ISPE Guide Technology Transfer

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ISBN 1-931879-88-5

TECHNOLOGYTRANSFER





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TECHNOLOGY TRANSFER

ACKNOWLEDGEMENTS

Technology Transfer Task Team Chairperson

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

Rich Poska Abbott Laboratories Regulatory/Stability

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

D. Phillip Cox Noramco Inc.

Frank Diana Dupont Merck

Steve Drucker Schering-Plough Technical Operations

Terry Dwyer Johnson & Johnson

Ed Elder Dow Chemical Co.

Bohdan M. Ferenc Bio-Pharma Technologies

Larry Hagerman Boehringer-Ingelheim (comments compiled from reviewers at various OPUs withinBoehringer-Ingelheim)





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TECHNOLOGY TRANSFER

Agber Ifan Pfizer Inc.

Pedro Jimenez Eli Lilly & Co.

Alex Jurgens Sepracor Canada Limited

Dean Kimbaris Noramco Inc.

Sonia D. McKelvy McNeil Consumer and Specialty Pharmaceuticals

Nick Montefusco Schering-Plough Corp.

Greg Needham Eli Lilly & Co.

John Peragine Bristol-Myers Squibb Co.

Brian Sherry Noramco Inc.

Guenter Solms Noramco Inc.

Carl Symecko Pfizer Inc.

Jim Tanguay KOS Pharmaceuticals Inc.

Chris Williamson GlaxoSmithKline

Karen Wolnik U.S. FDA

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 theprocess of the development of this Guide.

Joe Phillips ISPE

Phil Nethercoat GlaxoSmithKline

Ken Bassler Aventis

Paul Titley Quintiles





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TABLE OF CONTENTS

ACKNOWLEDGEMENTS .......................................................................................................................... 2

1 INTRODUCTION

1.1 BACKGROUND....................................................................................................................... 91.2 OBJECTIVE .......................................................................................................................... 10

1.2.1 Communication ........................................................................................................ 101.2.2 Life Cycle .................................................................................................................. 10

1.3 SCOPE ................................................................................................................................. 101.4 DEFINITIONS ....................................................................................................................... 11

2 TECHNOLOGY TRANSFER PLANNING AND SUCCESS CRITERIA

2.1 TECHNOLOGY TRANSFER SUCCESS CRITERIA ............................................................. 172.1.1 Experience and Knowledge Capture During Transfer ............................................... 19

3 ANALYTICAL METHODS/TECHNOLOGY TRANSFER

3.1 OBJECTIVE .......................................................................................................................... 233.2 SCOPE ................................................................................................................................. 233.3 RESPONSIBILITIES ............................................................................................................. 233.4 PROCEDURE ....................................................................................................................... 24

3.4.1 Methods to be Transferred ........................................................................................ 243.4.2 Pre-transfer Activities ............................................................................................... 243.4.3 Transfer Protocol ...................................................................................................... 243.4.4 Transfer Report ......................................................................................................... 25

3.5 EXPERIMENTAL DESIGN/ACCEPTANCE CRITERIA .......................................................... 263.5.1 Assay ....................................................................................................................... 263.5.2 Content Uniformity .................................................................................................... 263.5.3 Impurities/Degradation Products/Residual Solvents ................................................. 263.5.4 Dissolution ................................................................................................................ 273.5.5 Identification ............................................................................................................. 273.5.6 Automated Methods ................................................................................................. 283.5.7 Cleaning Verification ................................................................................................. 283.5.8 Microbiological Testing .............................................................................................. 293.5.9 Dose Delivery ........................................................................................................... 293.5.10 Particle Size ............................................................................................................. 32

3.6 ALTERNATE APPROACHES ................................................................................................ 34

4 ACTIVE PHARMACEUTICAL INGREDIENTS (APIs)

4.1 INTRODUCTION................................................................................................................... 354.2 SYNTHESIS, ROUTE, AND FORM SELECTION ................................................................. 35

4.2.1 Introduction .............................................................................................................. 354.2.2 Synthetic Route ........................................................................................................ 354.2.3 Rationale for Selection of Route and Form ............................................................... 364.2.4 Other Routes Considered ......................................................................................... 36

4.3 STABILITY DATA ................................................................................................................... 364.3.1 Quality Profile and Specifications ............................................................................. 364.3.2 Site Specific Stability Data - APIs ............................................................................. 37

4.4 RAW MATERIALS, STARTING MATERIALS, REAGENTS, AND CATALYSTS(PROCESS MATERIALS)...................................................................................................... 394.4.1 Approved Suppliers .................................................................................................. 39





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TABLE OF CONTENTS

4.5 HEALTH, SAFETY, AND ENVIRONMENTAL INFORMATION ............................................... 404.5.1 Health, Safety and Environmental Assessment of all Inputs, Outputs,

By-Products, and Wastes ......................................................................................... 404.5.2 Health and Safety Assessment of the Processes Used for Conversion .................... 424.5.3 Environmental Assessment of all Materials and the Process .................................... 42

4.6 PROCESS INFORMATION ................................................................................................... 434.6.1 Detailed Manufacturing Process Description ............................................................ 444.6.2 Plant Operating Procedures (Batch Instructions) ...................................................... 444.6.3 In-Process Controls .................................................................................................. 444.6.4 Detailed Characterization of APIs and Intermediates ............................................... 444.6.5 Chronology of Process Development ....................................................................... 474.6.6 Process Capability and Statistical Process Control .................................................. 474.6.7 Critical Aspects ........................................................................................................ 474.6.8 Batch and Campaign Histories/Pedigrees ................................................................ 474.6.9 Comparison of Biobatches with Subsequent Batches .............................................. 474.6.10 Cleaning Procedures ................................................................................................ 47

4.7 EQUIPMENT DESCRIPTION ............................................................................................... 484.7.1 Description of Major Process Items, Design Intent, and Capability ........................... 48

4.8 PACKAGING COMPONENT SPECIFICATIONS ................................................................... 484.8.1 Specifications ........................................................................................................... 484.8.2 Suitability/Compatibility ............................................................................................. 494.8.3 Regulatory Requirements and Guidelines for Label Content .................................... 49

4.9 FACILITY REQUIREMENTS ................................................................................................. 494.10 QUALIFICATION AND VALIDATION ...................................................................................... 49

4.10.1 Validation Plan .......................................................................................................... 494.10.2 Qualification of Plant, Process, and Product ............................................................. 504.10.3 Cleaning Validation ................................................................................................... 504.10.4 Computer Validation ................................................................................................. 50

4.11 SUCCESS CRITERIA (API SPECIFIC) ................................................................................. 504.11.1 Contract of Deliverables ........................................................................................... 504.11.2 Business Acceptance Criteria................................................................................... 504.11.3 Deliverables During Routine Manufacture (Aftercare) ............................................... 51

5 DOSAGE FORM (CLINICAL SUPPLIES AND COMMERCIAL PRODUCT)

5.1 INTRODUCTION................................................................................................................... 535.2 STABILITY DATA ................................................................................................................... 54

5.2.1 Quality Profile and Specifications: Chemical, Physical, and Microbiological ............. 545.2.2 Site Specific Data ..................................................................................................... 54

5.3 APIs, EXCIPIENTS, AND RAW MATERIALS ........................................................................ 565.3.1 Active Pharmaceutical Ingredients (APIs) ................................................................. 565.3.2 Excipients ................................................................................................................. 585.3.3 Oral Solid Dosage Form Excipients .......................................................................... 595.3.4 Parenteral Dosage Form Excipients ......................................................................... 605.3.5 Semi-Solid/Topical Dosage Form Excipients ............................................................ 615.3.6 Liquid Dosage Form Excipients ................................................................................ 615.3.7 Transdermal Dosage Form Excipients ...................................................................... 625.3.8 Inhalation Dosage Form Excipients .......................................................................... 63

5.4 HEALTH, SAFETY, AND ENVIRONMENTAL INFORMATION ............................................... 645.4.1 Health and Safety Assessment of all Materials, Products, and the Process ............. 64

5.5 PROCESS INFORMATION ................................................................................................... 655.5.1 Detailed Characterization of Product ........................................................................ 655.5.2 Chronology of Process Development ....................................................................... 65





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TABLE OF CONTENTS

5.5.3 Process Capability and Statistical Process Control .................................................. 665.5.4 General Aspects ....................................................................................................... 675.5.5 Critical Aspects by Dosage Form ............................................................................. 675.5.6 Detailed Manufacturing Process Description ............................................................ 715.5.7 Plant Operating Procedures/Documents .................................................................. 725.5.8 Cleaning Procedures ................................................................................................ 735.5.9 Regulatory Requirements ......................................................................................... 74

5.6 EQUIPMENT DESCRIPTION ............................................................................................... 755.6.1 Description of Major Process Items, Design Intent, and Capability ........................... 755.6.2 Standard Operating Procedures ............................................................................... 75

5.7 PACKAGING COMPONENT SPECIFICATIONS ................................................................... 755.7.1 Specifications ........................................................................................................... 755.7.2 Suitability .................................................................................................................. 765.7.3 MDI/DPI .................................................................................................................... 795.7.4 Labeling .................................................................................................................... 795.7.5 General Considerations ............................................................................................ 805.7.6 Rationale for Package Design .................................................................................. 805.7.7 Packaging Operational Considerations ..................................................................... 80

5.8 FACILITY REQUIREMENTS ................................................................................................. 815.9 QUALIFICATION AND VALIDATION ...................................................................................... 81

5.9.1 Qualification of the Equipment .................................................................................. 815.9.2 Validation Plan .......................................................................................................... 825.9.3 Validation of Process ................................................................................................ 825.9.4 Cleaning Validation ................................................................................................... 835.9.5 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 processesthat 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 beperformed 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 haveaccess to the most relevant and up-to-date information. Technology transfer is the process for ensuring thatthis 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 threeprincipal segments:

Analytical Methods

Active Pharmaceutical Ingredients (APIs)

Dosage Forms

Based on industry need, ISPE, with input from the U.S. Food and Drug Administration (FDA), Europeanregulatory authorities including the UKs MCA, Health Canada, the American Association of PharmaceuticalScientists (AAPS), and the Japanese Society of Pharmaceutical Machinery and Engineering (JSPME), havecreated 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 interpretationof 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 oftechnology 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 flexibleand innovative approach to technology transfer. A fundamental goal of this Guide is to provide value addedguidance 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, andtakes 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 ofindustry standards as of the publication date.





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INTRODUCTION

1.2 OBJECTIVE

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 theinformation 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 notwarrant, that a technology transfer performed in accordance with the recommendations in this Guide will beacceptable to regulatory authorities.

1.2.1 Communication

While it is critical that information is provided in appropriate documentation packs, the success of technologytransfer 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 thetransfer, 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. ThisGuide 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 thetransferring methods, products, or processes life cycle. It further assumes that the level of detail and depth ofinformation 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, andDosage Forms. It is intended to be useful from the earliest phases in a products life cycle through to, andincluding, post approval transfers (see Figure 1.1). It is intended to provide guidance and insight into theessential activities and documentation required to move a product, process, or method from one unit toanother. This document is equally applicable to innovator and generic products, as well as technologiesoriginating 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 theyrelate to the life cycle of a product, process, or method, and as a result the baseline level of specifications orperformance criteria will progressively improve. For the purpose of this guidance, development activities areexpected to be adequately complete, for the specific stage in the life cycle, and appropriately documentedprior 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 beused to confirm consistent performance against the then current baseline specifications.

This document does not explicitly offer specific guidance related to biological products, blood related prod-ucts, medical gasses, and medical devices. The concepts described herein are, however, broadly applicableand may be useful in these areas as well.





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INTRODUCTION

Figure 1.1 Scope of the ISPE Technology Transfer Guide

1.4 DEFINITIONS

Acceptance Criteria

Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures.

A/NDA Batches

Those batches produced, included, or referenced in the filing of a US New Drug Application (NDA) or Abbre-viated New Drug Application (ANDA).

Active Pharmaceutical Ingredient (API)

Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) productand that when used in the production of a drug becomes an active ingredient of the drug product. Suchsubstances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

Automated/Robotic

An automated/robotic method almost exclusively utilizes non-human, mechanical manipulations to preparesamples and analyze them. Typically, weighing, dilutions, filtering, and transferring are mechanically executed.Independent auto-injectors and auto-pipettors alone do not constitute an automated/robotic method.

Bracketing

An experimental design to test only the extremes of, for example, dosage strength. The design assumes theextremes will be representative of all the samples between the extremes.

Commissioning

A well planned, documented, and managed engineering approach to the start-up and turnover of facilities,systems, and equipment to the end-user that results in a safe and functional environment that meets estab-lished design requirements and stakeholder expectations.

Critical

The use of critical within this Guide means that the items have the identified potential to impact productquality or performance in a significant way. There may be other items, not associated with quality or perfor-





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INTRODUCTION

mance, that have a significant impact on, for example, safety, environment, or operations, and these mayneed to be identified as business critical items.

Development Unit

The involved disciplines at an organization that conducted the original development (method, product, orprocess).

Direct Impact System

A system that is expected to have a direct impact on product quality. These systems are designed andcommissioned in line with Good Engineering Practice and, in addition, are subject to Qualification practicesthat incorporate the enhanced review, control, and testing against specifications or other requirements nec-essary for cGMP compliance.

Enhanced Design Review (EDR)

A documented review of the design, at an appropriate stage in a project, for conformance to operational andregulatory expectations.

Enhanced Documentation

Required for Direct Impact systems. Enhanced Documentation may involve additional tests, documentation,QA change control, and QA review and approval.

Expiration Date

As defined in ICH Q1A (R), the date placed on the container label of a drug product designating the time priorto which a batch of the product is expected to remain within the approved shelf life specification, if storedunder defined conditions, and after which it must not be used.

F2

A similarity factor used to compare dissolution profiles: SUPAC Dissolution Testing of Immediate ReleaseSolid Oral Dosage Forms, August 1997.

Good Engineering Practice (GEP)

Established engineering methods and standards that are applied throughout the project life cycle to deliverappropriate, cost-effective solutions.

Impurity

Any entity of the drug substance (API) or drug product (final container product) that is not the chemical entitydefined as the drug substance, an excipient, or other additives to the drug product.

Installation Qualification (IQ)

Documented verification that a system is installed according to written and pre-approved specifications.

Intermediate

A material produced during steps of the processing of an Active Pharmaceutical Ingredient (API) that mustundergo further molecular change or purification before it becomes an API. Intermediates may or may not beisolated.





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INTRODUCTION

Intermediate Drug Product

Especially in chemical drug manufacturing, a drug compound that has not reached the state of final bulkproduct.

Operational Qualification (OQ)

Documented verification that a system operates according to written and pre-approved specifications through-out all specified operating ranges.

Performance Qualification (PQ)

Documented verification that a system is capable of performing or controlling the activities of the processesit is required to perform or control, according to written and pre-approved specifications, while operating in itsspecified operating environment.

pH

A means of expressing hydrogen ion concentration in terms of the powers of 10; the negative logarithm of thehydrogen ion concentration. This is a measure of whether the water is acidic or basic. pH is a measure of thehydrogen ion concentration in the water.

Process Validation (PV)

Establishing documented evidence which provides a high degree of assurance that a specific process willconsistently produce a product meeting its pre-determined specifications and quality attributes.

Q

The time point at which dissolution samples are tested, as described in USP 24 NF19 section .

Qualification

Action of providing evidence that equipment, methods, or ancillary systems are properly installed, workcorrectly, and actually lead to the expected results. Qualification is part of validation, but the individual quali-fication steps alone do not constitute validation.

Qualification Batches

Those batches produced by the Receiving Unit to demonstrate its ability to reproduce the product.

Quality Assurance (QA)

The activity of, or group responsible for, ensuring that all materials, personnel, facilities, and systems are ofthe quality required for their intended use or role, and that effective quality systems are maintained.

Quality Assurance Change Control

Process by which proposed changes to a qualified system are assessed before implementation to determinethe impact on the system. Proposed changes must be approved prior to implementation.

Quality Control (QC)

Checking or testing, that specifications are met, or the regulatory process through which the industry mea-sures actual quality performance, compares it with standards, and acts on the difference.





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INTRODUCTION

Quantitation Limit

The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample thatcan be quantitatively determined with suitable precision and accuracy.

Receiving Unit

The involved disciplines at an organization where a designated product, process, or method is expected to betransferred.

Reporting Limit

The minimum level of an Impurity that must be reported, as defined in ICH Q3B.

Retest Date

As defined in ICH Q1A (R), the date after which samples of the drug substance should be examined toensure that the material is still in compliance with the specification and thus suitable for use in the manufac-ture of a given drug product.

Retest Period

As defined in ICH Q1A (R), the period of time during which the drug substance can be considered to remainwithin the specification and, therefore, acceptable for use in the manufacture of a given drug product, pro-vided that it has been stored under the defined conditions. After this period, the batch should be retested forcompliance with specification and then used immediately. [Immediately will be as defined by the SendingUnit.]

Rf Value

The ratio of the distance moved by a particular solute to that moved by the solvent front.

Sending Unit

The involved disciplines at an organization where a designated product, process, or method is expected to betransferred from.

Standard Operating Procedure (SOP)

Written and approved procedures to ensure that activities are performed the same way each time. A compre-hensive SOP program must be in place in any regulated organization.

Spiking

The addition of a known amount of a compound to a standard, sample or placebo, typically for the purpose ofconfirming the performance of an analytical procedure.

Technology Transfer

The systematic procedure that is followed in order to pass the documented knowledge and experience gainedduring development and/or commercialization to an appropriate, responsible, and authorized party. Technol-ogy transfer embodies both the transfer of documentation and the demonstrated ability of a Receiving Unit toeffectively perform the critical elements of transferred technology, to the satisfaction of all parties and any, orall, applicable regulatory bodies.





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INTRODUCTION

Technology Transfer Documentation

The assembly of data and information as identified by predefined acceptance criteria and provided as adocumentation package, which is prepared and passed from the involved departments of the Sending Unitresponsible for product, process, or method development to a specified Receiving Unit. The ultimate sign-offof the technology transfer documentation by Development Units, Sending Units, and Receiving Units signi-fies mutual agreement among all involved parties that the process and test methodology have been devel-oped and demonstrated as satisfying predefined acceptance criteria.

Validation

A documented program that provides a high degree of assurance that a specific process, method, or systemwill consistently produce a result meeting pre-determined acceptance criteria.

Verification

The act of reviewing, inspecting, testing, checking, auditing, or otherwise establishing and documenting whetheritems, processes, services, or documents conform to specified requirements. (See: Installation Qualification:(IQ))

Acronyms and Abbreviations

ADR European Agreement on the Transport of Dangerous Goods by Road

ANDA Abbreviated New Drug Application

API Active Pharmaceutical Ingredient

CoA Certificates of Analysis

DMF Drug Master File

DPI Dry Powder Inhaler

GC Gas Chromatography

GMP/cGMP Good Manufacturing Practice/Current Good Manufacturing Practice

HPLC High Pressure Liquid Chromatography

HSE Health, Safety, and Environmental

HVAC Heating, Ventilation, and Air Conditioning

IMDG International Maritime Dangerous Goods Code

MDI/pMDI Metered Dose Inhaler/ Pressurized Metered Dose Inhaler

MSDS Material Safety Data Sheets

NDA New Drug Application

NF National Formulary





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INTRODUCTION

R&D Research and Development

SOP Standard Operating Procedure

SPC Summary of Product Characteristics

SUPAC Scale-Up and Post-Approval Changes

USP United States Pharmacopoeia

Organizations and agencies to which this Guide refers:

AAO American Academy of Ophthalmology

AAPS American Association of Pharmaceutical Scientists

ASTM American Society for Testing and Materials

DOT Department of Transport

FCC Federal Communications Commission

FDA US Food and Drug Administration

IATA International Air Transport Association

ICAO International Civil Aviation Organisation (a UN sub-organization)

ICH International Conference on Harmonization

IMO International Maritime Organization

MHLW The Japanese Ministry of Health, Labour, and Welfare

PDA Parenteral Drug Association (US)

UN United Nations

WHO World Heath Organization





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TECHNOLOGY TRANSFER PLANNING AND SUCCESS CRITERIA

2 TECHNOLOGY TRANSFER PLANNING AND SUCCESS CRITERIA

2.1 TECHNOLOGY TRANSFER SUCCESS CRITERIA

The transfer of technologies, methods, processes, and/or products, occurs for a variety of reasons and maybe based on a number of factors, including:

the natural progression in a product development life cycle, from a discovery laboratory, through scale-upand clinical development, to commercialization

the need for additional capacity

the strategic requirement to relocate business units because of economic advantages in different regionsof the world

the by-product of corporate mergers and consolidations

Whatever the reason, technology transfer is a part of the pharmaceutical business and has become a focalpoint of the regulatory agencies that govern this global business. Planning for technology transfer and defin-ing criteria for success, therefore, are as important an aspect of the technology transfer process as the actualexecution.

This section considers, within the scope of this Guide, the elements needed for a successful technologytransfer. As an aid to the users of this Guide, a tool set, including example templates for protocols, reports,and tracking documents has been included. It must be stressed that these templates are for example only.The reader is encouraged to develop a format and system that works best for their specific needs.

Simply stated, technology transfer can be considered successful if a Receiving Unit can routinelyreproduce the transferred product, process, or method against a predefined set of specifications asagreed with a Sending Unit and /or a Development Unit.

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.

The success of a technology transfer project will be largely dependent upon the skill and performance ofindividuals assigned to the project from both the Sending Unit and the Receiving Unit. It is, therefore, criticalthat a clear objective for any technology transfer project be developed. It is also critical that a project teamcomprised of individuals from both the Sending Unit and the Receiving Unit is established and that there is aprecise understanding of each team members role and responsibility prior to initiation of the technologytransfer project.

Skill alone will not ensure a successful technology transfer project. Once a project has been identified and ateam chosen, a clear and realistic project implementation plan is required to guide the project, manageexpectations, and handle the inevitable deviations and changes that may present themselves during imple-mentation. As the tool for users of this Guide, Template 4 provides a checklist for key technology transferactivities to be considered during the initial project planning phase. (See Template 4.)

Along with that plan comes the need to consider the temporal relationship between the various tasks associ-ated with a successful technology transfer. It should be clearly understood that each technology transferassignment is unique and it is, therefore, impossible to provide a generic technology transfer plan. Figure 2.1outlines the major elements in technology transfer project management and presents them in relationship toeach other. Please note, this is a general relationship model, all elements may not apply to each and everyproject, and there may be alternative alignments and sequencing of the various tasks.





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Regulatory Factors

It is generally recognized that the regulatory agencies, that govern the pharmaceutical industry products,processes, and methods, are not concerned with the business, economic, or strategic factors associatedwith a decision to transfer technology. The regulatory agencies are interested in consistency. From a regula-tory standpoint, the main factors for a successful technology transfer are:

1) The presence of an acceptance criteria or specification: has a clearly defined acceptance criteria orspecification for the product, process, or method, been established? In early stages of the developmentlife cycle of a product, process, or method, the specifications are often only loosely defined. As theproduct, process, or method, matures the specifications usually become more precise, until they aremodified into the final specification that is ultimately filed with a regulatory agency.

2) The establishment of adequate facilities and trained staff: does the Receiving Unit have the appro-priate facilities, equipment/instrumentation, and trained personnel to accept a transferred technology?

Figure 2.1 Technology Transfer Task Relationship Model

Key Tasks

Project Definition

Team Development

Facility Assessment

HS&E Assessment

Skill Set Analysis/Training

Process Development/Approval

Analytical Method Transfer

Raw Material Component Evaluation

Supply Quality

Equipment Selection and Transfer

Process Transfer

Verification

Data Review

Conclusion/Sign-off

Post Transfer Surveillance





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3) The establishment of protocols and Standard Operating Procedures: is there documented evidenceof a plan or protocol, agreed to by the Sending Unit and the Receiving Unit, by which the technologytransfer was executed?

4) Data: is there documented evidence that the product, process, or method can be successfully repro-duced by the Receiving Unit, in compliance with the agreed acceptance criteria?

Proper technology transfer is important during all phases in the life cycle of a product. A consistent approachto technology transfer during early research and development work forms the foundation for each subse-quent transfer step. The evolving history and documentation trail has the potential to significantly impact thecost and efficiency of all later transfer activities.

The format in which the four main factors for a successful technology transfer are executed and documentedis less important than the assurance that they have been executed and documented. In reality, during theearly phases of a product life cycle, i.e., research, it is likely that the exchange of protocols and results may bevia a laboratory notebook. As the life cycle of a product, process, or method progresses, a more formalapproach is warranted. The format established for the main factors for a successful technology transfer is atthe discretion of the individual organizations involved in the technology transfer.

2.1.1 Experience and Knowledge Capture During Transfer

In addition to a documented history of process and method development, all positive and negative experi-ences encountered during the development work should be recorded. The inclusion of such detail allowscautions, warnings, and important information to become a feature of the technology transfer and helps toprevent duplication or unnecessary activities in future technology transfers.

At the completion of the manufacturing process development, a comprehensive report/formal compilation ofinformation (database) should be written or created. Items included in the report/database vary depending onwhether the transfer is of a new product from a research and development site to a manufacturing site, or thetransfer of an in-line (mature or marketed) product from one manufacturing site to another manufacturing site.Possible items to be included are:

identification of critical processing parameters/specifications from the Sending Unit

qualitative and quantitative composition table: all known issues associated with differences in suppliersand performance

a side-by-side comparison of processing or analytical method steps and equipment/instrumentation

Research and Development (R&D) to Manufacturing Site

For new products transferred from a research and development site to a manufacturing site key experience/product knowledge is usually found in the form of development documents. These documents include:

formulation rationale

a development report that outlines the manufacturing process rationale; include prior validation reportsfrom the Sending Unit

technology transfer protocol, which captures the critical manufacturing process parameters, and a tech-nology transfer report detailing the success (or failure) of the technology transfer

history of clinical batches





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identify all pivotal batches (clinical/bio-equivalency/ICH - dossier stability)

history or evolution of the process through the clinical stage of development

Comparison between Receiving Unit qualification batches and reference batches (clinical, NDA, bio-batches). It is also important that an appropriate comparison and demonstration of equivalency betweenthe product/process from the Sending Unit and the Receiving Unit, and as appropriate against reference/pivotal batches, be made and documented accordingly.

history of critical analytical (release and stability) data

rationale for proposed specifications

Manufacturing Site to Manufacturing Site

Manufacturing site transfers usually involve in-line products, which are also known as marketed or matureproducts. A history of the process including the process rationale, justification of specification ranges, andvalidation activities should exist. The following activities should be performed and documented in order toensure a successful transfer:

technology transfer protocol, which captures the critical manufacturing process parameters, and a tech-nology transfer report detailing the success (or failure) of the technology transfer

include a development report that outlines the manufacturing process rationale; include prior validationreports from the Sending Unit

annual product review documentation (include process capability, rework procedure, process controltrend summaries, and process variations and the investigation of those variations, follow-up actions, anda rationale and summary of reworked product)

Comparison between Receiving Unit qualification batches and reference batches (clinical, dossier/appli-cation, bio-batches). It is also important that an appropriate comparison and demonstration of equiva-lency between the product/process from the Sending Unit and the Receiving Unit, and as appropriateagainst reference/pivotal batches, be made and documented accordingly.

history of critical analytical data (e.g., release and stability data)

rationale for proposed specifications

all batches produced (batch/trial number, purpose, size, results, comments)

identify all pivotal batches (clinical/bio-equivalency/ICH - dossier/application stability)

For older products it is recommended that analytical methods for stability are also reviewed for adequacy atthe time of transfer and agreed between the two parties.

Business Factors

In addition to regulatory factors that impact the success of a technology transfer there are certain businessdrivers that will influence the need to transfer technologies, methods, processes, and/or products. Thesedrivers will differ from company to company and, therefore, it would not be feasible to try and expand on themin this Guide.





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What is clear, from a business perspective, is that the success of a technology transfer is based on a balancebetween:

1) Cost

2) Capacity/Volume

3) Equipment and facility capabilities

4) Time frames

5) Regulatory requirements

The relative importance of each of these factors needs to be established by the individual organizationsengaged in the technology transfer.

If at the end of a technology transfer exercise the Sending Unit and the Receiving Unit can demonstratethrough clear documentation that: (1) the regulatory elements described above, and, if applicable, (2) therequisite business needs have been satisfied, then the technology transfer should be considered a success.

It should be noted that this ISPE Technology Transfer Guide is designed as a tool for industry and regulatorsto use in conducting and evaluating technology transfer activities. This Guide does not intend to be a definitivestandard operating procedure for technology transfer and, therefore, ISPE cannot guarantee that users ofthis document will be immune to questions/observations from regulatory agencies.





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ANALYTICAL METHODS/TECHNOLOGY TRANSFER

3 ANALYTICAL METHODS/TECHNOLOGY TRANSFER

Note to Reader: The success of a technology transfer will be based largely on documented evidence that amethod, process, or product can be reproduced against a pre-defined set of specifications. Given this premiseand the fact that analytical testing is likely to be the foundation from which many determinations of successwill be made, the authors of this document have included what are believed to be reasonable examples ofanalytical method transfer criteria. These are, however, only examples and the user is free to apply whateverstandard they feel appropriate for the task.

3.1 OBJECTIVE

This section of the ISPE Technology Transfer Guide aims is to describe the process by which analyticalmethods are transferred between pharmaceutical laboratories.

A successful technology transfer, based on meeting pre-defined acceptance criteria, will ensure that theReceiving Unit is able to implement qualified or validated procedures, using available personnel and equip-ment.

3.2 SCOPE

The procedure described in this section of the Guide concerns the transfer of analytical methodology be-tween laboratories for the testing of pharmaceutical products, their ingredients, and cleaning (residue) samples.The procedure includes release, stability, and in-process testing for a variety of dosage forms, in addition toDrug Substances (APIs), and critical excipients (where necessary), including:

Solids

Semi-solids

Parenterals

Liquids

Transdermals

Inhalation Products

Ophthalmics

3.3 RESPONSIBILITIES

The primary tasks of the Sending Unit are:

Create the Transfer Protocol

Execute Training

Assist in Analysis

Acceptance Criteria





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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.

3.4 PROCEDURE

3.4.1 Methods to be Transferred

All methods for testing a given product, ingredient, or cleaning sample should be provided (and approachesshould be justified). If it is deemed unnecessary to qualify the method in the Receiving Unit, the justificationshould be documented. Table 3.1 lists the tests for API and each type of dosage form that should be trans-ferred.

3.4.2 Pre-transfer Activities

The Receiving Unit should be provided with, and review, analytical methods prior to their transfer. The Send-ing Unit and the Receiving Unit should formally agree on criteria for success before execution of the transferprotocol.

As part of pre-transfer activities, the Sending Unit should provide all validation reports along with any otherreports on robustness studies.

The Sending Unit should provide training to the Receiving Unit. This should include a review of the methodsand transfer protocol, as well as laboratory work, if possible. Training should be documented.

If appropriate, the Receiving Unit should run the methods and identify any issues that may need to be re-solved, before finalizing the transfer protocol.

3.4.3 Transfer Protocol

The transfer protocol should contain the following sections:

Objective

Scope

Responsibilities

Materials/Methods/Equipment

Experimental Design

Acceptance Criteria - The criteria provided in this section of the ISPE Technology Transfer Guide areintended only as examples.





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Documentation

Deviations

References

Signature/Approval Page

Reference Samples, Actives, Intermediates, and Finished Products

Sampling should be statistically based so that sample variability does not contribute significantly to the differ-ences in results between laboratories.

This Guide recommends that acceptance criteria are established prior to the method transfer. Acceptancecriteria should be based on the intended use of the method, validation of the method, and historical datagenerated by the Sending Unit.

The documentation section of the transfer protocol may include report forms to facilitate the reporting ofresults and to ensure consistency in the reporting between the laboratories. This section should also includeinformation to be supplied with the results (i.e., chromatograms, deviation reports, spectra, etc.).

3.4.4 Transfer Report

The transfer report describes the results obtained in relation to the acceptance criteria. It should includeconclusions regarding the success of the transfer and confirm whether the Receiving Unit is qualified toperform each analytical method. Any deviations should be discussed and justified in the transfer report. (SeeTemplate 5.)

Table 3.1 API and Dosage Form Tests to be Transferred

TESTS API DOSAGE FORM

Semi-SolidsSolid Ointments/ Liquids/

Doses Parenterals Inhalation Creams Suspensions Transdermals Ophthalmic

Assay X X X X X X X X

Content Uniformity X X X X X X X

Impurities/ Degradants X X X X X X X X

Dissolution/Release Rate X X

Identification X X X X X X X X

Cleaning Verification X X X X X X X X

Microbiological X* X X X X X X X

Dose Delivery X

Physical Criteria** X X X X X X X X

Sterility X X

Typically, compendial methods do not need to be transferred. In certain cases, however, the compendial method may not be described in sufficientdetail or it may not include the critical parameters required to obtain accurate results. For these cases, a method transfer may be necessary.

* Microbiological testing is only appropriate for APIs that promote biological growth.

**The term Physical Criteria can be applied to different dosage forms in a variety of ways. For example, the term can mean clarity of solution or pHof a parenteral or ophthalmic, or hardness of a solid oral. For Inhalation Products, the term refers to particle size.





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3.5 EXPERIMENTAL DESIGN/ACCEPTANCE CRITERIA

3.5.1 Assay

This Guide recommends that at least two analysts (if available) at each laboratory should independentlyanalyze three lots (where available) in triplicate; resulting in eighteen different executions of the method.

For products with multiple strengths, bracketing may be appropriate. (See Section 6, Reference 5 and Refer-ence 6.) Each analyst should use a different set of the same instrumentation and/or columns, where avail-able, and independently prepare all solutions. All applicable system suitability criteria (as listed in the method)should be met.

The acceptance criteria should include a comparison of the mean and the variability of the results. Theacceptance criteria may be statistically derived (e.g., two one-sided T-test intersite differences of less than, orequal to, 2% with 95% confidence) Alternatively, acceptance criteria may be based on a direct comparison ofthe means and the variability.

3.5.2 Content Uniformity

If the method for performing content uniformity is equivalent to the assay method (i.e., standards and samplesare prepared at equivalent concentrations, and chromatographic conditions and system suitability criteria arethe same, etc.) then a separate method transfer for assay is not usually required.

If the assay method is different from content uniformity, then method transfer should be performed for both.

It is recommended that two analysts at each laboratory analyze at least one sample lot for content uniformity.For products with multiple strengths bracketing may be appropriate. Each analyst should use a different set ofthe same instrumentation and/or columns, where available, and independently prepare all solutions. All appli-cable system suitability criteria (as listed in the method) should be met.

The acceptance criteria should include a comparison of the mean and the variability of the results.

The acceptance criteria for this test may be statistically derived (i.e., two one-sided T-test intersite differenceof less than or equal to 3% with 95% confidence) or may be based on an absolute difference of the means(i.e., the Receiving Unit must obtain values within +/- 3% of the Sending Unit). In addition, data variance (%Relative Standard Deviation (RSD)) at both laboratories should be compared.

3.5.3 Impurities/Degradation Products/Residual Solvents

It is recommended that two analysts (if available) at each site analyze three lots (if available) in duplicate(triplicate if done together with the assay) on different days using different sets of the same instrumentationand columns, if possible.

All applicable system suitability criteria (as listed in the method) should be met. The limit of Quantitationshould be confirmed at the Receiving Unit, in addition to response factors for substances whose amounts arecalculated from their response relative to the drug peak. Chromatograms from both laboratories should becompared to ensure a similar impurity profile (similar relative retention time and peak response for knownsand unknowns above the reporting limit). It is particularly important that the samples tested at both laborato-ries are similar (representative of the batch) in regard to characteristics, such as:

Age

Homogeneity





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Packaging

Storage

If typical samples do not contain impurities above the reporting limit, then the use of spiked samples (ifavailable) is recommended to demonstrate equivalence between the laboratories. Accuracy and precisiondata should be generated at the specification limit.

The acceptance criteria should include a comparison of the mean and the variability of the results and willdepend on the levels determined in the samples. For moderately high levels of impurities, a statistical analy-sis may be used (i.e., two one-sided T-test intersite difference of less than or equal to 10% with 95% confi-dence). For impurities that are at lower levels but above the reporting limit, the acceptance criteria may bebased on an absolute difference of the means (i.e., the Receiving Unit must obtain values within +/- 25% ofthe Sending Unit or within +/- 0.05% of the mean value).

If spiking experiments are performed, the accuracy and precision of the results obtained at the Receiving Unitshould be similar to the results obtained at the Sending Unit, as part of the validation studies.

3.5.4 Dissolution

For Immediate Release (IR) products a single six units dissolution test may be sufficient. For ExtendedRelease (ER) products, or where the Receiving Unit does not routinely perform this kind of testing, a twelveunit dissolution test or profile is recommended. For products with multiple strengths, bracketing may beappropriate.

The dissolution data from both laboratories should meet the dissolution specifications for the product and (ifapplicable) the profiles generated at the two Units should be comparable. A statistical comparison of theprofiles (e.g., F2) or of the data at the Q timepoint(s) similar to that described for assay, (see Section 3.5.1)may be performed, or the acceptance criteria may be based an on absolute difference of the means (i.e., theReceiving Unit should obtain values within +/- 5% of the Sending Unit).

3.5.5 Identification

Identification tests can vary widely in complexity and techniques used. One determination is usually sufficientto demonstrate equivalence:

Where the identification test is based on the results of another test, such as the Retention Time (RT) inHPLC/GC, the transfer is usually included in the assay transfer and consists of confirming the retentiontimes. If the Rf value is used with a separate method, such as thin layer/paper chromatography, thetransfer should focus on the sample preparation, as well as the chromatographic technique.

Where the identification test is based on the interpretation of spectra, such as ultraviolet or infrared, thetransfer should be used to ensure that the sample preparation and instrumentation can produce equiva-lent results.

Where the identification test is based on a chemical reaction (i.e., colorimetric, titration, etc.) or physicalproperty (i.e., melting point, refractive index, etc.), the method does not need to be qualified, as long asthe technique is well established and the receiving laboratory personnel have sufficient training in thetechnique.

Microscopic identification should address the equipment and the ability of the Receiving Unit to properlyinterpret the data. Other unique identification tests should be evaluated and, depending upon the complexityof the procedure, may require a transfer, which should include the sample preparation and the data gener-ated.





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3.5.6 Automated Methods

The conversion of a manual method to an automated or robotic method should be qualified as part of anoverall method development and validation strategy and is outside the scope of this Guide.

The transfer of an automated or robotic method from one laboratory to another should focus on the ability ofthe equipment (hardware, software, glassware, filters, etc.) to generate equivalent and reproducible resultswith a minimum amount of sample carryover. If different automated system hardware manufacturers or differ-ent versions of software are being transferred, a complete revalidation is recommended.

Since the critical parameters of sample preparation are evaluated during the Qualification, the method trans-fer should focus on equivalency (automated to automated) and carryover. Examples of critical sample prepa-ration parameters include:

Weighing

Dilutions

Dispersing/Mixing

Filtering/Centrifugation

Injection/Dispensing

A strategy should be developed to deal with realistic laboratory workloads. Automated or robotic methods areused to analyze large numbers of samples and, therefore, the acceptance criteria should reflect the repetitivenature of this usage. In addition to the acceptance criteria listed in this Guide, there should be acceptancecriteria for the maximum amount of sample carryover after analysis of an individual preparation and for acumulative carryover after a series of sample preparations.

Example numbers of analyses for the cumulative carryover:

Assay: 6 sample preparations

Content Uniformity: 10 sample preparations

Dissolution: 6 sample preparations

Blank sample preparations should be dispersed throughout a run to measure carryover.

The acceptance criteria for individual and cumulative carryover should be very low (e.g., not more than 1.0%)based on the assumption that there is no carryover in a manual method. The equivalency acceptance criteriashould be the same as for manual methods.

3.5.7 Cleaning Verification

When process validation has been achieved, cleaning verification becomes, intrinsically, a limit test. Suchanalytical procedures may be transferred using replicate samples (spiked at levels of analyte both above andbelow the specification limit) and confirming both positive and negative outcomes. Under normal circum-stances, the spike levels should not deviate from the specification by an amount that is three times thevalidated standard deviation (repeatability) of the analytical procedure, or 10% of the specification, whicheveris the greater.





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All of the samples spiked above specification levels must demonstrate a failure to meet specification. Con-versely, an appropriate fraction of the low-level spikes (e.g., 90% of the total) must demonstrate a passingresult. For situations where the sample matrix contributes to the response, all results are corrected for amatrix blank before applying the above criteria.

Cleaning Validation

The Receiving Unit should review the swabbing material used in the method validation and update to swab-bing material used at the Sending Unit (if possible).

3.5.8 Microbiological Testing

It is recommended that an on-site validation approach is used for transferring qualitative and quantitativelimits tests such as:

Sterility

Antimicrobial Effectiveness

Microbial Contamination

This approach involves validation of the procedure in each individual laboratory by executing a commonmethod validation protocol. An on-site validation protocol should include:

Rationale

Method Identity

Validation Parameters

Data Summary

Acceptance Criteria

how data will be compiled and analyzed

how to handle data not meeting acceptance criteria

any follow-up requirements, where applicable

Since the purpose of such method validations is to demonstrate that, under test conditions, the methodallows recovery of microorganisms, both the Sending Unit and the Receiving Unit should use identical tech-niques and materials, including inoculum preparation. Quantitative microbiological tests should demonstraterecovery of test inoculum when compared to controls at levels specified in the protocol acceptance criteria. Itis recommended that each laboratory perform the validation in triplicate, utilizing different lots for each valida-tion exercise, if possible.

3.5.9 Dose Delivery

This section of the Technology Transfer Guide uses the term dose delivery in the context of testing drugproducts delivered by inhalation. Delivery mechanisms for these drug products include, but are not limited to:

Pressurized Metered Dose Inhalers (pMDI)





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Dry Powder Inhalers (DPI)

Nasal Sprays

Nebulizers

In all cases, the term dose delivery refers to the amount of drug emitted from the delivery device andavailable to the patient. In the case of the pMDI delivery system, the general transfer concepts discussedhere can also be applied to valve delivery studies where the amount of drug discharged by the valve andentering the delivery device is measured.

Further information regarding CMC aspects of specific delivery systems is available in the two FDA draftguidances Metered-Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products and Nasal Spray andInhalation Solution, Suspension, and Spray Drug Products. Information in these guidances will be super-seded when final guidances are issued.

Where practical, method transfer experiments should be performed using the same drug product and actua-tion device. This could involve the exchange of:

pMDI Canisters

Actuators

Reservoir DPI Devices

Nebulizers

Nasal Bottles Fitted with Pumps

To reduce experimental variability, transfer protocols should include device priming instructions, shake andhold criteria (if necessary), and device cleaning instructions.

It is recommended that two analysts at each laboratory independently analyze twenty delivery units from onelot of drug product. (A delivery unit could include a pMDI/actuator, pre-filled DPI device, pre-filled nasal bottlewith pump, etc.) Each analyst should perform their own analyses using separate standard solutions andinstrumentation. See Figure 3.1.

To minimize testing variables, one possible testing regimen is as follows for a product that typically meetsdose uniformity Stage I testing criteria (USP/NF , EP 2.9.18) (there are no criteria corresponding toUSP/NF described in the JP; however, a Content Uniformity Test exists for tablets or capsules).

1) Ten delivery units are arbitrarily selected (units 1 - 10) and assigned to be tested by analyst 1 in labora-tory A.

2) Upon completion of the testing, these units are then transferred to analyst 2 in laboratory A.

3) Upon completion of this testing, the testing units are transferred to laboratory B to be analyzed by ana-lysts 3 and 4.

4) Simultaneously, ten different delivery units (units 11 - 20) are arbitrarily selected and assigned to betested by analyst 3 in laboratory B.

5) Upon completion of the testing, these units are then transferred to analyst 4 in laboratory B.





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6) Upon completion of this testing the testing units are transferred to laboratory A to be analyzed by ana-lysts 1 and 2.

If the product typically requires Stage II testing, the testing regimen outlined above should be adjusted toinclude Stage II testing of each sample set by each analyst.

In addition to meeting USP/NF , or EP 2.9.18, the acceptance criteria should include a comparison ofthe performance of each delivery unit from analyst to analyst. (There are no criteria corresponding to USP/NF described in the JP; however, a Content Uniformity Test exists for tablets or capsules.) Resultsshould be reported in terms of amount of drug delivered. Information regarding particular attributes importantto dose delivery characteristics of specific delivery systems is available in the two FDA draft guidancesMetered-Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products and Nasal Spray and InhalationSolution, Suspension, and Spray Drug Products. Information in these guidances will be superseded whenfinal guidances are issued.

Figure 3.1 Example Testing Regimen for Method Transfer





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The measure of variance (e.g., coefficient of variance, standard deviation) of each testing laboratory shouldbe consistent with that reported for the method. The data should be compared for indications of differences indelivery and testing technique between laboratories or between analysts within a laboratory that indicate apositive or negative bias in the results. An assessment should be made of the Receiving Units ability togenerate equivalent data to that of the Sending Unit using appropriate statistics. For information regardingparticular attributes important to Dose Delivery characteristics of specific delivery systems the reader isreferred to the following two FDA draft CMC guidances Metered-Dose Inhaler (MDI) and Dry Powder Inhaler(DPI) Drug Products and Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products.Information in these guidances will be superseded when final guidances are issued.

3.5.10 Particle Size

Aerodynamic Particle Size

The term aerodynamic particle size refers to the particle or droplet size distribution of drug substance dis-charged from inhalation delivery systems. The delivery systems usually associated with these types of testsare pressurized metered dose inhalers (pMDI) and dry powder inhalers (DPI). Typical measurement tech-niques include multistage cascade impaction or liquid impingers. The USP describes various apparatus tomeasure particle size distribution. The general transfer concepts discussed in this section of the Guide maybe equally applied to all apparatus.

Where practical, method transfer experiments should be performed using the same drug product and actua-tion device. This may involve the exchange of pMDI canisters, actuators, or reservoir DPI devices. To reduceexperimental variability, transfer protocols should include device priming instructions, shake and hold criteria(if necessary), and device cleaning instructions.

It is recommended that two analysts (if available) at each laboratory independently analyze six delivery unitsfrom one lot of drug product. (A delivery unit may include a pMDI/actuator or a pre-filled DPI device.) SeeFigure 3.2.

Each analyst should perform their own analyses using separate standard solutions and instrumentation. Tominimize testing variables, one suggested testing regimen is as follows:

1) Three delivery units are arbitrarily selected (units 1 - 3) and assigned to be tested by analyst 1 in labora-tory A.

2) Upon completion of the testing, these units are then transferred to analyst 2 in laboratory A.

3) Upon completion of this testing the testing units are transferred to laboratory B to be analyzed by ana-lysts 3 and 4.

4) Simultaneously, three different delivery units (units 4 - 6) are arbitrarily selected and assigned to betested by analyst 3 in laboratory B.

5) Upon completion of the testing, these units are then transferred to analyst 4 in laboratory B.

6) Upon completion of this testing the testing units are transferred to laboratory A to be analyzed by ana-lysts 1 and 2.





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The acceptance criteria should include a comparison of the mass of drug recovered from the actuator, induc-tion port, and individual collection vessels (e.g., plates). Total drug recoveries for each analysis should bebetween 75% and 125% of theoretical yield for the analysis to be considered valid.

Drug amounts should be compared both in terms of absolute amounts recovered and as percentages of totalrecovery. Total drug recovered, mass median aerodynamic particle size (MMAD) and geometric standarddeviation (GSD) should also be calculated and compared. The data should be compared for indications ofdifferences in delivery and testing technique between laboratories or between analysts within a laboratory.

PARTICLE SIZE DISTRIBUTION

Analytical Sieving

It is recommended that at least two analysts at each laboratory independently analyze three lots of material(where available) in triplicate. Method transfer protocols should include specific criteria of sieves (e.g., mate-rial of construction), agitation method, and endpoint determination.

Figure 3.2 Example Testing Regimen for Method Transfer





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The acceptance criteria should include a comparison of the overall particle size distribution. As a minimum,the analysis of each test sample should meet product specifications and the overall distribution pattern shouldbe consistent between laboratories. The data should be compared for indications of differences in deliveryand testing technique between laboratories or between analysts within a laboratory.

Particle Size Analyzers: Instrumental

Since there are several different instrumental techniques (i.e., Microscopy, Light Scattering, Electrozone,Photozone, etc.) employed in particle size determination, the transfer of a specific method may be difficult.The transfer of a particle size method from one laboratory to another should focus on the ability of theindividual analyzer (type of analyzer and software) to generate comparable results. If different equipmentmanufacturers or different versions of the software are being transferred, a complete re-validation/qualifica-tion is recommended.

The acceptance criteria should include a comparison of the mass of drug recovered from the actuator, induc-tion port, and individual collection vessels (e.g., plates). Total drug recoveries for each analysis should bebetween 85% and 115% of theoretical yield for the analysis to be considered valid. Drug amounts should becompared both in terms of absolute amounts recovered and as percentages of total recovery. Total drugrecovered, mass median aerodynamic particle size (MMAD) and geometric standard deviation (GSD) shouldalso be calculated and compared.

The measure of variance (e.g., coefficient of variance, standard deviation, etc.) of each testing laboratoryshould be consistent with that reported for the method.

The data should be compared for indications of differences in delivery and testing technique between labora-tories or between analysts within a laboratory that indicate a positive or negative bias in the results.

An assessment should be made of the Receiving Units ability to generate equivalent data to that of theSending Unit using appropriate statistics. (See Templates 5 through 9.)

3.6 ALTERNATE APPROACHES

Appropriate justification for an alternate approach should be documented and based on scientific principles.One potential alternate approach is to perform re-validation of the method using the appropriate validationelements, such as those that may be performed when transferring microbiological methods. Another ap-proach would be for the Receiving Unit to participate in the method validation.

Approaches other than those discussed in this Guide may be applicable and acceptable. The number ofanalysts, samples, and distinct executions of the method given in this Guide are designed to demonstratethat the method(s) being transferred are reliable and robust.

The acceptance criteria stated throughout this Guide are based on typical industry analytical procedures(e.g., HPLC, GC, ultraviolet (UV)). These example acceptance criteria are not intended to be universallyapplied to all methods and dosage forms. Methodologies such as particle size analysis, or low parts permillion (ppm)/parts per billion (ppb) metal analysis may require more extensive acceptance criteria, while theassay for an API may have constricted acceptance criteria.





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ACTIVE PHARMACEUTICAL INGREDIENTS (APIs)

Figure 4.1 Scope of the ISPE Technology Transfer Guide

4 ACTIVE PHARMACEUTICAL INGREDIENTS (APIs)

4.1 INTRODUCTION

The quality of pharmaceutical products is dependent on the development of a robust, validatable, manufac-turing process and the constant operation of that process in accordance with cGMP. Fundamental to achiev-ing this is the availability of an extensive information set, which defines in detail all relevant activities that needto be performed to manufacture a quality product. This information set is put together during the developmentof the process and supplemented and updated as experience of the process is acquired. Critical, therefore, tothe manufacture of any pharmaceutical product, is the need for the personnel involved to have access to themost relevant and up to date information.

Effective transfer of API related technology has many facets. The timely transfer of analytical methods ispivotal to the success of the transfer, and although the analytical methods may not be fully validated duringdevelopment of an API, they are required to be scientifically sound. Fundamental chemical synthetic path-ways or routes should be communicated. Clear understanding of raw materials, starting materials, reagents,and catalysts should be conveyed. Finally, process technology for the synthesis of intermediates and finalproducts should be transferred. These complex elements are discussed in this section of the Guide.

4.2 SYNTHESIS, ROUTE, AND FORM SELECTION

4.2.1 Introduction

The level and type of detail to be provided varies, and depends on the particular technology transfer. Forexample, the first transfer from research and development into a manufacturing plant could require the entirerationale for the synthesis, route, and form selection to support further process development and enhance-ment. In contrast, a technology transfer from a manufacturing site to a third party, where no developmentwork is performed, would require less detail.

4.2.2 Synthetic Route

Details of the selected route from the starting material through all the intermediate stages to the API arerequired. It is important to note the difference between the actual sta

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