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May 20, 2014
Using Statistical Innovation to Impact Regulatory Thinking
Harry Yang, Ph.D.
MedImmune, LLC
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2 04/14/2008 – 6:00pm
How Do We Influence Regulatory Thinking?
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3 04/14/2008 – 6:00pm
An Old Tried and True Method
Throw statisticians at the deep end of regulatory interactions
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4 04/14/2008 – 6:00pm
An Old Tried and True Method (Cont’d)
Throw statisticians at the deep end of regulatory interactions
– Low success rate
– Lost potential/opportunities
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5
A More Effective Approach to Influencing Regulatory Thinking
Identify opportunities
Understand our own strengths
Influence thru collaboration
Opportunities
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Three Case Examples
Acceptable limits of residual host cell DNA
Risk-based pre-filtration limits
Bridging assays as opposed to clinical studies
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Acceptable Residual DNA Limits
Biological product contains residual DNA from host cell
Residual DNA could encode or harbor oncogenes and infectious agents
Mitigate oncogenic and infective risk thru restriction on DNA amount per dose and size
WHO and FDA guidelines recommend
– Amount ≤ 10 ng/dose
– Size ≤ 200 base pairs (bp)
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Safety Factor
Safety factor (Pedan, et al., 2006)
– Number of doses taken to induce an oncogenic or infective event
.][0 UE
M
mI
OSF
i
m
Om: Amount of oncogenes to induce an eventI0: Number of oncogenes in host genomemi: Oncogene sizesM: Host genome sizeE[U]: Expected amount of residual hose DNA/dose
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Revised Safety Factor (Lewis et al., 2001)
.][* 0 UE
M
mIP
OSF
i
m
Om: Amount of oncogenes to induce an eventI0: Number of oncogenes in host genomemi: Oncogene sizesM: Host genome sizeE[U]: Expected amount of residual hose DNA/doseP: Percent of DNA with size ≥ oncogene size
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DNA Inactivation
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Relationship between Enzyme Cutting Efficiency and Median DNA Size (Yang, et al., 2010)
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Medp1
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Probability of enzyme cutting thru two adjacent nucleotides, p, and median DNA size Med satisfy
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Safety Factor Based on Probabilistic Modeling (Yang et al., 2010)
I0: Number of oncogenes in host genomemi: Oncogene sizesM: Host genome sizeMed0: Median residual DNA sizeE[U]: Expected amount of residual hose DNA/dose
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Method Comparison
Theoretically it can be shown FDA methods either over- or under- estimate safety factor (Yang, 2013)
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Risk-based Specifications
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DNA Content and Size Can Be Outside of Regulatory Limits without Compromising Safety!
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Establishing Pre-filtration Bioburden Test Limit
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EMA Guidance (2008): Notes for Guidance on Manufacture of Finished Dosage Form
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EMA Guidance (2008): Notes for Guidance on Manufacture of Finished Dosage Form
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Risk Associated with Three Different Test Schemes
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20 CFU32 CFU
63 CFU
5%
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Mitigating Risk of Larger Number of Bioburden thru Sterial Filtration
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Sterile Filtration
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FDA guidance requires that filters used for the final filtration should be validated to reproducibly remove microorganisms from a carrier solution containing bioburden of a high concentration of at least 107
CFU/cm2 of effective filter area (EFA)
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Upper Bound of Probability p0 for a CFU to Go Thru Sterile Filter (Yang, et al., 2013)
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Upper Bound of Probability of Having at least 1 CFU in Final Filtered Solution
It’s a function of batch size S, pre-filtration test volume V, and the maximum bioburden level D0 of the pre-filtration solution
By choosing the batch size, this probability can be bounded by a pre-specified small number δ.
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Maximum Batch Sizes Based on Risks and Pre-filtration Test Schemes
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25 04/14/2008 – 6:00pm
Bridging Assays as Opposed to Clinical Studies
FFA and TCID50 are different assays but both used for clinical trial material release (Yang, et al., 2006)
Theoretical mean difference
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Other Ways to Influence Regulatory Thinking
Serve on committees such as USP Statistics Expert, CMC Working Groups, Industry Consortiums
Organize joint meetings/conferences/workshops
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USP Bioassay Guidelines
Originally USP <111> and EP 5.3 <111> was split into two chapters, USP <1032> Design and
Development of Biological Assays and USP <1034> Analysis of Biological Assays
<1033> Biological Assay Validation added to the suite
“Roadmap” chapter (to include glossary)
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Parallelism Testing
Significance vs. equivalence test (Hauck et al., 2005) Feasibility of implementation (Yang et al., 2012) Method comparison based on ROC analysis (Yang and Zhang, 2012) Bayesian solution (Novick, Yang, and Peterson, 2012)
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Testing Assay Linearity
Directly testing linearity (Novick and Yang, 2013)
Testing linearity over a pre-specified range (Yang, Novick, and LeBlond, 2014)
The method is being considered to be included in a new USP chapter on statistical tools for method validation
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A Few Additional Thoughts
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Conduct Innovative Statistical Research on Regulatory Issues
Solutions based on published methods are more likely accepted by regulatory agencies
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Take a Good Statistical Lead in Resolving Regulatory Issues
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Regularly Communicate with Regulatory Authorities
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34 04/14/2008 – 6:00pm
Conduct Joint Training
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References H. Yang, S.J. Novick, and D. LeBlond. (2014). Testing linearity over a pre-specified range. Submitted.
H. Yang, N. Li and S. Chang. (2013). A risk-based approach to setting sterile filtration bioburden limits. PDA J. of Pharm. Science and Technology. Vol. 67: 601-609
D. LeBlond, C. Tan and H. Yang (2013). Confirmation of analytical method calibration linearity. May – June Issue, Pharmacopeia Forum. 39(3).
D. LeBlond, C. Tan and H. Yang. (2013). Confirmation of analytical method calibration linearity: practical application. September - October Issue. Pharmacopeia Forum
S. Novick and H. Yang. (2013). Directly testing the linearity assumption for assay validation. Journal of Chemometrics. DOI: 10.1002/cem.2500
H. Yang. Establishing acceptable limits of residual DNA (2013). PDA J. of Pharm. Sci. and Technol., March – April Issue. 67:155-163
S. Novick, H. Yang and J. Peterson. A Bayesian approach to parallelism testing (2012). Statistics in Biopharmaceutical Research. Vol. 4, Issue 4, 357-374.
H. Yang, J. Kim, L. Zhang, R. Strouse, M. Schenerman, and X. Jiang. (2012). Parallelism testing of 4-parameter logistic curves for bioassay. PDA J. of Pharm. Sci. and Technol. May-June Issue, 262-269.
H. Yang and L. Zhang. Evaluations of parallelism test methods using ROC analysis (2012). Statistics in Biopharmaceutical Research. Volume 4, Issue 2, p 162-173
H. Yang, L. Zhang and M. Galinski. (2010). A probabilistic model for risk assessment of residual host cell DNA in biological product. Vaccine 28 3308-3311
H. Yang and I. Cho. (2006) Theoretical Relationship between a Direct and Indirect Potency Assays for Biological Product of Live Virus. Proceedings of 2006 JSM.
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36 04/14/2008 – 6:00pm
Q&A