Validating chromatographic methods : a practical guide

297 Pages·2006·2.128 MB·English

by  David M Bliesner

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VALIDATING
CHROMATOGRAPHIC
METHODS
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VALIDATING
CHROMATOGRAPHIC
METHODS
A Practical Guide
DAVID M.BLIESNER
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Copyright © 2006 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
Published simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data:
Bliesner, David M.
Validating chromatographic methods : a practical guide/by David
M. Bliesner.
p. cm.
Includes bibliographical reference and index.
ISBN-13: 978-0-471-74147-3
ISBN-10: 0-471-74147-7 (acid-free paper)
1. Chromatographic analysis––Validity. 2. Science––Methodology.
I. Title.
QD79. C4B57 2006
543(cid:1)8––dc22 2005036658
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
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CONTENTS
PREFACE vii
1. OVERVIEW OF METHODS VALIDATION 1
2. COMPONENTS OF METHODS VALIDATION 8
3. STEP 1:METHOD EVALUATION AND
FURTHER DEVELOPMENT 15
4. STEP 2:FINAL METHOD DEVELOPMENT AND TRIAL
METHODS VALIDATION 28
5. STEP 3:FORMAL METHODS VALIDATION AND
REPORT GENERATION 41
6. STEP 4:FORMAL DATA REVIEW AND
REPORT ISSUANCE 48
7. SUMMARY 55
APPENDICES
I. GLOSSARY OF METHODS VALIDATION
TERMS 57
II. TEMPLATE FOR AN EXAMPLE METHODS
VALIDATION STANDARD OPERATING
PROCEDURE (SOP) 72
v
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vi CONTENTS
III. TEMPLATE FOR AN EXAMPLE END-USER
REQUIREMENTS QUESTIONNAIRE 154
IV. TEMPLATE FOR AN EXAMPLE METHOD
REVIEW CHECKLIST 156
V. TEMPLATE FOR AN EXAMPLE STANDARD
TEST METHOD 159
VI. TEMPLATE FOR AN EXAMPLE METHODS
VALIDATION PROTOCOL 169
VII. TEMPLATE FOR AN EXAMPLE METHODS
VALIDATION REPORT 218
REFERENCES 283
INDEX 285
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PREFACE
Delphi Analytical Services,Inc. has spent the past several years helping com-
panies in the pharmaceutical industry improve their level of compliance with
current good manufacturing practices (CGMPs). This involvement has
included large and small companies who have already been subject to regu-
latory action from the Food and Drug Administration (FDA) as well as com-
panies who are taking preventative measures to avoid regulatory action. As
part of this effort,a significant amount of time has been spent reviewing ana-
lytical and bioanalytical methods and methods validation documentation.
Unfortunately, our experience leads us to conclude that despite improved
guidance from the FDA, leadership by the International Conference on
Harmonization (ICH), and the plethora of validation experts and courses, a
substantial need still exists for education,training,and periodic retraining in
the field of methods validation.
Make no mistake, analytical methods validation is not a trivial undertak-
ing. And like snowflakes,no two are exactly alike. However,our experience
has brought us in contact with what we consider to be the best practices in the
industry. In addition, we have seen some of the mistakes that often degrade
the overall quality of the finished product:A validated,transferable,analyti-
cal method that will serve its end users for an extended period of time with
minimal complications.
In our experience, very few labs have it “all together” and execute all the
components of a methods validation well. This guide was written with the
intent to bring order to the potentially chaotic process of methods validation.
vii
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viii PREFACE
If you are new to methods validation, we hope to provide you with enough
practical information and tools to keep you from having to reinvent the wheel
by having to develop your own systems and to attack methods validation
from scratch. If you are experienced with methods validation, we hope you
will use this guide to upgrade and improve your existing systems.
This guide focuses on chromatographic methods validation, specifically
high performance liquid chromatographic (HPLC) methods validation. This
approach was chosen in that HPLC is by far the most common analytical
technique used in modern pharmaceutical analytical R&D/QC laboratories.
However,the concepts are in many cases directly applicable to validation of
other analytical techniques as well.
In that CGMPs are always changing (hence the “C” meaning “current”)
and the industry is always improving and upgrading its best practices, we
encourage your feedback and comments so that we can keep this guide in line
with the best practices of the industry. We look forward to your input and
hope this guide assists you in your continuing quest for quality.
DAVIDM. BLIESNER
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CHAPTER 1
OVERVIEW OF METHODS VALIDATION
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 proce-
dures 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. [1]
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 concur-
rently. 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 assur-
ance (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.
Validating Chromatographic Methods. By David M. Bliesner
Copyright © 2006 John Wiley & Sons,Inc.
1
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2 OVERVIEW OF METHODS VALIDATION
(3) Show how you met the acceptance criteria in a final methods valida-
tion 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 labo-
ratory 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 hypothe-
sized 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.
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STEPS IN THE CHROMATOGRAPHIC METHODS VALIDATION PROCESS 3
STEP 1
Method Evaluation and Further Method Development
(~1 to 2 Months)
STEP 2
Final Method Development and Trial Methods Validation
(~3 to 4 Months)
STEP 3
Formal Methods Validation and Report Generation
(~1 to 2 Months)
STEP 4
Formal Data Review and Report Issuance
(~1 to 2 Months)
FIGURE 1.1 Steps in the chromatographic methods validation process. Total time for
method evaluation,validation,data/documentation review,and reporting is approximately 6to
10 months.
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 proj-
ect. There is an enduring myth in the pharmaceutical industry that it should
only take six weeksto 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 prod-
uct 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