TRACK 1: DRUG CLASSIFICATION, RELEASE, AND MODELING FOR SETTING CLINICALLY RELEVANT SPECIFICATIONS

Session 1: Biowaivers and Harmonization Guidelines for Class 1 and 3 Drugs Moderator: Mehran Yazdanian, Teva Speakers: Mehul Mehta (FDA), Barbara Davit (Merck) and Raimar Löbenberg (University of Alberta)

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1) Where are We on the Latest Draft Guidance on BA/BE Waivers for Class 1 and Class 3 Drugs Mehul Mehta, FDA

2) BCS Biowaiver Case Studies Barbara Davit, Merck

3) The BCS and Biowaivers – A Global Overview Raimar Löbenberg, University of Alberta

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Key Points from Dr. Mehta (1) • The 2015 revision of the draft guidance on BCS Class I and III

waivers for BA/BE is better harmonized with other guidelines (EMA, WHO) than the original 2000 draft.

• BCS Class I designation, as of 2015, 42/63 (67%) drug products. • Changes in pH range, high permeability, permeability markers,

dissolution volume, fixed dose combination products, and specifically, the impact of changes from “highest dose strength” to “highest strength” in definition of solubility.

• The next revision of the guidance expected in Sept. 2017 • BCS is now an ICH M9 topic. The first consensus document from

ICH is expected by the end of 2017.

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Key Points from Dr. Davit • Industry faces challenges due to lack of harmonization across

regions: • Some of the current inconsistencies will be resolved in the

new guidance • Three case studies illustrating how BCS evaluation affects drug

development and choices/decisions made along the way: • Preliminary BCS classification in early development • Pivotal studies to confirm classification later on

• Challenges still exist due to different criteria in US and EU regarding BCS Class I and III.

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Key Points from Dr. Löbenberg • Explained the approaches used in Canada compared with FDA

and EMA, examples for fixed dose drug combinations. • Presented IVIVC examples and challenges in developing different

dissolution methods for QC (simple) and for IVIVC (complex) • Made a case for replacing dissolution testing with disintegration

for routine QC and stability. • Surrogate for dissolution for routine testing (while all pivotal

work would be done with dissolution) • Showed lack of consistency in performance of “same” drugs

around the world due to differences in the reference product used in different countries. Global Comparator Pharmaceutical Products are needed.

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Panel Discussion and Q&As • With enabled formulations and other advances in attaining

supersaturation, could the industry change classification for a drug to BCS I? • If you cannot use the guidance but have the data to

justify your approach, come talk to the FDA

• What happens to “medium” permeability? • If it’s not “high”, it’s treated as low permeability. • But also look at the metabolism, it may help determine

classification

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Overall Conclusions • Progress has been made in harmonization efforts, and in

general understanding of BCS Class I and III classification for biowaivers.

• Some challenges still exist in harmonizing regulatory documents from FDA, EMA, and WHO, and the discussions are ongoing.

• Better convergence on the methods (not just definitions) could be the part of the next objectives for international harmonization efforts.

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Session 2: Dissolution Challenges for BCS Class 2/4 Drugs Moderator: Allen Templeton (Merck & Co., Inc.) Speakers: Rik Lostritto (FDA), Sandra Suarez (FDA), and Erika Stippler (USP)

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1) BCS Class 2 Immediate Release (IR)Dissolution in Two-Phase Media Rik Lostritto, FDA

2) Establishing Clinically Meaningful Drug Product Specifications: A Possibility without IVIVC? Sandra Suarez-Sharp, FDA

3) Development of Dissolution Methods for Class 2/4 Drugs – A USP Perspective Erika Stippler, USP

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Key Points (1) • 2-phase dissolution method could be useful for studying BCS II drugs

• E.g., aqueous and 1-octanol • Two independent paddles.

• Could be used for R&D and QC, as it simulates physiological absorption and sink conditions in vitro.

• Dr. Lostritto presented three case studies from published literature, demonstrating advantages of bi-phasic dissolution system

• Still needed: • Characterization and standardization of the apparatus and method • Publish data on a range of BCS II drugs using this approach • Industry submissions (e.g., IND) using this approach

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Key Points (2) • Use of PBPK modeling and simulations in setting Clinically Relevant Drug

Product Specifications (CRDPS) • It is important to have biopredictive methods. • Current approaches for setting specs are based on:

1. Batches in pivotal trials (still the prevalent approach) 2. Bioequivalence (BE) limits 3. IVIVC

• PBPK can guide IVIVC studies • Dr. Suarez-Sharp presented case studies, e.g.,

• wider specification limits for in-vitro attribute based on BE Cmax and AUC, PBPK

• PBPK used to identify the boundary of dissolution profiles that would ensure BE (but need to have batches that are and are not bioequivalent)

• Examples of attributes for which specifications could be set using PBPK: tablet hardness, water activity, PSD, dissolution

• FDA is gaining confidence with PBPK; would welcome more submissions

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Key Points (3) • USP Chapter <1092> official as of Aug. 2015.

• Explains how to develop and validate a dissolution method. • Includes table of surfactants.

• Important to consider:

• Solubility and stability in a range of aqueous media • Release mechanism • Compendial vs non-compendial apparatus • Type and concentration of surfactant

• Goal is to have a meaningful dissolution test

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Panel Discussion and Q&As • Q&As on 2-phase systesm:

• Would bi-phasic system work for carbazepam? • Possibly, in the future; not currently on the table

• Octanol might be unpleasant to work with; consider other solvents or other approaches to simulate sink conditions (e.g., USP App. 4 is open loop)

• FDA received no applications with bi-phasic systems to date • Early screening methods vs more discriminatory QC dissolution

methods • FDA does not see the early data, so may not understand the methods

industry is proposing. Should publish more, or put more data into submission explaining the thinking and justification

• What if dissolution changes on stability? • Something must be not well controlled or not well understood. Would

tighten specifications.

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Session 3: In-Vivo Predictive Dissolution Methods and Modeling Moderator: Greg Amidon (University of Michigan) Speakers: Justin Pennington (Merck), Nikoletta Fotaki (University of Bath), David Sperry (Eli Lilly)

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1) Building an Enhanced Analytical Toolbox for In-Vivo Predictive Dissolution Justin Pennington, Merck& Co., Inc.

2) Development of Biorelevant Dissolution Methods Nikoletta Fotaki, University of Bath

3) Dissolution Coupled with Oral Absorption Modeling to Predict Clinically Relevant Performance David Sperry, Eli Lilly and Company

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Key Points (1): Justin Pennington • Presented case studies illustrating tools to guide development :

• 1x biorelevant dissolution (partial dose dissolution. dose= solubility limit) • Transfer model for weakly basic APIs (acidic to weakly acidic media) • Identifies critical steps in dissolution (eg: tablet disintegration, granule

disintegration, deaggregation, etc) Compares dispersed API dissolution (eg: max dissolution rate possible) to dosage form dissolution to identify critical processes

• Atomic Force Microscopy is potential future tool to monitor dissolution in live time at nanometer-scale surface resolution • AFM challenges: slow down dissolution, grow crystal facets • AFM limitations : no chemical specificity, no quantitation

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Short term opportunities: • 1x biorelevant dissolution and transfer model may be sufficiently robust

and scientifically sound to pursue standardization

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Key Points (2): Nikoletta Fotaki • Dissolution method development should consider:

• API properties • Formulation properties • Media choice is critical

• Simulating fed and fasted conditions, range of pH, Viscosity to simulate GI fluids • Apparatus (USP or other) • Hydrodynamics • BCS Class is important (including subclass: (a) acid, (b) base, (c) neutral

• BCS I or III could use simple medium and method • BCS II or IV – biorelevant media very important

• Could consider transporter and metabolite data • PBPK can support biorelevant dissolution method development

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Short term opportunities: • Develop dissolution media selection decision tree (seems feasible now) • Select dissolution method depending on BCS Class and Subclass (a,b,c) • Apply PBPK modeling (eg: convolution) to identify/select/ in vivo relevant

dissolution methods

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Key Points (3): David Sperry • Emphasized need to understand mechanism of drug release

• eg: tablet and granule disintegration, dissolution • Integrates above with in vitro tests and mechanistic models to predict in vivo

absorption (ideally) • Utilizes variety of in vitro methods

• Artificial Stomach Duodenal (ASD) model • USP paddle method • Rotating disk • One-step and two-step (eg: pH change) dissolution methods • Microcentrifuge test • FBRM for particle size measurement during dissolution process

• Case studies: Modified release formulation, Free base conversion (in a salt-base mixture), System based pharmaceutics,Integrating ASD data

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Short term opportunities: • ASD, Rotating Disk, One-step, Two step disso may be sufficiently

robust and scientifically sound to pursue standardization

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Panel Discussion, Q&As • How close are we to rule-based decision trees for selecting dissolution

method for a given drug product? • There seems to be enough information in industry, academia, but it needs

to be combined and systematized. • For media, have more and better information than for methodology. • Collaborations are needed. • It is likely that no one model will fit all. There is some work on a decision

tree but it is very complex (nested trees, where one decision may lead to an entirely new tree). Could be available soon.

• We already are capable of predicting vast majority of cases.

• A mechanistic understanding of bioavailability is important

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Panel Discussion, Q&As (cont’d) • How do we make software tools available to others? Costs? Will the

new tools be validated? Will the various ongoing projects converge? • The cost of software could be offset by the savings from not having to do

clinical trials. • Validation must be case by case • A simpler/streamlined version might be possible but have not seen one.

• How far along are we testing with transporters across epithelial layer? • For some cases, information already exists

• Will modeling and simulations ever replace experiments? • Experimental approaches and modeling will both be needed, one

informing the other. • Experimental data will likely be going more and more often into

computation, to yield higher-level understanding

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Session 4: Drug Release from Non-Oral Routes Moderator: Wenlei Jiang (FDA) Speakers: Randy Mrsny (University of Bath), Brad Anderson (University of Kentucky), and Doug Mar (Liquidia Technologies)

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1) An In Vitro Approach to Model Specific Events Occurring at Injection Sites Randy Mrsny, University of Bath

2) Drug Release from Liposomes: Role of Mechanism-Based Models Bradley Anderson, University of Kentucky

3) Setting Size Specifications for PRINT® Particles Douglas Mar, Liquidia Technologies, Inc.

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Key Points (1) Background

• little understanding about events at the injection site and no in vitro method which can predict in vivo PK of biopharmaceuticals via SC.

• No good animal model that consistently correlates with human data • Protein formulations have high concentrations (due to minimized volume),

stabilizers, fillers, and other formulation components to ensure ~ 2yr shelf life, but these are not physiological conditions in the body

Summary • Developed a dialysis-based injection chamber to simulate biological

environment at injection site and examine post injection events • Diffused fractions of 4 model mAB have good correlations with human BA • Adapt to other physiological environment (e.g., ocular) • Now this apparatus is available commercially

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Key Points (2) Background • Liposomes allow more targeted delivery, e.g., to cancer cells

• Understanding of release process is needed to improve liposome formulation design.

Summary

• Developed mechanistic based models to describe dox release from liposomes

• Factors to consider: • Membrane permeability • Driving forces (species to be transported, membrane binding, drug

precipitation & self-association) • Environment (pH, temperature, media composition)

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Key Points (3) New technology (“PRINT®”) for particle manufacturing

• Roll-to-Roll process (“Ice-cube tray”)

• Precise control over size and shape, including nanoscale features

• Could be important for formulations where size or shape is critical to performance (e.g., inhalation products)

• Used for sustained release delivery

Characterization of these particles

• Select appropriate testing methods

• Establish correlations between different types of particle size measurements

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From concept to commercialization - About 3 years Application • Guide formulation screening/optimization during

development • Can also be used for small molecule s.c. formulation

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Panel Discussion and Q&As (1)

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Panel Discussion and Q&As (2)

• Are there analytical methods to determine free drug vs drug in

liposomes?

• Yes. Ultrafiltration, solid-phase extraction, gel filtration, and other methods

available.

• For a hydrophobic drug which resides in lipid bilayer, is it easier to

establish the model than Doxil?

• Maybe less complicated than Doxil.

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Panel Discussion and Q&As (3) • For the PRINT® particles, why cascade impactor data showed a broad

peak if the particles are all of same size?

• Method of particle fractionation inside the impactor is not deterministic but

probabilistic. Cascade impactor is not a filter. Therefore, even a tight

distribution of uniform particles translates into a broader distribution when

measured with cascade impactor.

• What molecules can be used with PRINT® technology?

• A broad range, e.g., biologics, peptides, sugars (as excipients), small

molecules.

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Session 5: Modeling for Oral and Non-Oral Routes Moderator: Filippos Kesisoglou (Merck & Co., Inc.) Speakers: Roberto Gomeni (Pharmacometrica), Maureen Donovan (University of Iowa), and David Good (Bristol-Myers Squibb)

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Background

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- Increased attention to alternate delivery routes and/or special populations (eg. pediatrics)

- Execution of both in vitro and clinical studies for these formulations and/or populations may be more challenging than traditional oral dosage forms

- Modeling and Simulation approaches may help with improving understanding and driving product quality

- Session focused on use of M&S in 3 areas - Long Acting Injectables - Pulmonary and nasal delivery - Pediatric oral dosage forms

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Summary of Presentations

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- Dr. Roberto Gomeni – Modeling of Long Acting Injectables - Time-dependent absorption an important characteristic of these systems - Adopting modeling approaches that incorporate dissolution/release rate is critical to

accurately describing the system behavior - Can be achieved by convolution-based modeling (both for simulation and IVIVCs) - Can adopt model structures to explain complex pharmacokinetic observations eg. burst

release - Dr. Maureen Donovan - Modeling Deposition in the Respiratory Tract

- Computational fluid dynamic models are now being used more in the biology/pharmaceutics space. Can be powerful tools to address questions regarding particle deposition and spray performance in the respiratory tract.

- Good correlations between modeling and experimental deposition patterns observed - CFD modeling will improve the opportunity to evaluate population-based differences (age,

race, disease state) in respiratory delivery system efficacy and optimize formulations (eg. selection of API particle size to drive nasal deposition without lung deposition)

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Summary of Presentations/Action Items

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Dr. David Good – Modeling for formulation and clinical designs for special populations • Access to special populations a challenge. M&S provides an alternative approach.

Utilization of M&S for these populations expected to increase • Pediatrics one of the most common areas. Case studies demonstrate power of M&S to

eg. assess formulation similarity, optimize formulation release rate or help with dose selection.

• Major challenge is the understanding of the physiology in the target population (eg. significant physiological changes in the first few years of life)

ACTION ITEMS - Potential BTC projects around • Synergies between CFD and PBPK to inform specific formulation questions for eg. pediatric nasal

sprays. • Improvements in physiology understanding can help propel application of models in special

populations • Link between convolution model parameters and physiological parameters

Session 6: Topical Classification System Moderator: Kailas Thakker (Tergus Pharma) Speakers: Vinod Shah (PQRI), Flavian Radulescu (University of Medicine and Pharmacy Carol Davila), and Sam Raney (FDA)

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Summary/Discussion Points

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• Presentation of Topical Classification System (TCS) • Review current PQRI studies to validate proposed TCS • Discussed the need for weight of evidence approach to obtain

biowaiver • What tests are required to characterize Q3 for topical applications?

Q3 defines organization of matter in topical dosage forms (e.g., microstructure); • IVRT (in vitro release test) • IVPT (in vitro permeation test) • Rheological characterization • pH • Viscosity • Water activity, etc….

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Next Steps • Address tests needed to characterize Class 3

requirements • What is needed for each dosage form • How to implement TCS

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