Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry-Sayeh Majzoob-Complete15Nov2016

Sayeh Majzoob
Pharm. D., Ph. D. in Pharmaceutics; Pharma MBA
Email address: smajzoob@yahoo.com
Cellphone: +98 912 1366744
Based on:
• ISPE Good Practice Guide-Technology Transfer-2003/2014
• WHO Technical Report Series, No. 961, 2011, Annex 7, WHO guidelines on
transfer of technology in pharmaceutical manufacturing
• Guideline for Technology Transfer-NIHS-Japan-2012
• ICH Q10-Scale-up & Technology Transfer as a Part of Pharmaceutical Quality
Systems
19-Nov-16 Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry- Sayeh Majzoob 1

Understand scope and stages in technology transfer, and it’s success
criteria including:
• Forming the transfer team and developing the project charter
• Consolidating knowledge for transfer and developing a technology
transfer proposal
• Identifying risks, conducting risk assessments and developing technology
transfer plan
• Executing the transfer
• Finalizing the transfer and performing the review
• Pitfalls

The ever-changing business strategies of pharmaceutical companies increasingly
involve intra- and inter-company transfers of technology for reasons such as the
need for:
• Product life cycle (from R&D to pilot/clinical scale and Industrial scale)
• Increasing access to medicine with better prices (NGO initiatives/ Social Responsibility
…)
• Additional capacity and freeing up capacity for new products
• Relocation of operations or consolidations and mergers
• Access to new markets on condition of Technology Transfer
• In-licensing
• Out-licensing
• Contract manufacturing
Research &
development,
Clinical
Phases Scale-up
Post-
approval
phase
Production
and launch
Scope of ISPE Technology transfer Guide

ISPE 2003/2014 and WHO Technical Report Series,
No. 961, 2011)
• The systematic [Step-by-step and
planned] procedure that is followed in
order to pass the documented knowledge
and experience gained during development
and/or commercialization to an appropriate,
responsible, and authorized party.
• Technology transfer embodies both the
transfer of documentation AND the
demonstrated ability of a Receiving Unit to
effectively perform the critical elements of
transferred technology, to the satisfaction of
all parties and any, or all, applicable
regulatory bodies.

ICH Q10- 3.1.2
• “The goal of technology transfer activities is to transfer product and
process knowledge between development and manufacturing, and
within or between manufacturing sites to achieve product
realization. This knowledge forms the basis for the manufacturing
process, control strategy, process validation approach and ongoing
continual improvement.”
Technology transfer (TT) comprises a science and risk-based principles
including:
• ICH Q8 Pharmaceutical Development
• ICH Q9 Quality Risk Management
• ICH Q10 Pharmaceutical Quality System
• ICH Q11 Development and Manufacture of Drug Substances (Chemical
Entities and Biotechnological/Biological Entities)
Transfer of technology requires a:
• Documented, planned approach using trained and knowledgeable
personnel working within a quality system, with documentation of data
covering all aspects of development, production and quality control.

Transfer of expertise and technology associated with:
• Analytical Methods
• APIs
• Dosage Forms
Useful from the earliest phases in a product’s life cycle through to, and
including, post approval transfers
ISPE and WHO guides currently does not explicitly offer specific guidance related to biological
products, blood related products, medical gasses, and medical devices.
The concepts described therein are, however, broadly applicable and may be useful in these
areas as well.

Development and optimization are dynamicas they relate to the life cycle of
a product, process, or method, and as a result:
• Development activities are expected to be adequately complete,
for the specific stage in the life cycle, and appropriately
documented prior to initiation of transfer.
However, the baseline level of specifications or performance criteria might
progressively improve (changes, variations, new methods, ….).

 If a Receiving Unit can routinely [consistently] reproduce the transferred product, process, or
method against a predefined set of specifications as agreed with a Sending Unit and /or a
Development Unit, the transfer is considered successful.
Depending on the reason for the technology transfer, the criteria for success may vary,
however, in all cases, because this work is in a regulated environment,
documentation for the transfer effort is critical.
It is critical that a clear objective for any technology transfer project be developed.
It is also critical that a project team comprised of individuals from both the Sending Unit and
the Receiving Unit is established and that there is a precise understanding of each team
member’s role and responsibility prior to initiation of the technology transfer project.

Skill alone will not ensure a successful technology transfer project.

 Once a project has been identified and a team chosen, a clear and realistic project
implementation, temporal plan is required to guide the project, manage expectations,
and handle the inevitable deviations and changes that may present themselves during
implementation.
 Along with that plan comes the need to consider the temporal relationship between
the various tasks associated with a successful technology transfer.
 It should be clearly understood that each technology transfer assignment is unique and
it is, therefore, impossible to provide a generic technology transfer plan.

• Effective Kick-off sessions so the team members
get to know each-other
• Be friendly, positive, helpful, polite, fair, unbiased,
flexible, professional and mature, understanding
and empathetic
• Teleconferences (TCs)
• Cellphone/Desktop apps such as Skype, IMO,
Telegram, Text messages, Whatsapp, …. can
expedite many issues (though unofficial, view
them as phone calls; Document and communicate
them officially immediately afterwards)
• Group Emails for information only
• Keep the relevant people in the loop, and
the assistants/ substitutes in cc to follow-
up in case the focal person is unavailable
• If you want an email unanswered and to
be overlooked, address it directly to
more than 1 person!
• Just pick up the phone
• Leave your desk and meet in person
• SharePoint
• Agendas
• Minutes of meetings
• Gantt charts (Excel, Word, MSP),…

• Pre-transfer
• Build transfer team and develop project charter (CEO/DIRECTORS level- estimates)
• Consolidate detailed knowledge for transfer and develop technology transfer protocol
(MANGERS level document-more in details and more accurate)
• Procurements/Supplies
• Regulatory
• Trainings
• Technical/Trouble shooting batches/runs
• Process/Procedure qualification/validation (depending on the stage of transfer, Pivot
batches, Bio-batches,.. can be included)
• Perform review
• Need to repeat any step
• Finalize transfer and Wrap-up
• Lessons-learned knowledge database

Based on:
• ISPE Good Practice Guide-Technology Transfer-2003/2014
• WHO Technical Report Series, No. 961, 2011, Annex 7, WHO guidelines on
transfer of technology in pharmaceutical manufacturing
• Guideline for Technology Transfer-NIHS-Japan-2012
• ICH Q10-Scale-up & Technology Transfer as a Part of Pharmaceutical
Quality Systems

•Pre-transfer
• Regulatory
• Trainings
• Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches,
Bio-batches,.. can be included)
• Perform review

• Memorandum of Understanding (MoU)
 Very general
 2 Bi-partite MoUs or 1 Tri-partite (inter- or Intra- sites)
 Name of products
 Scope
 Validity date
 Governing law (sometimes non-binding)
 ….

 General questionnaire (if applicable)
 Name/ Contact info/ Key persons and experience/
Company history/ Organization Chart
 Governmental/ Privately-owned/ Member of a
holding/ Possible contracts (Conflict of interests)
 Number of staff in each department:
 Manufacturing/ Packaging/
Warehouses/ QA/ QC/ Engineering/ IT,
…. (Ratios suitable based on the
company operations/size)- Turnovers
 Shifts/ Working Hours
 Dosage forms
 Cytotoxics/ Penicliins/ Cephalosporines/ Penems/
Sex hormones/ Biologics/ Herbal/ Live vaccines/
hazardous….
 In which activities are they willing to assist:
Procurement, QC, Technical …
 QC equipment: Types and Brands/ Models/ Numbers…
 Stability Chambers, Rooms
 Manufacturing/ Packaging technology: Types and
Brands/ Models/ Minimum and Maximum working
capacities/ Numbers…
 Facilities surface areas: Warehouses/ Manufacturing/
Packaging/ QC (Physicochemical, Microbiological)
 Engineering utilities: BMSs, EMSs, ….
 QMS
 Certificates (GMP, ISO, Audits by international
companies,…)
 Current and Pipe-line product list

 Due Diligence Visits/ Audits
• Initially a visit by the focal person for smooth Audit planning
• An opening session, Site walking tour, Documentation review, Wrap-up
• Visit/ Audit reports and possible required CAPAS with timeline
 Supply and Procurement/ Financial agreement
• 2 Bi-partite agreements or Tri-partite
• Transparent details of financial aspects and responsibilities in procurements, QC
tests/ Technical and Validation batches expenses/ Routine batch expenses

 Technical and Quality
agreement
• 2 Bi-partite agreements or Tri-partite
 Confidentiality agreement
(CDA-NDA)
…

• Pre-transfer
• Build transfer team and develop project charter (CEO/
DIRECTORS level- estimates)
• Consolidate detailed knowledge for transfer and develop technology transfer protocol (MANGERS level
document-more in details and more accurate)
• Regulatory
• Trainings
• Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches, Bio-batches,..
can be included)
• Perform review

• Setting focal persons in each party and having an introduction session (preferably face-to-face)
• Promoting project management skills, being organized, knowing the basics of modern
communication
• Clarifying responsibilities and authorities: no overlaps, gaps (RACI CHART, WBS)
• Emphasizing team-work spirit, keeping respective staff in the loop, not monopolizing, being fair,
fostering communication skills, no blame-shifting
• Encouraging open channels of communication: responding on time and willingly
• Considering language skills
• Choosing members based on technical knowledge of the process/ product: An experienced team
• Setting Channels of communication (Emails, TCs…; Having required forms, templates, SOPs, WIs,
Flowcharts, Protocols)
• Team members not working as isolated islands, since timings and tasks are often very much
interrelated and intertwined
Microsoft Word
Document

• Example of project charter (a high-level CEO/DIRECTORS document -estimates-
using previous history): DIRECTORS SHOULD BE INFORMED OF THE GENERALITIES OF
THE PROJECT BEFOREHAND, AND THEY SHOULD SUPPORT IT!
 Project name
 Approved by (Support by higher directors)
 Revision history
 Executive summary
 Goals
 Scope
 General Time-line and main milestones
 General risks (QRM):
to brief higher directors on the criticality and
reasons behind decisions
 Resources estimate (the Ms):
 Man
 Material
 Machinery
 Methods/Documents
 Money
 Management
 General WBS (Responsibilities matrix)
Microsoft Word
Document

• Pre-transfer
• Consolidate detailed knowledge for transfer and develop technology
transfer protocol (MANAGERS level document-more in details and more
accurate)
• Regulatory
• Trainings
• Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches, Bio-batches,.. can
be included)
• Perform review

• APPROVALS (by all relevant key people)
• SUMMARY
• RESPONSIBILITIES (name the persons)
• REGULATORY
• TRAININGS NEEDED
• PRODUCTS AND ACTIVITIES TO BE TRANSFERRED
• HYGIENE – SAFETY – ENVIRONMENT
• PRODUCT/ PROCESS HISTORY REVIEW BEFORE
TRANSFER
• ANALYTICAL TRANSFER
• MANUFACTURING PROCESS TRANSFER (if applicable)
• RAW MATERIAL AND SUPPLIERS
• PACKAGING MATERIAL (if applicable)
• STABILITY (If applicable)
• GAP ANALYSIS
• QRM (might be more detailed than the initial
QRM in the project charter)
• DOCUMENTS REQUIRED (SOPs, Protocols,
Checklists, Forms, Flowcharts, …)
• PLANNING (timelines)
• RELEASE/ APPROVAL CONDITIONS
• LOGISTICS
Microsoft Word
Document

•Gap analysis is Identiﬁcation of all critical elements of a process/
facility/staff… which are available at the Sending Unit but are missing from
the Receiving Unit, and to find and implement solutions for them.
Receiving Unit readiness assessment
Demonstration runs; Technical batches; Media fills
Processing/ Method Gaps
Information-training-experience gaps
Facility gaps

To achieve a higher assurance on quality
To reduce the probability of failure
To systematically break down complex
processes and their possible failures
To save time and resources
To facilitate and prioritize decision making
To communicate critical points to all team
members
To think critically about even simple
processes and gain in-depth knowledge of
each, and their consequences
 QRM (might be more detailed than the
initial QRM in the project charter);
ICH Q9
 Define stages and process flowchart
 Identify failure modes and their effects
 Root cause analysis: 5 whys, 2-Hs, Fish
bone diagram (Ishikawa), A3 problem-
solving, PDCA, or other methods
 Clear ranking basis
 FMEA, PHA, HACCP…
 Listing current control measures
 Prioritizing failure modes
 Implementing CAPAs based on priorities;
Risk mitigation
 Final review and assessment

A history of the process including:
→The development and process rationale,
justification of specification ranges, and
prior validation activities, hold times, CPP,
CQAs, Control strategies …
 Technology transfer protocol, which
captures the critical manufacturing process
parameters
 Technology transfer report template
detailing the success (or failure) criteria and
report of the technology transfer
 Batch record and Process Flow charts
and the relevant SOPs, Protocols, WIs,
tips…
 Specifications and supplier list of material,
machinery, equipment, reagents, size-
parts...
 Relevant Health, Safety and Environment
documents: MSDS of material,
Containment and leakage measures…
 Transport validation protocol and report
template (in case of transport of API,
Bulks, Intermediates….)
Sometimes the Focal Unit or the Receiving Unit participate in preparation of these documents.

Sampling plans, Sampling techniques,
Frequencies, IPC and IPQC samplings…
Methods of analysis and tips
Analytical transfer protocol
Stability study protocol and report
template
Cleaning instructions
Rework procedure
Required training documents
Artworks
 Annual product review documentation
and template (include process capability,
process control trend summaries, and
process variations and the investigation
of those variations, follow-up actions,
and a rationale and summary of
reworked product)

 General Technology Transfer Process description and
Flowchart
 Project Charter
 Contracts
 Project general and detailed time-line (Gantt charts, P
and inter-dependencies (Network Diagram)
 Responsibility Matrix and Work Breakdown Structure
(RACI CHART, WBS)
 Audits and Visits and CAPA follow-up forms
 Documents Transfer Receipt forms
 Material Transfer Receipt forms
 Training needs and records
 QRM documents in technology transfer
process
 Material/ Equipment procurement forms…
 Artworks and packaging material preparation
SOPs
 Regulatory processes SOPs
 Minutes of meetings
 Records of Technical batches
 Lessons-learnt database
Sometimes the Sending Unit or the Receiving Unit participate in preparation of these documents:
Microsoft Word
Document

 Site VMP (at least parts which are relevant to the
Technology transfer project at hand)
 Qualification documents of all relevant utilities,
machinery, equipment…
 QRM, PHA… at the receiving site
 Technology Transfer Validation Protocol and report
(both trouble-shooting trial technical runs and the
main runs)
 Stability study report
 Customized bi-lingual Batch Manufacturing and
Control Records and SOPs, WIs, Forms, (both for
trouble-shooting trial technical runs and the main
runs)
 Deviations and Change control documents
 PQR
 Cleaning validation documents, taking into account
the transferred products
 Sample retention
 Local Dossier (if relevant)

• Pre-transfer
• Procurements/ Supplies
• Regulatory
• Trainings
• Perform review

The suppliers list and detailed specifications of all required APIs, Excipients,
Components, Packaging material, Reagents, QC Supplies …. should be provided by
the Sending Unit
The criticality of using the exact same suppliers should be communicated with
the Receiving Unit
It should be noted that sometimes all of the critical attributes might NOT be
included in the CoA or Specification sheet or Dossier
In case of inability of the Receiving Unit to procure the required item (with
reasonable price and in a timely manner), the Sending Unit might facilitate its
supply
In case the same suppliers are not used, the vendor selection procedure should
be followed

!A Certain micronized purified API is exclusively supplied by the innovator
company, affecting dissolution, absorption and efficacy of the product
 A certain Ethanol grade is solely manufactured by one American Company,
exclusively for one customer
A certain PVC grade with low Water Vapor Transmission Rate (WVTR) is to be
used by the Receiving Unit for packaging, while due to local production of PVC,
imports of PVC is banned
Imports of a certain specific HPLC column or UV spectrophotometer cell-holder/
spacer, … takes 5 months and double the real price, delaying the analytical
transfer and making it very expensive

• Pre-transfer
• Regulatory
• Trainings
• Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches, Bio-
batches,.. can be included)
• Perform review

Authorizations (both for finished product and imported material, ….) and Data-matrix codes
(traceability), such as providing DIAFs (Drug Importing Application Form), CPPs (Certificate of
Pharmaceutical Product), legalized documents,… for the intermediate products…
Artworks management
Stability studies (what are accepted as commitment studies, which time points,…)
SUPAC and Dossier variations
Sampling plans
Product registration at different stages
Manufacturing and analysis change control and variations
Batch records
Local Dossier compilation (if relevant)
Complaints, Retained samples, Pharmacovigilance, PQR ….
Other Documentations…

• Pre-transfer
• Regulatory
• Trainings
• Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches, Bio-
batches,.. can be included)
• Perform review

Gap and risk analysis in trainings should be done in the Receiving Unit with a view for
determining organizational shortfalls, and correcting them:
Project management capability
Team-work ability, and culture and habits
GMP-compliant behavior, regulatory and safety issues, current state of product-related
process understanding, manufacturing processes, documents, analytical methods,
equipment, plant capabilities
Language skills
Novel technologies (communications, IT, ….)
Trainings should be assessed and documented
Hands-on experience/ Visit to Sending Unit should be arranged if necessary

• Pre-transfer
• Regulatory
• Trainings
• Perform review

Can be regarded as training and confidence-gaining opportunity for the transfer team
Can prevent waist of precious, and sometimes expensive material
Saves time and decreases the chances of failure in Validation/Qualification batches/ runs
Allows modifying several affecting parameters in a wide range to gain a better view of the design space
(particularly in case of scale-ups, batch-size changes, different machinery/technology in SU and RU)
Allows some overlooked and unidentified issues/risks to surface
Allows different processes in the process train to be assessed individually, with less time and continuity
constraint
Allows customization of batch records, documents …. to be more adapted to the real process
Can also be regarded as PQ of machinery
Sometimes placebo materials are used, and sometimes the exact original material

Using placebo powders for tablet manufacturing, coating packaging…
Using placebo solutions in aseptic filling
 Using trial runs in dissolution and HPLC tests, before the official analytical
transfer

• Pre-transfer
• Regulatory
• Trainings
• Process/Procedure qualification/validation (depending on the stage
of transfer, Exhibit, Bio-batches,.. can be included)
• Perform review

• Lab-scale:
 100–1000 times less than production scale
 Formulation and packaging development,
 Early clinical and/or preclinical stages.
 CQAs
• Pilot batches-Scale-up batches:
 Process-development or optimization stage
 Preclinical and mid- to later-stage clinical
evaluation
 Formal stability studies
 If supporting formal registration, size at
least 10% of the production-scale batch or
100,000 units, whichever is greater
• Exhibit batches-Qualification batches:
 In the manufacturing plant or the
plant with similar equipment
 For process qualifications
 For stability studies
 The reason Exhibit batches are used
by pharma/biopharma companies to
save time and money
 Hold time studies, change of
parameters within design space

• Biobatch-Pivotal batch:
 The size of the biobatch adequate to represent the production batch size, and with production machinery i.e.
no scale up beyond ten times.
 Scale up beyond ten times should be supported with a new biobatch/BW data to support the new size
(possible exception for low-risk cases if well-defined).
 A biobatch should be the greater of 100,000 units, or not less than 1/10th the proposed production size.
 A biobatch of < 100,000 units may be accepted, but then no scale-up is allowed. This should be clearly
indicated in reports for the product, as it affects allowable variations.
• Validation batches
The actual size and parameters and machinery
• Commercial batches

At successful completion of all previous tasks, the Process/Procedure
Validation Batches/Runs, can take place.
While it may be valuable to have personnel present from the Sending
Unit, it is critical that the Receiving Unit actually execute the study
(i.e., operate the equipment, take the samples, perform the testing,
etc.) so that the study is truly representative of what will occur at the
site post-validation.
The validation report should then be completed by the receiving site.

• Documentation of all observation (even those out of scope of Validation
Protocol);
• Constant precise observation even of the minute details
• Note-taking and Photographing, Video filming and any measure to help
future review of events
• Trying to resolve any issue with minimum modification to the previously-
approved protocol
• In case of need for change during the validation runs, it needs to be first
discussed and approved by relevant authorities
• In setting of parameters within the agreed ranges or in case of need for
change, try to modify one parameter at a time to be able to assess the
effects of individual parameters.

Best practices:
•Plan extra runs
•Prepare for deviations & conduct ‘in control’
approvals
•Follow in-process results closely

•Know your process
•Understand your variability
•Build a Control Strategy early
•Establish a lifecycle
• Revisit your Risk Assessment
• Monitor the process and
analyze your results
• Continued process
improvement will lead you to
the Future!

• Pre-transfer
• Regulatory
• Trainings
• Perform review

The completed Validation Report should be
reviewed against the previously set
Acceptance Criteria and Objectives (by
Sending Unit and/or the Focal Technology
Transfer Unit).
In case of failure in these runs, an official
Documented Root Cause Analysis should be
conducted.
The required steps should be modified
(having in mind a Risk Assessment concept),
in a documented and controlled manner, with
the involvement of all parties.
The technical runs can be repeated to
assist in RCA
 The validation runs then should be
repeated, until it can be concluded that
the Process/ Product/Technology… is
successfully transferred:
Assures consistency of
manufacturing
Reproducibility of process design
evaluated commercially
Provides assurance of commercial
readiness
At this stage the Project can be often wrapped up.

!In most cases some minor non-critical issues will remain, which need
CAPAs and follow ups for continuous improvement.
The Sending Unit might still remain in contact with Receiving Unit to assist in:
• Continuous process verification (3-stage process validation approach)
• Control strategy
• Ongoing assurance process is in control
• Trending/Statistical Analysis/Proactive Improvement

• Pre-transfer
• Regulatory
• Trainings
• Perform review
•Lessons-learned knowledge database

•Review the deliverables vs. plan
•Review budget vs. plan
•Review timeline vs plan
•Revise templates/documents … accordingly

Questionnaire to gather information
Group meetings to finalize the output
(Issue(s) faced within the project or the team)
What did you chose to do about the issue
and why?
What was done well/not done well?
Why do you think things went well/did not
go well?
What should be done similarly next time?
What could be improved next time?
Are there any generalizable LLs to be gained
from this experience? Are there any
generalizable LLs to be gained from this
experience?
Gaps
List actionable LLs
Key words:
(for archiving purposes)

 Differing technologies, machinery, control parameters
 Underestimating or overlooking analytical methods transfer
 No complete review of project charter by Top directors, leading to delays and lack of
timely support by them
 Lack or inefficiency of Quality Management Systems in any of the parties involved
 No proper development and validation of the case in the Sending Unit
 Overlooking trainings
 Differing batch sizes

 Differing excipient/ packaging material suppliers
 Language/ communication gaps and non-responsive and non-open channels; No face-face
visits, Lack of transparency
 Lack of project management skills and human resources skills and technical skills in focal
persons
 Not considering plan Bs for changes outside of one’s control area
 Lack of precise observation and documentation habits
 Unrealistic time-lines and commitments, leading to rush and subpar performance at the final
stages19-Nov-16 Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry- Sayeh Majzoob 66

• Based on
• USP 39 <1224> (Since USP 35-2012) Transfer of Analytical procedures
• USP 39 <1010> Analytical Data-Interpretation and treatment
• WHO Technical Report Series, No. 961, 2011, Annex 7, WHO guidelines on transfer of
technology in pharmaceutical manufacturing
Sayeh Majzoob
Pharm. D., Ph. D. in Pharmaceutics; Pharma MBA
Email address: smajzoob@yahoo.com
Cellphone: +98 912 1366744

Analytical transfer:
What is it, why should it be done? Definitions
Is it required to officially perform Analytical Method Transfer: FDA warning letters
Scope: In what situations might we need Analytical Method Transfer?
Method Validation? Method Verification? Method Transfer?
Types of Analytical Method Transfer: A risk-based approach-How it is done? :
Comparative testing
Co-validation
Re-validation-Partial Revalidation/Verification
Transfer waiver
Some possible designs of Analytical Method transfer
Acceptance criteria, Comparative testing, Statistical tests

Steps in Analytical Method Transfer
Pre-transfer:
Build transfer team and develop project charter (CEO/DIRECTORS level- estimates)
Consolidate detailed knowledge for transfer and develop technology transfer protocol (MANGERS level
Regulatory
Trainings
Technical/Trouble shooting batches/runs
Process/Procedure qualification/validation
Perform review
Need to repeat any step (non-conformance remedial action)
Finalize transfer and Wrap-up
Lessons-learned knowledge database
Case-study of an analytical transfer
Pitfalls and possible reasons for failure in Analytical Method Transfer

USP 39 <1224> (Since USP 35-2012)
• Analytical transfer is the documented process that qualifies a
laboratory (the receiving unit) to use an analytical test
procedure that originated in another laboratory (the
transferring unit), thus ensuring that the receiving unit has the
procedural knowledge and ability to perform the transferred
analytical procedure as intended*.
*(Under actual conditions of use)

The firm failed to perform finished product test method transfers for 34
products (W-187)
The firm has failed to perform method validations, method verifications, or
method transfers for any of the laboratory test methods used to test active
pharmaceutical ingredients (W-187)
Failure to establish and document the accuracy and reproducibility of test
methods employed. (W-186)
For example, methods that were validated at one facility and transferred to
xxx site are being used without a methods transfer or revalidation protocol.
(W-186)

Sponsor company Contract lab
Analytical development QC labs
Across different sites
• The same lab conditions
• Different lab conditions
Existing instrumentation New instrumentation
• With different specifications
• With different technology
Supplier of material Client
Transfer to new instruments with different instrument characteristics

For:
• APIs
• Excipients
• Finished Products
• Intermediates
• IPQC samples
• Packaging material
• Stability samples
• Cleaning validation analytical methods

Method Transfers are closely related to Validation/ Verification
More challenging: multiple laboratories and companies involved; comparison
and assessment of equivalence is the goal:
Different approaches to Validation/ Verification and Transfer
Different expectations of what is an acceptable Validation/ Transfer
Different instruments and facilities
The method should be adequately validated at the Sending Unit prior
to transfer
Balancing Act
Adapt method to new facility/instrument
Meet new facility validation requirements
Maintain validated state of method
 Typically Analytical Method Transfers are mostly concerned with Accuracy and Precision
(assuming the method should be validated at the sending unit).

Based on a risk assessment taking into account the complexity and criticality of the
analytical procedure and its purpose, as well as the experience and knowledge of the SU
or RU.
• Comparative Testing (with appropriate justifications) - Analysis on
samples, from the same lot, by both laboratories and acceptance
criteria is met.
• The acceptance criteria and variability are outlined in a transfer
protocol.

• Co-validation of Laboratories- The transferring laboratory works with the receiving laboratory in
an inter-laboratory validation effort at the transfer laboratory site. An assessment conducted,
using a transfer protocol, to evaluate the reproducibility of the process.
Receiving lab is part of original method validation
Transferring and receiving lab conduct the same validation experiments
Useful for methods not (fully) validated
Must be based on pre-approved validation protocols and acceptance criteria
Should challenge all USP or ICH validation parameters
Include receiving lab in validation through inter-laboratory tests.
Ensures harmonization of method at both sites

• Revalidation/Partial Revalidation- Complete or partial method validation
per <1225> Validation of Compendial Procedures by the receiving
laboratory:
Mostly when the transferring lab
is not available or participating

• Transfer waiver- Under certain circumstances, without comparison and generation of
inter-laboratory comparative data.
Some scenarios that may justify the waiver:
The new product's composition is comparable to that of an existing product
and/or the concentration of active ingredient is similar to that of an existing
product and is analyzed by procedures with which the receiving unit already has
experience.
The analytical procedure being transferred is described in the USP-NF, and is
unchanged. Verification can apply in this case (see <1226>).
The analytical procedure transferred is the same as or very similar to a
procedure already in use.
The personnel/[equipment] in charge of the development, validation, or routine
analysis of the product at the transferring unit are moved to the receiving unit.
If eligible for transfer waiver, the receiving unit should document it.

Some basic compendial procedures including, but not limited to:
• Loss on drying
• Residue on ignition
• Various wet chemical procedures such as acid value
• Simple instrumental determinations such as pH measurements
However, for the application of already established routine procedures to compendial
articles tested for the first time, it is recommended that consideration be given to any
new or different sample handling or solution preparation requirements.

Sample preparation and sample handling are the most critical issues and most common
reason for failure of method transfer.
Based on the intended use of method the samples can be:
Routine samples
 Expired
 Spiked samples
 Forced degradation samples
 Stability samples
 IPQC samples
 Intermediate products
Trainings:
Picture and video-based training- Face to face training and meetings (language barrier: can points be
transferred in detail? Specialized translation)
Tips (Formulation dependent,…), expertise, experience
Details of equipment, material, reagents,… to be disclosed

As the dossier does not disclose the QC details, so some Closed part info. might be
requested.
• The following data might be beneficial to be shared by the Sending Unit
Development data, SST results, unusual and OOS results
History of critical analytical data (e.g., release and stability data) and rationale for proposed
specifications
Stability results and tests are an excellent source to evaluate the real routine performance of an
analytical procedure
If needed, change control and regulatory implications should be addressed.
The analytical transfer should be made "Under actual conditions of use” in the Receiving
Lab.
In some contexts, the main responsibility might be with RU, due to more experience with
the Product type or Test or Transfer.

For older products it is recommended that analytical methods for stability are
also reviewed for adequacy at the time of transfer and agreed on.
The choice of particular strategy needs justification.
The type of transfer is defined for each method based on a risk assessment
taking the complexity and criticality of the analytical procedure and its purpose
into account as well as the experience and knowledge of the RU.
Possibility of a waiver
Microbiological and Biological methods?

Setting acceptance limits/ criteria:
• Somewhat challenging and daunting task
Types of comparisons:
• Direct comparison of mean values based on
common industry practice (a priori) for each type of
test (Precision and Accuracy)
!But with direct comparison, the number of
repetition and variability are overlooked
• (Schuirmann’s) Two one-sided t-test (TOST) (Not
student’s t-test)

USP 39<1010>ANALYTICAL DATA-INTERPRETATION AND TREATMENT
• COMPARISON OF ANALYTICAL PROCEDURES
• APPENDIX F: EQUIVALENCE TESTING AND TOST
•Classical statistical hypothesis testing:
e.g.: The null: Two means are equal.
The alternative: Two means differ.
The null hypothesis will rejected in favor of the alternative if the evidence is sufficient against the null.
A common error is to interpret failure to reject the null as evidence that
the null is true.
Actually, failure to reject the null just means the evidence against the null was not
sufficient.
For example, the procedure used could have been too variable or the number of
determinations too small.

• "Null Until Proven Alternative"
• Look at it in terms of "innocent until proven guilty" in a courtroom:
As the person analyzing data, you are the judge. The hypothesis test
is the trial, and the null hypothesis is the defendant. The alternative
hypothesis is like the prosecution, which needs to make its
case beyond a reasonable doubt (say, with 95% certainty).
• If the evidence presented doesn't prove the defendant is guilty
beyond a reasonable doubt, you still have not proved that the
defendant is innocent. But based on the evidence, you can't reject
that possibility.
• So how would that verdict be announced? It enters the court record
as "Not guilty."

 Therefore: To demonstrate similarity, (such as results from two laboratories), then
the similarity should be set as the alternative hypothesis (not the
difference).
 A statistical test for an alternative hypothesis of similarity is referred to as an
EQUIVALENCE TEST.
 It is important to understand that:
"equivalence" does not mean "equality."
 Equivalence should be understood as "sufficiently similar" for the purposes of
the laboratory(ies).
 As noted earlier in this chapter, how close is close enough, is something to be decided
a priori.

Accuracy and precision comparison:
• Comparison of the accuracy in two labs (USP<1225): useful in determining if the
procedures are equivalent, on the average.
• The confidence interval should be compared to a lower and upper range deemed
acceptable, (a priori), by the laboratory.
• If the confidence interval falls entirely within this acceptable range, then the two
procedures can be considered equivalent, in the sense that the average difference
between them is not of PRACTICAL concern.

• The lower and upper limits of the confidence interval only
show how large the true difference between the two
procedures may be, not whether this difference is consid-
ered tolerable.
• Such an assessment can be made only within the
appropriate scientific context. This approach is often
referred to as TOST (two one-sided tests; USP
39<1010>ANALYTICAL DATA-INTERPRETATION AND
TREATMENT: see Appendix F)

Possible reasons of False Significance or Non-significance if the difference in
averages is caused by applying simple T-tests:
! A statistically significant difference may not be large enough to
have practical importance to the laboratory because:
 It may have arisen as a result of highly precise data or a larger sample size.
! On the other hand, it is possible that no statistically significant
difference is found, and yet an important practical difference cannot
be ruled out.
This might occur, for example, if the data are highly variable or the sample size is too
small.
Thus, while the outcome of the t-test indicates whether or not a statistically
significant difference has been observed, it is not informative with regard to the
presence or absence of a difference of practical importance.

• Pre-transfer:
• Regulatory
• Trainings
• Process/Procedure qualification/validation
• Perform review
• Need to repeat any step (non-conformance remedial action)

Pre-transfer:
• MoU-Questionnaire-Audits-Visits-Detailed Contracts
Build transfer team and develop project charter (CEO/DIRECTORS level- estimates)
Consolidate detailed knowledge for transfer and develop technology transfer protocol (MANGERS
level document-more in details and more accurate):
• Tips-Details-Previous method development data-Key analysts-Sample storage and handlings-
MSDS-Safety points-Equipment comparison-Gap analysis-QRM-CAPAs
Procurements/Supplies:
• Samples (Stability indicating: Expired-Forced degradation-Spiked…)-Packaging material tests-
Reference Standards-Columns-Cells, Spacers, Reagents-Solvents …

RESPONSIBILITIES
The primary tasks of the Sending Unit are:
Create the Transfer Protocol
Execute Training
Assist in Analysis
Acceptance Criteria
The Receiving Unit provides:
Qualified Instrumentation
Personnel
Systems
Executes the Protocol
The Sending Unit and the Receiving Unit are jointly
responsible for issuing the final report.

Regulatory:
• Do the transfer strategy and QRM meet regulatory approval?
• Any variations compared to dossier-Is the receiving Lab accredited
• ….
Trainings:
• Transparent-Face to face-Tips-Pictures-Videos-Visit to the Sending lab
Technical/Trouble shooting batches/runs:
• As not to waste resources, to be clearly oriented
• Trial runs and pose any questions/ambiguity to the Sending Laboratory
Process/Procedure qualification/validation
Perform review
Need to repeat any step (non-conformance remedial action)
Finalize transfer and Wrap-up
Lessons-learned knowledge database

• Analytical
Transfer Protocol
should include:

• Analytical transfer
report form template to
be included for
harmonization

Unrealistic risk assessment of the complexity and criticality of the method, and the
two labs involved
Choosing un-scientific acceptance criteria and acceptance interval
Different equipment, in-experienced analysts and lab environment
Materials/ Reagents/ Accessories from difficult-to-purchase suppliers (Columns,
Special grade reagents,…)
Lack of Robustness and Reproducibility of method; Lack of full validation
Lack of documented and verified details
No open and responsive communication channel

Understand technology transfer and success criteria including:
Forming the transfer team and developing the charter
Consolidating knowledge for transfer and developing a technology
transfer proposal
Identifying risks, conducting a risk assessments and developing
technology transfer plan
Executing the transfer
Developing the process (procedure) qualification
Finalizing the transfer and performing the review
Developing an effective process for Technology Transfer including the
exchange of knowledge between the sending unit and the receiving
unit for drug substance, drug product and analytical procedures.
Pitfalls

Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry-Sayeh Majzoob-Complete15Nov2016

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