赵丕华课件CMC -Requirements for IND Phases I-II-III C-E
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新药I/II/III期临床阶段的CMC要求
赵丕华 华润赛科药业研发中心
2013.10.30
华润医药集团
主要内容：
IND
IND中的CMC
CMC与cGMP IND一期临床阶段对原料药和制剂的要求 IND二/三期临床阶段对原料药和制剂的要求 与FDA的IND会议 参考
华润医药集团 |
• Formulation of Drug in Nonclinical Studies Should Parallel Clinical Formulation
华润医药集团 |
11
临床需要提供多少CMC信息 视以下情况而定:
▪ 阶段 ▪ 药物的创新性 (NCE/NME/505 b (2)…) ▪ 已有的研究结果 ▪ 给药途径/方式 ▪ 临床研究时间 ▪ 病人分布 ▪ 已知或怀疑的风险
华润医药集团 |
3
IND的过程
* - Dr. Charles P. Hoiberg, DIA China, Beijing, May 2011
华润医药集团 |
4
IND的流程
华润医药集团 |
5
有关IND的法规
21 CFR 312
▪ 21 CFR 312.21: Phases of an Investigation – Phase I, II, and III ▪ 21 CFR 312.22: General Principles ▪ 21 CFR 312.23: Content – Drug Substance – Drug Product – Placebo – Labeling – Environmental Analysis
2
IND FD&C Act 505(i) exempts a drug intended solely for investigational use by qualified experts from filing a NewDrug Application (NDA) or ANDA – Application for this exemption is called an Investigational New Drug Application ( IND) – Unlike other drug applications, INDs are neither approved nor disapproved. The clinical studies are either permitted to proceed or are placed on clinical hold for safety reasons – After a new IND is filed, there is a mandatory a 30day safety waiting period to allow the FDA 30 days to make a safety assessment
华润医药集团 |
15
2008 – 临床一期的GMP
以下IND一期临床排除在cGMP之外 • Investigational recombinant and non-recombinant therapeutic products • Vaccine products • Allergenic products • In vivo diagnostics • Plasma derivative products • Blood and blood components • Gene therapy products • Somatic cellular therapy products (including xenotransplantation products).
华润医药集团 |
10
IND的CMC • Provide Data Supporting the Purity, Identity and Stability of Bulk Drug & Formulated Drug Substance • Impurity Profile in Clinical Material Should Be Consistent with Material Used in the Pivotal Nonclinical Toxicology Studies
华润医药集团 |
17
2008 – 临床一期的GMP
但是„
• Well-defined, written procedures • Adequately controlled equipment and manufacturing environment • Accurately and consistently recorded data from manufacturing (including testing) • …sufficient CMC information to assure the proper identification, quality, purity and strength of the investigational drug • Recommends appropriate QC procedures to ensure quality and safety of study drug • FDA continues to exercise oversight of the study drug under general CGMP authority and through review of IND
华润医药集团 |
6
IND的内容
CONTENTS OF APPLICATION This application contains the following items: (Check all that apply) 1.Form FDA 1571 [21 CFR 312.23(a)(1)] 2.Table of Contents [21 CFR 312.23(a)(2)] 3.Introductory statement [21 CFR 312.23(a)(3)] 4.General Investigational plan [21 CFR 312.23(a)(3)] 5.Investigator's brochure [21 CFR 312.23(a)(5)] 6.Protocol(s) [21 CFR 312.23(a)(6)] a.Study protocol(s) [21 CFR 312.23(a)(6)] b.Investigator data [21 CFR 312.23(a)(6)(iii)(b)]or completed Form(s) FDA 1572 c.Facilities data [21 CFR 312.23(a)(6)(iii)(b)]or completed Form(s) FDA 1572 d.Institutional Review Board data [21 CFR 312.23(a)(6)(iii)(b)]or completed Form(s) FDA 1572 7.Chemistry, manufacturing, and control data [21 CFR 312.23(a)(7)] Environment assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)] 8.Pharmacology and toxicology data [21 CFR 312.23(a)(8)] 9.Previous human experience [21 CFR 312.23(a)(9)] 10.Additional information [21 CFR 312.23(a)(10)]
cGMP没有级别，或者是，或者不是。
华润医药集团 |
14
对于IND, FDA怎么说？
但是„
- CDER, Guideline on the Preparation of Investigational New Drug Products (Human and Animal), March 1991
华润医药集团 |
12
临床需要提供多少CMC信息
华润医药集团 |
13
IND的GMP
A drug...shall be deemed adulterated...if...the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. - FD&C Act (21 U.S.C. 351 (a)(2)(B)), Section 501(a)(2)(B)
华润医药集团 |
7
IND的CMC部分 – 原料药
华润医药集团 |
8
IND的CMC部分 – 制剂
华润医药集团 |
9
IND的增补和年度报告
• 增补提交到IND下，无30天等待期
• 增补有关安全的CMC资料, 如,
– 灭菌方法改变 – 影响质量的Container-closure系统变化 – 产生不同杂质谱的合成变化 – 原料由合成改为生物来源的 (人或动物) • 其他CMC 改变和变更在年度报告中提交
- CDER/CBER/ORA, CGMP for Phase 1 Investigational Drugs, July 2008
华润医药集团 |
16
一期临床不需要完整CMC资料因为：
▪ ▪▪ ▪ ▪ ▪Fra bibliotek▪ ▪ ▪ ▪
Safety is the main concern which is addressed with pharm/tox data Drug substance has been tested, thus impurity profile and potency are known in animals before given to human Generally a small number of patients in Phase 1 Trial duration is normally short for Phase 1 Clinical trials are conducted under a controlled setting whereadverse events can be monitored There is continuous regulatory oversight and review throughput the development cycle Limited number and/or size of batches have been manufactured Formulation, analytical procedures, and manufacturing process are being refined and improved Drug substances and products are manufactured according to CGMP, even though Phase 1 IND drugs are exempt from CGMP requirements
赵丕华 华润赛科药业研发中心
2013.10.30
华润医药集团
主要内容：
IND
IND中的CMC
CMC与cGMP IND一期临床阶段对原料药和制剂的要求 IND二/三期临床阶段对原料药和制剂的要求 与FDA的IND会议 参考
华润医药集团 |
• Formulation of Drug in Nonclinical Studies Should Parallel Clinical Formulation
华润医药集团 |
11
临床需要提供多少CMC信息 视以下情况而定:
▪ 阶段 ▪ 药物的创新性 (NCE/NME/505 b (2)…) ▪ 已有的研究结果 ▪ 给药途径/方式 ▪ 临床研究时间 ▪ 病人分布 ▪ 已知或怀疑的风险
华润医药集团 |
3
IND的过程
* - Dr. Charles P. Hoiberg, DIA China, Beijing, May 2011
华润医药集团 |
4
IND的流程
华润医药集团 |
5
有关IND的法规
21 CFR 312
▪ 21 CFR 312.21: Phases of an Investigation – Phase I, II, and III ▪ 21 CFR 312.22: General Principles ▪ 21 CFR 312.23: Content – Drug Substance – Drug Product – Placebo – Labeling – Environmental Analysis
2
IND FD&C Act 505(i) exempts a drug intended solely for investigational use by qualified experts from filing a NewDrug Application (NDA) or ANDA – Application for this exemption is called an Investigational New Drug Application ( IND) – Unlike other drug applications, INDs are neither approved nor disapproved. The clinical studies are either permitted to proceed or are placed on clinical hold for safety reasons – After a new IND is filed, there is a mandatory a 30day safety waiting period to allow the FDA 30 days to make a safety assessment
华润医药集团 |
15
2008 – 临床一期的GMP
以下IND一期临床排除在cGMP之外 • Investigational recombinant and non-recombinant therapeutic products • Vaccine products • Allergenic products • In vivo diagnostics • Plasma derivative products • Blood and blood components • Gene therapy products • Somatic cellular therapy products (including xenotransplantation products).
华润医药集团 |
10
IND的CMC • Provide Data Supporting the Purity, Identity and Stability of Bulk Drug & Formulated Drug Substance • Impurity Profile in Clinical Material Should Be Consistent with Material Used in the Pivotal Nonclinical Toxicology Studies
华润医药集团 |
17
2008 – 临床一期的GMP
但是„
• Well-defined, written procedures • Adequately controlled equipment and manufacturing environment • Accurately and consistently recorded data from manufacturing (including testing) • …sufficient CMC information to assure the proper identification, quality, purity and strength of the investigational drug • Recommends appropriate QC procedures to ensure quality and safety of study drug • FDA continues to exercise oversight of the study drug under general CGMP authority and through review of IND
华润医药集团 |
6
IND的内容
CONTENTS OF APPLICATION This application contains the following items: (Check all that apply) 1.Form FDA 1571 [21 CFR 312.23(a)(1)] 2.Table of Contents [21 CFR 312.23(a)(2)] 3.Introductory statement [21 CFR 312.23(a)(3)] 4.General Investigational plan [21 CFR 312.23(a)(3)] 5.Investigator's brochure [21 CFR 312.23(a)(5)] 6.Protocol(s) [21 CFR 312.23(a)(6)] a.Study protocol(s) [21 CFR 312.23(a)(6)] b.Investigator data [21 CFR 312.23(a)(6)(iii)(b)]or completed Form(s) FDA 1572 c.Facilities data [21 CFR 312.23(a)(6)(iii)(b)]or completed Form(s) FDA 1572 d.Institutional Review Board data [21 CFR 312.23(a)(6)(iii)(b)]or completed Form(s) FDA 1572 7.Chemistry, manufacturing, and control data [21 CFR 312.23(a)(7)] Environment assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)] 8.Pharmacology and toxicology data [21 CFR 312.23(a)(8)] 9.Previous human experience [21 CFR 312.23(a)(9)] 10.Additional information [21 CFR 312.23(a)(10)]
cGMP没有级别，或者是，或者不是。
华润医药集团 |
14
对于IND, FDA怎么说？
但是„
- CDER, Guideline on the Preparation of Investigational New Drug Products (Human and Animal), March 1991
华润医药集团 |
12
临床需要提供多少CMC信息
华润医药集团 |
13
IND的GMP
A drug...shall be deemed adulterated...if...the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. - FD&C Act (21 U.S.C. 351 (a)(2)(B)), Section 501(a)(2)(B)
华润医药集团 |
7
IND的CMC部分 – 原料药
华润医药集团 |
8
IND的CMC部分 – 制剂
华润医药集团 |
9
IND的增补和年度报告
• 增补提交到IND下，无30天等待期
• 增补有关安全的CMC资料, 如,
– 灭菌方法改变 – 影响质量的Container-closure系统变化 – 产生不同杂质谱的合成变化 – 原料由合成改为生物来源的 (人或动物) • 其他CMC 改变和变更在年度报告中提交
- CDER/CBER/ORA, CGMP for Phase 1 Investigational Drugs, July 2008
华润医药集团 |
16
一期临床不需要完整CMC资料因为：
▪ ▪▪ ▪ ▪ ▪Fra bibliotek▪ ▪ ▪ ▪
Safety is the main concern which is addressed with pharm/tox data Drug substance has been tested, thus impurity profile and potency are known in animals before given to human Generally a small number of patients in Phase 1 Trial duration is normally short for Phase 1 Clinical trials are conducted under a controlled setting whereadverse events can be monitored There is continuous regulatory oversight and review throughput the development cycle Limited number and/or size of batches have been manufactured Formulation, analytical procedures, and manufacturing process are being refined and improved Drug substances and products are manufactured according to CGMP, even though Phase 1 IND drugs are exempt from CGMP requirements