Design of a Process Qualification and

Continued Process Verification

Program within an Enhanced Development
Framework

Ciaran Brady, PhD

Eli Lilly & Co.
Overview
• Control Strategy Development: enhanced process understanding
• PPQ Approach
• Continuous verification/ monitoring
• Summary
• Questions

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

2
 Stage 1: Control Strategy Evolution

Product Lifecycle
Control
clinical Studies
Research and

Patient Strategy
Process
Needs Validation/ Commercial
Product Process Technology
Process Manufacturing
Design Design Transfer
Business Performance CPV
Needs Qualification

Continued Process
QTPP Process Characterization: Process Validation Verification:
CQAs, CPPs, PARs (PPQ batches) Maintaining the
validated state

Stage 1 Stage 2 Stage 3

Increasing Process Understanding/

Control Strategy Evolution
 QbD Work Flow Leading to Control Strategy and CPV
PRODUCT PROCESS & ANALTICAL PROCESS & ASSAY MANUFACTURING
DEVELOPMENT DEVELOPMENT IMPLEMENTATION & LIFE CYCLE
MANAGEMENT
QTPP P&A
TPP CQA PIA VMP SDM PC Class Eng Intro Com PPQ CPM CPV CPI
CS

TPP Target Product Profile Control Strategy

QTPP Quality Target Product Profile (QTPP)

CQA Product Quality Attribute Assessment (Identification of CQAs)  CQAs

Process Parameter Impact PIA VMP Process Development and Validation Master Planning
Assessment
SDM Scale-down Model Development and Characterization

PC Process Characterization )  PARs/MARs

Class Parameter (Criticality) Classification
)CPPs
Product-specific Control Strategy PCS  IPCs
Engineering Design Eng

Process Introduction Intro

Process Performance
Equipment Com PPQ
Qualification
Commissioning/Validation
Continuous Process CPM
Monitoring
Continued Process CPV
Verification
Continuous Process CPI
5
Improvement
 Science and Risk Based approach to develop
comprehensive control strategy......

Process Development and Characterization Scheme

Process 2
Quality
Attributes Process 1 2 Life Cycle
Management

Prior Knowledge Design Space

Process
Process Process Final Control
Process Understanding Performance
Development Characterization Draft Control Strategy
Product Understanding Verification
Strategy

Process
Parameters
Risk Risk Risk Risk
Assessment Assessment Assessment Assessment

6
A-mAb Systematic Approach
Agitation
Shear/
Mixing
Production Working
N-1 Bioreactor Harvest
Bioreactor Volume
In Vitro Cell
Age # of
CO2 Impellers
Nominal
Seed Seed Density DO Control Vessel Volumne
Parameters Design Impeller Duration
Scale Design

1. Use of prior platform knowledge and

Temperature Viability Effects
pH Baffles
Procedures

Gas Airflow
pH Temperature
Transfer
Sparger Design
Aggredates

process risk assessments to identify

Antifoam Fucosylation
Galactosylation
Time of Feeding CEX AV
Filtration HCP
Volume of Operations
Amount Delivered
DNA
Feed Storage Procedures

those steps that need additional

Storage Temperature
Temperature Number of
Concentration Feeds Pre-filtration hold
Pre-filtration time
Preparation [Antifoam]
pH hold time Operations

Procedures Age [NaHCO3]

Timing

experimentation
Age
Age Preparation
[Glucose]

Filtration Osmolality

Feed Concentration
Glucose Feed Medium

2. Demonstration that laboratory scale Platform Tox PhI/PhII

models are representative of the full- Knowledge 500L 1,000L

scale operations
Optimization Optimization PhIII
3. DOE to determine parameter criticality DOE I - 2L DOE II - 2L 5,000L

4. Linkage of process parameters to Prediction Profiler

40

Galactosylation
product Quality Attributes to create a

±0.930555
32.02279
35
30

Design Space
25

4
35

36

37
30

40
50

60

70
40
50
60
70
80
90

90

95

90

95

86
88
90
92
94
3.8

4.2
4.4
4.6
4.8

18
100

100

105
110
400

420
440

460
480
35.5

36.5

100

105

110

16.8

17.2

17.6
70 100 100 90
36 50 Dissolved 4.3 Basal Strength 440 Feed Strength Feed 17.3778
Temperature DO CO2 Split Ratio (Dilution) Osmo (Dilution) Neutralization Duration

5. Use of statistical tools to model data

6. Final risk assessment and

categorization of process parameters to
develop control strategy

7
 Holistic Process Control Strategy Forms
the Basis for Process Validation
6 Capto d e e
s bo e
Step Elution
High Salt Wash
Column Pack Pre-Equil &
Equilibration pH

pH
Age & Use [NaCl]
History
CVs
[Acetate] [NaCl]
[NaCl]
Bed Height
pH FS Cut Volume

Charge % Monomer
[Tris] BS Cut
% Monomer Quality Parameters HCP
(HETP, Asym.)
HCP Flow Rate rPrA

CQA criticality
Flow Rate
rPrA CEX Variants
CEX Variants MS Volume
Concentration Flow Rate Flow Rate Flow Rate
Yield
[NaOH]
Volume Product, mg/mL
Concentration
pH Volume pH

Risk
Contact Time Volume Volume
Conductivity Conductivity
Resin Load (g/L resin)
[Acetic Acid]
[NaOH]
Volume (CV) pH
Contact Time Contact TIme
[NaCl]

Assessment
Frequency
Frequency
Frequency
Regeneration
Pre-use Load Sanitization
Cleaning

Process capability In process testing

Risk Assessment Risk Assessment
35oC

Temp.

Facility Fit & Facility based micro 33oC

Equipment Capability Risk Assessment p
6.95
H pH
6.65 DO
45% 75%
Prediction Profiler
100

99
±0.193366
98.6237
MS %M

98

97

96
0
20
25
30
35
40
45
50
50
70
90

50
4.5

4.7

4.9

5.1

110
130
150

100

150
200

250

300

350

400

100 0
4.903 40 Elution Eq/Ch/ 300
Elution pH Load [NaCl] Wash [NaCl] Flow , cm/hr
Product/Process Attributes

Parameters
 Control Points Matrix: Defines the PPQ
validation strategy……
• Unit Operation functional
claims
• Parametric Controls:
Production Bioreactor

CPPs/ OPPs

Filling, stopper, cap

Testing elements
Compounding
Nanofiltration
• In-process hold times
Low pH/VI
Protein A

Filtration
UF/DF
Product Quality
CQA

AEX
CEX
Attribute • Testing Strategy
• IPCs and validation
limits
Aggregate Yes Form Remove Form Remove Remove Form Form LR • Biochemical testing
Deamidated isoforms No Form PM
• Microbiological
Oligosaccharide Yes Form PM
testing
CHO HCP Yes Form Remove Remove Remove Remove PM
DNA No Form Remove None
• IP Specifications
Protein A No Form Remove Remove None • Release
Viral safety Yes Inact Clear Clear Biorx. IPC specifications
• Demonstrate consistent
process performance over
3-5 consecutive lots

9
 Other Elements to Stage 2……
Viral Clearance
Validation

Downstream PV Upstream PV
Protocol Protocol

Column 1 Nanofiltration
Lifetime PV Reprocessing
Membrane Protocol PV Protocol
Lifetime PV
Protocol Column 2
Final Filtration
Lifetime PV
Reprocessing
Protocol
PV Protocol
Upstream /
Downstream
Comparability
Approval to
Protocol
Validate

DS Processing
 Stage 3: CPV Program Overview
Objective: Demonstrate ongoing assurance that process remains in state of control
for commercial manufacturing

Upstream & Downstream

Orthogonal/ leading Process Monitoring
• Establish control
indicators of process (~150 additional
limits when process
performance parameters/ attributes)
variability
established (~30
Ongoing Process lots)
Critical parameter and • Measure of process
Validation/ Verification
process consistency capability (CpK)
(~100 parameters/
indicators: trending and attributes) • Drives continuous
assessment of state of improvement to
control improve robustness
(if needed)
Data oversight

Ongoing Process Monitoring Report after

Tech rep
(quasi) real Cross each campaign
presence on
time SME functional
the floor and
monitoring of data review
at Operations
parameters meetings
meetings
and attributes Annual Product Review
 Process Data acquisition and analysis
Source Systems
Analysis / Results

SAP LIMS

Read Only
MDI

Historian
PI SAD
Hierarchy
Process Driven
Manual
Data Entry
Roadmap for CPV

CQAs reassess variables and

CPP update control limits
IPC
Performance Indicators

capture maintain quantify

data control charts variability

Quantitative
Variables
CPV CPV
Batch Periodic Annual
PROTOCOL REPORT

Events

respond to respond to respond to

excursions trends, shifts performance

correlate events vs. CQAs

Changes
and facilitate PQR/APR
Deviations
Complaints

| IBEC PharmaChem Ireland | Fionnuala Langford, Novartis | 15Jun2015 | Business Use Only
 Stage 3a and 3b: reduced testing once
variability established
Stage I Stage II Stage III
Development Validation: PPQ Commercial Mfg: CPV

IIIa IIIb
Heightened Routine
Sampling & Monitoring
Testing until Program
variability
established
Oneway Analysis of Quality Attribute 2 By Unit operation

10000000
3000000

1000000
Key control points:
•Unit operation D Spike Residual
300000

100000
30000

10000 •Unit operation F

Attribute 2

2x <LOQ
Quality

Remove from in-process

3000

1000
300 Unit Operation F
100
30
No change during 5x <LOQ and DS analytical testing
10
DS storage or DP
3

1
A B D F G manufacturing and 2x <LOQ after variability established
Unit Operation G
Unit operation
storage 5x <LOQ
Oneway Analysis of Quality Attribute 3 By Unit operation

12

10 Key control point: Remove from in-process

8 •Unit operation G Spike Residual analytical testing after
Attribute 3
Quality

4
No change during 2x <LOQ variability established
Unit Operation G
2
DS storage or DP 5x >LOQ
0
manufacturing and Include in enhanced DS
D F G
storage
Unit operation
analytical testing program
14
Integration within the Quality System key to
maintain the validated state……….
Preventative Maintenance and Calibration
Ensures equipment and systems are maintained in a qualified state.

Annual Product Review

Monitor, measure and analyse manufacturing processes and
products, using statistical techniques, on a routine basis to evaluate
trends over time.

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

Deviation management
Provides a structured risk-based approach to the investigation,
determination of the root cause, documentation, identification and
implementation of any resultant corrective action and preventive
actions (CAPAs) for all departures

Periodic Review of Facilities, Utilities, Equipment and

Computer Systems
Evaluate trends, compare data with historical information to
determine shifts and assess the state of control of the facility, utility,
equipment and computer system.

15
 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
*BioPhorum Operations Group: Paper on Continuous Process strategy
Verification: An Industry Position Paper with Example Plan

16
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

17
 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

18
Acknowledgements
Mike De Felippis
Tongtong Wang/ BR&D
RA-CMC Colleagues
Matt Osborne
Graham McCartney
Stephen Galvin
Theresa Ahern
Marie Murphy
Seamus Malone
20