Risk Management for Complex Pharmaceuticals:

Steven Kozlowski, M.D., DirectorOffice of Biotechnology Products OPS/CDER

ACPS 10/6/06

An Awareness Topic

Overview

• Background

• Complex Product Risk Assessment

• Less than the Whole 9 Yards

• Future Considerations

Risk Management Tools (ICH Q9)• Basic risk management facilitation methods

(flowcharts, check sheets etc.); • Failure Mode Effects Analysis (FMEA);• Failure Mode, Effects and Criticality Analysis

(FMECA); • Fault Tree Analysis (FTA);• Hazard Analysis and Critical Control Points

(HACCP);• Hazard Operability Analysis (HAZOP);• Preliminary Hazard Analysis (PHA);• Risk ranking and filtering;• Supporting statistical tools.

Risk Management (ICH Q9)

Principles• Link to

patient protection

• Effort commiserate with potential risk

Risk Assessment (ICH Q9)Risk = Probability X Severity• What might go wrong? • What is the likelihood (probability) it will go wrong?• What are the consequences (severity)?

Use in Quality Management & Regulatory Operations– Inspections & Audits– Facilities, Equipment & Utilities– Materials Management– Manufacturing & Change Control

– Assessment of Product Quality• Complex Products

FMEA Bottom Up Semi-Quantitative

Minor Important Major Catastrophic

Severity

Frequent

Probable

Occasional

Remote

Improbable

Pro

babi

lity

FTA Top Down Quantitative

HEALTH AND SAFETY

BRIEFING No 26c

The IET

Quantitative Risk Assessment

Frequent

Probable

Occasional

Remote

Improbable

Minor Important Major Catastrophic

Severity

Pro

babi

lity

10-1

10-7

Probabilistic Risk Assessment (PRA)What it means?

Michael G. Stamatelatos, NASA

• Includes uncertainty of quantitation• Modeling for unknown information• Integration many initiating events

Examples of modeling Fayssal M. Safie, Chad Hoffman, Rich Pugh…AIAA

Pub

• Similarity Method• Probabilistic Structural Analysis

• Distributions of important variables• Simulations (Monte Carlo, etc.)

NASA PRA Fayssal M. Safie, Ph.D., CRE

Overview

• Background

• Complex Product Risk Assessment

• Less than the Whole 9 Yards

• Future Considerations

87 A o

Fab = ~1/3 mAb

PDB 2IG2, 1HW8

• 1 structure• higher order

structure• post-

translational modifications

• heterogeneity

11 Ao

Statin

Statin MW ~400 Da

Structure of complex molecules

Monoclonal Ab MW ~150,000 Da

Attributes & Combinatorics

• 2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600

K

pyro-E O

D

G

G

D

OD

• (9600)2≈ 108

O

O

• Methionine oxidation (2 x 2)

pyro-E • Pyro-Glu (2)

• High mannose, G0, G1, G1, G2 (5)

• Sialylation (5)

D

D

D• Deamidation (3 x 2)

G

G

• Glycation (2 x 2)

K

• C-term Lys (2)

Laurence J. Peter, American business humorist

Some problems are so complex that you have to be highly intelligent

and well informed

 

just to be undecided about them.

Probabilistic Risk Assessment• People tend to think that lack of data is a

reason not to perform a PRA, but the exact opposite is true– PRA is generally used for low-probability and high-

consequence events for which insufficient statistical data exist.

– If enough statistical data exist to quantify system or sub-system failure probabilities, use of some of the PRA tools may not be necessary

• Michael G. Stamatelatos, NASA

• May serve as organizing framework • Bilal Ayyub, U of MD

Protein Logic

Diagram

Protein

At Release Expected Stress

PrimaryStructure

ImpuritiesExcipients2o/3o

Struct.4o

Struct.ContainerClosure

....

GlycationOxidationDeamidation TruncationGlycosylation etc.

OxidationSite 1

OxidationSite 2

OxidationSite n

....

Functional Event Sequence Diagram

OxidationSite 1

Is Oxidation Without Impact

on Activity?Y

BatchFailure

Y

Is Level Low Enough not to Matter?

N

Detectability of Oxidation with Impact?

N

ClinicalFailure

N

AcceptableProduct

Y

Y

Safety

OxidationSite 1

AcceptableProduct

BatchFailure

ClinicalFailure

Is Level Low Enough (or High Enough) not to Generate an Immune Response?

Detectability of Oxidation with Impact?

Y

Y

Y

Y

N

N

N

Is Oxidation Without Impact

On Safety?(Immunogenicity)

Does the Immune Response Lack Clinical Significance?

N

Y

Functional Event Sequence Diagram

OxidationSite 1

Is Oxidation Without Impact

on Activity? AcceptableProduct

BatchFailure

ClinicalFailure

Is Level Low Enough not to Matter?

Detectability of Oxidation with Impact?

Y

Y

Y

Y

N

N

N

Event Tree (Quantification)

OxidationSite 1

LowLevel

NoImpact Detectable

Scenario#

EndState

POS1 =? 1 Accept.

Inv PNI =? 2 Accept.

Inv PLL=? 3BatchFails

Inv PD=? 4ClinicalFailure

Assigning ProbabilitiesInitiating Events Event Trees

Actual DataSimilarity Method • Same Product

– Models (animals, bioassays)• NASA Ground tests

• Related Product or Component– Direct Data (clinical) – Models (animals, bioassays)

Probabilistic Structure Analysis– e.g. probability of docking to all known receptors

• Far off

Biological Activity Matrix

One to some lots

Many lots

Validated Bioassay

Clinical Studies

Clinical Pharmacology (PK/PD)

Small Animal/Complex Bioassay

Multiple Binding/Cellular Assays

Clin

ical

Lo

ts

Clin

ical

Lo

t E

xtre

mes

Pu

rifi

ed/In

du

ced

Var

ian

ts

Str

esse

d L

ots

Dev

elo

pm

enta

l Lo

ts

Assessing Relatedness for Assigning Probabilities

• Same primary sequence• Alignment in shared framework/domains• BLAST surrounding sequences

– T-cell-like

• Protein Structure Databases– B-cell-like– Molecular Descriptors (Cramer)– In silico immunogenicity prediction

• Need measures of uncertainty associated with each strategy used

Evolution of Monoclonal Antibodies

Mouse

Chimeric

Human

Humanized

Monoclonal Antibodies as a Risk Management Platform

• 50% of licensed MAbs are IgG1– It is estimated that greater than 50% of Mabs

under development are humanized or human IgG1s

– 50% of products may share 95% of their sequence

• Valuable human in vivo MAb data– Isoform based PK data– Large safety database for shared attributes

• All IgG1 products• Endogenous IgG1 variants

– Radiolabeled antibodies & imaging (generally not humanized)

Monoclonal Antibodies as a Risk Management Platform

• Isoform bioassays– Fc binding & Effector Function

• Nature of target interaction– Soluble, host cell based or on pathogen– Accessibility of target– Ability of target to signal– Role of effector function– Cross-reactivity

Overview

• Background

• Complex Product Risk Assessment

• Less than the Whole 9 Yards

• Future Considerations

Even Without a PRA

• Nothing is more difficult, and therefore more precious, than to be able to decide. – Napoleon Bonaparte

• Even a correct decision is wrong when it was taken too late. – Lee Iacocca

FMEA for Product Quality RPN Severity Occurrence Detectability 5 Compromised product

quality resulting in a serious adverse event

Documented, Almost certain

Not all relevant attributes can be characterized/tested. Defect is not detectable by characterization tests/lot release/stability or in-process controls

4 Compromised product quality resulting in an adverse event

Documented and frequent

Not all relevant attributes on lot release. Defect is not detectable by lot release/stability or IPC

3 Compromised product quality resulting in no product efficacy

Documented but infrequent

Defect is not detectable by lot release/stability but exceeds IPC action limits ; QC releases inappropriately

2 Compromised product quality resulting in diminished product efficacy

Possible, but no known data

Defect is not detectable by lot release/stability but exceeds IPC action limits ; QC rejects appropriately

1 No effect on performance

No known occurrence

All relevant attributes tested. Defect is detected by lot release/stability

Patrick Swann

Combination Products

• Primary Mode of Action– Driver of jurisdiction between FDA Centers– Toxic component overrides targeting– Administrative Ease vs Risk Assessment

• Risk Assessment more Appropriate for Resource Allocation

Cruise missile

Antibody Conjugate

1 Accept.

ConjugateAntibody

MAbOK

ToxinOK

Detect-able

Scen-ario #

EndState

LinkageOK

2

3

Batch Fails

No Efficacy

P=?

P=?

4

5

Batch Fails

Toxicity

P=?

P=?

P=?

Toxicity7

6 Batch Fails

P=?

P=?Probabilistic

Risk Assessment

Very Complex Combinations

Overview

• Background

• Complex Product Risk Assessment

• Less than the Whole 9 Yards

• Future Considerations

Considerations

• Follow up on prior programs– Draft Report on Transdermal Patches– Plan for Conference on Risk Management &

Pharmaceuticals• Bilal Ayyub, U of MD

• Further OPS education on Risk Management– Seminar Series

• Consider approached to encourage exploration of of risk management strategies for complex products

• If Antibody Platform approach used in QbD– Strategize to best utilize Risk Management– Best initial system for PBR

Homework

• Fault Tree Analysis for above product • Assign probabilities to all possibilities• Due 5PM today

• Also…consider relative importance of investing in risk management for complex products