Design of a Process Qualification and Continued Process VerificationProgram within an Enhanced Development Framework

Ciaran Brady, PhDEli Lilly & Co.

Overview• Control Strategy Development: enhanced process understanding• PPQ Approach• Continuous verification/ monitoring• Summary• Questions

2

*BioPhorum Operations Group: Paper on Continuous Process Verification: An Industry Position Paper with Example Plan

Stage 1: Control Strategy Evolution

Patient Needs

Business Needs

Product Design

Process Design

Technology Transfer

Process Validation/Process

Performance QualificationR

esea

rch

and

clin

ical

Stu

dies

Commercial Manufacturing

CPV

Product Lifecycle

QTPP Process Characterization: CQAs, CPPs, PARs

Continued Process Verification: Maintaining the validated state

Process Validation (PPQ batches)

Stage 1 Stage 2 Stage 3

Increasing Process Understanding/Control Strategy Evolution

Control Strategy

QbD Work Flow Leading to Control Strategy and CPV

PROCESS & ANALTICAL DEVELOPMENT

PRODUCT DEVELOPMENT

PROCESS & ASSAY IMPLEMENTATION

MANUFACTURING& LIFE CYCLE MANAGEMENT

TPP QTPP CQA PIA VMP PC Class P&A CS PPQIntro CPM CPVSDM CPIComEng

Control StrategyTPP

QTPP

CQA

PIA VMP

PC

Class

PCS

PPQ

Intro

CPM

CPV

SDM

CPI

Com

Eng

Target Product Profile

Quality Target Product Profile (QTPP)

Product Quality Attribute Assessment (Identification of CQAs)

Process Parameter Impact Assessment

Process Development and Validation Master Planning

Scale-down Model Development and Characterization

Process Characterization )

Parameter (Criticality) Classification)

Engineering Design

Process Introduction

Equipment Commissioning/Validation

Process Performance Qualification

Continuous Process Monitoring

Continued Process Verification

Continuous Process Improvement

CQAs

IPCs

PARs/MARs CPPs

Product-specific Control Strategy

5

6

Science and Risk Based approach to develop comprehensive control strategy......

Prior KnowledgeProcess UnderstandingProduct Understanding

ProcessDevelopment

RiskAssessment

ProcessCharacterization

RiskAssessment

RiskAssessment

ProcessPerformanceVerification

RiskAssessment

Life CycleManagement

Final ControlStrategy

ProcessParameters

QualityAttributes

Design Space

Draft ControlStrategy

Process 2

Process 1 2

Process Development and Characterization Scheme

7

A-mAb Systematic Approach

1. Use of prior platform knowledge and process risk assessments to identify those steps that need additional experimentation

2. Demonstration that laboratory scale models are representative of the full-scale operations

3. DOE to determine parameter criticality

4. Linkage of process parameters to product Quality Attributes to create a Design Space

5. Use of statistical tools to model data

6. Final risk assessment and categorization of process parameters to develop control strategy

AggredatesFucosylation

GalactosylationCEX AV

HCPDNA

N-1 Bioreactor

Feed Glucose Feed

Production Bioreactor Harvest

Medium

ProceduresTemperature

pH

Seed

In Vitro Cell Age

Seed Density

Viability

Operations

Time of Feeding

Volume of Feed

Preparation

Concentration

pH

Age

DO

pH

Temperature

CO2

AgitationShear/Mixing

Gas Transfer

Airflow

Antifoam

Scale Effects

Amount Delivered

Number of Feeds

TimingPreparation [Glucose]

Osmolality

Concentration

ProceduresAge

Duration

Working Volume

[NaHCO3]

Pre-filtration hold time

Storage Temperature

[Antifoam]

Procedures

Age

Storage Temperature

Pre-filtration hold time

Filtration

Filtration

# of Impellers

Vessel Design

Baffles

Control Parameters

Operations

Impeller Design

Sparger Design

Nominal Volumne

Tox500L

PhI/PhII1,000L

Optimization DOE I - 2L

OptimizationDOE II - 2L

PhIII5,000L

PlatformKnowledge

25

30

35

40

Gal

acto

syla

tion

32.0

2279

±0.9

3055

5

35

35.5 36

36.5 37

36Temperature

30 40 50 60 70

50DO

40 50 60 70 80 90 100

70Dissolved

CO2

3.8 4

4.2

4.4

4.6

4.8

4.3Split Ratio

90 95 100

105

110

100Basal Strength

(Dilution)

400

420

440

460

480

440Osmo

90 95 100

105

110

100Feed Strength

(Dilution)

86 88 90 92 94

90Feed

Neutralization

16.8

17.2

17.6 18

17.3778Duration

Prediction Profiler

Holistic Process Control Strategy Forms the Basis for Process Validation

CQA criticality Risk

Assessment

Process capabilityRisk Assessment

In process testingRisk Assessment

Facility based microRisk Assessment

Facility Fit & Equipment Capability

% MonomerHCP rPrA

CEX VariantsMS Volume

YieldConcentration

pHConductivity

Column PackStep Elution

Load

Bed Height

Quality Parameters(HETP, Asym.)

pH

[NaCl]

Resin Load (g/L resin)

Flow Rate

pH

CVs

[Tris]

Flow Rate

Volume

[Acetic Acid]

Contact Time

Flow Rate

Volume

[NaCl]

pHAge & Use

History

[NaOH]

Contact Time

Volume (CV)

Frequency

Pre-use Cleaning

Product, mg/mL

Volume

High Salt Wash

Regeneration

Charge % Monomer

HCPrPrA

CEX VariantsConcentration

VolumepH

Conductivity

6 Capto d e es bo e

pH

[NaCl]

FS Cut

[Acetate]

[NaCl]

BS Cut

Flow Rate

Pre-Equil &Equilibration

Sanitization

[NaOH]

Volume

Flow Rate

Contact TIme

FrequencyFrequency

96

97

98

99

100

MS

%M

98.6

237

±0.1

93366

4.5

4.7

4.9

5.1

4.903Elution pH

20

25

30

35

40

45

50

40Load

50

70

90

110

130

150

100Elution[NaCl]

0

50

100

150

0Eq/Ch/

Wash [NaCl]

200

250

300

350

400

300Flow , cm/hr

Prediction Profiler

pH

Temp.

35oC

33oC

pH6.95

6.65 DO45% 75%

Prod

uct/

Proc

ess

Attr

ibut

es

Parameters

Control Points Matrix: Defines the PPQ validation strategy……

9

Product Quality Attribute C

QA

Prod

uctio

n B

iore

acto

r

Prot

ein

A

Low

pH

/VI

CEX

AEX

Nan

ofilt

ratio

n

UF/

DF

Com

poun

ding

Filtr

atio

n

Filli

ng, s

topp

er, c

ap

Test

ing

elem

ents

Aggregate Yes Form Remove Form Remove Remove Form Form LR

Deamidated isoforms No Form PM

Oligosaccharide Yes Form PM

CHO HCP Yes Form Remove Remove Remove Remove PM

DNA No Form Remove None

Protein A No Form Remove Remove None

Viral safety Yes Inact Clear Clear Biorx. IPC

• Unit Operation functional claims

• Parametric Controls: CPPs/ OPPs

• In-process hold times• Testing Strategy

• IPCs and validation limits

• Biochemical testing• Microbiological

testing• IP Specifications• Release

specifications• Demonstrate consistent

process performance over 3-5 consecutive lots

Other Elements to Stage 2……

Nanofiltration Reprocessing PV Protocol

Final Filtration Reprocessing PV Protocol

Downstream PV Protocol

Column 2 Lifetime PV

Protocol

Membrane Lifetime PV

Protocol

Column 1 Lifetime PV

Protocol

Upstream / DownstreamApproval to

Validate

DS Processing

Upstream PV Protocol

Viral Clearance Validation

Comparability Protocol

Stage 3: CPV Program Overview

Annual Product Review

Tech rep presence on the floor and at Operations

meetings

Cross functional

data review meetings

Ongoing (quasi) real time SME

monitoring of parameters

and attributes

Objective: Demonstrate ongoing assurance that process remains in state of control for commercial manufacturing

Upstream & Downstream Process Monitoring

(~150 additional parameters/ attributes)

Ongoing Process Validation/ Verification

(~100 parameters/ attributes)

Critical parameter and process consistency indicators: trending and assessment of state of control

Process Monitoring Report after each campaign

Orthogonal/ leading indicators of process performance

Data oversight

• Establish control limits when process variability established (~30 lots)

• Measure of process capability (CpK)

• Drives continuous improvement to improve robustness (if needed)

Process Data acquisition and analysis

Historian

ManualData Entry

Analysis / Results

Read Only

LIMSSAP

Source Systems

MDI

PI SADHierarchyProcess Driven

Roadmap for CPV

Annual

QuantitativeVariables

Events

CQAsCPPIPC

ChangesDeviationsComplaints

CPVPROTOCOL

respond toperformance

correlate events vs. CQAsand facilitate PQR/APR

CPVREPORT

capture data

maintaincontrol charts

quantifyvariability

reassess variables andupdate control limits

respond toexcursions

respond to trends, shifts

Batch Periodic

| IBEC PharmaChem Ireland | Fionnuala Langford, Novartis | 15Jun2015 | Business Use Only

Performance Indicators

Stage 3a and 3b: reduced testing once variability established

14

Stage I Stage II Stage III

Development Validation: PPQ Commercial Mfg: CPV

IIIa IIIb

Heightened Sampling & Testing until variability established

Routine Monitoring Program

1

103

10030

1000300

100003000

10000030000

1000000300000

100000003000000

Qua

lity

Attr

ibut

e 2

A B D F G

Unit operation

Oneway Analysis of Quality Attribute 2 By Unit operation

Key control points:•Unit operation D•Unit operation F

No change during DS storage or DP manufacturing and storage

0

2

4

6

8

10

12

Qua

lity

Attri

bute

3

D F G

Unit operation

Oneway Analysis of Quality Attribute 3 By Unit operation

Key control point:•Unit operation G

No change during DS storage or DP manufacturing and storage

Spike Residual

Unit Operation F2x <LOQ

5x <LOQ

Unit Operation G2x <LOQ

5x <LOQ

Spike Residual

Unit Operation G2x <LOQ

5x >LOQ

Remove from in-process and DS analytical testing after variability established

Remove from in-process analytical testing after variability established

Include in enhanced DS analytical testing program

Preventative Maintenance and CalibrationEnsures equipment and systems are maintained in a qualified state.

Annual Product ReviewMonitor, measure and analyse manufacturing processes andproducts, using statistical techniques, on a routine basis to evaluatetrends over time.

Change ControlAll changes proposed for a manufacturing system, equipment,method or process are evaluated to assess the impact on validation/qualification.

Deviation managementProvides a structured risk-based approach to the investigation,determination of the root cause, documentation, identification andimplementation of any resultant corrective action and preventiveactions (CAPAs) for all departures

Periodic Review of Facilities, Utilities, Equipment andComputer SystemsEvaluate trends, compare data with historical information todetermine shifts and assess the state of control of the facility, utility,equipment and computer system.

15

Integration within the Quality System key to maintain the validated state……….

Process Change Management

♦ Process changes can result from following: • Low process capability• Special cause variability• Monitoring program detects process shift/ trend• Process optimization to improve yields• Raw material supplier change or second source• New working cell bank • Equipment changes • Scale-up or Qualification of second site

♦ Changes assessed based on risk and science, controlled via change management system

• Small scale model data may be required to support

• Assess impact to control strategy and validated state

• Assess regulatory reporting category based on registered commitments and impact to control strategy

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*BioPhorum Operations Group: Paper on Continuous Process Verification: An Industry Position Paper with Example Plan

Summary

♦ Enhanced development program results in well understood, holistic and robust control strategy development

♦ PPQ program demonstrates process performance consistency prior to commercial manufacture

♦ CPV program and quality systems ensure process remains in state of control and continuous improvement opportunities identified and implemented appropriately

Results in a well understood and controlled process that produces high quality medicine over the lifecycle of the product

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Lessons Learned….

♦ Excellent feedback from regulators on control strategy and validation approach• Strong regulatory and business drivers to adopt QbD approach

♦ Strong data packages will allow for some regulatory relief• Testing strategies: validate out process-related impurities

♦ Learning and open questions• Non-CPPs expected as commitments in 2.2 and 2.4

– What parameters to pick?– 2 tier parameter classification system does not line up with this approach– Significant variability in these requirements exist between regulatory bodies

• Requirements emerging for additional data/ risk assessments: examples raw materials, extractables and leachables

• Release specifications: balance between manufacturing history and clinical history

– Common cause variability at time of filing may not be completely understood: examples: raw material variably and impact charge and glycosylation variants

• PALM plan: consider including elements in filing: address in Q12

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AcknowledgementsMike De Felippis

Tongtong Wang/ BR&DRA-CMC Colleagues

Matt OsborneGraham McCartney

Stephen GalvinTheresa AhernMarie Murphy

Seamus Malone

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