Über die Autorin bzw. den Autor

DAVID M. BLIESNER, PhD, is the founder and President of Delphi Analytical Services, Inc., an organization dedicated to improving clients' level of compliance with Current Good Manufacturing Practices, Quality System Regulations, and Current Good Clinical Practice Regulations by providing training technology, training, and compliance products and services. Dr. Bliesner also offers lectures, short courses, and hands-on training on compliance issues for analytical laboratories. He is the author of Establishing a CGMP Laboratory Audit System, also available from Wiley.

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All the information and tools needed to set up a successful method validation system

Validating Chromatographic Methods brings order and Current Good Manufacturing Practices to the often chaotic process of chromatographic method validation. It provides readers with both the practical information and the tools necessary to successfully set up a new validation system or upgrade a current system to fully comply with government safety and quality regulations. The net results are validated and transferable analytical methods that will serve for extended periods of time with minimal or no complications.

This guide focuses on high-performance liquid chromatographic methods validation; however, the concepts are generally applicable to the validation of other analytical techniques as well. Following an overview of analytical method validation and a discussion of its various components, the author dedicates a complete chapter to each step of validation:

• Method evaluation and further method development
• Final method development and trial method validation
• Formal method validation and report generation
• Formal data review and report issuance

Templates and examples for Methods Validation Standard Operating Procedures, Standard Test Methods, Methods Validation Protocols, and Methods Validation Reports are all provided. Moreover, the guide features detailed flowcharts and checklists that lead readers through every stage of method validation to ensure success. All of the templates are also included on a CD-ROM, enabling readers to easily work with and customize them.

For scientists and technicians new to method validation, this guide provides all the information and tools needed to develop a top-quality system. For those experienced with method validation, the guide helps to upgrade and improve existing systems.

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All the information and tools needed to set up a successful method validation system

Validating Chromatographic Methods brings order and Current Good Manufacturing Practices to the often chaotic process of chromatographic method validation. It provides readers with both the practical information and the tools necessary to successfully set up a new validation system or upgrade a current system to fully comply with government safety and quality regulations. The net results are validated and transferable analytical methods that will serve for extended periods of time with minimal or no complications.

This guide focuses on high-performance liquid chromatographic methods validation; however, the concepts are generally applicable to the validation of other analytical techniques as well. Following an overview of analytical method validation and a discussion of its various components, the author dedicates a complete chapter to each step of validation:

• Method evaluation and further method development
• Final method development and trial method validation
• Formal method validation and report generation
• Formal data review and report issuance

Templates and examples for Methods Validation Standard Operating Procedures, Standard Test Methods, Methods Validation Protocols, and Methods Validation Reports are all provided. Moreover, the guide features detailed flowcharts and checklists that lead readers through every stage of method validation to ensure success. All of the templates are also included on a CD-ROM, enabling readers to easily work with and customize them.

For scientists and technicians new to method validation, this guide provides all the information and tools needed to develop a top-quality system. For those experienced with method validation, the guide helps to upgrade and improve existing systems.

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Validating Chromatographic Methods

John Wiley & Sons

Chapter One

1.1 WHAT IS METHODS VALIDATION?

The FDA in its most recent publication, Guidance for Industry on Analytical Procedures and Methods Validation, states:

Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use. The methods validation process for analytical procedures begins with the planned and systematic collection by the applicant of the validation data to support analytical procedures.

What the FDA does not say is that the actual validation component of the methods validation process should be the culmination of a well-organized, well-planned, and systematically executed process that includes method development, prevalidation studies, and finally, methods validation itself. Gone are the days where one did methods development/validation concurrently. Validation is the end game where few surprises and deviations are expected. Validation is executed with a formal, approved and signed methods validation protocol in place which has been reviewed by the quality assurance (QA) unit. Validation is complete when you:

(1) Demonstrate that you have met all the acceptance criteria.

(2) Clearly document the results in a CGMP compliant fashion.

(3) Show how you met the acceptance criteria in a final methods validation report, including references to raw data, all of which have been reviewed and approved by the appropriate personnel including peers, management, and QA.

Some would even argue that the validation process is not complete until the methods are successfully transferred to their end-user laboratories.

This sounds like a daunting task. And to be completely honest-it is. There is nothing trivial or easy about methods validation. It takes time, resources, and rarely goes as easy as you think it's going to go. Methods validation is part science, part art, and a lot of bookkeeping and accounting. To be brutally honest, too few laboratories do a very good job executing all the components.

Due to the magnitude of the task, the time, and the perceived costs, many laboratories try to cut corners. At a minimum, this results in deviations from the protocol which no longer can be "arm waved" away. The FDA expects you to scientifically address failures as you would any other laboratory investigation. This takes more time and effort and often results in delays in the validation timeline. In the worst case, you end up validating a method that is transferred to quality control (QC) labs worldwide, and ends up being the root cause of untold laboratory investigations. It is hypothesized that many of the problems discovered during root-cause analysis of out-of-specification results (OOS) are a direct result of poorly or partially validated methods.

The sections that follow provide a road map and the tools to guide and assist you to properly and efficiently validate your chromatographic methods, ensuring your validated methods do not become the root cause of your future laboratory investigations.

1.2 STEPS IN THE CHROMATOGRAPHIC METHODS VALIDATION PROCESS

The process of validating chromatographic methods can be broken down into four steps. These steps include:

1. Method evaluation and further method development, 2. Final method development and trial methods validation,

3. Formal methods validation, and

4. Formal data review and report issuance.

Figure 1.1 graphically represents the process.

The estimates given in Figure 1.1 are only that-estimates. So many variables exist during methods validation that it makes it very difficult, if not impossible, to give an accurate prediction of the length of the validation project. There is an enduring myth in the pharmaceutical industry that it should only take six weeks to validate a method. The formal validation portion itself should only take about six weeks, but the preparation and documentation take significantly more time. Although it can be done, a complete validation, including proper data review and documentation, even for an established product with known properties, has not been satisfactorily completed in such a short time. Industry professionals believe that this is why there are so many bad methods in use today.

Details of the design and implementation for each step are described in the remaining sections of this guide. In addition, many of the tools, templates, and examples needed to complete methods validation are included in the appendices. As many examples, based on real-world scenarios, as practical have been provided to give you a framework to validate your own methods. In particular, the following key elements which constitute a methods validation program have been provided:

A template for a methods validation standard operation procedure (SOP) example

A template for a standard test method example

A template for a methods validation protocol example

A template for a methods validation report example

Each template for these examples represents a significant body of knowledge and experience. It would require a substantial amount of your time to create these templates independently. Modify them and use them to best fit the practices within your organization.

1.3 HOW TO USE THIS GUIDE

Before proceeding, here are some suggestions on how to use this guide. Although this document is a practical guide, it is by no means a technical cookbook on how to validate an analytical method. This would be impossible since every method has its own unique idiosyncrasies. Therefore, it is recommended that you take the following approach to best apply this guide:

Familiarize yourself with the standard methods validation terms listed in the glossary.

Read and understand the guide section titled "Components of a methods validation."

Review the template for the methods validation SOP example.

Review the template for the test method example.

Review the template for the methods validation protocol example.

Read the template for the methods validation report example.

Read and understand the flowcharts and checklist related to methods validation in steps 1- 4.

Develop your own systems and templates by adapting the systems and templates presented in this guide to your laboratory as appropriate.

Train your chemists on the systems.

Implement your systems.

1.4 ADDITIONAL POINTS TO CONSIDER WHEN VALIDATING CHROMATOGRAPHIC METHODS

In addition to the nuts and bolts of methods validation, many soft skills exist that will improve your chances of success during validation. Therefore, as you apply this guide to methods validation in your own laboratory, please keep the following points in mind.

Do Not Underestimate the Value of Planning and Organization

Much of methods validation is bookkeeping-both figuratively and literally. Therefore, much of the success of methods validation is dependent upon the amount of effort and attention to detail made in steps 1 and 2. The framework of what constitutes a methods validation is predetermined by FDA, ICH, and current industry practice. Think systematically and work with the end in mind. Therefore, by prioritizing and planning your...