Scientific Research Granted by the Ministry of Health, Labor and Welfare in 2003 Research on Current Quality System of Drug

Products Research Report Yukio Hiyama, Chief Researcher, Division of Drugs, the National Institute of Hea lth Sciences

Guideline for Technology Transfer (Draft)

Members of research group Chairperson Izumi Saitoh (Shionogi & Co., Ltd.) Kazufumi Ikeda (TANABE SEIYAKU CO., LTD.) Akio Imai (Eisai Co., Ltd.) Atsuo Oike (Fujisawa Pharmaceutical Co., Ltd.) Hiroshi Okada (Department of Health and Human Services, Saitama Prefecture) Ryoichi Kawakami (Fujisawa Pharmaceutical Co., Ltd.) Yukihiko Kimura (Chugai Pharmaceutical Co., Ltd.) Yasuyuki Sakai (Chugai Pharmaceutical Co., Ltd.) Yoshiyuki Sawabe (Osaka Prefectural Institute of Public Health) Masaaki Mikawa (Pfizer Japan Inc.) Noriyuki Muranushi (Shionogi & Co., Ltd.) Keiichiro Watanabe (JGC CORPORATION)

Introduction This research is intended to indicate appropriate guidance for technology transf er expected to increase under the new manufacturing and marketing approval syste m to be implemented by the revised Japanese Pharmaceutical Affairs Law, and supp lement the GMP regulations to be revised soon. The research is also intended to propose some regulations to realize technology transfer necessary for high quali

ty and stable manufacturing of developed products and existing products by revie wing technology transfer based on the following ideas. The technology transfer means actions to transfer information and technologies necessary to realize quality of design of drugs during manufacturing. Appropriate technology transfer is important to upgrade the quality of design t o be the quality of product, and ensure stable and high quality of the product. It should be noted that drugs may influence human lives and health, and their r aw materials, compositions and manufacturing methods are changed during their lo ng term manufacturing and marketing. To assure the drug quality, it is desired to make sure 5 Ws and 1 H, that is wha t, when and why information should be transferred to where and by whom and how t o transfer, then share knowledge and information of the drug product between tra nsferring and transferred parties. The technology transfer does not mean one time actions taken by the transferrin g party toward the transferred party, but means continuous information exchange between the both parties to maintain the product manufacturing. Basic Policies on the Establishment of the Guideline for the Technology Transfer The basic policies on the establishment of this guideline are shown as follows. 1) Assurance of consistency through development and manufacturing To make developed product have indications as assumed in clinical phases, the q uality of design should be reproducible as the quality of product. The transferring party in charge of development should fully understand what ki nd of technical information is required for the technology transfer, and should establish an appropriate evaluation method to determine whether a drug to be man ufactured meets the quality of design. It should be fully recognized that technical information of developed product a re generated from data of a limited amount of batches, various standards have be en established from the limited data, and quality evaluation method established in development phase is not always sufficient for factory production. Informati on of similar products of the past should be fully referred as well. 2) Embodiment of Quality by Specifications It is desired to verify that the specification adequately specifies the product properties and quality. The product specification should ensure that the quality assumed in the quality design is assured as the manufacturing quality, and the product satisfies the q uality of design. It should be fully understood that manufacturing quality is based on the produc t specification. Relations between control limits of manufacturing formula (com positions and manufacturing methods) and limits of the product specification sho uld be fully understood, and appropriate specifications and the control range sh ould

be established to maintain the consistency between the manufacturing quality and product specification. For specifications of raw materials, components, intermediates, and in process testing, consistency between test items, specification range, and product specif ications should be maintained. Since initial manufacturing formula and specification are established based on limited information, the consistency between the quality and specification after the start of manufacturing should be fully verified, and these should be revise d through appropriate change controls, if necessary. 3) Documentation Management and Update of Technical Information Responsibility system should be established in view of accountability (responsi bility for giving sufficient information) and responsibility (responsibility for conseq

uences of actions). For that purpose, appropriate documentation management of t echnology transfer ishighly desired. For drugs as they have long product shelf life, the documentation management sh ould be performed assuming that the technology transfer would occur several deca des after the completion of development. Initial manufacturing quality is established based on limited information. As a result, it may be necessary to propose revised technical information at regular intervals as additional information of the product quality is gained and accumu lated with improvements or revisions of specifications and test methods. Table of Contents The table of contents is shown as follows. The 1st chapter addresses background and the scope of the guideline. The 2nd chapter addresses handling and contents of technologies to be transferred at each process from research and development to manufacturing. The remaining chapters address procedures, documentation, and points of concern with regard to facilities, test methods, drug substances, and drug products all of which are closely involved with drug manufacturing. 1. 1.1 1.2 1.3 1.4 2. 2.1 2.2 ) 2.2.1 2.2.2 2.2.3 2.3 2.4 2.5 ransfer 3. Preface Background Objective Scope Organization

Technology Transfer Process Quality Design (Research Phase) Scale-up and Detection of Quality Variability Factors (Development Phase Research for Factory Production Consistency between Quality and Specification Assurance of consistency through development and manufacturing Technology Transfer from R&D to Production Validation and Production (Production Phase) Feedback of Information Generated from Production Phase and Technology T of Marketed Products Procedures and Documentation of Technology Transfer

3.1 Organization for Technology Transfer 3.2 Research and Development Report 3.3 Technology Transfer Documentation 3.3.1 Product Specification (Product Specification File) 3.3.2 Technology Transfer Plan 3.3.3 Technology Transfer Report 3.3.4 Check and Approval by Quality Assurance Department 3.4 For Implementation of Technology Transfer 3.5 Manufacturing Related Documents Including Drug Product Standards 3.6 Verification of Results of Technology Transfer 3.7 Points of Concern for Post-Marketing Technology Transfer 4. Examples of Technical Information to be Contained in Technology Transfer Documentation 4.1. Technical Information of Facilities and Equipments 4.1.1 Technical Information to Establish New Facilities and Equipments 4.1.2 Technical Information When Applied to Established Facilities and Equipme nts 4.2 Technology Transfer of Test Methods

4.2.1 Development Report of Test Methods 4.2.2 Technology Transfer Plan 4.3 Technology Transfer of Drug Substances 4.3.1 Information to be Collected During Quality Design (Research Phase) 4.3.2 Items to be Checked in the Review of Scale-up 4.3.3 Elucidation of Quality Variability Factors 4.3.4 Development Report on Synthetic Drug Substances 4.3.5 Technology Transfer of Synthetic Drug Substances from R&D Department to Manufacturing Department 4.4 Technology Transfer of Drug Products 4.4.1 Information to be Collected During Quality Design (Research Phase) 4.4.2 Scale-up Validation and Detection of Quality Variability Factors (Develo pment Phase) 4.4.3 Development Report 4.4.4 Information of Technology Transfer of Drug Products 5. Points of Concern For Preparing Technology Transfer Documentation 5.1 Documents To Clarify Applicable Technologies, Burden Shares and Responsi bility System, etc. Concerning Technology Transfer 5.2 Technical information to be Described in the Development Report, and Pro duct Specification, etc.

Acknowledgement This draft guideline is written by the members shown below. Our sincerest apprec iation should be extended to many people of the pharmaceutical industry and gove rnment offices for their valuable insights and proposals during drafting this guideline and their contributions to the completion of this draft guideline in line with the actuality of the technology transfer. Izumi Saitoh (Shionogi & Co., Ltd.) Kazufumi Ikeda (TANABE SEIYAKU CO., LTD.) Akio Imai (Eisai Co., Ltd.) Atsuo Oike (Fujisawa Pharmaceutical Co., Ltd.) Hiroshi Okada (Departm ent of Health and Human Services, Saitama Prefecture) Ryoichi Kawakami (Fujisawa Pharmaceutical Co., Lt d.) Yukihiko Kimura (Chugai Pharmaceutical Co., Ltd.) Yasuyuki Sakai (Chugai Pharmaceutical Co., Ltd.) Yoshiyuki Sawabe (Osaka Prefectural Insti tute of Public Health) Masaaki Mikawa (Pfizer Japan Inc.) Noriyuki Muranushi (Shionogi & Co., Ltd.) K eiichiro Watanabe (JGC CORPORATION)