CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
1
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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
2
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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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:
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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Bioprocessing Activities and Raw Materials
BuffersMedia and feedsAmino acidsElectrolytesMetabolic componentsProcessing aids
BuffersChromatographic resinsElectrolytesViral inactivation additivesAPI stability enhancers
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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?
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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?
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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Raw Material Risk Assessment’s Role in Product Development
Ref: Guillermo Miroquesada, (Eli Lilly)
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
Registration Stability Mfg Scale Launch
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”
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
Registration Stability Mfg Scale Launch
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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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
CMC Strategy Forum, Jan 11, 2009
Company ConfidentialCopyright © 2000 Eli Lilly and Company
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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.