Manual – 078 Technology Transfer of Established Medicine from One Commercial Site to Other

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:

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:

 – 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:

 – 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:

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