## In-House Training

## Practical Approaches to Statistical Design of Experiments (DoE) for Chemical Process R&D

Tutors: Dr Andrei Zlota

This course takes a balanced approach presenting basic DoE theory as well as numerous examples of DoE use in the pharmaceutical industry. The course will discuss statistical and practical significance, assumptions and limitations of DoE methodology, together with practical approaches for the process scientist to be in control of the DoE investigation (and not the computer).

Precedent and experience compel many chemists to use OVAT experimentation in spite of its incomplete nature, and in spite of its inability to detect factor interactions, e.g., cases when the impact of one factor depends on the level of another factor. When such interactions occur between scale dependent and scale independent factors, ignoring such factor interactions can lead to high risk process scale-up and technology transfer.

Participants will learn how to design effective screening experiments, how to use response surface methods for reaction and analytical method development, how to design robust processes, and how to quantify the risk associated with the implementation of the processes developed. Several commercial DoE software platforms will be reviewed.

For the benefit of process scientists, engineers, formulators*, analytical chemists and manufacturing personnel, this course includes highly interactive, hands-on workshops.

### Course Outline

#### Introduction

- Why DoE?
- Statistics for chemical process R&D: friend not foe
- Synergy between statistical, kinetic and engineering models
- Univariate experimentation limitations
- Design of experiments (DoE), a multivariate method to investigate multivariate processes

#### Statistical Design of Experiments (DoE)

- Requirements for a successful DoE
- Responses
- Scale independent and scale dependent factors
- Meaningful use of categorical factors
- Factor ranking; factors to be fixed, factors to be varied
- Ranges, number of levels
- Randomization, replication, centerpoints, blocking

#### Screening the Experimental Space

- DoE commercial software platforms
- Full factorial designs
- Fractional factorial designs: advantages and challenges
- Plackett-Burman designs
- Design efficiency, design resolution, statistical power of a design
- Chemical reaction, and workup: together or separate?
- Design augmentation; practical strategies for cost-effective screening
- Using DoE to set raw material specifications

#### Analyzing DoE screening investigations

- Objectives
- Key statistical concepts
- The value of redundancy, the power of visualization tools
- Practical vs. Statistical significance
- Case studies: chemical reactions, API crystallizations

#### Response Surface Methodology (RSM)

- Types of “optimization”
- RSM design options
- Analysis of RSM designs, model manipulation
- Model verification experiments
- Case studies: chemical reactions, API crystallizations

#### DoE and Quality by Design (QbD)

- The concept of design space; risk calcualtions using the DoE model
- Critical Quality Attributes and Critical Process Parameters
- DoE for process robustness assessment, and for process validation; process capability indices

#### “Advanced Topics” (time permitting)

- DoE and Principal Component Analyisis (PCA)
- DoE for process troubleshooting
- DoE investigating scale-dependent and scale-independent factors
- Mixture designs

#### Final Review

- Round table discussions; practical tips, references, software demonstration

### Benefits of Attending

Participants will learn how to design effective screening experiments, how to use response surface methods for reaction and analytical method development, how to design robust processes, and how to quantify the risk associated with the implementation of the processes developed. Several commercial DoE software platforms will be reviewed.

### Who Should Attend

For the benefit of process scientists, engineers, formulators, analytical chemists and manufacturing personnel, this course includes highly interactive, hands-on workshops.

### What's Included

The course fee includes:

- comprehensive course manual
- coffee/tea refreshments breaks throughout each day
- buffet lunch each day
- course dinner on the first evening
- course certificate