Technical Report No. 65

1 BethesdaTowers4350 EastWestHighwaySuite200 Bethesda, MD20814 USATel:1 (301)656-5900 Fax:1 Report No. 65 technology TransferParadigm Change in Manufacturing technology transfer Technical Report TeamAuthorsMirko Gabriele, EMPHA, Patheon Italia Spa, (Team Leader)Derek Blaettler, F. Hoffman-LaRoche, Elyath, Genzyme CorporationStephan Krause, , MedImmuneAndrea Morelli, Kedrion BiopharmaChittoor Narahari, GlaxoSmithKlineJamie Rogers, Biogen IdecVictor Sanchez, Pharma-Bio Serv Seymour, Biogen IdecYi Xie, , Eli Lilly and CompanyWayland Rushing, , Analytical Bio-Chemistry Laboratories, Wohlpart, , Merck & content and views expressed in this Technical Report are the result of a consensus achieved by the authoring task force and are not necessarily views of the organizations they TransferTechnical Report No. 65 ISBN: 978-0-939459-68-1 2014 Parenteral Drug Association, Inc.

2 All rights , MD20814 USATel:1 (301)656-5900 Fax:1 Change in Manufacturing Operations (PCMOSM)PDA launched the project activities related to the PCMO program in December 2008 to help imple-ment the scientific application of the ICH Q8, Q9 and Q10 series. The PDA Board of Directors ap-proved this program in cooperation with the Regulatory Affairs and Quality Advisory Board, and the Biotechnology Advisory Board and Science Advisory Board of PDA. Although there are a number of acceptable pathways to address this concept, the PCMO program fol-lows and covers the drug product lifecycle, employing the strategic theme of process robustness with-in the framework of the manufacturing operations. This project focuses on Pharmaceutical Quality Systems as an enabler of Quality Risk Management and Knowledge the Parenteral Drug Association s (PDA) membership expertise, the goal of the Paradigm Change in Manufacturing Operations Project is to drive the establishment of best practice docu-ments and /or training events in order to assist pharmaceutical manufacturers of Investigational Medicinal Products (IMPs) and commercial products in implementing the ICH guidelines on Phar-maceutical Development (ICH Q8, Q11), Quality Risk Management (ICH Q9) and Pharmaceutical Quality Systems (ICH Q10).

3 The PCMO program facilitates communication among the experts from industry, university and regula-tors as well as experts from the respective ICH Expert Working Groups and Implementation Working Group. PCMO task force members also contribute to PDA conferences and workshops on the follows the product lifecycle concept and has the following strategic intent: Enable an innovative environment for continual improvement of products and systems Integrate science and technology into manufacturing practice Enhance manufacturing process robustness, risk based decision making and knowledge manage-ment Foster communication among industry and regulatory authorities Product DiscontinuationCommercial ManufacturingTechnology TransferPharmaceutical DevelopmentThe Product Life CycleFor more information, including the PCMO Dossier, and to get involved, go to INTRODUCTION.

4 Purpose .. Scope .. GLOSSARY OF TERMS .. technology transfer PROJECT .. technology transfer Project Objectives .. Types of technology transfer .. TTP Oversight .. Multidisciplinary technology transfer Project Team .. Administrative and Regulatory Functions .. Project Committee .. Project Manager .. Budget Manager .. Legal Office Representative .. Project Facilitator .. QA Leader .. Operational Functions .. Sending Unit and Receiving Unit .. Team Leaders .. R&D Representative .. Combined Roles .. technology transfer Unit .. Organizational Model .. Communications .. Document Management .. Common technology transfer Documents .. Regulatory Documents .. technology transfer PROCESS .. Stage 1: Planning .. Project Rationale .. Project Scope .. technology to be Transferred .. Scale-up of Production Level .. Control Philosophy .. Control Strategy.

5 Machine .. Methods .. Material .. Manpower .. Measurement .. Mother Nature .. Feasibility Reviews .. Facility Design/Layout Considerations .. transfer from Non-GMP to GMP Facilities .. New Facility Construction .. Facility Fit Reports .. Environmental Variables .. Viral Segregation .. Support Laboratory .. transfer of Documents .. technology transfer Protocol .. Stage 2: Process Readiness .. Process Changes .. Training .. Development Data on Process Management .. Stage 3: TTP Implementation and Qualification .. Manufacturability Reviews .. transfer of Analytical Test Methods .. Monitoring .. Microbial Monitoring .. In-Process Monitoring .. Cleaning Validation .. Process Validation .. Components of Process Validation .. Process Validation Studies .. Required Documents .. Campaign Summary Reports .. Continued Monitoring .. Application of cGMPs.

6 Stage 4: Licensing and Manufacturing .. Process Scale Up .. Monitoring of Production Batches .. Stage 5: Project Closure .. APPLICATION OF QUALITY RISK MANAGEMENT TO technology transfer .. Overview .. QRM in technology transfer .. Stages of QRM in technology transfer .. QRM Planning .. QRM Implementation (Execution and Control Stage) .. Project Closure QRM .. Risks of technology transfer .. QRM Concepts and Approaches Used in technology QRM Planning .. Selection of a QRM Creation of a QRM plan ..35 Table of Identification of QRM Risk Assessment .. Types of Risk Assessment .. Risk Assessment 1 .. Risk Assessment 2 .. Risk Assessment 3 .. Risk Assessment Tools .. Risk Ranking and Prioritization .. Assessment of Regulatory Gaps .. Assessment of RU Readiness .. Risk Mitigation .. Experiments to Confirm Key Process Parameter Ranges .. Demonstration Runs.

7 Cycles of Risk Assessment, Data Collection, Risk Mitigation, and Closure .. CASE STUDIES .. Case Study 1: Analytical Method General AMT Strategy .. Design of Comparative AMT Test Studies .. Selecting AMT Performance Characteristics .. AMT Documents .. Case Study 2: Manufacturing Process transfer .. Overview of Manufacturing Process transfer .. Case Description: Development to Commercialization TTP .. Intracompany TTP .. Conclusion .. Case Study 3: Manufacturing Process transfer : QRM Application to Start-Up Evaluation .. Use of Quality-by-Design Principles .. REFERENCES .. ADDITIONAL READING ..58 FIGURES AND TABLES INDEXF igure Typical functions within a TTP ..5 Table technology transfer Organizational Components ..6 Table Responsibilities of the SU and RU ..7 Figure Common Flow of Information and Communication Within a technology transfer Team and Project.

8 10 Figure Example of Ishikawa Diagram ..15 Table QRM Approaches at Each Stage Gate of TTP ..34 Table Suggested AMT Responsibility Matrix ..42 Table General AMT Design Parameters and Considerations ..43 Table Examples of Method Types and AMT Performance Characteristics ..44 Table Typical AMT Protocol Sections ..44 Figure Process/Product Comparability Framework ..47 Figure Overall Process Mapping ..48 Table Example of Variable Example of Quality Attributes Definition ..49 Table Severity Definition and Rating ..50 Table Occurance Definition and Rating ..50 Table Detection Definition and Rating ..50 Table Risk Analysis .. Report No. 65 2014 Parenteral Drug Association, IntroductionPharmaceutical technology transfer consists of planned and controlled actions that are based on well-defined acceptance criteria to convey a manufacturing process, analytical method, packaging com-ponent, or any other step or process along the pharmaceutical drug lifecycle from an originator site, known as a sending unit (SU), to a new site, the receiving unit (RU).

9 Purpose The purpose of this Technical Report is to provide guidance and best practices for conducting technology transfer activities in the pharmaceutical industry. ScopeThe Report provides an overview of the knowledge and skills used during a successful technology transfer project (TTP) along with references to consult, if necessary. The Report includes practical examples of technology transfer activities. Rather than discuss a particular technology transfer topic, this Report aims to provide a guide to safe TTP management. This Report does not address logistics and bridging stocks, which are comprehensively discussed in Technical Report No. 52: Guidance for Good Distribution Practices (GDPs) (1). The technology transfer organizational elements outlined in this Technical Report might not be appro-priate for all companies.

10 Established practices or the availability of personnel will dictate how firms conduct technology transfer activities.