Analytical Control Strategy for Biologics

Stephan Krause

Principal Scientist, MedImmune

30 January 2013

WCBP Meeting – Washington, DC

Outline

Control strategy introduction

Identification and assessment of critical quality attributes (CQA)

Process mapping – aligning the CQA assessment process with:

– CMC and Tech Transfer Process

– Specification Life Cycle Management Steps

Conceptual example for drug product specification review and revision process

– Develop and justify release and shelf-life acceptance criteria

Control Strategy Elements

Raw Material Controls

Procedural Controls

Operational Parameters

Process Validation

Analytical Control Strategy

– Identification of CQAs– Lot release testing (specifications)– Stability testing (specifications) – In-process testing– Characterization and comparability testing– Process monitoring

Identification of Critical Quality Attributes

Patient impact severity assessment of the process and the product

– Potential impact of molecular attributes and formulation components

– Product- and process-related impurities and degradation products

– Contaminants (i.e., adventitious agents)

Severity risk assessment (scoring):

– Impact of the attribute on safety and efficacy

– Uncertainty in the knowledge regarding the Impact

– Severity (risk score) = Impact x Uncertainty

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Risk Assessment and Control Strategy

Severity (Define CQA)

Probability Impact on safety or efficacy

Relationship of product knowledge to process capability

Raw material control

Procedural controls

Lot release testing

Stability testing

Detectability

Capability of analytical methods

Process validation

In-process testing

Operational parameters

Characterization testing

Develop Control Strategy

Risk Assessment(Risk Priority Number: Severity x Probability x Detectability)

Re-assess as product knowledge

and process understanding

increase

Identify All Product Quality Attributes

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CQA Development, CMC Changes, and Specifications

FTIH POC BLA

Tox StudiesPhase 1

Phase 2Phase 3

Clinical ResupplyMfg/Formulation Change(s)

Specifications Revision(s)

Target Quality CriteriaCommercial

Specifications

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

op

men

t(Q

bD

Pro

cess

)S

pec

s L

ife

Cyc

le

Mg

mt

CM

C a

nd

Tec

h

Tra

nsf

er P

roce

ss Analytical

Manufacturing

Strategic or Tactical Changes

Method qualification

Dose change

Delivery Device

PQ lots

Setting of Initial Specifications

Specifications Review/Confirmation

Mfg Transfer

Method validation

Method transfer

Formulation Change

Process Verification

Method Maintenance

Global Supply

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CMC/Tech Transfer Process

FTIH POC BLAQTPP

Analytical

Manufacturing

Strategic or Tactical Changes

Dose change

Delivery Device

PQ lotsMfg Transfer

Mfg Process Change

Qualification

Process Verification

Global Supply

Development of Control Strategy

Specification Life Cycle Management

Validation

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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

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Setting and Justification of Specifications

10

Example for Specification Revision Process (Purity by HPSEC)

% M

on

om

er (

Inta

ct M

ole

cule

)

% A

gg

reg

ates

% F

rag

men

ts

Total of 3 Peak Areas = 100.0%

NLT 95.0%

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Example for Specification Revision Process (Purity by HPSEC)

95.0

96.0

97.0

98.0

99.0

100.0

NLT 95.0%

Phase 2 => Phase 3

N=1

Tox => Phase 1 (FTIH)

Phase 1 => Phase 2

T=2M

N=2

T=3M

N=3

T=12M

Phase 3 => (Pre-)

Commercial

Historical DP Release Results (T=0M)

DP Stability Results – Recommended Temperature

12

Example for Specification Revision Process (Purity by HPSEC)

95.0

96.0

97.0

98.0

99.0

100.0

NLT 95.0%

Phase 2 => Phase 3

N=1

Tox => Phase 1 (FTIH)

Phase 1 => Phase 2

T=2M

N=2

T=3M

N=3

T=12M

N=4

T=12M(new

stability study)

N=6

T=24MT=36M

N=10 N=15

T=48M

Phase 3 => (Pre-)

Commercial

Historical DP Release Results (T=0M)

DP Stability Results – Recommended Temperature

Process Change(s): Comparability Demonstrated

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Drug Product Release/Stability Specifications

95.0

96.0

97.0

98.0

99.0

100.0

NLT 95.0%T

igh

ten

DP

Sh

elf-

Li f

e L

imi t

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%

NLT 98.3%

Tig

hte

n D

P R

el e

as e

Li m

it

Analytical Method Variation (long-term)Analytical Capability

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Drug Substance Manufacturing Target

95.0

96.0

97.0

98.0

99.0

100.0

NLT 98.3% (DP Release)Representative Degradation

for Desired 1-Year DS Hold and Post-Thaw Handling

Estimated Degradation Uncertainty

NLT 98.7% (DS Mfg Target)

NLT 95.0%

Tig

hte

n D

P R

elea

s e L

i mit

Summary

In the HPSEC specification revision example:

– Drug product release specification (NLT 98.3%) is based on the expected manufacturing capability and clinical experience (n=12 batches from phase 2-3).

– Drug product shelf-life specification (NLT 97.0%, 3-year shelf-life) is based on the drug product release specification (NLT 98.3%) and the predicted degradation.

– Drug substance manufacturing target is set to ensure meeting drug product specifications.

The selection of a suitable control strategy element for a (critical) quality attribute depends on:

– The assessed (potential) impact on patient safety and efficacy. – The capability of the manufacturing process.– Specifications are only a part of the complete control strategy.

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Acknowledgement

Timothy Schofield

Patricia Cash

Ziping Wei (currently at Novavax)

Mark Schenerman

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