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The 2nd QbD Conference

QbD in Large Molecules:

Th A M b t d b th CMC Bi t h

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The A-Mab case study by the CMC Biotech Working groupDan Kenett

May 5 2010 Jerusalem

Background: Therapeutic Monoclonal Antibodies

Selected A-Mab chapters:

OUTLINE

Design of Molecule and Quality Attributes Assessment

Upstream Manufacturing Process Development

Control Strategy

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OUTLINE

Background: Therapeutic Monoclonal Antibodies

Selected A-Mab chapters:

Design of Molecule and Quality Attributes Assessment

Upstream Manufacturing Process Development

Control Strategy

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Therapeutic Monoclonal Antibodies

A total of 21 mAb products are approved in the US, with additional products marketed outside the US

mAb therapeutics are now being developed and marketed by most mAb therapeutics are now being developed and marketed by most major pharmaceutical firms

7 mAbs have global sales of over US$1 billion

In 2006 global market = US$20 billion ,

in 2010 expected to reach US$40 billion

over 200 mAb candidates are currently undergoing clinical study

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Reichert J.M. Current Pharmaceutical Biotechnology 2008, 9, 423-430

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Monoclonal antibody structure

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Schiesti M. (Sandoz) PMDA symposium 2009

Possible natural modes of action of mAbs versus cells cells

6 Schiesti M. (Sandoz) PMDA symposium 2009

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Cell fusion with cancerous cells recombinant DNA technology

1975 1986 1994 1997 2002

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Schematics of a manufacturing process of a monoclonal antibody

12000L

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Kozlowski and Swann , Quality by Design for Biopharmaceuticals 2009

Upstream Downstream

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FDA Initiatives and QbD Timeline

Small molecule ACEmock case study by

Conformia

Large molecule A-Mab mock case study by CMC

Biotechnology Working Group

2010

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QbD Mock Case studies

Small Molecules (Pharmaceutical)

1. Examplain (P2 module of CTD format) – 2006

EFPIA http://www.efpia.org/Content/Default.asp?PageID=450

2. Acetriptan (ACE) - 2008

cet pta ( C ) 008

Conformia software collaboration with Abbot, AstraZeneca, Eli Lilly, GlaxoSmithKline

3. Illustrain Hcl (S2 module of CTD format)- 2009 target

EFPIA

Monoclonal Antibody (Biopharmaceuticals)

1. A-Mab - 2009

CMC working group of 7 leading Biotech companies:Amgen,

Genentech, Abbot Bio MedImmune, GlaxoSmithKline Bio, Eli

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Genentech, Abbot Bio MedImmune, GlaxoSmithKline Bio, Eli

Lilly , Pfizer Biohttp://www.casss.org/displaycommon.cfm?an=1&subarticlenbr=286

2. Mockestuzumab (S2 and P2 module of CTD format) –2010 target

EFPIA

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What is A-Mab ?

Humanised IgG1 against Lymph-1 (a surface antigen on CD20 B cells) which is expressed at high levels at surface of B cells from NHL (Lymphoma) patients

A-Mab stimulates CD20 B cells killing primarily through ADCC and possibly also by CDC

It is produced by recombinant DNA technology in CHO cells It is produced by recombinant DNA technology in CHO cells

Delivered by IV administration at a weekly dose of 10mg/kg for 6 weeks

12http://images.google.com/imgres?imgurl=http://rss.xinhuanet.com/newsc/english/2008-03/11/xin_142030511140539054143.jpg&imgrefurl=http://rss.xinhuanet.com/newsc/english/2008-03/11/content_7765049.htm&usg=__oTBauuUxMAYhD-9QSKw8J0uKqs4=&h=442&w=450&sz=21&hl=

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The A-Mab chapters

1. Design of Molecule and Quality Attributes Assessment

2. Upstream Manufacturing Process Development

3. A-Mab Downstream Process Description and Characterization3. A Mab Downstream Process Description and Characterization

4. Drug Product

5. Control Strategy

6. Regulatory Section

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OUTLINE

Background: Therapeutic Monoclonal Antibodies

Selected A-Mab chapters:

Design of Molecule and Quality Attributes Assessment

Upstream Manufacturing Process Development

Control Strategy

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Initial Target Product Profile

TPP=Prospective and dynamic summary of the quality characteristics of a drug product that id ll ill b hi d t th tideally will be achieved to ensure that the desired quality, and thus the safety and efficacy, of a drug product is realized

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Quality attributes of Drug Product not yet defined

Design Features of A-Mab

The design strategy for A-Mab was:

To maximize clinical performance

To minimize potential impact on quality

To mitigate risk from the following product attributes:

By planning the DNA sequence

Unpaired cysteine residues (reduced risk of undesirable disulfide bond formation) Potential deamidation sites in the CDRs (reduced risk of deamidation) O-linked glycosylation sites (reduced risk of heterogeneity and impact on bioactivity)

N-linked glycosylation sites in the CDRs (reduced risk of heterogeneity and impact on bioactivity)

Acid labile (DP) sequences (reduced risk of fragmentation) Oxidation sites in the CDR

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Quality Attributes of monoclonal antibodies

Quality attributes that can vary quantitatively and qualitatively in a process

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Systematic Identification of critical Quality Attributes

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Overview of A-Mab Product Realization Process

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Overview of A-Mab Product Realization Process

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Platform Knowledge

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Quality Attribute Risk Assessment Tools

Three types of tools for assessing criticality of quality attributes are presented as examples:

Risk ranking (Tool #1)

Criticality = Impact x uncertainty Criticality = Impact x uncertainty

Preliminary hazards analysis (PHA) (Tool #2)

Criticality = Severity (safety,efficacy) x Likelihood (probability of AE due to out of range)

A safety assessment decision tree for evaluating process-related impurities that do not have biological activity based on ISF(Tool #3)

The impurity safety factor (ISF) = LD50 ÷ Level in Product Dose

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p y y ( )

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Quality Attribute Assessment Tool #1

Impact: The impact ranking of an attribute assesses either the known or potential consequences on safety and efficacy. The impact ranking considers the attribute‘s effect on:considers the attribute s effect on:

1. efficacy, either through clinical experience or results using the most relevant potency assay(s),

2. pharmacokinetics/pharmacodynamics (PK/PD), 3. Immunogenicity4. safety.

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Impact : Definition and Scale for Tool #1

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Uncertainty: Definition and scale for Tool #1

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Criticality: Definition

Criticality (Risk Score) = Impact × Uncertainty

All quality attributes are assigned a degree of criticality (criticality continuum) based on their respective risk score. Risk scores range between a low of 2 to a high of 140.

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Examples of Quality Attribute Risk Assessment with Tool#1

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(WHO)

A-Mab examples of Tool #1

Aggregation

DNAModerate high

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The individual impact category with the highest ranking determines

the overall impact ranking for an attribute

None Moderate

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Summary of Quality attribute Risk assessments

Vary according to mode of action

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Critical quality attribute includes H and VH

Critical Quality attributes and target ranges

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ualit

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ttrib

utes

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OUTLINE

Background: Therapeutic Monoclonal Antibodies

Selected A-Mab chapters:

Design of Molecule and Quality Attributes Assessment

Upstream Manufacturing Process Development

Control Strategy

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Design Space for Bioreactor Production with Reliability dimension Control Space Based on the Overall Reliability of

the Process (Predictive Bayesian Reliability approach)Design space for culture duration 15 days

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Regions in dark-red possess > 99%reliability to satisfy all the CQA limitsand determine the Control Space

To achieve a response surface model by DOE suitable to define a Design spaceN=40 bioreactor runs (4 blocks of 10, ~12 weeks) X-Mab data

2-11%

20-40%

Design space for Production Bioreactor

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Design space examples in A-Mab

Upstream production bioreactor

Low pH viral inactivation

Drug product compounding

Drug product sterile filtration

Bioreactor engineering

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OUTLINE

Background: Therapeutic Monoclonal Antibodies

Selected A-Mab chapters:

Design of Molecule and Quality Attributes Assessment

Upstream Manufacturing Process Development

Control Strategy

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QbD vs Traditional approach for the Control Strategy

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Risk Assessment Approach used through Development Lifecycle and for setting Control Strategy

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Prior knowledge and early development experience used to identify parameters and attributes that must be considered for process characterization studies

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Risk Assessment Approach used through Development Lifecycle and for setting Control Strategy

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The cumulative process understanding serves as the basis for the late-phase risk assessments used to finalize selection of Critical Process Parameters (CPPs) that underpin the proposed design spaces and control strategy.

Final Categorization of Process Parameters for A-Mab Control Strategy

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Example: Risk Assessment Results for Process Parameters in the N-1 and Production Bioreactor

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Categorization of Process parameters examples in A-Mab

Protein chromatography

Low ph viral inactivation

Cation exchange chromatography

Anion exchange chromatography

Small virus retention filtration

Drug product compounding

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Control Strategy for commercial manufacturing

Output of Risk assesment Tool #1

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Each CQA is evaluated independently to ensure that the proposed control strategy will deliver each CQA within its acceptable ranges established for safety and efficacy. A Failure Mode and Effects Analysis (FMEA) approach was used

Example: Final Risk Assessment Results for

Process Parameters in the Production Bioreactor

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Initial Process parameters categorization …And after Design space (Control space)fine tuning

Glycosylation: 8 WC-CPP, 3 CPP Glycosylation: 5 WC-CPP,

0 CPP

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Process Capability Scales for Severity, Occurrence and Detection

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The overall score (RPN=SxOxD) was calculated for each unit operations

Scoring for Process Capability Risk Assessment of Unit Operations

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Examples of Process Capability Risk Assessment

(Risk assessment #3)

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A-Mab Control Strategy

Control Strategy

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Product Understanding

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Elements of the Control Strategy

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Elements of the Control Strategy

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Specifications Tests

Based on the enhanced product and process understanding, specification tests are significantly reducedcompared to traditional approaches.

Some specification testing has been moved to in-processtests (including PAT) while other tests were eliminated because operation within the process design space provides a high degree of assurance that the process will deliver consistent product quality

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deliver consistent product quality

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Example: Control elements for Oligosaccharide Profile

Process capability risk assesment; RPN=30 Low

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Example: Integrated Control elements for Aggregation

RPN

Process capability risk

assesment

30 Low

90 Med.

300 High

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1000 High

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Control elements for Aggregate1 and Oligosaccharide2 profile in A-Mab

CQA Process capability Risk

Input material Testing

Procedural control

Process parameter control

In-process tests

Specification Process Monitoring

Stability Testing

Characterization Testing

Aggregate High Y Y N N Y Y Y Y

Oligosaccharide profile

Low Y Y Y N N Y N Y

1 summary of control elements assigned to various downstream process steps

2 control elements assigned to bioreactor production

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Arrow indicates differences

Control strategy examples in A-Mab

Upstream

Downstream

Drug product compounding

Drug product sterile filtration

Drug product filling, stopping, capping

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For the purposes of this case study, only a selected number of quality attributes were considered to define the Control Strategy. Normally, the approaches presented here would be expanded to include all critical quality attributes

Quality Attribute Ranges forA-Mab Process

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LRV=log reduction value

Summary

A-Mab is a document for public consumption and ultimately a backbone for further discussion between industry and agencies across 2009-2010 and beyond

First comprehensive exemplification of a Mock Biotech product developped with QbD principles

Essential in order to overcome “conceptual hurdles” facing those involved in applying QbD

Science based driven all the way

Risk assessment tools used for identification of CQA and categorization of Process parameters

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of Process parameters

Illustration of a complex Design Space for the Bioreactor production stage and of the innovative Engineering Design Space concept

The Control Strategy provides a high degree of assurance that the product quality specifications are met.

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Take away from A-Mab

Traditional Product Development

Quality by Testing (reactive)

Product=Process

Enhanced Product Development

Quality by Design (proactive)

Targetted Product=Characterised and controlled Process

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Targetted Product Characterised and controlled Process

And thanks to the Biotech CMC Working Group for this inspiring masterpiece !!!

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