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The Value of Applying Quality by Design - Not Just Monoclonals, But Across Products and Systems

Tony Mire-Sluis, Executive Director, Global Product Quality and Quality Sciences

There Are Four Basic Principals for QbD

• Design

• Develop

• Monitor

• Improve

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There Are Four Basic Principals for Developing Quality Systems

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• Plan

• Execute

• Monitor

• Improve

The Principles of QbD Are Not Unique to a Product or Process!

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We Don’t Need to ‘Invent’ Something New… Dr. Deming Figured It Out In ~1950

The Principles of QbD are not ‘a Regulatory Strategy’ but Provide Business and Quality Benefits

• QbD principles can provide:• Improved success rates for process and

product development through increased understanding

• Reducing risks• To patients, process failures, method invalids, NCs etc.

• Improving product quality• More robust and consistent processes• Less manufacturing failures• Reduced complaints• Continuous improvement

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How the Basic Principles Can Be Applied Regardless of Product or Process

EstablishDesignTargets

RPN (Severity x Likelihood)

0 10 20 30 40 50 60 70 80 90

Aggregate (HMW)

Iso-Asp (LC92)

Non-Glycosylated Heavy Chain

Oxidized Species

Dimer

Solubility/Precipitation

Fragments

Glycation

Sub-visible Particles

Cysteine Adduct

Pre-monomer

Free Cysteine

Sialylated Glycans

High Mannose Glycans

Fucosylated Glycans

Deamidated Species

Extent of Galactose

Free Light Chain

Primary Sequence

3D Structure Unfolded/Perturbed (conformation)

Disulfide Modification/Rearrangement

N-terminal Modification (Glutamine to pE)

C-terminal Lysine

EstablishDesignTargets

Develop Process to

Meet Targets

Understand Process

Effective and Efficient Control

Strategies

Post approval Lifecycle

Management

MolecularAssessments

And Engineering

Operational RangeOperational Range

Design space Risk based control

strategy

Fit for purpose processes

Efficient Continuous

Improvement

Integrated Controls• Operational • Testing • Raw materials • Continuous verification

• QbD filing/ECP• QMS

0.0

1.0

2.0

3.0

4.0

5.0

Column 1Pool

Filtered ViralInactivation

Pool

Column 2Pool

Viral FilteredPool

Column 3Pool

UF/DF Pool DrugSubstance

SE

-HP

LC

HM

WS

[%

]

Specification In-Process Control Action Limits ACO BI Pharma

Design Develop and Execute Monitor Improve

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Molecular Design Can Be Applied Across Any Product Class – Our Understanding of CQAs goes Beyond MAbs

• Sequence & hot-spot analysis• Engineering to impact CQA’s• Fit to FIH platform• High productivity• Optimal signal peptide usage• Downstream process performance• Compatibility with FIH platform formulation• pH-jump study• Serum based pH jump

• Particulation propensity• Develop predictive particulation assays

• Degradation specific screens• Develop degradation-rate database and Arrhenius models

to enable decisions based on predicted rate at 2-8 C

• Concentration & viscosity screen• Engineer in low-viscosity attributes by incorporating

principles of QbD

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Examples of Assays Used During Molecular Design to Select Best Lead Candidates

Sequence binning used to identify antibodies with diversity and desirable attributes

t=24h pH jump study performed to eliminate candidates with potential issues in vivo

Viscosity testing for ease of SC delivery at high concentration

Expression Assessment to achieve high productivity

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

60.0 70.0 80.0 90.0 100.0 110.0 120.0 130.0 140.0 150.0 160.0

Concentration (mg/ml)

Vis

cos

ity

(cP

)

Design Principles and their Benefits do Not Just Apply to Product or Process

• Product

• Manufacturing Process

• Equipment

• Facility

• Utilities

• Raw Materials

• Containers

• Transport

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Risk Assessment is a Critical Element of the Development of Many Systems

• Risk Assessments can be applied across many different programs:• Critical Quality Attributes• Equipment selection and maintenance• Non conformances• Facility design• Packaging• Supply • Finance

Overall RiskAssessment

RPN

Impact

Severity

Capability

Occurrence

TestingStrategy

Detection= X X

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Appropriate Monitoring is Also Neither Product or Process Dependant

Monitoring and analysis of data should be applied regardless of the product, process or system being used

Incoming Inspections

During the process

Lot Release

Stability

Non conformances

Complaints

APR

Frequent cross functional assessments

0

2

4

6

8

10

12

14

16

18

20

22

24

5017

5021

5029

5035

5040

5045

5050

6005

6012

6020

6029

6034

6039

6044

6053

6058

6064

6075

6080

6085

6091

6096

6103

6108

6113

6118

6125

6130

6136

7002

7009

7016

7021

7026

7032

T2R

ange

[1 -

7]

Obs ID (Primary)

AR5_N1_N_pls.M1 (PLS)T2Range[Comp. 1 - Last comp.]

T2Crit(95%)

T2Crit(99%)

SIMCA-P+ 11.5 - 4/23/2007 9:04:25 AM

Raw Data (Plant Level)

Deviation Diagnosis (Variable Level)

Abnormal Batch

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Applying QbD Principles to Raw Materials – A Case Study of Vials

Raw Materials are an Essential part of both Product and Process

• Raw materials and their controls are vital at all stages of manufacture

• In fact, they can make up the product itself beyond just the protein – water, buffering components, tonicity agents, polysorbate, primary packaging etc. and QbD principles apply to RMs at all stages of manufacture

• Application of the principles is carried out on a risk based approach depending where they are in the manufacturing process (downstream or upstream) or how much they impact the quality of the product (e.g. media components are downstream away from the final product but can have a tremendous impact on protein CQAs during fermentation)

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It is Essential to Understand a Raw Material - Design

• Initial Characterization• Raw material itself

• Design appropriate Analytical Methods• Lot to lot variability• Set Specifications

• Interaction with process• Impact to Critical Process Parameters

• Affect on Product• Impact on Critical Quality Attributes

• How much is required depends on where in the process the RM is used

• Managing Change over time• Supplier need to communicate when changes are proposed /

made• The company needs to evaluate if changes matter to their

processes… ideally before they are implemented

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What do you Need to Characterize in a Raw Material? – What is There

• Relying on the manufacturer’s CoA is often not be enough

• One needs to understand all the components of the raw material as the manufacturer may not even measure the parameters you require control of:• Product Heterogeneity• Additives• Preservatives• Degradation products• Contaminants

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What do you Need to Characterize in a Raw Material? – What Might Appear

• There must be a thorough understanding of the degradation pathway of the raw material – relying on an expiration date from the manufacturer may not be enough

• The impact of degradants on the product or process is needed

• There needs to be an understanding of the use of raw materials over time and the impact to the expiration date of the product

• The impact of handling the raw material over time must be assessed (aliquoting, light, temperature, oxygen etc.)

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Supplier Management is Necessary for Ensuring Raw Material Quality

Expectations must be clear

• We need to understand the manufacturing processes for raw materials so we know how they could impact product quality, allow us to set appropriate specifications and help us during investigations – Design and Monitoring

• Notification of change - Monitoring

• Thorough investigation of defects – Continuous Improvement

Supplier site visits are key

• Audit of Quality system - Plan

• Technical visits to understand processes, process capability and identify indirect product contact materials - Design

• Technical visits to evaluate changes and ensure that they are managed properly - Monitor

Low Medium High

PreferredAudits every 4 year Audits every 4 year Audits every 3 year

StandardAudits every 4 year Audits every 3 year Audits every 2 year

MarginalAudits every 3 year Audits every 2 year Annual Audits

Material and Supplier Criticality Assessment

SupplierPerformance Rating

One can Use a Risk-Based Approach to Segment the Supplier Base

• Quality Assessment = 40%• Technical Assessment = 40%• Business Assessment = 20%

• Quality 50%• Delivery 30%• Service 20%

CAPAs manage ‘up or out’ plans for marginal suppliers

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Vial FMEAs were conducted by a Global team - Design• Vials are an essential part of a product in which they are

filled, critical to product quality and close to the patient

• FMEAs were conducted at fill finish lines across internal and contractor manufacturing sites

• Risks were identified, mitigation plans developed, and CAPAs documented completion

• Identifying what were the important attributes for vials wasessential to develop appropriatespecifications:

•Extractables/Leachables•Interactions with equipment•Handling and Storage•Possible glass defects

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An Example of Specifications Required for Vials – Design/Monitor

1. Finish Inner Diameter (ID)

2. Finish Outer Diameter (OD)

3. Lip/Flange Height

4. “H” Dimension

5. Vial Length (Height)

6. Vial Outer Diameter

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2

3

5

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4

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Incoming Inspections of Raw Materials to Assure Specifications are Met

IQA review received docs (CoA, Receiving Inspection Report)

Sample as per SOP

IQA inspect samples as per SOP

IQA perform batch evaluation and disposition of material

IQA Receipt of Material

Inspection Evaluate & DispositionSampling

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Inspection for Tubular Glass Vials Includes over 50 Criteria

• Defect Classification: Critical Visual Examples:• Wrong component• Split on vial interior with nonremovable,

marked deposit• Internal Airline – Elongated gaseous inclusion

that appears as a vertical line.• Chipped (Broken Finish) – (if the seal is

compromised) A finish that has actual piece of glass broken out of it.

• Contamination – Foreign substance (particle, stain, dirt) deposited on the internal surface

• Crack – Fracture that penetrates completely through the glass wall

• Malformed – Finish is grossly distorted or deformed, if seal is compromised (lip malformed).

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Automated Inspection of Vials Prior to Lot Release - Monitor

Neck Inspection Camera C1/C6 Body Inspection

Camera C2/C7

Base Inspection Camera C3/C8

Cap Inspection Camera C4/C9

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A Global Primary Container Team was established to Monitor Vial Performance

• The Primary Container Team:• Comprises of all Amgen site, quality and technical groups• Tracks key glass metrics from the glass process monitoring,

NCs, and Product Complaints• Identifies and implements Glass Handling best practices• Alignment to new equipment requirements• Identifies Quality/Process improvements and container

standardization

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Embedding the Quality System - Improve

• Primary packaging issues are monitored globally and lessons learned applied

• A governance body is covering vial platform projects and tasks

• A global team is ensures Amgen wide scope and communication oftasks and work streams

• The team monitors Amgen production and CMC activities

The creation of a global team allows for continuous monitoring and improvement

RiskAssessment

Glass HandlingProject

Δ ControlNC

Glass Process

Monitoring

Product Complaints

Primary Packaging

Network

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In Summary

• The basic principals of QbD can (and should) be applied across product types as well as multiple processes and systems• We don’t have to label it QbD and treat it like something

special, it just makes good business sense and we have been doing it to a certain extent anyway and it can be applied to all products and across multiple systems/processes

• Using the principals of QbD in many cases does not require a great deal of cost – mostly good planning, increased understanding and more successful execution

• A risk based approach can be used to help appropriately focus QbD efforts