Quality by design and reproducible aspects. of a study on targetable polyacrylamide and ultrasound contrast agents

Transcription

1 Quality by design and reproducible aspects of a study on targetable polyacrylamide and ultrasound contrast agents 1

2 2 From Molecule to Market

3 Agenda QbD in Design, Analysis and Generalization of Statistically Designed Experiments (Ron) Background on QbD Design of experiments strategy Generalization of results for reproducibility A QbD example from targetable polyacrylamide and ultrasound contrast agents (Avri) 3

4 Agenda QbD in Design, Analysis and Generalization of Statistically Designed Experiments (Ron) Background on QbD Design of experiments strategy Generalization of results for reproducibility A QbD example from targetable polyacrylamide and ultrasound contrast agents (Avri) 4

5 ICH Q-Documents Q1 Stability Q2 Analytical Validation Q3 Impurities Q4 Pharmacopoeias Q5 Quality of Biotechnological Products Q6 Specifications Q7 Good Manufacturing Practice Q8 Pharmaceutical Development Q9 Quality Risk Management Q10 Pharmaceutical Quality Systems Quality by Design 5

6 Quality by Design (QbD) Design Space Product Understanding Quality by Design Process Understanding Control Strategy 6 Adapted from Moheb Nasr, 2005

7 Critical Quality Attributes Identify TPP Identify CQA Target Product Profile Risk assessment Define product design space Risk assessment QbD Roadmap Define process design space Define control strategy Process characterization Risk assessment Filing Process validation Process monitoring 7

8 QbD Roadmap Identify TPP 8

9 QbD Indications and Usage Dosage and Administration Dosage Forms and Strengths Contraindications Warnings and Precautions Adverse Reactions Drug Interactions Overdosage Description Identify TPP Roadmap The TPP summarizes the specific studies (both planned and completed) that will supply the evidence for each conclusion that is a labeling concept. The TPP should be organized according to key sections in the drug s labeling. Typical key sections from which a sponsor can choose, depending on the nature of the meeting, include: Use in Specific Populations Drug Abuse and Dependence Clinical Pharmacology Nonclinical Toxicology Clinical Studies References How Supplied/Storage and Handling Patient Counseling Information 9

10 10 Q8

11 Q8 The Pharmaceutical Development section provides an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management 11

12 Q8 It is important to recognize that quality cannot be tested into products; i.e. quality should be built in by design. 12

13 Design Space Q8 Multidimensional combinations of the product characteristics Interactions of inputs variables Interactions of process parameters Changes within the design space are not considered a regulatory change QbD information and conclusions need to be shared with the FDA 13

14 Design of Experiments Strategy Are Results Reproducible? Scoping Screening Optimizing Robustness Initial assessment Fractional designs Response surfaces Robust designs Gain Knowledge Build Confidence 14

15 15 Reproducible Research

16 Replicable Research E.B. Van Rest (1950), Nature, 165,

17 Reproducibility versus Replicability Proc. of the Evaluation Methods for Machine Learning Workshop at the 26 th ICML, Montreal, Canada, Reproducibility requires changes; replicability avoids them. A critical point of reproducing an experimental result is that irrelevant things are intentionally not replicated. One might say, one should replicate the result not the experiment. A highly standardized experiment supplies direct information only in respect of the narrow range of conditions achieved by standardization. Standardization, therefore, weakens rather than strengthens our ground for inferring a result, when, as is the case in practice, these conditions are somewhat varied. Ronald A. Fisher

18 Reproducibility in Animal Behavior Standardization is the attempt to increase reproducibility at the expense of external validity Standardization reduces external validity and thus also reproducibility Heterogenization increases external validity and thus also reproducibility Würbel et al Nature Genetics Richter et al Nature Methods Richter et al PLoS ONE 18

19 Information quality (InfoQ) 1. Data resolution 2. Data structure 3. Data integration 4. Temporal relevance 5. Chronology of data and goal 6. Generalizability 7. Operationalization 8. Communication InfoQ(f,X,g) = U(f(X g)) g A specific analysis goal X The available dataset f An empirical analysis method U A utility measure 19 Kenett and Shmueli, JRSS(A), 2014

20 Generalizability 20 Kenett and Shmueli, JRSS(A), 2014

21 Reproducibility of results 1. State the research goal 2. Describe the experimental set up 3. Present conclusions from experiments 4. G E N E R A L I Z E 21 Kenett and Shmueli, Nature Methods, 2015

22 Research findings Generalize with Alternative Representations Surface similarity (SS) Q1 Q3 Yes Yes Yes No No SS ME SS ME Yes No Yes No No SS ME SS ME Q2 No Q4 Yes Meaning equivalence (ME) 22 Shafrir and Kenett, 2015

23 Conceptual Representation of Research findings Surface similarity (SS) Q1 Q3 A conceptual reprsetntation generalized Yes from the research findings Yes No SS ME A concept Yesthat is different from Q1, but looks similar SS ME No Yes Alternative representations of The concept generalized No from the research findings Yes No No SS ME SS A concept different from Q1, that also looks different ME Q2 No Q4 Yes Meaning equivalence (ME) Shafrir and Kenett, 2015

24 Boundary of Meaning Q3 TS Q2 Q4 Q1 Q2 24 Shafrir and Kenett, 2015

25 Take away points Translational research involves statistical expertise in designing and analyzing experiments Quality by Design is about product understanding, process understanding and clinical understanding A Design Space maps a boundary identifying equivalent process parametrization set ups in terms of efficacy and toxicity Generalization of pre-clinical and clinical research is essential for enabling reproducible research, cross discipline knowledge transfer and accessibility of research findings to non specialized audiences A Boundary of Meaning maps alternative representations of 25 research findings in terms of meaning equivalence

26 References Kenett, R.S. and Shmueli, G. (2014) On Information Quality, Journal of the Royal Statistical Society, Series A (with discussion), 177(1), pp Kenett, R.S. and Shmueli, G. (2015) Clarifying the terminology that describes scientific reproducibility, Nature Methods, Vol. 12(8), p 699. Shafrir, U. and Kenett, R. S. (2010). Conceptual thinking and metrology concepts, Accreditation and Quality Assurance, 15(10), Shafrir, U. and Etkind, M. (2014). Concept Science: Content and Structure of Labeled Patterns in Human Experience. Version 32.0 Shafrir, U. and Kenett, R. S. (2015). Concept Science Evidence- Based MERLO Learning Analytics in Handbook of Applied 26 Learning Theory and Design in Modern Education, IGI Global.

27 Agenda QbD in Design, Analysis and Generalization of Statistically Designed Experiments (Ron) Background on QbD Design of experiments strategy Generalization of results for reproducibility A QbD example from targetable polyacrylamide and ultrasound contrast agents (Avri) 27