A Business Case for Quality by Design · • Understanding potential value of QbD lifecycle regulatory strategies • Guidance for filings: All files will include some QbD elements

A Business Case for Quality by Design

Duane Bonam

CMC Strategy Forum Europe – 2013

Outline

• Overview of Amgen’s approach to QbD development

• Synthesizing new QbD tools into a comprehensive control strategy

• Using control strategy to guide efficient development

• Lessons learned along the way

• Terminology

2 CMC Strategy Forum Europe 2013

Objective: efficiently and reliably deliver high quality products to patients

Production Process

Procedural controls (process design, facility, equipment and operational controls)

Input controls (raw materials and

components)

In-process testing (IPCs, process monitoring, validation)

End product testing (specifications, comparability, stability)

Rapid development of quality products and high reliability

processes requires efficient resource utilization and consistent

approaches and tools

QbD provides a consistent framework

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CMC Strategy Forum Europe 2013

Amgen’s QbD activities were focused into three areas

Molecule/Product

• Apply QbD principals to molecule selection and development • Identify, understand and justify PQAs / CQAs

• Understand impact of molecule attributes on pharmacokinetics, potency and safety

• Up-front investment in molecule selection can pay dividends

Process

• Utilize QbD concepts to design processes which control quality targets

• Risk assessments, process understanding, design space, control strategy

Note: a risk-prioritized, DOE approach to PC was already established, and therefore was not

explicitly considered part of the QbD program; many other companies consider this as a

new and novel element of QbD

Regulatory

• Understanding potential value of QbD lifecycle regulatory strategies

• Guidance for filings: All files will include some QbD elements • Information and documentation requirements, integration of QbD elements

QbD tools and concepts are now embedded into existing

commercialization processes, programs and Quality Systems

4

Molecule assessment ensures development with the end in mind

• Clinical performance and manufacturability, stability, etc. are all considered in lead molecule selection

• Facilitates process and product development

• Ability to meet FIH targets and adhere to platform

• Ensure productivity and robustness to meet future commercial demand

• Competitive target product profile

5

A molecule assessment tool-kit is used for lead molecule selection (examples) Study Objective

Sequence analysis &

Protein engineering

• Identify labile residues

• Design out undesirable product quality attributes

Fit to Process

Platform

• Ensure adequate productivity

• Ensure fit to commercial facilities

• Compatibility with platform formulation(s)

Biochemical

characterization &

In-process Stability

• Post-translational modifications, truncations,

product heterogeneity

• Assess short term stability in process streams

Degradation specific

screens (as needed)

• Evaluate degradation rate on identified hot-spots

• Design out chemical modification sites

pH jump,

Concentration &

viscosity screen

• Assessment of precipitation upon injection

• Solubility evaluation

• Select low viscosity molecules to enable high

concentration dosage forms

Up-front investment avoids problems and streamlines development

6

An effective control strategy is a regulatory expectation and good business practice

• Guidance documents set expectations

• Defined in ICH Q10 “A planned set of controls, derived from current product and process understanding, that assures process performance and product quality . . . ”

• ICH Q11: “Every drug substance manufacturing process . . . has an associated control strategy”

• ICH Q10: “Use quality risk management to establish the control strategy”

• Sound control strategies are good business practice

• Ensure quality of our products

• Provide focus for development and improvement efforts


QbD elements feed into a comprehensive, integrated and

effective control strategy

Risk assessments help drive effective prioritization and consistent outcomes

8

• Uses of risk assessment:

• Prioritization of process development/characterization activities

• Identify method development/remediation needs

• Control strategy development and refinement

• Documentation of control strategy justification and rationale

• Assessment of changes and mitigation strategies

A leaner and more focused development program

speeds up development while focusing on quality outcomes


9

Product quality risk assessment (PQRA) evaluates overall risk to patient

• Product Quality Risk Assessment

• Considers all known Product Quality Attributes

• Includes all steps leading up to administration to the patient

• Evaluates risk inherent in process design and test plan (i.e. the Control Strategy)

• Risk assessment inputs:

• Comprehensive understanding of quality attributes [Severity]

• Understanding of process impact on quality attributes [Occurrence]

• Testing strategy/method capability [Detection]

Risk Overall

PQA

Criticality

Severity

Process

Capability

Occurrence

Testing

Strategy

Detection

, ,


Product quality attribute (PQA) assessment determines criticality (severity)

Product

Quality

Attributes

Criticality Less More

PQA Package

(version x.x)

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• Comprehensive assessment

of all known quality attributes

• Foundation is systematic

scientific evaluation of

product attributes

• Severity scoring is based on

safety and efficacy for

product, platform and prior

knowledge

• Effective knowledge

management is key for state-

of-the-art assessments


Scoring of occurrence is aligned with QbD concepts

• Occurrence scoring decision tree

• Score reflects probability of attribute falling outside acceptable range

• Higher score if excursion likely and/or if no downstream redundancy / clearance capability

11


Scoring of detection is aligned with QbD concepts

• Detection scoring combines two concepts

• Method capability considers limit of quantitation, precision, specificity and orthogonality

• Control stringency accounts for frequency of testing and limits applied

12

Me

tho

d C

ap

ab

ilit

y (

n)

Control Stringency (i)

Detection score = f(i,n)


Detection scoring takes into account method capability and control stringency

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Detection Scoring

Control Stringency

Routine testing with reject limits

i=1

Routine testing with action limits

i=3

Routine monitoring

i=5

Periodic testing

i=7

Characterization

i=9

Qualitative n=9 5 6 7 8 9

Low precision, quantitative n=7 4 5 6 7 8

Not orthogonal, non-specific, precise n=5

3 4 5 6 7

Orthogonal, non-specific, precise n=3

2 3 4 5 6

Specific, precise n=1 1 2 3 4 5

Meth

od

C

ap

ab

ilit

y


Severity and Occurrence scores define a Preliminary Hazard Risk Level

• Highlights areas of process risk

• Inform process development and characterization

• Inform risk-based testing strategy

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Insignificant Minor Moderate Major Severe

1 3 5 7 9

Frequent 9 Medium Medium High High High

Likely 7 Low Medium High High High

Occasional 5 Low Medium Medium High High

Unlikely 3 Low Low Medium Medium High

Remote 1 Low Low Low Low Medium

Severity of Risk

Lik

elih

oo

d o

f

Oc

cu

rre

nc

e

Table 1


Detection and Preliminary Hazard are combined to determine Overall Risk Level

• Overall risk considers our ability to detect and control deviations to prevent impact to patients

15

Almost

Certain

Very High High Moderately

High

Moderate Slight Remote Very

Remote

Absolutely

Uncertain

1 2 3 4 5 6 7 8 9

High Low Medium Medium Medium High High High High High

Medium Low Low Low Low Medium Medium High High High

Low Low Low Low Low Low Low Medium Medium Medium

Detection

Ris

k C

las

sif

ica

tio

n

(fro

m T

ab

le 1

)


Example: CPD (process design) risk assessment identifies high risks

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Potential mitigation

actions:

• Characterize/

improve process

capability

(occurrence)

• Add action/

investigation limit

(detection

stringency)

• Improve method

specificity

(detection

capability)

• Establish clinical

relevance

(severity)


Example: control strategy refined following process characterization

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• Highly capable

process

• Periodic

comparability

testing to assess

process/site

changes


QbD-based processes are integrated throughout

development to support control strategy development

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• Product Quality Risk Assessment (PQRA) captures the control strategy; is revised

throughout development

• Defines key/critical testing points for Process Performance Qualification, comparability, in-process

controls, specification

• Establishes rationale for Justification of Specs, IPCs, and Continued Process Verification

Pre-clinical Phase 1 Phase 2 Phase 3 Filing Launch/

Post-Launch

Lifecycle

Management

Commercial Process Development (CPD)

Process

Characterization Continued Process

Verification

Process

Qualification

PQRA

Assessment

PQA

Assessment

PQRA

Assessment

PQA

Assessment

PQRA

Assessment

PQA

Assessment

PQA

Assessment

Raw Material

Assessment

Raw Material

Assessment Raw Material

Assessment

Prior Knowledge

Process

Understanding

Product

Understanding

Process

Optimization DOEs

(Risk prioritized)

Mutivariate DOEs &

Process Linkage Studies

(Risk prioritized)


PQRAs have provided value to teams

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• More focused process and method development

• Prioritized process development/characterization activities

• Streamlined identification of sample types for method development / remediation / qualification

• Improved technology transfer

• Identified gaps in process/product understanding

• More focused discussions (internal and with third party partners)

• Improved control strategy development

• Refined comparability test plan

• Reduced cost of quality by eliminating redundant, non-value added testing


Some Lessons Learned

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Definitions matter, and ICH terms are not always sufficient

• Criticality is a continuum, both for product quality attributes and process parameters

• Binary differentiation is problematic (CQA/non-CQA, and CPP/non-CPP)

• ICH only defines CQA and CPP

• “non-CQA” and “non-CPP” are not ICH terms

• Intermediate category (key?) enables visibility to less critical quality attributes and process parameters – measures of consistency

• Such a category provides guidance for inclusion in submissions

Process Parameter Risk Spectrum


Critical to

quality Contributors to

consistency, useful for

process description

Low risk parameters; well

controlled or assessed prior to

use - column equilibration, flush

volumes, process times, etc

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What does “Design Space” mean? ICH provides 2 definitions

Design Space

(ICH Q8)

The multidimensional combination and interaction of input variables (e.g., material attributes) and process

parameters that have been demonstrated to provide assurance of quality. Working within the design

space is not considered as a change. Movement out of the design space is considered to be a change

and would normally initiate a regulatory post approval change process. Design space is proposed by the

applicant and is subject to regulatory assessment and approval.

Design Space

(ICH Q10)


parameters that have been demonstrated to provide assurance of quality.

Note that this Q10 definition is a subset of Q8

Q10 definition (identical to first part of Q8 definition) is a useful scientific concept.

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What does “Design Space” mean? ICH provides 2 definitions

Design Space

(ICH Q8)


parameters that have been demonstrated to provide assurance of quality. Working within the design

space is not considered as a change. Movement out of the design space is considered to be a change

and would normally initiate a regulatory post approval change process. Design space is proposed by the

applicant and is subject to regulatory assessment and approval.

Design Space

(ICH Q10)


parameters that have been demonstrated to provide assurance of quality.

Note that this Q10 definition is a subset of Q8

Q10 definition (identical to first part of Q8 definition) is a useful scientific concept.

But, Q8 definition also states that design space “is subject to regulatory assessment and

approval” and that “Working within the design space is not considered as a change”.

Because of this, “Design Space” must also be viewed as a regulatory term.

Result is that agencies now have increased expectations for the rigor of DS justification and

for clarifying how you control and assess movement within DS

To avoid confusion, term is used at Amgen only if the intent is to file and seek

approval of a specific design space

Conclusions

• QbD provides a consistent framework for efficient product understanding, process development and control, and communication of an integrated control strategy

• QbD tools have developed over time and are now an integral part of the business processes and Quality systems

• Use of a QbD approach does not require a QbD/design space filing

• Certain QbD elements are now becoming “core” expectations and will be included in all filings


Acknowledgements

• Gregg Nyberg

• Bob Kuhn

• Amgen QbD team

• CASSS and conference organizers


Documents

A Business Case for Quality by Design · • Understanding potential value of QbD lifecycle regulatory strategies • Guidance for filings: All files will include some QbD elements