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stats in formulation development

The document discusses the role of statistics in pharmaceutical development through the Quality-by-Design (QbD) approach from an FDA perspective. It highlights FDA initiatives aimed at enhancing pharmaceutical quality, the importance of statistical tools in QbD, and the objectives of the FDA's CMC Pilot Program. The document emphasizes the need for collaboration among various professionals to successfully implement QbD in the pharmaceutical industry.

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Bhavya
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16 views

stats in formulation development

The document discusses the role of statistics in pharmaceutical development through the Quality-by-Design (QbD) approach from an FDA perspective. It highlights FDA initiatives aimed at enhancing pharmaceutical quality, the importance of statistical tools in QbD, and the objectives of the FDA's CMC Pilot Program. The document emphasizes the need for collaboration among various professionals to successfully implement QbD in the pharmaceutical industry.

Uploaded by

Bhavya
Copyright
© © All Rights Reserved
Available Formats
Download as PPT, PDF, TXT or read online on Scribd
You are on page 1/ 22

Role of Statistics in

Pharmaceutical
Development Using Quality-
by-Design Approach – an
FDA Perspective
Outline

 FDA initiatives for quality


 Pharmaceutical CGMPs for the 21st Century
 ONDQA’s PQAS
 The desired state
 Quality by design (QbD) and design space (ICH
Q8)
 Application of statistical tools in QbD
 Design of experiments
 Model building & evaluation
 Statistical process control
 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/o
ndc_reorg.htm
3
The Desired State
(Janet Woodcock, October 2005)

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

FDA’s view on QbD, Moheb Nasr, 6


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 QbD Approach
Quality assured by testing and Quality built into product &
inspection process by design, based on
scientific understanding
Data intensive submission – Knowledge rich submission –
disjointed information without showing product knowledge &
“big picture” process understanding
Specifications based on batch Specifications based on product
history performance requirements
“Frozen process,” discouraging Flexible process within design
changes space, allowing continuous
improvement
Focus on reproducibility – often Focus on robustness –
avoiding or ignoring variation understanding and controlling
variation 8
Pharmaceutical Development
& Product Lifecycle

Product Design & Development

Process Design & Development

Manufacturing Development

Continuous Improvement

Candidate Product
Selection Approval
9
Pharmaceutical
Statistical Tool
Development & Product
Lifecycle
Product Design & Development:
Initial Scoping Design of
Product Characterization Experiments
Product Optimization (DOE)

Process Design & Development:


Initial Scoping
Process Characterization Model Building
Process Optimization And Evaluation
Process Robustness

Manufacturing Development
and Continuous Improvement: Statistical
Develop Control Systems Process Control
Scale-up Prediction
Tracking and trending
Process Terminology
Critical Quality Attributes

Input Materials Output Materials


Process Step (Product or
Intermediate)
Design
Space
Input Measured
Process Parameters
Parameter or Attributes
s Process
Control Model
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
 Statistically designed experiments (DOEs)
 efficient method for determining impact of
multiple parameters and their interactions
 Scale-up correlation
 a semi-empirical approach to translate
operating conditions between different scales
or pieces of equipment
12
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 (2) Conduct randomized
(e.g., full factorial, d-optimal) experiments
Experimen Factor A Factor B Factor C
t

A
1 + - -
2 - + -
B
3 + + +
C 4 + - +

(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
 Models for manufacturing development
 Computational fluid dynamics
 Scale-up correlations
 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
 Applicable to any multivariate data:
 Spectroscopic data
 Manufacturing data

16
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
Upper Control Limit
Limit 3
Target
Lower Control
Limit Lower Specification
Limit
Special cause variation?
17
Process Capability Index (Cpk)

Cpk = 1.33 min (X  SL) Cpk = 0.33


Cpk 
3σ
Cpk |X - SL| Expected Avg. OOS%*
2 6 0 Industry Practice is to
1.7 5 0 consider processes with
Cpk below 1.33 as “not
1.33 4 0.003% capable” of meeting
1 3 0.135% specifications.
0.7 2 2.28%
0.33 1 15.9%

*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
 Statistical data presentation and usefulness
 Concise summary data acceptable for submission
and review
 Generally used by reviewers to understand how
optimization or design space was determined

21
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
 FDA’s 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

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