A LEADING ROLE ISOTOPE LAB CAN PLAY IN A SUCCESSFUL HUMAN ADME STUDY同位素实验室在人体ADME研究中可发挥的积极作用

-FROM LABELED MATERIAL SYNTHESIS TO CLINICAL SERVICE FORM APPROVALAmy Wu, Lawrence Jones, Tapan RayNovartis Institute for Biomedical Research

Content 内容概要

• Introduction and general process 简介

• Regulatory basis 法规

• GMP lab qualification GMP实验室认证

• IL role and activities before final manufacture 药物投产前同位素实验室发挥的功能

• Stability program for radiochemical purity放射化学纯度稳定性

• Formulation choices and improvement剂型选择和改进

• Case study 案例研究• Summary 总结

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Introduction 简介

§ In a human ADME study (hADME), the processes of absorption, distribution, metabolism and excretion of a radiolabeled drug are investigated in order to understand the pharmacokinetics, major clearance processes, and the fate of the drug in the body. The hADME study is a pivotal study within the drug development process. Comparison and quantification of metabolites observed in human and across the species used in the toxicology studies allows safety factors to be calculated. Some of the key study findings may appear in the package insert (Basic Prescribing Information (BPI)) of the drug.人体ADME研究是药物开发中的一个关键性项目，放射性标记药物在其中的应用是为了阐明药代动力学、主要消除途径和药物在体内的归趋

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Human ADME within the Drug Development人体ADME在药物开发中的应用

Lead Identification

Drug Discovery

Preclinical Development

Clinical Development

FDA Filing Approval &

Launch Prepareration

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Early Development

Late Development

Human ADME studies are usually performed in phase 1-2 of clinical development, after POC 人体ADME研究通常在临床1-2期时，在概念验证后进行

Department involved in Human ADME studies人体ADME研究设计的部门

§ Isotope Lab (IL) - Radiolabeled DS and DP放射性标记药物和产品

§ Non Clinical PK/PD-dosimetry calculation剂量计算

§ Biotransformation/Bioanalysis (BT/BA)-sample analysis生物样品分析

§ Clinical Trial Leader (CTL)- set up CRO and timeline.确定CRO及时间表

§ Technical Research and Development (TRD)- cold DS, formulation support非放射性药物，剂型研究

§ Clinical Manufacture Unit (CMU)- packaging supply供应

§ Drug Supply Management (DSM)-label design and shipping标签

§ Quality Assurance (QA)- Release specification and cofa发布规格及检验信息

§ Drug Regulatory Affair (DRA)-shipping ticket, documentation运输5

Why it is important for IL to be key player同位素实验室的重要性

§ In order to have the study done, the basic need is to have labeled DS/DP. IL timeline (syn. and stability of labeled DS/DP) are critical to the whole studies.

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IL

TRD

BT

QAClinical

CRO

同位素实验室的关键作用：合成标记药物及确定其稳定性

Regulatory Basis 法规

§ 1. ICH CGP guideline: “ Investigational products should be manfactured, handled and stored in accordance with applicable CGP”国际医药法规协和会相关法规

§ 2. US FDA: “The radiolabeled drug meets appropriate...standards.. as needed for safety and.. to give significance to the research study conducted”美国FDA相关法规

§ 3. EU authorities: For human ADME studies, GMP requirements should be implemented in an adequate reasonable way.欧盟相关法规

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Process developed at Novartis since 2005诺华自2005至今采取的措施

§ 1. Global SOP written

§ 2. A Complete training material is available both online and in classroom (especially useful to CTL, PTR and anyone who is new to the process)

§ 3. Qualified GMP manufacture unit within IL including analytical equipments.

§ 4. Accelerated stability program to evaluate radiochemical purity

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IL-GMP Lab Qualification同位素实验室- GMP实验室认证

§ In 2008, IL-EH had set up a GMP lab for manufacture radiolabeled drug product.

§ Different zoning requirement was established following Corporate GMP quality manual and qualified by QA.

§We also established SOP for using and operation of this lab.• Personal flow, material flow, Gowning• Labeling of the lab for before/during/after manufacture time• Preparation and Operation of the laminar Flow Hood and the drying

oven• Cleaning and Sanitization procedure; Sampling plan/procedure

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Prework need to be done by IL同位素实验室需完成的工作

§ 1. Synthesis/purification of labeled compound (preparation of surrogate batch) 标记化合物的合成/纯化

§ 2. Analytical method development and validation 分析方法建立和确证

§ 3. Stability testing for labeled DS and DP 标记药物稳定性

§ 4. Finalize formulation procedure with surrogate batch 剂型确定

§ 5. c-of-a and TSE(transmissible spongiform encephalopathies) from venders 检验证书和TSE

§ 6. Cold drug substance and impurity standard from TRD药物和杂质标准品

§ 7. Set specification based on above result 确立规格

§ 8. Specification send to CMU to generate project master for manufacturing the DP 根据规格应用于生产

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What are some of the challenges挑战

§ Less stable- common for radiolabeled material

§ Limited formulation can be used

§ Small batch size- limited test can be done• e.g Heavy metal testing, special impurity with low limit, particle size

§ Solutions:• Work with TRD formulator as early as possible• Surrogate batch

- Dissolution test- replacement for particle size test

• Calculation- ICH guideline - Based on the ratio of isotope dilution, certain test can be waived

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Stability Test- DS and DP药物稳定性测试

§ Radiolabeled Compound is less stable compare to non labeled compound, Because:• 1. There is primary decomposition where emitted radiation is

absorbed by other radioactive molecules creating impurities. • 2. Chemical decomposition as nonlabeled material.

In general, if the compound with higher sa will have lower radiochemical stability

§ Stability data will be required prior to specification can be approved.• Stability of DS• Stability of DP

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Accelarated Stability加速稳定性

§ Based on Novartis drug stability policies:• In general, for every new dosage form the stability should be tested

continuously. However, an accelerated conditions for the new form can be used to predict the real storage condition. Typically, due to the four fold higher rate of chemical degradation in accelerated conditions, it is considered safe to assume that the stability at storage condition will be satisfactory for a four-times longer.

• E.g. 25 C 1 month stability can be used for 4 month at 2-8 C• We normally run the accelerated stability program for 14C DS and

DP to save time since there will be 6 month preparation time from synthesis of radiolabeled compound to the clinical dosing.

• Final analysis will be done after the last patient was dosed.

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Dealing with OOS and OOE 非期盼数据的处理

§ Due to small synthesis scale and alternate route, sometimes we will get result which did not meet pre set specification based on tox test on the cold material.

§ We will first do LIR and if that does not solve the problem, FIR will be initiated by TRD-QA and the summary will be send to TOX and clinical for approval.• e.g.• Assay fail• Specific activity out of range • Certain impurities are over the limit

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Formulation considerations剂型选择

§When possible, formulation should be the same or similar to that used in clinical trials already conducted with unlabeled medication

§ However, lower stability of radiolabeled medication and /or manufacturing constraints associated with the use of radioactive material often requires modification of the existing formulation

§ Currently, the following formulation can be prepared by IL-EH

- PIB, capsules, non-sterile liquid, micro emulsion pre-concentrate.

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Content Uniformity- Capsule formulation均一性 –胶囊剂型

§ USP requirement for clinical study: Chemical Assay 90-110%

§ Human ADME study would like tighter assay range since only 4 patients will be used

§ Formulation development with 14C DS can be tested out during stability batch preparation

§ Replacing blend uniformity with:• Radioactivity counting at 4-5 different spot• Individual weighed capsules

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Further improve content uniformity提高均一性

§ TF2 automatic blending machine replace motor/pastol

§ Sieve recipients prior to mixing

§ Particle size control for drug substance

§Work closely with TRD colleagues

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Case study 1- 14C Compound L for oncology patient案例1:14C 标记的抗肿瘤药物L

§ Formulation: Hard Geletin Capsule

§ Challenge: Stability for DS and DP were only good for 3 month while patients recruitment rate is one per two month.

§ Solution: • Store radiolabeled API starting material, start final synthesis,

purification 6 weeks prior to dosing date.• Choose reputable CRO to have better patient recruitment program.

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Case study 2 – Three13C Compounds for absolute bioavailablity study (IV)案例2：3个13C标记药物的绝对生物利用度(IV)§ Challenge:

• Difficult synthesis- very small batch size• Compound is extremely hygroscopic• No existing iv formulation for non labeled drug

§ Solution:

§ Developing cold i.v formulation procedure with cold surrogate batches

§ Modify release analysis, certain ID tests performed on intermediates

§ Add concentration testing for drug product release

§ Sterility test on DP only not DS

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Case study 3- 14C Compound P (antibiotic) IV formulation案例3: 14C 标记药物P（抗生素）的静注剂型§ Formulation- IV

§ Challenge: • Compound is not stable in water but it is only soluble in water-cannot

make final DS by isotope dilution• Compound is light sensitive, all operation need to be under dark

§ Solution:Develop crystallization method to purify highly labeled 14C compound P.Develop IV formulation procedure to mix cold and hot material on site.Three validation run were performed prior to actual dosing.

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Summary 总结

§ Human ADME study is a special clinical study where radiolabeleddrug product is used. Due to its uniqueness, many department and expertise will be involved in this study.

§ Radiolabeled drug substance and drug product are the key to the study, expert from isotope lab can play important role to guarantee the success of the study.

§ GMP lab is important to allow us manufacture radiolabeled DP to support global study. Doing everything within IL will also benefit us with less material consumption and shortest timeline.

§ A clearly defined functional responsibilities and frequent communication help smooth the project flow.

§ Accelerated stability study, working closely with formulator for radiolabeled drug product development will help us better utilize labeled material.

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Acknowledgment

§ Novartis DMPK Management

§ Mark Kagan; Alana Upthagrove; Jimmy Flarakos; James Mangold – DMPK Biotransformation

§ Haiying Sun; Shazia Ali-Clinical PK and Clinical Pharm.

§ Stephen Palermo- TRD-QA

§ Bohdan Markus; Kirk Bordeaux; Grazyna Ciszewska; Zhigang Jian- DMPK-IL

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