FDA (invited) Presentation - Specifications and Analytical Method Lifecycle for Accelerated...

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




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


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




Commercial Specifications Negotiations, Final

Commercial Specifications and/or Post-BLA

commitmens

QTPP




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



Dose change

Delivery Device

PQ lots


Mfg Transfer

Method validation

Method transfer


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





QTPP




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



Dose change

Delivery Device

PQ lots


Mfg Transfer

Method validation

Method transfer


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


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.)


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)


Not Parallel Step

Process Color Legend:

Method Qualified

(SOP Lock)

Ideal Analytical Method Lifecycle Preparing for Tech Transfer (Pilot to Commercial Plant)

12


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)


13


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)


14


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)

Ideal Analytical Method Lifecycle Preparing for PQ (at Commercial Plant)

15


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)

Ideal Analytical Method Lifecycle Preparing for PQ (at Commercial Plant)

16


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)

Ideal Analytical Method Lifecycle Executing PQ Studies (at Commercial Plant)

17


for New Method


QCDev.

AMVStudies

(QC-Comm.)

PQ Lots Mfg

Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


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


QCDev.

AMVStudies

(QC-Comm.)

PQ Lots Mfg

Completed

In progress

Not started

AMV completed

MaintenanceAMM

(QC-Comm.)

Robustness Studies

Master Plan

AMT Studies





Not Parallel Step

APT MethodAMV and AMM

(QC)

Analytical Platform Technology

APT Method

Robustness and AMT


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


APT Robustness

(QC-Dev.)

Feasibility Testing

(QC-Comm.)

Simultaneous ?

Simultaneous ?

Completed

In progress

Not started

AMV completed

Not Parallel Step



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


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 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


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


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)



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


and 3)



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


and 3)



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%


35

M%

A% F%

Spiking highly degraded Product (A% and F%)


36

M%

A% F%

Spiking highly degraded product (A% and F%)

- Start with high purity product (A% + F% < 1.0%)


37

M%

A% 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%)


38

M%

A% 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%


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


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


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


To In-Country Release Lab AMT

1 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



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

54

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





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


Internal AMT

To/from CMO AMT

Internal AMT

To/from CMO AMT


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


based


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

FDA (invited) Presentation - Specifications and Analytical Method Lifecycle for Accelerated...

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