Validation of Biopharmaceutical Manufacturing Processes

195 Pages·1998·16.14 MB·English

by  Brian D. Kelley and R. Andrew Ramelmeier (Eds.)

Validation of Biopharmaceutical
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In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
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In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
ACS SYMPOSIUM SERIES 698
Validation of Biopharmaceutical
Manufacturing Processes
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19 Brian D. Kelley, EDITOR
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A San Francisco, California,

April 13-17, 1997
AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC
In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
RS 380 .V34 1998 C.1
Validation of
biopharmaceutical
Library of Congress Cataloging-in-Publication Data
Validation of biopharmaceutical manufacturing processes / Brian D. Kelley, R.
Andrew Ramelmeier.
p. cm.—(ACS symposium series, ISSN 0097-6156; 698)
"Developed from a symposium sponsored by the Division of Biochemical
Technology at the 213th National Meeting of the American Chemical Society,
San Francisco, California, April 13-17, 1997."
1 Includes bibliographical references and indexes.
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0
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8.f ISBN 0-8412-3567-8
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6
8-0 1. Pharmaceutical biotechnology—Congresses.
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1 I. Kelley, Brian D., 1964- . II. Ramelmeier, R. Andrew. III. American
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b Chemical Society. Division of Biochemical technology. IV. American Chemical
21/ Society. Meeting (213th : 1997: San Francisco, Calif.) V. Series.
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10. RS380.V34 1998
cs.org 98 | doi: 615'.19—dc21 98-186C1IP7
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In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
Advisory Board
ACS Symposium Series
Mary E. Castellion Omkaram Nalamasu
ChemEdit Company AT&T Bell Laboratories
01 Arthur B. Ellis Kinam Park
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06 Jeffrey S. Gaffney Katherine R. Porter
998- Argonne National Laboratory Duke University
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2 University of Kansas
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cs.org 98 | doi: Nabisco Foods Group MEasatmrtainn CRh.e Tmaicnalt Co.
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1D Research Institute
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In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
Foreword
THE ACS SYMPOSIUM SERIES was first published in 1974 to provide
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00 a mechanism for publishing symposia quickly in book form. The pur
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In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
Preface
The papers published in this volume were drawn from a session entitled Vali
dation of Biopharmaceutical Manufacturing Processes held at the 1997 Ameri
can Chemical Society National Meeting in San Francisco. The session was
sponsored by the Division of Biochemical Technology. Attendance at the ses
sion was strong throughout the day, as eighteen papers were presented on many
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0 aspects of process validation. We believe this reflects the importance of valida
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8. tion in the licensure and manufacturing of biopharmaceuticals, including recom
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0 binant and non-recombinant proteins, vaccines, agents for genetic therapies, and
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99 carbohydrate-based drugs.
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21/ which may lead to a complex mixture of product isoforms; often, these are
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0.1 poorly characterized in comparison to low molecular weight compounds. This
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must remain focused on the primary motivation for completing a process vali
dation package, which is to demonstrate both an understanding of the manufac
turing process and how to control the process so that product of sufficient qual
ity and yield is produced in a consistent manner. The application of sound
scientific, engineering, and statistical methods are necessary to complete this
task.
The intent of this volume is to provide a forum for the presentation of vari
ous components of a process validation package. The papers address all aspects
of biopharmaceutical manufacturing processes, including cell culture and fer
mentation, product purification, and fill-finish operations. A symposium series
book of this size cannot possibly convey information on all topics required for
ix
In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
complete process validation; however, we hope that this book is useful as a ref
erence which provides insights into the design and execution of process valida
tion studies from a number of companies, many of which hold licenses for the
manufacture of biotherapeutics and vaccines.
Acknowledgments
The editors thank all those who made oral presentations at the ACS meeting, and
especially those who contributed manuscripts for this book. We recognize the
sensitive nature of preparing material on process validation to be shared with a
larger audience, and are deeply grateful to those who persevered through it all.
We also thank the reviewers, whose efforts have assured that the chapters in this
book are of the highest technical and compositional quality.
1
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69 Genetics Institute, Inc.
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0 Merck Research Laboratories
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In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
Chapter 1
Historical, Current, and Future Trends for Validating
Biological Processes
R. Andrew Ramelmeier1, Brian D. Kelley2, and Christi Van Horn3
1Merck Research Laboratories, West Point, PA, 19486
2Genetics Institute, Inc., Andover, MA, 01810
3Merck Manufacturing Division, West Point, PA 19486
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0 Since the early 1970's, the FDA has stressed the importance of process
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c validation for manufacturing drugs and medical devices. The emphasis was placed first
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9 on sterilization validation and aseptic processing. More recently, however, the
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9 established specific requirements in the CFR and issued guidelines (1), but the
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bk- interpretation of the validation requirements, especially for biological products, can
21/ vary. This is attributed, in part, to rapidly advancing technologies in the biotechnology
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0.1 industry. To facilitate the "validation process" in the biotech industry, some
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gu cleaning validation). The latter are described in great detail in other texts (2-5). The
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well as those presented or published by others in the industry (2,3,6,7).
Background
Incentive for validating a biopharmaceutical manufacturing process. Those who
do not fully grasp the fundamental significance of process validation often view it as
tedious, repetitive and time consuming. So, why do it? The most compelling reason is
that validation makes good scientific and engineering sense. Other industries
(aerospace, automotive, and cosmetic, for example) have long embraced the concept of
validation to assure safe and high quality products. If experiments, analytical assays,
©1998 American Chemical Society 1
In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
2
equipment operations, vendor evaluations, process scale-up and other related activities
are completed and documented properly from process development through production
start-up, then the validation package is developed with the process. In this way, the
quality assurance and FDA compliance goals are achieved as well. A solid validation
strategy can also result in significant economic benefit as lot rejection or recall can be
prevented and less troubleshooting will be required. In addition, early consideration of
validation requirements and development of a validation plan can save a company time
and money by preventing costly delays.
Definitions As many organizations and companies have adopted their own "language"
for describing the validation process, the authors felt the need to define the key terms
and concepts that will be used throughout this chapter and this book. Consistent and
proper use of these terms and concepts will reduce confusion when discussing process
1 validation. The key terms are as follows:
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99 its pre-determined specifications and quality characteristics (1).
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1 what it purports to do based on a pre-planned protocol (9). Often, these activities are
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A Critical Process Parameters - the important process variables which affect the

process outcome.
Critical Quality Attributes - the corresponding critical measures of process
outcome or performance.
Scaled-down model - an accurate representation of the full-scale production
process at a smaller scale. Generally, before a scaled-down model is used for validation
studies, the model must be qualified with respect to performance at full-scale.
Worst-case - the conditions where upper and lower processing limits and
circumstances, including those within standard operating procedures, which pose the
greatest chance of process or product failure when compared to ideal conditions (1).
This condition, however, should not result in process failure.
In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1998.