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Assigning Potency to Reference Standards Matthew Borer, Ph.D. Corporate Reference Standards Advisor, Analytical Sciences Eli Lilly and Company
CMC Strategy Forum - Summer 2013: Reference Standards for Therapeutic Proteins - Current Regulatory and Scientific Best Practices and Remaining Needs July 15 – 16, 2013 Gaithersburg, Maryland USA
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 2
Terminology
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 3
Inconsistent Nomenclature
Certified Property Value (ISO)
Calculation Value (USP)
Assigned Content (PhEur)
Defined Potency (Lilly)
(JP)
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 4
Expression of Certified Properties
Attribute
• Main Peak (Free)
• Main Peak (Compound + Salt)
• Total Enantiomers
• Total Isomers
• Identity
• Bioactivity
• Monomer
• Total Protein Content
Basis
• Weight Percent
– As Is
– As Is (after defined equilibration)
– As Is (with exposure limits)
– Anhydrous (corrected for water at time of use)
– Dried (specified conditions)
– Volatile Free
• Solution Concentration
– mg/ml
• Per Vial Basis
– Milligrams
– Units
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 5
Reference Standard Intended Use
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 6
Regulations: Characterization
Reference standard characterization must be customized to support its specific intended use
ICH Q3a, IV • Reference standards used in the analytical procedures for control of impurities should
be evaluated and characterized according to their intended uses.
WHO, Annex 3, Technical Report Number 885,3. • It is necessary to consider all data obtained from testing the material by a wide variety
of analytical methods. When taken as a whole, this will ensure that the substance is suitable for its intended use. The extent of the analyses required depends on the purpose(s) for which the chemical reference substance is to be employed, and may involve a number of independent laboratories.
ISO 34, 4.1.1 • It should be recognized that a reference material needs to be characterized mainly to
the level of accuracy required for its intended purpose…
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 7
Certified Property Value: A Key Expression of Intended Use
68.4% LY123456 on an "as is" basis. 99.9% compound LY123456 Dimesylate on an "as is" basis.
84.9% LY456789 on an anhydrous basis when corrected for KF titration at time of use
1394 units of activity per mg when dried at 60 C for 3 hours under vacuum (20-25 mm Hg)
3.80 mg itsamab main peak per vial for HPLC assay; 3.95 International Units per vial for biopotency assay; 2.99 mg total protein per vial for non-specific analysis. DO NOT WEIGH; reconstitute entire vial contents.
2.0 mg total protein per mL. 100% potency for bioassay.
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 8
High-Level Approaches for Determination of Property
Values
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 9
Determining Certified Properties
Mass Balance • Weight based
• Total protein based
Comparative Assay • HPLC
• UV
• Bioassay
“Absolute” Measures • Titration
• Thermal Methods
• NMR
• UV Extinction Coefficient
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 10
Chaining by Comparison to Previous Reference Standard
Chaining can lead to a drift in assignment
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 11
Assign Chemical Content: Independent Means
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 12
Assign By Comparison to a Primary Reference Standard
The range of relative potencies depends on the overall uncertainty in the reference standard property value
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 13
Desired Situation
No measurable shift between RS batches
Example: Reporter Gene Assay for a mAb
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 14
Reference Standard Transition
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 15
Specific Property Value Assignment Strategies: Monoclonal Antibodies
Potency Assignment Strategy: Initial Batch
First Laboratory RS is assigned a value of 100% Relative Potency (RP)
• Subsequent Laboratory RS batches are assigned relative to the previous Laboratory RS
The Primary RS is assigned a value of 100% RP • Confirmation of a dose response relationship
• For-information-only Bioassay comparison to Laboratory RS
– more extensive for IgG1 mAbs due to greater potential for potency change
• Extensive physicochemical comparability testing to Laboratory RS
The initial Secondary RS is based on the same characterization tests as the Primary RS (same source material)
• A subsequent Secondary RS is assigned a value of 100% RP if the bioassay versus the Primary RS is within a pre-defined window
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 16
Laboratory RS
Primary RS
Secondary RS
Potency Assignment Strategy: Replacement Batch
Analyzed by the biological assay using 5 independent measurements relative to the previous RS
If the average relative potency is within 80-120% RP, the new reference standard will be assigned a value of 100% RP
If the average potency falls outside of the interval, an investigation is conducted.
• Question the suitability of the material
• Consider a larger number of replicate measurements in order to assign the RP directly to the previous standard
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 17
Laboratory RS
Potency Assignment Strategy: Replacement Batch
Analyzed by the biological assay using 10 independent measurements relative to the Primary RS
If the average relative potency is within 95-105% RP, the new reference standard will be assigned a value of 100% RP
If the average potency falls outside of the interval, an investigation is conducted
• Question the suitability of the material
• Consider a larger number of replicate measurements in order to assign the RP directly to the previous standard
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 18
Secondary RS
Sample Size Determination
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 19
Sample size determination
S an estimate of the intermediate precision of the method performed as written
a the desired level of confidence for the computed confidence interval, e.g. if 95% confidence is desired, then a=0.05 , calculated as ((100-95)/100)
w the desired half-width of the confidence interval for the reference standard defined potency (expressed as a percent of the defined potency)
g the probability that the confidence interval half-width is greater than w (expressed as the decimal equivalent of the percent probability)
For most situations, a=0.05, g=0.10 .
Then choose the smallest n that meets the criteria ag
1,1,1
2
1,1
2
1 nn Fw
snn
where 2
1,1 g n is the upper one-sided (1-g) percentile of a chi-square
distribution with (n-1) degrees of freedom
a 1,1,1 nF is the upper one-sided (1-a) percentile of an F-distribution
with 1 numerator degree of freedom and (n-1) denominator
degrees of freedom
Source: Kupper, Lawrence L., Hafner, Kerry B., “How Appropriate Are Popular Sample Size
Formulas?”, The American Statistician, 43(2), May 1989, pp. 101-105.
Sample Size Calculation
s = 10.0%, estimated intermediate precision of the
Bioassay method
a = 0.05, desired level of confidence for the confidence
interval (95% CI)
w = 20.0%, desired half-width of the confidence interval
for the Reference Standard Potency (80% - 120%)
g = 0.10, probability that the confidence interval half-
width is greater than w (10% chance of being out)
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 20
ag
1,1,1
2
1,1
2
1 nn Fw
snn …is true at n = 5
Independent Measurement Defined
Independent Measurement - In General • An average reported result based on a replication strategy that
encompasses appropriate variance components associated with the measurement
Independent
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 21
Independent Measurement for Bioassay
• Three plates
• Three replicates at each dose level for each:
• Sample
• Standard
• Control sample
Why Assign 100% Instead of the Comparative Test Result?
Avoids drift due to chaining
Useful when a material can be assumed to be stable – extensive measures have been taken to assure stability
• In this situation, departures from 100% potency are more likely to represent method variability.
Useful in situations where the reference standard is sourced from a validated process
Assumes that method variability is greater than material variability
Comparative assay is still done, so changes will be detected M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 22
Conclusions
Terminology differences exist – propose use of “Certified Property Value”
The Certified Property Value must be specifically designated on the CoA and must tie directly to the intended use
A Primary Reference Standard must be established prior to pivotal clinical studies to serve as the line-of-sight to the original clinical experience
It is not necessary to directly assign property values using comparative results as long as the assigned value maintains the most consistent measurement of potency
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 23
Thanks To:
Kimberley B. Dancheck
Kristi L. Griffiths
Bryan J. Harmon
Jerry J. Lewis
David L. Lytle
Jerry Zhirui Lian
Bhavin S. Parekh
13-May-2011, M. Borer, et al. © 2011 Eli Lilly and Company 24
M. Borer, CASSS CMC Strategy Forum - July 2013
Copyright © 2013 Eli Lilly and Company 25
Thank you!