Approaching Risk in Break Through

Therapy Applications

PQRI Conference September 2014

Eric Thostesen

"It is literally true that you can succeed best and quickest by helping others to succeed." - Napoleon Hill

Agenda

• Perspectives on the Hurdles FDA and Industry Face in Accelerating

CMC Sections.

• Example of How One Company Presents and Navigates risks on a

rolling timeline.

• Potential Opportunities to Apply Similar QRM Approaches to

Streamline the BT CMC Review

There's a simple reason why so many brainstorm sessions are a waste of time. The problem statement being pitched to participants is the wrong one. The Heart of Innovation Website

The Briefing Book Approach

• Outline the Topic of Interest

• Describe an Actionable Proposal for

Consideration

• Provide data and discussion in support of your

proposal having a low residual risk to the patient

with the great benefit of making the product

available.

Benefits/Limitations

• Allows for Complete

Explanations

• Helps Companies

Understand their Own

Message.

• Precipitates a meeting.

• Doesn’t Provide Visibility

to items already

completed.

• Requires a Full Review of

Other Areas.

• Iterative and Time

Consuming

• Wordy

• Non-circular, Feedback is

delayed through General

Advice Letters.

Opportunity to Apply QRM

A systematic process for the

assessment, control, communication and review of

risks to the quality of the medicinal product across the product lifecycle.

Reference ICH Q9

Product Lifecycle Stages

• FDA Validation Guide

–Stage One is Developmental and Equates to

Early and Late Stage Development

–Stage Two is Transformational Equates to

Being Ready to Launch

–Stage Three is Transitional and Equates to

Stabilizing Base Business

New Product Lifecycle – Stage Gates and

Milestones CMC # Stage Gate/Milestones Comments

1 STAGE GATE: Phase 1 Strategy (prior to NME selection)

2 TECH REVIEW: NA

3 STAGE GATE: FIH review & Phase 2a strategy Do We Have a Potential

Breakthrough ?

4A -API

4B -DP

TECH REVIEW: API Synthesis lock and DP concept lock for

phase 2b

5 STAGE GATE: Entry into Full Development •Late-Stage CMC Strategy Definition

Plan Breakthrough Review Cycle

with FDA Present Key Timelines Vs

Millstones

6A -API

6B -DP TECH REVIEW: Ph III Mfg. Readiness •Commercial TPP-CMC Lock

7 STAGE GATE: Entry into Phase 3 •Registration Batch & Process Validation Strategy

8A -API

8B –DP TECH REVIEW Registration Batch Mfg readiness •Commercial API process and DP process lock

9A -API

9B –DP TECH REVIEW Process Validation Mfg Readiness

9C Extended TECH REVIEW: Endorsement Commercial

specifications

10 STAGE GATE: Ready to File

11 TECH REVIEW: Ready to Launch

12 TECH REVIEW: Transfer of Ownership Could FDA Adopt this Mode going

form Review to OMPQ?

Typical Topics of Interest

• Leveraging Developmental and Limited

Registration Stability Data to Support Commercial

Supply.

• Limited Data Sets to Statistically Develop

Specifications

• Timing of Performance Qualification vs CMC

Submission.

• Using Comparability Protocols to Allow for Timely

Transfers, Formulation Changes and Scale-ups.

Decision Tree for access to CMC Council or Tech

Review Governance

PROJECT RISK AREA MITIGATION

Risk # Risk & Impact Owner Risk

Score Mitigation

Risk

Score

1

Only Six months stability at commercial scale or

in commercial packaging there is a risk that

new impurities or a different degradation profile

is encounter due to the effects of scale-up or

packaging material

Eric 5

See Hazard Analysis Report 1 . Accelerated

studies in the final package and developmental

trials using the same formulation and inactive

ingredients that are not reactive

3

2

Final Selection or a commercial manufacturing

site with suitable capacity to meet expended

post approval demand occurred concurrently

with Phase 3. Early clinical approval will not

allow time to complete all phases of transfer

and PQ.

Eric 9

Based on the Criticality Analysis and proposed

controls strategy resulting form development and

clinical experience, assess CCPs against the

established controls and good history with

comparative product at the chosen site. Propose

a strategy to present on PQ Batch for Filing and a

plan to provide stabilization data post approval

3

3

Insufficient data to support a process capability

based setting of the final API and Drug Product

The current data set is low and tight but

establish specifications at that level could

present unnecessary supply interruption post

launch,

Eric 5

Based on tox and pK data create interim

specifications sufficient to ensure safety and

create a Stage 2 to Stage 3 validation plan to

predefine the statistical approval to generating

control limits for purposes of monitoring process

performance

5

4 9 5

5 5 3

Stage Gate 10 – Ready to File

Stage Gate 12 Transfer of Ownership

Product Stabilization Summary Small Molecule

Metric Measure Actual Mitigation

DP performance against Cpk targets for defined

CQA's

Green: All cPK values ≧ 1.33

All in spec

Yellow: One cPK value between 1.0 - 1.33

Red: More than one cPK less than 1.33 and/or more than one cPK

< 1.0

API performance against Std. Deviation targets

for defined CQA's

Green: All cPK values ≧ 1.33

no data

Yellow: One cPK value between 1.0 - 1.33

Red: More than one cPK less than 1.33 and/or more than one cPK

< 1.0

Number of months before product expires

based on product stability

Green: expiry ≧ 24 mo.

≧ 24 Yellow: expiry < 24 and ≧ 18 mo.

Red: expiry < 18 mo.

% of API batches that have deviations related to

the product or process

Green: ≦ 5%

no data Yellow: between 5% - 8%

Red: ≧ 8%

% of DP batches that have deviations related to

the product or process

Green: ≦ 5%

green Yellow: between 5% - 8%

Red: ≧ 8%

# of deviations that are related to

understanding or knowledge transfer that

resulted in a human error

Green: ≦ 2

green Yellow: between 3 - 5

Red: ≧ 5

% Deviations per method, per assay related to

the method

Green: ≦ 1%

green Yellow: between 1% - 2%

Red: ≧ 2%

# of method deviations that are related to

understanding or knowledge transfer that

resulted in a human error

Green: ≦ 2

green Yellow: between 3 - 5

Red: ≧ 5

OTD = On time delivery

Green: ≧ 90%

yellow Yellow: between 90% - 75%

Red: ≦ 75%

First Pass Quality

Green: ≧ 90%

green Yellow: between 90% - 75%

Red: ≦ 75%

COGS

Green: under or ≦ 10% over target

green Yellow: between 10% - 20% over target

Red: ≧ 20% over target

Criticality and Risk

Relationship between risk and criticality: Risk includes severity of harm, probability of occurrence, and detectability, and therefore the level of risk can change as a result of risk management. Quality Attribute criticality is primarily based upon severity of harm and does not change as a result of risk management. Process Parameter criticality is linked to the parameter’s effect on any critical quality attribute. It is based on the probability of occurrence and detectability and therefore can change as a result of risk management. Considerations for identifying and documenting CQAs can include the: Severity of harm (safety and efficacy) before taking into account risk control and the rationale for distinguishing CQAs from other quality attributes. Link to the patient as described in the QTPP. Basis on which the CQAs have been developed (e.g., prior knowledge, scientific first principles, and experimentation). Inter-dependencies of the different CQAs.

I.7 Preliminary Hazard Analysis (PHA) PHA is a tool of analysis based on applying prior experience or knowledge of a hazard or failure to identify future hazards, hazardous situations and events that might cause harm, as well as to estimate their probability of occurrence for a given activity, facility, product, or system. The tool consists of: (1) the identification of the possibilities that the risk event happens, (2) the qualitative evaluation of the extent of possible injury or damage to health that could result, (3) A relative ranking of the hazard using a combination of severity and likelihood of occurrence, and (4) the identification of possible remedial measures

Preliminary Hazard Analysis

Preliminary Hazard Analysis

Potential Areas of Use(s)

PHA might be useful when analyzing existing systems or prioritizing hazards where

circumstances prevent a more extensive technique from being used. It can be used for product,

process and facility design as well as to evaluate the types of hazards for the general product

type, then the product class, and finally the specific product. PHA is most commonly used early

in the development of a project when there is little information on design details or operating

procedures; thus, it will often be a precursor to further studies. Typically, hazards identified in

the PHA are further assessed with other risk management tools such as those in this section.

Opportunities Going Forward

• Industry and FDA Collaborating on Best Practice

and Guidance for:

–Understanding of the Criticality to the Patient

–Understanding the Degree of Uncertainty

–Understanding The Control Strategy Moving

Forward

–Creating a Better Mechanism for Interfacing

with the Agency Post Approval

"If everyone is moving forward together,

then success takes care of itself." - Henry

Ford