2015

Technical Report No.65

Technology Transfer
PDA 2014
Authors
Mirko Gabriele, EMPHA, Patheon Italia Spa (Team leader)
Derek Blaettler, F.Hoffman-LaRoche, Ltd.
Amnon Elyath, Genzyme Corporation
Stephan Krause, Ph.D., MedImmune
Andrea Morelle, Kedrion Biopharma
Chittoor Narahari, GlaxoSmithKline
Jamie Rogers, Biogen Idec
Victor Sanchez, Pharma-Bio Serv S.L.
Melissa Seymour, Biogen Idec.
Yi Xie, Ph.D., Eli Lilly and Company
Wayland Rushing, Ph.D., Analytical Bio-Chemistry Laboratories, Inc.
Dave Wohpart, Ph.D., Merck & Co.

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Table of Contents
1.0 Introduction

2.0 Glossary of terms

3.0 Technology Transfer Project

4.0 Technology Transfer Process

5.0 Application of Quality Risk Management to Technology Transfer

6.0 Case Studies

7.0 References

8.0 Additional Reading

Figures and Tables Index

Figure 3.4-1 Typical Functions within a TTP

Table 3.4-1 Technologhy Transfer Organizational Components
Table 3.4.2.1-1 Responsibilities of the SU and RU
Figure 3.4.5-1 Common Flow of Information and Communication Within a Technology Transfer Team
and Project
Table 5.4-1 QRM Approaches at Each Stage Gate of TTP
Table 6.1-1 Suggested AMT Responsibility Matrix
Table 6.1.2-1 General AMT Design Parameters and Considerations
Table 6.1.3-1 Examples of Method Types and AMT Performance Characteristics
Table 6.1.4-1 Typical AMT Protocol Sections
Figure 6.2.3-1 Process/Product Comparability Framework
Figure 6.3.1-1 Overall Process Mapping
Table 6.3.1-1 Example of Variable Definitions
Table 6.3.1-2 Example of Quality Attributes Definition
Table 6.3.1-3 Severity Definition and Rating
Table 6.3.1-4 Occurance Definition and Rating
Table 6.3.1-5 Detection Definition and Rating
Table 6.3.1-6 Risk Analysis

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1.0 introduction
Pharmaceutical technology transfer consists of planned and controlled actions that are based on well
defined acceptance criteria to convey a manufacturing process, analytical method, packaging component,
or any other step or process along the pharmaceutical drug lifecycle from an originator site, known as a
sending unit (SU), to a new site, the receiving unit (RU).

SU
RU

1.1 purpose /

The purpose of this technical report is to provide guidance and best practices for conducting technology
transfer activities in the pharmaceutical industry.

1.2 scope /

The report provides an overview of the knowledge and skills used during a successful technology transfer
project (TTP) along with references to consult, if necessary. The report includes practical examples of
technology transfer activities. Rather than discuss a particular technology transfer topic, this report aims
to provide a guide to safe TTP management.
TTP

TTP

This report does not address logistics and bridging stocks, which are comprehensively discussed in
Technical Report No. 52: Guidance for Good Distribution Practices(GDPs)(1).
52 GDP

The technology transfer organizational elements outlined in this technical report might not be appropriate
for all companies. Established practices or the availability of personnel will dictate how firms conduct
technology transfer activities.

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2.0 Glossary of Terms
Failure Mode Effects Analysis (FMEA) / FMEA

A tool for analyzing processes or systems to evaluate all operating steps in order to identify and assess the
risk associated with any potential failures(2).

Planning Bill of Materials (BOM) / BOM

A complete list of the raw material (chemicals, media, powders, resin, etc.) and consumables/ components
(filters, bags, tubing, containers, etc.) that are required to manufacture the product.
/

Process Flow Diagram (PFD) / PFD

A document, typically prepared by R&D, that describes the intended manufacturing process. The PFD
includes all relevant information for the operation of the manufacturing process, organized by unit
operation. The PFD serves as the source document for the initial development of the master production
records and is locked down once development has determined that the process can be controlled.
PFD
PFD

Receiving Unit (RU) / RU

Term for the internal or external recipient or site where the technology is being transferred to.

Sending Unit (SU) / SU

Term for the internal or external source or originator site of the technology to be transferred.

Work Breakdown Structure (WBS) / WBS

A hierarchical and incremental decomposition of a project into phases, deliverables, and work packages;
commonly a tree structure that shows a subdivision of effort required to achieve an objective.

Material Safety Data Sheet (MSDS) / MSDS

Information provided with chemicals and other materials intended to provide workers and emergency
personnel with procedures for handling or working with that substance in a safe manner.

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3.0 Technology Transfer Project
A technology transfer procedure is more of a project than a process, as described by the Project Management Body of
Knowledge (PMBOK) Guide. The guide describes a project as a defined sum of non-repetitive activities that are
designed to achieve a goal, are performed in a defined time range, employ defined resources, and are managed by a
team. A process, by contrast, is the steps a given project follows (3).
(PMBOK)

A TTP typically provides governance for technology transfer by grouping similar activities together and moving them
through each step. In this report, the technology being transferred is related directly or indirectly to a drug (small and
large molecule) that is being developed or manufactured, and the manufacturing process, analytical testing, and/or other
aspects of its processing and packaging are transferred either within the innovator organization or to a contract
manufacture/packager/testing facility. Preservation of the products quality and performance is a critical aspect of the
TTP.
TTP

// TTP

Technology transfer can be applied to analytical methods and partial production steps (e.g., intermediates manufacturing,
a filling or packaging step, or a cleaning procedure). Technology transfer procedures can also be applied to manage the
transfer of individual analytical methods or process phases (e.g., filling, packaging, or manufacturing of specific
intermediates).

The transfer of individual process steps must be supported by stability data, validation of transport of intermediates, and
a gap analysis of premises and equipment. The result of this type of technology transfer is generally an increase in
manufacturing flexibility and capacity.

3.1 Technology Transfer Project Objectives /

The objectives of TTP typically are to:

Complete process performance qualification to demonstrate repeatability of manufacturing
Demonstrate the similarity of the product produced at the end of the TTP at the RU
Obtain licensing approval to manufacture and market the product
Demonstrate robust manufacturing over a sufficiently large number of lots, including process, product, operations, and
testing
Comply with in-process intermediates and final product analytical specifications; process specifications (e.g., pH and
temperature); expected yield; regulatory and quality requirements; and environment, health, and safety requirement
TTP

TTP


pH

A successful TTP does not guarantee zero future rejects. Rather, it provides assurance that the process and the product
knowledge is fully understood and properly transferred from the SU to the
RU.
TTP TTP SU RU

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3.2 Types of Technology Transfer /

TTPs can be classified into several groups. For example, for the transfer of a drug manufacturing process, types of
approaches include:
TTP

Development to commercialization (intracompany): During the drug lifecycle, the product and the process through
different phases, such as discovery, development, validation, registration, and commercialization. Transition between
each phase requires a TTP for scale-up and activities management. The goal is to bring a process in a development phase
to a robust and reproducible commercial process able to consistently guarantee the market supply.

TTP

Commercial to commercial (intercompany): Established processes can be transferred from one commercial site to
another commercial site for business continuity or strategic reasons.

Development-to-commercialization, or intracompany, TTPs are usually easy to manage due to the existing relationship
between the SU and RU. Since they are part of the same company, procedure, mindset, and governance are similar.
TTP SU RU

Commercial-to-commercial transfer generally presents some advantages:

Both sites have experience in regulatory authority inspections.

Quality systems are in place.

Personnel are trained and experienced.

The product (e.g., intermediate or final) is well characterized.

Product and process specifications are well established.

The process is statistically under control.

The main disadvantage of commercial-to-commercial is that the development resides with SU and is usually not part of
the information shared due to intellectual property concerns. A deep involvement of the R&D group, therefore, is
required independently from the fact that the process under transfer is well-established, commercial process. A
significant, initial milestone of a commercial-to-commercial TTP should be the establishment of governance suitable for
both the
SU and RU.
SU

TTP SU RU

3.3 TTP Oversight / TTP

Managing TTPs, especially their organization and communication, is a challenge for any company. Teams must be
created and motivated and project activities must be executed and monitored while the members still accomplish their
routine work. In addition, interaction between different sites (often located in different countries) and external parties can
be difficult.
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TTP

Based on the potential complexity of the TTP, usually three groups are involved in successful technology transfer
governance:
TTP 3

Technology transfer unit/department

/
Multidisciplinary technology transfer project team

Project committee

3.4 Multidisciplinary Technology Transfer Project Team /

Each pharmaceutical TTP requires the involvement of a well-trained, multidisciplinary team at both the SU and RU. The
team needs such soft skills as leadership, effective communication, and pharmaceutical market access principle. The
team also needs the following technical proficiencies to drive the team toward a positive outcome:
TTP SU RU

Quality assurance (QA)

Quality control (QC)
Manufacturing /
Engineering /
Finance /
Maintenance /
Environment, health, and safety / EHS
Research and development /
Regulatory affairs /
Legal issue /
Project management /

The multidisciplinary technology transfer project team should be responsible for filing the relevant documentation for
the transfer, including that exchanged between the SU and RU. The
team prepares the following key documents
SU RU

Project plan (includes project management documents, and tools, work breakdown structure, responsibility assignment
matrix, and Gantt chart)

Technology transfer protocol

Technology transfer report

The team is responsible for the transfer and implementation of the technology in a regulated context, such as a
manufacturing facility, according to predefined acceptance criteria, such as process, intermediates, and finished product
specifications.

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Establishing two distinct teams and related team leaders is not uncommon. Assignment of more active role to the RU
(e.g., management of its own team) should help lessen the impact of any resistance to the TTP.
RU
TTP

The essential functions to be included in TTPs are shown in Figure 3.4-1, although more may be required depending on
the complexity of the project.
3.4-1 TTPs

Upper Management Budget Manager

Project Committee Project Facilitator

Project Manager Other Parties/Regulatory

Authorities
Business
Administrative/Regulatory
Development
Process

Operational
Sending Unit Leader Receiving Unit
Leader Project
Implementation
Sending Unit Receiving Unit Operational
Translation

/

/

3.4-1 TTP

Depending on the size and organizational style of the firm, the roles outlined above and the responsibilities listed in
Table 3.4-1 should be accounted for by, but not necessarily assigned to, individual personnel. Section 3.4.1 and 3.4.2
provide further detail regarding the administrative and regulatory functions and operational functions, respectively.
3.4-1 3.4.1 3.4.2

3.4-1

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/ TTP

3.4.1 Administrative and Regulatory Functions /

3.4.1.1 Project Committee /

Within the SU and RU, a dedicated project committee should be appointed and charged with monitoring the TTP. The
members of the project committee must represent the interests of upper management during the project.
SU RU TTP

The committee should provide advice and consultation and should act as the performance monitoring unit. The
committee members should be well informed about the project and have authority to act in the case of events that could
disrupt the TTPs critical path. A strong reporting procedure also needs to be in place.

Monthly meetings can be set up as part of project governance. In these meetings, the project committee members should
review prior meeting minutes, management files, operating expense, and capital expense records.

3.4.1.2 Project Manager /

The project manager should have technical, relational, and managerial skills to fulfill the varied responsibilities of this
position, described in Table 3.4-1 above. The use of typical tools of project management described in the PMBOK to
plan and monitor the project activities strongly recommended (3). These tools can identify activities that could prolong
the project unless they are properly controlled and monitored.
3.4-1
PMBOK

At an organizational level, the project manager should be able to mitigate any differences in a approach between R&D
scientists and production/quality people even if R&D scientists were already involved in the scale-up and
commercialization of the process. The various technology transfer personnel involved should advise the team leaders and
mediate between manufacturing and R&D views. Reporting responsibilities are up to the project manager, as well. The
technology transfer unit and project committee should be routinely updated on the status of the project.
/

3.4.1.3 Budget Manager /

A budget manager should monitor the budget and investment expense forecasts.
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3.4.1.4 Legal Office representative /

A legal office representative is required for any intercompany transfers regulated by legal contracts.

3.4.1.5 Project facilitator /

A project facilitator should serve as a liaison with regulatory authorities and other parties involved in the process, (e.g.,
applicable engineering societies in foreign countries).

3.4.1.6 QA Leader /QA

The person who is responsible for QA should oversee process documentation and change control, quality risk
management (QRM), and validation documentation.
QA QRM

3.4.2 Operational Functions /

3.4.2.1 Sending Unit (SU) and receiving unit (RU) / (SU) (RU)

Regardless of the context, technology transfer always involves an SU and an RU. The SU and RU are generally defined
as the originator and the receiver of the technology, respectively. However, the composition of the units is varied and can
be groups within a company, a specific site, or any other organization based on company needs. The responsibilities of
the SU and RU are outlined in
Table 3.4.2.1-1
SU RU SU RU
SU RU
SU RU 3.4.2.1-1
3.4.2.1-1
SU RU
SU

RU

RU


RU

RU



RU
RU

RU

The SU and RU leaders provide regular updates to the project manager about the progress of the activities, spending on
the TTP, potential technical or financial concerns, and proposed corrective actions.
SU RU TTP

The RUs functional routine is often disrupted by events unrelated to the TTP but are nonetheless necessary as part of
their normal functions within their company. Assignment of a more active role to the RU (e.g., management of its own
team) should help lessen the occurrence and effects of any internal or external resistance to the TTP. Resistance events
can include:
RU TTP RU
TTP

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Routine daily activities that dont include TTP activities Lack of experience with technology transfer and project
management tools Different prioritization of project within the RU
TTP RU

In general, the RU needs to review the technology transfer information provided by the SU to analyze possible gaps in
training or experience of laboratory personnel. The RU then works with SU to describe possible training needs or
additional information/questions regarding the process.
RU SU RU SU
/

3.4.2.2 Team Leaders /

Each team in the RU and SU should be coordinated by a team leader who is the owner of the TTP and is responsible
for implementing the technology at the RU or SU (e.g., manufacturing in the case of transfer of an industrial process)
RU SU TTP RU SU

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.
SU RU

3.4.2.3 R&D Representative /

R&D needs to be included whenever it is the SU or whenever preliminary tests of the technology at laboratory/pilot
scale are foreseen.
SU R&D

3.4.2.4 Combined Roles /

Delegation of roles or combining different roles into a single function is a common practice for effective technology
transfer. For example, the budget manager task could be assigned to the project manager or a team might not need a
project facilitator.

3.4.3 Technology Transfer Unit /

Companies conducting technology transfer should evaluate the need for a dedicated technology transfer unit. This could
be a dedicated department or a group composed of personnel from the appropriate functional areas. Many companies
eventually establish a technology transfer unit within a department at least. If a company chooses not to create a
technology transfer unit or department, the companys engineering and R&D departments can dedicate select staff
members to a TTP.


TTP

Technology transfer units are responsible for the execution of the technology transfer projects and define the technology
transfer policies for the company; they should have process and engineering competencies at a minimumwith the
addition of R&D expertise as needed. Technology transfer units should leverage the expertise of their staff in support of
the SU, the RU, the team leader, and the project manager, identifying best practices and gaps to be resolved.

SU RU

Based on experience and the results of the transfer, the technology transfer unit determines whether the technology
transfer was successful or not and identifies corrective actions as appropriate.

3.4.4 Organizational Model /

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An organizational or governance model that identifies the people or groups responsible for each task must be developed
and identify which matters are subject to risk-based decisions. The risk determination of the subjects will provide the
group with the necessary awareness of risk. A policy for enterprise risk management should be in place at this stage.

Regardless of the context of the TTP, technology transfer always involves an SU, an RU, and the key activities identified
during the operational phase. From these pieces, a well-defined organizational set-up can be established. This set-up is
implemented only after the project progresses to the operational phase, which is detailed further in Section 4.3: TTP
Implementation and Qualification.
TTP SU RU
4.3 : TTP

Use of a light matrix organizational model can minimize of the impact of the transfer activities on the routine of the units
activities involved in the transfer. Other approaches (e.g., hierarchical reports within a unit and within the transfer set-up
or set-up roles engaged hierarchically in the transfer activities) may be appropriate, depending on the context and
importance of the project.

The following project relationships need to be determined:

Project team internal dynamics /

Dynamics between project team and external partners /
Organizational dynamics that could affect the operational context /

3.4.5 Communications /

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 carefully regulated and conducted in accordance with company policies.
TTP TTP

During a TTP, communication should be carefully regulated and conducted in accordance with company policies. The
success of TTP is related to the communication skills of and relationships between the technology transfer team
members (described below). Open communication between team members, effective and timely communication, and
direct communication between subject matter experts are key aspects to be considered and reinforced routinely by the
project leader and sponsor.
TTP TTP

Communication between the teams should be both vertical (SU with SU leader, and RU with RU leader) and horizontal
(SU with RU and RU leader). Technology transfer unit staff should communicate directly with the project as well as with
the SU, RU, and respective leader. The project committee should interact primarily with the project manager, budget
manager, and project facilitator. The project manager should act as a liaison between those responsible management
functions (project committee, project facilitator, and budget manager) and those overseeing the technical functions
(technology transfer team, team leaders, and technology transfer unit or department). The project manager and the
project budget manager should remain in close communication with each other, other manager (e.g., project facilitator),
and those responsible for technical components of the TTP (SU leader, RU leader, and technology unit or department).
SU SU RU RU SU RU RU
SU RU
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TTP SU RU

To maintain project communication channels and avoid miscommunication, direct communication between team
members and the project or budget managers should be avoided. The unit leaders should act as the primary liaison
between team members and management (i.e., project facilitator, budget manager, and project manager).


Technology Transfer Team (TTT)

Upper Management
Administrative/
Consulting support Regulatory
Information
Decision Making
Consulting

Project Committee

Budget Manager
Consulting
Information Information
Decision
Consulting Consulting Information Information
Making
Consulting Consulting

Budget Manager Project Manager Project Facilitator

Business
Development
Process
Information Coordination Information
Consulting Consulting Support Consulting

Sending Unit Leader Receiving Unit Leader

SU RU

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(TTT)

SU RU

Figure 3.4.5-1 depicts this flow of communication.

3.4.5-1

3.4.6 Document Management /

The SU should provide all relevant documents to the RU.

SU RU

3.4.6.1 Common Technology Transfer Documents /

Documents related to the transfer of the process could include:

Batch records
Planning 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 MSDS
Assayrelated documents
Drug master file for active pharmaceutical ingredients (APIs) and excipients DMF
Qualification of bioburden tests
Solubility profiles
Process flow diagram that provides a rationale for the selection of the synthesis, route, form, technology, equipment,
clinical tests, and production composition

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Vendor qualification (for transfers to contract manufacturing organizations[CMOs])
[CMO]
Training protocols
Process validation report and master plan
Cleaning validation protocols and reports
Project implementation plan
Risk assessments performed for the process or testing

All documents generated during the project should be collected and filed by the RU together with the technical
documents that are relevant to the project (e.g., know-how documentation). All documents related to the transfer should
be collated in a comprehensive package and taken into account during approval inspections. The document package
should be acknowledged by the RU, which generates its own process and validation documents (4). All documents
associated with the technology transfer should be archived at the RU. Internal RU procedures for documentation
handling and filing are necessary and routinely inspected by QA at the site.
RU
RU
RU RU QA

3.4.6.2 Regulatory Documents /

The project team must consider the TTPs regulatory requirements and the potential impact of any step in the process on
regulatory filings or authorizations. Some technology transfer documents can be filed for regulatory authorization and
may be inspected during regulatory audits. For these reasons, document management has a very important role in each
TTP step.
TTP
TTP

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4.0 Technology Transfer Process
A structured approach to the TTP is used to organize common activities into distinct stages and make the projects clear
and logical progression evident to the team. Such an approach also provides defined points for review by senior
leadership (stage gateway reviews). Stages are logical groupings of associated activities and tasks, and the stage gates
are predefined review points for the governance team. The stages can reflect common project management approaches
but are tailored for technology transfer.
TTP

The stages are demonstrated on the chevron below and discussed in more detail in the following chapters.

4.1 Stage 1: Planning 1

During this preliminary stage, the SU and RU collaborate to develop a TTP plan that will govern the entire project.
Critical inputs to the TTP include a regulatory strategy and a gap analysis (a comparison of the process, equipment, and
facility between SU and RU; a risk assessment of the changes; and planned risk mitigation actions).
SU RU TTP TTP
SU RU

During the planning stage, requirements and constraints, goals and objectives, and key performance indicators (including
the success criteria) must be determined and agreed upon. The technology transfer team should design a plan that takes
into account cost (including materials and people), schedule (including supply of the product being transferred), scope,
technology, and quality.

Outputs of this stage include a finalized project plan detailing activities, resources, and schedule, and a risk assessment
for the project. A gateway review by senior leadership is used to make visible the plans and risks and provides approval
to move to the next stage.

4.1.1 Project Rationale

Technology transfer is generally aimed at introducing innovation (e.g., a new commercial product or new productions in
existing plants) for the company, which, in turn, engages in TTPs for business opportunities.
TTP

The project rationale and project relationships (analytical/management/social) must be developed before the project
starts. The rationale defines the project plan and the relationships define the social intelligence. Both are fundamental
to the success of a TTP.
//
TTP

4.1.2 Project Scope

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Applications of technology transfer must be GMP based and rely on well-documented knowledge. Specific acceptance
criteria (objectives), batch sizes, and intended production capacity must be defined in advance. The scope of the TTP
must be clearly stated and agreed upon by the TTP team.
GMP
TTP TTP

The knowledge (technology) to be transferred from SU to the RU should include:

SU RU

Product critical quality attributes (CQAs) (CQA)

Impurity profile
Specifications (e.g., for drug substance; drug product; starting materials; raw materials; and auxiliary materials, such
as filtration devices) API
Critical and noncritical process parameters and ranges and proven acceptable ranges

Evaluation results for process and assay robustness
Manufacturing procedures
Procedures for process-related activities
Equipment management and maintenance procedures (if applicable)
Technical description of the process and flows for raw and auxiliary materials, waste, personnel, starting materials,
intermediates, drug substance, and drug product API

Process flow charts with material balancing
Validation documents, including process validation, cleaning validation, and equipment validation (if applicable)

Stability data
Product quality and performance history review and statistical analysis (is available)

Safety precautions, material data safety sheets, and special material handling procedures
MSDS
Team member skills
Technical and instrumental resources and procedures
Timelines
Finance/costs /

As these activities occur, it is also necessary to transfer process knowledge, equipment, and material to the recipient
facility in a timely and accurate manner. This will ensure that product quality, regulatory, and business needs are met.

4.1.2.1 Technology to be Transferred

To aid in the assessment and development of a transfer strategy, a detailed description of the technology to be transferred
(including the synthetic route, starting materials, reagents, and catalysts) needs to be prepared by the SU.
SU

Depending on the stage of development, the information to be collected on the technology being transferred may differ.
The requirements for transferring a Phase 3 process from one CMO to anther will differ significantly, for example, from
the assessment performed when moving from an R&D environment into a manufacturing scale (scale-up) environment.
CMO CMO

The description may include the following:

Flow chart of the process with a description of each step

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The amounts of materials/reagents and stoichiometry required
/
Order of addition of reagents
Specific conditions required (e.g., temperature, humidity, times, and pressures)

Yields of each reaction step
Compound attributes (e.g., pH in solution, bulk physical properties, particle size and size distribution, moisture content
and hygroscopic nature, partitioning coefficient, solubility profile, and degradation profiles)
pH

Historical process information
Designation of registered starting material /
- Depending on the stage of transfer, the registered starting material might be important. Steps prior to this material do
not need to be performed under CGMPs, although the concepts discussed in this document could still be applied.
CGMP

Designation of CQAs CQA
Allowable variations in scheme and permitted ranges based on historical information or quality-by-design information
QBD

4.1.2.2 Scale-up of Production level

When a process is transferred from a development facility to a manufacturing facility, the level of production is probably
scaled up along with the process transfer. In such cases, either equipment modification or installation of new equipment
is probably required to accommodate the increased manufacturing scale.

Therefore, the scale-up philosophy chosen will influence the equipment used in production. Once a scale-up philosophy
has been identified for each unit operation, it should be documented in the technology transfer plan or in the individual
technology transfer study protocol/report.

/

Along with a formal development of scale-up and control philosophies, the technology transfer team should define
requirements for:

Data gathering: the appropriate requirements are specified for the data historian

Criticality of instruments: may be based on the criticality of the corresponding process parameter

Tolerances for instruments: may be based on control requirements (e.g., pH)
pH
Alarming requirements: may be based on the criticality classification of the process parameters

After a formal assessment of equipment, instruments, and control needs, the technology transfer team can incorporate the
scale-up or design philosophy requirements into a set of user requirement specifications (URSs). In practical, the URS
are general documents containing environment, health and safety, GMP, and other requirements. The URS will form the
basis for the design/fabrication/procurement of the equipment. Simultaneously, functional and design specifications may
be defined for any equipment used in the process.

URS URS GMP URS
/ /

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For example, a production bioreactor or fermentor might be scaled up. While the vessel volume is scaled up, some
factors, such as the volumetric oxygen mass transfer coefficient (kLa) or power input per unit volume of bioreactor,
might be able to remain constant. If the kLa is to be kept constant across scales, then the fermentors gas supply
capability may need to be upgraded. In either case, a different type of reactor modification may be required based on the
scale-up philosophy chosen (5).

kLa kLa

4.1.2.3 Control Philosophy /

Like a scale-up philosophy, a control philosophy needs be identified for each of the major pieces of equipment that will
be used in the process.

In a fermentor, for example, the dissolved oxygen (DO) used may be process specific and may need to be calibrated and
optimized for specific operation. Control of DO may be affected by cascade control whereby a change in the agitator
speed is the first change in response to a DO change. This agitator control loop is a slave to the master DO control
loop. An alternative to cascade control is a simple increase in air or oxygen sparge rate. A similar discussion may also be
given for the trans-membrane pressure control of tangential flow filtration unit operations employed in many
bioprocesses.
DO DO
DO
DO

4.1.3 Control Strategy /

As defined by ICH, Q10 control strategy is: ICH Q10

A planned set of controls, derived from current product and process understanding that ensures process performance
and product quality. The controls can include parameters and attributes related to drug substance and drug product
materials and components, facility and equipment operating conditions, in-process controls, finished product
specifications, and the associated methods and frequency of monitoring and control(6).


6

Control strategy provides critical governance throughout the product lifecycle. The control strategy evolving as the
product moves through development, technical transfer, commercial production, and discontinuation. Although the
strategy varies at different stages, the core purpose of the control strategy remains the same: to ensure process
performance and product quality. The principles of QRM can be applied to identify the control strategy.

From a control strategy management perspective, the application of risk analysis and human/ technical/economic
resources management tools should also be taken into consideration.
/ /

A general analysis of production feasibility, using risk management principles, should be conducted prior to beginning
transfer activities. The feasibility reviews are used to create and update the process risk assessment (described in the
following sections) and identify potential manufacturing challenges. They also provide recommendations for process
modifications needed to address manufacturing constraints and/or desired utilization strategies (e.g., yield or process
time targets).

/

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Fishbone (Ishikawa) analysis is commonly used in risk assessment to identify the risks by laying out causes and effects
(Figure 4.1.3-1)
( 4.1.3-1)

4.1.3-1

The principles of fishbone analysis can be applied to identify the control strategy. The effect would be adverse effects on
product quality, which are defined by CQAs. The causes can be laid out according to six main components (the six Ms
in an Ishikawa, or fishbone, diagram) (7, 8):
CQA
6 6 M 7,8

1. Machine (equipment)
2. Methods (documentation)
3. Material
4. Manpower
5. Measurement
6. Mother nature (environment)

The six Ms are described in detail bellow. 6 M

4.1.3.1 Machine
The technical transfer team needs to identify the key sets of equipment used to control the CPPs. The operating ranges of
the key equipment at the RU need to be checked, and their capability to achieve the critical process parameter (CPP)
range needs to be evaluated. Any gaps revealed during the evaluation are documented as part of the risk assessment.
CPP RU
CPP

Equipment operational qualification should be performed as a prerequisite of process validation at the RU. Preventive
maintenance programs should be established at the RU, and the SUs project management program can be referenced for
consistency.
RU RU
SU

If the technology is transferred from a development site to a commercial site, the scalability of the equipment needs to be
evaluated. The CPPs developed at laboratory or pilot scale may be scale dependence.

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The CPP ranges at the receiving commercial scale should be corrected to account for the scale-up factors. For example,
if the agitation rpm of a crystallizer is chosen as a CPP based on the development-scale models, the appropriate range of
rpm at the commercial scale needs to be established. This should be based on a comparison of factors, such as mixing
and shear stress between the crystallizers, at the pilot scale and at the commercial scale.
CPP
CPP

4.1.3.2 Methods ( )

The technical documents from SU need to be examined; practices and instructions described should be consistent with
each other and with regulatory registration.
SU

Inconsistencies or gaps among these documents and difficulties in their execution should be highlighted in the initial risk
assessment summary report and should be corrected or assessed in terms of risks prior to commercial production at the
RU. Inconsistencies could lead to confusion in operation, failure to ensure product quality, or noncompliance with the
registration after the technology is transferred to the RU.
RU
RU

If the SU is a development site, a development history report (DHR) (where the product control strategy identified
during the product development stage is documented) should be available for review as a part of the technology transfer.
The RU should create the process flow diagram (PFD), SOPs, etc. according to the DHR.
SU DHR
RU DHR PFD SOP

The SU should review the key technical documents to ensure that the information in the DHR is captured appropriately.
SU DHR

4.1.3.3 Material
The SU needs to provide the raw material specifications. If an API process with multiple intermediate products is
transferred, all intermediate product specifications need to be provided by the SU.
SU API SU

The SU needs to ensure that the specifications listed in the local documents are consistent with the registered
specifications. The RU is responsible for qualifying the raw material suppliers (unless the agreement between the two
units states otherwise).
SU RU

If the process is transferred from a development site to a commercial site, the suppliers sustainable capacity needs to be
examined during the suppler qualification. The storage conditions of the raw materials (including the intermediate
products) should be specified, and associated hold times (or expiry dates or reevaluation periods) should be available to
the RU. The constraints of transporting raw materials across different regions or countries should be considered. Delays
in obtaining these materials as a result of customs clearance procedures may occur, and the storage conditions might
therefore change temporarily. The impact of delays and temporary storage condition changes on intermediate product
quality should be assessed.

RU

4.1.3.4 Manpower

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The RU should clearly define the roles and responsibility of each technology transfer team member and ensure adequate
operation and supporting staffing for commercial production at its facility. A training or personnel qualification should be
established at the RU. Proof of training completion for each person is needed prior to process validation.
RU RU

4.1.3.5 measurement

Analytical methods should be validated prior to the process validation at the RU, regardless of whether the methods have
been validated at the SU. The analytical methods to be validated include those for both routine samples, such as
intermediate products and buffers, and for nonroutine samples, such as samples for process-related impurities. The
sampling plan, including sample location, size, frequency, method, and handling, should be clearly defined. The
instruments used to measure in-process parameters should be qualified. The measurement uncertainty for CPPs needs to
be calculated at the RU.
SU RU

RU
CPP

This information is used to set the operation targets to ensure that the true CPP values are within the predefined limits
when instrument measurement uncertainty is considered.
CPP

4.1.3.6 Mother Nature

Whether the RU is prone to nature disasters and how well it is designed to minimize their impact should be evaluated.
This may have been done when the RUs facility was built. If the RU and SU have a dramatic climate difference,
temperature and moisture control would need additional consideration, particularly for raw material storage and
transportation.
RU RU RU
SU

4.1.3.7 Feasibility Reviews

Regardless of the knowledge and different type of TTP (e.g., inter-or intracompany transfer of a manufacturing process
from a multi-purpose department to a dedicated department), the feasibility analysis and the six Ms described above in
this section have to be accounted for by both SU and RU teams.
TTP
SU RU 6 M

The preliminary feasibility study should consist of at least a gap analysis that compares the SUs manufacturing
plant/department to the RUs manufacturing plant/department. It should identify potential differences that could make
the process/product fail the set specifications and identify corrective actions. The results of this analysis should be
recorded in a controlled document and be approved by the SU and RU as well as the project manager. This document
should officially state the suitability of the RU to reproduce the process to be transferred.
SU RU /
SU RU
RU

4.1.4 Facility Design/Layout considerations /

It is very common to design and develop the manufacturing technology in a non-GMP facility, which allows for
flexibility and is more cost effective than performing these activities under GMP conditions. As a result, the process may
be transferred from a non-GMP to a GMP facility.
GMP GMP
GMP GMP

4.1.4.1 Transfer from Non-GMP to GMP Facilities GMP GMP

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Per regulatory guidelines, all GMP facilities must maintain certain standards for facility layout, design, and controls
(e.g., temperature, air pressure, and humidity) in addition to the basic elements of facility design (e.g., animal and pest
control and environmental monitoring)(9).
GMP

The process development work may have been performed using non-GMP utilities (e.g., plant steam instead of process
steam or plant air instead of clean air). When such a process is transferred from the development facility to a GMP
facility, the technology transfer team should examine the use of the appropriate utilities at appropriate stages in the
process. The RU might have general policies guiding the use of GMP and non-GMP utilities for various activities (e.g.,
use of plant steam for steaming non-product contact small parts as part of cleaning). Any dedicated/special equipment
used for the process may be outside the scope of the facility guidelines, so the technology transfer team may need to
determine the appropriate type of utilities to be used for those pieces of equipment.
GMP
GMP
RU GMP GMP
/

4.1.4.2 New Facility Construction

If the transfer activity involves the construction of a new facility, the RU should generate a user requirement-like
document that describes the facility characteristics needed to meet the process/ product specifications, which in turn
drive the engineering development of the facility. The transfer of the process can sometimes be conducted using the
transferred documents to define the requirement. It is well understood that this approach could lead to mistakes due to
incomplete evaluation of all variables; therefore, a common solution is to define the requirements starting from the
transferred information, proceed with a deep gap analysis, and then determine whether the documents are sufficient to
support those requirements.
RU URS /

4.1.5 Facility Fit Report

Facility fit reports (FFRs) are a key deliverable in steps 2 and 3 to aid in the transfer of the late-phase development and
commercial processes to the commercial facility. These reports translate the process description details into an
operational map of how the process is to be executed at the site.
FFR 2

Process ranges, buffer volumes, column volumes, tank assignments, and step durations are examples of the type of
information included in these reports. These reports are typically authored by the RU process subject matter experts (e.g.,
commercial technical support personnel) and reviewed and approved by SU process subject matter experts (e.g.,
manufacturing, facilities, supply chain, and quality personnel).

RU SU

These reports govern the transfer of process details into manufacturing batch records and solution preparation records
and serve as a guide for the flow of the process through the facility. FFRs may include summaries of process risks, raw
material safety risks, and action items resulting from fit-to-plant exercises.
FFR

Other information typically found in the FFR includes: FFR

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Detailed process descriptions by unit operations and associated process flow diagrams that reflect the commercial
scale of operations and fit considerations

Process sample plan with in-process control limits, where appropriate

Comprehensive list of raw materials and components used in the process

Gap/risk analyses related to process fit, including new capital equipment or modifications of capital equipment
required, equipment/facility gaps, clean-in-place/steam-in-place flow path utilization, new materials or manufacturing
supplies needed, and/or automation gaps
/ /
/

4.1.5.1 Environmental Variables

Environmental variables are normally controlled within set tolerances at given facilities. However, an assessment should
cover the potential that, even though both facilities operate within given tolerances, facility differences may have an
impact on the product or the tests to be performed. The assessment should be based on the available process information
or analytical tests performed and their susceptibility to environmental factors.

The following are examples of some environmental condition that, even if properly controlled within set tolerances, may
have impact on product production or testing:

Humidity and Temperature: Humidity and temperature are controlled in most facilities, but they should be assessed
to determine whether potential differences could affect product production or testing. This testing may involve
evaluating trends over a year in addition to the allowed range.


Light The source and type of lighting should be evaluated. Particular attention should be given to possible source of
natural light due to their impact on photosensitive compounds when these sources are compared to the lighting of the
RU.
RU

Pressure: Pressure does not to be controlled, but it may have undesirable consequences for final dosage forms that are
liquids, ointments, or creams that are filled in flexible containers. A light-density polyethylene bottle filled at a plant at
3,000 m altitude could be aesthetically affected, for example, when marketed at sea level and vice versa.

PE 3000m 0

4.1.5.2 Viral Segregation

Transfer of processes for biotechnology-derived products expressed in animal cells (e.g., monoclonal antibodies from
Chinese hamster ovary [CHO] cells) requires consideration of the impact of viral segregation on facility design/layout.
CHO cells are known to endogenously express retrovirus-like particles. Although dedicated steps for virus clearance
(i.e., inactivation and removal) are built into the purification scheme, these steps may not occur until midway through the
purification process. In such cases, an effort should be made to segregate virus-related process streams from non-virus-
treated process streams, especially if open processing is used. The technology transfer team should consider initiating
specific clearance steps prior to exposing the treated and nontreated process steams if physical segregation or completely
closed processing is not feasible.
[CHO]
/ CHO

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4.1.5.3 Support Laboratory

Finally, using an on-site support laboratory (which can be non-GMP) to help with troubleshooting and routine support
for the production facility can also be considered. Performing scale-independent technology transfer studies in an on-site
development laboratory will help share knowledge between production and support personnel.
GMP

An example of such support work is evaluation or generation of worst-case soil for use in facility cleaning validation
studies. If the philosophy used for cleaning validation is to use worst-case process soils to demonstrate the efficacy of
clean-in-place cycles, this material can be generated from the on-site support laboratory. Generation of this material in
the support laboratory early during technology transfer (instead of generating this material at scale in the production
facility) allows sufficient time for experimentation/development of cleaning cycles.


/

4.1.6 Transfer of Documents

Technology transfer presents challenges relating to the documentation provided by the SU and its implementation by the
RU, especially in the transfer from R&D to manufacturing due to the nature of the project step.
SU RU R&D

Specifically in these cases but applicable to all technology transfer projects, the documents transferred by the R&D unit
should include at least the following:
, R&D

Product CQAs
Impurity profile
Specifications (at least for drug substance/product and packaging components)
/
Critical and noncritical process parameters along with ranges and proven acceptable ranges

Manufacturing instructions
Procedures for process-related activities
Raw and auxiliary materials
Cleaning procedures
Available stability data
Validation documents (at least aseptic process and pathogen clearance validation reports)

Analytical method SOPs SOP
Process development documents (e.g., key technical reports and process development history reports)

Previous regulatory filing
Manufacturing process flow and instructions
Analytical methods and procedures
Development report

The following information might also need to be provided to the new product producer:

Clearance of process impurities

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Virus clearance
Hold times of the process steps
Mix times of the solutions and the product
Chromatography, filter, and membrane lifetimes
Container closure study descriptions
Reprocessing or rework data
Stability of raw materials, APIs, or cell lines API
Polymer materials that have direct contact with the product (compatibility/leakage)
/
Annual product review for trending

4.1.7 Technology Transfer Protocol

A road map 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 (described in Section 5.7). Outputs of this stage include a
finalized project plan describing the activities, resources, schedule, and project risk assessment.
SU RU TTP
TTP 5.7

The TTP plan should drive the overall process and define the strategic approach by describing:
TTP

The manufacturing process being transferred

- Sampling and testing steps
Roles and responsibilities of the SU and RU SU RU
RUs equipment and facilities RU
- If the transfer is from one manufacturing facility to another, a description of both sites 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
Backup plans for critical tasks to avoid delaying or stopping the project due to unforeseen events

Status monitoring
Correlations to previous and subsequent tasks

The technology transfer protocol must establish 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.
TTP

All personnel with management roles in the transfer, including the two team leaders, should agree to and sign the project
plan. The exception is the project committee, which functions primarily as a consultant. A gateway review by senior
leadership is used to make visible the plans and risks and provides approval to move to the next stage.

4.2 Stage 2: Process Readiness 2

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The goal of this stage is to achieve readiness of the process, equipment, automation, facility, operations, and assays to
successfully execute process performance qualification (PPQ) lots. Shakedown activities culminate in the production of
engineering lots that provide conformation that all systems are sufficiently ready to perform PPQ lots. Training at the RU
is a key goal of this stage. A gateway review is used to highlight the rationale for proceeding to the next stage and should
include a discussion of the potential risks to the successful execution of PPQ lots.

PPQ PPQ
RU PPQ

At the end of the assessment and planning phases and before the start of the TTP implementation, the technology transfer
team sets up a stage/gateway step. The purpose of this step is to confirm that the process is ready, that all critical aspects
of the project have been deeply analyzed, and that the potential associated risks have been identified and properly
mitigated.
TTP /

The formalization of the assessment and appropriate training of personnel impacted by the transfer are critical. Thus, the
proper procedures have to be in place in the RU and SU.
RU SU

4.2.1 Process Changes

The RU should manage the transfer via its change control procedure, and a general risk management analysis should be
performed to evaluate the impact of the process on the affected departments.
RU

The RU should then translate the R&D information and procedures (e.g., specific activities and batch records) and adapt
the process flow to fit the designated department through creation of specific procedures. Analysis of raw and auxiliary
materials should be performed to identify and qualify suitable suppliers and materials. A risk management approach
should also be applied to classify and evaluate the impact of process changes aimed at optimizing the process itself.
RU

In the course of scale-up, process parameters and equipment may be subjected to change. Procedures should be in place
at the RU to efficiently manage any changes while maintaining traceability. The procedures must take into account any
documents submitted to regulatory authorities and the possibility of the need for amendments. Affected processes and
equipment include:
RU

Filtration areas
Media
Operating pressures and flow rates
Process hold times
Cleaning solutions/procedures and rinse volumes /
Devices (e.g., changing from housing to a filter-press for depth filtration)
Disposable versus stainless steel containers

Process development reports should detail the rationale to support any changes. The application of good documentation
practices and design of experiment (DoE) techniques during process development are fundamental to support these
changes and the application of GMPs during clinical manufacturing. Insertion of new steps into, or modification of, the
process flow should be carefully evaluated from quality and regulatory points of view. In the event of a substantial
process modification, the transfer should be put on hold and feasibility studies should be performed again.

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DoE GMP

4.2.2 Training

Based on an evaluation of the RUs experience, the SU should provide hands-on training for specific steps in the process
as needed. This training may be performed either at the SU or the RU facility. The type and the amount of training vary
depending on the complexity of the steps and the experience of the RU personnel in performing the specific steps.
RU SU
SU RU RU

Training should be divided into two steps:

1. The RU technology transfer team members managing the TTP (e.g., RU leader, manufacturing department head, plant
maintenance head, and engineers) and other key personnel (e.g., head of shift for manufacturing or maintenance
departments) should be trained in the process at the SU (i.e., on-the-job training, training the trainer).
RU TTP RU
SU

2. Trained personnel should draft the process-related procedures for the RU and for training the operating personnel.
RU

4.2.3 Development Data on Process Management

Development Data are the data captured during the R&D phase of creating a new product. This may consist of data from
quality of design, the CQAs, the specifications, and the assurance of product and process consistency. The data relay
how the process performs; whether it can perform consistently; and whether it ensures the purity, quality, safety, and
efficacy of the drug product or drug substance.
R&D CQA
API

Development data are derived from analytical methods, testing of the product during the R&D phase, and scale-up of the
process. Process management during the development phase is critical in light of compressed time-to-market
expectations. As a result, development strategies and milestone dates for chemistry, manufacturing, and control activities
needs to support requirements for product development and should be described in development plans. During process
development, it is important to understand the production environment, the equipment, the parameters that need to be
developed, and the operations to be used.
R&D

The development phase data are critical because they verify that the safety and efficacy of the product align with the
specification and ensure consistency from development to manufacturing. The data from the development phase are part
of the TTP from R&D through production as the ranges are refined throughout the process.

TTP R&D TTP

Critical process parameters should be defined during development. These parameters establish criteria that are consistent
with process stability. The key is to characterize the range that will result in producing a product that meets certain CQAs
or proven acceptable ranges while keeping other parameters constant, as defined in ICH Q8 (R2). Many organizations
also establish normal operating ranges that are tighter and can identify the need for investigation (2).
ICH
Q8 R2 CQA

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To assess risks and establish critical process parameters, a top-down approach, such as a fault tree analysis, can be used
to identify critical subprocesses within the overall process. The subprocesses identified can then be assessed through a
failure mode and effects analysis (FMEA)-based approach to identify root causes and critical manufacturing steps.

FMEA

4.3 Stage 3: TTP Implementation and Qualification 3 TTP

During TTP implementation, equipment is installed and qualified, preliminary laboratory or manufacturing trials are
conducted, and the PPQ lots are manufactured to satisfy the requirements for demonstrating reliable manufacturing. A
gateway review is used to critically evaluate the performance of the PPQ lots, including stability data when applicable
and any risks posed to the successful licensure of the facility.
TTP PPQ
PPQ

As discussed previously, the design of the plant and process is crucial to the success of the technology transfer and
should be monitored closely by the appropriate transfer team members. Moreover, the transferred know-how should be
the basis for scale-up evaluations or established process transfer and to organize the new plant and process to meet
product specifications and process requirements. R&D scientists should be involved in such activities.


R&D

4.3.1 Manufacturability Reviews

Upon completion of each cycle of process development, detailed facility and process fit assessments and manufacturing
information reviews are conducted prior to creation of manufacturing batch records. These represent a key deliverable
for this step in the TTP.

TTP

Manufacturability reviews are an end-to-end product review of the proposed late-phase development and commercial
processes to be manufactured at the commercial site. These reviews are facilitated by the RU and conducted jointly by
the SU and RU process subject matter experts (SMEs; e.g., commercial technical support and process development
personnel) in collaboration with unit SMEs (e.g., facilities and engineering personnel).
RU
SU RU SME SME

Key outcomes of the manufacturability review at the early stages of the TTP are facility and equipment gaps and
recommendations for process changes. Preliminary reviews may be needed for more complex processes to identify
equipment and facility modifications requiring long lead times.
TTP

Another key output of manufacturability reviews is the plan of record. This document describes stage-appropriate
assumptions approved by both the RU and SU. It also lists the process targets planned by the SU and the facility
modifications and schedule planned by the RU. For example, this document lists the commercial titer to be targeted for
the production bioreactor, the number and size of chromatography columns, and the cycle time for the bioreactor.
SU RU
SU RU

4.3.2 Transfer of Analytical Test Methods

Analytical test methods are well defined and are used for QC of raw materials, intermediates,

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APIs, or final drug products. The analytical control methods should be transferred before the manufacturing process to
ensure proper testing of the products.
QC API

The SU should prepare the following information for evaluation to conduct a risk assessment of the analytical test
methods:
SU

Detailed description of the test method procedure

Method validation report
Prior method transfer data
Historical method performance information
Detailed description of instrumentation used
Examples of generated data (e.g., spectra and chromatographic plots)

The RU should review this information and evaluate it for possible gaps (e.g., lack of experience in method type or
differences in instrumentation to be used). Any gaps identified should be assessed for risk of failure by both the SU and
the RU.
RU
SU 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.

Examples of the types of approaches described in USP <1224> are shown below, but other transfer designs may be
acceptable. The approach used should be justified and evaluated during the risk assessment (10).
USP 1224
10

Comparative Testing: The RU and SU both analyze a predetermined set of samples and perform a comparative
analysis of the results generated. RU SU

Covalidation between two or more laboratories: The SU includes the RU in the validation team for the validation
exercise to obtain data on reproducibility. SU RU

Revalidation: The RU can perform a revalidation or partial validation of the method. RU

Transfer Waiver: During the assessment, the given method does not require official transfer. The USP chapter
contains examples of this situation, such as compendial methods, which do not need to be transferred between the SU
and RU. However, the RU would need to perform method verification testing as defined in USP<1225> (11).
USP SU
RU RU USP 1225

Other study designs for method transfers are provided in PDA Technical Report No.57: Analytical Method Validation
and Transfer for Biotechnology Products. Ultimately, the approach chosen should be based on the results of the risk
assessment for the methods and this choice should be justified in writing (12).
PDA 57
12

As part of the assessment of the transfer, the actual tests to be performed for the transfer need to be evaluated. The tests
performed may depend on the experience of the laboratory, any gaps determined during the assessment, and the nature of
the method to be transferred.


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4.3.3 Monitoring

4.3.3.1 Microbial Monitoring

Depending on the transfer phase and the type of product being transferred, an assessment will need to be performed of
the applicability of microbial control and monitoring. The type and extent of microbial control and monitoring (e.g.,
sterility, endotoxins, bioburden, or container/closure integrity testing) will depend on the manufacturing process
assessment and the probability of microbial contamination along with the final products ability to support microbial
growth.

/

If microbial monitoring methods are required, these methods should be transferred from the SU to the RU by on-site
validation of the methods. Assessments should be performed of the RU facilitys ability to support microbial testing or
appropriately outsource the work to a third party. For implementation of compendia microbial monitoring methods, the
USP contains descriptions of the necessary steps to perform the required verifications/validations.
SU RU RU
USP
/

4.3.3.2 In-Process Monitoring

The assessment of the manufacturing process should include the need for in-process analytical testing. Most steps are
likely to be well defined and controlled, whereas other steps may require monitoring to ensure completion of reaction or
maintenance of specific process tolerances (e.g., moisture content, extent of reaction, and pH). In-process methods may
be continuous monitoring of a key attribute (e.g., pH), or may be performed at a single time intervals (e.g., moisture
content or extent of reaction). The need and type of in-process method should be based on the results of the overall
assessment of the process.

pH
pH

For the selected in-process analytical methods, the level of information to be provided and the requirements for transfer
will vary. The assessment should determine the difficulty of the method as applied and the criticality of the method.
Methods determined to be more complex and critical may require additional information and evaluation during the
transfer process. The information should include a sufficiently detailed description for performance of the method.
Additional information may be required for more complex methods (e.g., chromatographic analysis).

In-process analytical methods do not require the rigorous level of transfer that is required for QC analytical methods, but
the principles used for QC methods may be applied to the in-process methods. It may be useful to rank each of the
methods to determine the extent of transfer required using the following criteria:
QC QC

Analytical Complexity: Including requirements for a specific academic or scientific background, extensive instrument
expertise or an extensive set of method particularities impacting the results of the analysis (pH is classified as a simple
method, whereas an HPLC assay is classified as complex)
pH HPLC
Product Specific or Product Independent: For example, pH monitoring is a product-independent method whose
result is not affected by the chemical, whereas the extent of reaction assays is product specific
pH

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RU Experience: The RUs history of using the analytical methods required /RU RU

The necessity to monitor the manufacturing process can be also faced with a process analytical technology approach that
is based on accurate risk analysis and process knowledge.

According to the current guidance, process analysis technology is a system for designing, analyzing, and controlling
manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of
raw and in-process materials and processes with the goal of ensuring final product quality (13). Process analytical
technology, when proven, can provide a comparable and valid alternative to traditional in-process analyses.

13

4.3.4 Cleaning Validation

An important part of TTP implementation is the cleaning of the equipment train and facility used for the manufacturing
process. The objective of cleaning is to confirm the reliability of the cleaning procedure so that routine analytical
monitoring may be reduced. During the manufacturing process, pharmaceutical products and APIs can be contaminated
by other pharmaceutical products or APIs if the facility processes multiple products. Virus segregation should also be
considered in relevant cases for API manufacture (e.g., mammalian cell). Adequate cleaning procedures are essential to
minimize the risk of contamination and cross-contamination, operator exposure, and environmental effects. Once the
cleaning has been validated, a risk assessment may be performed to determine whether the level of routine monitoring
has been reduced. This risk assessment must include the risk of cross-contamination.
TTP
API API
API

Analytical methods should be challenged in combination with the sampling methods to demonstrate both the levels of
recovery from the equipment surface and the reproducibility of the results. Analytical testing of swab or rinse samples
should be validated before the cleaning validation study is carried out.

The unit transferring a process should provide information on cleaning procedures that have minimized cross-
contamination, including:

Solubility information on active ingredients, excipients, and vehicles

Minimum therapeutic doses of active ingredients
Therapeutic category and toxicological assessment
Existing validated cleaning procedures
Cleaning validation reports (chemical and microbiological)
Cleaning agents used (efficacy and evidence that they do not interfere with analytical testing for residual active
ingredients)
Recovery studies to validate the sampling methodology

Limits should be established for product residues, including a rationale that takes into account relevant characteristics of
the starting material (e.g., potency, toxicity, solubility, corrosiveness, and temperature sensitivity), manufacturing
equipment design and configuration, cleaning agent used and its residue, and rinsing processes. A risk assessment may
be performed of these limits as well, and its results should be shared with the RU.


RU

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The quality unit at the RU should have validated cleaning and maintenance procedures for buildings, equipment,
services, and support systems that affect the product, process, or method being transferred.
RU

Based on information on product residue limits identified by the SU, the RU should determine its own practical,
achievable, and verifiable cleaning validation limits based on the materials involved, their properties, and their
therapeutic dose. A risk assessment can be performed to help establish these limits.
SU RU

4.3.5 Process Validation

Process validation is the collection and evaluation of data from the process design stage through commercial production.
These data provide science evidence that a process is capable of consistently delivering high-quality product. Process
validation is part of the technology transfer to a new building, a new company, a new partner, etc. successful process
validation depends on the development of a reproducible and reliable process during process development. Process
validation is a major objective of a TTP (4.14). Successful process validation allows for regulatory approval submission
and subsequent commercial manufacturing.


TTP 4.14

Process validation should be performed under a pre-approved protocol detailing acceptance criteria, and the results
should be summarized in a final report.

Strategic planning for process validation begins during step 2, and the team is formally launched after this process is
successfully completed. Successfully completing deliverables for step 2 allows the initiation of actual process validation
campaign runs, and the results of these runs are summarized for submission readiness. The deliverables in step 4 include
elements needed for process performance qualification and continued process verification. A full explanation of details
regarding process validation can be found in PDA Technical Report No. 60-Process Validation: A Lifecycle Approach
(4).
2 2
4
PDA 60 -
4

4.3.5.1 Components of Process Validation

It is crucial that TTPs take into account all aspects of the process validation lifecycle. Key items that need to be
identified during process validation are:
TTP

Process parameters
Critical process parameters
In-process controls
Critical in-process controls
Process ranges/boundaries /

Further prerequisites for a successful process validation include:

Risk assessments at stages 1, 2, and 3 1 2 3

Process parameter reports summarizing the rationale for parameter categorization and ranges

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Qualification and validation of manufacturing equipment and automation, including associated utilities/facilities
/
Effective manufacturing procedures
Qualification and validation of analytical methods and instruments

For legacy products, revises of historical data can be used along with control charts, process capability, and the six-sigma
methodologies. For more complex operations, a design of experiments may be used.
6-

4.3.5.2 Process Validation Studies

Full-scale manufacturing consistency studies should be performed for each step in the process or each unit operation.
The studies should demonstrate that process parameters can be maintained within pre-established set-points and limits
and that outputs from each process step are consistent with expectations. These studies should be performed
prospectively, and the number of lots to be validated should be documented.

Validation of the equipment should be carried out by the RU with the cooperation of the SU, with special attention to the
review of qualification protocols. Installation qualification (IQ) requirements should be determined by a mechanical
completion analysis for confirmation and verification of all of the required equipment parts. This is especially important
for newly built departments/plants. Verification of the correct assemblage of the system (commissioning) should be
followed by IQ, operational qualification (OQ), and performance qualification (PQ).
RU SU IQ
/ IQ OQ PQ

4.3.5.3 Required Documents

The minimum required information and/or documents required for process validation are:
/

Definition of the critical product attributes based on known or expected clinical effects of the measured product
attributes (determined in risk assessment 1

Classification of controlled parameters (process inputs) as minor, major, or critical. Process development and
process characterization studies based on risk assessment 2 and 3 provide the rationale for the categorization of
parameters. These also set parameter ranges for the process validation studies.
2 3

- Critical control points: steps at which control can be applied and that can reduce or eliminate a risk to an acceptable
level
- In-process control: checks during production that monitor the process and allow adjustment within normal operating
parameters that result in maximum yield or business
efficiency

- Critical in-process control: checks during production that monitor the process and allow adjustments within
specified limits. This could include environmental controls as well.

A process flow diagram that describes the details of process steps for each unit operation.

Process parameter reports that summarize the rationale for the categorization and ranges for the process parameters,
including critical process parameters, in-process controls, and critical in-process controls.

Review of potential process hazards regarding chemical, biological, physical, and environmental impacts. The
environment, health, and safety groups should work with the manufacturing group to remove or minimize the risks
34 GMP
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identified.

Both parties should jointly write the process validation report and the process validation master plan. The process
validation report should be approved by the quality unit, summarize specific tests performed and their results along with
pre-defined acceptance criteria, and address deviations encountered during the study. A process validation master plan
report should summarize the results and draw conclusions as to whether the overall process is validated (4.14).


4.14

4.3.6 Campaign Summary Reports

The campaign summary reports capture lessons learned from manufacturing batches and are useful baseline reports for
reference during subsequent analysis for regulatory filling or process history.

4.3.7 Continued Monitoring

Once the strategy is developed, regular meetings should be scheduled to manage the project timeline. Identify all
activities and responsible parties, and maintain process visibility. Agendas and meeting minutes should be maintained for
all meetings. These meetings ensure that documents are reviewed and approved within agreed timelines and provide
routine updates to involved parties, including QA, manufacturing, and development units.


QA

4.3.8 Application of cGMPs GMP

The ease with which a TTP progresses depends on the stage of development and the level of application of cGMPs.
Process transfer aiming at the production of batches with increasing cGMP expectations must meet the requirement of
improving some steps of the process itself.
TTP GMP GMP

In the European Union, cGMPs dedicate a specific annex to investigational medicinal products manufacturing (15).
GMP 15

In this instance, change control procedures should take into account this potential need for increased GMP expectations.
Products manufactured at later stages of development (Phase 2 or 3 of clinical studies) should have a nearly complete
level of cGMP application.
GMP 2 3
GMP

As such, the transfer from clinical manufacturing stage to full commercial scale should be managed as a transfer between
commercial sites. The organization of TTP activities and macro-activities are still valid for this process and will need to
be considered.
TTP

4.4 Stage 4: Licensing and Manufacturing 4

The license document is completed and submitted to regulatory agencies, and routine commercial manufacturing is
initiated. An after-action review is an important activity during this sage as a means to drive continuous improvement of
the technology transfer business process. The risk ranking in the previous stage can be revised based on the results of the
risk mitigation actions implemented. A final gateway review occurs to decommission the technology transfer team.

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4.4.1 Process Scale Up

Technology transfer between development and commercial production generally involves a scale-up activity and requires
attention to the process and product requirements. For this reason, the preliminary assessment and gap analysis step
needs to take into consideration this critical difference between the SU and the RU. Involvement of the R&D department
is usually greater than in the transfer of an established commercial process. Strong regulatory and quality compliance
assessments are done immediately after the TTP generation, to evaluate the impact on the regulatory submission.

SU RU
TTP

Change management is considered even more critical due to the nature of the project for the unavoidable changes that
the process required during scale-up. Appropriate procedures for tracking these changes should be in place, and the
report issued at the end of the project has to summarize reasons for changes, and the scientific rationale for decisions
taken during the project. After a scale-up process is finalized and validated, the monitoring step assumes a key role to
properly evaluate the reproducibility and the consistency of the changes adopted during the project. Annual or biannual
verification steps are suggested to measure trends in results and highlight any activities that need to be implemented.

4.4.2 Monitoring of Production Batches

Follow-up involved the strict monitoring of the production batches by the SU and the RU for an established period of
time or number of batches. This occurs during the licensure and manufacturing stage in the business process.
SU RU

After the follow-up period, the technology transfer personnel should prepare the technology transfer report that describes
whether the RU is able to reproduce the technology according to the expected quality specifications. Approval of the
report should state officially the acceptance of full responsibility for the transferred technology by the RU. A pre-
determined number of batches produced at the RU should also undergo a stability study.
RU
RU RU

Statistical comparison between historical data at the SU and start-up/following-up data at the RU is recommended to
highlight any differing data trends or distributions.
SU RU /

4.5 Stage 5: Project Closure 5

After licensure, the technology transfer closure is formalized in a dedicated document (i.e., a technology transfer report).
Main tasks, milestones and changes to the original plan along the project are summarized. Lessons learnt are described
and deeply analyzed to provide strong background for further improvements. Moreover a verification plan needs to be
set up in this phase of the project for the continuous monitoring of the technology transferred.

This stage begins when the goals and objectives of the TTP are finished. Benefits, whether tangible or intangible must be
identified and communicated during this stage, allowing the organization to improve future projects by preventing
problems and creating contingency plans. This closing stage involves a confirmation of the appropriateness and risk
tolerance of the organizations risk management policies.

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TTP

In fact, based on the assessment done in the planning phase of the project, potential risks are identified and a mitigation
plan is set up and implemented afterwards. As a part of the project closure step, effectiveness of actions is verified. The
same approach used in risk definition (such as QRM tools; see Section 5.0) Can be used to recalculate the risk priority
number (RPN) at the end of the mitigation action.

QRM 5.0
RPN

The technology transfer is considered officially completed and closed if the corrective actions are successful.

A summary report should be generated containing information related to the non-GMP (such as development and
laboratory trials) and GMP manufacturing activities, including:
GMP GMP

Process overview
In-process and drug substance release and characterization data
Equipment list
Critical/major deviations /
Lessons learned
Technology transfer metrics
Results of all the deliverables in the technology strategy document
Verification schedule for the process

The operations groups should sign both the technology transfer protocol and report. Signing of the report by the RU
establishes the acceptance of responsibility for execution of the transferred technology and the conclusion of the follow-
up period. Implementation of agreed-upon corrective actions should be considered part of the follow-up period and
overseen by both the SU and RU.
RU
SU RU

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5.0 Application of Quality Risk Management
to Technology Transfer
5.0
5.1 Overview

During the TTP, internal (mainly related to the RU) and external (mainly related to the SU and external suppliers)
variables place it at risk. The TTP team must identify and mitigate the impact of these variables. ICH Q8, Q9, Q10, and
Q11 provide examples of tools and principles to achieve this objective. The approach used to design space in
pharmaceutical development, in which the relationship between the process inputs (material attributes and process
parameters) and the CQAs are assessed and described, can be applied during TTP management (2, 6, 16, 17).
TTP
ICH Q8, Q9, Q10 Q11

CQAs TTP (2, 6, 16, 17)

As applied to technology transfer, QRM should cover the risks involved in the process being transferred from the SU to
the RU as they relate to the maintenance of product quality (meeting the defined specifications or quality attributes) or
the performance quality of an analytical method (depending on the stage of qualification or validation).
QRM SU RU

This technical report only addresses aspects of QRM that are specific to technology transfer activities. PDA has
published several reports on QRM to which readers should refer for further discussion, analysis, and practical
applications of QRM. The main tenets are detailed in PDA Technical Report No.54-Implementation of Quality Risk
Management for Pharmaceutical and Biotechnology Manufacturing Operation (7).
QRM PDA QRM
QRM PDA 54 -
7

5.2 QRM in Technology Transfer QRM

QRM principles are broadly accepted in industry and are enablers of the pharmaceutical quality system. The primary
purpose of QRM in biopharmaceutical manufacturing is so identify and evaluate modes of product or process failures for
the purpose of ensuring product quality and patient safety. The benefits of QRM in TTPs include leveraging information
from the design and qualification stages to provide information back to process validation activities as part of continuous
process verification.
QRM QRM
TTPs QRM

Applied to technology transfer, QRM may be used to evaluate risk associated with each step of the project as well as the
impact of the new product/process and related raw materials on existing products and/or facility and process controls.
QRM / /

The purpose of QRM applied to a TTP is to review the proposed transfer of manufacturing process to ensure that
potential risk to the patient regarding the quality, safety, and efficacy of the drug product have been identified and are
adequately controlled.
QRM TTP

Specifically, this QRM should ensure that:

QRM

38 GMP
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The sources of variability that have the potential to impact CQAs have been identified
CQAs

The appropriate risk mitigation strategies and controls have been integrated into the process to minimize and
control potential change-related hazards that could result in the production of batches that do not meet
predetermined specification/CQAs

/CQAs

All critical unit operations and associated quality and critical parameters that must be controlled to ensure final
drug product quality are identified

The expectations of such a multidisciplinary QRM review of the proposed commercial/development process are:
/ QRM

Ensuring that sources of variability that could impact final drug product CQAs have been identified
CQAs

Ensuring that appropriate risk mitigation strategies and controls have been integrated into the process to
minimize and control potential quality hazards to the patient

Identifying critical unit operations and associated critical parameters that have a high risk of affecting CQAs
CQAs

QRM should address at least:

QRM
Processing operations and parameters (including batch record instructions)

Impact of new equipment, facilities, and supporting utilities (e.g., clean air, WFI, cleanrooms)
WFI

Potential for contamination from internal sources

Potential for contamination from external sources

Training of management, engineering staff, operators, and QA/QC personnel on the transferred process
- QA/QC

QRM must be focused on key areas such as:

QRM :

Identifying critical unit operations and CPPs that could be impacted by the transfer
CPPs

Identifying potential for contamination from internal and external sources

Ensuring that batch record instructions are adequate to document operations and control human variables
1.

5.3 Stages of QRM in Technology Transfer QRM

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The stages of QRM in technology transfer are as follows.
QRM

5.3.1 QRM planning QRM

The technology transfer team must establish the context for the TTP. This will include the identification of internal and
external factors as well as which QRM tools to use. External context may involve competitive, financial, regulatory,
legal, environmental and cultural aspects. Internal context may involve company policies and procedure, system,
operational objectives, personnel training and knowledge, available resources, and culture. A governance model,
including responsibility and accountability assignments, must be developed in this step and include the matters that are
subject to risk-based decisions. The risk determination of the subjects will provide the group with the necessary
awareness of risk. A policy for enterprise risk management should be in place at this stage. Requirements and constrains,
goals and objectives, and key performance indicators (including the success criteria) must be determined and agreed
upon. The technology transfer team should be skilled in basic project management to design a plan that takes into
account cost (including material and personnel resources); scheduled (including supply of the product being transferred;
scope; technology associated with the project; and the quality, safety, and efficacy of the product.
TTP QRM



( )

5.3.2 QRM Implementation (execution and control stage) QRM

It is not expected that many risk management activities will be performed during the execution stage. A rigorous
planning stage reduces the need for decision-making during the execution process. Processes where contingency plans
(e.g., use of alternate suppliers or contract manufacturers) have been developed from the beginning may help to manage
new unforeseen risks. The same risk assessment tools and control mechanisms must be used to manage those new risks.
It is important to monitor risks and factors affecting risks to ensure that the initial context determination is still valid.

5.3.3 Project Closure QRM QRM

This stage begins when the goals and objectives are fulfilled. Benefits, whether tangible or intangible, must be identified
and communicated by the project leader to the project committee during this stage to allow the organization to improve
future projects and avoid recurrence of problems or create contingency plans. This closing stage is a confirmation of the
appropriateness and risk tolerance of the organizations risk management policies.

QRM performed correctly during the development phase may mitigate inherent hazards and reduce the criticality of this
step. This is true provided that the risk assessments are thorough and define the impact and uncertainty of each step of
the development phase, process, and specifications.
QRM

5.4 Risks of Technology Transfer

Often, poor attention to its objectives (e.g., process specifications that are too tight or too broad) destines a TTP to
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

40 GMP
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impact of technology transfer failure.
TTP

Some common risks that are often overlooked and can negatively affect the TTP are:
TTP

Objective that is not clear (or clearly defined)

Objective that is not properly communicated and/or shared

/

Objective that cannot be operationally translated

No assessment of the effects of changes to the objective

Lack of change control

Among the risks to be considered prior to embarking on a TTP, regardless of its scope, are the cost of the project and
potential return on investment to determine an acceptable cost/benefit ratio based on internal RU and SU targets or
criteria.
TTP RU SU

5.5 QRM Concepts and Approaches Used in Technology Transfer

QRM

QRM tools used in accordance with ICH Q9 can facilitate the deliverables for each step in the TTP outlined in this
section. The ICH Q9 briefing book also provides general templates to use for QRM. Table 5.4-1 outlines the application
of QRM concepts and approaches at each step.

ICH Q9 QRM TTP ICH Q9

QRM 5.4-1 QRM

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Table 5.4-1 QRM Approaches at Each Stage Gate of TTP
5.4-1 TTP QRM
Stage Gate Strategy Analytical &QC Regulatory Process Facilities/Engineering Risk Management and
Testing / Components
QC
1 Perform preliminary risk assessment prior to beginning late-phase development using risk ranking and/or preliminary hazards analysis approach.
Planning /

2 Update preliminary risk Update risk assessment Risk mitigation through Update risk assessment Update risk assessment Update risk assessment
Process Readiness assessment (transition to (transition to PHA) for service level agreement (transition to PHA) for (transition to hazard (transition to PHA) for
preliminary hazard SU and RU readiness for (SLA) and quality manufacturability of late- operability analysis RMs/components, including
analysis [PHA] analytical method transfer agreement between SU phase development [HAZOP] for operating assessment of the impact of any
(AMT) and RU process process at manufacturing changes in the suppliers or
PHA site manufacturing sites of the RMs
[PHA] SU RU SLA SU RU /
PHA PHA
AMT
[HAZOP]

3 Review and update risk assessment/PHA from stage gate 2 if necessary.

TTP Implementation & Mitigate identified high risk.
Qualification /PHA 2
TTP

4/5 Convert PHA risk assessment from stage gate 3 to FMEA/failure mode, effects, and criticality analysis (FMECA) risk assessment, including reevaluation of risk ranking after
Licensure / risk mitigation plan implementation.
Manufacturing/Project 3 PHA FMEA/ FMECA
Closure
/ /
Update risk assessment Complete risk assessment Risk mitigation through Update risk assessment for Update risk assessment Update risk assessment for
from stage gate 4 for for SU and RU readiness SLA and quality manufacturability of (HAZOP) for operation RMs/components, including
commercial process for AMT agreement between SU commercial process process at commercial site assessment of the impact of any
4 SU RU AMT and RU changes in the suppliers of
SLA SU RU manufacturing sites of the RMs
HAZOP /

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5.6 QRM Planning QRM
As a company begins to apply a QRM approach, the first step will consist of providing training to personnel involved in
GMP operations to familiarize them with ICH Q9 and the principles laid out in the document. As a result of the above
approach, technology transfer team members, trained in the QRM approach, will act according QRM principles and tools
throughout the life of TTP.
QRM GMP ICH Q9
QRM QRM
TTP

It is highly recommended, as a second step, to set policies and procedures determining the use of various qualitative and
quantitative tools and their application. To select where first to apply QRM, companies may consider implementation of
QRM for a particular product or family of products. If this method is chosen, special attention must be paid to avoid the
creation of different layers of compliance.
QRM
QRM

Finally, companies must include their decision for using QRM in the technology transfer strategy document at the project
start.
QRM

5.6.1 Selection of a QRM Approach QRM

The selection of a risk management approach should be 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.
TTP TTP

To realize the utmost benefit from QRM, companies must adapt their culture, system, and procedure. 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.
QRM QRM
TTP

It may be helpful to refer, for project management purposes, to the elements of the risk management process as defined
in PDA Technical Report 54, ISO 31000 (project considerations), and ICH Q9 (process/product considerations) (2, 16,
18-20).
PDA 54 ISO 31000 ICH Q9 /
(2, 16, 18-20)

5.6.2 Creation of a QRM plan QRM

Firms should develop a plan to implement and maximize the use of QRM throughout all operational systems and
company areas. This plan should be documented in the site master file and/or the master validation plan.
QRM
/

A roadmap must be designed from the very beginning of the project to ensure comprehensive project management,
including the risk assessment steps below. The roadmap for QRM implementation should be established as a holistic
approach rather than a project-specific approach. It may be helpful for the technology transfer team to refer, from a
project management perspective, to the elements of the QRM process as defined in the literature (2, 16, 18-20).
QRM
(2, 16, 18-20)
QRM

Successful application of QRM in technology transfer requires establishment of a QRM plan early in the TTP and

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formalization of the plan (where applicable) in the technology transfer protocol. The QRM plan should describe the
TQM tools to be used, the rationale for their selection, the risk ranking/filtering criteria to be used, and any underlying
assumptions. This document serves the following purposes:
QRM TTP QRM
QRM TQM /

Aligns cross-functional participants regarding the basis of the transfer teams decision-making

Informs senior management on project analysis, risk identified, and mitigation plan

Ensures consistency over time as ongoing development or validation information supporting the transfer is
used to update risk assessments and influence future decision and/or activities
/

Identifies participants and their responsibilities in risk assessment

Defines the responsibilities of the applicable management teams or functional leaders that approve risk
reduction activities and authorize acceptance of unmitigated related risks. The technology transfer team must
define the criteria for selection of management teams with oversight of the transfer as well as key stakeholders
accountable for the overall success of the project. These teams and individuals provide appropriate sponsorship
of the project and secure resources for QRM activities (in addition to other transfer related activities), and they
must be informed of or approve critical risk acceptance decisions across the entire project. These teams and
stakeholders should be identified on a master transfer plan.


QRM

The QRM plan should define criteria for identifying critical risk factors and hazards so that senior management is
informed of critical issues and their status and remains informed.
QRM

Risk assessment teams, as part of the technology transfer teams, should refer to the master technology transfer plan to
ensure that the proper stakeholders are used for the risk assessment. The QRM plan should also define criteria for
identifying critical risk factors and hazards so that senior management is informed of critical issues and their status.

QRM

It is recommended to define project triggers and milestones for the TTP based on general QRM concepts. It is also
advisable to evaluate the transfer environment using the volatility, uncertainty, complexity, and ambiguity (VUCA)
model. The VUCA elements present the context in which organizations view their current and future state. The VUCA
tool can be used in strategic leadership environment to present boundaries for planning and policy management. QRM
tools will be preferentially used from a project perspective. The roadmap defined at the project level must include
triggers for all stages: planning, process readiness, qualification, and licensure and manufacturing.
QRM TTP VUCA
VUCA VUCA
QRM

5.6.3 Identification of QRM Personnel QRM

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Stemming from the previous concepts, it is reasonable to include the determination of the risks and risk tolerance for the
project in the goal of the TTP team that is composed of the transferring and receiving operations, quality, and enabling
functional groups (e.g., finance, engineering, and logistics). Risk tolerance is defined by two considerations: the project
and the process/product.
TTP
/

At a minimum, the team should include representative from the process development, manufacturing, analytical
development, QA, and QC units. Special emphasis must be placed on including information that could indicate an
impact on product safety, identity, stability, purity, and quality. By using a cross-functional team, issues impaction
stability, specifications, and the use of analytical methods can more easily be identified and addressed. Failure to take
these issues into account can lead to transfer delays or even failure as there may be unknown factors related to the
change that could impact stability or drive a process closer to specification limits compared to its performance at the
originating site.
QA QC

A variety of stakeholders outside the project team include local, regional, and international regulatory authorities. Patient
safety, through managing the risk to quality, should be of prime importance (2). Risk is evaluated by the diverse risk
assessment by the stakeholders involved because each stakeholder may perceive different potential risks, assign each a
different probability of occurrence, and attribute different severities to each other.

(2)

5.7 Risk Assessment

Based on the overall project knowledge and the initial tasks agreed on and completed, the same systematic process for
the assessment, control, communication, and review of risk described in ICH Q9 to identify and rank project variables
and inputs with a potential impact on the project goals can be used by the technology transfer team. Moreover, due to
quantitative output of the risk assessment, in which the risk is not only described but also ranked, a well-defined
decisional critical path can be properly identified. The financial and time requirements for each task can be assessed on
the basis of a scientifically sound approach, allowing for project management that is in compliance with regulatory
authority expectation.
ICH Q9

The deliverer of the TTP should provide criteria and information regarding hazards and critical steps associated with the
product, process, or method to be transferred, which will serve as a basis for a QRM exercise.
TTP QRM

Risk assessment is completed by comparing each step against the CQAs to determine which ones require further
characterization or assessment of historical data (if available). The application of a risk process considering process
development allows for scientific understanding to identify potential parameters that may affect the process CQAs. This
can reduce the number of process steps to be further characterized and provide a baseline for establishing independent
parameters during scale-up or transfer.
CQAs
CQAs

Identification and scoring of risk factors and their associated hazards based on predetermined severity and occurrence
criteria should result in a comprehensive list of activities to be completed to facilitate the successful completion of the
GMP 45
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transfer. The product of these two criteria provides a risk-based means of prioritizing hazards and risk-reduction
activities. These activities could include additional characterization or validation studies, facility modifications, or
acquisition of new equipment or expertise. Input from the technical subteams and other SMEs should establish a detailed
understanding of the effort and time required to complete the identified items.


SME

5.7.1 Types of Risk Assessment

The RU and SU can decide on the particular parameters for choosing the type of risk assessment. Indeed, the team could
decide to use all of them to assess risks. The following are three possible types of risk assessments:
RU SU

5.7.1.1 Risk Assessment 1 1

A risk assessment can be performed to include the identification, documentation, and risk assessment of the product
attributes and of the CQAs and their target ranges. Individual quality attributes are assessed to determine their impact on
product safety and efficacy as well as performance characteristics that affect safety and efficacy (e.g., stability,
pharmacokinetics and clearance along with immunogenicity). This assessment helps determine the ranges, the basis for
these rangers, and the potential impact. This assessment also provides reference to the data for each product attribute (if
available). This risk assessment is a living document that needs to be revised throughout the lifecycle of the product to
take into consideration and properly evaluate all of the changes that are happening.
CQA

5.7.1.2 Risk Assessment 2 2

A second type of assessment uses a system of risk ranking and filtering in which the individual process parameters and
noncompendial raw materials are evaluated for their potential impact on product quality and process consistency. Results
from these risk assessments can be a guide to the level of process characterization needed to understand the impact of
each process parameter on quality attributes and process consistency. The intent of this assessment is to provide a risk
rating from a product quality and/or process performance perspective.


/

5.7.1.3 Risk Assessment 3 3

A third type of risk assessment is an inductive risk analysis designed to identify potential modes of process failure
associated with operations parameters that may affect product quality and/or process consistency. This assessment should
include risk identification and prioritization and a mitigation plan. It may also reduce the amount of additional data
needed to complete the TTP.
/
TTP

5.7.2 Risk Assessment Tools

Some risk management tools mentioned in ICH Q9 are (16):

ICH Q9
Basic risk management facilitation methods (flowcharts, check sheets, etc.)
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FMEA FMEA
FMECA FMECA
Fault tree analysis FTA
Hazard analysis and critical control points (HACCP) HACCP
HAZOP HAZOP
PHA PHA
Risk ranking and filtering
Supporting statistical tools

QRM tools are useful in prioritizing transfer team activities in two ways: 1) they provide the means to quantitatively
rank (prioritize) and filter risk factors and risk-reduction activities across the entire project, and 2) they provide a means
for documenting risk-ranking criteria and rationales for prioritization Application of QRM tools can assist in identifying,
quantifying, and prioritizing risk associated with the TTP. However, the output from using these tools is only as good as
the information entered, so it is crucial to ensure that the risk assessment is performed by a broad cross-functional group.
QRM 1
2 QRM
TTP

PDA Technical Report No. 44: Quality Risk Management for Aseptic Processes and Technical Report 54:
Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations provide
guidance on how to apply risk assessment tool to pharmaceutical processes (7, 21). The ISPE Baseline Engineering
Guide Volumes 1 (Active Pharmaceutical Ingredients) and 7 (Risk-Based Manufacture of Pharmaceutical Products) are
other potential resources (22, 23).
PDA 44 54
(7, 21) ISPE 1 7
(22, 23)

5.7.2.1 Risk Ranking and Prioritization

Following completion of the site selection process, the product to be transferred and the recipient facility may be
evaluated using a risk ranking and filtering (RRF) tool. The RRF tool is used to determine potential risk factors and
hazards across all aspects of the transfer, such as adequacy of the recipient facility quality system, introduction of new
raw materials, or process changes impacting product stability. This method provides a highly selective list of risk factors
and associated corrective or preventive measures that reflect the priorities, constraints, and available resources of the
transfer team.
RRF RRF

RRF typically includes application of risk-based scoring criteria. Using resource, financial, or time-based scoring criteria
will enable the transfer team to prioritize risk factors using multiple filters. This method provides a highly selective list
of risk factors and associated corrective or preventive measures that reflect the priorities, constraints, and available
resources of the transfer team.
RRF

Scoring transfer-related risk in aggregate can be helpful given the broad range of hazards evaluated across multiple
disciplines and the difficulty of evaluating multiple risk assessment (conducted for each individual problem or event)
separately. In addition, performing this risk ranking exercise using a high-level, cross-functional transfer team (as
opposed to technical subteams) ensures that prioritization decisions are made at appropriate levels in the organization
and with representation from multiple impacted stakeholder groups. The risk ranking can be revised based on the results
of the risk mitigation actions implemented. An illustration of this process is outlined in Table 6.3.1-6: Risk Analysis.

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6.3.1-6: .

For example, the transfer team may identify several unacceptable hazards and many less critical hazards but lacks the
resources to sufficiently address all risk factors within a given time frame. By applying both risk-based and resource-
based filters, the team can quickly narrow down the list of risk-reduction activities and focus on only those high-priority
risks that the team has available resources to address.

Performance of this ranking exercise by the transfer team is critical to ensure that resource-based prioritization decisions
are made with full consideration of transfer team priorities, resource availability, and budgetary constraints. Generally,
the transfer team is better suited to make these decisions than technical teams with less cross-functional representation
and a potentially narrow view of general organizational concerns.

The complexity of the RRF activity should reflect the complexity of the process being transferred. For example, TTPs
typically require participation from multiple units or require long-team dedication of specific resources. Filtering criteria
may be set up to reflect resource availability so that high-priority, cross-functional projects are preferentially selected
based on the availability of limited personnel or other resources.
RRF TTP

5.7.2.2 Assessment of Regulatory Gaps

An analysis should be performed to identify gaps between applicable SU environmental, health, and safety regulations
and those that govern the RU. It may be useful to create a list of all of the chemical/material inputs, outputs, by-products,
and wastes used and/or generated by the process to aid in the analysis. Risk assessment should be performed on
differences to determine their potential impacts on the TTP. The differences in regulations between regional governments
could potentially impact how materials are handled, stored, and disposed. Areas that could have an overall impact on
how the materials are handled or processed due to varying regulatory requirements and to QA, technical, and
environmental, health, and safety considerations are:
SU RU /
/
TTP
QA

Occupational exposure limits

Compound hazard categories
Fire/explosion regulations
Personal protective equipment requirements
Regional bands or limitations on compound classes
Waste disposal requirements
Environmental assessment requirements

5.7.2.3 Assessment of RU Readiness RU

The SU and RU need to evaluate the RUs readiness to perform the chemistry as part of the risk assessment. This may
involve evaluation of the RUs experience in performing the types of processes described by the SU. It may be useful to
rank each of the reaction steps from easy to complex.
SU RU RU RU SU

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5.8 Risk Mitigation

To accomplish a successful technology transfer, QRM must be both efficient and effective. Efficiencies in prioritizing
transfer team activities, identifying resource requirements, and establishing meaningful timelines can be realized through
the tools used for risk analysis.
QRM

5.8.1 Experiments to Confirm Key Process Parameter Ranges

The purposes of the experiments during the TTP are to confirm key process parameters and fill in the gaps identified in
the risk assessment. The experiments are not designed to redevelop or optimize the process.
TTP

Qualified laboratory-scale or pilot-scale models should be established, preferably at the RU. Depending on the
agreement between the SU and the RU, the qualified models may be maintained at the SU if they are not established at
the RU.
RU SU RU
RU SU

Experimental design and protocol are based on the established scale-down models and the ranges of the key process
parameters provided by the SU. Design-of-experiment methods need to be used in the experimental design. These
methods call for the use of raw materials from approved vendors that will supply the commercial operations in the scale-
down model experiments. The acceptance criteria should be clearly defined in the protocol. The experimental results are
documented in the summary report, and conclusions should be drawn as to whether the key process parameter ranges are
confirmed.
SU

5.8.1.1 Demonstration Runs

After the key process parameter ranges are confirmed at the laboratory or pilot scale, additional experiments maybe run
at the commercial scale (depending on the complexity of the process) prior to process validation, such as demonstration
or engineering runs. Products generates from the demonstration runs must not be used commercially.

For well-defined platform or relatively simple processes, demonstration runs may not be necessary. For complicated
processes, demonstration runs are suitable to demonstrate the scalability of the process at the RU. Demonstration runs
also help discover potential gaps in equipment, instrumentation, automation, utility, CIP, etc.

RU CIP

A PFD based on the develop history report should be ready prior to the demonstration runs. The PFD should capture the
process and equipment flow, general process chemistry, CPPs, raw material specifications, forward processing criteria
(or intermediate specifications), sampling plan, etc. A protocol for the demonstration runs should be prepared to
document, at a minimum, the purpose, scope, roles and responsibilities, test plan, and acceptance criteria. Batch
production records must be available to document the appropriate operating conditions and any special instruments for
the demonstration runs.
PFD PFD CPP



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Intentional deviations in operating parameters from the target set point may be used to test process robustness during the
demonstration runs.

Depending on how well controlled the CPPs are at the commercial scale, the CPP ranges may need to be adjusted after
the demonstration runs. The demonstration run results and gaps found, corrections made during the runs, and
recommendations are documented in a summary report.
CPP CPP

Additional demonstration runs may be required if the recommended actions must be taken prior to process validation.
Demonstration runs can be costly. Cost and benefits need to be considered carefully in conjunction with the risk
assessment.

5.8.2 Cycles of Risk Assessment, Data Collection, Risk Mitigation, and Closure
5.8.2

To bridge the gaps identified during the initial risk assessment and mitigate the risks, data can be collected through
experimentation at different scales and/or data mining of the SUs database.
/ SU

Data calibration is a process to assess whether the risk-mitigation results are acceptable and whether the technology
transfer is successful. Data evaluation is not one-time exercise and should be incorporates into milestone (or stage gate)
reviews. Examples of stage gates are the laboratory-scale data review prior to the pilot plant testing; the pilot scale data
review prior the production scale testing; the data review of the demonstration runs prior to the process validation; and
post-process validation data review.

Two questions need to be answered at each data review:

Are the data sufficient to support the mitigation plans developed based on the risk-assessment results?
Have the critical success factors been produced as demonstrated by the data?

The personnel involved in the data evaluation should include the technology transfer project leader (or project manager);
experienced scientists and engineers from SU and RU; and representatives of QA, QC laboratories, operators, and senior
management. The data review results should be documented, and conclusions need to be drawn regarding whether each
milestone has been successfully achieved. Any action items from the data review team should be addressed by the
project leader/manager.
SU RU
QA QC
/

Additional risk assessment may be needed after more knowledge is acquired through data reviews. When new high risks
are identified, whether these risks are acceptable must be determined. If they are not acceptable, new risk mitigation
measures must be developed and additional data should be collected. This risk assessment/data collection/data review
circle continues until all risks are reduced to an acceptable level.

//

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6.0 Case Studies

6.0
In the following pages, three cases are provided to show the application of the principles, concepts, and tools of QRM to
the TTP.
3 QRM TTP

The first case study focuses on the analytical transfer of a method, whereas the second and third case studies focus on
manufacturing activities.

6.1 Case Study 1: Analytical Method Transfer

6.1 1

Although an AMT may occur at any point in the method and product lifecycle, analytical methods are often co-
transferred with the manufacturing process during product development and/or after commercial licensure.
AMT
/

The stages of an AMT include a preliminary evaluation and preparation of the new laboratory to receive the test method,
development of an approved method transfer protocol, and application of suitable statistical tools to analyze the results.
The outcome is documented in a method transfer report.
AMT

For all AMTs, the responsibilities of the SUs and RUs laboratories should be established. The quality and/or service
agreement(s) should clarify all conditions and responsibilities. In addition to the preparation and sharing of samples,
critical reagents, and standards to be used during the AMT studies, some continuous post-AMT testing (monitoring)
should be considered (4, 12). Table 6.1-1 lists the suggested responsibilities for each laboratory and provides some
examples of how tasks and responsibilities could be shared by both laboratories during AMT.
AMT SU RU /
AMT AMT
(4, 12) 6.1-1 ATM

Table 6.1-1 Suggested AMT Responsibility Matrix

laboratory Suggested Responsibility

SU laboratory Assess feasibility/readiness

Compile QC/process data
Organize training, if required
Establish the transfer package
Write transfer protocol based on requirement of both laboratories and knowledge methods prior
to transfer
Establish protocol acceptance criteria
Allocate resources for training and transfer study
Provide critical reagents and samples
Provide troubleshooting support
Approve the transfer report

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RU laboratory Review the transfer package
Define the transfer process, including training requirements
Inform the donor laboratory of potential issues identified (such as different suppliers of critical
equipment)
Allocate resources for training and transfer study
Analyze transfer data
Write the transfer report
Inform the donor laboratory of the outcome of the transfer
Approve the transfer report

6.1-1 AMT

SU /
QC/

RU

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6.1.1 General AMT strategy

6.1.1 AMT

The strategy used for an individual method to be transferred and/or to support a product transfer can vary depending on
the exact circumstances. Options for strategies are illustrated in USP <1224> Transfer of Analytical Procedure (10). A
comparative study model is further described below.
/ USP <1224>
(10)

6.1.2 Design of comparative AMT Test Studies

6.1.2 AMT

The AMT protocol should include a study design specifying method parameters to compare, samples to test, justifies
acceptance criteria, and the statistical methodology to evaluate the results (see Table 6.1.2-1).
AMT
( 6.1.2-1)

Table 6.1.2-1 General AMT Design Parameters and Considerations

AMT Design Parameters Consideration
How many representative Two or three batches bracketing the expected active protein concentration ranges could be
batches?- Matrix approach used. The selected materials should be representative of routine samples.
(number of different sample Retain samples, reference standards, samples at the extremes of acceptance limits,
types and/or batches to be stability samples, and/or spiked samples should be used, depending on the situation.
evaluated) For impurity test, samples may be spiked or degraded so that the level of the impurity is
below and/or above the acceptable quality limit (AQL) (and/or specification limit). If
samples with a measurable impurity level are not available, it might be necessary to
prepare spiked samples to evaluate the accuracy and precision of measurable amounts of
impurity/degradation levels during the AMT studies.
If there are differences in the formulation, the range of formulation differences should be
tested. The rationale for the selection of representative AMT samples should be
documented in the AMT protocol.
How many replicates per The number of replicates depends on the repeatability and intermediate precision
sample and laboratory? performance of the method to be transferred and the desired confidence level(s) for
(number of independent meeting product specifications. The AMV report and other related data sources (for
runs) example, routine test results) should be reviewed.
How many intermediate At least two critical factors should be selected based on prior knowledge of which
precision variability factors factor(s) may have the greatest expected impact on variations in test results.
are used?

6.1.2-1 AMT
AMT

-
/ /
/
AQL / AMT
/
AMT
AMT

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? ( AMV
)

6.1.3 Selecting AMT Performance Characteristics

6.1.3 AMT

The intended purpose of the method should be used to justify the rationale of the study design and acceptance criteria for
each method transfer. Table 6.1.3-1 provides an example of performance characteristics to be compared between
laboratories for different types of methods. Other performance characteristics covered during the validation studies may
also be considered.
6.1.3-1

Table 6.1.3-1 Examples of Method Types and AMT Performance Characteristics

Type of method Sample AMT Performance Characteristics
Identity tests System suitability, specificity, and qualitative comparison (if applicable)
Process- and/or System suitability, precision, and accuracy
product-related Consider several concentration levels: minimum reportable quantity and/or quantitation limit(s)
impurities and 120% of the product specification
(quantitative) Stability samples may need to be included to assess stability-indicating capabilities when relevant

Impurities System suitability, and detection limit(s)

(qualitative, limit)
Assay content and System suitability, precision, accuracy, range, and stability samples may need to be included to
potency assess stability-indicating capabilities, as relevant

6.1.3-1 AMT
AMT

/
/ 120%

(, )

6.1.4 AMT documents

6.1.4 AMT

AMT processes are documented through AMT protocols and AMT reports. The AMT protocol typically consists of the
sections listed in Table 6.1.4-1.
AMT AMT AMT AMT 6.1.4-1
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Table 6.1.4-1 Typical AMT Protocol Sections
Section No. Section Title subsections

NA Protocol approval Protocol title and signatures with job titles and
responsibilities
NA List of protocol sections Table of contents, list of figures (if available), and list
of tables
1 Introduction Intended use and sample(s) description
2 Method and product/process Brief description and (target) specifications
3 Samples, materials, equipment, and instruments Sample preparation and storage, materials, equipment,
instruments, and personnel
4 Historical assay performance Summary of historical data for assay control, samples,
process capability, design space limits (if available),
and prior analytical platform technology method
performance (if applicable)
5 Amt characteristics and design AMT characteristics, statistics, acceptance criteria,
and justification(s)
6 Amt execution matrix Visualized execution process map(s) and/or execution
matrix tables
7 Data analysis Calculation samples and proposed statistical tests
8 Procedures, references, and guidelines SOP(s), AMV protocol/report(s) and other references

6.1.4-1 AMT

NA

NA , ( )

2 /

5 Amt AMT

6 Amt (s)/

8 SOP(s), AMV / (s)

The AMT report describes the results of implementation of the protocol, compares these results to the acceptance
criteria, and draws a conclusion regarding the acceptability of the transfer.
AMT
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6.2 Case Study 2: Manufacturing Process Transfer
6.2 2

6.2.1 Overview of Manufacturing Process Transfer

6.2.1

The installation of the manufacturing process for a recombinant protein-based vaccine occurred through two different
TTPs. The initial technology transfer from the R&D unit to the manufacturing unit (development to commercialization
TTP) resulted in the manufacturing of lots that were used in Phase 3 clinical trials and for launch supply. After this initial
TTP, a second TTP was conducted (intracompany TTP) to a scaled-up purification facility, which was required to meet
the projected market supply requirements.
TTP R&D
TTP 3 TTP TTP
TTP

The manufacturing process consists of yeast-based fermentation, purification, and reassembly of the recombinant protein
virus-like-particles (VLPs); adsorption to an adjuvant; and sterile formulation and filling. Key challenges during process
development included protein expression in a defined media fermentation and control of VLP aggregation and stability.
These challenges were outcome via the TTP to produce a small-scale process suitable for early-phase clinical testing.
VLPs
VLP TTP

6.2.2 Case Description: Development to Commercialization TTP

6.2.2 TTP

The TTP was initiated with a facility fit analysis to compare the unique aspects of the processing equipment in the
existing fermentation facility to the process as defined in R&D. This led to targeted development work to better fit the
process into the intended manufacturing facility. For example, the relative scale of the fermentation seed process was
modified and tested to fit into the fixed equipment in the existing facility. In addition, some facility changes were
required to meet the needs of the process. A new purification facility was required, and close collaboration between the
R&D and filling process was transferred to an existing facility.
TTP R&D

R&D

A risk assessment was performed to characterize the process parameters and attributes. The products CQAs were
identified, and the process experts determined the associated CPPs that were responsible for controlling the CQAs.
CQA CQA CPP

Other attributes that were important for process consistency (key product attributes and operating parameters) were also
identified to further define the manufacturing process. The ranges associated with these attributes and parameters were
determined experimentally. However, in most cases, the limits were known success values rather than those at the
boundary of failure due to the complexity of the process and product. The ranges were approved by the R&D unit and
the manufacturing organization (operations, quality, and technical operations) and were the basis for process validation.
The ranges for CQAs and CPPs were maintained for all components, except that some were changed due to process scale
and planned process changes.


R&D
CQA CPP

A well-defined business process existed in the enterprise and was used to organize and manage the TTP for the product.
The features of the business process included:
TTP
Formation of a technology transfer team that was responsible for executing the technology transfer plan. Members

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of this team included representatives of R&D, operations, quality, technical operations, and regulatory units.
Appointment of a technology transfer leader who was responsible for organizing and managing the team and
reporting progress to a governing authority.
A governance team of cross-functional leaders that oversaw the technology transfer plan and served as a decision-
making body when issues were encountered. The team chartered the project and team and oversaw the project using
a stages and gates approach. Stages are logical groups of associated activities and tasks that are part of a TTP.
Stage gates are reviewed points that are defined in advance by the governance team and focus on project status, key
milestones for the next stage, and, importantly, the risk and risk mitigation plans for the project. For example,
production of process validation lots was considered a distinct stage, and a stage gate review was conducted by
senior leadership to ensure readiness for the process validation series and communication of the potential risks to
the process validation lots.
A project management system used to ensure sound project definition and execution control. During the initiation
and planning stage, a project plan was produced and was reviewed by the governance team. The plan resulted in
approved schedule milestones that the technology transfer team was expected to meet. This stage also included
definition of key assumptions and project risk that governed the project plan.
An execution stage consisting of process readiness in the manufacturing facilities (for example, IQ/OQ and
engineering lots), completion of process validation lots, and licensure of the facilities.
R&D



TTP






- IQ/OQ

The process validation lots were used in Phase 3 clinical trials, which conclusively demonstrated the successful transfer
of the process technology from the R&D to the manufacturing unit. Approval of the manufacturing facilities occurred
concomitantly with product regulatory approval.
3 R&D

6.2.3 Intracompany TTP

6.2.3 TTP

To limit the capital expenditures before obtaining critical performance data, a small-scale purification facility was used
as the initial manufacturing facility to produce process validation lots used in the Phase 3 clinical studies and to
manufacturing drug substance for product launch. However, the expected market demand exceeded the capacity of the
launch facility. Consequently, a scale-up purification facility was constructed.

The process for the new facility was scaled up, which required targeted process changes to manage the larger production
scale. For example, filter configuration were changed to reflect limitations in mechanical equipment design. In addition,
a planned material manufacturing change by the vendor was evaluated in R&D to ensure success in the new factory.

R&D

A project team was assembled in the manufacturing organization for the startup of the new facility and technology
transfer from the initial purification facility. This team had a similar structure to that described above, although it was
based at the manufacturing site. A governance team oversaw project execution and was responsible for rapid decision-
making and resolution of issues escalated by the project leader. A communication plan was defined and implemented to
ensure alignment in the organization concerning project implementation.
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Because the drug substance was a recombinant protein that was considered a well-characterized biologic, a
comparability approach was taken for licensure of the new purification facility. This approach was aligned with the
guidance in ICH Q5E comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing
Process and provided a framework for evaluating the impact of the process changes and scale-up on product safety and
quality (22).

ICH Q5E /

6.2.3-1 /

Process and Product characterization

Analytical Impurity
Measures Stability

Manufacturing Manufacturing diversity

Database Analytical variability

Expected Acceptance criteria (primary Limit)

Results Alert Limit (secondary Limit)

Meets acceptance Process Meets acceptance

Criteria and alert Change Criteria but falls
Comparable Investigate
limits outside alert limits

Investigation includes:
Weighting of Parameters
Fails acceptance criteria Data evaluation from all lots
Clinical experience
Not Comparable Results from other parameters

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The process validation lots made in the new purification facility were tested according to the requirements in the
comparability protocol. All lots made were deemed to be comparable to the small-scale launch facility, which led to the
successful licensure of the facility without clinical studies.

6.2.4 Conclusion

A successful production history lasting more than five years after licensure demonstrates the success of the technology
transfer processed used for this product.
5

6.3 Case Study 3: Manufacturing Process Transfer: QRM Application to Start-up Evaluation
6.3 3 QRM

6.3.1 Use of Quality-by-Design Principles

6.3.1

The example of this section shows how quality-by-design principles can help the technology transfer team plan
appropriate activities to mitigate risks along the project path (23).

(23)

The objective of this example is the technology transfer of an injectable, small-volume parenteral solution from the
manufacturing site of the originator firm (SU) to the manufacturing site of a CMO (RU). Supporting information and
concepts can be found in PDA Technical Report No. 44: Quality Risk Management for Aseptic Process and PDA
Technical Report No. 54: Implementation of Quality Risk Management for Pharmaceutical and Biotechnology
Manufacturing Operations (7, 21).
SU CMO (RU)
PDA 44 PDA 54
(7, 21)

As described in Figure 6.3.1-1, by processing the deliverables received by the SU, including information on the process
and product to be transferred to the new site, the RU can conduct a risk analysis followed by a mitigation plan using a
risk priority numbering approach.
Figure 6.3.1-1 SU RU

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Client Drug
Manufacturing
Process Information

Analysis

CMO Drug
Manufacturing
Finished Product Process Definition
Information

Analysis
Analysis

Finished Product Main Variables

Quality Attributes (QA)

Risk Analysis (RPN)

Mitigation plan
and action list

Figure 6.3.1-1 Overall Process Mapping

CMO

(QA)

(RPN)

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As a first activity based on site knowledge, the RU develops a new manufacturing process scheme that accounts for the
modifications needed to implement the original manufacturing process at the new site.
RU

The RU defines the main variables that could affect product quality attributes based on the new process scheme (table
6.3.1-1). The main variable categories include:
RU table 6.3.1-1)
Process/facility
Primary packaging components
APIs and excipients
/

API

Table 6.3.1-1 Examples of Variable Definitions

List of Main Items Relative Variables
Considered for the
Evaluation

Process Mixing Filling Identification

Holding Stoppering Wrapping
Compounding Crimping Visual inspection
Grade C filtration Solution transfer Secondary packaging
Grade A filtration Steam terminal sterilization Line cleaning
Primary packaging and Stoppers Filters Fixed tube
GMP materials Vials Disposable tubes Gasket
Seals Disposable bag
APIs and excipient API pH API density Excipient attributes
attributes API appearance API osmolality

6.3.1-1

C
A

GMP

API API pH API

API API

The SU transfers the quality attributes of the products to the RU (Table 6.3.1-2)
SU RU ( 6.3.1-2)

Table 6.3.1-2 Examples of Quality Attributes Definition

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Quality Attribute

Appearance pH Volume in container

Identity Density at 20 Cosmetic apperance

Assay Osmolality sterility

Impurity Particle matter Endotoxins

6.3.1-2

pH

20

The two teams merge the newly developed manufacturing process with the quality attributes of the product received to
assess which could affect the product and how they can be controlled.

To take further advantage of the analysis, a risk number can be assigned to each variable based on its severity,
occurrence, and detection.

This activity, done at the beginning of the project, can detect the most likely potential caused of technical failures during
the TTP and allow planning for mitigation those risks. Following ICH Q9, the risk can be estimated based a combination
of three main factors:
TTP
ICH Q9 3
Severity (S)
Occurrence (O)
Detection (D)
(S)
(O)
(D)

Severity considers the potential impact on the quality attributes of the product and, hence, on patient health. It can be
rated based on the table below:

Table 6.3.1-3 Severity Definition and Rating

SEVERITY RISK CLASSIFICATION VALUE
No impact on products quality attributes or on patient health Low 1
Moderate impact on products quality attributes or on patient health Medium 2
Severe impact on products quality attributes or on patient health High 3

6.3.1-3
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The occurrence factor is defined as the frequency of occurrence of the event. In can be rated as shown in Table 6.3.1-4.
6.3.1-4

Table 6.3.1-4 Occurrence Definition and Rating

OCCURENCE RISK CLASSIFICATION VALUE
Highly improbable or impossible that the negative event will occur Low 1
Some possibility that the negative event will occur Medium 2
Highly probable or certain that the negative event will occur High 3

6.3.1-4

The detection factor is defined as the probability of detecting the events if they occur, based on the control system in
place. In can be rated as shown in Table 6.3.1-5.
6.3.1-5

Table 6.3.1-5 Detection Definition and Rating

PROBABILITY RISK CLASSIFICATION VALUE
Highly probable or certain that the negative event will be detected by the Low 1
control system in place
Some possibility that the negative event will be detected by the control Medium 2
system in place
Highly improbable or impossible that the negative event will be detected High 3
by the control system in place

Table 6.3.1-5

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3

Based on the definitions and ratings of severity, occurrence, and detection, risk rank can be calculated using the formula
R=SOD.
R=SOD

A team evaluation is needed to identify acceptance criteria. For example, in Table 6.3.1-6, a risk (R) < 9 is deemed
acceptable and no actions are needed to mitigate this risk.
6.3.1-6 R < 9

Based on the risk criteria and ranking, a mitigation plan is established by the team. After the plan is implemented, the
risks are evaluated again to conform that they have been mitigated.

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Table 6.3.1-6 Risk Analysis
6.3.1-6

Analysis Risk Priority Number Evaluation Mitigation Plan

Potential criticality/cause of lack of

Item Variable QA Impacted Severity Occurrence Detection Consideration/Action
quality attribute description RPN
/

Dissolution speed is insufficient for

complete dissolution and a
pH homogenous system. 3 3 1 9 During the performance qualification, the mixing device of the tank
used in the RU will be challenged.
RU
Dissolution speed is insufficient for Mixing studies will be agreed on by the SU and performed during the
complete dissolution and a engineering batch.
Osmolality SU
homogenous system. 3 3 1 9



Mixing and
compounding The user requirements of the RU tank have properly defined the
Process
mixing needs based on the characteristics of the colloidal system.
RU
The initial evaluation and information sharing between SU, RU, and
Mixing system is not appropriate to the disposable technology Supplier have identified the appropriate
Appearance guarantee uniform batch mixing mixing device.
3 3 3 27
SU RU

The PQ challenge of the mixing system will include appropriate tests
suggested by the supplier/owner of the technology.
PQ /

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No further action needed. The colloidal system is not sensitive to

Temperature of the system is outside
temperature. The RU WFI loop cooling and temperature control
the range specified by the SU
2 1 1 2 system will guarantee a 15-25 range.
SU
RU WFI

15-25

Density

The sampling system will be made of pharmaceutical-grade glass. The
Sampling mode device can affect the SU has collected data on compatibility, and the solution is declared
analysis 3 2 2 12 compatible with glass devices.
SU

Validation activities will include hold time challenges according to a

Preparation time can affect the
dedicated protocol.
bioburden level of the final
Sterility
compound solution 3 2 2 12
Chemical characteristics and microbiological attributes of the solution

will be analyzed.

Use Silicon, platinum-cured, disposable hose certified for

pharmaceutical use for solution transfer.

To address particle release from the hoses used in grade C, filter the
Particles release from disposable solution three times before filling (0.45um+0.22/0.2um in grade C area
Particulate hoses may impact the particulate and 0.22/0.2um in grade A area)
matter matter profile 3 2 3 18 C 3
C 0.45um+0.22/0.2umA 0.22/0.2um
Regarding the particle release from the hoses used on the filling
machine, a final 100% visual inspection will be done. Vials with a
particle matter defect will be rejected.
100%

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Supplier has provided leachable/extractable documentation and

Mixing system shedding may impact certifications.
the particulate matter profile /
3 2 3 18
Compatibility studies to be conducted with specified analytical
methods with the supplier.

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Table 6.3.1-6 Continued
6.3.1-6
Analysis Risk Priority Number Evaluation Mitigation Plan

Potential criticality/cause
of lack of quality
Item Variable QA Impacted Severity Occurrence Detection Consideration/Action
attribute description RPN
/

Regarding the release from the filters used in grade C, the

Release from the filter
solution is sterile filtered before filling. A final 100% visual
membrane may impact
inspection will be done. Vials with a particle matter defect
Particle matter the particle matter profile
Process 3 2 3 18 will be rejected.
of the solution.
C

100%

The filter arrives in the RU with the integrity certification of

Grade C and the supplier. According to the RUs procedure, each 0.22/0.2
grade A um filter is tested after and before use.
filtration RU
C A RU 0.22/0.2 um
A filter with an integrity

issue can compromise
Leachable/extractable documentation and certifications will
the sterility of the
Sterility be provided by the supplier.
solution 3 1 1 3
/

If needed, specific analyses can be done by the supplier to

identify possible leachables and extractables.



Adsorption and compatibility studies will be performed as a
part of the filter validation.

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Clogging of the filter will potential impact on the sterility of

the overall process is evaluated in a preliminary phase of the
transfer, including supplier trial for scale up of their size.
Analysis of the exact filtration system and critical process
parameters that will be used during drug manufacturing are
necessary. Both velocity max or pressure max trials are
reliable and can anticipate potential failures. Media fill
A filter can become challenge of the filter change procedure is a valid practice to
clogged 3 1 1 3 downgrade the associated risk and estimate the impact on
sterility as a result of the filter change.

Adsorption on the Adsorption studies will be done as a part of the filter

membrane filter can validation.
impact density, High impact has to be considered in the case of biological
osmolality, and pH of the compounds due to the potential impact of changes in
pH 3 3 3 27
solution preservative concentration.


pH

Incompatibility between
filter and solution can
Compatibility studies will be done as a part of the filter
Density modify the systems
3 3 3 27 calidation.
chemical profile

GMP 69
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The appropriate size of the filter will be defined in the RU

with a specific laboratory trial with the filter supplier. The
Clogging issue can have
solution will be filtered through the filter until clogging
an impact on the
occurs. Volume filtered, time of filtration, surface area, and
microbiological growth
flow rate will be analyzed and correlated.
attributes and chemical
Sterility RU
characteristics of the 3 3 2 18

solution


The RUs minimum filter size will be defined. A dedicated

protocol and report will be issued with the results of the trial.

RU

During the validation activities, the holding times will be

Holding time before
Grade C and challenged according to a dedicated protocol.
filtration can increase the
grade A
Sterility bioburden of the
filtration 3 2 2 12
compounded solution
C A The chemical characteristics and microbiological growth

attributes of the solution will be analyzed.

Incorrect filling weight No further actions are needed because the RUs procedures
Volume in can result in out-of-range are already in place to periodically check the weight of the
Filling
container container volume. 3 1 1 3 solution dosed into the vials during filling activities.

RU

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(Table 6.3.1-6 Continued)

6.3.1-6

Analysis Risk Priority Number Evaluation Mitigation Plan

Potential
criticality/cause of lack
Item Variable QA Impacted of quality attribute Severity Occurrence Detection Consideration/Action
RPN
description /

Certified silicon, platinum cured, disposable hose for

Particles released from pharmaceutical uses will be chosen for the solution
the tube can impact the transfer.
particle matter profile of
Filling Particle matter
the solution 3 2 3 18

A final 100%visual inspection will be done. Vials with
a particle matter defect will be rejected.
100%

Incorrect positioning of
the stopper on the vials An appropriate sensor device is in place in the RU to
can result in incorrectly check the correctness of the position of the stopper on
Stoppering Sterility
Process closed containers. 3 1 1 3 the vials before the crimping step.

RU

No further actions are needed because according to the

Incorrect sealing of the receiving Unit standard approach, a validation of the
Cosmetic vials can result in crimping will be done.
Crimping
appearance cosmetic defects 2 1 1 2 RU


The validation will take into consideration the
cosmetic appearance of the vials.

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Moreover, according to the RUs standard approach,
the cosmetic appearance of the crimped vials is
periodically checked during the batch.
RU

Validation of the crimping step will be done. During

validation, the correctness of the crimping step will be
challenged from a cosmetic point of view and from a
Incorrect sealing of the container closure point of view by a dye intrusion test.
vials can result in non- Vials will be analyzed by ultraviolet-visible light
Sterility
closure of the vials. 3 3 3 27 spectroscopy after immersion in a solution of

methylene blue.

Assurance of an
appropriate sterility
cycle has to be
Steam terminal The terminal steam sterilization cycle will be validated
Sterility guaranteed to provide
sterilization 3 3 2 18 to guarantee sterility assurance.
the required lethality

A technical steam report on the previous lots

pH shift due to thermal manufactured will be shared between RU and SU. The
characteristics and, pH shift will be calculated.
consequently, the RU SU
Steam terminal stability of the solution pH
sterilization pH after the terminal 3 3 1 9 Based on the report, an appropriate pH range prior to
sterilization. terminal sterilization will be set.
pH

pH An in-process control and an appropriate pH
adjustment step prior to terminal sterilization will be

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introduced in the batch record to guarantee the correct
pH of the final sterilized solution.

pH pH
The validation batched manufactured in the RU will
undergo a stability study to confirm that no changes of
the system profile have occurred.
RU

An incorrect setting of No further actions are needed, the RUs procedure that
the laser printer used for is already in place guarantees the correctness of the
the identification of the setting of the laser print. Moreover, during the
Cosmetic
Identification vials could impact vial production activities, the accuracy of the vial
appearance 3 1 1 3
identification. identification label is checked periodically.

RU

Wrapping (bulk
package)

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(Table 6.3.1-6 Continued)

Analysis Risk Priority Number Evaluation Mitigation Plan

Potential criticality/cause of
lack of quality attribute
Item Variable QA Impacted Severity Occurrence Detection Consideration/Action
description RPN
/

A defects checklist that has A checklist dedicated to the products will be generated
not been properly reviewed based on the RUs experience and the SUs
can lead to vials sent to the requirements. The checklist will be reviewed and
Visual Cosmetic
SU not matching the SUs approved by the SU as well. Appropriate training will be
inspection appearance 3 1 1 3
expectation. conducted for the visual inspection department operators.

RU SU
SU SU

Secondary
packaging

Process
Possible residual material
from the previous batch may
be transferred to the next
Specific cleaning validation activities will be done to
batch and could modify the
validate the cleaning procedure to be applied after each
chemical profile of the
2 3 1 12 batch is manufactured.
solution.

Density,

osmolality, and
Line cleaning
impurity



An incorrect average run As a part of the cleaning validation, appropriate
length (ARL) can lead to a calculation will be done to define the ARL based on
false evaluation of the current guidelines.
cleanliness status of the line. 3 1 2 6 All cleaning validation activities will be detailed in
dedicated protocols and reports reviewed and approved
ARL by the SU.

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ARL

SU

A specific method to analyze the WFI at the end of the

Use of an inappropriate cleaning procedure will be developed and validated to
analytical method can lead guarantee the accuracy and reproducibility of the results
to false results. 3 1 2 6 obtained.
WFI

Cross-contamination with
other products can All lines and machine parts in contact with the product
compromise the quality of will be dedicated to avoid cross contamination.
3 2 3 18
the solution

An impurity from the

stopper can modify the
solutions chemical profile. 3 2 3 18


Impurity

The coating material can
modify the solutions The stopper components have been chosen by the SU
chemical profile. 3 2 3 18 during the development studies.
SU
The same stoppers will be used to guarantee the lack of
Primary
anomalous interactions with the stopper coating and
Packaging &
Stoppers Substances released from rubber.
GMP material
the stopper or from the
&GMP coating can include
flocculation or coagulation Stability data were collected by the SU no interaction
3 2 1 6 issues were reported to RU.
events in the solution.
SU RU

Appearance

Substances released from

the stopper or from the
coating can modify the
3 2 1 6
appearance of the solution.

GMP 75
 2015
A risk assessment will be done to compare the stoppers
The bioburden of the currently used in RU with the SU stoppers to evaluate
stopper can impact the the possibility for using a sterilization cycle already
effectiveness of the validated by the SU. In case which no comparable
Sterility currently used and validated stoppers are found, a new stopper sterilization cycle will
3 1 3 9
sterility cycles. be validated.
RU SU
Primary
SU
Packaging &
Stoppers
GMP material


&GMP
Release from the stopper
may impact the particle A final 100% visual inspection will be done. Vials with a
Particle matter matter profile of the solution particle matter defect will be rejected.
3 2 3 18
100%

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(Table 6.3.1-6 Continued)
6.3.1-6
Analysis Risk Priority Number Evaluation Mitigation Plan

Potential criticality/cause of lack

Item Variable QA Impacted Severity Occurrence Item Variable QA Impacted
of quality attribute description

Impurity released from the glass

can impact the solution profile
3 2 3 18

Impurity
Type 1 glass of USP/EP grade will be used. The
Leachables and extractables from validation batches produced will be analyzed via a
the glass can modify the chemical stability study. All release tests will be repeated regularly
profile of the solution. 3 2 3 18 during the stability program to confirm that no
anomalous changes to the system profile have occurred.
USP/EP 1

Process Visuals Leachables, extractables, and

irons can induce flocculation or
Appearance
coagulation of the system. 3 2 1 6

No further actions are needed. Incoming statistical

checks will be done on each lot of vials prior to use. An
Vials of finished product can be agreement with the supplier is in place that defines
Cosmetic
rejected for cosmetic defects. appropriate AQL for each defect. These AQLs are in line
appearance 2 2 1 4
with the cosmetic requirements received by the SU.



AQL AQL SU

GMP 77
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Validation activities will be done on the tunnel to
determine an appropriate depyrogenation cycle.

An incorrect depyrogenation
cycle can impact the endotoxin A maintenance program is in place for all of the
Endotoxins
level of the final product. 3 1 3 9 equipment used in production.


The raw data of each vial depyrogenation cycle must be
attached to the executed BR.

BR

Type 1 glass of USP/EP grade will be used. A validated

cycle will be applied to wash the vials before the
Material released from the glass depyrogenation step.
can modify the partical matter USP/EP 1
Partical matter
profile of the final product. 3 1 1 3

A final 100% visual inspection will be done. Vials with a
particle matter defect will be rejected.
100%

Damaged seals can impact the

No further actions are needed. Incoming statistical
Cosmetic crimping step and/or lead to
Seals checks will be done on each lot of seals prior to use.
appearance rejected vials. 2 2 1 4



/

Filters See filtration step of the process section

Plastic Leachables/extractabkes documentation and

disposable Bag Density, Impurity from the product contact certifications will be provided by the supplier.
for solution osmolality, and layer can modify solution /
preparation pH chemical characteristics. 3 3 3 27 In case of further necessity, specific analyses can be
done by the supplier to identify possible leachables and
pH extractables.


Compatibility studies will be done together with the
supplier using specific analytical methods.

Appropriate in-process controls of pH, osmolality, and

78 GMP
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appearance, are established to check the correctness of
Release from the product contact
the prepared solutions attributes.
layer of the bag can generate
A final 100% visual inspection will be done. Vials with a
Appearance flocculation or coagulation
3 3 1 9 particle matter defect will be rejected.
events.
pH



100%

Leachables and extractables from

the product contact layer can
Impurity modify the chemical profile of
3 3 3 27
the solution

Release from the product contact

layer of the bag can modify the
Particle matter particulate matter profile of the
3 1 1 3
final product.

Filters See filtration step of the process section.

GMP 79
 2015

(Table 6.3.1-6 Continued)

Analysis Risk Priority Number Evaluation Mitigation Plan

Potential criticality/cause of lack of

Item Variable QA Impacted Severity Occurrence Item Variable QA Impacted
quality attribute description

The chemical and microbiological characteristics of the solution

Adsorption to the lines or product
prepared will be analyzed prior to filling, and a complete set of
contact parts can impact the
analyses will be done at the end of the manufacturing for release
chemical profile of the solution. 3 2 2 12
of the lots.




Density,
osmolality, and
pH

The compatibility of the system with all the materials used
pH
throughout the process will be confirmed with the SU. If there are
Fixed transfer Incompatibility issue can modify
no data available or in case of doubt, appropriate compatibility
line and the chemical profile of the solution
3 2 2 12 studies can be agreed with the SU and performed in RU.
contact parts
SU
of the filling
Process SU
machine
RU




A validation of the SIP cycle will be done. Dedicated procedures
will be issued to manage the sterilization of the line.
SIP
Inappropriate sterilization
All the raw data of the temperature profile during sterilization
procedures can negatively impact
will be attached to the executed BR for each batch.
Sterility the sterility assurance of the
3 1 3 9
process.
A bioburden analysis of the solution at the end of the preparation

and prior to terminal sterilization will be established as in-process

controls.

80 GMP
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The chemical and microbiological characteristics of the solution
Adsorption to the lines can impact prepared will be analyzed prior to filling and a complete set of
the chemical profile of the solution. analyses will be done at the end of the manufacturing for release
3 2 2 12
of the lots.


Density,
osmolality, and
impurity

The compatibility of the system with all the materials used along

the process will be conformed with the SU. If there are no data
Incompatibility issues can modify
available or in case of doubt, appropriate compatibility studies
Gasket the chemical profile of the solution
3 2 2 12 can be agreed on with the SU.
(PTFE and
SU
silicon)


SU
PTFE

No further actions are needed. Regarding the release from the

gaskets used in the solution preparation grade C area, the solution
Material released from the gasket is filtered o.22/0.2 um before the acquasant (or surge tank) of the
material can modify the particle filling machine. Moreover a final 100% visual inspection will be
Particle matter
matter profile of the solution. 3 1 1 3 done. Vials with a particle matter defect will be rejected.

C

0.22/0.2um 100%

API Anomalous appearance of the API

Appearance
appearance can modify solution appearance. 3 1 1 3
API

API An internal API specification will be issued with well-defined
range for each test.
API attributes API
API Each lot will be analyzed and released prior to its used in
Insoluble matter in the API can
API particle production.
impact the solutions particle matter
matter Particle matter
level. 3 1 2 6
API
API

GMP 81
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API density, Anomalous pH, density, or
pH, density, and
pH, and osmolality can impact the chemical
osmolality
osmolality characteristics of the solution 3 1 1 3
pH
API pH

pH

High bioburden of the API can

API impact the overall bioburden
bioburden Sterility prefiltration of the compounded
3 1 2 6
API solution
API

pH, density,
osmolality, Internal specifications will be issued with well-defined ranges for
appearance, and Each excipient characteristic can each excepient test.
Excipients
particle matter impact the final product quality.
attributes 1 2 2 4
sterility Each lot of each excipient will be analyzed and released prior to

pH its use in production.

82 GMP
 2015

7.0 References

1. Technical Report No.52: Guidance for Good Distribution Practices (GDPs); Parenteral Drug
Association: 2012. www.pda.org/bookstore. (accessed May 15, 2013)
2. Quality Guideline Q8 (R2): Pharmaceutical Development: Technical Requirements for
Registration of Pharmaceuticals for Human Use; International Conference on Harmonisation:
2009. www.ich.org (accessed May 13, 2013)
3. Project Management Institute. A Guide to the Project Management Body of Knowledge
(PMBOK Guide)-Fifth Edition; PMI Publications: Atlanta, GA, 2013. ISBN13:9781935589679
4. Technical Report No.60: Process Validation- A lifecycle Approach; Parenteral Drug
Association: 2013. www.pda.org/bookstore. (accessed May 15, 2013)
5. Garcia-Ochoa, F.; Gomez, E. Bioreactor scale-up and oxygen transfer rate in microbial
processes: An overview. Biotechology Advances. 2009, 27, 153-176
6. Quality Guideline Q10: Pharmaceutical Quality systems; International Conference on
Harmonisation: 2008. www.ich.org (accessed May 13, 2013)
7. Technical Report No.54: Implementation of Quality Risk Management for Pharmaceutical
and Biotechnoloy Manufacturing Operations; Parenteral Drug Association: 2012.
www.pda.org/bookstore. (accessed May 15, 2013)
8. Ishikawa, K.Guide to Quality Control; Tokyo: Asian Productivity Organization, UNIPUB: White
Plains, New York, 1976
9. Guidance for Industry Sterile Drug Products Produced by Aseptic Processing-Current Good
Manufacturing Practices; US Food and Drug Administration: 2004.
www.fda.gov/downloads/Drugs/.../Guidances/ucm070342.pdf (accessed May 29, 2013)
10. General Chapter <1224> Transfer of Analytical Procedures. USP-35/NF-30 U.S.
Pharmacopeia: 2012. www.usp.org.
11. General Chapter <1225> Validation of Compendial Procedures. USP-30/NF-25 U.S.
Pharmacopeia: 2008. www.usp.org.
12. Technical Report No.57: Analytical Method Validation and Transfer for Biotechnology
Products; Parenteral Drug Association: 2012. www.pda.org/bookstore. (accessed May 15,
2013)
13. Guidance for Industry PAT-A Framework for Innovative Pharmaceutical Development,
Manufactureing, and Quality Assurance; US Food and Drug Administration: 2004.
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation
/Guidance/ucm070305.pdf (accessed May 22, 2014)
14. Guidance for Industry Process Validation: General Principles and Practices; US Food and
Drug Administration: 2011. www.fda.gov/downloads/Drugs/.../Guidance/ucm070336.pdf
(accessed May 13, 2013)
15. EudraLex, EU Guidalines to Good Manufacturing Practice (GMP) for Human and Veterinary
Medicinal Pproducts.-Annex 13 Investigational Medicinal Products; European Commission:
2010 ec.europa.eu/health/files/eudralex/vol-4/2009_06_annex13.pdf (accessed May 27,
2014)

GMP 83
 2015

16. Quality Guideline Q9: Quality Risk Management; International Conference on

Harmonisation: 2005. www.ich.org (accessed May 13, 2013)
17. Quality Guideline Q11: Development and Manufacture of Drug Substances (Chemical Entities
and Biotechnological/Biological Entities); International Conference on Harmonisation: 2012.
www.ich.org (accessed May 13, 2013)
18. ISO 31000:2009. Risk Management-Principles and guideline; International Organzation for
Standardization: 2009. www.iso.org (accessed May 29, 2013)
19. ISPE Baseline Guide Volume 1, 2nd Edition: Active Pharmaceutical Ingredients Revision to
Bulk Pharmaceutical Chemicals; International Society of Pharmacuetical Engineers: 2007.
www.ispe.org (accessed May 29, 2013)
20. ISPE Baseline Guide Volume 7, Risk-Based Manufacture of Pharmacuetical Products (Risk
MaPP); International Society of Pharmacuetical Engineers: 2010. www.ispe.org (accessed
May 29, 2013)
21. Technical Report No.44: Quality Risk Management for Aspetic Processes; Parenteral Drug
Association: 2008. www.pda.org/bookstore. (accessed July 14, 2014)
22. Quality Guideline Q5E: Comparability of Biotechnological/Biological Products Subject to
Changes in their Manufacturing Process; International Conference on Harmonisation: 2004.
www.ich.org (accessed May 13, 2013)
23. Guidance for Industry Q8(R2) Pharmaceutical Development; US Food and Drug
Administration: 2009.
www.fda.gov/downloads/Drugs/Guidances/ucm073507.pdf (accessed May 22, 2014)

84 GMP
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8.0 Additional Reading

1. EudraLex, EC Guidelines to Good Manufacturing Practice (GMP) for Human and Veterinary
Medicinal Products- Annex 17 Parametric Release; European Commission: 2001. ec.europa.eu/
health/files/eudralex/vol-4/pdfs-en/v4an17_en.pdf (accessed February 25, 2014)
2. General Chapter 5.1.1 Methods of preparation of sterile products. European Pharmacopoeia
6.7:2009, www.edqm.eu
3. International Society for Pharmaceuutical Engieering, Good Practice Guide: Technology
Transfer, Tampa (FL): ISPE 2003
4. Krause, S., Qualifying Release Laboraties in Europe and the United States, BioPharm
Internatinal, March 1, 2004
5. Krause, S., Validation of Analytical Methods for Biopharmacuticals: A Guide to Risk-Based
Validation and Implementation Strategies, PDA/DHI Publicatiions, 2007
6. ORA Quality Manual; US Food and Drug Adminstration: 2012. www.fda.gov/downloads/
AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/UCM136320.pdf
(Accessed May 22,2014)
7. Pharmacopoeial Forum 35(2), Proposed General Chapter: <1333>, Biological Assay
Validation
8. PI 005-3 PIC/S Guide: Parametric Release; Pharmaceutical Inspection Convention (Scheme):
2007 www.picscheme.org/ (Accessed February 25, 2014)
9. Technical Report No.30 Parametric Release of Pharmaceuticals and Medical Device Products
Terminally Sterilized by Moist Heat, Parenteral Drug Association: 2012. www.pda.org/bookstore.
(acccessed February 25, 2014).
10. WHO QAS/10.349: Quality Requirements for Artemisinin as a Starting Material in the
Production of Antimalarial Active Pharmacuetical Ingredients (APIs); World Health Organization:
2010. www.who.int/ (accessed May 13, 2013)
11. WHO Technical Report Series 961: WHO Expert Committee on Specifications for
Pharmacuetical Preparations: World Health Organzation: 2011. Whqlibdoc.who.int/trs/WHO_TRS
_961_eng.pdf (accessed May 13, 2013)
12. WHO QAS/08.259 WHO Guiding Principles on Transfer of Technology: World Health
Organzation: 2010. www.who.int/immunization/sage/9_TOT_QAS08_259Rev2_27072010.pdf
(accessed May 13, 2013)
13. WHO Technical Report Series 961: Annex 7 Guidelines on Transfer of Technology in
Phramceutical Manufacturing: World Health Organzation: 2011. apps.who.int/prequel
Info_general/documents/TRS961/TRS961_Annex7.pdf (accessed February 27, 2014)

GMP 85