FDA Risk Assessment Principles for the Product Quality Initiatives

7/28/2019 FDA Risk Assessment Principles for the Product Quality Initiatives

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Risk Assessment

Principles for the

Product QualityInitiatives

H. Gregg Claycamp, Ph.D., CHP

Center for Veterinary MedicineOffice of New Animal Drug [email protected] 25, 2003


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Outline

Overall Premise and Questions

Basics of Risk Analysis

Possible Stages of Risk Assessments for PQ

Initiatives

Risk Ranking Model for a PQ Initiative?

Pilot Scale

Conclusions

The opinions and ideas presented here are those of the author and do not

represent policy or opinion of the FDA. This material is intended for

discussion purposes only.


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Premise: Links Among Process (GMP)Risks and Patient Risks are Lost

RISK

P

rocessInspection

Risks

cGMP

RISK

Quality(Pa

tient)

Factors

Patient

Corr

elations?Models?


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Goal: Re-Link cGMP (PQ) Risks with Actual

Risks to the Patient

RISK

Pro

cessInspection

Risks

RISK

Quality(Patient)

Factors

cGMP Patient


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The Question

Can Risk Management theory, tools, practice andphilosophy be employed to re-link risks to the patientwith the risks identified, perceived or otherwise

implicated in product quality terms?

How can we share a common language about risk, riskmanagement,and science-based decision making so that

we can focus on developing a high-quality riskmanagement model for product quality?


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Getting Started

What theories, tools and lessons learned in riskanalysis can help address these questions?

Given the need for a significant shift in the

approach to risk management, how do we beginthe change process?

Are there off-the-shelf models and tools thatmight be used, i.e., at a pilot-scale?

What kinds of RM processes can be used tofoster changes needed both the regulatoryand industrial spheres?


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Basic Risk Analysis


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Starting with the Some Basics

Riskis intuitive and familiar to everyone, yet few

among us define risk carefully and formally

enough for complex risk analysis.


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Risk = exposure to a chance of loss(or, Risk = chance of losing something

we value)

Risk = Hazard x Exposure

RiskConsequence = Hazard x Exposure


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Contemporary Risk Analysis

Includes four major activities:

Hazard Identification

Risk Assessment

Risk Management

Risk Communication


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Risk Assessment Precedes Risk

Management

Risk assessment is not a single process, but a

systematic approach to organizing and analysing

scientific knowledge and information to support a riskdecision. NRC (1994)

Various paradigms exist for the execution of a risk

assessment in public health; however, all paradigmshave in common fundamental scientific principles.


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Risk Assessment Asks:

What can go wrong?

What is the likelihood it would go wrong? What are the consequences?


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Risk Management Asks:

What can be done?

What options are available?

What are risk trade-offs in terms of risks,benefits and costs?

What are the impacts of currentmanagement decisions on future options?


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Roles/Tasks (--short list)

Pose the risk question.

Charge the RiskAssessors with the RiskAssessment Task.

Convene stake holders.

Analyze decision options. Make/recommend the

decision.

Identify data and gatherinformation on the nature,

extent, magnitude anduncertainty of the risk.

Write the RiskAssessment.

Recommends changes toRM questions.

Risk Managers Risk Assessors


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Risk Assessments

Regulatory PolicyRisk Assessment: (e.g.,Biotechnology RA to determine the need for riskmanagement regulation.)

Applied Risk Assessment: To determinecompliance with a regulation or policy.

Safety Assessments: Highly defined riskcalculations. Usually under a bright line safetypolicy.


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Safety vs. Risk

Risk Limit

e.g., Limit exceeded

10 times in 100

Safety Limit

UnsafeSafe

e.g., Declared unsafe

Estimates of risk


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Risk Analysis in a Democracy

Risk assessmentsprovide the facts for riskanalysis.

Risk

Risk

Risk

Risk

RiskRisk

RiskRisk

Assessment

Risk

Risk

Risk

Risk

Risk

Risk

Risk

Wors

t


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Risk Analysis in a Democracy

The risk managementdecisions about whichrisks to manage are value-laden decisions.

Risk

Management

Risk

Risk

Risk

Risk

RiskRisk

Risk

Risk

Risk

Risk

Risk

Risk

Risk

Risk

Values

Costs

Wors

t

RiskM

an

ag

emen

t

Rank


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Translating Risk Analytic Paradigms

Risk Analysis

Risk Assessment

Release Assessment

Exposure Assessment

Consequence Assessment

Risk Estimation

Risk Management

Risk Communication


What can go wrong? What are the consequences?

What is the likelihood that it

would go wrong?

What can be done?

What are the trade-offs in termsof costs, benefits and risks?

What is the impact of decisions

on future RM options?

Risk Assessment

PQ Failures

Exposure Assessment


Risk Estimation


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Possible Stages of RiskAssessment for WorkPlanning


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What can go wrong? Identify hazards: events

Identify hazardous agents (chemical, biological,physical)

How severe are the potential consequences?Given the event occurs, is the consequence

catastrophic? Mildly annoying?

How likely are the events to occur? Essentially a crude risk estimate for initial prioritization

purposes.


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Exposure Assessment

Release Assessment: How much of thehazardous event occurs?

Example: Does a non-sterile event involve 1

or 10,000 vials?

Pathway analysis: If the hazardous eventoccurs, what pathways are there that expose

humans to the hazard?

Extent of exposure: If a hazardous event occurs,how many people are potentially exposed?


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GMP Failure (Release) Assessment

How frequent are the identified PQ events(hazards)?

Boundary of release? Process line, plant,warehouse, distributor?

Release rates (PQ Faults) are obtained in fault

tree assessments, empirically, historical data,

expert analyses.

Example: FMEA


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Consequence Assessment*

Given exposure to the hazardous event/agent,what is the likelihood of harm under a pre-defined endpoint?

Endpoint examples: Death Illness

Worry

OAI

*A.K.A. Dose-Response Assessment (see next slide)


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Quant i tyof contamination (non-sterility)

i.e., in bacteria counts per vial

P

roportionofex

posed

personswhobec

omeill

100%

50%

0%ED50


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Qualitative Consequence Assessment

High

Medium

LowRelativeEffect/Impact

Quantitative

relationships knownin fewcases

Low Medium High

(Exposure or Dose Metric)


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Risk Estimation

Bring together the information about

the hazard,

the extent of exposure to the hazard,

the consequences of exposures, and then

estimate the risk.

Includes a critical analysis ofuncertainty inboth the data and risk assessment models.


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Uncertainties in Risk Assessment

Knowledge Variability

Data

Parameters

Model

Temporal

Spatial

Inter-individual


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Conceptual Models for

RM in PQ Initiative


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The PQ Risk Management Problem

Diverse PQ failure (hazards) are identified.

Wide-ranging risk (= chance that exposure to thehazard will result in harm [adverse outcome]).

Wide-ranging consequences (death to worry).

Quantitative risk analysis hazard-by-hazard toovast an undertaking.

Ranking of risks for re-linking worst PQ riskswith worst health risks, etc.

How can we ob ject ively rankapples and oranges among the

potatoes and beans?


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From the Beginning

Is risk analysis for each hazard

independentlyfeasible?


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Bulb

Fails

Noelectricity

Power Plant

Fails

Power Line

Fails

GlassBroken

FilamentBroken

Connector

Corroded

VacuumLeak

Tree BreaksLine

Wind BreaksLine

Impurities Vibrations

Fault Trees for each process?


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Faults Magnified N-fold for a Simple

Manufacturing Process


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Decision Analyses for Each Hazard MultipliesComplexity!

e.g.,


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Solution? A Multifactor Approach to PQ

Risk Management Multifactor methods already exist.

Some tools (software) already developed.

Appropriately-scaled approach to

the question,

the data quality, the nature of the decision, and

the understanding of the overall process.


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State the Assumptions

E.g., assume that health risks were linked toPQ compliance risks previously, i.e., thehistorical basis of regulation.

Historically based assumption:compliance Health riskquality

Given the assumption, can GMP compliance

risk be modeled as a surrogate of health risk?


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Identify the PQ Failures (Hazards)

What can go wrong?

Top level organization of hazards:

Health | Compliance | Resources | Sociopolitical

Second level (detail) organization:

Sterility (microbial contamination)

Dose (formulation)

Toxicity (chemical contamination)

Physical hazards (physical contamination/defect)

Fine detail: risk factor event descriptors.


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Sort the Hazards/Risks by Major

Categories Start with assumptions.

State questions to be answered.

Sort under the questions. Re-sort if new patterns emerge.

For example, (next slide)


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Risk

Health Compliance Resource

Death

Chronic Illness

Acute Illness

Mental Health

VAI

OAI

Human

Inspection $

Socio-Political

Public

Industry

The Hill

Organizing a Multi-factorial Risk Model


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Risk factors for a given endpoint

Health

Death

Sterility

Lyophilization

Final Sterility

etc.

Compliance

OAI

Sterility

Lyophilization

Final Sterility

etc.


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Estimate the Prevalence

The prevalence of inspection findings for agiven type of event are initial estimates ofprobabilities necessary for risk

management modeling.

Failure analysis in plant.

Failure in compliance inspections. Human adverse events.


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For each hazard

Health

Endpoint

Probability of Occurrence

Very

Low Low Medium High

Very

High

Death Medium Medium High High High

Chronic

IllnessLow Medium Medium High High

Acute

IllnessLow Low Medium Medium High

Worry Low Low Low Medium Medium


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The modelers view (for example)

Health

Endpoint


Very

Low Low Medium High

Very

High

Death 5 4 3 2 1

Chronic

Illness6 5 4 3 2

Acute

Illness7 6 5 4 3

Worry 8 7 6 5 4


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For each hazard

Compliance

Endpoint

Prior History of Actions

Never

Violations

Few

Viol.

Average

Viol.

Some

Viol.

Many

Viol.

OAI Medium Medium High High High

VAI Low Low Medium High High

Other? Low Low Low Medium High


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Scoring, then prioritize multiple hazards

Endpo

int


Very

Lo

w Low

Medi

um

Hi

gh

Very

Hig

h

Death

Me

dium

Med

iumHigh

Hi

gh

Hig

h

Chron

icIllness

Lo

w

Med

ium

Medi

um

Hi

gh

Hig

h

AcuteIllness

Low

LowMedium

Me

dium

High

WorryLow

Low LowMediu

m

Medium

Endpoint


Very

Low Low

Medium

High

Very

High

Death

Me

dium

Medium

HighHigh

High

Chronic

Illness

Low

Medium

Medium

High

High

AcuteIllness

Low

LowMedium

Mediu

m

High

WorryLo

wLow Low

Mediu

m

Med

ium

Endpo

int


Very

Lo

w Low

Medi

um

Hi

gh

Very

Hig

h

Death

Me

dium

Med

iumHigh

Hi

gh

Hig

h

Chron

icIllness

Lo

wMed

ium

Medi

um

Hi

gh

Hig

h

Acute

Illness

Lo

wLow

Medi

um

Me

dium

Hig

h

WorryLow

Low Low

Me

dium

Medium

Endpo

int


VeryLo

w Low

Medi

um

Hi

gh

Very

Hig

h

DeathMediu

m

Medium

HighHigh

High

Chronic

Illness

Lo

wMed

ium

Medi

um

Hi

gh

Hig

h

Acute

Illness

Lo

wLow

Medi

um

Me

diu

m

Hig

h

WorryLo

wLow Low

Me

dium

Med

ium

1. PQ Fault A

2. PQ Fault T3. PQ Fault C

4. PQ Fault D

5. PQ Fault X

6. PQ Fault M

Scored and Prioritized


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Risk Ranking & Filtering Model

Health

Compliance

Other

1. PQ Fault M2. PQ Fault T

3. PQ Fault C

4. PQ Fault D

5. PQ Fault X

6. PQ Fault A

Scored and Prioritized

Under Multiple Criteria

(Risk Ranking and Filtering)


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Risk Analysis Cycle

Multi-Factorial

Risk ModelRisk Ranking

and Filtering

Work Planning

cGMP/Compliance

Inspections

Assessments

(Data Bases)

Risk ManagementRisk Assessment

Start


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Conclusions

Risk Assessment provides a process fororganizing information in support of risk-baseddecision making.

Risk assessment is one of the tools available forRisk Management, the activity in which theoptions for controlling risks are examined in lightof costs, benefits and risk trade-offs.

Multifactor Risk Ranking and filtering approachmight be robust enough to employ in the GMPInitiative.

Documents

FDA Risk Assessment Principles for the Product Quality Initiatives