Predictability & Performance Through the Product Lifecycle Thought Provoking Perspectives

Transcription

1 Quality by Design & Clinical Relevance: Moving Forward Predictability & Performance Through the Product Lifecycle Thought Provoking Perspectives Roger Nosal 1 & Ravi Shanker 2 1 Vice President & Head Global Chemistry, Manufacturing & Controls 2 Senior Research Fellow Pharmaceutical Sciences (Biopharmaceutics) Worldwide R&D, Groton, CT (roger.nosal@pfizer.com and ravi.m.shanker@pfizer.com)

2 Contents What does clinically relevant mean? What are meaningful, in vitro specification criteria that effectively predict in vivo product performance? Influencing Factors for IVIVC & Thought Provoking Perspectives? 2

3 What Does Clinically Relevant Mean? 3

4 What is a Clinically Relevant Specification? A clinically relevant specification is composed of critical quality attributes & acceptance criteria that predictably assure patient safety & efficacy. 4

5 Clinical Performance & Quality Specification* Limits on quality attributes are often set empirically to ensure production of batches that resemble those tested in clinic for consistent clinical performance Relationship between those attributes/limits and clinical outcome is not always understood Limits could be overly wide, unnecessarily tight, or completely irrelevant to clinical performance Other critical attributes may not be identified, measured, or controlled *Janet Woodcock, American Pharmaceutical Review, March

6 Specification Criteria - Purpose Confirm safe levels of critical contaminants Known or potential toxicity; Q3 guidances Confirm released lots are similar to lots used in clinical trials Attributes relevant to safety & efficacy Confirm the manufacturing process is under control In process testing; limits; sparse sampling; PAT Clinically relevant process parameters * *Adapted from Phil Krause by Steve Poehlein, Jim Baker, Steve Kozlowski, Drug Specifications for the 21 st Century,

7 Specification Criteria & Clinical Relevance The combination of controls for all product CQAs provide assurance of quality including in vivo performance Specification criteria may be clinically relevant MEASURE OF PREDICTABILITY Link in vivo product performance to specific CQAs Opportunity for IVIVC/IVIVR* * Specification criteria may serve only as measures of product & process control RELIANCE ON MFG. CONSISTENCY No direct link to in vivo product performance Dissolution frequently provides no clinical relevance (~75%) Increased control of product physical characteristics A process control failure does not necessarily impact in vivo performance Process capability may provide a measure of product consistency Surrogate for assuring in vivo performance CPk requires significant manufacturing process experience (~30 batches) Process variability does not necessarily translate to IVIVC/IVIVR are mathematical models that quantitatively describe the relationship between in vitro dissolution data & in vivo PK that inform specifications (dissolution conditions) that are discriminating & predict impact of formulation changes on PK profiles (Cmax and AUCs) & can assist formulation optimization 7

8 Clinical Relevance & Process Robustness Demonstrate Consistency Commercial product representative of clinical product Accommodate changes to commercial product Lifecycle Confidence IVIVC/IVIVR can improve regulatory flexibility 8

9 What are Meaningful, in vitro Specification Criteria that Effectively Predict in vivo Product Performance? 9

10 Demonstrating Clinical Relevance: Factors to Consider PK/PD profile in vivo product performance Therapeutic index Patient characteristics - genotype/phenotype, demographics Dosing duration (chronic vs. acute) Bioavailability Product solubility & permeability GI Physiology Process & product variability Analytical methods can be more discerning than clinical endpoints Acceptance criteria should depend on therapeutic window Acceptance criteria set based on PK variability Multivariate analysis of product attributes & clinical measurements Product complexity &/or delivery systems vs. IR tablets Comparative analysis of clinical, animal & in vitro data Validation of therapeutic models, i.e., aerosol impactor studies, transdermal diffusion, ophthalmic irritation studies 10

11 A Clinical Perspective of in vitro Specifications Efficacy/(Safety) PD PK In Vitro Criteria Without IVIVC & PK/PD correlation, most clinical studies are not sensitive enough to detect quality deviations At best, for efficacy, an IVIVC/IVIVR must include dose-response context to ensure assay sensitivity Epidemiological studies & spontaneous reports are not necessarily definitive indicators of quality differences Exceptions for safety Heparin Procrit Peter Honig, DIA Washington, DC,

12 A Quality Perspective of in vivo Performance In vitro Criteria PK PD Efficacy/(Safety) IVIVC Design Space Serves as a primary bridge to clinical environment Must identify ADME characteristics where IVIVC approaches are unlikely to be developed Industry Experience Generally confined to IR MR switch Route of administration may determine viability One size does not fit all Inconsistent criteria for IR products Inconsistent regulatory acceptance When adopted retrospectively (pre 2012) IVIVC often non-robust Could be used to reset approved commercial product specifications Adapted from James McLeod, DIA Washington, DC,

13 Fundamental Challenges & Options Validating a model with sub-optimal, non-be product is not necessarily appropriate or aligned with requisite regulatory guidance Challenges Clinicians are reluctant to use suboptimal (non-be) material to validate IVIVC Modifying clinical protocols to establish specifications may not be feasible Costs to over-validate an IVIVC What formulation differences constitute appropriate demonstration of IVIVC? Fasted vs. Fed constraints may be arbitrary & inappropriate Challenges Variability in the fed state contributes to in vivo non-discrimination Options Challenging for drugs with significant pre-systemic clearance and/or prodrugs Use differentiating batches, e.g. fast & slow release profile to substantiate model Validate with external product test does not require non-be Options IVIVC studies should align with product design & actual use 13

14 Global Harmonization? IVIVC/IVIVR rules are different globally US prescriptive EU inconsistent Japan Not acknowledged ROW Limited acceptance 14

15 Influencing Factors for IVIVC & Thought Provoking Perspectives? 15

16 Recognition of key influencing factors Yet differing outcomes on deciding factors for quality, safety & efficacy. Solubility Opportunity to enhance decision making through stronger partnership Dissolution Permeability Solid Oral GI Physiology Science Driven Risk Based Guideline Assisted Product Specific DECISIONS C max, AUC Clinical Relevance 16

17 Key Opportunity Space Divergent Views Between Industry & Regulatory Bodies Each drug and drug product is unique and reviewed on its own merits. Necessity for general guidelines is recognized and appreciated. However, guidelines are implemented as laws rather than based on science, clinical relevance and understanding of risk specific to the drug and drug product. DECISIONS On Drug Product Quality & Performance - Clinically Relevant - Science Driven - Risk Based 17

18 Today s focus on one topic of divergent Dissolution (IR) Fundamental science of Noyes-Whitney, Nernst Bruner etc. dates back to early 19 th Century (1897..) but advances continue to occur Science, models, simulation and understanding continues to evolve but still it is not possible to accurately predict dissolution profile from first principles or from limited, fundamentally relevant experimental measurements e.g. solubility and particle size distribution. views & decision making DECISIONS On Drug Product Quality & Performance - Clinically Relevant - Science Driven - Risk Based 18

19 Biopharmaceutics Modeling is a part of Biopharmaceutics Risk Management Through Development Life Cycle Integrated, science based, development milestone based, drug product design centered, dynamic and patient focused biopharmaceutics risk management strategy Uncertainty All models are wrong but some are useful George Box Confidence What is limiting the exposure? Enabling API form to maximize exposure Formulations for FIH Food effect Enabling API Form Enabling Dosage Forms Bioequivalency between clinical dosage form versus commercial image BE risk? mitigation strategy? BE Project initiation Pre-clinical Phase I Phase II Phase III Product approval Post Launch Product Enhancement Solid dosage form (tablet) performance Filing strategy, BCS, Biopharm section of CTD SUPAC Will MR dosage form provide better efficacy/safety profile or establish PK-PD? CR dosage Form; IVIVC strategy 19

20 Case Study 1 non-ionizable, high dose drug: pre-fih effort to identify dissolution and solubility limited absorption regimes 20

21 Case Study 2 non-ionizable Class 2 drug: post marketed effort to develop product to improve patient acceptance % Dissolved Celecoxib Capsule and Tablet Formulations: relative BA Evaluation (BCS Class II Drug) Dissolution Profiles of Tablet Formulations Under Sink Conditions Oral Solution Significant difference in in vivo performance not captured by sink dissolution test Reference Capsule Wet Granulation, 60 um Dry Granulation, 120 um Time, min Dry Granulation B, 120 um Wet Granulation, 60 um Dry Granulation A, 60 um Release Target at 45 min Dry Granulation, 60 um Similar dissolution profiles for: Different particle size (60 vs 120 um) Different manufacturing process (wet vs. dry granulation) Can a more predictive test be developed? Thought Provoking Question: what is the clinical relevance of approved dissolution test? Can an alternate, predictive but non-compendium test be acceptable for routine testing? 21

22 Case Study 3 Highly Soluble Drugs (BCS Class 1 and 3): dissolution modeling, data and clinical relevance Time to 85% Dissolution (min) Impact of Particle Size Distribution and Solubility on achieving 85% in 30 min or 15 min (Dose Number = 1) 1mg (0.004mg/ml) 10mg (0.04mg/ml) 100mg (0.4mg/ml) Thought Provoking Question: Is the requirement of rapid and very rapid dissolution clinically relevant? What is its relationship 45to T max? 60 Particle size (µm) 22

23 Case Study 4 BCS Class 4 (pka 5.4, 8.9; log P 4.7 ): relevance of dissolution testing in context to BE study results Dissolution testing of 250 mg powder in capsule, tablet, formulated capsule used in BE study % Dissolved ph RPM Additional relevant information: All solid oral dosage forms BE to oral solution No significant food effect No effect of PPI on absorption 20 0 Dose number (ph 1.0) = Time (minutes) Q=80% 250 mg Tablets (BE lots) 250 mg PICs (BE lots) 250 mg Capsules (BE lot) ph RPM % Dissolved 60 Thought Provoking Question: Is dissolution test relevant at all for this BCS Class 4 drug? Dose number (ph 4.7) = Time (minutes) 250 mg PICs (BE lots) 250 mg Tablets (BE lots) 250 mg Capsules (BE lot) 250 mg PICs (Representative lots) 250 mg Tablets (Representative lots) 23

24 Case Study 5 BCS Class 2 (pka 4.2 ; log P 3.5): polymorph control and particle size control important mg capsule, 50 rpm (1mg) 0.1 N HCl ph (1mg) 0.01 N HCl ph (1mg) USP ph Time (minutes) Mean % Dissolution Thought Provoking Question: How should a clinically relevant dissolution test be developed that can routinely be used as release test? Mean % Dissolution Particle size acceptance criteria was set based on observed equivalence studies. Dissolution test discriminated polymorph and particle size at different phs but are not consistent with clinical results mg capsule, 50 rpm Time (minutes) (5mg) 0.1 N HCl ph 1.2 (5mg) 0.01 N HCl ph 2.2 (5mg) USP ph 4.5 (5mg) USP ph

25 Case Study 6 General Biowaiver Considerations for Innovative Products and RLD : API specifications, drug product specifications Process modification, process optimization, site transfer etc. Strive to achieve high degree of similarity to original approved product Comparative dissolution testing with f2 analysis used to justify BCS based biowaiver Lack of clinically relevant dissolution testing in original submission (context of this presentation) Thought Provoking Question: How can drug specific and drug product specific discussions be facilitated to provide case by case justification for biowaiver by following the principles of BCS based biowaiver guidelines but not make all tests conditions mandatory but use tests that are clinically relevant? 25

26 Conclusions Clinically relevant specifications MUST be drug and product specific Guidelines for testing are necessary for the patient, industry and regulatory agency Application of guidelines across all drugs and all drug products even on the basis of BCS categorization do not provide clinical relevance Drug discovery and development process typically involves obtaining thorough understanding of drug properties, its absorption characteristics and their clinical relevance however not all the insightful data may meet validation criteria how can sharing these understanding influence regulatory outcomes? Thought Provoking Question: Can a stronger partnership between industry and regulatory agency be forged that is based on science, risk and trust which will then translate to positive regulatory outcomes? 26

27 QUESTIONS?? THANK YOU! Can the right balance be achieved through collaborative science, risk and outcome based regulations? 27