In order to more easily understand the information presented in this
chapter, it may be helpful for the reader to consider the activities that are
involved with making, operating, and maintaining a reliable automobile.
Automobiles are designed and tested to meet functional requirements; are
manufactured with assembly lines, properly trained personnel and use of
SOPs to ensure that a consistent product is created; then depend upon
owners to ensure that periodic oil changes and other maintenance activities
are conducted to keep the car in a reliable state. Many parallels exist
between this paradigm and that of computer validation. Specific examples
are included in this chapter.

5.1 Introduction

Overview

Processes used in the manufacture of pharmaceuticals for human
consumption must be validated. The scope of validation includes not
only the chemical processing unit operations themselves but also the
supporting aspects of manufacturing operations such as assay validation,
cleaning validation, utility validation (e.g., use of purified water), and
computer validation.

A validated process is one that reproducibly meets expectations. It is generally
perceived as containing four key elements:

• Process Definition; i.e., a description of the process when it runs
  correctly.
• Demonstration; i.e., via the successful execution of test lots.
• Documentation; i.e., if a company didn't document an activity,
  then it is assumed that they did not do it.
• Maintenance; i.e., the activities in place that provide assurance
  that the process will continue to operate correctly in the future.

The regulatory expectations for validating a process are found in references
[5.1] through [5.5].

They include cGMPS (current Good Manufacturing Practices for finished
pharmaceuticals in the US), the EU (European Union) GMPs (which also
apply to active pharmaceutical ingredients), the Food, Drug, and Cosmetic
Act, and the ICH (International Conference on Harmonization)
Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients.

One of the drivers for the expectation of validated processes is the FDA's
fundamental belief that quality cannot be tested into a product but must
be built into the process of making the product. Therefore, the FDA is
looking for a plant's ability to manufacture a consistently high quality
product from lot to lot.

To help readers in understanding the concept that "quality cannot be
tested into a system," consider a typical pharmaceutical process that
makes millions of tablets (or capsules, vials, or cartridges) per day. A certain
small percentage of these are removed from the production lines for
testing. The process of testing, depending on the tests involved, often
destroys the tablet so these tested items never reach the patient. Conversely,
the tablets that do reach patients, while probably having received
several non-destructive tests (such as visual inspections, weight verification,
etc.), have not received the total battery of tests needed to prove the
safety, identity, strength, purity, and quality of the tablet. Therefore, a
company must make medicines using validated processes, which provides
a high level of assurance that the product (e.g., every tablet) reaching the
customer is exactly what the company represents the product to be.