1. Purpose
To describe a process for the transfer of manufacture of an established drug product [DP], from one established commercial manufacturing site to additional/alternative sites. This will include the associated quality control procedures and health safety and environmental information.
2. Scope and Applicability
Technology Transfer [TT] procedures presented in this guideline describes all the procedures that need to be followed to successfully transfer a DP from one already established manufacturing site to one or more additional/alternative sites. The need to establish manufacture at other sister sites or at ‘contractors’, may be required:
– When there is a need to establish local or regional supply to satisfy the requirements of markets not included in the early launches.
– When there is a need to establish manufacture at additional sites to satisfy market demand through a product’s life cycle.
– When additional capacity is required to ensure security of supply throughout the life cycle of the product
3. Definitions
3.1 Drug Product (DP)
The formulated drug packaged in its primary packaging used for clinical trials, validation or sale. Note: Drug Product may also be referred to as Formulated Product
3.2 Manufacture
Used herein refers to the processing of DP, primary packaging (including bulk containers) and quality control operations involved in providing a finished product for secondary packing and labeling to meet specific market requirements.
3.3 Quality Control Procedures
Refer to all analytical methods and specifications used to control the quality of the processes and product, including real time testing. [Process Analytical Technology]
3.4 Technology Transfer (TT)
Used herein refers to the documented transfer of DP, manufacturing processes and quality control procedures within a regulatory compliant environment to support successful commercialization.
3.5 Manufacturability
To assure that manufacturing processes and analytical methodologies are defined and optimized in such a way that appropriate quality products will be manufactured safely and without risks to people and the environment at the commercial scale. Manufacturability is defined as ‘The ability to manufacture product routinely and predictably to the desired quality and cost, in compliance with the appropriate Regulatory Authority and Health and Safety regulations’.
3.6 Primary Packaging
Any material employed in the packaging of a pharmaceutical product, excluding secondary packaging and any outer packaging used for transportation or shipment. Primary packaging material(s) form the container/closure system for the product and therefore may be in direct contact with the product. Examples include HDPE bottles/caps, blister strip packs, tubes/caps for ointments, syringes.
3.7 Lead Site
Is the site that is accountable for conducting specified QA activities, notably QC analysis and release, as recorded in the QA agreement between the Lead Site and the Receiving Site. Within this definition, Lead site is defined as a single global or regional “factory” and free movement (i.e. without repeat analysis) of API, bulk formulated product, part-packed and finished packs within this ‘factory’ is equivalent to transfer within a manufacturing site, assuming national regulations permit this. A Lead Site is also identified for each product manufactured by a particular contractor.
4. Responsibilities
4.1 Sponsor: Operations – Supply & Capability
The overall co-ordination of the activities within Operations required to transfer, establish and validate the manufacture and supply of established DP’s at alternative/ additional sites shall be sponsored by the Supply & Capability Group
4.2 Operations – Transferring and Receiving Sites
A product introduction project manager should be appointed from each of the [‘transferring’ and ‘receiving’] manufacturing sites, to manage the site activities and should be responsible for ensuring a successful technology transfer through participation in a TT Manufacturing team. This should be agreed with the Sponsor at the start of the project. Each manufacturing site should maintain written procedures, which at a minimum are consistent with this guideline and follow these when receiving or transferring the manufacture of a drug product.
5. Guideline
5.1 Procedures and Documentation
The overall plan and timetable for technology transfers should be based on the schematic outline of in Appendix 4. In consultation with the involved parties, the product introduction project manager (PIPM) starts the activities required to transfer manufacture of a product to the additional/alternative site. This should include the activities required to provide the information/data necessary to obtain regulatory approval of the supply from the site. Following support through the Management of Change Process [MCM], the PIPM should prepare an ‘Integrated Product Transfer Plan’ [IPTP] and timetable, together with the ‘transferring’ and ‘receiving’, sites, in consultation with others, eg. Analytical & Research Development Team, Regulatory Group, Dossier Management Group [DMG], Compliance Management Group, Engineering Group, as appropriate. The IPTP should be approved by the Site PIPM of the ‘transferring’ and ‘receiving’ sites, together with the site QA Managers and the initiator of the change. The PIPM should ensure that the MCM change is managed throughout the life of the project, as defined by the approval timetable laid down by Regulatory Group. The PIPM should therefore take the appropriate steps to ensure that the IPTP is implemented, that the regulatory authorities of the markets concerned approve product from the additional/alternative site and that product is available for distribution at the time required.
5.2 Document Approval and Distribution
Each document defined in this guideline should be signed by sending and receiving department as indicated. The issuing department/site should archive the original signed copies (‘master copies’). All documents must be readily available for reference during inspections by regulatory agencies. All documents should be written in English, unless an alternative language has been agreed.
5.3 Technology Transfer Support
Where necessary R&D should provide appropriate support to both the ‘transferring’ and ‘receiving’ sites during TT. This should be discussed and agreed as part of the IPTP.
5.4 Management of Change
Proposals for sourcing must be referred to the product specific MCM team for support before being progressed [unless already approved as part of the original sourcing strategy]. Regulatory submissions for changes in sourcing should be based on the process and quality control procedures and primary packaging transferred from R&D to the manufacturing site during the initial New Product introduction. No changes to the registered processes and quality control procedures should be made during the TT unless supported by the Product specific MCM Team set up at the time of the original regulatory submission. As part of this process, regulatory advice will be provided to ensure correct documentation and data are generated and submitted to the Authorities. Sign off of any regulatory submission should follow MCM guidelines.
6. Appendices
APPENDIX 1
Technology transfers between manufacturing site[s]
Note: The Manufacturing site[s] should normally carry out all pharmaceutical processing steps and quality control procedures required to manufacture the finished dosage form and pack this into bulk containers for onward shipment to designated ‘ Packing’ sites. However, some products may require enclosure in the final primary container to complete the last processing steps, e.g. sterile products. Sites making such products should be within the definition of a ‘ manufacturing ‘ site. Note: In most cases, the additional Manufacturing Site[s] will also be one of the designated Packing sites.
Section 1 Contents
1.1 THE INTEGRATED PRODUCT TRANSFER PLAN – IPTP
1.2 PRE – TT
1.2.1 Manufacturing and Quality Assurance Documentation to be transferred
prior to TT1
1.2.1.1 Development Reports, Product Reviews and Registered Chemistry and
Pharmacy Information
1.2.1.2 Quality Control Procedures
1.2.1.3 Formulation and Manufacturing Process Information
1.2.4 Interface with the Manufacturing Change Management Process (MCM)
1.2.5 Provision of Safety, Health and Environment Information (SHE)
1.3 TT1
1.3.1 Process, Primary Packaging and Quality Control Procedures ‘Freeze’
1.3.2 Responsibilities during TT1
1.3.3 TT1 Report
1.3.4 Statement of ‘Readiness to progress to the Process Validation Phase’
1.4 TT2 – PROCESS VALIDATION
1.4.1 TT2 Protocols
1.4.2 Responsibilities during TT2 manufacture
1.4.3 TT2 Reports
1.4.4 Manufacturing Change Management Process (MCM)
1.4.5 Project Review
1.1 THE INTEGRATED PRODUCT TRANSFER PLAN – IPTP
After approval by MCM of the revised DP sourcing strategy, the PIPM together with the
‘transferring’ and ‘receiving’ manufacturing sites, should produce an ‘Integrated Product
Transfer Plan’ [IPTP] timetable for the transfer of all technology required to reach a position
of being ‘ready to validate’ the manufacturing process(es).
The IPTP should address the issues and timing of the transfer from the ‘transferring’ site to
the ‘receiving’ manufacturing site[s]. It should include outline relevant information on the
process, bulk packaging (and primary packing if necessary), formulation(s),excipients,
primary packaging, safety, health and environmental information, analytical methods and
specifications, (including microbiology, in-process tests), equipment cleaning
process, process and analytical technology and any special requirements that would influence
the approach to TT.
The IPTP should be presented under the following headings:
* Introduction and Objectives [including product use]
* Outline approach for technology transfer
* Special features (e.g. atypical requirements, site specific issues)
* Materials (drug substance and special excipient requirements)
* Facilities / equipment provision
* Accountabilities / Responsibilities (for TT project management, document
preparation, signature, analytical and microbiological testing and product release)
* EHS
* Quality Assurance
* Regulatory
* High-level documentation Plan (identifies various types of required documents needed for the
activities in pre-TT, TT1 and TT2).
* Key milestones
* Criteria for completion
Further details of the IPTP are provided in Appendix 3
The transfer will normally be effected in three phases:
* Pre Technology Transfer [Pre-TT]. To provide all relevant information from the
‘transferring’ site to the ‘receiving’ site to enable TT1 to start
* Technology Transfer 1 [TT1]. To establish processes at the ‘receiving’ site.
* Technology Transfer 2 [TT2]. To plan, perform and report validation.
The TT to each designated manufacturing site shall be regarded as complete only when the
site has successfully validated the process, regulatory approvals in the designated markets
have been obtained and the MCM process completed.
A regular review of the status of the TT will be held between the manufacturing sites within
the TT manufacturing team.
A schematic outline of the technology transfer process is provided in Appendix 4.
1.2 PRE – TT
The objectives of this phase are to:
* Transfer all quality control methods and specifications, including stability
methods [Note: commercial stability testing is a Commercial Stability Centre
responsibility and this may be either the ‘lead site’ or the ‘receiving’ site as
agreed within the particular project.]
* Transfer the manufacturing process, and associated in-process tests, to a
facility at the ‘receiving site’
* Identify the minimum adaptations to the (registered) process required by
differences in the facility/ equipment at the ‘receiving site’
* Identify the critical parameters for the product/equipment combinations
* Confirm the suitability of local suppliers of excipients/primary packaging
* Confirm suitable equipment cleaning processes.
1.2.1 Manufacturing and Quality Assurance Documentation to be transferred prior to
TT1
1.2.1.1 Development Reports, Product Reviews and Registered Chemistry and
Pharmacy Information
The Development Reports produced by R&D will be made available to the
‘receiving site’ by the ‘transferring’ site, if applicable.
The ‘transferring site’ will prepare and send a summary report of the product’s
manufacturing/control history during commercial manufacture to the ‘receiving
site’.
Documentation Management Group should provide the ‘receiving
site’ with copies of the regulatory documents filed for markets to be supplied by
that site.
1.2.1.2 Quality Control Procedures
The transfer of all methods and specifications required to control the quality of the
product (analytical, microbiological and physical tests) and conduct stability studies,
should be completed before manufacture is initiated at the ‘receiving site’. The
information should include:
* Test methods and specifications for all materials that will be tested by the
‘receiving site’ e.g. contributory (formulation excipients) and non contributory
(processing solvents) raw materials, and primary packaging components.
Note: When the ‘receiving site’ proposes to use the same suppliers as the ‘transferring site’,
the latter will provide copies of its ‘Vendor Assurance Audit’ reports to the former.
For certified suppliers, the ‘receiving site’ only will perform ID testing.
* ‘Transferring site’ must inform ‘receiving site’ about any excipients that contain
materials of animal origin and provide copies of the relevant certification for
Transmissible Spongiform Encephalopathies TSE regulations or access to
documents held by DMG.
* ‘Transferring site’ must inform ‘receiving site’ about any special local
requirements needed to support local manufacture, quality control and regulatory
requirements.
* Drug substance quality control procedures and specifications
* Finished product quality control procedures and specifications, including physical
appearance standards and associated Acceptance Quality Levels for solid dosage
forms
* ‘Transferring site’ sampling plans for raw materials, intermediates, finished
product and packaging where special sampling requirements are needed.
* Finished product stability tests, together with protocols and results of stability
studies at the ‘transferring site’
* Validation reports for all methods
Note: These may be copies of the reports produced initially by the R&D, provided
that no changes in methodology have been made at the ‘transferring site’ subsequent to
the initial transfer from R&D.
* Transfer protocols and acceptance criteria for the above, (as agreed between
‘transferring’ and ‘receiving sites’).
* Analytical methods used to demonstrate the effectiveness of equipment cleaning
at the ‘transferring site’, together with supporting information, eg. validation data.
It is the responsibility of the ‘receiving’ site to ensure that cleaning has been effectively
achieved to enable manufacture of other products to continue..
Note: The QA/QC department of the ‘transferring site’ should be responsible for providing
information on cleaning to the ‘receiving site’, together with test samples previously
examined by the ‘transferring site’ and the results obtained.
The ‘receiving site’ should obtain the required reference standards from R&D or the
‘transferring site’ [as appropriate] and carry out ‘verification studies’, using the samples from
the ‘transferring site’. The QA/QC department of the ‘receiving site’ should produce a report
of its method verification studies and obtain its approval by the ‘transferring site’.
The QA/QC department of the ‘receiving site’ should also be responsible for the adaptation
and validation of the analytical methods to be used to demonstrate the effectiveness of
equipment cleaning, should this be required, after manufacture of the product at the ‘receiving
site’, with appropriate support from the ‘transferring site’.
1.2.1.3 Formulation and Manufacturing Process Information
The ‘transferring’ site should provide current information on:
Parameters of the bulk drug, excipients and primary packaging which may affect
the manufacture and/or performance of the formulation, in addition to those
covered in the regulatory specification.
Formulation and primary packaging details.
Current manufacturing and primary packaging processes used at the ‘transferring
site’, together with supporting information, eg. validation reports, maximum
holding times, etc.
Copies of the Master Batch Sheets used at the ‘transferring site’.
The equipment cleaning process used at the ‘transferring site’, together with
supporting information, eg. sampling protocols, sampling methods, acceptance
levels and results obtained.
In-process tests, including transfer protocols and acceptance criteria (where
required).
Excipient and primary packaging suppliers, grade and specifications, including
key physical characteristics.
Equipment requirements (specific needs).
Transport and storage requirements of the finished product.
Criteria for completion
Unless otherwise agreed, these documents should be provided (and approved) by
‘transferring site’ with an acceptance signature being provided by the ‘receiving site’.
Primary packaging information included in this phase may involve only the bulk pack
used to ship the product to the packing site. However, information on the final primary
packaging should be included when the ‘receiving site’ will also carry out final primary
packing or where the primary pack is an integral part of the DP eg. sterile products
1.2.4 Interface with the Manufacturing Change Management Process (MCM)
The PPM should submit the proposal to the Product specific MCM Team, describing the
changes being proposed, compared with the process, packaging and quality control
information registered [market specific] for the ‘transferring site’. TT1 manufacture should
not be undertaken until MCM support has been obtained and sanctioned in the MCM
database.
1.2.5 Provision of Environment Health and Safety Information (EHS)
Environment Health and Safety (EHS) issues are crucially important in the manufacture of a
Drug Product. National and international EHS regulations must be satisfied before
commercial manufacture can be established at a site.
EHS& R&D should have generated information on the materials and
processes to allow manufacture to take place safely and to minimize risks to people and the
environment. EHS is also responsible for the provision of information to meet
legislation on notification of raw materials and intermediates, safety data sheets, materials
classification and labeling for use and transport. This includes the product safety data sheet
when requested.
This information is generated throughout the development process. Information, on chemical
and operational hazards and process environmental information should
form the data package for the manufacturing site to enable them to develop the appropriate
procedures for control of their operations. The basic package of information which the
‘receiving’ site should have available prior to TT contains:
* The safety data sheet for each material and excipients
* Occupational Exposure Limit for the drug substance
* Analytical methodology for determination of the active material in air
* Health surveillance procedures if required
* Assurance that all new materials have been notified to the competent authorities
* Classification and labeling information for transport and use
Process environmental assessment.
1.3 TT1
The objectives of this phase are to:
* Provide an opportunity to ‘rehearse’ the work to be carried out during the
‘Process Validation’ phase
* Provide samples for bioavailability studies (where relevant), stability studies,
and registration purposes.
* Confirm [where used] the suitability of local suppliers of primary packaging
to be used in the ‘Establishment Phase’.
* Confirm the commercial manufacturing processes, together with primary
packaging and quality control procedures / specifications to be registered.
Manufacture should not commence until all the Pre TT documentation has been provided to
the ‘receiving site’ and MCM approval for the proposed sourcing changes have been
supported.
1.3.1 Process, Primary Packaging and Quality Control Procedures ‘Freeze’
Processes, packaging and quality control procedures transferred by the ‘transferring site’ and
accepted by the ‘receiving site’ should be changed only under exceptional circumstances.
Proposed changes to be made subsequently to the ‘TT1 manufacture should be agreed
between the two sites and submitted to the MCM Team by the ‘PIPM for its approval. No such
change should be implemented without the prior approval through the MCM Process
1.3.2 Responsibilities during TT1
Manufacturing activities should be organized broadly as described below. Additional support
may be provided by R&D to the extent agreed in the IPTP. Established site procedures
for the production of experimental protocols should be used where these exist.
The ‘receiving site’ should produce experimental protocols. The ‘transferring site’
and the ‘receiving site’ should approve them.
The ‘Receiving site PIPM Manager’ should ensure that an adequate quantity of
suitable quality bulk drug is provided to the ‘receiving site’.
Raw materials and packaging should be procured, tested and released by the
‘receiving site’.
The ‘receiving site’ should produce master batch documentation using approved
site procedures.
The ‘receiving site’ should be responsible for EHS assessments, plant availability,
GMP compliance [including deviation reporting during manufacture and plant
cleaning following manufacture].
The ‘receiving site’ should carry out the manufacture, in process testing, quality
control and packing under the guidance of the ‘transferring site’ and in line with
local protocols and procedures
The ‘receiving site’ should be responsible for the production of ‘registration
samples’, for the markets to which it will supply packed stock for commercial use.
At the discretion of the ‘receiving site’ QA department, the batches made during
the TT1 manufacture may be released for commercial use, following successful
completion of the ‘Validation’ phase and the receipt of appropriate regulatory
approvals for the change in sourcing.
Procurement of raw materials should be organized as follows:
| Material | Procurement | Quality Control | ||||
| Responsible | Order | Approval | Responsible | Order | Approval | |
| Drug Substance | Receiving site | Receiving site | Receiving site | Receiving site | Receiving site | API site |
| Excipient with existing site use | Receiving site | Receiving site | Receiving site | Receiving site | Receiving site | Receiving site |
| Excipient with no existing site use | Receiving site | Receiving site | Receiving site | Transferring/ Receiving site | Transferring site | Receiving site |
Note 1: If DS is supplied from one EU site to another, there is no requirement for the ‘receiving site’
to retest. Product may be accepted on a C of A [except in France, at present]
The ‘receiving site’ QA department should also be responsible, when relevant, for
ensuring that appropriate quantities of the DP to be used in any bioequivalence
studies are retained, so that regulatory requirements are met.
The ‘receiving’ site should carry out all quality control tests on the finished
products [assuming that all methodology has been transferred].
The Commercial Stability Centre QA department [See also Appendix 1.2 above]
should be responsible for all stability studies carried out on product manufactured
at the ‘receiving’ site, commencing with the commercial [‘commitment’] batches.
DMG should be responsible for identifying stability needs for registration
purposes and recording these in the Stability Master Plan.
The ‘receiving’ site QA department should be responsible for the subsequent
release of the finished product for commercial use (if appropriate).
The ‘receiving’ site should keep batch records and information on key process
parameters examined during TT1. As the batch record document and plant
recording systems may not be finalized, it is important to record and archive all
relevant parameters
Responsibilities for this phase of development are shown in the Table below:
| TT1 Activity | Accountable | Responsible / Approval * |
| Manufacture | ‘Transferring’ site | ‘Receiving’ site |
| Analysis | ‘Transferring’ site | ‘Receiving’ site |
| Release | ‘Transferring’ site | ‘Receiving’ site |
| TT1 protocols | ‘Transferring’ site | ‘Receiving’ site |
| Analytical methods | ‘Transferring’ site | ‘Receiving’ site |
| Analytical methods TT protocols | ‘Transferring’ site | ‘Receiving’ site |
| Analytical methods establishment report | ‘Transferring’ site | ‘Receiving’ site |
| TT1 report | ‘Transferring’ site | ‘Receiving’ site |
* Approval refers to documents / reports
* Testing of cleaning is the responsibility of the ‘receiving’ site.
* Detailed guidance on responsibilities for packaging TT is provided in the Packaging
Guideline
1.3.3 TT1 Report
The ‘receiving site’ should produce a report at the completion of TT1. Both the ‘receiving
site’ and the ‘transferring site’ should approve the report. QA at both sites should be included
in the report sign off. The key information to be included in the report is:
* Number of batches manufactured and commentary on usage eg bioequivalence,
stability, commercial etc
* Summary of processing conditions used, changes made during TT1 and rationale
* Sample plan / samples taken.
* Results of in-process tests.
* Cleaning.
* Review of critical parameters and confirmation of acceptable ranges.
* Results of drug product tests.
* Review of processes used in TT1 to ensure an understanding of similarities and
differences from those being transferred.
* Discussion section to include
* Manufacturability issues
* List of changes needing approval from the MCM system
* Conclusions and outstanding issues.
* Recommendations for protocols to be used during TT2.
1.3.4 Statement of ‘Readiness to progress to the Process Validation Phase’
Following issue of the TT1 Report, the ‘transferring site’, the ‘receiving site’, and when
appropriate, R&D, should review the success of the transfer of the manufacturing
process, quality control procedures, stability data [where appropriate] and specifications as
outlined in the IPTP.
A brief summary report should be prepared by the ‘receiving site’ and be approved by the site
PIPMs and QA managers of both ‘transferring’ and ‘receiving sites’ as defined in the IPTP.
This will confirm the ‘receiving site’ readiness to proceed to the ‘Process Validation’ phase
[TT2].
1.4 TT2 – PROCESS VALIDATION
The objective of this phase is to provide documented evidence that the processes used to
manufacture the product provide a high degree of assurance that the product will
consistently meet its pre-determined specifications and quality attributes throughout its
registered shelf life.
1.4.1 TT2 Protocols
TT2 protocols should be prepared by the ‘receiving’ site and approved by both’ transferring’
and ‘receiving’ sites. [signature to include QA at both sites]
1.4.2 Responsibilities during TT2 manufacture
Validation of the manufacturing process should commence at the ‘receiving’ site at a time as
defined in the IPTP. The on-site preparations and manufacturing activities should be
organized broadly as follows:
* Process validation protocols should have been considered by both ‘transferring’
and ‘receiving’ sites prior to completion of TT1. At the time(s) required by the
product specific plan, these protocols should be finalised and approved by both
sites; the ‘receiving’ site should issue the protocol.
* Master batch documentation should be produced using ‘receiving’ site procedures
and be approved using normal site procedures.
* The ‘receiving’ site should be responsible for SHE assessments, plant availability,
GMP compliance [including deviation reporting during manufacture, and plant
cleaning following manufacture].
* The ‘receiving’ site should carry out the manufacture and in-process tests in line
with agreed protocols
* The ‘receiving’ site should carry out all quality control tests on the drug product.
* The Commercial Stability Centre QA department shall be responsible for all
commercial stability studies carried out, commencing with the validation batches.
* The ‘receiving’ site should be responsible for the release of the drug product for
commercial use.
The ‘receiving’ site should keep all batch records and information on manufacture
and analytical testing in line with site procedures.
Responsibilities for this phase of development are shown in the Table below:
| TT2 Activity | Accountable | Author | Responsible/Approval * |
| Manufacture | ‘Receiving’ site | N/A | ‘Receiving’ site |
| Analysis | ‘Receiving’ site | N/A | ‘Receiving’ site |
| Release | ‘Receiving’ site | N/A | ‘Receiving’ site |
| Stability – commercial | ‘Lead’ site | N/A | ‘Lead’ site |
| TT2 protocols | ‘Receiving’ site | ‘Receiving’ site | Both sites |
| TT2 report | ‘Receiving’ site | ‘Receiving’ site | Both sites |
* Approval refers to documents / reports
Raw materials
Procurement of drug substance and excipients should be the responsibility of the ‘receiving’
site in all cases as follows:
| Material | Procurement | Quality Control | ||||
| Responsible | Order | Approval | Responsible | Order | Approval | |
| Drug substance | Site | Site | Site | Site | Site | Site |
| Excipient with existing site use | Site | Site | Site | Site | Site | Site |
| Excipient with no existing site use | Site | Site | Site | Site | Site | Site |
1.4.3 TT2 Reports
The ‘transferring and receiving sites ‘should jointly issue a TT2 Report covering all aspects
of the technology transfer. This report should confirm the successful validation of the
product in the ‘receiving site’; a comparison of the stability profile generated from
commercial stability studies of the product produced at both sites should be included, to
confirm consistency in quality. The report should be approved by both ‘transferring’ and
‘receiving’ sites, and if completed prior to any pre-approval inspections by regulatory
agencies, should be available for reference.
Note 1: There is no regulatory requirement for TT2 to be completed prior to any regulatory
submission. However, it must be completed before any product from the ‘receiving
site’ is supplied to the market.
1.4.4 Manufacturing Change Management Process (MCM)
The overall technology transfer process to the ‘receiving site’ shall only be regarded as
complete when ‘Process Validation’ has been successfully completed and approved by the
‘receiving site’, regulatory submissions made and approved by the regulatory authorities in
the designated markets and the project approved and signed off in the MCM database.
1.4.5 Project Review
At the completion of the TT, the key performance indicators established as part of the project
and any performance improvement / manufacturability recommendations should be reviewed
and appropriate follow up actions and responsibilities agreed
APPENDIX 2
TECHNOLOGY TRANSFERS TO ‘CONTRACTORS’
In principle, technology transfers between transferring site and managed contractors will be
conducted as described above, with the following exceptions:
The technology transfer activities should proceed only after the contractor’s
facilities and procedures have been audited by an appropriate Site QA unit and
have been approved.
The responsibility for carrying out the various activities in the technology transfer
strategy should be the subject of a contractual agreement between transferring site
and the ‘contractor’.
The currently registered process/methods etc. should be given to the contractor,
so that compliance can be maintained. It must also be ensured that the contractor
understands/knows what might be audited/inspected against. The contractor
should be given the regulatory documents with which it is expected to comply.
However, the information supplied to the contractor should be restricted to that
required for transferring site to discharge its ‘duty of care’ responsibilities and to
allow the contractor to carry out manufacture safely, to the required standard and
in compliance with product licenses. Quality control methods transferred should
be the minimum required to demonstrate conformance with the contractual
specifications.
The ongoing manufacturing responsibilities should be the subject of a written
contract between transferring site, contractor and any sites involved in ongoing
supply and/or QA activities.
All documentation should be routed through ‘ Project Manager’. On completion
of the transfer the PM should lodge a copy of all such documentation /correspondence
with the DMG.
APPENDIX 3
CONTENTS OF A TYPICAL ‘INTEGRATEDL PRODUCT TRANSFER PLAN’ [IPTP]
Introduction and Objectives
Describe the product for transfer
Roles and responsibilities of the sites post TT
Countries affected by the change
Success criteria
Outline approach for technology transfer
Scope of the manufacturing activities to be transferred
Scope of quality control transfers
The alternative/additional-sourcing site (the ‘receiving site’)
The currently established site (the ‘transferring site’) which will provide the
technology to the alternative/additional site
Extent of R&D involvement
The proposed route for transfer of technical information, taking into account any
legal issues
Special features
Atypical requirements
Site specific issues
Materials
Drug substance properties
(Basic physicochemical characteristics of the drug substance [name, formula
structure, molecular wt, chirality, physical form, solubility, melting point etc.] DS
specification features relevant to DP processing)
Special excipients / raw material requirements
Different drug substance flavours and how to manage including link with regulatory
Aspects
Facility / equipment provision
Assessment of facility/equipment [process and quality] requirements
Capital/ revenue requirements
Technical assessment of significance of equipment differences from those currently used for manufacture.
Accountabilities / Responsibilities
Document preparation, signature, analytical testing, microbiological requirements and
product release
EHS
Safety and toxicology data – Include summary info such as MED/NED etc for
cleaning validation, OEL, any special features such as low ignition energy.
EHS safety package
Outline cleaning issues and recommendations for managing.
Quality Assurance
QC Testing and release principles
Change Control Strategy
Proposed changes from currently approved equipment/process/QA procedures
Regulatory
Interface with Manufacturing Change Management Group
Review of license compliance at the ‘transferring site’
Product license update, master file updates
Manufacturing license update and Pre-Approval Inspections
Chemistry and pharmacy packages to support regulatory submissions
High Level Documentation Plan
Indicate the documents to be supplied during Pre TT, TT1 and TT2
Supply Strategy
Use of product made during technology transfer activities
Key Milestones
Criteria for Completion
APPENDIX 4
SCHEMATIC OUTLINE
TECHNOLOGY TRANSFERS BETWEEN BULK FORMULATION SITES
INTEGRATED PRODUCT TRANSFER PLAN
|
|
|
SITE PREPARATIONS FOR MANUFACTURE
|
|
TT1
| <- — — DEVELOPMENT REPORT, PRODUCT REVIEW AND
| REGULATORY INFORMATION
| <- — — QUALITY CONTROL TRANSFER
|
TRANSFER DOCUMENTS AND PROTOCOLS
|
MANUFACTURE
|
TT1 REPORT
|
|
STATEMENT OF READINESS TO PROGRESS TO THE PROCESS
VALIDATION PHASE (I.E. PROCESS, QC & PRIMARY PACK)
|
TT2 [VALIDATION] PHASE
|
|
VALIDATION PROTOCOLS
|
|
VALIDATION REPORT
NOTE: ONLY THOSE VALIDATION DOCUMENTS REQUIRED TO DEMONSTRATE SUCCESSFUL
COMPLETION OF TECHNOLOGY TRANSFER ARE INCLUDED ABOVE