fda (invited) presentation - specifications and analytical method lifecycle for accelerated...
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Stephan O. Krause, PhDDirector, QA TechnologyAstraZeneca Biologics
Presentation to CDER/OBP28 September 2015 White Oaks Campus, MD
Analytical Method Lifecycle for Accelerated Biological Products
2
Outline
• Review of analytical method and specification lifecycles and CMC processes for typical and accelerated development
• Specification revision rationale and case study (HPSEC method)
• Review of strategic opportunities to reduce analytical method lifecycle steps for accelerated programs
- analytical platform technology (APT) methods- Product and process characterization methods
• Goal: Understand how APT methods can greatly support accelerated development programs (focus is on late-stage development opportunities)
• APT verification case Studies (HPSEC and AUC)
• Analytical Method Transfer Survey Summary 2
The content and views expressed in this presentation by the author are not necessarily views of the
organization he represents.
3
Risk Assessment(s) and Control Strategy Elements During Product Development
4
FTIH POC BLAQTPP
Final CQAs & Control Strategy Approval
Potential CQAsProduct & Process Design
Life-CycleManagement
POST-APPROVALCHANGES
PHASE 3PHASE 1/2Pre-IND
CQA
Patient Impact Severity
Assessed(Safety and
Efficacy)
Overall Risk Assessment (ex., FMEA)
Final Assessment
Uncertainty
Detectability
Occurrence
Control Strategy
Procedural Control
Process Validation
Lot Release Testing
Raw Material Control
Stability Testing
Operational Parameters
Risk(s)
Control(s)
Re-assessed R
e-as
sess
ed
In-Process Testing
Characterization Testing
5
CQA Development, CMC Changes, and Specifications
From: Krause, S., WCBP, 30Jan13, Washington, DC.
FTIH POC BLA
Tox Studies Phase 1Phase 2
Phase 3
Clinical ResupplyMfg/Formulation Change(s)
Specifications Revision(s)
Negotiations, Final Commercial Specifications
QTPP
Final CQAs & Control Strategy Approval
Potential CQAsProduct & Process Design
Life-CycleManagement
POST-APPROVALCHANGES
PHASE 3PHASE 1/2Pre-IND
CQ
A D
evel
opm
ent
(QbD
Pro
cess
)Sp
ecs
Life
Cyc
le
Mgm
tC
MC
and
Tec
h Tr
ansf
er P
roce
ss Analytical
Manufacturing
Strategic or Tactical Changes
Method qualification
Dose change
Delivery Device
PQ lots
Setting of Initial Specifications
Specifications Revision(s)
Mfg Transfer
Method validation
Method transfer
Formulation Change Process Verification
Method Maintenance
Global Supply
Commercial Specifications
Accelerated CQA Development, CMC Changes, and Specifications
6
FTIH POC BLA
Tox Studies Phase 1Phase 3
Clinical ResupplyMfg/Formulation Change(s)
Specifications Revision(s)
Commercial Specifications Negotiations, Final
Commercial Specifications and/or Post-BLA
commitmens
QTPP
Final CQAs & Control Strategy Approval
Potential CQAsProduct & Process Design
Life-CycleManagement
POST-APPROVALCHANGESPIVOTAL PHASE (3)PHASE 1 Pre-IND
CQ
A D
evel
opm
ent
(QbD
Pro
cess
)Sp
ecs
Life
Cyc
le
Mgm
tC
MC
and
Tec
h Tr
ansf
er P
roce
ss Analytical
Manufacturing
Strategic or Tactical Changes
Method qualification
Dose change
Delivery Device
PQ lots
Setting of Initial Specifications
Mfg Transfer
Method validation
Method transfer
Formulation Change Process Verification
Method Maintenance
Global Supply
Method Change
Accelerated Development
From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.
Accelerated CQA Development, CMC Changes, and Specifications
7From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.
FTIH POC BLA
Tox Studies Phase 1Phase 3
Clinical ResupplyMfg/Formulation Change(s)
Specifications Revision(s)
Commercial Specifications
QTPP
Final CQAs & Control Strategy Approval
Potential CQAsProduct & Process Design
Life-CycleManagement
POST-APPROVALCHANGESPIVOTAL PHASE (3)PHASE 1 Pre-IND
CQ
A D
evel
opm
ent
(QbD
Pro
cess
)Sp
ecs
Life
Cyc
le
Mgm
tC
MC
and
Tec
h Tr
ansf
er P
roce
ss Analytical
Manufacturing
Strategic or Tactical Changes
Method qualification
Dose change
Delivery Device
PQ lots
Setting of Initial Specifications
Mfg Transfer
Method validation
Method transfer
Formulation Change Process Verification
Method Maintenance
Global Supply
Method Change
Accelerated Development
CompLots
PQ lots CompLots =
Typical Analytical Method and Specification Lifecycle(s)
8
AMVStudies
Start PV Stage 2(PQ Lots)
Maintenance (continuous
AMV)
AMT Studies
Commercial Specifications
Method Qualified
Pivotal/Phase 3 Specifications
Phase 1/2 Specifications
Specs covered in AM
V ?
From: Krause, S., PDA Journal of Pharmaceutical Science and Technology, Sep/Oct 2015.
9
Retrospective and Prospective Use of Data for AMV Studies from other Processes Prior to AMV – New Method
Krause, PDA Workshop (2013)
10
Retrospective and Prospective Use of Data for AMV Studies from other Processes Prior to AMV – Analytical Platform Method
Method Qualification
(AMQ)
Method Validation (AMV)
Method Transfer (AMT)
(Less)AMQ
Studies
“Verification” Focus on: Accuracy, Specificity
PVFTIH BLA
Historical Data - SU
Assay Control
Tech Transfer
(Less) Interm.
Precision & Reprod.
Historical Data - RU
Assay Control
“Approved” Method
Krause, PDA Workshop (2013)
Ideal Analytical Method Lifecycle Clinical Phase 1-2 (prior to transfer from Pilot to Commercial Plant)
11
DS/DPSpecificationTest Methods
for New Method
Robustness Studies Execution
QCDev.
AMVStudies
(QC-Comm.)
Start PV Stage 2(PQ Lots)
Completed
In progress
Not started
AMV completed
Maintenance(QC-Comm.)
Robustness Studies
Master Plan
AMT Studies
(QC-Dev. & QC-Comm.)
SOP-specific Min/Max Method
Conditions (for PB Design)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Preparing for Tech Transfer (Pilot to Commercial Plant)
12
DS/DPSpecificationTest Methods
for New Method
Robustness Studies Execution
QCDev.
AMVStudies
(QC-Comm.)
Start PV Stage 2(PQ Lots)
Completed
In progress
Not started
AMV completed
Maintenance(QC-Comm.)
Robustness Studies
Master Plan
AMT Studies
(QC-Dev. & QC-Comm.)
SOP-specific Min/Max Method
Conditions (for PB Design)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Preparing for Tech Transfer (Pilot to Commercial Plant)
13
DS/DPSpecificationTest Methods
for New Method
Robustness Studies Execution
QCDev.
AMVStudies
(QC-Comm.)
Start PV Stage 2(PQ Lots)
Completed
In progress
Not started
AMV completed
Maintenance(QC-Comm.)
Robustness Studies
Master Plan
AMT Studies
(QC-Dev. & QC-Comm.)
SOP-specific Min/Max Method
Conditions (for PB Design)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Preparing for Tech Transfer (Pilot to Commercial Plant)
14
DS/DPSpecificationTest Methods
for New Method
Robustness Studies Execution
QCDev.
AMVStudies
(QC-Comm.)
Start PV Stage 2(PQ Lots)
Completed
In progress
Not started
AMV completed
Maintenance(QC-Comm.)
Robustness Studies
Master Plan
AMT Studies
(QC-Dev. & QC-Comm.)
SOP-specific Min/Max Method
Conditions (for PB Design)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Preparing for PQ (at Commercial Plant)
15
DS/DPSpecificationTest Methods
for New Method
Robustness Studies Execution
QCDev.
AMVStudies
(QC-Comm.)
Start PV Stage 2(PQ Lots)
Completed
In progress
Not started
AMV completed
Maintenance(QC-Comm.)
Robustness Studies
Master Plan
AMT Studies
(QC-Dev. & QC-Comm.)
SOP-specific Min/Max Method
Conditions (for PB Design)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Preparing for PQ (at Commercial Plant)
16
DS/DPSpecificationTest Methods
for New Method
Robustness Studies Execution
QCDev.
AMVStudies
(QC-Comm.)
Start PV Stage 2(PQ Lots)
Completed
In progress
Not started
AMV completed
Maintenance(QC-Comm.)
Robustness Studies
Master Plan
AMT Studies
(QC-Dev. & QC-Comm.)
SOP-specific Min/Max Method
Conditions (for PB Design)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Executing PQ Studies (at Commercial Plant)
17
DS/DPSpecificationTest Methods
for New Method
Robustness Studies Execution
QCDev.
AMVStudies
(QC-Comm.)
PQ Lots Mfg
Completed
In progress
Not started
AMV completed
Maintenance(QC-Comm.)
Robustness Studies
Master Plan
AMT Studies
(QC-Dev. & QC-Comm.)
SOP-specific Min/Max Method
Conditions (for PB Design)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Analytical Method Lifecycle APT Opportunities following AMV Study Completion and BLA Approval
18
DS/DPSpecification
Test Methods for Same SOP andNew Product
Robustness Studies Execution
QCDev.
AMVStudies
(QC-Comm.)
PQ Lots Mfg
Completed
In progress
Not started
AMV completed
MaintenanceAMM
(QC-Comm.)
Robustness Studies
Master Plan
AMT Studies
(QC-Dev. & QC-Comm.)
SOP-specific Min/Max Method
Conditions (for PB Design)
Commercial Specifications
Not Parallel Step
APT MethodAMV and AMM
(QC)
Analytical Platform Technology
APT Method
Robustness and AMT
Process Color Legend:
Method Qualified
(SOP Lock)
APT Method
AMQ
Analytical Method Lifecycle for Accelerated ProgramsAPT Opportunities following prior AMV Study Completion
19
DS/DP Specification
APT Test Methods (not compendial)
APT Transfer (feasibility only, no formal AMT)
Partial AMV StudyExecution
Start PV Stage 2
(PQ Lots)
APT Maintenance
VMP Analytical Methods
APT Qualification
Studies
Commercial Specifications
APT Robustness
(QC-Dev.)
Feasibility Testing
(QC-Comm.)
Simultaneous ?
Simultaneous ?
Completed
In progress
Not started
AMV completed
Not Parallel Step
Analytical Platform Technology
Process Color Legend:
Analytical Method Lifecycle for Accelerated ProgramsAdditional APT Opportunities
20
Qualification of Test Methods
Process and/or Product
Characterization
Representative Samples
Available (Dev.)
Execution Reqs: (1. IOQ Instrument)(2. Analyst Training)3. Final SOP version
QC Dev. or QC Comm.
Confirm Method
Suitability
Start PV Stage 2(PQ Lots)
Qualify (as relevant):A. Accuracy/MatchingB. Precision/Reliability
C. SpecificityD. DL or QL
Qualification Report(s)
Method Qualification Master Plan
Final PV Process Ranges and/or Analytical Control Strategy
APT (Reduced) Qualification Opportunity
Completed
In progress
Not started
AMV completed
Not Parallel Step
Analytical Platform Technology
Process Color Legend:
Analytical Method Lifecycle for Accelerated ProgramsLimited APT Opportunities
21
DS/DPSpecificationTest MethodsCompendial
Representative DS/DP Samples (from QC-Dev. or QC-Comm.)
Execution Reqs: 1. IOQ Instrument2. Analyst Training
3. Qualified Material4. Final SOP version
Start PV Stage 2(PQ Lots)
Completed
In progress
Not started
AMV completed
Verify (as relevant):A. Accuracy/MatchingB. Precision/Reliability
C. SpecificityD. DL or QL
Verification Report(s)
Method Verification Master Plan
Commercial Specifications
Not Parallel Step
Process Visual Legend:
QC Comm.
Risk/Uncertainty Levels and Risk-Based Opportunities (Typical)(Analytical Method Lifecycle Steps in Typical Order)
22
AMQ-Robustness-AMT-AMV Class Description Typical
Risk / Uncertainty
Level (1=Low, 5=High)
Suggested Prospective AMQ Studies
(QC-Dev.)
Suggested Prospective Robustness
Studies(QC-Dev.)
Suggested Prospective AMT Studies(QC-Dev./ QC-
Comm.)
Suggested Prospective AMV Studies(QC Comm.)No. Analytical
MethodProduct / Process Sample
A New New 4-5 Full Qualification
Full Robustness
StudiesFull AMT studies Full Validation
B New Old (Validated) 3-4(1)
Full Qualification Plus AMC(2)
Studies
Full Robustness
Studies Full AMT Studies
Full Validation Plus AMC(2)
Studies
CAnalytical Platform
TechnologyNew 1-2 Qualification Robustness
Studies AMT Studies Validation
D Compendial New 1-2Verification
per USP <1226>
N/A N/AVerification
per USP <1226>
EProduct/Process Characterization
TestsNew 2-3 Qualification N/A N/A N/A
(1) If a new analytical method (forced method replacement) is needed due to supply reasons, the risk level can be generally considered higherbecause no other option may exist. Unforced test method replacements can be considered to be a lower risk level as more time may be availableto optimize the method performance.(2) AMC = Analytical Method Comparability: A study to confirm that a new analytical method can perform equally or better than the existing one.
Krause/PDA-DHI Publications, 2007, PDA TR 57 (2012)
23
Example of Specification Revision Process (HPSEC Analytical Platform Technology (APT) Method)
24
Specification Setting Process
Acceptance Criteria
Existing Knowledge of Mfg/Analytical
Capability
Historical Data from this
specific Product and Process
Clinical Consideration
and/or Experience
“Platform” Knowledge from Similar Product
and Process
Specification Revision and AMV Study Example(s) Purity by HPSEC
25
HPSEC Specification Revision Process – Comparability, Manufacturing, and Clinical Experience
26
95.0
96.0
97.0
98.0
99.0
100.0
NLT 95.0%
Phase 2 => Phase 3
Rel
e ase
an d
St a
bil it
y S p
ecs
Rev i
sio n
N=1
Tox => Phase 1 (FTIH)
Phase 1 => Phase 2
T=2M
N=2
T=3M
N=3
T=6M
N=4
T=12M
N=6
T=24MT=36M
N=10 N=15
T=48M
(Pre-) Commercial (PV Stage 2)
Historical DP Release Results (T=0M)
DP Stability Results – Accelerated Condition
DP Stability Results – Recommended Temperature
Process Change(s): Comparability Demonstrated
Com
mer
cial
R
elea
se a
nd
Stab
ility
Spe
cs
HPSEC DP Specification Revision Process for Phase 3/Pivotal Studies and PQ Lots
27
95.0
96.0
97.0
98.0
99.0
100.0
NLT 95.0% (S)
Tig h
ten
D P S
helf-
Life
Li m
it
Representative Degradation for 3-years
N=12 DP batches (clinical phase 2
and 3)
Historical DP Release Results (T=0M)
DP Stability Results – Recommended Temperature
Statistical Tolerance Limit
Mean Purity Level
Estimated Degradation Uncertainty
NLT 97.0% (S)
NLT 98.3% (R)
Tigh
t en
DP R
elea
se L
imit
Analytical Method Variation (long-term)Analytical Capability
NLT 96.0% (R)
Tigh
ten
DP
Rele
ase
Lim
it
NLT 95.0% (R + S)
Specs Revision for Phase 3
Specs Revision for PQ Lots
HPSEC DS Specification (and Release Target) Revision Process for Phase 3/Pivotal Studies and PQ Lots
28
95.0
96.0
97.0
98.0
99.0
100.0
NLT 98.3% (DS Release) Representative Degradation for Desired 1-Year DS Hold and Post-Thaw
Handling
Estimated Degradation Uncertainty
NLT 98.7% (DS Mfg Target)
NLT 96.0%
Tigh
ten
DS/D
P Re
leas
e Li
mit
Specs Revision for
Phase 3
Specs Revision for
PQ Lots
Tigh
ten
DS/D
P Re
leas
e Li
mit
NLT 95.0%
Specification Example (% Purity): Manufacturing Capability vs. Clinical Experience
29Krause, S., PDA Journal of Pharmaceutical Science and Technology, Sep/Oct 2015.
95.0
96.0
97.0
98.0
99.0
100.0
NLT 95.0%
Tig h
ten
DP
S he l
f-Life
Li m
it
N=12 DP batches (clinical phase 2
and 3)
Historical DP Release Results (T=0M)
DP Stability Results – Recommended Temperature
Estimated Clinical Purity Patient Exposure Level
(for 3-year old DP)
NLT 97.0%
NLT 97.6%
Proposed Shelf-Life Specification (3 Years) Based on Predicted
Manufacturing Capability (3 SD; n=12)
Specification Example (% Purity): Manufacturing Capability vs. Clinical Experience
30Krause, S., PDA Journal of Pharmaceutical Science and Technology, Sep/Oct 2015.
95.0
96.0
97.0
98.0
99.0
100.0
NLT 95.0%
Tig h
ten
DP
S he l
f-Life
Li m
it
N=12 DP batches (clinical phase 2
and 3)
Historical DP Release Results (T=0M)
DP Stability Results – Recommended Temperature
Estimated Clinical Purity Patient Exposure Level
(for 3-year old DP)
NLT 97.0%
NLT 97.6%
Proposed Shelf-Life Specification (3 Years) Based on Predicted
Manufacturing Capability (3 SD; n=12)
Difference Acceptable ?
31
HPSEC AMV Study Example for an Analytical Platform Technology (APT) Method
32
Supporting Method Performance Characteristics Example for HPSEC (ideally pre-AMV)
Analytical Method Performance Characteristic
Retrospective (AMD/AMQ) or Prospective Evaluation During AMV Studies
Robustness Deliberately perform minor changes to critical assay parameters such as incubation temperature or time. DOE matrix.
Signal Response Factors Establish analyte response factors whenever multiple components are present.
Degradation (For Stability –Indicating Methods)
Establish stability profile and degradation pathways of samples, impurities, and by-products.
Stability of All Material Evaluate the short-term (during testing) and long-term (during storage) stability of samples, standards, controls, reagents, and material.
System Suitability Establish that components of the test system are suitable for routine testing.
Sample Suitability Establish that sample and/or testing replicates are appropriate to routinely support accurate and reliable test results.
Significant Digits Establish maximum number of significant digits to be reported (aligned with specifications) from repeatability data (n=6 reported results).
AMV Study Example(s) Purity by HPSEC
33
% M
onom
er (I
ntac
t Mol
ecul
e)
% A
ggre
gate
s
% F
ragm
ents
NLT 97.0 – 98.7%DP EOSL to DS
AMV Study Example(s) Purity by HPSEC – Initial AMV Study
34
% M
onom
er (I
ntac
t Mol
ecul
e)
% A
ggre
gate
s
% F
ragm
ents
M%: NLT 97.0 – 98.7%DP EOSL to DS
A%: NMT 3.0% – 1.3%DP EOSL to DS F%: Similar to A%
AMV Study Example(s) Purity by HPSEC – Initial AMV Study
35
M%
A% F%
Spiking highly degraded Product (A% and F%)
AMV Study Example(s) Purity by HPSEC – Initial AMV Study
36
M%
A% F%
Spiking highly degraded product (A% and F%)
- Start with high purity product (A% + F% < 1.0%)
AMV Study Example(s) Purity by HPSEC – Initial AMV Study
37
M%
A% F%
Spiking highly degraded product (A% and F%)
- Start with high purity product (A% + F% < 1.0%)
- Add multiple degraded product levels, so that: (A% + F% > 5.0%)
This will then cover future products (M% NLT 95.0%)
AMV Study Example(s) Purity by HPSEC – Initial AMV Study
38
M%
A% F%
Spiking highly degraded product (A% and F%)
Demonstrate:- QLs for A% and F% - Peak ID- Peak separation- Accuracy (expected peak recoveries)- Other AMV parameters: Linearity, range, precision levels(Robustness completed before AMV)
AMV Study Example(s) Post-BLA APT AMV Study
39
M%
A% F%
For APT method:- Continue use of validated sample preparation- Same assay control and system suitability conditions
Prior to APT method verification:- historical method performance data from other product(s)- product-specific data
For APT method verification:- Run limited spiking study with degraded product to confirm:- QLs for A% and F% - Peak ID- Peak separation- Accuracy/specificity for all spiked levels- Repeatability precision- Use formal verification protocol and justified acceptance criteria
40
Typical AMV Execution Matrixfor APT Methods (ex. HPSEC - Quantitative Limit Test)
ICH Q2(R1) Validation Characteristic
Analyst Number
Day Number
Instrument Number
Validation Design(Spiked Analyte Concentration)
Accuracy 1 1 1 Spike A%/F% (to final %):0.5, 1.0, 2.0, 4.0% (run each 3x)
Repeatability 1 1 1 From accuracy
Specificity 1 1 1 Formulation matrix interference tested (and Inferred from accuracy)
Linearity 1 1 1 From accuracy
Assay Range 1 1 1 From accuracy
QL 1 1 1 From accuracy
41
Analytical Ultracentrifugation (AUC) AMQ Study Example for an Analytical Platform Technology (APT) Method
(Test method is used to support product/process characterization and comparability studies, process validation studies)
Sedimentation Velocity (SV): a method orthogonal to SEC for detecting protein species with different molecular weights
In SV, the time dependent morphology changes of the protein/buffer boundary of a sample subjected to centrifugal force are determined by the contents of size variants.
42
AMQ Study Example(s) SV Method – Initial AMQ Study
43
M%
A%
(Dim
er, e
tc.)
F%
Spiking highly degraded product (A% and F%)
Confirm (for quant. limit test):- QLs for A% and F% - Peak ID- Peak separation- Accuracy (expected peak recoveries)- Other AMQ parameters: Linearity, range, specificity, precision
AMQ Study Example(s) Post-BLA APT AMQ Study
44
M%
A%
(Dim
er, e
tc.)
F%
For APT method:- Continue use of qualified sample preparation- Same assay control and system suitability conditions
Prior to APT method verification:- historical method performance data from qualified method
For APT method verification:- Run limited spiking study with degraded product to confirm:- QLs for A% and F% - Peak ID- Peak separation- Accuracy/specificity for all spiked levels- Repeatability precision- Use product-specific verification master plan and acceptance criteria
Typical Specifications and Test Methods for Drug Substance for Process Qualification (PV Stage 2)
45
Test / Specification
Analytical Method Status Typical Specifications for PQ Reported Results
Example
Appearance Compendia
Clarity: NMT EP RS III
Color: NMT Y5Particles: Free from or practically free from visible particles
Clarity: EP RS I
Color: Y7Particles: Free from visible particles
Total protein APT nominal value ± 10.0% 52.0 mg/mL
cIEF APTPeak pattern consistent with Reference StandardMonomer: NLT 65%
Total acidic peaks: NMT 30%
Peak pattern consistent with Reference Standard;Monomer: 72%
Total acidic peaks: 14%Target binding
bioassay Qualified / Validated N/A 98%
MOA-simulated bioassay Validated
90-120% (symmetrical) of Reference Standard binding
90-125% (geometrical) of Reference Standard binding98%
Reducing gel electrophoresis APT
Area percent purity of heavy + light chains: NLT 98.5%
Total area percent of impurities: NMT 1.5%
Area percent purity of heavy + light chains: 99.2%
Total area percent of impurities: 0.8%
Non-reducing gel electrophoresis APT
Major product peak: NLT 98.5%
Total area percent of impurities: NMT 1.5%
Major product peak: 99.2%;
Total area percent of impurities: 0.8%
HPSEC APTMajor product peak: NLT 98.3%;Aggregates: NMT 1.7%
Fragments: NMT 1.7%
Major product peak: 99.2.0%Aggregates: 0.5%
Fragments: 0.3%Host cell DNA APT LT 20 pg DNA/mg protein 2 pg DNA/mg proteinCHO host cell
protein APT NMT 20 ng/mg protein 2 ng/mg protein
Protein A APT NMT 10 ng/mg protein 1 ng/mg proteinBioburden Compendia NMT 10 CFU per 100 mL 0 CFU per 100 mL
Endotoxin (LAL) Compendia NMT 0.20 EU/mg protein 0.01 EU/mg protein
AMV Data Submission for APT Method Verification in BLAVarious Options
• Sponsor submits only APT method verification study results/reports.- Test method is described in CTD.- Initial AMV results not provided and not directly visible to reviewer (reference to previous
product approval).
• Sponsor submits initial AMV study results in summary table plus product-specific verification acceptance criteria and results (and reports).
- Summary table(s) highlight which data is from the initial AMV study vs product-specific verification data.
- If initial AMV results may have had more replicates (confidence), verification results may not replace the initial AMV results in CTD (ex., QL) ? Both reported ?
- Use post-AMV assay control data to represent intermediate (long-term) precision ?
• Sponsor submits initial AMV study report and product-specific verification results (and reports).
• Sponsor submits results/reports and commits to a CPV concept.- APT results could be reported annually (test system in control, submit assay control summary
data to confirm no drift, etc.).
• PAI could focus on post-AMV analytical method maintenance program (change control).
46
47
Summary
• Setting specifications for late-stage/commercial products is challenging.
• Opportunities exist to reduce typical analytical method lifecycle steps for accelerated programs.
• Use of (analytical) platform technology can greatly support accelerated development programs.
References: 1. Krause et al., PDA TR 57, Analytical Method Validation and Transfer for Biotechnology Products, August 2012.2. Krause, Setting Specifications of Biological IMPs, PDA J. Pharm. Sci. Tech., Sep/Oct 2015.
47
Survey of Analytical Method Transfer Conditions of Global Biologics Manufacturers
• A brief survey was conducted to evaluate how biologics manufactures transfer analytical methods.
• Pre- and post-licensure analytical method transfer (AMT) conditions surveyed for:
- AMT execution model- Sample size- Acceptance criteria
• A total of eight large pharma/biotech manufacturers, representing the three major regulatory regions of US, EU, and Asia, were surveyed. All eight have global operations, multiple commercial biologics, and more than 3000 employees.
• Most large manufacturers follow TR 57 for AMT execution matrix and sample size calculations.
Survey Information
48
Survey of Analytical Method Transfer Conditions of Global Biologics Manufacturers
AMT Options
A. Co-validation – Sending and receiving laboratories participate in the AMV study execution.
B. Comparative study – AMT study performed concurrently by sending and receiving laboratories. Acceptance criteria determine the equivalence of the two laboratories.
C. Performance Verification - The receiving laboratory may already perform the method for a similar product or for another type of sample for the same product. In this case, a formal method transfer may not be required.
D. Waiver - The receiving laboratory may already perform the method for a similar product or for another type of sample for the same product. In this case, a transfer may be waived. Any waived study should be properly justified using available data.
49
Survey of Analytical Method Transfer Conditions of Global Biologics Manufacturers
Execution Matrix Used for Comparative Study (Option B)
50
B-1. Fixed AMT execution matrix does not integrate known test method result variation and has therefore an identical set of comparative data generated between both laboratories for each method transfer executed. A fixed execution matrix can be more advantageous when transferring multiple products to/from multiple locations. B-2. Variable execution matrix does consider test method result variation and may require a larger data comparison set for highly variable test methods. A variable execution matrix may be advantageous when transferring bioassays and/or ELISA-type assays with a relatively high degree of test result variation.
1. Different model, sample size(s) and/or acceptance criteria used for:a. Clinical vs. commercial AMT studies ?b. Internal vs. external (to/from CMO) AMT studies ?c. To/from CMO vs. non-US in-country batch release lab AMT studies ?
2. Total number of samples/replicates tested by both labs, SU and RU ?
3. Are you using a Fixed AMT execution matrix (ex., n=6, 12, 18 at SU/RU) ? or, Variable AMT execution matrix (n is calculated) ?
4. Intermediate precision-type comparison used (at least two variation factors) ? 5. Acceptance criteria for RU are: Fixed or risk-based ?
Fixed = ex., NMT 1.0 SD difference between SU and RURisk-based = calculated by considering specification, process capability, maximum allowed result drift/variation from SU to RU ?
Survey Questions
51
52
SurveyParticipant:
1-8Clinical Trial DS/DP Commercial DS/DP Comments
Internal AMT To/from CMO AMT
Internal AMT To/from CMO AMT
To In-Country Release Lab AMT
1 All (A-D) are allowed
All (A-D) are allowed
All (A-D) are allowed
All (A-D) are
allowed
All (A-D) are allowed
AMT model used depends on RU capability and experience, whether method has been
previously validated, number of RUs and other project
requirements.
2 B B B and C B BMost AMTs use B. Some
individual co-validation (Model C) AMTs have been used.
3 A and B B A and B B B N/A
4 A and B A and B A and B A and B A and B A and B are most common approaches.
5 B B B B B N/A6 A or B B or C A or B A or B B N/A
7 A, B, C C, D A, B, C and D C, D C, D All transfer models are practiced as applicable.
8 B B B B B N/A
Typical AMT Model Used ?(A=co-validation; B=comparative study, C=performance verification, or D=waiver)
53
SurveyParticipant:
1-8
Clinical Trial DS/DP Commercial DS/DP Comments
Internal AMT To/from CMO AMT
Internal AMT To/from CMO AMT
To In-Country Release Lab
AMT
1 B-1 B-1 B-1 and B-2 B-1 and B-2 B-1 and B-2 Procedure allows for use variable execution matrix.
2 B-1 B-1 B-1 B-1 B-1 Bioassay can use B1 (6-18) or B2 (variable).
3 B-1 B-1 B-1 and B-2 B-1 and B-2 B-1 and B-2 N/A4 B-1 B-1 B-2 B-2 B-2 N/A 5 B-2 B-2 B-2 B-2 B-2 N/A6 B-1 B-1 B-1 B-1 B-1 N/A
7 B-1 and B-2 B-1 and B-2 B-1 and B-2 B-1 and B-2 B-1 and B-2B-1 for analytical assays, B-2 for Bioassay and ELISA based methods The number of replicated are chosen based on method complexity and variation.
8 B-1 B-1 B-1 B-1 B-1 N/A
Typical Execution Matrix UsedB-1 or B-2
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SurveyParticipant:
1-8Clinical Trial DS/DP Commercial DS/DP Comments
Internal AMT
To/from CMO AMT
Internal AMT
To/from CMO AMT
To In-Country Release Lab AMT
1Phase
appropriate AMT design
Phase appropriate AMT design
minimum 6 minimum 6 minimum 6N/A
2 6 6 18 18 18 Bioassay can use B1 (n=18) or B2 (variable).
3A: 24
B: 12B: 12
A: 24
B: 12B: 12 B:12
For model A, n=24 is used. For model B, n=12 is used.
4 6 6 4x6 4x6 4x6Typically, n=6 for clinical and n=24 (4x6) for commercial are used but n can also be
variable and risk based.
5 12 12 12(+) 12(+) 12(+)A fixed sample size is used for clinical trial
DS/DP. For commercial DS/DP AMT, sample size is calculated based on analytical and process capability
6 6 6 24 24 24 N/A7 6-12 3-6 6 3-6 3-6 N/A
8 Variable Variable Variable Variable VariableFixed AMT sample size for a particular method but variable AMT sample size
among different methods (n is calculated based on method and process capability)
Typical Sample Size(s) Used: (n = 6, 12, 18, 24…)
55
SurveyParticipant:
1-8
Clinical Trial DS/DP Commercial DS/DP Comments
Internal AMT To/from CMO AMT
Internal AMT To/from CMO AMT
To In-Country Release Lab
AMT
1Phase-
appropriate AMT design
Phase-appropriate AMT design
Yes Yes YesIntermediate precision design is used for quantitative, product-specific methods
2 Yes Yes Yes Yes Yes Intermediate precision design is used3 Yes Yes Yes Yes Yes
4 Yes Yes Yes Yes YesDirect transfer is also allowed (repeatability study only)
5 Yes Yes Yes Yes Yes Minimum of 2 factors are used6 Yes Yes Yes Yes Yes N/A
7 Yes Yes Yes Yes YesACs are based on SU intermediate precision and method development
history.
8 Yes Yes Yes Yes Yes N/A
Intermediate Precision (see AMT Model B)Yes/No
56
SurveyParticipant:
1-8
Clinical Trial DS/DP Commercial DS/DP Comments
Internal AMT
To/from CMO AMT
Internal AMT
To/from CMO AMT
To In-Country Release Lab
AMT
1 Generally fixed Generally fixed Both Both Both Procedures allow for use of both. Justification
for use of fixed or risk-based is required.2 Fixed Fixed Risk-Based Risk-Based Risk-Based N/A
3Combination
Fixed and Risk-based
Combination Fixed and Risk-
based
Combination Fixed and Risk-based
Combination Fixed and Risk-
based
Combination Fixed and Risk-
based
Bioassay is only AMT which has risk-based ACs.
4 Fixed Fixed Risk-Based Risk-Based Risk-Based
For clinical, fixed but based on the number of n used in the study is most common
approach. For commercial, ACs based on specification or tightest release limit, method
variability.
5 Risk-based Risk-based Risk-based Risk-based Risk-basedRisk-based ACs with respect to specification, known variability of both process and test
method.
6 Fixed Fixed Fixed Fixed FixedFixed acceptance criterion (NMT 1.0 SD) for maximum difference between SU-RU is set
from SU performance.
7 Fixed Fixed Fixed Fixed Fixed Fixed ACs used for most of the AMTs. Some AMT’s prior to CTM have risk based ACs.
8 Risk-based Risk-based Risk-based Risk-based Risk-based
Acceptance Criteria: Fixed or Risk-Based (ex., fixed = NMT 1.0 SD difference, risk-based = calculated)
AMT model options• Two of eight manufacturers use all or most of the available models regardless of the stage of
product development. • As expected, all manufacturers use model B and this option is by far the most often used
model. Fixed vs. variable matrix
• Results show significant variation with four possible variations represented (only B-1; only B-2; only B-1 and B-2; and B-1 => B-2 for post-validation AMTs).
• Six of eight use fixed execution matrices for pre-validation AMTs. • Post-validation, a variable execution matrix is used by three manufacturers. • Evaluation of test method precision performance adapted under intermediate precision
conditions. Sample Size(s)
• Results varied significantly from n=3 to as much as n=24. • Most use a larger sample size for post-validation AMTs. This can be explained by the increase
in “product value” and desired confidence in the AMT results for late-stage/commercial products.
Acceptance criteria • For post-validation AMTs more than half of the AMT acceptance criteria are risk-based
(calculated primarily by considering specifications and process capability and the maximum acceptable result drift (from SU to RU) and result variation at RU).
• Some manufacturers move from fixed (ex. NMT 1.0 SDs) to risk-based acceptance criteria for post-validation AMTs.
• The higher level of uncertainty in the required method performance and/or product/process capability in early product development stages can lead to setting fixed acceptance criteria. 57
AMT Survey Result Summary
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