implementing risk assessment tools for identifying ... · efficient study designs that are...

CMC Strategy Forum, Jan 11, 2009

Company ConfidentialCopyright © 2000 Eli Lilly and Company

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Implementing Risk Assessment Tools for Identifying Critical Raw

Material Attributes

Gregory M. Beck, Ph.D.Research AdvisorBioproduct Research and Development

CMC Strategy ForumRaw Material Control Strategies for BioprocessesJanuary 11, 2009



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Background ..the manufacture of a biological product of defined quality relies on thorough description, characterization, and testing that begins with source materials, reagents, ingredients and components used throughout the manufacturing process. (Dr Fink, CBER)

The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials. (ICH Q10)

Material Supply API DPRaws

SpecificationsPATControl Strategy

Validation

PatientSafe

Effective

CQAIdentityPurity

Potency

cGMPs



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Issue:

• Identifies and ranks risk components for raw materials

• Allows for platform specific raw material control strategies

• Information to streamline change control, deviation resolution and regulatory management

Need for a risk-based, phase appropriate means to define critical quality attributes for raw materials.

A process that:



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Bioprocessing Activities and Raw Materials

BuffersMedia and feedsAmino acidsElectrolytesMetabolic componentsProcessing aids

BuffersChromatographic resinsElectrolytesViral inactivation additivesAPI stability enhancers



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Raw Material Control IssuesWhat attributes of the raw materials are important to the final biological product?

• When do we invest in characterizing the materials?• What properties are critical to control for both the user and supplier?

How do we identify information requirements and criteria for efficient study designs that are meaningful for both developmentand commercial manufacturing?

• What raw material characteristics are important to evaluate when the biological product process is modified?

• What characteristics are important to evaluate when the raw material process is modified?

How do we share information between development projects and the eventual commercial manufacturing sites?

• How do we capture and use risk assessments?



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Quality Risk Management Approach(ICH Q9)

Risk Review

Risk Assessment

Risk Evaluation

unac

cept

able

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

InitiateQuality Risk Management Process

Output / Result of theQuality Risk Management Process

Risk M

anagement Tools

Ris

k C

omm

unic

atio

n

Identification: Gather Information about process and raw materials

Analyze Raw Material Risks/Establish Risk Level

Evaluate Raw Materials withHigh Level Risks



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Raw Material Information –Risk Assessment

1. Potential to impact the drug substance quality2. Ability to introduce bioburden, endotoxins, or viral

contaminants (Adventitious Agent Assessment Strategy).3. Historical knowledge of the raw material 4. Raw material molecular complexity5. Safety and handling6. Vendor experience7. Custom raw materials8. Area of use in the process 9. Is the raw material primarily manufactured for the

pharmaceutical industry?



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Raw Material Risk Assessment Tool

1. Pote

ntial

to im

pact

the

drug s

ubsta

nce q

uality

2. Abil

ity of

RM to

intro

duce

biobu

rden,

endo

toxins

, vira

l

conta

minants

3.

Known I

ssue

s with

RM

(i.e. p

eroxid

es in

Tween)

4. Mole

cular

Com

plexit

y

5. Pote

ntial

to Im

pact

Proces

s Perf

orman

ce

6. Exp

erien

ce w

ith Ven

dor

7. Cus

tom R

aw M

ateria

ls

8. Im

pact

on pr

oduc

t relat

ed

to are

a of u

se9.

Mfg

for ph

arma i

ndus

try

Combined Rati

ng

Risk Element Weighting 5 5 5 3 3 2 2 2 1

Description VendorIntended

UseReasons for ranking risk

Buffer A 1 1 1 1 1 1 1 5 1 36Buffer B 1 1 1 1 1 1 1 5 3 38Acid 1 1 1 1 1 1 1 5 3 38Base 1 1 1 1 1 1 1 5 3 38Electrolyte 1 1 1 1 3 1 1 5 1 42Growth additive A 3 1 1 1 5 1 1 5 1 58Growth additive B 3 3 1 3 1 1 1 5 1 62Growth additive C 3 3 3 1 3 1 1 5 3 74Growth additive D 5 1 1 1 1 1 1 5 1 56Cell culture media 5 5 1 5 1 1 5 5 1 96Cell culture feed 5 5 1 5 5 1 5 5 1 108

Purification

Cell Culture

Final API



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Comparison between products

Raw

Materia

ls

Molecule

Candidate

AMolec

ule

Candidate

BDescription<buffer A> 40 36<buffer B> 38 38<buffer C> 44 38<acid> 38 38<base> 38 38<electrolyte - A> 42 42<electrolyte - B> 42 42Cell culture feed 74growth additive - A 68 62growth additive - B 42 56growth additive - C 64Cell culture media - A 96 96Cell culture media - B 108 108Cell culture media - C 108 108Cell culture media - D 108 108Process additive - A 100Process additive - B 64Process additive - C 58

Cell Culture



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Benefits of Raw Material Assessment

• Consistency in assessment approaches

• Leadership understands level of risk between products and processes

• Information leading to meaningful development study designs

• Align discussions and expectations between development groups

• Cost savings in Development’s time

• Alignment of development process with QbD guidance



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Raw Material Risk Assessment’s Role in Product Development

Ref: Guillermo Miroquesada, (Eli Lilly)



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Quality Risk Management Approach(ICH Q9)

Risk Review

Risk Assessment

Risk Evaluation

unac

cept

able

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

InitiateQuality Risk Management Process

Output / Result of theQuality Risk Management Process

Risk M

anagement Tools

Ris

k C

omm

unic

atio

n

Identification: Gather Information about process and raw materials

Analyze Raw Material Risks/Establish Risk Level

Evaluate Raw Materials withHigh Level Risks

Propose Mitigation/Control Plans



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Example: Cell Culture MediaBioprocess and Analytical Needs:• Consistent desired quality • Appropriate stability• Fits development platform with acceptable

product yield• Understanding of how media quality impacts the

pharmaceutical product

Raw M

ateria

ls

Produc

t qua

litybio

burde

n, en

dotox

ins, v

iral

conta

minants

Prior h

istory

Molecu

lar co

mplexit

y

Safety

and h

andli

ng

Compa

ny E

xperi

ence

with V

endo

r

Custom

Raw

Materia

ls Area

of us

eMfg

for ph

arma

indus

try

Combined R

ating

Description VendorCell culture media - A 5 5 1 5 1 1 5 5 1 87Cell culture media - B 5 5 1 5 5 1 5 5 1 95Cell culture media - C 5 5 1 5 5 1 5 5 1 95Cell culture media - D 5 5 1 5 5 1 5 5 1 95

Cell Culture



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C2 to C3Before C0 C1 to C2C0 to C1

Evaluate Concentration of Bulk raw material in

Process Robustness Study(Level I on C&E Tool)(1)

Initial Estimate of purpose and function GM

Evaluate groups (Level II on C&E) GM

Identify Appropriate Evaluation Model

GM

RMAT GB

HIgh RMAT Score

Is Effect Acceptable? GM

Identify groups that causes unacceptable score in C&E

matrix GM

Can an analytical method to monitor

whole group be developed? GB

Group is CQA

Raw Material Control Strategy

(Baseline Tests:E.g. NIR, Growth Promotion Testing, Assay Components

before mixed?) GB

Evaluate Individual Components of Critical

Group(s) (Level III) (2) GM

Is there an analytical method to monitor component? GB

Develop Analytical Method (Lilly or Vendor)

GB

Do lot-to-lot variability study (Ensure lots cover

range of CQA) GM

Yes

No

No

Identify component(s) that cause unacceptable score

in C&E matrix GM

Component is CQA

H

Special Cause

Experimentation SR

Yes

Update RMATDoc Intended

Use GB

Results Acceptable and Consistent with

concentration studies SR

Review model or potential impurities or other quality attributes

that changed among the lots SR

NoH

Adventitious Agent

Assessment Tool

Yes

RMATDoc Intended

Use GBLow

Newly Identified Highs

RMAT, Doc Intended use

GB

Evaluate. Include Multiple lots in

Development GM

Update RMATDoc Intended

Use GB

C

A

A

A

B

Update Preliminary

Control Strategy GB/MM

Yes

B

Low

Preliminary Control

Strategy GB/MM

Low

C

No

FTA SR

FMECA, Raws only (O x S) SR

L

pFMEA (Process + Raws)

SR

Validation Process

L

L

H

Evaluate Bulk Media

AdventitiousAgent

AssessmentTool

RMAT(low and high

risk)

Evaluate Groups

Evaluate Components

Document Results

Lot to Lot variability

Failure mode analyses

Control Strategy

IND Product Decision Registration Stability Production



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Robustness & Optimization Exampleim

purit

y

Impurity Predicted

Continuous factors centered by mean, scaled by range/2

InterceptTempD3 Feed (X)Feed (X)D9 Feed (X)pH(Seed Density (Meas)-1.29778)*(Temp-34.75)(Seed Density (Meas)-1.29778)*( Feed (X)-473.25)(Seed Density (Meas)-1.29778)*(Day of Culture-15.5)(Temp-34.75)*( Feed (X)-473.25)(D3 Feed (X)-1.4)*( Feed (X)-473.25)(D3 Feed (X)-1.4)*(D9 Feed (X)-0.6)(D3 Feed (X)-1.4)*(Day of Culture-15.5)( Feed (X)-473.25)*( Feed (X)-473.25)

Term2.440.98

-0.47-1.90-0.420.480.591.050.36

-1.301.120.41

-0.192.46

Scaled Estimate0.100.090.080.140.100.100.220.250.100.140.110.090.070.17

Std Error<.0001*<.0001*<.0001*<.0001*<.0001*<.0001*0.0100*0.0001*0.0005*<.0001*<.0001*<.0001*0.0125*<.0001*

Prob>|t|

Scaled Estimates

0

2

4

6

8

10

12

14

Rel

. im

p(p

pm) A

ctua

l

0 2 4 6 8 10 12 14Rel. imp (ppm) Predicted

P<.0001 RSq=0.98 RMSE=0.4523

1417

Day of Culture

Actual by Predicted Plot

0

4

8

12

Rel

.Impu

rity

(ppm

)1.

9978

28±0

.165

813

33.5 34

34.5 35

35.5 36

35.017Temp

.9 1.1

1.3

1.5

1.7

1.9

2.1

1.3D3 Feed (X)

-100 100

300

500

700

630

Feed (X)

-0.1 .1 .3 .5 .7 .9

0.7889D9 Feed (X)

6.7

6.75 6.8

6.85 6.9

6.95 7

6.85pH

.9 1.1

1.3

1.5

1.7

1.2911Seed Density

(Meas)

13.5

14.5

15.5

16.5

17.5

15.5Day ofCulture

Prediction Profiler



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Example: Alignment of Raw Material with Product Critical Quality Attributes

Modification Likely Source of Modification CQA Raw MaterialN-terminus Pyruvylation High

HighLowLowLowLow

High

Oxidation

Media components

Growth additiveNone

Growth additiveNone

Growth additive

Deamidation Bioreactor and purificationGlycosylation Bioreactor

Glycation Bioreactor

Resin

Free Sulfhydryl

Aggregation

Bioreactor

Bioreactor and purification

Bioreactor and purification

Purification steps and storage

Ref: Kozlowski & SwannAdvanced Drug Delivery Reviews 58 (2006) 707– 722



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Cell Culture Media:Specification Development

Baseline SpecificationsExtended Specifications (Example)

Physical Evaluation

Packaging Appearance Visual

Physical Appearance Visual

Identification Test

Spectroscopy NIR, Raman

Suitability Test

Growth Promotion Null strain

Other Tests

Endotoxin USP

Bioburden USP

Physical Evaluation

Packaging Appearance Visual

Physical Appearance Visual

Identification Test

Spectroscopy NIR, Raman

Suitability Test

Growth Promotion Null strain

Amino Acids HPLC

Lipids GC

Vitamins HPLC

Electrolyte content ICP

Other Tests

Endotoxin USP

Bioburden USP

Sterility USP



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Phase Appropriate DevelopmentQ1Q2 Q2 Q2 Q2 Q2 Q2Q3 Q3 Q3 Q3 Q3 Q3Q4Q4 Q4 Q4 Q4Q1 Q1 Q1 Q1

Registration Stability Mfg Scale Launch

Q1Q2 Q3 Q4

Pre-IND

Q1

StartAPI

CTM

Decision

• Provide list of raw materials used in process

• Quality Assurance Review• ASMs, vendor audits/qualification, etc.

• Assess raw material risk elements using RMAT• No requirement for commercial appropriateness

• Identify potential need for alternate sources of High Risk raw materials

• All raw materials in Materials and Laboratory Information Management Systems



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Phase Appropriate Development

API

CTM

API

CTM

API

CTM

Q1Q2 Q2 Q2 Q2 Q2 Q2Q3 Q3 Q3 Q3 Q3 Q3Q4Q4 Q4 Q4 Q4Q1 Q1 Q1 Q1


Q1Q2 Q3 Q4

Pre-IND

Q1

Start Decision

• Reassess raw material risk elements to incorporate knowledge from additional processing experience

• Risks incorporate commercial manufacturability

• Control strategy for High Risk raw material’s known and evaluated for suitability for current process

• Assessment of raw materials in collaboration with potential manufacturing site for suitability, availability, handling and disposal.

• Preliminary rationale for “Intended Use”



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Q1Q2 Q3 Q4

Pre-IND

Q1

StartAPI

CTM

API

CTM

API

CTM

API

CTM

Decision

Critical Quality Attributes of high risk raw materials defined using tools such as:

• Literature Review• Data Mining (e.g. previous manufacturing of this molecule)• DOE’s (including multiple lots of high risk raw materials as necessary)• Prior knowledge based on platform

Defined Process – Final list of raw materials• With rationale for “Intended Use”• Consider all potential raw materials and sources



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Phase Appropriate Development

API

API

API

CTM

CTM

CTM

API

CTM

API

CTM

API

CTM

API

CTM

API x 3

CTM x 3

Q1Q2 Q2 Q2 Q2 Q2 Q2Q3 Q3 Q3 Q3 Q3 Q3Q4Q4 Q4 Q4 Q4Q1 Q1 Q1 Q1


Q1Q2 Q3 Q4

Pre-IND

Q1

Start Decision

• Raw material specifications identified and linked to product quality attributes

• Finalize sourcing strategy with manufacturing site

• Develop vendor qualification and change management strategy

• All raw materials in Manufacturer’s Information Management Systems

• Transfer raw material analytical methods to manufacturing site

• Raw material control strategy documentation finalized



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Q1Q2 Q3 Q4

Pre-IND

Q1

StartAPI

API

API

CTM

CTM

CTM

API

CTM

API

CTM

API

CTM

API

CTM

API x 3

CTM x 3

Decision

Initial RMATPlatform knowledge

RMAT reviewSmall scale studiesHandling/storage informationQA information

Cause-Effect dataMedium scale studies

FMEA updateRaw Matl CQA’sSourcing Strategy

RISK CONTROL



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Example: Raw Material Risk Process and Impact to Change Management Functionality• Development determined risk levels (tool)

• What is predicted impact to product CQAs?

Complexity• How well is the compound known?

Magnitude of change• Process Technical Services review of changes/qualifications

• Facility/process change

• Raw material change

• New supplier



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In Summary…

In order to develop a successful manufacturing process that:

• ensures reproducible and consistent product • defined quality suitable for commercial distribution• supports complex and novel platform technologies create greater,

more varied number of product development issues

Setting up a proactive system for raw materials qualification ensures a constant supply of materials of appropriate quality and enhances the safety and consistency of a pharmaceutical product.



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Questions?

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