The scientific bases for characterization of the commercial process are developed during this stage of process validation. Process knowledge is gained, documented, and defined through laboratory and pilot scale studies. Sources of variability are identified and understood with respect to product quality and patient safety. Risk assessments are conducted to determine the degree of management and control reasonably required for the sources of variability.

Critical process parameters and critical product quality attributes are identified and evaluated through multivariate analyses. The effects of scale are assessed. Design of experiment (DOE) methodologies are used to perform mechanistic modeling to establish process design and operating spaces that confirm acceptable operating ranges for process critical control parameters. Process controls are established to manage critical process parameters and variability of process inputs. As a part of the establishment of design and operating spaces, “worst-case” conditions and parameters are evaluated. The Stage 1 work defines the process in enough detail such that the control of critical parameters and sources of variability is effective at commercial scale. The resulting design and operating spaces are as outlined in ICH Q8 Pharmaceutical Development.

This special edition is a collection of articles and papers from the Journal of Validation Technology and the Journal of GXP Compliance that expound such topics as knowledge building with probability distributions, a step-by-step process for design-of-experiment, quality-by-design, and hypothesis testing, this e-Book will firmly establish the scientific foundations of a manufacturing process.

Table of Contents

Estimation: Knowledge Building with Probability Distributions
David LeBlond

FDA Lifecycle Approach to Process Validation—What, Why, and How?
Paul L. Pluta

First Steps in Experimental Design—The Screening Experiment
John A. Wass

First Steps in Experimental Design II: More on Screening Experiments
John A. Wass

A Further Step in Experimental Design (III): The Response Surface
John A. Wass

Patent Potential
John F. Bauer

Understanding Physicochemical Properties for Pharmaceutical Product Development and Manufacturing—Dissociation, Distribution/Partition, and Solubility
Deliang Zhou

Understanding Physicochemical Properties for Pharmaceutical Product Development and Manufacturing II: Physical and Chemical Stability and Excipient Compatibility
Deliang Zhou

PQ=Confirmation
Paul L. Pluta

The Forgotten Origins of Quality by Design
John McConnell, Brian K. Nunnally, and Bernard McGarvey

Understanding Hypothesis Testing Using Probability Distributions
David LeBlond