

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 Technology Transfer – Risk Management

The selection of a risk management approach should be done at the beginning and applied
along the TTP. This approach will facilitate decision-making at different points throughout the TTP
while ensuring that all activities are performed in a manner that protects patient safety.

To realize the utmost benefit from QRM, companies must adapt their culture, systems, and
procedures. They must shift from a risk-averse to a risk-aware culture by creating procedures and
tools that enable individuals to apply benefits from QRM to the TTP

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Technology Transfer – Risk Management

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 Technology Transfer – Risk Management

As applied to Technology Transfer (TT), this activity, done at the beginning of the project, can
detect the most likely potential causes of technical failures and allow planning for mitigating
those risks.

Following ICH Q9, the risk can be estimated based a combination of three main factors:
•Severity (S)
•Occurrence (O)
•Detection (D)

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 Technology Transfer – Risk Management

Severity considers the potential impact on the quality attributes of the product and hence on patient health.

It can be rate based on the table below

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 Technology Transfer – Risk Management

The occurrence factor is defined as the frequency of occurrence of the event. In a TTP phase, occurrence is
based on the combination of the SU knowledge of the product and the RU experience on process.

It can be rate based on the table below

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 Technology Transfer – Risk Management

The detection factor is defined as the probability of detecting the events if they occur, based on the control
system in place.

It can be rate based on the table below

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Technology Transfer RA Approach

Data collection

Data evaluation

Data use

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 Technology Transfer RA Approach

Our Risk Assessment and Mitigation approach is based on several Source of information, linked to create a TT Starting
Story

Source 1 – Definition of the Main Process Variables of the product (SU -> RU) (examples below)

Source 2 – Definition of the Quality Attributes (RU) (examples below)

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 Technology Transfer RA Approach

Risk Assessment and Mitigation Approach:

 is part of part of Company DNA, therefore application is a must for all our TTs and during the whole project lifecycle;
 Has to be in line with the current regulatory guidance, GMP and based on scientific sound
 Has to be managed by appropriate flexible, robust and efficient tools
 Is a multifactorial exercise that takes in considerations internal and external variables of the
project/process/product/lines
 Provides a clear path forward starting with QbD and development (where necessary) and ending with a reproducible,
efficient and in quality market supply

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Technology Transfer RA Approach

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 Technology Transfer RA Approach…in GMP

Technology Transfer involves:

 Procedure in place to handle documentation exchange, review and evaluation

within unit and between S & R units

 Reviewers list and approvers list

 QA/RA overall super-visioning of the document and its contents

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 Technology Transfer RA Approach

Knowledge management and transfer are key requirements of the TTP for preserving product quality

and process performance after technology transfer.

Because of the large amount of multidisciplinary information collected, evaluated, and elaborated

during the TTP, a systematic approach to acquiring, analyzing, storing, and disseminating information

related to the technology should be considered and customized on the basis of the team and the

project.

Appropriate level of training in place

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 Technology Transfer RA Approach

• Batch records & Bill of materials

• Item specifications and justifications
• Summary of stability
• Lists of potential impurities and degradants and typical levels
• Starting materials and material safety data sheets
• Assay-related documents
• Drug master file for active pharmaceutical ingredients (APIs) and excipients
• Qualification of bioburden tests
• Solubility profiles
• Process flow diagram that provides a rationale for the synthesis, route, and form selection; technology
selection; equipment;, clinical tests; and product composition
• Vendor qualification (for transfers to contract manufacturing organizations [CMOs])
• Training protocols
• Process validation report and master plan & Cleaning validation protocols and reports
• Project implementation plan & Risk assessments performed for the process or testing.
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 Technology Transfer RA Approach

Technology Transfer Protocol

A roadmap must be designed from the very beginning of the project to ensure comprehensive
project management. The SU and RU should jointly develop a TTP plan that will govern the entire
project. Critical inputs to the technology transfer plan include a regulatory strategy and a gap
analysis

Outputs of this stage include a finalized project plan describing activities,

resources, schedule, and project risk assessment.

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 Technology Transfer RA Approach

The Technology Transfer Protocol document should drive the overall process and

define the strategic approach by describing at least:

• The manufacturing process being transferred

• Sampling and testing steps

• Roles and responsibilities of the SU and the RU

• RU’s equipment and facilities

• A brief description of both sites (SU and RU) that includes gaps and/or differences

• Documentation requirements

• Project schedule, including roles and responsibilities of personnel (a Gantt chart is helpful here)

• Technology transfer tools, including templates

• Risk list and mitigation plan

• Correlations to previous and subsequent tasks

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 Technology Transfer RA Approach

SOP for TT Protocol/report handling

 Chapter 1. Application area: Which kind of documents are needed

 Chapter 2. Responsibilities: Who is responsibile for what

 Chapter 3. Documentation flow:

 How the documentation is received from the SU

 How it’s distributed among the team

 How it’s stored and numbered

 Chapter 4. Project identification: procedure (codes, numbering)  Chapter 4. Project Story

 Chapter 5. Project planning tools  Chapter 5. Project Results

 Chapter 6. Project monitoring tools  Chapter 6. Lesson Learnt and CPV

 Chapter 7. Project closure tools  Chapter 7. Document Closure

 Chapter 8. Document History  Chapter 8 . Document History

 Appendix. Template and signature page

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 Technology Transfer RA Approach

Visual Management support

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 Technology Transfer take away from day 1

 TT is a multidisciplinary envirnoment

 Process Mapping and R&R matrix are key for site/company TT performance

 Two main areas of working: planning & social intelligence with appropriate tools and rules

 Communication and Teamworking are key for the success of the TT

 Two main kinds of risks have to be considered during TT planning & execution:

 Project and Process risks

 Risk Assessment and Risk Management exercises have to be initiated as soon as possibile at the beginning

of the projects and mantained along the project lyfecycle

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Technology Transfer – Analytical Transfer
 Technology Transfer Analytical transfer Pillars*

 An analytical procedure is developed to test a defined characteristic of the drug substance or

drug product against established acceptance criteria for that characteristic;

 Each NDA and ANDA must include the analytical procedures necessary to ensure the identity,
strength, quality, purity, and potency of the drug substance and drug product.8 Each BLA must
include a full description of the manufacturing process, including analytical procedures

 Data must be available to establish that the analytical procedures used in testing meet proper
standards of accuracy, sensitivity, specificity, and reproducibility and are suitable for their
intended purpose

* Analytical Procedures and Methods Validation for Drugs and Biologics – guidance for industry – FDA;
VALIDATION OF ANALYTICAL PROCEDURES: TEXT AND METHODOLOGY – ICH Q2
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 Technology Transfer Analytical transfer Pillars

 Early in the development of a new analytical procedure, the choice of analytical instrumentation and
methodology should be selected based on the intended purpose and scope of the analytical method and
robustness of the methodology should be challenged

 Parameters that may be evaluated during method development are specificity, linearity, limits of detection
(LOD) and limits of quantitation (LOQ), range, accuracy, and precision.

 Typical validation characteristics which should be considered are listed below:

 Accuracy  Intermediate Precision  Quantitation Limit

 Precision  Specificity  Linearity
 Repeatability  Detection Limit  Range

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 Technology Transfer Analytical transfer Pillars

 …..To fully understand the effect of changes in method parameters on an analytical procedure,
you should adopt a systematic approach for a method robustness study (e.g., a design of
experiments with method parameters). You should begin with an initial risk assessment and
follow with multivariate experiments. Such approaches allow you to understand factorial
parameter effects on method performance.

 You should describe analytical procedures in sufficient detail to allow a competent analyst to
reproduce the necessary conditions and obtain results within the proposed acceptance
criteria

92
 Technology Transfer Analytical transfer Pillars

 Three approaches are suggested to be analyzed case by case:

 Analytical Validation (single lab or multi lab)

 Method verification – compendial methods suitability verification

 Analytical comparability exercise when validated method are transferred between two

labs

 A sufficient number of representative test articles (e.g., same lot(s) of drug substance or drug product)

are used by the originating and receiving laboratories. The comparative studies are performed to

evaluate accuracy and precision

93
 Technology Transfer Analytical transfer Pillars*

 The following is a list of essential information you should include when describing an
analytical procedure:
 Principle/scope

 Equipment

 Operating Parameters

 Reagents and Standards

 Sample preparation

 Standards control solution preparation

 Procedure

 System Suitability

 Calculation

 Data Reporting

94
 Technology Transfer Analytical transfer Pillars*

 Why speak about RA in Analytical transfer?

The simplistic Validation/Comparability/Verification exercise without and additional

consideration on level of method development, RU expertise and knowledge, method

history and performance is not enough to guarantee a reproducible and effective

analysis of our product during the transfer and during the commercial manufacturing

production

95
 Technology Transfer Analytical transfer Pillars

 Prior to initiation of method transfer / implementation a ‘paper based’ method Risk Assessment
should be performed within the RU.

 Serves as both a ‘knowledge transfer’ document and a tool for identifying areas of concern /
potential improvement prior to use in a GMP setting.

 Risks are evaluated on specific method parameters and classified based on potential impact and
likelihood of occurrence:

 The competed risk assessment is shared with the SU and may drive the design of formal method
evaluation / transfer / validation activities.

 Upon completion of the laboratory method implementation activities a RU version of the method
incorporating any incremental changes and/or cautionary statements is forwarded to the SU for
approval. 96
 Technology Transfer Analytical transfer Pillars

Impact (I) of method issue Acceptable

Likelihood (L) of method issue Risk Rating
Chromatographic conditions Details/Information (Min=1; Mod=2; Maj=3; Risk
(R=1; U=2; P=3; C=4) (L x I)
Cr=4) (Y/N)
Manufacturer of HPLC system
Y
defined/appropriate See test procedure 1 2 2
Relevant LC detection technique See test procedure 1 3 3 Y
Appropriate LC detection wavelength (Assay
and Rel Subs) See test procedure 1 2 2 Y
Single method for assay and related
substances See test procedure 1 1 1 Y
Type of HPLC column acceptable for chemical
structure See test procedure 1 3 3 Y
HPLC column stable under conditions of
method See test procedure 1 2 2 Y
Column temperature acceptable See test procedure 1 3 3 Y
Sample temperature acceptable See test procedure 1 3 3 Y
Injection volume suitable for instrumentation See test procedure 1 3 3 Y
Mobile phase constituents
(complexity/additives etc) See test procedure 1 3 3 Y
HPLC Method pre-column required See test procedure 1 2 2 Y
Needle wash appropriate See test procedure 1 2 2 Y
Length of HPLC run (Isocratic vs Gradient)
acceptable See test procedure 1 1 1 Y
Complexity of HPLC gradient acceptable (if
appropriate) See test procedure 1 1 1 Y
pH of mobile phase 4
Flow rate
Robustness of method (If known) Mobile phase composition lack of Robustness details into 4 16 N
Column Temperature the method validation provided
Wavelength 97
 Technology Transfer Analytical transfer Pillars

 The RU should review the analytical information and perform an analysis to

evaluate gaps

 Any gap identified should be assessed for risk of failure by both the SU and the RU.

 After the initial assessments of the methods, a pre-approved protocol will be

prepared to describe the experiments to be performed.

There are a number of ways in which the transfer may be performed, you need to be
sure you are taking the right one!

98
Technology Transfer Analytical transfer Pillars

99
 Technology Transfer Analytical transfer Pillars

 Since a successful validation requires the cooperative efforts of several departments including
Regulatory Affairs, Quality Control and Analytical Research and Development, it is essential that
the organization has a well defined Validation Master Plan (VMP) for analytical methods.

 The Analytical strategy has to be detailed in a dedicated GMP document (Analytical transfer
Plan/Protocol)

 A well developed VMP must clearly define the roles and responsibilities of each department and
Units involved in the validation of analytical methods

 A well developed VMP must clearly define the activities to be done for each method to be
imported in the RU with the scientific sound rationale used to establish it

100
Technology Transfer – PMO…one answer
102
 Index

 What is the PMO?

 Why setup the PMO?

 What can the PMO be?

 What would the PMO provide?

 Why does the PMO fail?

 Prioritization and portfolio management

 Questions and answers

103
 What is the PMO?

An organizational body …
assigned various responsibilities related to the centralized and coordinated
management of those projects under it’s domain.

There in no such thing as a „universal solution“.

To be effective, a PMO must be tailored to your organisation‘s

project types, management/staff capabilities, and organisation
culture

104
 Why setup the PMO?

 Limited resources (financial, human staff, …)

 Multiple projects

 Time to market is a critical factor

* Condition is full executive support

105
Time for Dilbert

106
 What can the PMO be?

Supportive PMO
Generally provides support in the area of expertise, templates, best practices,
access to information

Controlling PMO
It also requires that support to be used (pass the regular reviews, audits, …)

Directive PMO
Only professional project managers are assigned to the projects
High level of consistency across all projects because PMs are reporting back to the
PMO

107
 What would the PMO provide?

 Methodology

 Terminology

 Project managenet processes

 Supporting tools

 Reporting

 Training and mentoring

 Best practices collecting

 Project Managers services

Continuous improvement of level of sucess within
 organisation 108
 Why does the PMO fail?

One example from many posibilities

Scope
Defining processes
Defining best practices
Have executive level support

PMO cops
Similar problem as IAD (Internal
Staffing affairs department) inside PD
• Process oriented staff without
(Police department)
significant experience in delivering
projects, aren‘t respected
• Push to the teams to get information
that the top management wants

109
Technology Transfer – day 2
Technology Transfer – day 2 – brief recap
 Teamworking in TT

https://www.youtube.com/watch?v=nF_77OdTNS4

112
Technology Transfer – Feedback from PDA TT IG
 Technology Transfer

Key factors for success no matter which kind of TT we are considering

• Sending unit and receiving unit work closely with each other.

• Clear understanding of roles and responsibilities of both sending unit and

receiving unit team members.

• Complete technology transfer package.

• Quality Risk Management.

• Effective knowledge transfer and training.

• Stage Gate Approach

114
 Technology Transfer

Why do we do TT

•Product life cycle management, from R&D through scale-up to routine manufacturing –

Segmentation of Business Core Activites

•Post-approval changes to implement new process versions

•Need for additional manufacturing capacity driven by increased demand or risk mitigation

•Strategic requirements to relocate manufacturing sites for rationalization or economic

advantages in different regions of the world (e.g. market access, supply chain optimization,

contract manufacturing)

•Needs of Technical competencies

115
Technology Transfer

Which is your TT RoadMap?

116
 PDA TT IG Survey

1. Which is the main difficulty during a Development to Clinical phase TT?

Lack of information regarding robustness of process

2. Which is the main difficulty during a Clinical Phase to Commercial TT?

Appropriateness of batch scale based on market demand

3. Which is the main difficulty during a Commercial to Commercial TT?

MSA negotiation and agreement (in case of external TT)

R&R between sites (in case of internal TT) 117

Technology Transfer – Recap on RA
Technology Transfer RA Approach

Data collection

Data evaluation

Data use

119
 Technology Transfer – Risk Management

Severity considers the potential impact on the quality attributes of the product and hence on patient health.

It can be rate based on the table below

120
 Technology Transfer – Risk Management

The occurrence factor is defined as the frequency of occurrence of the event. In a TTP phase, occurrence is
based on the combination of the SU knowledge of the product and the RU experience on process.

It can be rate based on the table below

121
 Technology Transfer – Risk Management

The detection factor is defined as the probability of detecting the events if they occur, based on the control
system in place.

It can be rate based on the table below

122
 Technology Transfer RA Approach

Our Risk Assessment and Mitigation approach is based on several Source of information, linked to create a TT Starting
Story

Source 1 – Definition of the Main Process Variables of the product (SU -> RU) (examples below)

Source 2 – Definition of the Quality Attributes (RU) (examples below)

123
Technology Transfer RA Approach

124
 Technology Transfer RA Approach - OverReaction

Info coming from development department: API oxidizes quickly if exposed to Air/O2. Dispensing is done under N2.
Small quantity per batch: approx. 0.8 g per 95Lt of bulk solution

• Main commercial variable considered: Dispensing

• QA Impacted: Impurity Profile & Assay

• Severity 3 – Occurance 3 – Detection is 1

• Risk acceptance level was < 6

Mitigation Plan: Purchase and installation of a Dispensing Hood allowing O2 residual less than 0,5% during dispensing

• QA Impacted: Impurity Profile & Assay

• Severity 3 – Occurance 1 – Detection is 1

• Risk acceptance level was < 3

125
 Technology Transfer RA Approach - OverReaction

First TT Batch failed for API assay

Investigation identified the root cause in the Dispensing Hood

The N2 atmoshpere created with the hood enhances the «electrostatic charge environment» which impacts the
accurancy of the API weight

Action: development activities to explore «API oxides quickly»

Mitigation Plan: Defined an appropriate holding time of dispensing based on degradation/stability of the API in Air

126
Technology Transfer – Some exercises
Workshop

128
 Workshop

Background:
A product dedicated to EU market, has to be outsourced from one of your site in US. The
manufacturing history of the product in the current manufacturing site is not robust.

Questions

Which Criteria will you use to select a partner?

 US Regulatory History
 Technical expertise in process development

129
Workshop

130
 Workshop

Background:
A product dedicated to EU market, has to be outsourced from one of your site in US. The
manufacturing history of the product in the current manufacturing site is not robust.
The partner has been identified and selected in US

 Questions

Describe the main milestones to bring the product from the SU to the RU including
stage/gate and upper management main updates

131
Workshop

132
 Workshop

Background:
A product dedicated to EU market, has to be outsourced from one of your site in US.
The manufacturing history of the product in the current manufacturing site is not
robust.
The partner has been identified and selected.

Questions
Group 1. SU Describe the project team member mainly impacted in each
milestone with an “allocation curve”
Group 2. RU Describe the project team member mainly impacted in each
milestone with an “allocation curve”
133
Workshop

134
 Workshop

Background:
A product dedicated to EU market, has to be outsourced from one of your site in US. The
manufacturing history of the product in the current manufacturing site is not robust.
The partner has been identified and selected. Agreement is in place, team members identified

Questions

Group 1. SU. Define the list of information/document you would prepare for the transfer

Group 2. RU. Define the list of information/document you would request for the transfer

135
Workshop

136
 Workshop

Background:

A product dedicated to EU market, has to be outsourced from one of your site in US. The

manufacturing history of the product in the current manufacturing site is not robust.

The partner has been identified and selected. Agreement is in place and path defined.

Questions

Group 1. SU. Define timelines for the main milestones of the project

Group 2. RU. Define timelines for the main milestones of the project

137
Workshop

138
 Workshop

Background:

A product dedicated to EU market, has to be outsourced from one of your site in US. The

manufacturing history of the product in the current manufacturing site is not robust.

The partner has been identified and selected. Agreement is in place and path defined; timelines

are defined.

Questions

Group 1. Thinking as Prj manager, define your idea of Value/for the Project team

Group 2. Thinking as Project team member, define your expectation of support from the Prj

Manager

139
Workshop

140
 Workshop

Background:
A product dedicated to EU market, has to be outsourced from one of your site in US. The
manufacturing history of the product in the current manufacturing site is not robust.
The partner has been identified and selected. Agreement is in place…

Questions
Define the Process Variables
Prepare a Risk Assessment based on the quality attributes defined by the SU and the
Process Variables identified by the RU

141
 Workshop

Product YYY

API and
No special RA concern categories
Pharmacological use

Sterile lyophilized DP.

Pharmaceutical dosage form
0.0050 mg/vial

Product phase Commercial

•API: 5.0 mg
•Citric Acid: 22.8 mg
•Polysorbate 20: 0.8 mg
Unit Dose composition •Phosphoric Acid: 7.0 mg
•Sucrose:190.0 mg
•Vit E: 0.008 mg
•Potassium Phospate, Dibasic: 18.0 mg
Fill Volume
10 mL
(Including overfill)
Batch Size 120K Vials
API Storage condition -70°C
Finish Product Storage 2-8°C
Finish Product Shipment 2-8°C
142
 Workshop
Nitrogen Sparging
WFI
Excipients

Compounding of Bulk
Excipient solution
Polysorbate 20

NMT 12 h
Sparged WFI

Dispensed
Polysorbate
Bulk Excipient solution Filtration (class C)
API storage 0.22 µm Filter
at -80°C

API dispensing Compounding of Bulk DP

at 15°-25°C API dissolution solution

Return of not dispensed

• Q.S. with WFI
API Dilution to • pH adjustment
target concentration
In Process Testing
• Appearance
• Density
• pH
NMT 15 h • Bioburden
Filtration (class C) • Assay by HPLC (barrier test)
0.22 µm Filter
Grade C Area
Grade A Area
Filtration (class A)
2 x 0.22 µm Filter

Filling and
Pre-stoppering

Lyophilization

Crimping
143
 Workshop

Class C

• Sparged WFI
• Excipients Nitrogen sparging
Oxigen content: NMT 1ppm

Glass Lined
Compounding
Vessel
CIP/SIP

Glass
Carboy

Excipient solution for API

dissolution

144
Workshop

Class C

• Polysorbate
• Sparged WFI

Sparged WFI
Glass
Carboy

Glass
Polysorbate Solution Carboy
Conc 1

Polysorbate Solution
Conc 2

145
 Workshop

Class C

Glove Box
Nitrogen atmosphere
Sincalide Analytical scale
container

API into a dessicator

from -70°C storage 3- Add Weighted API

Glass Glass
Carboy Carboy

Glass
Carboy
1- Add Excipient solution 2- Add Polysorbate
solution
API solution
Nitrogen Purged

146
Workshop

Class C

1- Add Sincalide Solution

2- Rinse with all remaining pre-dispensed excipient solution
3- Rinse with purged WFI

G rb
la oy
C
a
ss
4- Q.S. with WFI to final weight Nitrogen sparging
5- Adjust pH if needed

Glass Lined
Compounding
Vessel

147
 Workshop

Class C Class B/A

Disposable line

Glass
Surge
Glass Lined Tank
Compounding
Vessel

Peristaltic filling pumps

Bioburden redution Redundant sterile
filtration
0.22 µm 0.22 µm 0.22 µm

Peristaltic pump

148
 Workshop

Product Quality Attributes

Micro Attributes

Endotoxins
Sterility

Chemical & Physical methods

• Moisture content by KF
• Appearance of the solution (after reconstitution)
• Density of the solution (after reconstitution)
• pH of the solution (after reconstitution)
• Appearance and colour of lyophilized cake (DP)
• Particles of the solution (after reconstitution)
• Oxygen in headspace of drug product vial (CCI test).
• Uniformity of dosage units
• Cosmetic appearance of the cake
• Impurity profile and assay
• Amorphous at X ray of the cake

149