An FDA Perspective on Drug Development and the Global Regulatory Landscape

AAPS Annual Meeting Washington, DC 25 October 2010

Christine M. V. Moore, Ph.D. Acting Director ONDQA/CDER/FDA
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Outline
Trends in New Drug Applications Background on QbD and Product Understanding Examples of Product Understanding in Pharmaceutical Development Challenges for a Global Regulatory Environment Concluding Thoughts
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Trends in New Drug Approvals

CDER New Molecular Entity Approvals (NDA & BLA*)

30 NME Approvals 25 20 15 10 5 0 2006 2007 2008 2009 2010 2011
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As of 10/24/11

Calendar Year
* Does not include biologics in CBER

2010 New Drug Approvals (NDA & BLA*)

94 total approved applications (NME & non-NME)
6 biologics 20 combination products (more than one active ingredient)

Dosage forms including:

Nasal spray Auto injector Bowel prep kit Lotion Gel Buccal Tablet Sublingual film - Opthalmic solution - Tablets for oral suspension - Powder for inhalation - Intrathecal solution - Chewable tablets - Transdermal - Foam

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.ReportsMenu 5 * Does not include biologics in CBER

Summary of New Drug Trends

New drug applications are becoming more complex
Wide variety of dosage forms Combination drug and drug/device products Complex molecules Low solubility compounds

Good science in development is needed to take turn these molecules into successful products
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Quality by Design (QbD) in Pharmaceutical Development

What is Quality by Design (QbD)?

Systematic approach to pharmaceutical development and manufacturing Begins with predefined objectives Emphasizes product and process understanding and process control Based on sound science and quality risk management From ICH Q8(R2)

Quality by Design

Clarifying Some Misconceptions of QbD

QbD doesnt change/reduce regulatory requirements
Opportunities for flexible regulatory approaches

QbD doesnt equal Design Space and/or Design of Experiments (DOEs) QbD is important for all products including generics and biotech QbD doesnt have to be expensive
Increased product and process understanding can reduce manufacturing and regulatory costs
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Example QbD Approach - ICH Q8(R2)

Product profile CQAs

Risk assessment

Design space

Control strategy

Continual Improvement

Target the product profile Determine critical quality attributes (CQAs) Link raw material attributes and process parameters to CQAs and perform risk assessment Develop a design space Design and implement a control strategy Manage product lifecycle, including continual improvement
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QbD Approach
Product profile

Understand the Product

CQAs

Risk assessment

Understand the Process

Design space

Control strategy

Continual Improvement

Control the Process Over the Product Lifecycle

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Understanding the Product

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Understanding the Product

Product understanding questions include: What defines good quality drug substance? How do the formulation components interact during and after processing? How does the drug product interact with the container closure? How does the drug become available at the site of action? How might the patient incorrectly use or misuse the drug product?
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Examples of Traditional Studies for Product Understanding

Drug substance properties selection
Polymorph screening Particle size evaluation

Formulation selection
Excipient selection and compatibility Container closure leachables and extractables

Drug distribution within the body

Pharmokinetic/Pharmodynamic (PK/PD) studies Bioequivalence studies to previous formulations
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Challenges in Product Development

Traditional approaches to product development often have been:
Focused on optimization and not robustness Developed with little or no input from manufacturing Performed without understanding the relevance to bioavailability Not performed with the patient use in mind
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Opportunities for Product Understanding

Application of formal Quality Risk Assessment early in development
Involve of all stakeholders Define potential failure modes Include patient use factors

Understand how variability of excipients and raw materials affects product performance Integrate biopharmaceutics into product development Use of advanced analytics for complex molecules or products 16

Examples of Product Understanding

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Risk Assessment Example

Ishikawa Diagram for Tablet Compression
Machines
Press Speed Pre and Main Compression Material Addition Method Drop Height Feeder Speed

Methods

Measurements
Weight Thickness Precompression Force Main Compression Force

SOPs

Batch records

Cam Size/Tooling Machine set-up

Metal Check Cylindrical fill height Turret RPM

Manufacturing Suite Operators Experience Training Internal Temp Humidity External Temp Age

Drug Substance P.S. LOD ID Diluent Other Excipients Quantity Properties

Tablet Quality Dissolution, Hardness, Appearance

P.S. LOD Batch Size

Personnel

Environment

Materials

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Example of Understanding Excipient Variability: Artificial Neural Network Example

Problem: Dissolution is highly dependent on polymer properties Method: ANN dissolution model developed from from pilot and commercial batches Results: Dissolution properties successfully predicted based on excipient attributes
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Artificial Neural Network (ANN)

Input layer Hidden layer Output layer

Polymer Properties

%Dissolved

Product Understanding: Extractables and Leachable Studies

Used to screen for and monitor presence of toxic materials from container closure system (CCS)
Usually related to plastic components of the CCS

A risk-based approach can be used to:

Determine likelihood and identity of leachables Based on prior knowledge and experimentation Utilizing a team approach, including toxicologists Consider risk to patient, based on route of administration

Understanding can provide basis for effective and safe product design and CCS specifications 20

Extractables and Leachables

Extractables Leachables

Not all extractables are leachables Not all leachables are extractable When possible, develop a correlation between extractables and leachables Control and/or characterize the non-correlatable leachables
Anthony Grilli, Leachables and Extractables Testing, A Primer on Regulations and Methods 21

Approach for Product Understanding: Biopharmaceutics Studies

The science and study of the ways in which drugs influence their pharmacodynamic and pharmacokinetic behavior
Typically uses plasma concentrations as biomarker for safety and efficacy

Strives to relate in vivo performance of a drug to in vitro measurements

Enables development of clinically relevant specifications Understand the impact of manufacturing process variables

Supports control strategy development through setting clinically meaningful dissolution specifications to assure consistent therapeutic benefit
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Example In vitro/In vivo Correlation (IVIVC) Approach

In Vivo Response
(Plasma Conc. Profile) In Vitro/In Vivo Correlation

In Vitro Release
(Dissolution Profile) Predictive Model

Formulation and Manufacturing Process

Reference: Medscape, 2002

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In vivo/In vitro correlations (IVIVC)

A predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response Links in vitro dissolution data to plasma drug concentration or amount of drug absorbed
May predict concentration-time profiles and/or exposure (depending on type of correlation)

Assists formulation development and optimization Supports development and selection of release (e.g., dissolution) methods Can facilitate the use of in vitro dissolution data as a surrogate for human BE studies (e.g. biowaivers)
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Example Bioequivalence without IVIVC

Multiple batches are produced with widely varied dissolution rates Clinical relevance is assured within established range Assures product robustness, and can achieve a wider dissolution specification
A, B, C, & clinical are BE
90

80

70 Form A Clinical Trial Form Form B Form C

Std approach dissolution spec: Q= 80 at 30 min.

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% Drug Release

50

40

BE approach dissolution spec: Q= 80 at 45 min

0 10 20 30 Time (min) 40 50 60

30

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Example Patient Use Factors:

Alcohol Induced Dose Dumping
100
% Drug Released

80 60 40 20 0 0 3 6 9 12
time (hr) Control 4% EtOH 20% EtOH 40% EtOH

Some modified release solid oral dosage forms can contain drugs or excipients that are highly soluble in ethanol (EtOH) Ingestion of alcohol could lead to dangerously high drug exposure - Either intentionally or unintentionally

Dose dumping should be considered when designing 15 modified release formulations

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Alcohol Induced Dose Dumping

QbD Approach:
Consider clinical impact during formulation development Develop greater scientific knowledge and understanding of properties that induce dose dumping
Vulnerability of existing ER and MR products Vulnerability of new ER and MR designs

Develop formulations and dosage designs not sensitive to dose dumping Perform failure mode analyses (i.e., risk management) early in development IND formulations
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Characterizing Complex Products

Characterization of complex / heterogeneous products can be difficult
Identity, purity
Heparin NMR Data

Chemometrics allows extraction of information from analytical methods

Ability to handle multidimensional data Can be used to simultaneously evaluate data from multiple analytical methods to make decisions

Good Produ

May lead to discovery of hidden/unexpected patterns

Fingerprint approach May be used to identify trace contaminants in products
Expert Analyst Expert System

Contaminant

Reference: Q.Zang, et. al, J.Pharm.Biomed.Anal.(2011), doi:10.1016/j.jpba.2010.12.008

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Wednesday Poster: W5374

Newer Guidance Including Aspects of Product Understanding

Residual Drug in Transdermal and Related Drug Delivery Systems Final, Aug 2011
Recommendations for development and throughout lifecycle to minimize residual drug in transdermal, transmucosal and topical products

Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation Draft, Aug 2011
Recommendations on evaluation of tablet scores and data to provide in the applicaiton

Size of Beads in Drug Products Labeled for Sprinkle Draft, Jan 2011
Recommendations for size of particles for drug products to be administered via sprinkling
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Global Regulatory Environment

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Global Regulatory Environment

Enhanced development approach should not be problematic for the global regulatory environment Opportunities for flexibility regulatory approaches might not be available in all regions, e.g.,
Acceptance of design space approach Agreement on PAT and/or RTRT approaches Establishing clinically relevant specifications

Further collaboration, communication and education with non-ICH regions may be needed
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ICH Quality Implementation Working Group (Q-IWG)

Scope: Ensuring harmonized implementation of ICH Q8, Q9 and Q10 Identified areas needing further clarification: Knowledge Management Design Space, Real Time Release, Control Strategy Pharmaceutical Quality System Publication of Q&A Training issues Collaboration
(Adapted from: M. Nasr, J-L Robert, 2011 DIA Annual Meeting)
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ICH Q-IWG Achievements Summary

Published 45 Q&As Training has been a major achievement
ICH regions: EU: Tallinn June 2-4, 2010 US: Washington October 6-8, 2010 Japan: Tokyo October 25-27, 2010 ASEAN, Kuala Lumpur: July 2010 IFPMA/DIA, Seoul April 2011 HC, Ottawa September 2011 APEC/AHC, Seoul October 2011

Training material available at ICH website

http://www.ich.org/products/guidelines/quality/training-programme-forq8q9q10.html

(Adapted from: M. Nasr, J-L Robert, 2011 DIA Annual Meeting)

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ICH Q-IWG Achievements Summary (cont)

Points to Consider endorsed June 2011
Criticality of Quality Attributes and Process Parameters Control Strategy Level of Documentation in enhanced (QbD) Regulatory Submissions

Points to Consider document to be developed

Process validation/process verification Role of modeling in QbD Design space

IWG work to be completed by end of 2011

(Adapted from: M. Nasr, J-L Robert, 2011 DIA Annual Meeting)
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FDA Efforts in International Collaboration

(Outside of ICH)
FDA-EMA Parallel Assessment Pilot
Set up a pathway for knowledge sharing between FDA/ONDQA and EMA reviewers/assessors Ensure consistent implementation of ICH guidelines Encourage FDA-EMA joint pre-approval inspections At least one application will include Japanese regulators as observers

Pharmaceutical Inspection Cooperation Scheme (PIC/S)

Collaboration between regulatory agencies on pharmaceutical inspection and training

CDER Forum for International Drug Regulatory Authorities

Training and information exchange forum for non-US pharmaceutical regulators Typically offered twice per year; no registration fee
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Summary of Progress in Global Harmonization

Progress has been made in harmonizing implementation of ICH Q8, 9, 10
Both in ICH and non-ICH regions

Efforts are ongoing within FDA and other regulatory agencies to increase global collaboration and harmonization Challenges still remain, including
Establishing an enhanced global quality culture Clarity of global regulatory and GMP expectations Role of compendial standards and lack of harmonization among pharmacopeias

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Concluding Thoughts
New drug development is becoming more complex Using a science and risk based approach for product development can facilitate successful products, throughout product lifecycle
Quality built into product design for its intended use Can increase product and subsequent process robustness

In some cases, regulatory flexibility can result from increased product and process understanding and controls
Good progress through ICH documents and IWG activities Increased global coordination will be necessary to fully 37 harmonize these approaches

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Questions, comments, concerns: NewDrugCMC@fda.hhs.gov
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