Tech Transfer ISPE

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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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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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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 UK’s 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 product’s 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 <711>.

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 member’s 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 <601>, EP 2.9.18) (there are no criteria corresponding toUSP/NF <601> 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 <601>, 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<601> 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 guidances“Metered-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 Unit’s 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 Unit’s 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 starting material and the ‘registered’ APIstarting material.

Registered API starting materials relate to materials used in the production of an API, which are incorporatedas a significant structural fragment into the structure of the API.


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Technology transfer of stages before the registered API starting material does not need to meet GMP and,therefore, a less formal technology transfer may be appropriate. The principles described by this Guide maystill be applied. Information on the synthesis of the starting materials and other possible synthetic routes maybe provided for background information. Technology transfer of the established synthesis stages from theregistered starting materials to the API must be conducted to GMP and, therefore, formal documentation ofthe technology transfer is required.

The information in this section should include:

• a flowchart

• the detail of the chemistry and reaction conditions necessary to effect the conversions

Where appropriate, specific and critical details should be included, especially those relevant to meetingspecifications.

4.2.3 Rationale for Selection of Route and Form

Information in this section may be necessary to support the choice of route and the physical form and shouldbe reviewed before technology transfer to different facilities. Factors and constraints that could be taken intoaccount during selection may include the following:

• quality, chemical, and physical considerations (e.g., the number and level of impurities, or impurities withundesirable properties, and information on salt selection if appropriate)

• health, safety, and environmental aspects

• materials availability

• cost and economy

• operational and handling considerations

• special aspects required by the technology transfer Receiving Unit (e.g., availability of specialist equip-ment)

4.2.4 Other Routes Considered

It may be useful for further process optimization at a later stage in the product life cycle to detail all otherchemical approaches considered.

4.3 STABILITY DATA

Data on the stability of the API and intermediates are necessary to establish a retest period under appropri-ate packaging and environmental conditions. The conditions for assessment of the API should follow theguidance in ICH Q1A (R) “Stability Testing of New Drug Substances and Products” (see Section 6, Reference3), recognizing that there might be unique and/or more stringent regional requirements. It is also important tonote that these conditions could be varied depending on the known storage and transport conditions. Thesesame conditions may be used for the stability assessment of marketed intermediates.

4.3.1 Quality Profile and Specifications

The stability program should cover appropriate chemical, physical, and microbiological parameters.


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4.3.1.1 Chemical

The program should concentrate on those parameters that could change during storage and are likely toinfluence quality, safety, and/or efficacy. (See Section 6, Reference 3.) Examples include:

• Moisture Content

• Residual Solvent

• Impurities

• Assay

• pH

The methods used for the API must be stability indicating.

4.3.1.2 Physical

The tests applied should monitor those parameters that could affect bioavailability or the suitability of thematerial for further manufacture. Examples include:

• Morphic Form

• Cohesivity

• Particle Size

For intermediates, the physical attributes would probably be limited.

4.3.1.3 Microbiological, including Sterility, Bioburden, and Endotoxin Considerations

An assessment of the manufacturing process to determine its susceptibility to microbiological contaminationand the ability of the API to support microbiological growth should be undertaken before establishing anymicrobiological testing as part of the stability program. Where microbiological contamination and growth arepossible, then bioburden testing should be included.

Microbiological considerations, including sterility, bioburden, and endotoxin considerations, should look atthe preserving effects and neutralization of any preservatives added.

4.3.2 Site Specific Stability Data - APIs

4.3.2.1 Background

One significant regional recommendation that goes beyond ICH Q1A (R) is the US FDA’s policy on stabilitydata from the final manufacturing site (Site Specific Stability or ‘SSS’). In a 1987 Guideline, the FDA explicitlystates:

“For a proposed change to a new manufacturing facility for the same licensed product using similar equip-ment, accelerated data should be submitted, if feasible. A commitment to conduct stability studies on aminimum of the first three lots produced in the new facility should also be submitted. Ordinarily, the previouslyapproved expiration dating period may be used under these circumstances”. (See Section 6, Reference 2.)


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Following a rewrite of this guideline, an entire section of the Draft Guidance for Industry on Stability Testingwas devoted to site specific stability Data for New Drug and Biologic Applications. (See Section 6, Reference3.) The explicit recommendations for data from at least one batch of drug substance/product generated fromthe intended commercial site to be included in a New, or Abbreviated New, Drug Application were not em-braced by industry.

Numerous comments to this draft guidance recommendations resulted in a public meeting, in which the FDAand industry worked out a more flexible policy on site specific stability testing recommendations. Two optionswere found to be acceptable to industry, and endorsed by the FDA:

• Option 1: site specific stability with modified timing

• Option 2: certification that process validation from the commercial site needs to be provided to the FDAfor review prior to NDA/ANDA approval

These are the proposals that are detailed in the following sections. Until the FDA finalizes the Stability Guid-ance, the FDA reviewing division should be contacted to determine requirements to support stability at thecommercial site.

4.3.2.2 Site Specific Data

In principle, the primary stability batches for drug substance should be made at the intended commercial site.If these primary stability batches are not manufactured at the intended commercial site, two options may beconsidered for the original application:

Option 1

Using the FDA proposal, the timing for generating this data depends on the drug substance characteristicsand the risk to negatively impact the safety and efficacy of the drug substance; typical examples are shown inTable 4.1.

Option 2

The alternative to generating these site specific stability data is the proposal using validation batches tocertify that the process is adequately controlled. This option entails the submission of certificates of analysis(CoA) for the validation batches prior to the expected FDA action date. It would be expected that thesevalidation batches (no less than three) would be placed on a commercial stability program and the dataupdated in the annual report.

Risk Level

Major

Moderate

Minor

Timing of Data Provision

At time of NDA, ANDA, BLA, or PLAfiling

Midpoint in the (application) reviewcycle

Post-approval in the annual report

Example

Polymorphism or critical particle sizesensitivity towards drug performance

Operational sensitivity to technology,process, or site conditions (biotech-nology/biologicals, environmentallysensitive products)

All others

Table 4.1 Typical Examples of Site Specific Stability Data Provision


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If the submission includes data from stability studies on at least three production batches, a commitmentshould be made to continue long-term studies through the proposed retest period and to perform acceleratedstudies for six months.

If data on fewer that three production batches is available, a commitment should be made to continue long-term studies as above and to place additional production batches to a total of at least three, on long-termstability studies through the proposed retest period and to perform accelerated studies for six months.

If the submission does not include any stability data on production batches, a commitment should be made toplace the first three batches on long-term stability, through the proposed retest period, and to perform accel-erated studies for six months. (See Section 6, References 2, 3, and 4.)

Note: ICH Q1A (R) “Stability Testing of New Drug Substances and Products” does not require performanceof accelerated studies for six months.

4.4 RAW MATERIALS, STARTING MATERIALS, REAGENTS, AND CATALYSTS(PROCESS MATERIALS)

API starting materials are raw materials, intermediates, or another API that are used in the production of anAPI and that are incorporated as a significant structural fragment into the structure of the API. Reagents arethose materials that effect the chemical transformations and become ‘spent’. Catalysts are similar to re-agents and increase the rate of the chemical transformations, but remain chemically unchanged and arerequired only in small, non-stoichiometric quantities.

Chemical and Physical Characterization of Process Materials

The transfer should include specifications, tests and methods, and characterization of key process materials,for example:

• purity, identity, and appearance

• critical impurities and impurity profiles for critical raw materials/starting materials

• morphology, form, physical property information, where appropriate, e.g., where the particle size has asignificant impact on the process performance or product quality, or where it has a significant impact onbulk handling or dose form performance

• supporting information and justification for setting limits applied to the specifications

4.4.1 Approved Suppliers

The technology transfer team may establish a list of suppliers whose material has been shown to performsatisfactorily as a means of ensuring consistency of quality and source of input materials. For critical materi-als an appropriate Qualification will have been carried out, e.g., for registered starting materials or when thetransfer process is in a phase where products are being administered to humans. In this situation, docu-mented evidence should be provided to demonstrate that the materials meet pre-determined specifications.A system to manage and control changes of supply source should be operated.


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4.5 HEALTH, SAFETY, AND ENVIRONMENTAL INFORMATION

In order to properly handle, use, and store materials and to provide safe working arrangements and appropri-ate environmental safeguards, information related to the Health, Safety, and Environmental (HSE) aspects ofthe materials and processes should be provided, understood, and acted upon.

There is an ongoing obligation for both parties involved in a technology transfer to exchange updates fromexperiential knowledge. The information exchange should include lessons learned from previous technologytransfers and any new information as it becomes available.

This information forms the basis of the HSE risk assessment process performed at the Receiving Unit.Template 2 provides a checklist of areas to be considered. Depending on the nature of the technology trans-fer, areas may be mandatory or essential.

4.5.1 Health, Safety and Environmental Assessment of all Inputs, Outputs, By-Products,and Wastes

4.5.1.1 Material Safety Data Sheets

Health, safety, and environmental data should be reviewed for all inputs, outputs, by-products, and wastesprior to technology transfer. Any critical data gaps should be identified and necessary testing initiated. Ex-amples of data that could significantly affect the Receiving Unit’s ability to conduct an adequate risk assess-ment are listed in the attached template (Template 3). It is recommended that a customized approach toobtaining environmental data be undertaken, in consideration of the Receiving Unit’s waste disposal or recy-cling capabilities.

Health, safety, and environmental data is typically communicated in a material safety data sheet (MSDS),which provides critical health, safety, environmental, and regulatory information and handling advice to recipi-ents of hazardous chemicals. There are international regulations or standards (e.g., the EU Dangerous Sub-stances Directive [67/548/EEC] and the US ANSI Standard [ANSI-Z400.1]) that specify the format of MSDSsand make recommendations about content. In most countries it is a regulatory requirement that MSDSs aresupplied to the recipient of a hazardous chemical before they handle that chemical.

4.5.1.2 Handling and Containment Methods

Engineering solutions to minimize occupational exposure during manufacturing operations may need to bedeveloped and transferred to the Receiving Unit. Occupational hygiene air sampling data that demonstratesthe effectiveness of controls should also be developed and communicated. When developing engineeringcontrols, it is important that issues such as manual handling or ergonomics are considered. Tighter controlswill be applied to the more hazardous materials, such as potent APIs.

Occupational exposure limits (OELs), hazard categories, or exposure bands should be calculated for mate-rials to be transferred, so that appropriate handling and containment methods can be selected. An Occupa-tional Exposure Limit (OEL) is typically defined as the airborne concentration of a substance to which work-ers may be repeatedly exposed without suffering adverse health effects. For substances without regulatoryOELs (e.g., a threshold limit value (TLV) or Occupational Exposure Standard/Maximum Exposure Limit (OES/MEL)) companies may set an ‘in-house’ limit based on any health hazard data they may have generated.Exposure bands or hazard categories may be developed for those substances for which there are insufficientdata to set a ‘health-based’ OEL.

OELs should be communicated to the Receiving Unit to allow them to select appropriate engineering controlsand handling precautions.


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Effective cleaning and decontamination procedures and protocols may be required prior to technology trans-fer to reduce the possibility of development of adverse systemic effects or skin sensitization from skin contactwith contaminated surfaces. (See Section 6, Reference 9.)

4.5.1.3 Personal Protective Equipment (PPE)

The primary method of controlling risks from chemical exposure should be by engineering control. However,there are times that the use of personal protective equipment is unavoidable, e.g.:

• emergency situations

• maintenance activities

• product change over

• situations where engineering control has yet to be validated via occupational hygiene air sampling

The selection of PPE should be based on the likely airborne exposure level, as well as the predicted route ofexposure (e.g., inhalation, eyes, and dermal). Details of applicable PPE should be transferred to the Receiv-ing Unit.

4.5.1.4 Occupational Health and Hygiene

Occupational hygiene analytical methods, which are appropriately validated, and procedures for samplecollection should be developed and transferred. These are necessary, along with OELs, to establish theadequacy of selected engineering and procedural controls and help in the prevention of work related ill healthfrom chemical exposure. Details of occupational hygiene air sampling results obtained from the developmentor Sending Unit should also be made available.

Medical health surveillance methodologies and information of adverse health events experienced at theDevelopment Unit or Sending Unit should also be transferred.

4.5.1.5 Compliance with Laws, Regulations, and Licenses

A formal review of all applicable HSE regulations and laws should be made prior to any technology transferactivity. This review should address local country regulations at the Receiving Unit.

Examples of HSE regulations that could have a major impact on the technology transfer process are de-scribed.

Transport of material across international boundaries is covered by legislation for which certain Health, Safety,and Environmental information is required. Many of these legislative requirements are based on the conceptof national chemical inventories whereby substances not listed cannot be used without obtaining consentfrom the regulators. An example is the “Notification of New Substance Regulations 1993 (NONS 93)” thatapplies across the European Community. Although APIs are exempt from this legislation, starting materialsand intermediates are not.

Any ‘new substance’ (i.e., a substance not on the EINECS (European INventory of Existing CommercialChemical Substances) or ELINCS (European LIst of Notified (New) Chemical Substances)) list that is trans-ferred to a separate legal entity within the European Community will require notification with the relevantcompetent authority. An appropriate health, safety, and environmental data package should be developed tosupport the notification procedure.


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Similar legislation and requirements for data apply in other countries, such as Japan (e.g., Ministry of Interna-tional Trade and Industry (MITI)), although pharmaceutical intermediates are exempt. In the US the Environ-mental Protection Agency (EPA) regulates chemicals by means of a notification scheme under the powers ofthe Toxic Substances Control Act 1976 (TSCA). Unlike the European and Japanese notification schemes, theEPA does not possess the power to request a standardized set of basic data, but can request specific data ona case by case basis before granting manufacturing approval. In common with Japan, pharmaceutical inter-mediates and APIs are exempt from the Toxic Substances Control Act.

It has been estimated that there are at least ten countries or regions in the world that operate regulatoryschemes based on chemical inventories, and it is recommended that specialist advice is obtained beforeconducting a technology transfer to a region that is unfamiliar. (See Section 6, Reference 9.)

4.5.1.6 Major Accident Hazard Regulations

Examples of other legislation that should be consulted include those related to control of major accident sitessuch as the Seveso II Directive (implemented in the UK as the Control of Major Accident Hazard Regulations(COMAH)).

4.5.1.7 Scheduled Drug Substances

Implications of sites manufacturing scheduled or controlled drug substances should also be addressed be-fore technology transfer. (See Section 6.)

4.5.2 Health and Safety Assessment of the Processes Used for Conversion

4.5.2.1 Process Risks and their Control

Information about the inherent risks of the manufacturing processes (e.g., reactive chemical hazards, fire,and explosion risks) should be provided. Document research is the minimum requirement, but this may needto be supplemented by reaction calorimetry and other methods, where appropriate, and suitable controlsimplemented. Process Hazard Analysis (PHA) techniques, such as a Hazard and Operability Studies (HAZOP),should be used to assess, and as far as reasonably practicable, eliminate HSE risks presented by proposedprocesses and associated ancillary equipment. Copies of the PHAs and physical and chemical data gener-ated by the Sending Unit should be provided to the Receiving Unit.

4.5.2.2 Compliance with Health Laws, Regulations, Permits, or Other Standards

Local rules and regulations may apply to Health and Safety assessments. These should be considered.

4.5.2.3 Emergency Planning Considerations

An adequate plan for response to various scenarios such as gas or dust release, spillage, fire, and firewaterrun-off should be developed, as a contingency.

4.5.3 Environmental Assessment of all Materials and the Process

Local rules and regulations may be applicable.

4.5.3.1 Identification of Waste Streams

The list will comprise:

• input and output materials


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• efficiencies of use

• reactant excesses

• utilities required

• process by-products, such as off-gases venting patterns, solid and liquid waste stream data, and wastepackaging

Composition, quantity, destination, and special provisions required to deal with waste streams (e.g., re-use/recycling options, disposal methods and routes, and abnormal wastes during start up or shut down) shouldbe considered.

4.5.3.2 Identification of Releases to Air, Land, and Water

This section will require the detailed quantification and a detailed description of all waste minimization andprocess intensification projects associated with the process, prior to control of all emissions to atmosphere,discharges to drain, and management and disposal of solid and liquid waste. Environmental monitoring tech-niques and analytical methodology required to validate legislative requirements should be developed andtransferred.

4.5.3.3 Provision of Environmental Fate and Effects Data

The Development Unit or Sending Unit should have information available on the known (or probable) fate andeffects of materials used and generated in the manufacturing process. This will be required for the purpose ofan assessment at the Receiving Unit.

4.5.3.4 Environmental Risk Assessment

A formal assessment should be completed and documented. Environmental monitoring data should be com-pared against any regulatory or company developed discharge limits. Comparison with the most stringentglobal limits may be a useful indicator of potential future changes.

4.5.3.5 Environmental Impact Assessment

A formal assessment should be completed and documented, and may require specialist input.

4.5.3.6 Compliance with Environmental Laws, Regulations and Licenses

A formal comparative review and assessment should be completed and documented.

4.5.3.7 Potential Off-site Impacts

An adequate plan to various hazard related scenarios, e.g., spills and emergency releases, should be devel-oped, as a contingency.

4.6 PROCESS INFORMATION

This refers to detailed information about the selected process. It is an expansion of the route selected anddescribed in Section 4.2. Detailed information is required for all intermediate steps and the final API step inthe process (unless only intermediates are being transferred).


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4.6.1 Detailed Manufacturing Process Description

The following information is required:

• flow chart of the process stages

• quantities of all materials and stoichiometry of the starting materials, intermediates, and reagents

• scale of historic manufacture versus proposed scale of operation

• specific processing conditions (e.g., times, temperatures, and pressures)

• sequence of the activities (e.g., order of addition of reagents)

• expected theoretical yield and output weight of product

• quality critical parameters (i.e., factors impacting on product quality)

• permitted tolerance ranges for key parameters (e.g., yield impacting parameters)

• detail of other materials and by-products generated and their fate

• detail of material recycle and solvent recovery procedures, and any materials requiring special disposal

• mass and energy balance information

• a representative and predictive laboratory scale process

4.6.2 Plant Operating Procedures (Batch Instructions)

In order to carry out the specified process it will be necessary to provide detailed instructions of how toperform the operations in the selected plant.

• master production/batch instructions from the technology transfer Sending Unit

• develop master production/batch instructions for proposed plant

• confirm master production/batch instructions following successful technology transfer

Note: Following process transfer, a number of modifications to batch instructions may be expected.

4.6.3 In-Process Controls

Most of the operating parameters and ranges in the process will be well defined and predictable, but there aresome which will require monitoring during the process to ensure adherence to the necessary conditions, e.g.,pH, or completion of sensitive chemical steps, such as hydrogenation. These need to be defined and speci-fied; some may be a point check in the process or may be a continuous measurement.

4.6.4 Detailed Characterization of APIs and Intermediates

For the API, formal specifications and associated methods of analysis that fully define quality, both chemi-cally and physically, should be provided. These, especially physical criteria, should relate to the usability andhandling of the API in the dosage form and will vary depending on the dose form; for those in solution, for


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example, the physical criteria are related mainly to solubility and rate of solution but for tablets and particu-larly inhaled products, the physical criteria are of major significance and require very specific and sophisti-cated control.

The technical transfer team will need to determine if additional data on the API need to be generated orwhether the existing data is sufficient.

For intermediates, formal specifications and associated methods of analysis should be provided. These mustfully define chemical quality and in certain circumstances physical quality (e.g., where either its ability toprovide satisfactory APIs is significant, or where bulk handling systems make special demands on the mate-rials).

The following is a listing of information and attributes that should be considered when characterizing an API.This list is not exhaustive, does not represent a mandatory listing, each situation should be considered inspecific detail:

a) Manufacturer(s): name and address for each manufacturing site or contract manufacturing facility re-sponsible for APIs and all intermediates.

b) Flow chart of synthetic pathway: a flow diagram outlining each step of the process and showing whereall raw materials enter the process. All critical steps, process controls and intermediates should be iden-tified.

c) Form/morphology (including photomicrographs): the definitive form of the API should be describedand any polymorphic and solvate forms identified. Photomicrographs and other relevant data should beprovided (i.e., X-ray, DSC, Melting Point/Range, etc.).

d) Solubility: a solubility profile should be presented. Typical solvents included are:

• Water

• Methanol

• Ethanol

• Acetone

• DMSO

• Tetrahydrofuran

• Methylene Chloride

• any other solvents used in the final stage of synthesis

The pH rate profile should be determined and included.

e) Partition coefficient: the partition coefficient and reference to manner in which determined (i.e., water/octanol, calculated and by which method/commercial program, etc.) should be provided.

f) Intrinsic dissolution: the intrinsic dissolution rate and reference to method for determination should beprovided.


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g) Particle size and distribution: the particle size distribution characteristics and reference to method fordetermination (i.e., sieve analysis, dynamic light scattering, laser diffraction, or aerodynamic) and type ofcharacterization for the distribution (i.e., number/weight, length, surface area, or volume) should be pro-vided.

h) Bulk physical properties: bulk and tap density data should be provided. Surface area and porosity datashould be included for further characterization, as appropriate.

i) Water content/hygroscopicity: water content and determination of hygroscopicity should be provided.Water activity data should be included for further characterization, as appropriate. Special handling re-quirements based on this data should be included.

j) Microbiological considerations (if applicable): assessment of microbiological attributes should beconducted in accordance with regional pharmacopoeial requirements, i.e.:

• USP/NF <61> Microbial Limit Tests

• USP/NF <151> Pyrogen Test (when necessary)

• USP/NF <1111> Microbiological Attributes of Nonsterile Pharmaceutical Products

• EP 2.6.12 Microbial Examination of non-sterile Products (Total viable aerobic count)

• EP2.6.13 Microbial Examination of Non-sterile Products (Test for specified micro-organisms)

• EP 2.6.14 Bacterial Endotoxins

• EP 5.1.4 Microbial Quality of Pharmaceutical Preparations

• JP 35. Microbial Limit Test (Page 58-64), (Part I, General Tests, Process and Apparatus)

• JP 36. Microbial Limit Test for Crude Drugs (Page 64-70), (Part I, General Tests, Process and Appa-ratus)

• JP 47. Pyrogen Test (Page 78-79), (Part I, General Tests, Process and Apparatus)

• Other requirements, as appropriate

k) Specifications: specifications and justification for release and end-of-life limits should be provided.

l) Stability: a summary of the studies conducted and the results obtained should be provided. Typicallystudies should conform to current ICH Guidelines or other appropriate guidance. Conclusions and rec-ommendations regarding retest date should be provided.

m) Synthetic impurities: a listing of potential and observed synthetic impurities should be provided. Data tosupport proposed specifications and typically observed levels should be included.

n) Degradants: a listing of potential and observed degradation products should be provided. Data to sup-port proposed specifications and typically observed levels should be included.

o) Potency factor: typical, observed purity and justification for any recommended adjustment to the inputquantity of APIs for drug product manufacturing (based on purity, water content, salt form, etc.) should beprovided. Example calculations should be included.


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p) Special considerations (i.e., sensitivity to light, moisture, etc., safety and environmental): recom-mendations and justification for special handling precautions should be provided.

4.6.5 Chronology of Process Development

All relevant process development information should be made available to support any subsequent processoptimization work. It is important to reference the work carried out to determine acceptable ranges.

4.6.6 Process Capability and Statistical Process Control

In determining the acceptable ranges, it is important to identify what aspects should be controlled in order toassure quality and to reduce process variability. Carefully designed experimentation on a statistical basis(design of experiments) is valuable in this respect. For mature processes, there may be metrics and robust-ness indices, which are useful to include in the technology transfer package. This information forms the basisof any subsequent process optimization program.

4.6.7 Critical Aspects

Those factors and parameters that have a disproportionate effect on product quality need to be speciallyidentified and quantified. Critical aspects are subject to strict control, either through manual or instrumentedsystems, which are controlled to ensure consistent performance and product quality. In transferring criticalranges, it is important to identify ‘alert’ and ‘action’ limits.

4.6.8 Batch and Campaign Histories/Pedigrees

Full records of all development, commissioning and validation batches need to be available and shouldinclude performance, quality, and disposal details. It is also important to record the sources, origins, andpedigrees of all materials. This information would be important for transfers in the early life cycle of a product,but less important for transfers of well established products.

4.6.9 Comparison of Biobatches with Subsequent Batches

In order to confirm equivalence of all subsequent batches of an API with the first clinical material, they shouldbe tested against the specification, as a minimum. It may also be necessary to carry out additional tests onthe validation batches to ensure that an API performs satisfactorily in the dose form process.

4.6.10 Cleaning Procedures

Cleaning procedures should be a part of the development work. After completing work on any chemicalprocess stage, it is essential to clean the plant to defined limits so that the following process stage is notcontaminated with any undesirable material. The levels of cleanliness should be defined using acceptedmethodology and rationale (see Section 6) and related to the potency of the material. The following should beconsidered:

• solubility of APIs and intermediates

• details of cleaning methods tried

• detail of analytical methods

• sampling and swabbing recommendations

• recommended cleaning procedure


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• recommended standards and acceptable limits

• detail of critical and difficult cleaning requirements

• plant standards of the Sending Unit

4.7 EQUIPMENT DESCRIPTION

Key information on equipment should be provided at the same time as the process information. Where thereare specialized areas of the plant and pieces of equipment, it may be necessary to provide information aboutthese together with detailed operational instructions. This could apply, for example, to automated filtration anddrying equipment. An automated plant is subject to extensive levels of such information. (See Section 6,Reference 1.) Critical pieces of plant and equipment should be controlled to ensure consistently satisfactoryperformance and product quality.

4.7.1 Description of Major Process Items, Design Intent, and Capability

These could include, but are not limited to:

• proposed design philosophy and rationale for pilot and commercial plants

• description of major items and their functions

• capacity and capability information

• materials of construction

• a review of Receiving Unit equipment and details of any differences that may impact performance orproduct quality

• process control systems, ensuring capability to meet critical operating ranges

4.8 PACKAGING COMPONENT SPECIFICATIONS

4.8.1 Specifications

Recommended packaging arrangements need to be provided. These should be compatible with the productsand ensure safety in handling and transport of the material. There will usually be two containers: an inner oneto ensure cleanliness of the material and an outer one to ensure protection from contamination. Factors suchas sensitivity to light should be considered.

United Nations (UN) specifications [Globally Harmonized System of Classification and Labelling of Chemi-cals (GHS)] need to be met and checking that packaging meets these standards can be a lengthy process.Since January 1, 1991, all dangerous goods in international marine and international or domestic air trans-port are required to be in packaging displaying the UN marking. Details are provided in the “Recommenda-tions on the Transport of Dangerous Goods Model Regulations” (commonly known as the Orange Book).These are adapted into specific modal regulations for air, land, and sea by the respective modal bodies(ICAO, IMO, and ADR in Europe). Under certain circumstances, international dangerous goods regulations(i.e., IATA and IMDG) may be used as substitute for national regulations.


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4.8.2 Suitability/Compatibility

Product-contact packaging materials should have no deleterious effects on the product. Stability testing maybe required to ensure that there are no extractable/leachable issues and/or barrier property issues involvingproduct contact packaging materials.

4.8.3 Regulatory Requirements and Guidelines for Label Content

Label content should meet regulatory requirements and guidelines. Various international regulations exist forworkplace and transport labeling. In the USA, the Hazard Communication Standard, written by the Occupa-tional Safety and Health Administration (OSHA) in 1983 mandates companies to advise workers of the po-tential hazards of handling hazardous substances in the workplace (Standard 29 CFR 1910.1200). TheAmerican National Standard Institute (ANSI) has issued a labeling standard (ANSI Z129.1-2000) to helpcompanies comply with the labeling requirements of 29 CFR 1910.1200). Similar legislation for workplacehazard labeling applies in the European Community (Dangerous Substances Directive 67/548/EEC) andJapan (e.g., Industrial Safety and Health Law, Fire Service Law). Under most workplace hazard labelingregulations chemical intermediates, starting materials, and other raw materials are fully covered but drugsubstances in the finished state intended for final user are exempt.

Extra labeling is required to transport hazardous substances by road, rail, sea or air. International or Nationalstandards such as those specified by ADR, IMDG, IMO, ICAO, IATA, and the US Department of Transporta-tion (DOT) specify the labeling that is required for the different modes of transportation.

An example of an EC supply label is attached to this Guide. (See Template 1.)

4.9 FACILITY REQUIREMENTS

Suitably designed and constructed facilities for manufacture should be available. Further information is avail-able in the ISPE Baseline® Pharmaceutical Engineering Guide Series (see Section 6, Reference 8) and ICHQ7A (see Section 6, Reference 7).

4.10 QUALIFICATION AND VALIDATION

The objectives of validation are to ensure that all facilities, processes, systems, procedures, and equipmentthat may affect the quality of Active Pharmaceutical Ingredients (APIs) operate reliably and reproducibly.

Qualification is the recording of performance tests to determine if a component of a manufacturing processhas the attributes required to obtain a specified quality of product. Qualification deals with the individualphases of validation, while validation deals with the entire program to demonstrate control in the manufactureof a product.

Further information is available in the ISPE Baseline® Pharmaceutical Engineering Guide Series (see Sec-tion 6, Reference 8) and ICH Q7A (see Section 6, Reference 7).

4.10.1 Validation Plan

A plan or protocol should be prepared (if required) by the Receiving Unit, possibly with input from the SendingUnit who may be involved in agreeing or approving the plan. Agreement will also be required on whichprocess stages need be validated, e.g., all registered stages or those that are critical for product quality.Criteria to demonstrate equivalence with previously manufactured material will need to be established.


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4.10.2 Qualification of Plant, Process, and Product

The sequence of Design, Installation, and Operational Qualification steps are normally completed in advanceof Process (or Performance) Validation. Different terms may be used for the same activity. (See Section 6,Reference 8.)

4.10.3 Cleaning Validation

Cleaning of the complete manufacturing equipment train using the methods and materials identified in Sec-tion 4.6.10 should be completed following a written protocol. Verification of cleaning methods may need toprecede validation.

4.10.4 Computer Validation

All computer systems associated with manufacture of the materials should be validated. This is a significantaspect and guidance is available in the GAMP Guide for Validation of Automated Systems, published byISPE. (See Section 6, Reference 1.)

4.11 SUCCESS CRITERIA (API SPECIFIC)

4.11.1 Contract of Deliverables

The overall technology transfer plan and team working structures should be agreed at the outset; earlydialogue between the parties is most important. The expected outcomes or deliverables should be definedand agreed at this point. Consideration needs to be given to whether the expectations are achieved progres-sively or once and for all; for example they may be split into those expectations for commissioning, validation,and routine manufacture. This will reflect the nature of the technology transfer, for example, whether it is a firsttransfer from R&D to a site, or transfer of a mature process to a third party.

4.11.2 Business Acceptance Criteria

Each project should be judged on its own merits. Some of the listed criteria will also be a part of the processvalidation. Key aspects may include:

• satisfactory product quality, chemical, physical, and usage in the dose form

• conversion efficiencies and output weights within the predicted ranges

• successful operation of the specified process over an agreed number of batches

• successful use of the analytical methods and specifications over an agreed number of batches and tests

• material usage within the predicted ranges

• health, safety, and environmental objectives achieved

• successful operation of the plant and equipment with regard to operability, labor, and utilization plantoccupancy times

• cost and economy factors are important and will probably have been included in any contractual agree-ment


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• documentation fully and satisfactorily completed within the defined timescale

• successful regulatory review

4.11.3 Deliverables During Routine Manufacture (Aftercare)

After the business acceptance criteria have been satisfied, an agreement on the continued and routine op-eration of the process is required and the following need to be considered for ongoing operations:

• The technology transfer Receiving Unit will operate the specified process.

• An appropriate change control procedure should be in place.

• Deviations should be noted and evaluated for communication with the Sending Unit. Based on agreedcriteria deviations may need to be sent to the Sending Unit.

• Further development of the process may be appropriate and initiated by either party, but only by prioragreement and through an appropriate change control procedure.

• obligation to provide updated health, safety, and environmental information


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DOSAGE FORMS (CLINICAL SUPPLIES AND COMMERCIAL PRODUCTS)

5 DOSAGE FORMS (CLINICAL SUPPLIES AND COMMERCIAL PRODUCTS)

5.1 INTRODUCTION

The search for new and improved medicines is a collaborative effort, in which Research and Development(R&D), together with Marketing and Operations Departments, bring together diverse scientific and engineer-ing expertise directed toward the achievement of therapeutic goals.

In Research, studies are undertaken that, hopefully, result in new active pharmaceutical ingredients or thedevelopment of a novel drug delivery mechanism. This research may be undertaken internally, within anorganization, licensed, or purchased externally. Development, together with Marketing and Operations De-partments, is then charged with creating dosage forms that are:

• Bioavailable

• Stable

• Aesthetically Pleasing

• capable of being manufactured reproducibly on a large scale

The effective transfer of dosage form related technology is complex. The timely transfer of validated analyticalmethods is pivotal to the success of the technology transfer, as it provides the criteria by which success isgauged. To be successful, the basis of formulation and/or product design should be communicated. Clearlydefined active pharmaceutical ingredient, excipient, and raw material specifications, and functional attributesshould be conveyed. Formulation science and process technology need to be delivered, as does the criticalinformation associated with environmental conditions required to protect personnel, facilities, and the envi-ronment.

The scale-up, commercialization, and transfer process for dosage forms can be initiated through differentroutes. As shown in the flowchart in Figure 5.1, new dosage forms requiring transfer to a commercial manu-facturing facility are developed through internal and external R&D, while existing commercial dosage formsmay require transfer to other commercial manufacturing facilities to meet a business or technical need. Thissection of the ISPE Technology Transfer Guide discusses how these factors combine, and outlines the keyelements of technology transfer associated with pharmaceutical dosage forms.

Figure 5.1 Focus of the Dosage Form Section


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5.2 STABILITY DATA

Data on stability of the dosage form and the API should be established under appropriate packaging andenvironmental conditions. The conditions for assessment of the dosage form should follow the guidance inICH Q1A (R), recognizing that there might be unique and/or more stringent regional requirements. It is alsoimportant to note that these conditions could be varied depending on the known storage and transport con-ditions. The same conditions may be used for the stability assessment of marketed intermediates.

5.2.1 Quality Profile and Specifications: Chemical, Physical, and Microbiological

Stability data for physical, chemical, and microbiological characteristics of a dosage form should be recorded.Microbiological information should provide details of:

• Preservative System

• Objectionable Organisms

• Bioburden Limits

• Sterility Requirements

5.2.2 Site Specific Data

In principle, the primary stability batches for drug product should be made at the intended commercial site;however, other sites may be used and pilot scale manufacture may be acceptable. The required number ofbatches to be manufactured will depend on the amount of stability data included in the submission and theneed to demonstrate equivalency.


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Option 1

Risk Level

Major

Moderate

Minor

Timing of Data Provision

At time of filing

Midpoint in the (application) reviewcycle

Post-approval in the annual report

Example

Modified Release Solid Orals

Sterile LyophillizedLiposomalMetered Dose InhalersDry Powder InhalersTransdermal Patches

Immediate Release Solid Orals(low solubility with either low or highpermeability)

Suspensions, semisolids, sterilesolutions (nasal, ophthalmic, topical)

Sterile powders

Products with API that is susceptibleto manufacturing conditions (biotech,biologicals, environmentally sensitive)

Immediate Release Solid Orals(high solubility with either low or highpermeability)

Non-sterile solutions, powders for oralsolution or suspension

Table 5.1 Typical Examples of Site Specific Stability Data Provision

The complexity of the dosage form is a critical factor in determining the site specific stability data for anoriginal submission. The FDA has defined complex dosage forms as those where quality and/or stability aremore likely to be affected by site transfer because the release mechanism, delivery system, and manufactur-ing process are more complicated and thus more susceptible to site transfer. For these products, threemonths of accelerated stability on three lots of product manufactured at the commercial site are recom-mended at the time of application submission.

Dosage forms with a moderate risk potential for stability issues upon site transfer would require three monthsof accelerated stability from a single batch produced at the commercial site, depending on whether sufficientprimary stability data are available in the submission. The primary stability data could be provided during thereview cycle of an application, ideally by the midpoint of the review.

Other dosage forms, which present a minor risk, would require a commitment for long-term stability studiesand accelerated studies, if NDAs on the first three production batches is sufficient. Data could be submittedin the annual report.


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Option 2

The alternative to generating site specific stability data is the proposal to use validation batches to certify thatthe process is adequately controlled. This option entails the submission of certificates of analysis (CoA) forthe validation batches, prior to the expected FDA action date. It would be expected that these validationbatches (no less than three) would be placed on a commercial stability data program and the data updated inthe product’s annual report. (See Section 6, Reference 11.)

5.3 APIs, EXCIPIENTS, AND RAW MATERIALS

Data for Active Pharmaceutical Ingredients (APIs) and all excipients should be consistent with the referencebatches (i.e., development batches or batches manufactured at the transferring site).

5.3.1 Active Pharmaceutical Ingredients (APIs)

The physical/chemical properties of the API, considered most likely to influence the product/process, shouldbe identified and well characterized. This section provides a listing of information and attributes that should beconsidered when characterizing an API. For marketed, mature products being transferred site-to-site, thisdata may not be as comprehensive or complete as it is for new products being transferred from R&D. Thetechnical transfer team should determine if additional data on the API needs to be generated, or if the existingdata are sufficient.

a) Manufacturer(s): name and address for each manufacturing site or contract manufacturing facility re-sponsible for APIs and all intermediates. Further information is available in the ISPE Baseline® Pharma-ceutical Engineering Guide Series. (See Section 6, Reference 7.)

b) Flow chart of synthetic pathway: a flow diagram outlining each step of the process and showing whereall raw materials enter the process. All critical steps, process controls and intermediates should be iden-tified.

c) Form/morphology (including photomicrographs): the definitive form of the API should be describedand any polymorphic and solvate forms identified. Photomicrographs and other relevant data should beprovided (i.e., X-ray, Differential Scanning Calorimetry (DSC), Melting Point/Range, etc.).

d) Solubility: A solubility profile should be presented. Typical solvents included are:

• Water

• Methanol

• Ethanol

• Acetone

• DMSO

• Tetrahydrofuran

• Methylene Chloride

• any other solvents used in the final stage of synthesis

The pH rate profile should be determined and included.


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e) Partition coefficient: the partition coefficient and reference to manner in which determined (i.e., water/octanol, calculated and by which method/commercial program, etc.) should be provided.

f) Intrinsic dissolution: the intrinsic dissolution rate and reference to method for determination should beprovided.

g) Particle size and distribution: the particle size distribution characteristics and reference to method fordetermination (i.e., sieve analysis, dynamic light scattering, laser diffraction, or aerodynamic) and type ofcharacterization for the distribution (i.e., number/weight, length, surface area, or volume) should be pro-vided.

h) Bulk physical properties: bulk and tap density data should be provided. Surface area and porosity datashould be included for further characterization, as appropriate.

i) Water content/hygroscopicity: water content and determination of hygroscopicity should be provided.Water activity data should be included for further characterization, as appropriate. Special handling re-quirements based on this data should be included.

j) Microbiological considerations (if applicable): assessment of microbiological attributes should beconducted in accordance with regional pharmacopoeial requirements, e.g.:


• USP/NF <151> Pyrogen Test (when necessary)



• EP 2.6.13 Microbial Examination of Non-sterile Products (Test for specified micro-organisms)


• EP 5.1.4 Microbial Quality of Pharmaceutical Preparations)


• JP 47. Pyrogen Test (Page 78-79), (Part I, General Tests, Process and Apparatus)

• JP 7. Microbial Attributes of Nonsterile Pharmaceutical Products (Page 1310-1312), (General Infor-mation)

• other requirements, as appropriate

k) Specifications: specifications and justification for release and end-of-life limits should be provided.

l) Stability: a summary of the studies conducted and the results obtained should be provided. Typicallystudies should conform to current ICH Guidelines or other appropriate guidance. Conclusions and rec-ommendations regarding retest date should be provided.

m) Synthetic impurities: a listing of potential and observed synthetic impurities should be provided. Data tosupport proposed specifications and typically observed levels should be included.


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n) Degradants: a listing of potential and observed degradation products should be provided. Data to sup-port proposed specifications and typically observed levels should be included.

o) Potency factor: typical, observed purity and justification for any recommended adjustment to the inputquantity of API for drug product manufacturing (based on purity, water content, salt form, etc.) should beprovided. Example calculations should be included.

p) Special considerations (i.e., sensitivity to light, moisture, etc., safety and environmental): recom-mendations and justification for special handling precautions should be provided.

5.3.2 Excipients

In general, each excipient should be identified by function and the physical/chemical properties consideredmost likely to influence the product/process should be identified, characterized, and controlled. The givenlisting of characteristics by dosage form is extensive and all may not apply to the specific dosage form beingtransferred. It is the responsibility of the technology transfer team to determine which characteristics areappropriate for the dosage form for which they are responsible.

Description of Functionality

The function of each excipient included in the formulation should be identified. Justification for inclusion of anantioxidant, preservative level, and levels of any excipient above guideline recommendations (WHO limits,FCC limits, or FDA Inactive Ingredients Guide) should be included.

Manufacturer(s)

Name and address for manufacturer(s) of each excipient should be included.

Specifications

• Compendial excipients: usually references compendial monograph. Appropriate information on char-acteristics that may affect drug product processing or quality attributes. Additional specifications andjustification for release limits should be included.

• Non-compendial excipients: a complete listing of specifications for all non-compendial excipients in-cluding appropriate analytical methods and justification for release limits should be included. Appropriateinformation on characteristics that may affect drug product processing or quality attributes should beincorporated.

• Novel excipients: novel excipients are those that are used for the first time in a human drug product orby a new route of administration. The manufacturing, chemistry, and controls (CMC) information for anovel excipient should be provided at the same level of detail as that provided for a drug substance. TheCMC information, or a cross-reference to a Drug Master File (DMF) that provides the CMC information,should be included.

Special Considerations

• Information concerning sensitivity to light, moisture, and safety and environmental considerations shouldbe provided.

• Recommendations and justification for special handling precautions should be provided.

• Detailed information regarding special storage conditions, e.g., refrigeration, low humidity, should beprovided.


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Regulatory Considerations

• Compendial status/grade: compendial status and other appropriate attributes should be listed.

• Validation status: appropriate information to support use of excipients from multiple suppliers should beprovided.

• Vendor qualification/audit(s) (Approved Suppliers): current status, in accordance with internal sup-plier assessment program, should be indicated.

• DMF number and reference letter(s) (if applicable): the supplier DMF number and reference letterinformation (including regulatory contacts at the supplier) for all non-compendial excipients should beincluded.

• Residual solvents/organic volatile impurities (OVIs): information on specific requirements for anyexcipient(s) should be included.

BSE/TSE concerns: appropriate justification other applicable information for animal derived raw material(s)and documentation to support compliance with current regulations should be provided.

• Range of concentration used in development (per SUPAC allowable changes): appropriate infor-mation to justify allowable ranges for excipients, where applicable, should be provided.

5.3.3 Oral Solid Dosage Form Excipients

In addition to the general considerations for all excipients listed in Section 5.3.2, the following should beevaluated for all solid dosage forms:

Form/Morphology

If necessary, the definitive form of the excipient should be described.

Particle Size and Distribution

If necessary, the particle size distribution characteristics and reference to method for determination (i.e.,sieve analysis, dynamic light scattering, laser diffraction, or aerodynamic) and type of characterization for thedistribution (i.e., number/weight, length, surface area, or volume) should be provided.

Bulk Physical Properties

Bulk and tap density data should be provided. Surface area and porosity data should be included for furthercharacterization.

Compaction Properties

If necessary, the appropriate compaction properties of the excipient should be described.

Solubility

If necessary, appropriate solubility data should be included.


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Water Content/Hygroscopicity

Water content and determination of hygroscopicity should be provided. Water activity data should be includedfor further characterization, as appropriate. Special handling requirements based on these data should beincluded.

5.3.4 Parenteral Dosage Form Excipients

In addition to the general considerations for all excipients listed in Section 5.3.2, the following should beevaluated for all parenteral forms.

pH/Ionic Strength

The appropriate pH range and ionic strength for any excipient should be provided.

Specific Gravity/Density

The appropriate specific gravity/density for any excipient should be provided.

Viscosity/Viscoelasticity

The appropriate viscosity and/or viscoelasticity for any excipient should be provided.

Moisture

The appropriate moisture content range for any excipient should be provided.

Osmotic Characteristics

The appropriate osmolarity for any excipient should be provided.

Microbiological Considerations

Complete assessment of microbiological attributes should be conducted in accordance with the regionalpharmacopoeial requirements, i.e.:


• USP/NF <151> Pyrogen Test

• EP 2.6.12 Microbial Examination of Non-sterile Products (Total viable aerobic count)



• EP 5.1.4 Microbial Quality of Pharmaceutical Preparations)

• Other requirements, as appropriate (e.g., Water For Injection (WFI); EP 01/2002:0169; JP Water forInjection (Page 1078-1079), (Part II Official Monographs)




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5.3.5 Semi-Solid/Topical Dosage Form Excipients

In addition to the general considerations for all excipients listed in Section 5.3.2, the following should beevaluated for all semi-solid/topical dosage forms.

pH

The appropriate pH range for any excipient should be provided.



Viscosity

The appropriate viscosity for any excipient should be provided.

Moisture



Assessment of microbiological attributes should be conducted in accordance with the regional pharmaco-poeial requirements (i.e., USP/NF <1111> Microbiological Attributes of Nonsterile Pharmaceutical Products,EP 2.6.12, JP 7. Microbial Attributes of Nonsterile Pharmaceutical Products (Page 1310-1312), (GeneralInformation), and other requirements.

Melting range

The appropriate melting point range for any excipient should be provided.

5.3.6 Liquid Dosage Form Excipients

In addition to the general considerations for all excipients listed in Section 5.3.2, the following should beevaluated for all liquid dosage forms.

pH




Viscosity

The appropriate viscosity for any excipient should be provided.

Moisture



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Assessment of microbiological attributes should be conducted in accordance with the regional pharmaceuti-cal requirements, i.e.:





• EP 5.1.4 Microbial Quality of Pharmaceutical Preparations

• JP 7. Microbial Attributes of Nonsterile Pharmaceutical Products (Page 1310-1312), (General Informa-tion)

• Other requirements

5.3.7 Transdermal Dosage Form Excipients

In addition to the general considerations for all excipients listed in Section 5.3.2, the following should beevaluated for all transdermal dosage forms.

pH




Viscosity/Viscoelasticity

The appropriate viscosity and/or viscoelasticity for any excipient should be provided.

Solubility

If necessary, appropriate solubility data for any excipient should be included.

Partition Coefficient

The partition coefficient for any excipient should be determined.

Intrinsic Dissolution

The intrinsic dissolution rate should be determined.


The particle size distribution characteristics and reference to method for determination (i.e., sieve analysis,dynamic light scattering, laser diffraction, or aerodynamic) and type of characterization for the distribution(i.e., number/weight, length, surface area, or volume) should be provided.


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Moisture



Assessment of microbiological attributes should be conducted in accordance with the regional pharmaceuti-cal requirements (i.e., USP/NF <1111> Microbiological Attributes of Nonsterile Pharmaceutical Products, EP2.6.12 Microbial Examinations of non-sterile Products (Total viable aerobic count), EP 2.6.13 Microbial Ex-amination of Non-sterile Products (Test for specified micro-organisms), EP 2.6.14 Bacterial Endotoxins, EP5.1.4 Microbial Quality of Pharmaceutical Preparations) and other requirements.

Adhesives

Ensure that all adhesives meet peel, sheer, and adhesion design criteria.

5.3.8 Inhalation Dosage Form Excipients

In addition to the general considerations for all excipients listed in Section 5.3.2, the following should beevaluated for all inhalation dosage forms.

Form/Morphology

If necessary, the definitive form of the excipient should be described.


The particle size distribution characteristics and reference to method for determination (i.e., sieve analysis,dynamic light scattering, laser diffraction, or aerodynamic) and type of characterization for the distribution(i.e., number/weight, length, surface are or volume) should be provided.

Bulk Physical Properties

If necessary, bulk and tap density data should be provided. Surface area and porosity data should be in-cluded for further characterization.

Solubility

If necessary, appropriate solubility data for any excipient should be included.

Water Content/Hygroscopicity

Water content and determination of hygroscopicity should be provided. Water activity data should be includedfor further characterization, as appropriate. Special handling requirements based on this data should beincluded.


Assessment of microbiological attributes should be conducted in accordance with regional pharmacopoeialrequirements (i.e., USP/NF <1111> Microbiological Attributes of Nonsterile Pharmaceutical Products, EP2.6.12 Microbial Examination of non-sterile Products (Total viable aerobic count), EP 2.6.13 Microbial Exami-nation of Non-sterile Products (Test for specified micro-organisms), EP 2.6.14 Bacterial Endotoxins, EP 5.1.4Microbial Quality of Pharmaceutical Preparations) and other requirements, as appropriate.


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For information regarding the control of particular excipient attributes important to inhalation dosage forms isavailable in the two FDA draft guidances: “Metered-Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) DrugProducts” (see Section 6, Reference 12) and “Nasal Spray and Inhalation Solution, Suspension, and SprayDrug Products” (see Section 6, Reference 11). Information in these guidances will be superseded when finalguidances are issued.

5.4 HEALTH, SAFETY, AND ENVIRONMENTAL INFORMATION

5.4.1 Health and Safety Assessment of all Materials, Products, and the Process

5.4.1.1 Process Risks and Controls

Information about the inherent risks of the manufacturing processes (such as reactive chemical hazards,exposure limits, fire and explosion risks, etc.) should be provided. Desk screening is the minimum require-ment, but laboratory studies and other testing methods should supplement this, as appropriate. ProcessHazard Analysis (PHA) techniques, such as a Hazard and Operability Studies (HAZOP), should be used toassess and as far as reasonably practicable eliminate HSE risks presented by proposed processes andassociated ancillary equipment. This should be conducted before transfer is started. Copies of the PHAs andphysical and chemical data generated by the Sending Unit should be provided to the Receiving Unit.

5.4.1.2 Compliance with Health Laws, Regulations, Permits, or other Standards

Local rules and regulations may apply for Health and Safety assessments and these should be considered.Recommendations for appropriate personal protective equipment and gowning requirements should be pro-vided.

5.4.1.3 Emergency Planning Considerations

An adequate plan for response to various scenarios such as gas or dust release, spillage, fire, and firewaterrun-off should be developed, as a contingency.

5.4.1.4 Identification of Waste Streams

The list will comprise input and output materials, efficiencies of use, utilities required, as well as process by-products such as off-gas venting patterns and waste packaging. Consideration should be given to:

• Composition

• Quantity

• Destination

Special provisions required to deal with waste streams (e.g., reuse/recycling options, disposal methods androutes, abnormal wastes during start up or shut down)

5.4.1.5 Identification of Releases to Air, Land, and Water

This section will require the detailed quantification and a detailed description of all waste minimization andprocess intensification projects associated with the process prior to control of all emissions to atmosphere,discharges to drain, and management and disposal of solid and liquid waste. Environmental monitoring tech-niques and analytical methodology required to validate legislative requirements should be developed andtransferred.


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5.4.1.6 Provision of Environmental Fate and Effects Data

The Development Unit or Sending Unit should have information available on the known (or probable) fate andeffects of materials used and generated in the manufacturing process. This will be required for the purposesof an assessment at the Receiving Unit including:

Environmental Risk Assessment

A formal assessment should be completed and documented. Environmental monitoring data should be com-pared against any regulatory or company developed discharge limits. Comparison with the most stringentglobal limits may be a useful indicator of potential future changes.

Environmental Impact Assessment

A formal assessment should be completed and documented and may need specialist input. There is also theoption to request a waiver from the Environmental Impact Assessment. This option, however, requires carefulassessment and planning.

Compliance with Environmental Laws, Regulations, and Licenses

A formal comparative review and assessment should be completed and documented.

Potential Off-Site Impacts

An adequate plan for response to various scenarios should be developed, as a contingency.

5.5 PROCESS INFORMATION

5.5.1 Detailed Characterization of Product

Important to any product technology transfer is the detailed characterization of the product/process beingtransferred. Information, such as qualitative composition, quantitative composition, physical description, methodof manufacture (narrative and flow chart), in-process controls and specifications, and packaging componentsand configurations, which can be used for a CMC section of a regulatory filing would provide a useful basis forprocess information. Supplemental information, such as safety and handling considerations, classification ofproduct, and indication, is also important to aid in product understanding at the Receiving Unit.

5.5.2 Chronology of Process Development

Review of manufacturing processes used during early phase of development:

• Powder-in-bottle (PIB)

• Hand filled capsules (state if capsules were filled with drug substance only, or if some manipulation withexcipients was needed)

• Small-scale manufacture: state technology (dry granulation, wet granulation, etc.) and equipment trainused. State if this is the start of market image development. Were any of these batches used in clinicaltests? State composition and manufacturing process of the batch used in clinical testing.

Review of scale-up activities and process optimization:

• Identify critical process parameters


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• statistical optimization of critical process parameters

• Pilot-scale development activities. Define what constitutes pilot-scale, and the number of batches made.What was the disposition of these batches?

• Full-scale development activities. Define what constitutes full-scale, and the number of batches made.What was the disposition of these batches?

• pilot-scale and full-scale development report (See Section 5.5.3.)

Regulatory related process development activities:

• review history of composition and process changes for all clinical batches

• Provide qualitative and quantitative composition of formula. State the suppliers for excipients and drugsubstance. Provide the narrative and the flowchart of the manufacturing process used for the pivotalclinical and generation of ICH registration stability data.

5.5.3 Process Capability and Statistical Process Control

R&D to Manufacturing

The transfer of technology from the R&D (Sending Unit) to Manufacturing (Receiving Unit) is the first key stepto getting a high quality product to the marketplace. The transfer of the process technology from the R&Dbench to large-scale manufacturing presents some unique challenges.

A thorough review of the R&D process development history and how processing parameters were set isessential. Based on this review, manufacturing modes of operation (including batch sizes and recommendedequipment) can be proposed for the initial scale-up batches. R&D should recommend any in-process testsand tentative finished product specifications, which have been optimized for the formula.

During the initial scale-up batches, all processing parameters and finished product specifications should bechallenged. Once a final manufacturing process has been established, key process data and product speci-fications should be tracked closely to establish normal process variability.

With more manufacturing history and data over time, the capability of the process to meet the establishedspecifications can be measured via Statistical Process Control (SPC) techniques. A robust process is onethat is routinely capable of meeting the finished product criteria and remains ‘in control’ (i.e., with processvariations due to normal variation only - no special causes of variation). If the process is not robust or capable(i.e., ‘out of control’), SPC tools provide a valuable way to further study and improve the process. These dataare also very valuable when transferring technology from one manufacturing site to another.

Site to Site Transfers

Before a currently approved commercial product is transferred from one manufacturing site to another, docu-mentation and information about the process and testing should be gathered, evaluated, and transferred.Approved manufacturing, packaging, cleaning, testing, and storage procedures should be in place at theReceiving Unit.

A review of existing process validation reports and annual product reviews should be conducted prior to thestart of any validation efforts. A justification for all processing ranges and all in-process specifications shouldbe confirmed.


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Operations and Quality Departments at both the Sending and the Receiving Units have responsibilities intransferring the manufacturing, packaging, storage, and testing of products from one site to another, andassuring that the product produced at the new site is of comparable quality to product produced at theprevious site. An additional responsibility is to ensure that all filing and regulatory requirements are met.

5.5.4 General Aspects

The following identifies the key general aspects of a technology/process transfer that should be addressedregardless of the dosage form:

• facility and equipment suitability in consideration of products such as penicillins, cephalosporins, cyto-toxic compounds, hormones/steroids, high potency compounds, etc.

• process technology selection

• equipment selection/materials of construction (compatibility)

• equipment IQ/OQ status

• in-process controls

• identification of process control points

• identification of product quality attributes

• qualification of critical processing parameter ranges

• qualification of in-process hold times/conditions (between two manufacturing steps)

• raw material order/method of addition

• bulk transfers (between processing steps)

• qualification of sub-steps due to equipment size and site applications, such as multiple granulation batchesbeing combined into one blend or volume of solution preparation

• special registration/regulatory requirements

• required documentation, e.g., SOPs, batch records

One approach that many companies use to ‘formalize’ their technology transfer activities is to develop a‘checklist’ specific to a dosage form type. This ensures that a consistent approach is being taken betweensites and it provides external partners with guidance for what information a company requires.

5.5.5 Critical Aspects by Dosage Form

For each dosage form, there are critical processing parameters that should be optimized, documented, andcontrolled to assure manufacturing process reproducibility. A statistical optimization of such parameters shouldbe attempted and documented. Furthermore, there are ‘critical performance aspects’ for dosage forms thatdefine the physical characteristics of the dosage form. These ‘critical performance aspects’ are followedduring manufacturing by measurement of in-process tests (also known as in-process controls). These in-process tests are established to better control the process and increase the ability of the dosage form toultimately meet all filed regulatory specifications. The following sections highlight some of the critical aspectsby dosage forms that should be documented and tracked.


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5.5.5.1 Solid Oral Dosage Forms

• technology used in making the dosage form, e.g., direct compression, wet or dry granulation

• granulation solution, or suspension hold time; granulation endpoint determination

• for wet granulated batches, technology employed in the drying of batches; determination of drying end-points.

• information about sampling techniques, unit sampling, and a definition of sampling points within theequipment

• particle size, bulk, and tap volume determinations; content uniformity or homogeneity determination

• definition of compression or encapsulation process; speed of compression or encapsulation; range quali-fication for force of compression, hardness, friability, weight uniformity, and thickness

• application of film coating, and definition of coating process endpoint; film coat weight gain

• imprinting, sorting, and packaging

5.5.5.2 Parenteral Dosage Forms

• cycle development of component preparation, sterilization, and depyrogenation

• product specific filter validation

• particulate inspection and corresponding process operating parameters

• classification of critical zones in the facility

• powder fill: particle size distribution/tap density/angle of repose, compressibility

• liquids: order of addition and mixing, pH adjustment, pH (final) and concentration, bioburden, oxygencontent, and sparging (agitation via the introduction of air or gas)

• media fill/environmental monitoring: viable and non-viable

• sterile filtration: integrity test, product potency sample (profile), single or tandem filtration, fill weight

• lyophilization: transfer, loading, and unloading of freeze dryer

• lyophilization cycle: development and optimization, stoppering and chamber bleed, cap skirt length, quali-fication of seal range parameters, and seal force monitor

• terminally sterilized: cycle development of product sterilization

5.5.5.3 Semi-Solid/Topical/Non-sterile Liquid Dosage Forms

Semi-solid dosage forms generally refer to topical lotion, cream, and ointment finished product forms. Non-sterile liquids refer to lower viscosity products and can include suspensions and solutions.


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• Batch Compounding:

- type of agitation

- mixing speed

- mixing time

- overall batch cycle time

• Emulsions:

- homogenization parameters (important to the particle size)

- in addition to mixing parameters

- temperature, heating, and/or cooling parameters (time, rate)

- vacuum or deaeration parameters

- product screening or filtration and material handling techniques (holding in a storage tank, pumping,etc.)

5.5.5.4 Inhalation Dosage Forms

Delivery mechanisms for these drug products include but are not limited to pressurized metered dose inhal-ers (pMDI), dry powder inhalers (DPI), nasal sprays, and nebulizers. Effective from May 27, 2002, Guidancefor Industry, Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products - Chemistry, Manu-facturing, and Controls Documentation, aqueous-based drug products for oral inhalation are required to bemanufactured as sterile products. Therefore, the critical aspects for parenteral dosage forms (see Section5.5.5.2) should be considered for these types of inhalation dosage forms as well.

Metered Dose Inhalers (MDIs)

• Compounding processes to include:

- rate and method of addition of the active ingredient

- mixing times and speeds

- configuration of the mixing vessel (baffles, agitator blades, homogenizer type, etc.)

- temperature during mixing

- agitation in the vessel during the filling process

- holding times and temperatures

• Filling:

- filling rate

- recirculation design and rate


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- overall processing time

- fill weights for both suspension and propellant

- If the propellant is filled through the metering valve, after the valve has been crimped onto the canis-ter: filling pressure and/or temperature and cycle time

• Crimping:

- heating the canisters to the desired temperature range and heat measurement technique

• Valve Functionality Testing:

- actuation force, dwell-time

• Product Testing:

- checkweighing including upper and lower limits of the finished product canisters

- establishing a minimum equilibration time between manufacturing and further processing

• Storage Configuration:

- upright or inverted

5.5.5.5 Transdermal Dosage Forms:

• Drug-in-adhesive type systems:

- homogeneity (uniformity) of drug-in-adhesive for ‘matrix’ systems

- solids content

- volatile substances: verify loss, if any, during mixing

• Gel viscosity test for reservoir type systems

- homogeneity (uniformity)

- solids content

- volatile substances: verify loss, if any, during mixing

- containing the gel/ointment inside of the heat-sealed area

• Solutions mixing time/speed studies, hold time/overall processing time

- If equipment is the same, this is part of the development scale-up and validation program. Much ofthis work is done prior to technology transfer. Hold times and stability are linked.

• Address oxygen and light effects


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• Storage of the reservoir and occlusion from light and oxygen for the finished system if necessary. Pouch-ing can address these issues for the finished product. The proper storage vessel will address the bulkreservoir.

• Laminate manufacture operating parameters (temperature, airflow, speed):

- hot melt laminating is more environmentally friendly

- solvent-based coating has more environmental concerns for venting/recovery/burning off solvents

It is strongly recommended that the process be formally transferred from development to production:

• If the equipment is different (smaller scale), the process should be developed, optimized, and validated.

• to address degradation products

• to determine formulation with use of approved preservatives

• to determine alternate storage conditions if possible to reduce/eliminate degradation

• to determine laminate slitting operating parameters (speed, tension):

- based on characteristics of jumbo roll and components including narrow roll slit width: narrow rolldiameter

• to determine membrane characterization parameters (for membrane controlled systems only):

- determine composition and ratios based on drug molecule, pressure gradients, rate of delivery, de-sired adhesion, and flexibility qualities, etc.

• to determine fabrication, die cutting, and pouching operating parameters (speed, temperature, and dwelltime)

- Equipment design varies. Continuous motion and intermittent motion equipment may be used. Levelof work and documentation required during technology transfer depends on whether the processwas developed on similar equipment to that in manufacturing. It is strongly recommended that this isvalidated and computer validation requirements (if any) are considered.

5.5.6 Detailed Manufacturing Process Description

A good definition of a manufacturing process encompasses several key aspects of a plant.

The facility layout is integral to the type of products and dosage forms that can be produced with consider-ation to a compliant process.

The utilities at a GMP site should be installed and operated following guidance given in the ISPE Baseline®

Guide on Commissioning and Qualification. Utilities, such as HVAC, specialty water, compressed air andspecialty gasses, require a design that incorporates good engineering practices to satisfy the preliminarysteps at a regulated site. The engineering department is responsible for designing a facility and correspond-ing layout to match the documented requirement specifications of the plant. An approved design qualificationprovides the background and next steps to purchase and install a utility system. A commissioning documentis always required for all equipment and systems. However, an Installation Qualification (IQ) program ismandatory for GMP related systems.


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The IQ can provide the documented evidence to support the utility layout, which in turn supports the otherkey aspects of a manufacturing process.

The utility layout supports the critical equipment requirements to manufacture a drug product. The IQ of GMPequipment is also driven by an engineering design qualification document to assure the user requirementspecifications. The equipment IQ will encompass the necessary facility layout and all utility systems support.

The transition or movement of raw materials, drug product, components, and personnel are also consideredintegral elements to a manufacturing process. Each of these transition elements is important to define appro-priate separation and segregation of blends to maintain quality standards. The distinction between all thetypes of products at the plant will facilitate the appropriate flow of each element. The design of individualprocess maps or flow charts of each of these elements would be an important consideration for a finalprocess flow chart.

Once a process flow chart is documented, a facility can manufacture a quality drug product. The clear defini-tion of this manufacturing process also provides the appropriate steps to sample and test all materials,products, components, etc., according to specifications.

5.5.7 Plant Operating Procedures/Documents

Before a technology transfer can proceed, documentation and information about the product and processshould be gathered and evaluated by the Sending Unit, and sent to the Receiving Unit. Required documenta-tion includes:

• master manufacturing batch records

• ancillary batch documentation (e.g., drying charts, SPC charts)

• storage requirements for raw materials and finished product

• process validation reports

• CMC (regulatory) documents

• analytical methodology

• stability information

• applicable material safety data sheets

• cleaning procedures

The Receiving Unit evaluates the information provided and prepares the same documents applicable to itsfacility. Careful attention should be paid to the types of equipment utilized in the process at the Sending Unit.The Receiving Unit should also take into consideration all requirements for changes made to approved dos-sier/application or other regulatory dossiers if changes to the equipment or batch size will be made whenplanning their transfer validation activities. FDA guidance such “SUPAC” (Scale-Up and Post Approval Changes)or “Changes to an Approved NDA or ANDA” guidance document should be utilized.

The manufacturing, packaging, cleaning, testing, and storage procedures should be written and approved atthe Receiving Unit prior to the start of the transfer activities. The Receiving Unit should have current docu-mentation in support of its equipment and facility. Equipment and facility IQ/OQ documentation, maintenance


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and calibration records, and SOPs should be in place and current. The Receiving Unit should operate underthe same Validation Master Plan as the Sending Unit if both are from the same organization. If the product isbeing transferred to a site belonging to a different organization, a Validation Master Plan should be in place.

5.5.8 Cleaning Procedures

Potency description of the API (operator/environmental exposure, skin permeability).

APIs may be grouped by similar characteristics:

• potency, toxicity

• cleaning to a specific limit, such as: none detected, or a therapeutic daily dose safety factor (e.g., 1/1000daily dose)

Operator exposure limits and routes of entry need to be determined:

• ingested

• inhaled

• skin absorption

• Personal protective equipment needs to be matched to the type of API (and any hazardous excipients)for the route of exposure

Disposal of rinsing process:

• facility drain system:

- public water supply concerns

• capture rinse:

- drum and remove as hazardous waste

- recover and recycle

• solubility of APIs, excipients, vehicles and any other relevant characteristics (e.g., corrosiveness, tem-perature sensitivity)

Grouping similar products:

• solubility factors (least soluble)

• most potent/toxic

• most difficult of group to clean: API, excipient, etc.

• must not be harmful to equipment

- egrade seals, packings, gaskets, etc.


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- etching metal and plastic surfaces (corrosives, electro-chemical reactions, etc.)

- deforming/damaging parts (corrosive, temperature, chemical reactions, e.g., oxidation or reduction)

Description of cleaning procedures tried and recommended cleaning procedure:

• based on specific requirements of product family, manufacturing equipment design and configuration,levels of cleanliness required, and limits of detection.

Cleaning procedure designed for:

• Manual Cleaning

• Clean in Place (CIP)

• Clean out of Place (COP)

Consider:

• cleaning agent and residue

• environmental concern

• exposure concern

• ability to perform meaningful sampling and analysis

• ability to develop meaningful test methods and validate the items in this list

Description of any difficult to clean areas/equipment or materials of construction requiring special attention:

• dead ends

• vertical versus horizontal surfaces:

- method of applying cleaning agent

- cleaning agent contact time

• special polymers used in equipment construction

• ability to sample from areas that are difficult to access

5.5.9 Regulatory Requirements

For a new product, the process information as described in Section 5.5.1 should be included in the “Methodof Manufacturing and Packaging” section of the NDA (or corresponding section of the New Animal DrugApplication (NADA) or ANDA) or appropriate sections of other regulatory dossiers. It is critical that this infor-mation reflects the process as it is to be executed at the commercial site of manufacturing.

For changes to approved products, all requirements for changes made to approved NDAs/ANDAs or otherregulatory dossiers should be taken into consideration if changes to the equipment or batch size will be madewhen planning their transfer validation activities. FDA guidance such “SUPAC” (Scale-Up and Post ApprovalChanges) or “Changes to an Approved NDA or ANDA” guidance document should be used.


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5.6 EQUIPMENT DESCRIPTION

5.6.1 Description of Major Process Items, Design Intent, and Capability

5.6.1.1 Design and capability of process equipment are equivalent in bioequivalence batches,the NDA, full-scale manufacture, etc.

• capacity (minimum and maximum)

• material of construction

• critical operating parameters

• critical equipment components (e.g., filters, screens, temperature/pressure sensors)

• determine range of intended use

5.6.1.2 Location

• facility and building specific

5.6.1.3 Description of differences and potential impact for development, scale-up and fullscale production equipment (facility to facility)

• comparison of functionality

• make/model differences

5.6.1.4 Process capability and systems validation documentation

• impact of new product on products currently manufactured with the equipment

5.6.1.5 Necessity to transfer equipment with product from Sending Unit (See Section 5.9.)

5.6.2 Standard Operating Procedures

5.6.2.1 Equipment specific procedures

• set-up

• operation included operating and validated ranges

• maintenance requirements, frequency, and critical parts/components

5.7 PACKAGING COMPONENT SPECIFICATIONS

5.7.1 Specifications

In general, there are two types of package component specifications. The first type that is most germane to atechnology transfer is the specification that was developed for the regulatory filing. These specificationsconsist of those critical elements needed to ensure a suitable container/closure system as further defined inthis section. The purchase specification must at least contain the critical elements in the filing specification


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but may further elaborate additional design, packing, processing, or labeling requirements. In addition tocontainer/closure specifications, there are also a number of considerations based on labeling, cGMP, pro-cessing, and business requirements that should be addressed.

5.7.2 Suitability

Suitability refers to the tests and studies used and accepted for the initial qualification of a component or acontainer/closure system for its intended use. Suitability also includes associated components, such as drop-pers and secondary components that provide protective properties or may migrate into a permeable primarypackage. Suitability is broken down into the four sub-groups:

1) Protection: this refers to those properties of the container closure system that protects the product fromthose environmental issues that can lead to degradation such as light, water vapor transmission, tem-perature, etc.

2) Safety: the materials of construction of the components must not leach harmful or undesirable amountsof substances into the product to which a patient will be exposed when treated with the product.

3) Compatibility: the materials of construction of the components must not interact with the product in away to adversely impact its quality.

4) Performance: this represents those functions that are critical to the functionality of the system or thedelivery of the drug.

These sub-groups are further refined based on the dosage form. The key dosage forms are as follows:

• Injectable or ophthalmic products

• Liquid–based oral and topical drug products and topical drug delivery systems

• Solid oral drug products and powders

For marketed, mature products being transferred site-to-site, this data may not be as comprehensive orcomplete as it is for new products being transferred from R&D. The technology transfer team will need todetermine if additional data on the suitability of packaging components needs to be generated or whether theexisting data are sufficient.

Protection

Injectable or ophthalmic products:

• light exposure, when appropriate

• reactive gases (e.g., oxygen)

• moisture permeation (powders)

• solvent loss (liquid-based dosage forms)

• sterility (container integrity) or increased bioburden

• seal integrity or leak testing of tubes (ophthalmics)


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Liquid-based oral and topical drug products and topical drug delivery systems:

• light exposure

• reactive gases (e.g., oxygen)

• solvent loss

• moisture permeation (liquid-based oral products would typically meet USP requirements for a tight orClass A container)

• microbial contamination (container integrity, increased bioburden, microbial limits, as appropriate)

• seal integrity or leak testing of tubes (topical drug products) and unit dose containers (liquid-based oraldrug products)

Solid oral drug products and powders:

• light exposure

• moisture permeation

• seal integrity or leak tests for unit-dose packaging

Safety


• manufacturer, grade, safety data, and chemical composition of all plastics, elastomers, adhesives, andassociated additives, as appropriate

• for elastomeric closures: USP Elastomeric Closures for injections testing USP/NF <381>, EP 3.1.6, JP59. Test for Rubber Closure for Aqueous Injection (Page 92-93), (Part I, General Tests, Process andApparatus)

• for glass components: USP Containers: chemical resistance - glass containers USP/NF <381>, EP 3.2.1,JP 57. Test for Glass Containers for Injections (Page 91-92) (Part I, General Tests, Process and Appara-tus)

• for plastic components and coatings for metal tubes: USP Biological Reactivity Tests USP/NF <381>, EP3.1.9, JP 11. Plastic Containers for Pharmaceutical Products (Page 1319-1321) and JP 61. Test Methodsfor Plastic Containers (Page 99-101), (Part I, General Tests, Process and Apparatus)

• If the extraction properties of the drug product vehicle may reasonably be expected to differ from that ofwater (e.g., due to high or low pH, or due to a solubilizing excipient), then drug product should be used asthe extracting medium.

• If the total weight of extracts significantly exceeds the amount obtained from water extraction, then anextraction profile should be obtained.

• For plastic or elastomeric components undergoing heat sterilization, it is current practice to request thatthe extraction profile be obtained at 121°C/1 hour using an appropriate solvent.


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• use of American Academy of Ophthalmology (AAO) cap and label color coding by therapeutic class

• depyrogenating and sterilizing procedures

• tamper/broached container evidence



• for most liquid-based oral drug products: appropriate reference to the indirect food additive regulations

• for liquid-based oral drug products with chronic dosing regimens that contain alcohol or a co-solvent:information to establish that exposure to extractables will be no greater than that expected to result fromthe use of similar packaging components when used with foods of similar extraction characteristics orthat the exposure is acceptable based on toxicological data

• for topical drug products (plastic coatings for metal tubes), and plastic drug delivery system components:USP containers testing

• for topical delivery systems: appropriate reference to indirect food additive regulations

• sterility methods or microbial limits based on area used

• child resistance

• tamper evidence



• for tablets, capsules, and powders, appropriate reference to the indirect food additive regulation may besubmitted, but may not be appropriate for powders for reconstitution

• for rayon and cotton fillers, data from USP monographs. For non-USP materials, data and acceptancecriteria should be provided.

• for desiccants and other absorbent materials: the size and shape should differ from that of the dosageform

• child resistance

• tamper evidence

Compatibility


• for coatings on metal tubes: coating integrity testing

• for elastomeric components: evaluation of swelling effects


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• for plastic components (including tube coatings): USP Containers USP/NF <381>: physicochemical tests- plastics testing, EP 3.1.9, JP 61. Test Methods for Plastic Containers (Page 99-101), (Part I, GeneralTests, Process and Apparatus)

• for ophthalmics: particulate matter and eye irritants

• stability studies also support compatibility


• for Low Density Polyethylene (LDPE) and glass components, USP containers testing on the actual con-tainer

• for coatings for metal tubes: coating integrity testing


• for glass and plastic containers, data from USP containers testing on the actual container

Performance


• functionality and/or drug delivery

• syringe force to initiate and maintain plunger force



• sizes of containers must be conducive to delivering the labeled volume

• bottle for suspensions must provide adequate geometry and headspace for agitation



5.7.3 MDI/DPI

5.7.3.1 Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products

Refer to Draft Guidance dated 10/98, Guidance for Industry Metered Dose Inhaler (MDI) and Dry PowderInhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation (see Section 6, Refer-ence 12).

5.7.4 Labeling

• use of American Academy of Ophthalmology (AAO) cap and label color coding by therapeutic class

• reference to tamper-evidence systems used

• manufactured/distributed by statements


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• customs information (country of origin)

• expiration dating

• ingredient listing

• how supplied and product description sections

• labeling controls (e.g., barcodes, punch holes luminescence, visual bars)

• design layouts compatible with machine designs (e.g., carton layout roll sizes and unwind direction)

• adequate provisions for coding methods (e.g., unvarnished areas, laser coding black area)

5.7.5 General Considerations

In the case of products made at multiple locations, it is important to minimize differences. This includessecondary packaging that could impact distribution centers and wholesalers.

The process must be considered for those attributes that are critical to the process but not container/closureintegrity. The use of automated vial inspection technology may dictate that tubing vials are required, as anexample. There could also be subtle differences, such as the type of knurling on a cap could scuff based oncapping methods.

5.7.6 Rationale for Package Design

The rationale for package design is to provide a technical summary of why certain decisions were made. Thissection provides a historical perspective of packages that were found unsuitable through actual studies orpackages that were determined unsuitable due to properties of the product. Examples include adsorption ofthe active into certain plastic compounds or a known reaction of the active to aluminum.

Evolution of Design Development from Clinical Packaging to Market/Final Market Image Package

The data and processing experience from clinical packaging is often used to support the market imagepackage. There may be some differences between the clinical package, the registration lots and the finalmarketed package. The purpose of this section is to provide a technical rationale for all changes. Typicaltypes of changes that occur could be bracketing a different fill or blister card configuration. All changes shouldbe reviewed against the FDA Guidance for Industry “Changes to an Approved NDA or ANDA” 11/99 (SeeSection 6) and data available to support all changes.

5.7.7 Packaging Operational Considerations

Environmental consideration noted under the facility requirements must also be considered in packaging(humidity, temperature, controlled drug security, sterile classification, safety classifications, etc.). The equip-ment must also be evaluated against known product sensitivities such as heat, potential for materials ofconstruction to adsorb the product, transfer pumps shearing, etc. In addition, some package features may beincorporated in the dossier/application. One example is the crimp pattern used on a tube. It is important thatthis information is specified.

In-Process Controls

There are a number of in-process controls that are typically used for the packaging operation. Some of theseparameters are dictated through equipment qualification, such as thermoforming temperatures. Some in-


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process controls are dictated by dossier/application commitments, such as seal integrity testing of blisters.Typical packaging tests include the following:

• torque testing

• fill (volume, weight, or units)

• delivery testing for systems

• seal integrity for vials, blisters pouches

• peal testing

• attribute

• particulate (sterile, ophthalmic)

• blister wall thickness

Test Methods

Test methods need to be qualified. Some of the sources for typical packaging test methods may be foundthrough a number of publications and organizations. The following are some of the more common sources:

• USP/NF

• EP

• JP

• PDA

• ASTM

Juran’s Quality Handbook (see Section 6, Reference 10) is a good source for setting up an attribute inspec-tion program.

5.8 FACILITY REQUIREMENTS

Manufacturing facilities receiving transferred product from either R&D or another manufacturing site musthave the infrastructure (i.e., facility, utility, and equipment) qualified for receipt of the specific dosage form.Further information is available in the ISPE Baseline® Pharmaceutical Engineering Guide Series. (See Sec-tion 6, Reference 8.)

5.9 QUALIFICATION AND VALIDATION

5.9.1 Qualification of the Equipment

The facility should always have a current inventory list of GMP impacted equipment and utilities. Most impor-tantly, the list should indicate the status of those qualifications.


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All new equipment and utility systems should have an engineering design specification to allow for an instal-lation and operation qualification program.

The IQ/OQ documentation of existing equipment and utility systems should be assessed as to whether thedocuments conform to current industry standards. A gap analysis should be performed and a correctionaction plan implemented with a time line to achieve conformance.

A review of operating parameters of equipment and utility systems should be assessed and documented. Afurther assessment of operating parameters with relation to product characteristics is typically done with aPerformance Qualification (PQ) program.

Applicable operating procedures for set-up, operation, cleaning, storage, and maintenance should be devel-oped by the conclusion of the OQ. Supporting documents such as drawings, manuals, maintenance logs,and calibration records are required to sustain a conforming qualification.

A formal change control program should be in place to describe the process for proposing a change toequipment and utility systems. This results in the documentation of the requirements to support the changeand the approvals of the approach.

5.9.2 Validation Plan

A plan or protocol should be prepared (if required) by the Receiving Unit, possibly with input from the SendingUnit who may be involved in agreeing or approving the plan. Agreement is also required on which processstages need be validated, e.g., all registered stages or those that are critical for product quality. Criteria todemonstrate equivalence with previously manufactured material will need to be established.

5.9.3 Validation of Process

Sending Unit to Provide to Receiving Unit:

• development report(s)

• change control documentation

• current master manufacturing and packaging procedures

• audit by Receiving Unit of current process (include non-process related practices that benefit the pro-cess)

• review of DMF

• review of API validation status/report(s)

• MSDS information on the dosage form, active ingredient, and excipients

• existing process validation reports

• quality control procedures, analytical test methods, and specifications

• product stability data

• investigations and complaint reports

• annual product reviews


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Receiving Unit Evaluation of Documentation and Preparation

The Receiving Unit should prepare a master batch record, and corresponding manufacturing and packagingprocedures for the product being transferred. These documents are critical to the validation exercise becausethey define the process being validated. These documents should be prepared after a thorough evaluation ofthe corresponding documents in place to manufacture and package the product at the Sending Unit. Docu-mentation should account for the specific differences that might exist between the sites (R&D versus Opera-tions or two different Operations sites). Additionally, existing site SOPs should be reviewed and updatedwhere necessary to include the product being transferred.

The process validation protocol would then be prepared, based on the definition of the process as describedabove, and based on the identification of critical process parameters and critical quality attributes, as ex-tracted from the information sent to the Receiving Unit (e.g., the development report). In order to include thetesting requirements in the validation protocol, the analytical methodology (test methods, test procedures,sampling plans, specifications) must be put in place at the Receiving Unit (see Section 3). If the validationprotocol includes any new or specialized sampling/monitoring requirements, these should be identified, sothat procedures/training for the validation personnel can be updated accordingly.

The Receiving Unit should incorporate any new manufacturing, packaging, and testing procedures into thesite’s training program to ensure that operators and analysts are trained, prior to conducting the processvalidation studies. This should ensure that the manufacturing process (and associated testing) is properlyexecuted.

Upon approval of all applicable batch documents, SOPs, test methods and the validation protocol, and aftersuccessful training, the Receiving Unit should execute the process validation study. While it may be valuableto have personnel present from the Sending Unit, it is critical that the Receiving Unit actually execute thestudy (i.e., operate the equipment, take the samples, perform the testing, etc.) so that the study is trulyrepresentative of what will occur at the site post-validation.

The Receiving Unit should then prepare a validation report, which summarizes the results of the study anddraws a conclusion regarding the validation status of the process. The Receiving Unit should also assess theregulatory requirements for commercialization of the transferred/validated process (e.g., approval of dossier/application and A/NDA Prior-Approval Supplement for a site change).

5.9.4 Cleaning Validation

Sending Unit to Provide to Receiving Unit:

• solubility information of actives, excipients, and vehicles

• minimum therapeutic doses of actives

• therapeutic category and toxicological assessment/evaluation

• existing validated cleaning procedures

• cleaning validation reports including chemical and micro data

• cleaning agents information

• transfer of cleaning analytical methods, analytical method for active residue, with documented evidencethat the cleaning agents do not interfere with the assay

• recovery studies to validate the sampling methodology


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Receiving Unit to Review Documentation and Prepare/Perform:

• evaluate/validate analytical methods

- develop or accept transferred methods

• new cleaning SOP

- based on transferred SOP if possible

• site specific

- permit requirements (if any)

• equipment specific

- match to transferred process if equipment and cleaning agent is the same

• develop SOP that it conforms to manufacturing site requirements for:

- document formats

- employee training requirements

- environmental requirements

• assess equipment configuration (i.e., same, similar, or different)

• batch confirmation (i.e., size or campaign)

• assess alternate cleaning agent effectiveness, if necessary

• review swabbing material used at the Sending Unit and update to Receiving Unit standard material (ifpossible)

• cleaning validation protocol

• perform cleaning validation study

• update procedures if necessary based on validation study

5.9.5 Computer Validation

For issues related to the validation of automated or computer systems, please refer to GAMP 4, Guide forValidation of Automated Systems. (See Section 6, Reference 1.)


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REFERENCES

6 REFERENCES

1. GAMP 4, GAMP Guide for Validation of Automated Systems, ISPE (Publishers), 2001.

2. Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics, US FDA, Febru-ary 1987.

3. Draft Guidance for Industry, Stability Testing of Drug Substances and Drug Products, US FDA, June1998.

4. ICH Q1A (R) Stability Testing of New Drug Substances and Products. (Published in the Federal Register(US FDA), Vol. 66, No 216, November 7 2001.)

5. ICH Q1B Photostability Testing. (Published in the Federal Register (US FDA), Vol. 62, No. 95, May 161997.)

6. ICH Q1D Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products.(Published in the Federal Register (US FDA), Vol. 66, No 186, September 25 2001.)

7. Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (available at http://www.fda.gov/cder/guidance/4286fnl.pdf). The Notice of Availability for Q7A published in the Federal Reg-ister on September 25, 2001 (Volume 66, No 186)The official Web site for the ICH may be visited at: http://www.ich.org/

8. ISPE Baseline® Pharmaceutical Engineering Guides for New and Renovated Facilities:Volume 1: Bulk Pharmaceutical ChemicalsVolume 2: Oral Solid Dosage FormsVolume 3: Sterile Manufacturing FacilitiesVolume 4: Water and Steam SystemsVolume 5: Commissioning and Qualification

9. Occupational Medicine: State of the Art Reviews Volume 12, Number 1, January-March 1997 (GreggStave and Ron Joines, Editors). Hanley & Belfus, Inc., (Publishers).

10. Joseph M. Juran and A. Blanton Godfrey (Editors), Juran’s Quality Handbook 5th Edition, (McGraw-HillEducation, 1999; ISBN: 007034003X).

11. Guidance for Industry, Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products -Chemistry, Manufacturing, and Controls Documentation, U.S. Department of Health and Human Ser-vices, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2002CMC.

12. Guidance for Industry Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chem-istry, Manufacturing, and Controls Documentation, U.S. Department of Health and Human Services Foodand Drug Administration Center for Drug Evaluation and Research (CDER) October 1998 CMC.


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REFERENCES

Useful Web sites include:

• FDA Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug ProductsChemistry, Manufacturing, and Controls Documentation http://www.fda.gov/cder/guidance/2180dft.htm

• FDA Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products- Chemistry, Manufacturing, and Controls Documentation http://www.fda.gov/cder/guidance/4234fnl.htm

• FDA Guidance for Industry: Changes to an Approved NDA or ANDA http://www.fda.gov/cder/guidance/2766fnl.htm

• FDA Guidance for Industry: Changes to an Approved NDA or ANDA Questions and Answers: http://www.fda.gov/cder/guidance/4163fnl.htm

• The Japanese Pharmacopoeia, Fourteenth Edition in English (ISBN4-8408-0672-1 C3047) http://jpdb.nihs.go.jp/jp14e

• UN Economic Commission for Europe Transport Division: http://www.unece.org/trans/danger/danger.htm

• US DOT Hazardous Materials Regulations: http://www.text-trieve.com/dotrspa/dotbody.asp

• Canadian Transport Dangerous Goods Regulations (CTDGR): http://www.tc.gc.ca/tdg/menu.htm

• Mexican Standards for Land Transport: http://hazmat.dot.gov/nomslst.htm

Further information for scheduled or controlled drug substances may be found at:

• UK: http://www.homeoffice.gov.uk/drugsfor/domesticlic.htm

• US: http://www.usdoj.gov/dea/pubs/schedule.pdf or

• US: http://www.usdoj.gov/dea/concern/abuse/chap1/penal/chart3.htm

Further information on cleaning validation may be found at:

• http://www.fda.gov/ora/inspect_ref/igs/valid.htm

Note: ISPE cannot guarantee and is not responsible for broken or faulty links.


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TEMPLATES

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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TEMPLATES

Template 1 Example of an EC Supply Label (Nitric Acid)

NITRIC ACID

‘XYZ’ Chemicals, Chemicals Road, London, UK. Tel: 0208 111 222

OXID CORR

EC LABEL 231-714-2

Contact with combustible material may cause fire

Causes severe burns

Keep locked up and out of the reach of children

Do not breathe vapour

In case of contact with eyes, rinse immediatelywith plenty of water and seek medical advice

Wear suitable protective clothing

In case of accident or if you feel unwell, seekmedical advice immediately (show the label wherepossible)


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TEMPLATES

Template 2 HSE Checklist - General Facilities

{Project Number}

{Product, Process, or Method Name}

Prepared By: ________________________ Reviewed By: _________________________Date: ________________________ Date: _________________________

{Enter Responsible Party} {Enter Responsible Party}Sending Unit Receiving Unit

Reviewed By: ________________________ Reviewed By: _________________________{Enter Responsible Party} {Enter Responsible Party}Sending Unit Receiving Unit

Approved By: ________________________ Approved By: _________________________Date: ________________________ Date: _________________________

{Enter Responsible Party} {Enter Responsible Party}Head Sending Unit Receiving Unit

Reviewed By: _________________________Date: _________________________

StatisticianReceiving Unit


Quality Assurance Quality AssuranceSending Unit Receiving Unit

1.1 ISSUE YES/NO Comments

General:

Do existing facilities of Receiving Unit meet current Companyand regulatory EHS standards?

Does the facility have capacity for process on scale-up?

1.2 HAZARD AND PROCESS INFORMATION YES/NO Comments

Are company MSDSs available for all proprietary materials/products?

Are generic/vendor MSDSs available for commercialchemicals/excipients?

Is phys-chem hazard information available for proprietary andvendor materials/products?

Is occupational toxicology hazard information available forproprietary and vendor materials/products?

Have inherent risks of the manufacturing processes (such asreactive chemical hazards, fire, and explosion risks) beenidentified?


91

TEMPLATES

1.3 OCCUPATIONAL EXPOSURE/OCCUPATIONAL HYGIENE YES/NO Comments

Have OELs or Occupational Hazard Categories (OHCs) beenestablished for all process materials

Are Occupational Hygiene (OH) monitoring data available?

Is an OH sampling and analytical method required?

Is there a schedule for the development of an OH samplingand analytical method?

1.4 OCCUPATIONAL HEALTH YES/NO Comments

Will there be a requirement to conduct health surveillance orbiological monitoring?

Have health surveillance or biological monitoring methodsbeen developed and are they available?

Are there any potential employees at higher risk due topre-existing illnesses or conditions?

1.5 ENVIRONMENTAL ISSUES YES/NO Comments

Is all eco-tox data available for available for proprietary andvendor materials/products?

Have all treatability issues been resolved for wastewater,solvent recovery, air emissions, solid waste?

Have all cleaning issues been addressed?

Have all spill and disposal issues been addressed?

1.6 PLANT DESIGN & ENGINEERING YES/NO Comments

Are there any outstanding issues associated with exposurecontrol/process safety control/other safety and ergonomiccontrols?

Are there any outstanding issues associated with cleaning,wastewater treatment, waste incineration/waste management,solvent recovery, and air pollution control?

Are there any outstanding issues associated with receipt/storage/handling of hazardous materials?

Are there any outstanding issues associated with spill anddisposal methods?

Has account been taken of energy efficiency considerations?


92

TEMPLATES

1.7 RISK ASSESSMENTS YES/NO Comments

Has Receiving Unit used an appropriate Process HazardAnalysis technique such as a HAZOP?

Has Receiving Unit initiated appropriate risk assessments(e.g., COSHH)?

Is an Environmental Risk Assessment in preparation?

Are other EHS risk assessments underway?

1.8 REGULATORY ISSUES YES/NO Comments

Has the EINECS/ELINCS status been identified forintermediates and commercial chemicals and appropriatenotification actions initiated?

Have Receiving Unit Control of Major Accident Hazard(COMAH) Regulations implications been addressed?

Are there any other EHS Regulatory issues that requireaddressing?

Are there any outstanding issues with environmental operatingpermits/consents?

Are there any outstanding issues with safety and fire protectionoperating permits/consents?

1.9 TRANSPORTATION/LABELLING ISSUES YES/NO Comments

Have all transport/labelling issues been identified?

Have materials been properly classified for transportation andsupply?

Have appropriate transport/supply labels been identified?

Has proper packaging been identified?

Are selected carriers competent to transport the materialsinvolved?


93

TEMPLATES

Template 3 HSE Data Checklist - Detailed

{Project Number}







Reviewed By: _________________________Date: _________________________




DUST ELECTROSTATIC PROPERTIES (Solids)

Minimum Ignition Energy

Resistivity @ Ambient Humidity

Resistivity @ Low Humidity

Charge Relaxation Time @ Ambient Humidity

Charge Relaxation Time @ Low Humidity

DUST EXPLOSION PROPERTIES (Solids)

Group (A/B)

Pmax

DP/DT

DATA(Y/N)

DATA GAPCRITICAL

(Y/N)

COMMENTSCOMPLETIONDATE FOR

OUTSTANDINGDATA

PROPERTIES


94

TEMPLATES

DATA(Y/N)

DATA GAPCRITICAL

(Y/N)


OUTSTANDINGDATA

PROPERTIES

Kst

St

LOC

FLAMMABILITY (Solids)

Train Fire

Minimum Ignition Temperature - Cloud

Minimum Ignition Temperature - Layer

FLAMMABILITY (Liquids)

Flash Point

Auto-Ignition Temperature

LOC (Liquid)

GENERAL PHYSICAL PROPERTIES

Melting Point

Boiling Point

Relative Density

Water Solubility

Partition Coefficient (Log P)

pH

Particle Size

TOXICOLOGICAL PROPERTIES

Acute Toxicity

Repeat Dose Toxicity (target organs)

Skin Irritation

Eye Irritation

Skin/respiratory sensitization


95

TEMPLATES

Reproductive Effects

Genetic Toxicity

Carcinogenicity

Pharmacological Effects (if drug substance)

OCCUPATIONAL HYGIENE (OH)

Occupational Exposure Limit (OEL)

Exposure Hazard Category (EHC) orOccupational Exposure Band (OEB)

Occupational hygiene analytical method

Occupational hygiene sampling method

Occupational hygiene monitoring data

ENVIRONMENT DATA

Water Solubility

Dissociation Constants (pKa)

Vapor Pressure

Volatility

Distribution Coefficient (Log Dow)

Activated Sludge Respiration Inhibition Test (ASRIT)

Sludge/soil adsorption/desorption

Microbial Toxicity

Acute toxicity to Daphnia (EC50, 48hrs)

Acute toxicity to algae (IC50, 72hrs)

Acute toxicity to fish (LC50, 96hrs)

Degradation Mechanisms -1. Photodegradation2. Biodegradation3. Hydrolysis

DATA(Y/N)

DATA GAPCRITICAL

(Y/N)


OUTSTANDINGDATA

PROPERTIES


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TEMPLATES

1 TECHNICAL EVALUATION

A. regulatory strategy, process description, product monograph

B. assess APIs and Excipients

C. selection of packaging components

D. verify final product specifications

E. PTD process review (Process Flow Diagram)

F. obtain product forecast

G. facility infrastructure capability

H. product sourcing strategy

I. issue stability protocol

J. determine batch size and number of batches

K. cleaning

Template 4 Checklist for Technology Transfer of:

{Project Number}







Reviewed By: _________________________Date: _________________________





97

TEMPLATES

• determine if site SOP is adequate

• identify any needs for special cleaning

a. detergents (specific)

b. decontamination procedures

c. request for special SOP cleaning method

• develop appropriate equipment cleaning procedure

• develop analytical methods

a. bulk drug

b. granulation

c. tablets

• transfer final method to site

L. EHS process review

• toxicity assessment

• explosiveness

• waste Disposal

M. machinability studies (line trial)

N. preliminary tooling/equipment selection

O. third party development report/Filing

P. D-value testing (sterile)

Q. preliminary filter studies

2 PROCESS JUSTIFICATION STUDY PLAN

A. develop/obtain process parameters

B. draft available for review

C. review study plan

D. finalize plan

E. approve


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TEMPLATES

F. coordinate analytical testing (internal or third party laboratory)

G. kick-off meeting with Plant Technology Transfer Team

3 LABORATORY PREPARATION

A. QC laboratory qualification

• provide product, test standards, and methods

• verify laboratory equipment in place (HPLC columns, etc.)

• verify transfer of laboratory methods/laboratory qualification

• provide draft laboratory qualification protocol

• finalize laboratory qualification protocol

• execute laboratory protocol

B. approval for laboratory

4 LONG TERM STABILITY STUDIES/TECH TRANSFER

A. prepare Time and Events (T&E)

B. plant equipment

• assess equipment needs

a. equipment needs list

b. determine if dedicated equipment is needed

c. provide approved drawings for equipment/tooling

d. order equipment

• receive equipment/tooling

a. inspect equipment/tooling

b. qualifications (IQ/OQ/PQ/validation)

c. run equipment troubleshooting

• LTSS/technology transfer (continued)

C. plant readiness

• pharmacy


99

TEMPLATES

• room availability

• equipment: bins, presses, mixers, etc.

• operators

D. prepare batch records

• provide FMDs

• draft batch records

• complete draft review

• issue master batch record

• master batch records signed

• tablet weight control records (solid dosage only)

E. materials for manufacturing

• request and obtain product list numbers, SAP numbers, and legacy

• estimate raw materials requirements

• prepare Bill of Materials (BOM)

• issue shop order against BOM

• supply materials

a. bulk drug substance

1. order

2. receive

3. QC release

b. excipients

1. order

2. receive

3. QC release

c. packaging components

1. order

2. receive

3. QC release


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TEMPLATES

5 TRAINING OF PLANT PERSONNEL

A. batch record review

B. cleaning

C. equipment training

D. EHS/safety/MSDS

6 MANUFACTURING ACTIVITIES

A. issue batch records

B. issue lot numbers

C. manufacture batches

• delivery of materials to manufacturing area

• room and equipment approval

• production

• in-process sampling

D. submission of all samples for testing

E. cleaning - swab sampling

7 POST-PROCESS MANUFACTURING

A. executed batch record review

B. deviation reports, approve batch records

C. release testing

D. packaging (as per release testing requirements)

E. shipment of product to sites of CSO, stability testing, etc.

F. initiate stability studies

G. issue Certificates of Analysis

H. obtain P.J. physical and analytical test results

I. storage of finished product

J. complete batch disposition


101

TEMPLATES

K. wrap up meeting (lessons learned)

L. release of batch records

M. write P.J. technical report

N. review and approval

O. validation support


102

TEMPLATES

Transfer of Potency Testing of {Product} by {Method Name/Number}

From {Sending Laboratory} to {Receiving Laboratory}

Note to Reader: This template uses potency testing as an example. The template may be applied to othertypes of analytical procedure and the reader is encouraged to modify the template, accordingly.

1.1 INTRODUCTION

1.2 PURPOSE

The purpose of transferring the {Product} potency method from {Sending Laboratory} to {Receiving Labora-tory} is to consolidate all lot release potency assays into one area. {Sending Laboratory} will perform all

Template 5 Transfer of Analytical Procedures

From {Sending Laboratory}

To {Receiving Laboratory}

PROTOCOL

{Product Name}

{Analytical Property}

{Procedure Number}


Scientist ScientistSending Laboratory Receiving Laboratory

Reviewed By: ________________________ Reviewed By: _________________________Analyst AnalystSending Laboratory Receiving Laboratory


Laboratory Head Laboratory HeadSending Laboratory Receiving Laboratory

Reviewed By: _________________________Date: _________________________

StatisticianReceiving Laboratory




103

TEMPLATES

potency assays for lot release and stability and {Receiving Laboratory} will perform customer service assaysfor {Product}.

1.3 SPONSOR AND TESTING FACILITIES

Sponsor: (Testing Lab)

Testing Facility:

1.4 RESPONSIBLE PERSONNEL

Validation Director:

Responsible Analysts:

Quality Assurance:

1.5 MATERIALS AND EQUIPMENT

1.6 EXPERIMENTAL DESIGN

Method {Method Name} is the validated assay method used to test premixes, soluble powder, and injectableproducts for {Product} potency. {Laboratory Name} has the training and technology to perform turbidimetricassays and the analyst currently performing the product release assays in {Laboratory Name} is being trans-ferred with the assays, so no training or technology transfer for the receiving laboratory is required. Thetransfer will focus on the differences between the laboratories, such as media preparation or equipment andenvironment, to determine if there are differences between the laboratories. The same analyst will be per-forming the analysis in both laboratories.

Sample preparations are not required to transfer this method; therefore, to reduce variation due to samplepreparation, one solution of an internal control standard will be prepared and used for all sample analysis.This study will transfer, from {Sending Laboratory Name} to {Receiving Laboratory Name}, the followingmethods which use:

{List of relevant Method Names /Method Numbers}

1.7 METHODOLOGY

One stock reference standard solution will be prepared at a concentration of approximately 1000 mcg ofactivity/ml according to {Method Number}. This solution will be designated for making the internal controlstandard samples for all the assays.

A different stock reference standard solution, used to make the test standard curve, will be prepared for eachsetup.

Perform 5 setups in the transferring laboratory and 5 setups in the receiving laboratory. A setup consists of aseparate standard curve preparation, different day, separate preparation of inoculated media {media may bethe same lot number} and separate sample preparations {from the same stock solution}.


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TEMPLATES

Samples are prepared from the 1000 mcg of activity/ml stock solution to target the midpoint of the standardcurve (3 - 4 mcg of activity/ml). For each setup, prepare 3 separate samples. Test the samples as directed in{Method Number}.

1.8 ACCEPTANCE CRITERIA

Test to determine if a statistically significant difference (a = 0.05) exists in the means and variability betweenthe different laboratory preparations. If no significant differences are found between the laboratory prepara-tions, the two laboratories will be considered equivalent. Any statistically significant differences found will besubject to a technical review.

1.9 DOCUMENTATION AND ARCHIVING

All raw data will be recorded on the proforma results sheets attached and submitted to the Validation Directorfor compilation into a report.

All raw data generated from the study must be retained as detailed in SOP No:_______ and _______ for atleast 5 years after issue of the final report.

1.10 AMENDMENTS AND DEVIATIONS

No changes revisions or modifications should be made to this protocol unless approved by the ValidationDirector following consultation with the sponsor; any such changes should be recorded in an amendment inaccordance with SOP No:_______ .

The details and procedures set out in this protocol should be followed at all times during the conduct of thestudy. Should any deviations from this protocol occur they should be recorded and reported in writing to theValidation Director immediately.

1.11 FOLLOW-UP

After the transfer of the method to the receiving laboratory, the assay result for each of 10 internal controlsamples will be evaluated by the receiving laboratory using control charts to ensure no significant shift inresult values has occurred.

1.12 REFERENCES

{References to methods and other appropriate documentation.}


105

TEMPLATES

Template 6

Data Report Form

Identification - IR

{Company Name: Site Name}Site: _______________________________________________

{Name of Analyst (not signature)}Analyst: ____________________________________________

Instrument I.D. _______________________________________

{ATTACH IR SPECTRA OF SAMPLE AND STANDARD}

Data File Name: _____________________________________ (if applicable)

Notebook Reference: _________________________________ (if applicable)

Analyst: ____________________________________________ Date: _________________________

Checked By: ________________________________________ Date: _________________________

Supervisor: _________________________________________ Date: _________________________


106

TEMPLATES

Template 7

Data Report Form

Assay: System Suitability - Resolution



HPLC I.D. __________________________________________

The resolution is calculated using the equation provided below or another suitable equation.

1.18 (t2 - t1) x 60Resolution = ________________

(w2 + w1)

t1 = retention time of {Drug Substance}: Lot 1 = ____________________________ minutes

t2 = retention time of {Drug Substance}: Lot 2 = ____________________________ minutes

w1 = peak width at ½ height of {Drug Substance}: Lot 1 = ____________________________ seconds

w2 = peak width at ½ height of {Drug Substance}: Lot 2 = ____________________________ seconds

Resolution = ________________________________________

Data File Name: _____________________________________

{Attach Chromatogram and Injection Report. If resolution is calculated electronically, attach report.}


Analyst: ____________________________________________ Date: _________________________

Checked By: ________________________________________ Date: _________________________

Supervisor: _________________________________________ Date: _________________________


107

TEMPLATES

Template 8

Data Report Form

Assay: System Suitability - Precision



HPLC I.D. __________________________________________

AREA OF ASSAY STANDARD:

Injection Number1 Peak Area Injection Number Peak Area

1 __________________ 6 __________________

2 __________________ 7 __________________

3 __________________ 8 __________________

4 __________________ 9 __________________

5 __________________ 10 __________________

11 __________________

12 __________________

Mean Peak Area: _________________________ Mean Peak Area: _________________________

Standard Deviation: _______________________ Standard Deviation: _______________________

% RSD2 (first 5 injections): _________________ % RSD (all injections): _____________________

Data File Name: _____________________________________

{Attach the complete set of chromatograms and injection reports in order for all chromatographic runs.Include printouts for the run sequence file and electronic integration parameters.}


Analyst: ____________________________________________ Date: _________________________

Checked By: ________________________________________ Date: _________________________

Supervisor: _________________________________________ Date: _________________________

1 Injections for calculation of RSD throughout the run. Number of injections should be determined by number of samplesin each individual analysis. Use additional forms if necessary to show all data.

2 %RSD = (Standard Deviation/Mean) x 100%.For individual use only. © Copyright ISPE 2003. All rights reserved.

108

TEMPLATES

1.1 INTRODUCTION

1.2 PURPOSE

The purpose of this protocol is to describe the ruggedness evaluation for the transfer of the Dissolution(Standard Test Method-XXX-00, Attachment 1) {Product Name} Tablets from the personnel of {Sending Labo-ratory (Location)} to the personnel of {Receiving Laboratory (Location)}. The purpose of conducting theruggedness evaluation is to establish documented evidence that the results generated by the personnel of{Receiving Laboratory} and of the {Sending Laboratory} on identical samples are equivalent within pre-deter-mined acceptance criteria. The {Sending Laboratory} will issue a final report summarizing all the resultsobtained during this study.


Sponsor: {Testing Lab}

Testing Facility:

Template 9

DISSOL-QAL-003PDissolution Test for {Product Name} Tablets

Method Transfer from the {Sending Laboratory Name}to {Receiving Laboratory Name}

PROTOCOL






Reviewed By: _________________________Date: _________________________





109

TEMPLATES




Quality Assurance:



The following batches of samples will be used for the method transfer:

1.7 METHODOLOGY

1.7.1 Dissolution

Referring to Analytical Method STM-XXX-00, perform one (1) six (6) unit dissolution for each batch.


The acceptance criteria for each test will be those used for method transfers as established in SOP-QL-XXX-00. They are as follows:

1.8.1 Dissolution

The absolute difference between the average of the dissolution results at the Q value (20 minutes) does notdiffer more than 6.0% between the two laboratory groups.

Results should be reported to the nearest whole number.

If these requirements are not met, both laboratory groups will review the data, and recommendations forcorrective actions will be made. Any proposed action will be documented in writing and attached to thisprotocol.

Method Test Dosage Batch Number

STM-XXX-00 Dissolution2mg EXM56098A

2mg EXP55098B


110

TEMPLATES


Both laboratory groups will summarize the results obtained during the transfer. The ABC Laboratory willgenerate a transfer report, and it will be reviewed and approved by both the sending and receiving laboratorygroups. The transfer report will contain the following:

• a reference to the protocol and any amendment

• results tabulated for each lot and a summary table comparing all laboratory groups

• a statement indicating the qualification status

• approval signatures from both the Sending Laboratory and Receiving Laboratory. The signatures indi-cate agreement with the qualification statements included in the document.

The {Sending Laboratory} will keep in their transfer file copies of all data and data analysis from both labora-tory groups. This will include the tables or parts of tables contained in this transfer protocol, completed andapproved by a laboratory authorized individual. The {Sending Laboratory} will maintain the original raw data.





111

TEMPLATES

% Dissolution

Batch EXM56098A (2mg) EXP55098B (2mg)

Vessel ABC XYZ ABC XYZ

1

2

3

4

5

6

Average (%)

Difference

Pass or Fail

1.11 RESULTS

Results: Dissolution

Acceptance Criteria: The absolute difference between the average of the dissolution results at 20 minutesdoes not differ more than 6.0% between the two laboratories. Results should be reported to the nearestwhole number.


112

TEMPLATES

1.1 PURPOSE

To verify that a membrane filtration method for the sterility test of the product conforms to the Ph. Eur. 3, 2000.The data generated will consist of the growth rates of each organism, comparing test systems exposed to theproduct to those not exposed to product (positive controls).

This protocol serves as the method for one validation run that will be performed using this product. Separateworksheets will be generated for the validation set-up.

1.2 REFERENCES

• Ph. Eur. 3, 2000 Sterility Test <2.6.1>

• (Local sterility test method also listed)

For equipment and material used in the testing of this product, see the worksheet section of this protocol.

Template 10

Method Validation Protocol

Sterility Test

{Product Name}






Reviewed By: _________________________Date: _________________________





113

TEMPLATES

1.3 ORGANISMS AND ORGANISM PREPARATION

Prior to the validation experiment, dilute organisms to a concentration of between 10 and 500 organisms perml using sterile saline. Use a volume of each diluted organism, which contains less than 100cfu for theinoculum. Perform a plate count for each organism, in duplicate, to verify the number of viable organismspresent. Incubate all plates at 30-35ºC for at least 40 hours before counting the colony forming units (cfu).Incubate the Clostridium plates anaerobically in a Gaspack jar. Refrigerate the organism suspensions untilready to use the validation studies.

Aspergillus niger ATCC 16404

Bacillus subtilis ATCC 6633

Candida albicans ATCC 10231

Clostridium sporogenes ATCC 19404

Staphylococcus aureus ATCC 6538

Pseudomonas aeruginosa ATCC 9027

(The organisms used in these studies are listed in the Ph. Eur. 3, 2000.)

1.4 PROCEDURE

1.4.1 Test Procedure

1) Prepare area, supplies and equipment by appropriate sanitization.

2) Pool the entire contents of 40 units into a sterile container and slowly pump the entire solution from the 40units through a pair of Steritest canisters, which contain cellulose nitrate membranes.

3) Rinse each of the filter canisters continuously with two 100 ml portions of NaCl-phosphate-peptone-buffer pH 7.0 with 0.1 % Tween80.

4) Fill each of the filter units a third time with approximately 100 ml of above-mentioned buffer, but do notfilter through. Inject an aliquot containing 10 – 100 cfu of the Bacillus subtilis working inoculum into eachof the filter canisters. Inject through the tubing close to the canister’s tubing connection.

5) Filter the inoculated rinse portion through the canisters and cap the bottom port of each canister with thesupplied cap.

6) Fill each canister with approximately 100 ml of the appropriate media (see Table 1).

7) Seal each canister by closing the transfer tubing near the point of attachment to the canister using thepinch clamp. Cut the transfer tubing upstream of the pinch clamp and attach the open end which isconnected to the canister to the canister’s air vent.

8) Repeat steps 2-7 for additional canister pairs, so that that there is one canister representing each inocu-lum/media configuration given in Table 1.


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TEMPLATES

Table 1

9) For the positive controls, use approximately 100 ml of sterile water to simulate the product and repeatsteps 2-9, generating one positive control for each organism/media combination.

10) For the negative control, repeat steps 2- 7, using approximately 100 ml of sterile water to simulate prod-uct, except, do not add any inoculum in step 5. Fill one canister with approximately 100 ml Tryptic SoyBroth and one canister with approximately 100 ml of Fluid Thioglycolate Medium.

11) Incubate all Fluid Thioglycolate Medium canisters at 32.5ºC +/- 2.5ºC anaerobically and all Tryptic SoyBroth canisters at 22.5ºC +/- 2.5ºC under aerobic conditions. Examine the canisters periodically forturbidity. Negative control canisters must be incubated at least 168 hours.

12) Record all data, including plate counts confirming inoculum, the length of time in days to observe positivegrowth in each canister, and the Gram stain from each canister confirming the challenge organism.


Comparable early growth of the challenge bacteria should appear, in the positive control canisters as well asthe product exposed canister. The bacterial cultures should show positive growth within 3 days, except theBacillus subtilis in Tryptic Soy Broth, which should show positive growth within 7 days. The fungal cultureshould show positive growth within 5 days. All bacterial and fungal culture growth must be microscopicallyexamined and the correct inoculum confirmed. No growth should occur in the negative controls.

Tryptic Soy Broth Fluid Thioglycolate Medium

Aspergillus niger, ATCC 16404 Bacillus subtilis, ATCC 6633

Bacillus subtilis, ATCC 6633 Clostridium sporogenes, ATCC 19404

Candida albicans, ATCC 10231 Staphylococcus aureus, ATCC 6538

Staphylococcus aureus, ATCC 6538 Pseudomonas aeruginosa, ATCC 9027

Pseudomonas aeruginosa, ATCC 9027


115

TEMPLATES

1.1 INTRODUCTION

{Receiving Laboratory} will commence manufacture of {Product Name}. The purpose of this study is to vali-date the method for total aerobic viable count and the combined yeast and mould aerobic viable count for{Product Name/Item}, which conforms to United States Pharmacopoeia (USP) 24, European Pharmaco-poeia 3rd Edition 1997 - supplement 2000 (Ph. Eur.) and to Pharmacopoeial Previews, General Chapters,Microbiological Test Chapter <61> Microbial Enumeration Tests in Pharmacopoeial Forum Volume 25, Num-ber 2. Although membrane filtration is not in the current United States Pharmacopoeia it is in the Pharmaco-poeial Review and it is anticipated that this technique will be adopted.

Three different lots of product will be used in this verification study. One lot has already been manufactured;the other two lots will be manufactured in {month, year}. This study will form part of Validation Project num-ber:_______ .

Template 11

Validation Protocol

{Validation Protocol Number}

Total Aerobic Viable Count, and Combined Yeast and Mould Aerobic Viable Count for:

{Product Name}






Reviewed By: _________________________Date: _________________________





116

TEMPLATES

1.2 PURPOSE

To assure that the proposed Method of Analysis for the total aerobic microbial count and combined yeast andmould count of {Product Name} gives valid recoveries, reproducibility, and is suitable for use on a routinebasis.


Sponsor: {Testing Lab}

Testing Facility:




Quality Assurance:


• Sterile Containers

• Sterile Tryptic Soy Agar Plates

• Sterile Sabouraud Dextrose Agar Plates

• Sterile Filter Unit

• Incubator 20°C - 25°C

• Incubator 30°C - 35°C

• Sterile 1ml Pipettes

• Sterile 10ml Pipettes

• Colony Counter

• Laminar Flow

• Disposable Gloves

• 70% Isopropyl Alcohol

• Vacuum Manifold

• Bunsen Burner

• Pipette Aid


117

TEMPLATES

• Forceps

• ¼ Strength Ringers Solution

• Sterile 0.45 µm Cellulose Nitrate Filter Membrane

• {Product Name}

• Butterfields Buffer

• Method Number/Title

• United States Pharmacopoeia 24, Microbial Limits Test <61>, Pages 1814 - 1818


• Pharmacopoeial Previews, General Chapters, Microbiological Test Chapter <61> Microbial EnumerationTests in Pharmacopoeial Forum Volume 25, Number 2

• European Pharmacopoeia 3rd Edition 1997 - supplement 2000 (Ph. Eur.)

• SWMB-144 Introduction and Background to Total Viable Count (Bioburden and Pathogens Testing)

• Escherichia coli ATCC 8739/NCIMB 8545

• Pseudomonas aeruginosa ATCC 9027/NCIMB 8626

• Staphylococcus aureus ATCC 6538/NCIMB 9518

• Salmonella typhimurium ATCC 14028/NCIMB 13284

• Bacillus subtilis ATCC 6633/NCIMB 8054

• Candida albicans ATCC 10231/NCPF 3179

• Aspergillus niger ATCC 16404

• Micrococcus luteus Environmental Isolate

• Staphylococcus epidermidis Environmental Isolate


To test products for Total Viable Count, it is necessary to sufficiently reduce any inhibitory properties of theproduct to allow for the recovery of any viable microorganisms. This study is designed to use a membranefiltration method and appropriate solid culture media.

The data generated will be in the form of the number of colony forming units recovered from each pair ofmembrane filters inoculated with challenge organisms during the final rinse step of the proposed test method.One group of membranes (test group) will be exposed to product, while the other set (positive controls) willnot. The count data from each pair will be collected on worksheets, averaged, and a percentage recovery willbe calculated for the test group versus the control group in the study report. Three different lots of product willbe used for the verification study.


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TEMPLATES

1.7 METHODOLOGY

1) Prepare the challenge organism suspensions using sterile ¼ strength Ringers solution to carry out serialdilutions to give an inoculum of approximate concentrations of between 10 - 100 cfu/ml.

2) Carry out environmental monitoring of workstation and personnel as outlined in SOP No:_______ .

3) Dilute a 10ml aliquot of product in 100ml of Butterfields Buffer and filter through a sterile filter unit contain-ing a 0.45µm cellulose nitrate membrane filter. Repeat to give a duplicate test.

4) Rinse each sterile filter membrane unit twice with 100 ml aliquots of sterile Butterfields Buffer.

5) Rinse each filter membrane a final time with a 100 ml aliquot of sterile Butterfields Buffer to which 1ml ofone of the working inoculum of Esherichia coli ATCC 8739/NCIMB 8545 has been added.

6) Remove each membrane from the filter units and place on Tryptic Soy Agar (TSA) plates, each contain-ing approximately 15ml of solidified agar.

7) Repeat steps 3 - 6 for each of the test microorganisms listed:

Pseudomonas aeruginosa ATCC 9027/NCIMB 8626

Staphylococcus aureus ATCC 6538/NCIMB 9518

Salmonella typhimurium ATCC 14028/NCIMB 13284

Bacillus subtilis ATCC 6633/NCIMB 8054

Candida albicans ATCC 10231/NCPF 3179


Micrococcus luteus Environmental Isolate

Staphylococcus epidermis Environmental Isolate

8) For positive controls filter 100ml of diluent through a sterile 0.45µm membrane, then rinse the membranewith two 100ml aliquots of Butterfields Buffer. Rinse the membrane a third time with 100ml of ButterfieldsBuffer to which 1ml of the working inoculum of Esherichia coli ATCC 8739 has been added. Remove themembrane and place on the surface of a TSA plate. Repeat the filtration to give a duplicate plate. Repeatthe filtrations using each of the test microorganisms, listed in step 7, for each pair of membranes.

9) For negative controls, repeat steps 4 - 6, with the exception that no test organism is to be added at step6. Place the membranes on Tryptic Soy Agar.

10) Invert and incubate all agar plates at 30°C to 35°C for five days.

11) After the incubation period count the number of colonies appearing on each set of plates and for each setdetermine the average.

12) For the combined yeast and mould viable count the same test procedure will be used, replacing TrypticSoya agar with Sabouraud dextrose agar. The challenge microorganisms are Candida albicans andAspergillus niger. Plates will be incubated at 20°C to 25°C for 5 days.


119

TEMPLATES


Acceptance Criteria for Compliance with the Ph. Eur.

The Ph. Eur. acceptance criterion is that the count from the test organisms in the presence of the productmust not vary from the value obtained from the positive controls by more than a factor of five.

The negative control plates and environmental monitoring results will indicate the level of background con-tamination from testing area and inherent bioburden.

If the Ph. Eur. acceptance criterion is not met the study design must be modified and repeated. (All changesand amendments will be documented as required in the Amendments and Deviations section of this docu-ment (see Section 1.10).

The Ph. Eur. does not allow for the validation of the total aerobic viable count or the combined yeast andmould aerobic viable count test, if any of the challenge organisms fail to satisfy the acceptance criteria of nomore than a factor of five difference between the number of colony forming units recovered from the positivecontrols and the challenge organisms.

All bacterial and yeast culture growth must be microscopically examined and confirmed as the correct inocu-lum.

Acceptance Criteria for Compliance with the USP

The USP acceptance criterion is that the recovery in the presence of the product must be at least 50% of thechallenge inoculum.

If the acceptance criterion is not met for any organism, repeat that part of the study in duplicate to confirm theresults. If the original results are confirmed then the study design must be modified and repeated. (All changesand amendments will be documented as required in the Amendments and Deviations section of this docu-ment (see Section 1.10). If in spite of the incorporation of suitable inactivating agents and a substantialincrease in the volume of diluent it is still not possible to recover the viable cultures then the test cannot bevalidated to comply with the United States Pharmacopoeia 24. However, the Pharmacopoeial Preview, Gen-eral Chapters, Microbiological Tests does allow for the validation of the test as follows:

“If unable to recover all or some of the test micro-organisms, even after trying to eliminate the inhibitorysubstances by several methods, assume that the article is not likely to be contaminated by these micro-organisms”.

All bacterial, yeast and fungal isolates must be examined microscopically and confirmed as the correct inocu-lum.

The negative control plates and environmental monitoring results will indicate the level of background con-tamination from testing area and inherent bioburden.


All raw data will be recorded on the Proforma results sheets attached and submitted to the Validation Directorfor compilation onto a report.

All raw data generated from the study must be retained as detailed in SOP No:_______ and _______ for atleast 5 years after issue of the final report.


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TEMPLATES




APPENDIX 1

Environmental control results for laminar flow used for aerobic microbial count and yeast and mold count for{Product Name}.

Equipment Date SampledNumber Sampled By

55mm Contact Batch Number Expiry:

90mm Settle Plate Batch Number Expiry:

Time Sampled:

Settle Plate from _______ to _______ Contact Plate FingerDabs:

Time Incubated at:

Settle Plates: Contact Plate FingerDabs:

Results

Type of Monitoring Location Number of Colony Forming Units

Settle Plates Right

Center

Left

Contact Center

Finger Dabs Right

Left

All plates with colony forming units must be kept for identification purposes.

Comments:

Read by: Date and Time:

Verified by: Date:

(Responsible Analyst)


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TEMPLATES

APPENDIX 2

Total aerobic viable count, and combined yeast and mould aerobic viable count verification worksheet for{Product Name}.

1.1 ORGANISMS

The organisms chosen to evaluate microbial recovery in the test method are listed in the Preparatory TestingSection of the USP Microbial Limits Test. Bacillus subtilis was added to represent a spore forming organismtypical of a natural bioburden. Candida albicans and Aspergillus niger were chosen to represent typical yeastand mould. Micrococcus luteus and Staphylococcus Epidermis were chosen to represent typical environ-mental isolates.

Escherichia coli ATCC 8739/NCIMB 8545

Pseudomonas aeruginosa ATCC 9027/NCIMB 8626

Staphylococcus aureus ATCC 6538/NCIMB 9518

Salmonella typhimurium ATCC 14028/NCIMB 13284

Bacillus subtilis ATCC 6633/NCIMB 8054

Candida albicans ATCC 10231/NCPF 3179


Micrococcus luteus Environmental Isolate

Staphylococcus epidermidis Environmental Isolate

{Product Name} Lot Number: ____________________________________________________________

Incubator 30°C - 35°C Equipment Number: _________________________________________________

Incubator 20°C - 25°C Equipment Number: _________________________________________________

Laminar Flow Equipment Number: ________________________________________________________

Filter Unit Batch Number: _____________________________________ Expiry: _________________

Filter Membrane Batch Number: ________________________________ Expiry: _________________

Butterfields Buffer Batch Number: _______________________________ Expiry: _________________

Tryptic Soy Agar Batch Number: ________________________________ Expiry: _________________

Sabouraud Dextrose Agar Batch Number: ________________________ Expiry: _________________


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TEMPLATES

1.2 RAW DATA

Incubation Time: (Days)

TSA Sign and Date Sign and Date Read IncubatedOn Test Days

Day 2 Day 3 Day 4 Day 5

Escherichia coli

Pseudomonas aeruginosa

Staphylococcus aureus

Salmonella typhimurium

Bacillus subtilis

Candida albicans

Aspergillus niger

Micrococcus luteus

Staphylococcus epidermidis

SABs

Candida albicans

Aspergillus niger

Negative Control Plate Count Colony Forming Unit (*cfu)

TSA Plate Count Average Gram Stain

Plate 1 Plate 2

-Control

SAB’s

-Control

*Colony Forming Unit


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TEMPLATES

Plate Count (cfu) - Day 2/Day 3/Day 4/Day 5 * (Delete as Appropriate)

Positive Control Sample Sign and Date

TSA Plate Plate Average Plate Plate Average1 2 1 2

Escherichia coli




Bacillus subtilis

Candida albicans

Aspergillus niger

Micrococcus luteus


SABs

Candida albicans

Aspergillus niger

Checked by _______________________________________________ Date __________________


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TEMPLATES

Mean cfu per Petri Plate

TSA +Control Sample %Recovery*

Escherichia coli




Bacillus subtilis

Candida albicans

Aspergillus niger

Micrococcus luteus


SABs

Candida albicans

Aspergillus niger

*Percent recovery - Sample Average/Control Average x 100 = % Recovery

Analyst Signature __________________________________________ Date __________________

Checked by _______________________________________________ Date __________________


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