View
220
Download
5
Category
Tags:
Preview:
Citation preview
Quality Risk Assessment: a Lifecycle Approach in Evaluating Quality Attributes for Bioproducts
2009 MBSW, May 18-20
Suntara Cahya, PhD
Outline
• “Biomolecule Diversity”
• Molecule Risk Assessments
• Risk Scoring
• Relation with CQA’s
• Concluding Remarks
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 2
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
GemzarMW 300 Da
InsulinMW 5808 Da
MAbMW 150 kDa
Fusion MoleculeMW 65kDa
Molecular Size & Higher Order Structure
3
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Potential to Impact:
• Manufacturing consistency (lot-to-lot variability)
• Stability
• Toxicity
• Efficacy
• Safety
• Immunogenicity
• PK/PD
Translational Events• Splicing• Frame shifts• Intron read-through
Post-Translational Modifications• Glycosylation (N- & O-linked)
– Site occupancy– Glycan structures
• PhosphorylationChemical & Enzymatic Modifications
• Aggregation• Proteolytic clipping• Deamidation• Isomerization• Oxidation• Glycation• Pyruvylation• Pyroglutamatation
CM&C
Toxicology
Clinical
ADME
Molecular Heterogeneity
4
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Monoclonal Antibody VariantsPredominant
pyroglutamation of Gln1
Predominant loss of Lys447
Heterogeneous glycosylation of Asn297
Partial oxidation of Met252
Partial glycation of several lysines
Partial succinimide & isomerization of Asp56 (CDR)
Partial deamidation of Asn315, Asn384 & Asn389
Partial succinimide & isomerization of Asp401
Partial loss of Gln1
Incomplete disulfide
Partial cleavage at Pro329-Ser330
(2x2x2x22x2x8x2x33x2x2x2)2/2 = >1010 variants 5
Molecule Risk Assessments
• Complexity in managing the risks (Safety & Efficacy)
• Impact on control strategies
• Had historically been part of dev process– Assessments more subjective
– Opinions could vary depending on the individuals
• Motivation: More standard & objective ways of performing the risk assessment
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 6
Molecule Risk Assessments
• Motivation cont’d• Consistent approach that works for multiple molecules
(Antibodies, Fusion Proteins, Peptides)• Phase appropriate assessments• Documentations at key points during molecule
development• Consistent with ICH guidance on risk assessments
and QbD (ICH Q9 and ICH Q8)• Focused on molecule quality attributes and analytical
control strategy
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 7
Risk Components
• Broken down into three risk components
• Severity:The impact of the particular quality attribute on the pharmacological properties of the biomolecule, including toxicity, safety, efficacy, PK/PD profile, and immunogenicity
– Location of modification – is it in a region critical to molecule’s activity
– Documented evidence of impact
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 8
Risk Components
• Detectability:The capability of the analytical methods to detect and quantify the particular quality attribute (i.e., specific vs. non-specific method) as well as the use of the method in the analytical control strategy (i.e., routine vs. non-routine method)
– Routine method developed– Non-routine developed
– Attribute is not currently monitored
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 9
Risk Components
• Occurrence:The likelihood of the particular quality attribute to exceed a specified level of concern (“Exposure Limit”), based upon API and drug product manufacturing process variability as well as the stability of the API and drug product throughout their respective shelf-lives
– Stage of development– Platform modification– Data that is available– Growth on stability
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 10
Risk Scoring
• Each risk component has different levels of risk scoring
• Overall risk scored based on Risk Priority Number (RPN) = Severity X Occurrence X Detectability
• Flowcharts to facilitate scoring evaluation
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 11
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Risk Assessment Flow Chart - Severity
12
Documented Negative Impact on toxicity, safety,
efficacy, PK, PD or immunogenicity?
Quality Attribute or Modification
Located in region likely to impact activity (e.g.
CDR)?
Impact on in vitro bioactivity OR Impact on
in vivo toxicity, safety, efficacy, PK, PD or immunogenicity?
1
No
Yes
9
Yes
Platform Modification?
Impact on in vitro Bioactivity?
No
Yes
Yes or Unknown
Yes
No
No
No
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Detectability
“1”: Modification is detected and accurately quantified by a specific, routine test method
OR
Modification is detected by a non-specific, routine test method AND accurately quantified by a specific, non-routine test method,
“3”: Modification is detected by a non-specific, routine method
OR
Modification is detected and accurately quantified by a specific, non-routine test method
“9”: Appropriate methods are not currently available or used for detection and accurate quantification of the modification.
13
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Occurrence – Part 1
14
SPM Gate?
C1 or afterPre C1
Measurable or Expected Growth at Long-Term Storage Condition?
No
Yes
QualitativeNon-Stability
Qualitative Stability
Quantitative
Quality Attribute
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Occurrence – Qualitative Non-Stability
15
Is Modification or Impurity Common to Molecule
Platform OR Present at < 1.0%?
QualitativeNon-Stability
Are Levels at Release
Comparable to Similar Platform Molecules
(OR is Modif. Present at < 1.0%)?
Y to Either Question
P score = 1
P score = 1NAre Data for
Other Clinical/Tox Lots of the Product
Available?
P score = 7
N*Are Initial Levels Consistent or Below Previous Clinical/Tox
Lots (or below)?
Y
Y
*consider process & method variability
N to Both Questions
Y to Either Question
Y
NP score = 7
P score = 7N
P score = 4
Are Data for Other Clinical/Tox Lots Available? OrRelevant Literature
Refs?
*Are Levels at Release Consistent w/ Previous Clinical/Tox Lots (or below)?
Y
*consider process & method variability
N to Both Questions
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Occurrence – Qualitative Stability
16
Can an Appropriate Molecule-Specific Exposure Limit Be Established for the
QA?
Qualitative Stability
Is Modification Common to Molecule
Platform?
Is Growth Rate Similar to (or less than)
Platform Molecules?
Establish P score on a case-by-case basis
N
Y
P score = 7
N
P score = 1Y
Clinical/Tox Experience w/ Modification at Levels
Consistent w/ “Aged” Material (or below)?
YP score = 1
N
Is There Risk of Exceeding
Exposure Limit at End ofShelf-life?
Y
P score = 9
Y
Don’t Know
P score = 7
N
P score = 1
N
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Occurrence – Quantitative
Quantitative
Measurable Growth at Long-Term Storage Condition?
How Much Representative Lot Data is Available?
0 < N < 6 N > 6
Note: Limits used in the k-factor calculation should be representative of anticipated commercial specifications. Early-phase limits that are too wide relative to the commercial specs will result in k-factors that are artificially high (and corresponding P scores that are artificially low).
Growth = 0Growth =
Rate per month x shelf-life (months)
N Y
Calculate the mean & stdev from the n lots for one-sided upper limit:
stdev
growth mean limitk
UU )(
for one-sided lower limit:
stdev
limitgrowth meank
LL
)(
For two-sided limits ),min(, LULU kkk where:
life-shelf month per %
limitlower
limitupper
growth
limit
limitL
U
if k ≤ 5 score = 9 5 < k ≤ 7 score = 4 k > 7 score = 1
Calculate the max and/or min of the n lots for one-sided upper limit:
ettlimit
growthmaxlimitk
U
UU
arg
for one-sided lower limit:
L
LL
limittarget
limitgrowthmink
for two-sided limits: ),min(, LULU kkk where:
life-shelf month per %
monomerfor 100% relsubs,for 0% e.g.
valuesor target nominal arget
limitlower
limitupper
growth
T
limit
limitL
U
if k ≤ 0.5 score = 9 0.5 < k ≤ .8 score = 4 k > 0.8 score = 1
17
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
k = 0.5
k = 0.8
Occurrence – Quantitative n<6
nominallimit
growthmaxlimitk
U
UU
Init Shelf-life
LimitU
“Nominal”
xxx
Growth over shelf-life
nominallimitU
growthmaxlimitU
k ≤ 0.5 score = 9 0.5 < k ≤ .8 score = 4 k > 0.8 score = 1
18
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Occurrence – Quantitative n≥6
Init Shelf-life
LimitU
xxx
xxx
Growth over shelf-life
stdev
growth mean limitk
UU )(
k ≤ 5 score = 9 5 < k ≤ 7 score = 4 k > 7 score = 1
k-sigma Cpk3 1349.9 / million 1.04 31.7 / million 1.35 0.3 / million 1.76 0.987 / billion 2.07 0.001 / billion 2.3
P (exceed limit)
19
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
RPN ScoringRPN = Severity x Occurrence x Detectability
Overall risk: High• Two components are rated high• Minimum RPN = 63
Overall risk: Low• Method exists AND either severity/occurrence rated low • Highest RPN = 27
Severity Occurrence Detectability RPN9 7 1 631 7 9 639 4 3 108
Severity Occurrence Detectability RPN9 1 3 271 9 3 27
Risk Severity Occurrence Detectability
High 9 9 & 7 9
Medium 4 3
Low 1 1 1
20
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
RPN Scoring
Degree of “Harm”
Chance of
“Harm”
Occurrence DetectabilityDetectability x Occurrence 1 9
9 9 81 81 729
7 9 63 63 567
4 9 36 36 324
9 3 27 27 243
7 3 21 21 189
4 3 12 12 108
9 1 9 9 81
1 9 9 9 81
7 1 7 7 63
4 1 4 4 36
1 3 3 3 27
1 1 1 1 9
RPN Scores Severity
21
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Relation with CQA’s
• Tool to assess criticality of molecule attributes and identify potential CQA’s
• List of potential CQA’s are broader than just molecule modifications
• Some quality attributes are likely to always be “critical” due to their known potential to impact patient safety and product efficacy.
• Examples Include: Host Cell Proteins, DNA, Endotoxin, Bioburden, Sterility, Viruses, Content/Protein Concentration, etc
22
Concluding Remarks
• Risk Mitigations• Gaining additional information (more data: literature, in-vivo,
additional lots, etc)
• Better detection methods
• Improved mfg process (level and/or variability)
• Improved analytical method precision
• “Exposure limit” vs Specification limit• Commercial specifications has been historically set based on
process capability, may be tighter than the exposure limit
• May re-assess the occurrence risk risk of OOS
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 23
Concluding Remarks
• “Lifecycle” approach• Deliverables at gate reviews throughout development cycle
• Documentations at key gate reviews
• Guidance on roles and responsibilities: RACI diagram
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 24
Summary
• The approach provides the basic framework to perform risk assessment of biomolecules
• Consistency and objectivity across molecules
• Phase appropriate evaluations
• Continual revisions are expected as more experience is gained overtime
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company 25
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Risk Assessment Team
Mike DeFelippis
Bryan Harmon
Cathy Srebalus Barnes
Sarah Demmon
Suntara Cahya
26
Suntara Cahya, 2009 MBSW Company Confidential Copyright © 2009 Eli Lilly and Company
Acknowledgments
Susan Janes Matt Hilton
Melody Gossage Bruce Meiklejohn
Juliana Kretsinger Jill Olinger
Mandy Dorsey Owen Van Cauwenberghe
Jeff Schwartzenhauer Kristi Griffiths
Kamal Egodage Gary Sullivan
Sacha Storms
Chi Nguyen
Agatha Feltus
27
Recommended