Role of Statistics in Pharmaceutical Development Using Quality-by-Design Approach an FDA Perspective

Chi-wan Chen, Ph.D. Christine Moore, Ph.D. Office of New Drug Quality Assessment CDER/FDA
FDA/Industry Statistics Workshop Washington D.C. September 27-29, 2006

Outline

FDA initiatives for quality

Pharmaceutical CGMPs for the 21st Century ONDQAs PQAS The desired state Quality by design (QbD) and design space (ICH Q8)
Design of experiments Model building & evaluation Statistical process control

Application of statistical tools in QbD

FDA CMC Pilot Program Concluding remarks

2

21st Century Initiatives

Pharmaceutical CGMPs for the 21st Century a risk-based approach (9/04)

http://www.fda.gov/cder/gmp/gmp2004/GMP_ finalreport2004.htm

ONDQA White Paper on Pharmaceutical Quality Assessment System (PQAS)

http://www.fda.gov/cder/gmp/gmp2004/ondc_ reorg.htm

(Janet Woodcock, October 2005)

A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight
A mutual goal of industry, society, and regulator
4

The Desired State

FDAs Initiative on Quality by Design

In a Quality-by-Design system:

The product is designed to meet patient requirements The process is designed to consistently meet product critical quality attributes The impact of formulation components and process parameters on product quality is understood Critical sources of process variability are identified and controlled The process is continually monitored and updated to assure consistent quality over time
5

Quality by Design

FDAs view on QbD, Moheb Nasr, 2006

Design Space (ICH Q8)

Definition: The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval
7

Current vs. QbD Approach to Pharmaceutical Development

Current Approach
Quality assured by testing and inspection

QbD Approach
Quality built into product & process by design, based on scientific understanding

Data intensive submission disjointed Knowledge rich submission showing information without big picture product knowledge & process understanding Specifications based on batch history Specifications based on product performance requirements

Frozen process, discouraging changes

Focus on reproducibility often avoiding or ignoring variation

Flexible process within design space, allowing continuous improvement

Focus on robustness understanding and controlling variation
8

Pharmaceutical Development & Product Lifecycle

Product Design & Development

Process Design & Development

Manufacturing Development Continuous Improvement

Candidate Selection

Product Approval
9

Pharmaceutical Development & Product Lifecycle

Product Design & Development: Initial Scoping Product Characterization Product Optimization Process Design & Development: Initial Scoping Process Characterization Process Optimization Process Robustness Manufacturing Development and Continuous Improvement: Develop Control Systems Scale-up Prediction Tracking and trending

Statistical Tool
Design of Experiments (DOE)

Model Building And Evaluation

Statistical Process Control

Process Terminology
Critical Quality Attributes
Input Materials Output Materials

Process Step Design Space

Input Process Parameters Control Model

(Product or Intermediate)

Measured Parameters or Attributes

Process Measurements and Controls

11

Design Space Determination

First-principles approach

combination of experimental data and mechanistic knowledge of chemistry, physics, and engineering to model and predict performance efficient method for determining impact of multiple parameters and their interactions a semi-empirical approach to translate operating conditions between different scales or pieces of equipment
12

Statistically designed experiments (DOEs)

Scale-up correlation

Design of Experiments (DOE)

Structured, organized method for determining the relationship between factors affecting a process and the response of that process Application of DOEs:

Scope out initial formulation or process design Optimize product or process Determine design space, including multivariate relationships
13

DOE Methodology
(1) Choose experimental design (e.g., full factorial, d-optimal) (2) Conduct randomized experiments
Experiment Factor A Factor B Factor C

1
A

2 3
B C

+ + +

+ + -

+ +

(3) Analyze data

(4) Create multidimensional surface model (for optimization or control)

www.minitab.com

14

Model Building & Evaluation Examples

Models for process development

Kinetic models rates of reaction or degradation Transport models movement and mixing of mass or heat Computational fluid dynamics Scale-up correlations

Models for manufacturing development

Models for process monitoring or control

Chemometric models Control models

All models require verification through statistical analysis

15

Model Building & Evaluation Chemometrics

Chemometrics is the science of relating measurements made on a chemical system or process to the state of the system via application of mathematical or statistical methods (ICS definition) Aspects of chemometric analysis:

Empirical method Relates multivariate data to single or multiple responses Utilizes multiple linear regressions Spectroscopic data Manufacturing data
16

Applicable to any multivariate data:

Statistical Process Control Definitions

Statistical process control (SPC) is the application of statistical methods to identify and control the special cause of variation in a process.

Common cause variation random fluctuation of response caused by unknown factors Special cause variation non-random variation caused by a specific factor
Upper Specification Limit

Upper Control Limit Lower Control Limit

3s

Target Lower Specification Limit

Special cause variation?

17

Process Capability Index (Cpk)

Cpk = 1.33

Cpk
Cpk 2 1.7 1.33 1 0.7 0.33 |X - SL| 6s 5s 4s 3s 2s 1s

min (X SL) 3
Expected Avg. OOS%* 0 0 0.003% 0.135% 2.28% 15.9%

Cpk = 0.33

Industry Practice is to consider processes with Cpk below 1.33 as not capable of meeting specifications.

*Percent out of specification beyond the high risk specification limit.

Quality by Design & Statistics

Statistical analysis has multiple roles in the Quality by Design approach

Statistically designed experiments (DOEs) Model building & evaluation Statistical process control Sampling plans (not discussed here)
19

CMC Pilot Program

Objectives: to provide an opportunity for

participating firms to submit CMC information based on QbD FDA to implement Q8, Q9, PAT, PQAS

Timeframe: began in fall 2005; to end in spring 2008 Goal: 12 original or supplemental NDAs Status: 1 approved; 3 under review; 7 to be submitted Submission criteria

More relevant scientific information demonstrating use of QbD approach, product knowledge and process understanding, risk assessment, control strategy
20

CMC Pilot - Application of QbD

All pilot NDAs to date contained some elements of QbD, including use of appropriate statistical tools

DOEs for formulation or process optimization (i.e., determining target conditions) DOEs for determining ranges of design space Multivariate chemometric analysis for in-line/at-line measurement using such technology as near-infrared
Concise summary data acceptable for submission and review Generally used by reviewers to understand how optimization or design space was determined
21

Statistical data presentation and usefulness

Concluding Remarks

Successful implementation of QbD will require multi-disciplinary and multi-functional teams

Development, manufacturing, quality personnel Engineers, analysts, chemists, industrial pharmacists & statisticians working together

FDAs CMC Pilot Program provides an opportunity for applicants to share their QbD approaches and associated statistical tools FDA looks forward to working with industry to facilitate the implementation of QbD
22