ISPE Good Practice Guide: Technology Transfer© Copyright ISPE 2003.
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TECHNOLOGY TRANSFER
Fred Sexton KOS Pharmaceuticals Inc. Chairman
Technology Transfer Task Team
Contributor Company Core Area
Randy Dias Novartis Pharmaceuticals Corp. Facilities and Post Approval Transfer
Fred Fricke U.S. FDA Analytical Methods
Tony Barcia Johnson & Johnson Analytical Methods
Georgia Keresty Bristol-Myers Squibb Co. Dosage Forms
Larry Kranking Eisai Inc. Japanese Liaison
Brian Laundon GlaxoSmithKline APIs
Bernadette Doyle GlaxoSmithKline APIs
Lou Schmuckler Geneva Pharmaceuticals Inc. Quality Assurance
Alpaslan Yaman Purdue Pharma LP AAPS Liaison
Contributors to the Technology Transfer Guide
Carl Baker Purdue Pharma LP
Paul Butterly GlaxoSmithKline
Frank Diana Dupont Merck
Terry Dwyer Johnson & Johnson
Larry Hagerman Boehringer-Ingelheim (comments compiled from reviewers at various OPUs within Boehringer-Ingelheim)
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Dean Kimbaris Noramco Inc.
Nick Montefusco Schering-Plough Corp.
Brian Sherry Noramco Inc.
Guenter Solms Noramco Inc.
Carl Symecko Pfizer Inc.
Chris Williamson GlaxoSmithKline
Lino Tavares Purdue Pharma LP
Tony Tutino Novartis Pharmaceuticals Corp.
The Technology Transfer Task Team would like to thank the following for their contribution to the process of the development of this Guide.
Joe Phillips ISPE
Phil Nethercoat GlaxoSmithKline
Ken Bassler Aventis
Paul Titley Quintiles
1.3 SCOPE ................................................................................................................................. 10 1.4 DEFINITIONS ....................................................................................................................... 11
2 TECHNOLOGY TRANSFER PLANNING AND SUCCESS CRITERIA
2.1 TECHNOLOGY TRANSFER SUCCESS CRITERIA ............................................................. 17 2.1.1 Experience and Knowledge Capture During Transfer ............................................... 19
3 ANALYTICAL METHODS/TECHNOLOGY TRANSFER
3.1 OBJECTIVE .......................................................................................................................... 23 3.2 SCOPE ................................................................................................................................. 23 3.3 RESPONSIBILITIES ............................................................................................................. 23 3.4 PROCEDURE ....................................................................................................................... 24
3.4.1 Methods to be Transferred ........................................................................................ 24 3.4.2 Pre-transfer Activities ............................................................................................... 24 3.4.3 Transfer Protocol ...................................................................................................... 24 3.4.4 Transfer Report ......................................................................................................... 25
3.5 EXPERIMENTAL DESIGN/ACCEPTANCE CRITERIA .......................................................... 26 3.5.1 Assay ....................................................................................................................... 26 3.5.2 Content Uniformity .................................................................................................... 26 3.5.3 Impurities/Degradation Products/Residual Solvents ................................................. 26 3.5.4 Dissolution ................................................................................................................ 27 3.5.5 Identification ............................................................................................................. 27 3.5.6 Automated Methods ................................................................................................. 28 3.5.7 Cleaning Verification ................................................................................................. 28 3.5.8 Microbiological Testing .............................................................................................. 29 3.5.9 Dose Delivery ........................................................................................................... 29 3.5.10 Particle Size ............................................................................................................. 32
3.6 ALTERNATE APPROACHES ................................................................................................ 34
4.1 INTRODUCTION................................................................................................................... 35 4.2 SYNTHESIS, ROUTE, AND FORM SELECTION ................................................................. 35
4.2.1 Introduction .............................................................................................................. 35 4.2.2 Synthetic Route ........................................................................................................ 35 4.2.3 Rationale for Selection of Route and Form ............................................................... 36 4.2.4 Other Routes Considered ......................................................................................... 36
4.3 STABILITY DATA ................................................................................................................... 36 4.3.1 Quality Profile and Specifications ............................................................................. 36 4.3.2 Site Specific Stability Data - APIs ............................................................................. 37
4.4 RAW MATERIALS, STARTING MATERIALS, REAGENTS, AND CATALYSTS (PROCESS MATERIALS)...................................................................................................... 39 4.4.1 Approved Suppliers .................................................................................................. 39
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4.5 HEALTH, SAFETY, AND ENVIRONMENTAL INFORMATION ............................................... 40 4.5.1 Health, Safety and Environmental Assessment of all Inputs, Outputs,
By-Products, and Wastes ......................................................................................... 40 4.5.2 Health and Safety Assessment of the Processes Used for Conversion .................... 42 4.5.3 Environmental Assessment of all Materials and the Process .................................... 42
4.6 PROCESS INFORMATION ................................................................................................... 43 4.6.1 Detailed Manufacturing Process Description ............................................................ 44 4.6.2 Plant Operating Procedures (Batch Instructions) ...................................................... 44 4.6.3 In-Process Controls .................................................................................................. 44 4.6.4 Detailed Characterization of APIs and Intermediates ............................................... 44 4.6.5 Chronology of Process Development ....................................................................... 47 4.6.6 Process Capability and Statistical Process Control .................................................. 47 4.6.7 Critical Aspects ........................................................................................................ 47 4.6.8 Batch and Campaign Histories/Pedigrees ................................................................ 47 4.6.9 Comparison of Biobatches with Subsequent Batches .............................................. 47 4.6.10 Cleaning Procedures ................................................................................................ 47
4.7 EQUIPMENT DESCRIPTION ............................................................................................... 48 4.7.1 Description of Major Process Items, Design Intent, and Capability ........................... 48
4.8 PACKAGING COMPONENT SPECIFICATIONS ................................................................... 48 4.8.1 Specifications ........................................................................................................... 48 4.8.2 Suitability/Compatibility ............................................................................................. 49 4.8.3 Regulatory Requirements and Guidelines for Label Content .................................... 49
4.9 FACILITY REQUIREMENTS ................................................................................................. 49 4.10 QUALIFICATION AND VALIDATION ...................................................................................... 49
4.10.1 Validation Plan .......................................................................................................... 49 4.10.2 Qualification of Plant, Process, and Product ............................................................. 50 4.10.3 Cleaning Validation ................................................................................................... 50 4.10.4 Computer Validation ................................................................................................. 50
4.11 SUCCESS CRITERIA (API SPECIFIC) ................................................................................. 50 4.11.1 Contract of Deliverables ........................................................................................... 50 4.11.2 Business Acceptance Criteria................................................................................... 50 4.11.3 Deliverables During Routine Manufacture (Aftercare) ............................................... 51
5 DOSAGE FORM (CLINICAL SUPPLIES AND COMMERCIAL PRODUCT)
5.1 INTRODUCTION................................................................................................................... 53 5.2 STABILITY DATA ................................................................................................................... 54
5.2.1 Quality Profile and Specifications: Chemical, Physical, and Microbiological ............. 54 5.2.2 Site Specific Data ..................................................................................................... 54
5.3 APIs, EXCIPIENTS, AND RAW MATERIALS ........................................................................ 56 5.3.1 Active Pharmaceutical Ingredients (APIs) ................................................................. 56 5.3.2 Excipients ................................................................................................................. 58 5.3.3 Oral Solid Dosage Form Excipients .......................................................................... 59 5.3.4 Parenteral Dosage Form Excipients ......................................................................... 60 5.3.5 Semi-Solid/Topical Dosage Form Excipients ............................................................ 61 5.3.6 Liquid Dosage Form Excipients ................................................................................ 61 5.3.7 Transdermal Dosage Form Excipients ...................................................................... 62 5.3.8 Inhalation Dosage Form Excipients .......................................................................... 63
5.4 HEALTH, SAFETY, AND ENVIRONMENTAL INFORMATION ............................................... 64 5.4.1 Health and Safety Assessment of all Materials, Products, and the Process ............. 64
5.5 PROCESS INFORMATION ................................................................................................... 65 5.5.1 Detailed Characterization of Product ........................................................................ 65 5.5.2 Chronology of Process Development ....................................................................... 65
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5.5.3 Process Capability and Statistical Process Control .................................................. 66 5.5.4 General Aspects ....................................................................................................... 67 5.5.5 Critical Aspects by Dosage Form ............................................................................. 67 5.5.6 Detailed Manufacturing Process Description ............................................................ 71 5.5.7 Plant Operating Procedures/Documents .................................................................. 72 5.5.8 Cleaning Procedures ................................................................................................ 73 5.5.9 Regulatory Requirements ......................................................................................... 74
5.6 EQUIPMENT DESCRIPTION ............................................................................................... 75 5.6.1 Description of Major Process Items, Design Intent, and Capability ........................... 75 5.6.2 Standard Operating Procedures ............................................................................... 75
5.7 PACKAGING COMPONENT SPECIFICATIONS ................................................................... 75 5.7.1 Specifications ........................................................................................................... 75 5.7.2 Suitability .................................................................................................................. 76 5.7.3 MDI/DPI .................................................................................................................... 79 5.7.4 Labeling .................................................................................................................... 79 5.7.5 General Considerations ............................................................................................ 80 5.7.6 Rationale for Package Design .................................................................................. 80 5.7.7 Packaging Operational Considerations ..................................................................... 80
5.8 FACILITY REQUIREMENTS ................................................................................................. 81 5.9 QUALIFICATION AND VALIDATION ...................................................................................... 81
5.9.1 Qualification of the Equipment .................................................................................. 81 5.9.2 Validation Plan .......................................................................................................... 82 5.9.3 Validation of Process ................................................................................................ 82 5.9.4 Cleaning Validation ................................................................................................... 83 5.9.5 Computer Validation ................................................................................................. 84
6 REFERENCES .................................................................................................................................. 85
ATTACHMENTS
Template 1: Example of an EC Supply Label (Nitric Acid) .............................................................. 89
Template 2: HSE Checklist - General Facilities .............................................................................. 90
Template 3: HSE Data Checklist - Detailed .................................................................................... 93
Template 4: Checklist for Technology Transfer of New, Existing, and Third Party Products ............ 96
Template 5: Transfer of Analytical Procedures ............................................................................. 102
Template 6: Data Report Form: Identification (IR) ........................................................................ 105
Template 7: Data Report Form Assay: System Suitability (Resolution) ........................................ 106
Template 8: Data Report Form Assay: System Suitability (Precision) .......................................... 107
Template 9: Method Transfer from the ABC Laboratory (Sending) to XYZ Laboratories (Receiving) ............................................................................... 108
Template 10: Method Validation Protocol: Sterility Test ................................................................... 112
Template 11: Validation Protocol .................................................................................................... 115
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INTRODUCTION
1 INTRODUCTION
The quality of pharmaceutical products is dependant on the development of robust manufacturing processes that allow the consistent and predictable operation of those processes, in accordance with cGMP, and facili- tate ease of validation.
The availability of an extensive information set, which defines, in detail, all relevant activities that need to be performed to manufacture, control, and measure a quality product is fundamental to achieving robust manu- facturing processes. The information set is compiled during the development of the process and supple- mented and updated as experience is acquired.
It is critical to the manufacture of a pharmaceutical product that those involved in that manufacture have access to the most relevant and up-to-date information. Technology transfer is the process for ensuring that this information is available when and where required.
The ISPE Technology Transfer Guide has been designed to present a standardized process and recom- mends a minimum base of documentation in support of the transfer request. The Guide is divided into three principal segments:
• Analytical Methods
• Dosage Forms
Based on industry need, ISPE, with input from the U.S. Food and Drug Administration (FDA), European regulatory authorities including the UK’s MCA, Health Canada, the American Association of Pharmaceutical Scientists (AAPS), and the Japanese Society of Pharmaceutical Machinery and Engineering (JSPME), have created a user-friendly document that presents a clear and concise, general process for transferring technol- ogy between two parties.
1.1 BACKGROUND
The cost and time required to transfer technology, in many cases, has risen due to inconsistent interpretation of regulatory requirements. The ISPE and technical representatives from a broad base of healthcare compa- nies (e.g., pharmaceutical, device, biotechnology) recognized the need to develop guidance in the area of technology transfer. The guidance provided in the ISPE Technology Transfer Guide is the result of the collabo- ration of many individuals representing a broad spectrum of the healthcare industry.
This Guide is intended to define key terms and offer a consistent interpretation, while still allowing a flexible and innovative approach to technology transfer. A fundamental goal of this Guide is to provide value added guidance to industry, which will facilitate timely and cost effective transfer of technology between two parties. Advice and guidance is provided which may be applied to Analytical Methods, APIs, and Dosage Forms, and takes account of requirements in the US, Europe, and Asia.
This Guide has been prepared by ISPE and has incorporated comments from regulators and industry repre- sentatives from all areas and disciplines.
It is recognized that industry standards evolve. The Technology Transfer Guide reflects the understanding of industry standards as of the publication date.
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INTRODUCTION
The objective of the ISPE Technology Transfer Guide is two-fold:
1) To describe the appropriate information set that needs to be compiled to support the transfer of the information and provide regulatory filing documents.
2) To provide guidance on effective approaches for ensuring this information is available at ‘point of use’. Where guidance on specific topics already exists this will be referenced.
The ISPE Technology Transfer Guide is, by its nature, interpretive and ISPE cannot ensure, and does not warrant, that a technology transfer performed in accordance with the recommendations in this Guide will be acceptable to regulatory authorities.
1.2.1 Communication
While it is critical that information is provided in appropriate documentation packs, the success of technology transfer is largely related to the communication and relationships between key personnel in technology trans- fer teams. At the start of a technology transfer, it may be useful to spend time defining key roles and respon- sibilities of specific transfer team members, who are responsible and accountable for key components of the transfer, and defining communication channels and methods (e.g., reports) to effect this transfer of informa- tion.
1.2.2 Life Cycle
Technology Transfer expectations are different during the different phases of the life cycle of a product. This Guide addresses the transfer of technology from a Sending Unit to a Receiving Unit. In order to be a manage- able and useful tool it assumes all work done prior to initiating a transfer is adequate for that stage of the transferring methods, products, or processes life cycle. It further assumes that the level of detail and depth of information transferred will increase for each successive transfer step.
1.3 SCOPE
This Guide applies to the transfer of expertise and technology associated with Analytical Methods, APIs, and Dosage Forms. It is intended to be useful from the earliest phases in a product’s life cycle through to, and including, post approval transfers (see Figure 1.1). It is intended to provide guidance and insight into the essential activities and documentation required to move a product, process, or method from one unit to another. This document is equally applicable to innovator and generic products, as well as technologies originating from any region of the globe.
The relationship between development activities, technology transfer, and validation tasks warrants clarifica- tion with regard to using this Guide. It is assumed that development and optimization are dynamic as they relate to the life cycle of a product, process, or method, and as a result the baseline level of specifications or performance criteria will progressively improve. For the purpose of this guidance, development activities are expected to be adequately complete, for the specific stage in the life cycle, and appropriately documented prior to initiation of transfer. Technology transfer is the systematic means of conveying ability, documentation, equipment, skills, and systems between parties. Validation or verification, as the case may be, is the tool to be used to confirm consistent performance against the then current baseline specifications.