AMV final 20Jun17

Stephan O. Krause, PhDDirector, QA TechnologyAstraZeneca Biologics

PDA Biosimilar Conference (co-sponsored by PQRI)20-21 June 2016

Analytical Method Validation for Biosimilars

2

Outline

1) Review of strategic opportunities to reduce analytical method lifecycle steps for accelerated programs

- Analytical platform technology (APT) methods for Tier 2 category- Product and process characterization APT methods for Tier 3

category- APT conditions

2) Review of need for increased analytical method performance

- Difference(s) and challenges for Biosimilars - AMV acceptance criteria for Tier 1 and 2

2

The content and views expressed in this presentation by the author are not necessarily views of the

organization he represents.

3

4

Analytical Platform Technology (APT) Method

• An APT method is an analytical method used for multiple products and/or types of sample matrix without modification of the procedure.

• Similar to compendial methods, an APT method may not require full validation for each new product or sample type.

• A test method becomes an “approved” (APT) method when included in a marketing license application, and the license is approved.

4

5

Typical 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


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.


7From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.

FTIH POC BLA





QTPP





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


CompLots

PQ lots CompLots =


8From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.

FTIH POC BLA





QTPP





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


CompLots

PQ lots CompLots =

RP vs. BP (Tier 1-3)

Covered: RP vs. BP results

9

Analytical Method Selection

Pharmaceutical Development Supporting Studies:Process characterizationProduct characterizationProcess validation

Routine Testing (registered methods):Raw materialsIn-process Release Stability

Intended Use (defined)

AMD Studies

AMD Studies

AMQ ReportAMQ Report

Intended Use (re-defined)

AMV Report

IdentitySafetyPurity

QualityPotency

Quality Target Product Profile (QTPP)Critical Quality Attributes (CQA)

Critical Process Parameters (CPP)

Krause et al., PDA TR 57, 2012

Analytical Method Development

Analytical Method Development

10

Analytical Method Selection

Pharmaceutical Development Supporting Studies:Process characterizationProduct characterizationProcess validationTier 3 Analytical Similarity

Routine Testing (registered methods):Tier 1 Analytical SimilarityTier 2 Analytical Similarity Release/StabilityRaw materials

Intended Use (defined)

AMD Studies

AMD Studies

AMQ ReportAMQ Report

Intended Use (re-defined)

AMV Report

IdentitySafetyPurity

QualityPotency

Quality Target Product Profile (QTPP)Tier 1-3 Analytical Similarity

Critical Process Parameters (CPP)

Typical Analytical Method Lifecycle

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)


Not Parallel Step

Process Color Legend:

Method Qualified

(SOP Lock)

Typical Analytical Method Lifecycle (=> BLA Submission)

12

DS/DPSpecificationTest Methods

for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed

Maintenance(QC-Comm.)

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

13

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

Krause, S., CDER/OBP Training Presentation, White Oak, MD, 28Sep15.

Analytical Method Lifecycle for Accelerated ProgramsAdditional APT Opportunities (also for Tier 3)

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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 Platform Technology


Krause, S., CDER/OBP Training Presentation, White Oak, MD, 28Sep15.

Typical Specifications and Test Methods for Drug Substance for Process Qualification (PV Stage 2)

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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

Brief Summary from OBP/CDER Presentation – White Oak (28Sep15)

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• APT status can be extended to additional products if the test method remains essentially unchanged through proper use of change control.

• Similar to compendial method verification, “approved” test methods can be verified (versus validated) for use of additional products.

• Reduced method qualification and transfer studies could then be executed, provided the same sending and receiving units are used.

• For additional product license applications, the sponsor should resubmit the initial method validation study report together with product-specific verification results (and reports).

• For separation tests, an actual manufacturing batch should be used for test system control as test result drift and/or variation could be observed over time; degraded batch samples closer to the out-of-specification (OOS) level could provide better system suitability control, and they may also provide more confidence in the test results when results are close to the OOS level.

Krause, S., PDA Letter, May 2016Krause, S., PDA J Pharm Sci Tech, (TBD) 2016

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Outline

1) Review of strategic opportunities to reduce analytical method lifecycle steps for accelerated programs

- Analytical platform technology (APT) methods for Tier 2 category- Product and process characterization APT methods for Tier 3 category- APT conditions

2) Review of need for increased analytical method performance

- Difference(s) and challenges for Biosimilars - AMV acceptance criteria for Tier 1 and 2

17

Typical Analytical Method and Specification Lifecycle(s)

18

AMVStudies


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.

Biosimilar Analytical Method and Specification Lifecycle(s)

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AMVStudies

Analytical Similarity

Studies


AMV)

AMT Studies

(if needed)

PQ (PV Stage 2)Studies

Method Qualified


Initial Specifications

Tier 1 Equivalence Tier 2 Quality Range

Tier 3 Methods

Proposed Commercial Specifications

Biosimilar Analytical Method and Specification Lifecycle(s)

20

AMVStudies


Studies


AMV)

AMT Studies

(if needed)


Method Qualified




Tier 3 Methods


AMVStage 2

AMVStage 3

Biosimilar Analytical Method and Specification Lifecycle(s)Use of APT Method Concept

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AMVStudies


Studies


AMV)

AMT Studies

(if needed)


Method Qualified




Tier 3 Methods


APTVerification

Continuous methodverification (stage 3)

already ongoing

APTVerification

Not needed if SU and

RU unchanged

Typical Risk-Based AMV Acceptance Criteria

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Specifications

Consider Type of

Specifications

Acceptance Criteria

Existing Knowledge

One-Sided Specifications(NMT, NLT, LT)

Two-Sided Specifications

(Range)

Regulatory Requirements

Historical Method

Performance

Historical Data from this

Product and Process

Knowledge from Similar Product and

Process

Krause et al., PDA TR 57, 2012.

Tier 1 and 2 Risk-Based AMV Acceptance Criteria

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Available RP Lot Variation

and Mean

Consider Type of

Specifications

Acceptance Criteria

Existing Knowledge



(Range)


Historical Method

Performance


Product and Process


Process


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and Mean

Consider Type of

Specifications

Acceptance Criteria

Existing Knowledge



(Range)


Historical Method

Performance


Product and Process


Process

Tighter AMV acceptance criteria neededfor Tier 1 or Tier 2


25


and Mean

Consider Type of

Specifications

Acceptance Criteria

Existing Knowledge



(Range)


Historical Method

Performance


Product and Process


Process


Tier 1 equivalence or Tier 2 quality range


26


and Mean

Consider Type of

Specifications

Acceptance Criteria

Existing Knowledge



(Range)


Historical Method

Performance


Product and Process


Process



This part essentially goes away for AMV stage 2


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and Mean

Consider Type of

Specifications

Acceptance Criteria

Existing Knowledge



(Range)


Historical Method

Performance


Product and Process


Process




Critical review for APT methods performance (AMV stages 2 and 3)


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and Mean

Consider Type of

Specifications

Acceptance Criteria

Existing Knowledge



(Range)


Historical Method

Performance


Product and Process


Process




Critical review for APT methods performance (AMV stages 2 and 3)- which AMV stage 2 parts not repeated ?

29

Equi

vale

nce

Lim

it

- 1.5x RP SD 0 + 1.5x RP SD

Equi

vale

nce

Lim

it

No difference

Tier 1 Equivalence TestingRP SD = Reference product variation (standard deviation) as tested

(Equivalence Demonstrated)

RP S

peci

ficati

ons

RP S

peci

ficati

ons

90% 2-sided CI for ∆ (RP-BP)

Chow, SC, “On Assessment of Analytical Similarity in Biosimilar Studies.” Drug Des, 2014.

Tier 1 Equivalence Testing

• RP lots (n) tested for equivalence ≈ BP lots (n)- Example n=10 RP lots and n=10 BP lots

• Use available n=20 RP lots- Randomly select n=10 RP lots (1st set) to set equivalence limits (+/- 1.5 RP SDs)- Use remaining n=10 RP lots (2nd set) to test for equivalence vs. n=10 BP lots- Mean/SD of 1st set of RP lots (n=10) ≈ 2nd set

• RP lot SDobserved = SQR [(RP lot SDtrue)2 + (RP SDanalytical)2]

• RP SDanalytical ≈ BP SDanalytical

• Tier 1 potency test considerations:- Is RP and BP dosing done with potency units or total protein ?- Is there a “gold” reference standard ?

Assumptions and Conditions => AMV Acceptance Criteria

30Chow, SC, “On Assessment of Analytical Similarity in Biosimilar Studies.” Drug Des, 2014.

Simulated Tier 1 Example

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Equ

ival

ence

Lim

it

- 1.5x RP SD 0 + 1.5x RP SD

Equ

ival

ence

Lim

it

No difference

RP 1.0 SDs (n=10)

Simulated Tier 1 ExampleRP – BP = 0.5 SD

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Equ

ival

ence

Lim

it

- 1.5x RP SD0

+ 1.5x RP SD

Equ

ival

ence

Lim

it

RP 1.0 SDs (n=10)

BP 1.0 SDs (n=10)

90% CI RP-BP

Simulated Tier 1 Example calculated RP – BP = 0.5 SD

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Equ

ival

ence

Lim

it

- 1.5x RP SD0

+ 1.5x RP SD

Equ

ival

ence

Lim

it

RP 1.0 SDs (n=10)

BP 1.0 SDs (n=10)

90% CI RP-BP

RP lots 1-10 = RP lots 11-20

= [(1.0)2 + (1.0)2] / 2 = 1.0

= = sqr [(2(1.0) / 10] = 0.447

Lower 90% CI Limit = 0.50 - (1.734)(0.447) = -0.275Upper 90% CI Limit = 0.50 + (1.734)(0.447) = +1.275


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Equ

ival

ence

Lim

it

- 1.5x RP SD0

+ 1.5x RP SD

Equ

ival

ence

Lim

it

RP 1.0 SDs (n=10)

BP 1.0 SDs (n=10)

90% CI RP-BP

RP lots 1-10 = RP lots 11-20

= [(1.0)2 + (1.0)2] / 2 = 1.0

= = sqr [(2(1.0) / 10] = 0.447



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Equ

ival

ence

Lim

it

- 1.5x RP SD0

+ 1.5x RP SD

Equ

ival

ence

Lim

it

RP 1.0 SDs (n=10)

BP 1.0 SDs (n=10)

90% CI RP-BP

RP lots 1-10 = RP lots 11-20Note: No advantage of using lots 1-10 for +/- limits

= [(1.0)2 + (1.0)2] / 2 = 1.0

= = sqr [(2(1.0) / 10] = 0.447


Tier 1 Equivalence Testing



• Typical AMV acceptance criteria example: Use product specifications (no potency loss over DP shelf-life):

• If (RP and) BP potency specs are 80-125% (geometrical) or 80-120% (symmetrical), and BP CPK = 1.00: AMV Int. Precision to be NMT 1.0 SD (7%)

• Biosimilar Tier 1 AMV acceptance criteria example(s) for analytical similarity: - AMV Int. Precision RP/BP NMT 0.7 SD (in %CV) of RP lot SDobserved (assuming CPK ≥

1.00): Approx. NMT 5%- RP lot SDobserved = 1.0 = SQR [(RP lot SDtrue = 0.7)2 + (RP SDanalytical = 0.7)2] = 0.49 + 0.49 = 1.0

• AMV Accuracy and/or Specificity (“matching” or “recovery”) acceptance criteria to be for mean difference NMT +/- 0.2 SD for BP (vs. RP)

Assumptions and Conditions => AMV Acceptance CriteriaHow “good” does my (potency) test performance need to be ?

36

Additional Points to Consider for Tier 1N = 10 for both reference and test product

Data from Gaussian distribution with , where and are the true variance values for the manufactured lots and for the analytical method, respectively. - Only about 82% expected pass rate when the

mean difference is truly equal to zero (products are exactly biosimilar). The 1.5 multiplier () may be too small ?

- For our example (0.5 SDs true difference), pass rate is 63%. The 1.5 multiplier may be too small.

- When the analytical variation is very high relative to product variability, the tier 1 pass rate remains relatively high for both small and large product mean differences. When analytical variation is high relative to the total standard deviation, true product differences can be obscured. Manufacturer’s risk is greatest when it pursues to lower analytical variation.

Courtesy of Steven Novick, MedImmune, USA

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∆ of 0 => 82% pass

∆ of 0.5 => 63% pass

Tier 2 Quality Range Testing (One-Sided)Assumptions and Conditions => AMV Acceptance CriteriaHow “good” does my potency test performance need to be ?

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+ 2.0x SD of RP Mean

Qua

lity

Ran

ge L

imit

RP

Mea

n (n

=20)

RP 1.0 SDs (n=20)

0.0%Impurity

Tier 2 Quality Range Testing

• A one-sided (non-inferiority) test model is used for a one-sided specification (NMT X.X% impurity).

• Use all available n=20 RP lots to set mean + 2.0 SD limit for quality range.- Data transformation is used as data is not symmetrical.- 90% of BP results (9/10) are expected to fall within 2.0 SD limit.(2/100 (2%) are expected to be > 2.0 SD limit if RP mean/SD = BP mean/SD)

• RP lots (n) tested for equivalence > BP lots (n)- Example n=20 RP lots and n=10 BP lots- No side-by-side testing (to reduce analytical variation)



Assumptions and Conditions => AMV Acceptance Criteria

39

Tier 2 Quality Range Testing



• Typical AMV acceptance criteria example: Use product specifications (Impurity NMT 2.0%)

• If (RP and) and BP CPK = 1.00: AMV Int. Precision to be NMT 1.0 SD (ex., 0.5%)

• Biosimilar Tier 2 AMV acceptance criteria example(s): For analytical similarity: AMV Int. Precision RP/BP NMT 0.7 SD (in %CV) of RP lot SDobserved (likely CPK ≥ 1.00), therefore, NMT 0.35%

• AMV Accuracy and/or Specificity acceptance criteria to be for mean difference NMT +/- 0.2 SD (ex., 0.1%) for RP vs. BP.

• Note: Conceptually, the same issues arise as those noted for Tier 1.

Assumptions and Conditions => AMV Acceptance CriteriaHow “good” does my analytical method performance need to be ?

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Summary of Biosimilar AMV

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• To be fast and successful, we should use an APT concept for Biosimilars.

• More stringent method performance expectations (ideally) exist for AMV (Tier 1 and 2 methods) although the current Tier 1 and 2 analytical similarity acceptance criteria may not be in the interest of patients.

• The most critical CMC success step is passing the formal analytical similarity study (not PPQ).

Krause, S., PDA J Pharm Sci Tech, (TBD) 2016

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Back-up slides(APT examples)

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HPSEC AMV Study Example for an Analytical Platform Technology (APT) Method

AMV Study Example(s) Purity by HPSEC – Initial AMV Study

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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 Tier 2 ExamplePost-BLA APT AMV Study

45

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

46

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

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Analytical Ultracentrifugation (AUC) AMQ Study Example for an Analytical Platform Technology (APT) Method

(Test method is used as part of the Tier 3 analytical similarity testing program)

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.

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AMQ Study Example(s) SV Method – Initial AMQ Study

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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

50

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

AMV final 20Jun17

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