ICH 교육가이드라인 [ 안전성 & 품질 ]

Transcription

1 ICH 교육가이드라인 [ 안전성 & 품질 ]

2 1 SAFETY ( 안전성 ) Safety Series / 11 월 27 일 ( 화 )

3 ICH S9 guideline is focused on anticancer drugs. However, for better understanding, the presentation will give the comparison with anticancer drugs and other pharmaceuticals. The main contents of this presentation will cover below parts with comparison. - Pharmacology: similar with other pharmaceuticals - Safety Pharmacology: can be included in general toxicology studies - PK: ADME data con be generated in parallel with clinical development - General tox: Dosing schedule, dosing duration, dose selections and animal species - Repro tox: when & what studies are needed - Genotoxicity: when & what studies are needed - Carcinogenicity: not warranted for advanced cancer drugs - Immunotox: combined with general tox. Except immunomodulatory drugs - Photosafety: which drug & when needed - Starting dose of FIH: compare with anticancer drugs and other pharmaceuticals - Dose escalation and highest dose in a clinical trial: case by case - Combination of pharmaceuticals: method of safety evaluation - Pediatric populations: method of safety evaluation - Other considerations: Case by case 1 SAFETY ( 안전성 ) Safety Series / 11 월 27 일 ( 화 ) S9

4 1 SAFETY ( 안전성 ) Safety Series / 11 월 27 일 ( 화 ) S9 Keiji HIRABAYASHI Principal Assessor, PMDA 1/2013-9/2013 Reviewer, Office of Cellular and Tissue-based Products, Pharmaceuticals and Medical Devices Agency 9/2013-9/2015 Reviewer, Office of New Drug II, Pharmaceuticals and Medical Devices Agency 10/ /2018 Principal Assessor, Office of New Drug V, Pharmaceuticals and Medical Devices Agency 10/2018-Present Principal Assessor, Office of New Drug I, Pharmaceuticals and Medical Devices Agency To facilitate and accelerate the development of pharmaceuticals in patients with serious and life-threatening cancer, the recommendations on nonclinical evaluation for anticancer pharmaceuticals have been discussed and developed as ICH S9 Guideline in 2009, and the guideline notification was released in Japan in In implementation of the guideline, ICH regions using the guideline have experienced differences in interpretation of the guideline between regulatory authority and pharmaceutical companies, leading to the need for clarification of interpretation of the guideline. For this reason, an Implementation Working Group was set up in 2014 to develop ICH S9 Guideline Questions and Answers (ICH S9 Q&As), and ICH S9 Q&As reached Step 4 in The objective of ICH S9 Q&As are to clarify ambiguity of ICH S9 Guideline and to continue the process of harmonization, where possible. ICH S9 Q&As provides additional guidance on scope of ICH S9 Guideline, need and design of toxicology study for anti-cancer pharmaceuticals, etc., and are expected to further facilitate development of anti-cancer pharmaceuticals. However, as advances in development of anti-cancer drugs continues, there could be cases that are not assumed by the present guideline. Therefore, it is also necessary to take case-by-case approaches for nonclinical safety assessment of anti-cancer drugs. This presentation will introduce an overview of ICH S9 Q&As and provide points to consider in planning and designing toxicology studies.

5 1 SAFETY ( 안전성 ) Safety Series / 11 월 27 일 ( 화 ) S2 ICH S2(R1) 의의약품의유전독성시험및결과해석에대한전반적인가이드라인을설명하며, 가이드라인의목적과배경, 적용범위와일반원칙그리고유전독성시험의표준시험조합에대한이론적근거와표준시험조합의두가지선택사항에대한내용과시험조합의변경이권고되는사례를살펴보며, 체외 (in vitro) 시험과체내 (in vivo) 시험에대한권고사항과결과평가에대한후속조치등을살펴본다. - 의약품의안전성평가는의약품국제조화회의 (International Council for Harmonization of Technical Requirements for Registration of Parmaceutical for Human Use, ICH) 의제시된가이드라인을기준으로한다 년에의약품의안전성평가를위한유전독성시험및자료해석가이던스 (ICH S2(R1)) 를발효하여기존의가이드라인인 의약품유전독성시험관련분야의가이드라인 (S2A, 1995 년 ) 과 의약품의유전독성시험표준시험가이드라인 (S2B, 1997 년 ) 을통합개정하였다. ICH S2(R1) 은표준조합시험법을두가지종류의조합시험법을선택할수있도록하였으며, 표준조합 1 은기존유전독성시험의기본배터리시험법에체외소핵시험법을추가하였고, 새로이추가된표준조합 2 는체외포유류세포시험을제외하고, 골수또는혈액을이용한소핵시험과조직을이용한코멧시험을제시하였다. 체외시험에서의주요변경사항은기존의 ICH S2A/S2B 에서복귀돌연변이시험을수행하였을때, 음성혹은모호한판정 (equivocal) 의결과가도출되었을때, 추가농도를설정하여 2 회반복시험을요구하였다. 그러나개정된 ICH S2(R1) 에서는명확한양성혹은음성의결과가도출되었을때, 추가시험없이 1 회만실시하도록권고하고있다. 체내시험에서의주요변경사항은기존의매시험마다양성대조군이반드시필요하다는내용이언급되었으나, 개정된 ICH S2(R1) 에서는명확하고동일한양성판정이있을시에매시험마다양성대조군을추가할필요가없음을제시하였다.

6 1 SAFETY ( 안전성 ) Safety Series / 11 월 27 일 ( 화 ) S6 고우석은학부는생화학을석박사는독성학을전공하였으며안전성평가연구소, 코어톡스컨설팅, 한화케미칼을거쳐현재대구경북첨단의료산업진흥재단에서근무중이다. 안전성평가연구소에근무시국내에서개발되는생물의약품 ( 세포 / 유전자치료제및단백질의약품 ) 의비임상시험에관심을갖고다수의생물의약품의비임상시험디자인과비임상및임상시료의생체시료분석등에참여하였으며한화케미칼근무시바이오시밀러인다빅트렐의비임상시험에참여하여품목허가를받는데기여한바있다. Biopharmaceuticals, recombinant protein-based drugs such cytokines, enzymes, and antibodies, are expanding their realm toward the treatment for diseases which have no appropriate drug developed yet or show low treatment response to chemically synthesized preexisting drugs. Although biopharmaceuticals are more target-specific and efficacious than conventional medicines in some diseases and have a good track record with patient safety, all biopharmaceuticals also have common potential problems and side effects due to the fact that they are proteins or large peptides with highly specific binding characteristics. These differences from conventional chemical drugs bring many questions regarding animal species, dose selection, dosing and recovery period, immunogenicity, and toxicity study compositions. For instance, the difference of amino acid sequences between human and animal protein causes differences in target binding affinity, production of anti-drug antibody, and subsequent changes in pharmacokinetic / pharmacodynamic profiles of drug in nonclinical studies. ICH has published general guidelines to answer the questions on these differences. This presentation will review the current version of ICH S6 guideline (Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals, 2011) and propose some representative nonclinical study programs for biopharmaceuticals.

7 1 SAFETY ( 안전성 ) Safety Series / 11 월 27 일 ( 화 ) S6 Mineo MATSUMOTO Associate Senior Scientist for Toxicology, PMDA 8/2009-9/2013 Principal Assessor, Office of vaccine and cellular products, etc 10/2013-9/2016 Principal Assessor, Office of clinical and non-clinical conformity 10/2016-present Associate Senior Scientist for Toxicology, Office of New Drug II, Pharmaceuticals and Medical Devices Agency An addendum to ICH S6 Guideline (the safety guidelines on Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals [S6] of the International Conference on Harmonization of Technical Requirement for Registration of Pharmaceuticals for Human Use [ICH]) reached step 4 of the process of harmonization among regulatory authorities of Europe, Japan and the US at ICH and was released via the ICH website as part 2 of ICH S6(R1) Guideline at the end of June, The original ICH S6 guideline was retained as is but renamed part 1 of ICH S6(R1). Scientific advances and experiences gained since the publication of the original ICH S6 Guideline necessitated this addendum to clarify and update the following topics discussed in the original ICH S6 Guideline: species selection, study design, immunogenicity, reproductive and developmental toxicity and assessment of carcinogenic potential. The harmonized addendum provides further complementary guidance to the ICH S6 Guideline and helps in defining the current recommendations and in reducing the likelihood of substantial differences existing among regions. In this session, a summary of each topic in this addendum including some discussion made during the harmonization process will be provided. In addition, some points to consider in relation to nonclinical safety evaluation studies in the future will also be explained: i.e., issues concerning (1) the utilization of alternative methods, in which the number of test animals is decreased, to replace conventional studies, (2) prediction if immunogenicity in humans and (3) specific concerns on the preclinical safety evaluation of oligonucleotide- and/or peptidemimicking drugs to which the ICH S6 principle can be applied at least in part.

8 2 QUALITY ( 품질 ) Quality Series / 11 월 28 일 ( 수 )

9 2 QUALITY ( 품질 ) Quality Series / 11 월 28 일 ( 수 ) ICH Stability Q1A, Q1B, Q1E Q Stability 김창주대표는현재서치앤트랜에서기술이전사업화자문서비스를제공하고있으며구체적으로는국내대학의바이오관련우수기술을발굴하여업그레이드과정을통해건강기능식품, 화장품, 의료기기, 신약개발을위한전문컨설팅을수행하고있다. 주요경력으로는한미약품, 광동제약, CJ 헬스케어, 드림파마에서근무하였으며품질관리및제제개발업무를통해제네릭부터신약개발경험을보유하고있다. 기술보증기금, 서울아산병원, 부산대학교, 경북대학교, 한국과학기술원등의자문및평가위원으로활동중이다. This presentation is based on the ICH Guidelines (Q1A, Q1B, Q1E) related to stability testing. We will seeks to exemplify the core stability data package for new drug substances and products, the recommendations for photostability testing, intended to provide recommendations on how to use stability data generated in accordance with the principles detailed in the ICH guideline

10 2 QUALITY ( 품질 ) Quality Series / 11 월 28 일 ( 수 ) Overview of ICH Q5 and its application to biopharmaceutical industry Q Stability ICH Q5 guideline provides an internationally accepted guide to establish a stability program for the maintenance of biotechnological/biological product quality during its storage and distribution. Test methods, test period and frequency, study conditions (temperature and light), container system and target batches for the stability study are described. Test methods: Adequate physiochemical, biochemical and immunological test which can ensure purity and molecular characteristic of the product should be utilized in the study. Key method, stability indicating method should be investigated and considered for a stability study. Period and frequency of testing: A stability program should include at least 3 representative batches with at least 6 month to claim longer than 6 month of shelf life. Study conditions (temperature and light): Storage temperature should be determined prior of the study and stability study should be performed in the proposed storage condition. Accelerated and stress study will provide additional information on the products when they are exposed in a adventitious excursion during storage or distribution. Container system: Container system used in the stability study should be able to address products are stable to the interaction with container during storage. The guideline doses not describe the detail of the stability studies because it is virtually impossible to provide proper guide to all the variety of biotechnological/biological products. Appropriate decision for a stability study of each product should be made based on scientific background, GMP system of a corporation and related research.

11 2 QUALITY ( 품질 ) Quality Series / 11 월 28 일 ( 수 ) Overview and Application of ICH Q11 for API Unit Operation Q11

12 2 QUALITY Quality Series / 11 월 28 일 ( 수 ) Q11 Kazuhiro OKOCHI/ Director, Takeda Pharmaceutical Company Limited Kazuhiro Okochi has thirty years of industry experience developing pharmaceutical products, manufacturing and Quality Assurance, and expertise in bio-equivalence, data integrity, computer system validation and Pharmaceutical Quality System. He has fifteen years experiences contributed to industry's association, such as expert of ICH Q8, Q-IWG, and Q11 Q&A from Japan Pharmaceutical Manufacturers Association (JPMA). Currently, he is a leader of Quality & Technology committees in JPMA. Since the ICH Q11 guideline was finalised, worldwide experience with implementation of the recommendations on the development and manufacture of drug substances has given rise to requests for clarification relating to the selection and justification of starting materials. ICH Q11 Question and Answer (Q&A) document is intended to provide additional clarification and to promote convergence and improve harmonisation of the considerations for the selection and justification of starting materials and of the information that should be provided in marketing authorisation applications and/or Master Files. The focus of the Q&A document is on chemical entity drug substances. The scope of Q11 Q&A document follows that of ICH Q11. ICH Q11 is applicable to drug substances as defined in the Scope sections of the ICH Q6A and Q6B guidelines, but might also be appropriate for other types of products following consultation with the appropriate regulatory authorities. ICH Q11 does not apply to contents of submissions during the clinical research stages of drug development. Nevertheless, the development principles presented in ICH Q11 and this supporting Q&A document are important to consider during the investigational stages. Generally, it is anticipated that API starting materials that have already been accepted by regulatory authorities (e.g., for use in authorized medicinal products) would not need to be re-justified against the ICH Q11 general principles or the recommendations included in this Q&A document, unless significant changes are made to the manufacturing processes and controls. However, a starting material accepted for one manufacturer's process may not be considered acceptable for a different manufacturer's process, if the proposal does not comply with the guidance in ICH Q11. Applicant is used throughout the Q&A document and should be interpreted broadly to refer to the marketing authorization holder, the filing applicant, the drug product manufacturer, and/or the drug substance manufacturer. Designation of starting materials should be based on process knowledge of the intended commercial process. A decision tree is available in Annex 1 to serve as a pictorial exemplification to apply all ICH Q11 general principles for the selection and justification of a starting material.

13 2 QUALITY ( 품질 ) Quality Series / 11 월 28 일 ( 수 ) Q3A / B Guidelines for Drug Development Q3 A/B 제약회사의분석업무 ( 연구 / 허가 /GMP) 를 20 년간수행. 다양한의약품 ( 신약 ) 의미국 DMF 와 IND 승인경험을가지고있으며, 인허가부분의한국보건산업진흥원장표창을수상하였다. 현재한국의약분석연구회의임원으로, 허가와분석에관한교육을꾸준히진행해오고있다. The regulation on impurities has been increasingly strengthened and segmentation. Therefore, management and experimental strategies for impurities are important. It is very important for pharmaceutical companies to understand and apply regulations related to impurities. Would like to discuss Q3A /Q3B(below) among ICH Q3 guidelines and how to apply it. Q3A Impurities in New Drug Substances contains recommendations for reporting impurities in new drug substances produced by chemical syntheses. (ICH Q3A(R) Impurities in New Drug Substances, 2002) Q3B Impurities in New Drug Products contains recommendations for reporting only those impurities in new drug products classified as degradation products. (ICH Q3B(R) Impurities in New Drug Products, 2003)

14 2 QUALITY ( 품질 ) Quality Series / 11 월 28 일 ( 수 ) ICH Q3D : Guideline For Elemental Impurities Q3D 신약을개발하고의약품품질관리분야에약 30 년종사하고있다. LG 생명과학에서분석팀장으로서신약과바이오시밀러의분석법을개발하였다. 현재는의약생산센터의센터장으로근무하고있다 년에연세대화학과, 1986 년에연세대에서분석화학으로석사를마쳤으며고려대생명공학과에서생물법제학으로이학박사를취득하였다. Current control of metal impurities is primarily based on pharmacopoeial requirements for Heavy Metals, which have been widely used for routine screening of pharmaceutical ingredients since the early 20th century. The commonly used methodology was mainly intended to control metals which form a sulphide precipitate, such as lead, copper and other metals. Although the risk factors for metal contamination have changed dramatically, the standards for their control have changed little for more than 50 years, and most Heavy Metals limits have little basis in toxicology. But this method is not a specific analytical method for each metal element and it is not quantitative analytical method. ICH new Q3D Guideline would focus on the establishment of appropriate limits for specific metals. This new ICH Guideline for metal impurities would emphasize control of supply chains and risk assessment, as was done with Q3C. Such an approach would be outside the usual scope of pharmacopoeias and would require significant input from regulatory authorities In order to provide benefit to public health, it is envisioned that a safety-based approach would be taken for the control of metal impurities. It is especially important to establish appropriate controls for those metals with clearly established toxicological concerns