The 2nd QbD Conference

QbD in Large Molecules: The A Th A-Mab M b case study t d b by th the CMC Bi Biotech t h Working group
Dan Kenett May 5 2010 Jerusalem
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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

OUTLINE
Background: Therapeutic Monoclonal Antibodies Selected A-Mab chapters:
Design of Molecule and Quality Attributes Assessment Upstream Manufacturing Process Development Control Strategy

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 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

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

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Monoclonal antibody structure

Schiesti M. (Sandoz) PMDA symposium 2009

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Possible natural modes of action of mAbs versus cells cells

Schiesti M. (Sandoz) PMDA symposium 2009

1975

1986

1994

1997

2002

Cell fusion with cancerous cells

recombinant DNA technology

Schematics of a manufacturing process of a monoclonal antibody

12000L

Upstream

Downstream

Kozlowski and Swann , Quality by Design for Biopharmaceuticals 2009

FDA Initiatives and QbD Timeline

Small molecule ACE mock case study by Conformia

Large molecule A-Mab mock case study by CMC Biotechnology Working Group

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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 cet pta ( (ACE) C ) - 2008 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 Lilly , Pfizer Bio
http://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 Delivered by IV administration at a weekly dose of 10mg/kg for 6 weeks

http://images.google.com/imgres?imgurl=http://rss.xinhuanet.com/newsc/english/2008-03/11/xin_142030511140539054143.jpg&imgrefurl=http://rss.xinhuanet.com/newsc/english/200803/11/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 A-Mab 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 will ideally ill b be achieved hi dt to ensure th that t the desired quality, and thus the safety and efficacy, of a drug product is realized

Quality attributes of Drug Product not yet defined

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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: 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

By planning the DNA sequence

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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 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 p y safety y factor ( (ISF) ) = LD50 Level in Product Dose

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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 attributes 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. Immunogenicity 4. 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

(WHO)

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A-Mab examples of Tool #1

Aggregation

Moderate high

DNA

None

Moderate

The individual impact category with the highest ranking determines the overall impact ranking for an attribute
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Summary of Quality attribute Risk assessments

Vary according to mode of action

Critical quality attribute includes H and VH 29

Critical Quality attributes and target ranges

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8 Quality Attributes

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 Control Space Based on the Overall Reliability of dimension Design space for culture duration 15 days the Process (Predictive Bayesian Reliability approach)

20-40%

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

2-11%

To achieve a response surface model by DOE suitable to define a Design space N=40 bioreactor runs (4 blocks of 10, ~12 weeks) X-Mab data 33

Design space for Production Bioreactor

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Design space examples in AMab

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

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

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.

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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

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
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Example: Final Risk Assessment Results for Process Parameters in the Production Bioreactor

Glycosylation: 8 WC-CPP, 3 CPP

Glycosylation: 5 WC-CPP, 0 CPP

Initial Process parameters categorization

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And after Design space (Control space) fine tuning

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Process Capability Scales for Severity, Occurrence and Detection

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

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 reduced compared to traditional approaches.

Some specification testing has been moved to in-process tests (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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Example: Control elements for Oligosaccharide Profile

Process capability risk assesment; RPN=30 Low

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Example: Integrated Control elements for Aggregation

Process capability risk assesment

RPN

30 Low

90 Med. 300 High

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 Inprocess tests Specification Process Monitoring Stability Testing Characterization Testing

Aggregate

High Low

Y Y

Y Y

N Y

N N

Y N

Y Y

Y N

Y Y

Oligosaccharide profile

1 summary of control elements assigned to various downstream process steps 2 control elements assigned to bioreactor production

Arrow indicates differences

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Control strategy examples in AMab

Upstream Downstream Drug product compounding Drug product sterile filtration Drug product filling, stopping, capping

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Quality Attribute Ranges for A-Mab Process

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

LRV=log reduction value

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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 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) Product=Characterised Characterised and controlled Process Targetted Product

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

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