下游工艺开发中质量源于设计(QbD)和纯化工艺的验证

下游工艺开发中质量源于设计(QbD)和纯化工艺的验证

Liu Jing jingliu@http://www.77cn.com.cn Product support manager GE Healthcare Life Sciences

质量源于设计 Quality by design-有效过程开发的框架

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什么是质量源于设计(QbD)Definition–“A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.”

“在充分的科学依据和质量风险管理基础之上的，预先定义好目标并强调对产品与工艺的理解及工艺控制的一个系统的研发方法。”ICH Harmonised Tripartite Guideline, Pharmaceutical Development Q8(R1), November 2008 FDA Guidance for Industry, Q8(R1) Pharmaceutical Development, June 2009

系统性研究方法预先设定目标强调对产品和工艺的理解，及对工艺的控制基于充分的科学依据和质量风险管理3 GE Title or job number 5/30/2013

为什么FDA要推行QbD

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Why QbD? 企业对药品质量的监控更加主动，大大减少对最终检测手段的依赖，减少不合格批次，减少召回事件。

鼓励新技术新工艺的开发，减少审批次数。 持续改进产品质量，企业提高竞争力。 利用平台和历史数据加快新药开发从2005年7月开始，FDA招募了9个企业的12个项目进行QbD注册申报试点。到2009年，已经有10个项目注册成功。

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QbD过程需求向下决定控制策略预先的知识和临床数据Quality Target Product Profile目标产品质量要求 Critical Quality Attributes (CQA)关键质量属性 Critical Process Parameters (CPP)关键工艺参数

预先的产品知识，临床数据和质量风险评估

预先的工艺知识，风险分析和试验设计DoE风险分析和试验设计DoE预先的工艺和产品知识，风险分析和DoE

Design space设计空间

Control strategy控制策略6 GE Title or job number 5/30/2013

QbD过程能力向上决定产品质量Identifying Critical Process Parameters and controlling them correctly will guarantee that the Critical Quality Attributes are met which in turn guarantees the product fulfills its’ Quality Target Product Profile确定关键过程参数并正确的控制，可以保证关键质量属性得以满足，从而最终满足产品质量要求Quality Target Product Profile目标产品质量要求 Critical Quality Attributes (CQA)关键质量属性 Critical Process Parameters (CPP)关键工艺参数 Design space设计空间

Control strategy控制策略7 GE Title or job number 5/30/2013

举例：单抗的关键质量属性(CQAs)CQA指需要被控制在一定范围和参数内对产品质量有确切的影响的理化，生物学等方面性质。

活性构象

均一性

浓度表面电荷Charge variants电

荷不均一 Deamidation脱酰胺

大小Aggregation聚体 Fragmentation分解断裂

纯度Product related impurities Host Cell Proteins PrA leakage Cell culture components DNA Endotoxin Subvisible particles

结构序列N-terminal C-terminal Glycosylation糖基化 Disulfide bonds二硫键8 GE Title or job number 5/30/2013

质量属性的风险评估工具Tool#1失效模式Preliminary Hazards Analysis (PHA):失效严重度(1-9);严重度发生可能性(1-9)

危险程度(Risk Priority Number[RPN]) )=失效的严重度 x严重度发生可能性(1-81) Tool#2风险评级risk ranking:影响性(2-20)包括有效性，PK/PD,免疫原性，安全性；不确定性(1-7)危险程度(Risk Score)=影响性 x不确定性 (2-140) Tool#3杂质安全性影响因子impurity safety factor ISF= LD50÷不纯物在每剂量中的含量

聚体在某Mab中的风险分析失效模式失效的严重度 5有效性 PK/PD严重度发生可能性=频度X探测度 5风险评级免疫原性安全性风险评分评分(RPN) 25

2X3=6

12x5=60

4X2=8

2X2=4

60

Design Space设计空间Definition: The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.已经被证明能提供产品质量保证的输入变量(如材料属性)及工艺参数的多维组合及相互的关联。根据ICH Q8,可以在对工艺进行注册之前，开发出“设计空间”,这个空间是通过对知识空间的风险分析与试验设计而取得的。这样的话，只要所有的控制空间都在设计空间的范畴内，那么控制策略在各个控制空间之间移动时，如材料的属性和工艺参数产生变化时，就不需要再进行注册，

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质量源于设计(QbD)的工艺空间产品质量目标关键质量属性CQAs的可接受范围范围

单个关键参数CPPCharacterization range特征范围 Acceptable range设计范围 Operating range操作范围

关键工艺参数CPPs的研究

多个关键参数CPPsCharacterized space特征空间 Design space设计空间

control space控制空间

风险分析透明化鉴定优先级与风险降低

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风险分析FMEA -失效模式及结果分析风险评估的三个提问1. 2.

3.

S - Severity失效的严重度 (1-10) O - Occurrence频度 (1-10) D - Detection探测度 (1-10)什么可能出错 RPN (风险顺序数)= S x O x D会出错的可能性(概率)是什么 RPN是一项设计风险的指标。当RPN较高时结果(严重性)是什么﹐设计小组应提出矫正措施来降低RPN值. RPN值高于100时必须做对应处置。

Important that as many as possible are included from multiple functions: R&D, Process development Manufacturing, Sourcing, QA, QC etc14 GE Title or job number 5/30/2013

SOD水平定义举例水

平9-10 7-8

严重度S事故可能使在故障或操作期间涉及到个人的安全问题；或不适合该生产线继续从事生产任务.

频度O每一批次/运行

探测度D现行系统几乎不可能检测到失效

严重失效，TI>=1440 min或出现因设备精度下降产生废品.几个批次报废，对设备有损坏主要的失效，需长期的行动， 480 min≤TI<1440 min或影响到设备的精度，被设备的使用者注意到并在设备人员的作用下得到纠正.部分产品须报废轻微影响，需要短期的修理，60 min≤ TI<480 min,产品须筛选和部份重工较小的失效，对设备的使用无主要影响，修复时间TI<60 min

2~10批次发生一次

内部不能发现，没有任何手段可以在该失效模式发生前被探测到. (设备厂商可以检测到)难于发现，失效模式或原因被发现是很困难的，或探测元件几乎不能使用.(设备专业技术工程师可探测到)便于发现，失效的原因或模式是可发觉的，但有一种或少数几种不能被探测到.(设备维护检修人员可探测到)操作者可探测到

5-6

每年两次，每10个批次发生一次

3-4 1-2

一年一次/每 50个批次发生一次非常低/几乎不发生

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Example: FMEA分数卡RPNItem/ Process Step Potential Failure Mode(s) Potential Effect(s) of Failure Carry over S Potential Potential O e Mechanism(s) c Cause(s) of c v of Failure Failure 7 Insufficient cleaningu r 3 Operator

Current Process Controls

D e t

R P N

Recommende d Action(s)

Actions Taken

Concentration Below limit of CIP solution

Double/Instrument check calculation s

7 147 On line TOC, Check conductivity of the solution

On line TOC, 7 1 1 7 Check conductivity of the solution

RPN> 50 was further examined* in process characterization

*

New Occ

New Det New RPN

New Sev

Action Results

High level process mapCapture Sample conditioning Capacity-load Clarification Upstream Flux Porosity Area Antifoam Yield Intermediate wash: pH Conductivity& additives Elution conditions Yield Purity Product Integrity and activity Buffer exchange

CaptoTM adhereConductivity pH Capacity-load Elution conditions Yield Purity Product Integrity and activity Formulation Flux Area Yield Bulk product Yield Purity: -HCP Virus filtration Flux Area Yield -Protein A -Aggregates Product Integrity and activity

FluxArea Yield

2-step process

Bulk storage Titer Virus inactivation Time pH pH adjustment Yield Aggregates Product Integrity and activity Filtration

3-step process

Sterile filtration Flux Area Yield Polishing Conductivity

Depth filtration Flux Area Yield

Polishing Conductivity pH Capacity-load Elution conditions Yield Purity Product Integrity and activity

Buffer exchangeFlux Area Yield

pHCapacity-load Elution conditions Yield Purity Product Integrity and activity

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CaptoTM adh

ere步骤的鱼骨图Column PackingHETP Assymetry Resin Volume Flow Distribution Leakage Bed Stability Resin Id

SampleConcentration ofTarget Molecule pH Conductivity Temperature Sample Variability

WashAdditives pH Conductivity Wash Volume (CV) Flow Rate

StripAdditives pH Conductivity Wash Volume (CV) Flow Rate

Measurement SystemsBias– Too high/low readingsVariability Measurement Noise Robustness within Measurement Space Robustness over time

Intermediate Wash Temperature

Buffer and Salt Types Temperature Resin Stability

ViscosityHold Times

Active Monitoring ofpH, Conductivity, UV

YieldpH

Flow Path Design Reliability of Monitors, Valves and Pumps Servicability Availability

Equilibration pre Load pH, Cond, Vol Sample Flow Sample Pressure

Viscosity/Pressure pH and Conductivity Concentration/Stabililty Volume

HCP Purity

Conductivity Volume Flow Rate

Sample AmountTemperature Buffer and Salt Type Passive Monitoring of Flow, Pressure, Amount, pH, Conductivity

Flow RateTemperature Buffer and Salt Type

Temperature Buffer and Salt Type Resin Stabililty

Resin StabililtyAdditives Gradient Profiles

Additives

Systems Hardware

Load

Elution

CIP

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FMEA: CaptoTM adhere mab polishingWhat is the defect? What is the impact on the process customer? S e v What causes the defect? O c c u r Sources of Variability (think Fishbone) D e t R P N Responsibility& Target Completion Date Action ResultsNew Occ New Sev

Item/ Process Step

Potential Failure Mode(s)

Potential Effect(s) of Failure

Potential Mechanism(s) of Failure

Potential Cause(s) of Failure Mechanism

Current Process Controls

Recommended Action(s)

Actions Taken

Sample conc. Sample conc. System assembly System assembly CIP volume Sample load CIP cond Sample load CIP cond CIP cond CIP cond

Above limit Below limit Wrong flow path Wrong flow path Below limit Above limit Above limit Below limit Above limit Above limit Below limit

Low purity Low yield Multiple Multiple Risk of carry over/Build up Low purity Loss of media Low yield Low purity Low yield Risk of carry over/Build up Low purity Low purity Low purity Low purity Low purity Low purity Low yield Low yield Low yield Loss of product Low yield Low yield Air on column Low purity

6 Analysis error 6 Analysis error 9 Multiple 9 Multiple 7 Insufficent cleaning 7 Wrong sample amount applied 8 7

3 Operator, dilution 3 Operator, dilution 3 Operator 3 GE manuals/SOPs 1 Operator/instrument 3 Operator 1 Operator/instrument 3 Operator 1 Operator 1 Operator 1 Operator/instrument 1 Operator

No controll No controll Visual inspection Visual inspection No controll at line In line at line In line In line Scale

7 7 4 4 10 3 7 3 7 7 7 6 2 2 2 2 2 6 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 2 2 3 3 3 3 3 3 3

126 126 108 108 70 63 56 54 49 49 49 42 42 42 36 36 36 36 36 36 30 30 30 28 21 21 21 21 21 21 21 21 21 20 18 18 18 18 18 18 18 18

Buffer preparation

6 Wrong sample amount applied

Loss of capacity/

Ligand 7 Loss of capacity/Ligand7 Insufficent cleaning 7 Wrong column volume 7 Buffer prepparation 7 Buffer prepparation 9 UF/DF 9 UF/DF 9 UF/DF 6 Wrong column volume 6 6 5 5 5 Buffer prepparation Buffer prepparation Buffer blending Buffer prepparation Buffer prepparation

84 parameters identified to possibly affecting 94 failure modes identified to potentially influence the unit unit operation scoring from 1-126 operation. RPNthe scores from 1-126.Sample load Elution pH Above limit Below limit Batch release pH meter

Control column packing and testing

3 Operator/instrument 3 Operator/instrument 2 Operator/instrument 2 Operator/instrument 2 Operator/instrument 1 Operator

Elution Cond Sample pH Sample pH

Above limit Above limit Below limit

Cond meter

In-line monitoring In-line monitoring In-line monitoring Batch release pH meter Cond meter In-line monitoring pH meter Cond meter Air-sensor Standard sample At line At line At line Pressure UV Collected volume At line At line In-line monitoring In-line monitoring Standard sample At line At line At line At line Collected volume Collected volume

Meassur pH of UF/DF pool

Sample conductivity Sample load Elution pH Elution Cond Eq. pH Wash pH Wash Cond Eq. volume Sample conc. Sampel agg. Sample flow Wash flow Elution buffer volume buffer Elution volume buffer Elution volume Flow Elution Strip flow Eq. pH Eq. pH Sample conc. Sampel agg. Sample HCP level Sample Sure level DNA sample level volume Elution Elution volume

Above limit Below limit Above limit Below limit Below limit Below limit Above limit Below limit Above limit Above limit

Control column packing and testing

3 Operator/instrument 3 Operator/instrument 3 Operator 3 Operator/instrume 3 Operator/instrume

nt7 Buffer blending 7 Analysis error 7 2 Operator 1 Instrument error 1 Operator/instrument 1 1 1 1 1 1 1 2 3 1 1 1 1 1 1 1 Wrong Flow meter Wrong Flow meter Air trap can not take all air Air trap can not take all air Air trap can not take all air Flow meter Wrong Wrong Flow meter Valves Operator Instrument error Operator/instrument

Low purityLow purity Low purity Low yield Low yield Low yield Low purity Insuficent strip/Carry over Loss of product Dilution of product Low yield

Analysis error

Above limitAbove limit Below limit Below limit Below limit Above limit Above limit Below limit Below limit Below limit Below limit Above limit Above limit Above limit Above limit Above limit

Low yield Low purity Low purity Low purityLoss of material Loss of material

7 Iinstrument error 7 Iinstrument error 7 Air on column 7 Air on column 7 Air on column 7 Iinstrument error 7 Iinstrument error 5 Instrument 3 Buffer blending 6 Analysis error 6 Analysis error 6 Process error 6 Process error 6 Process error 6 Elution vessel too 6 Elution vessel too

Operator/instrume Operator/instrume Operator/instrumeWrong Flow meter UV cell error

small small

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