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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
16
*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
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
AcknowledgementsMike De Felippis
Tongtong Wang/ BR&DRA-CMC Colleagues
Matt OsborneGraham McCartney
Stephen GalvinTheresa AhernMarie Murphy
Seamus Malone