The Challenge of CMC Regulatory Compliance for Biopharmaceuticals

446 Pages·2019·7.672 MB·English

by  John Geigert

John Geigert
The Challenge of
CMC Regulatory
Compliance for
Biopharmaceuticals
Third Edition
The Challenge of CMC Regulatory Compliance
for Biopharmaceuticals
John Geigert
The Challenge of CMC
Regulatory Compliance
for Biopharmaceuticals
Third Edition
John Geigert
BioPharmaceutical Quality Solutions
Carlsbad, CA, USA
Originally Published with the title: “The Challenge of CMC Regulatory Compliance
for Biopharmaceuticals and Other Biosimilars”
ISBN 978-3-030-13753-3 ISBN 978-3-030-13754-0 (eBook)
https://doi.org/10.1007/978-3-030-13754-0
Library of Congress Control Number: 2019934774
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Preface
If you are humble, nothing will touch you, neither praise nor disgrace, because you know
what you are.
Mother Teresa, Missionaries of Charity in Calcutta, India, 1910–1997
Preparing the third edition of my book was a most humbling experience for me. My
primary purpose for updating the second edition was to continue to provide relevant
insight and practical suggestions for a risk-managed, common-sense, practical busi-
ness approach to managing the chemistry, manufacturing, and controls (CMC) reg-
ulatory compliance requirements and expectations for biopharmaceuticals as human
medicinal products. But the scope of this approach was almost overwhelming as
there was so much that could not be included in the updated edition. Also, the more
I evaluated what to include in the updated edition, the more I realized how little I
really understood about everything that has occurred over the past 5 years, and con-
tinuing to occur, in this field of biopharmaceuticals. I trust that my choices will be
of the most benefit.
The magazine, Popular Mechanics, www.popularmechanics.com, made a bold
prediction in their January 2000 issue. Looking forward to 2050, it stated, “We
expect the first part of the twenty-first century to usher in a new golden age of phar-
maceuticals. It will begin with the introduction of a powerful arsenal of weapons
against the 200 or so diseases we call cancer.” Well, we are not there yet by any
means, but so much has changed since the second edition of this book was pub-
lished in 2013. The degree of change is reflected in the over 400 CMC regulatory
compliance references listed in this book that were either issued or updated since
the release of the second edition.
Since the second edition, there continues to be a surge of additional recombinant
proteins and monoclonal antibody medicines reaching the marketplace. Commercial
monoclonal antibodies today now include linkage with a chemical drug (referred to
as antibody-drug conjugates, ADCs) as well as antibodies genetically engineered to
have dual functional binding activities (referred to as bi-specific mAbs). The mono-
v
vi Preface
clonal antibody Humira (adalimumab) continues to be the best-selling medicine in
the world, annually since 2014.
Since the second edition, biosimilars not only have made a major impact in Europe
but also the United States. Currently, there are biosimilars of all major classes of recom-
binant proteins and monoclonal antibodies that have lost their patent protection.
But, the greatest surprise in biopharmaceuticals since the second edition is the
explosion of interest and clinical success in gene therapy products – the living
genetically engineered viruses and cell biopharmaceuticals. These living biophar-
maceuticals (referred to as Cell & Gene Therapy Products (CGTPs) in the United
States and Advanced Therapy Medicinal Products (ATMPs) in Europe) have intro-
duced a totally different set of CMC challenges compared to the nonliving protein-
based biopharmaceuticals.
I am indebted to two major regulatory authorities: the United States Food and
Drug Administration (FDA) and the European Medicines Agency (EMA). These
two regulatory authorities publish on their websites an abundance of guidance to
help our biopharmaceutical industry. But they also upload pieces of their CMC
discussions and meetings with biopharmaceutical manufacturers seeking market
approvals, thus providing insights into how the regulatory authority thinks about
CMC strategy. The vast majority of references listed in this book are from informa-
tion that I have been able to readily download from their websites. Praise also goes
to the International Council for Harmonisation (ICH), in there harmonizing of CMC
guidances. Not only have they harmonized CMC content guidances for biopharma-
ceuticals been issued (e.g., for viral safety evaluation, comparability of biopharma-
ceuticals after a manufacturing process change, etc.) but also CMC strategic
guidances (i.e., Q8, Q9, Q10, Q11, Q12). These strategic ICH regulatory guidances
have driven the biopharmaceutical industry to a higher standard of manufacturing
excellence and quality control, introducing the principles of quality by design
(QbD), quality risk management (QRM), pharmaceutical quality systems (PQS),
and knowledge management (KM). It is for this reason that I have provided website
addresses for the regulations, guidance documents, and case examples that were
used in the preparation of this book.
A profound change since the second edition of this book has been the introduc-
tion of expediting pathways offered to speed up clinical development – break-
through therapy designation and regenerative medicine advanced therapy (RMAT)
designation in the United States and PRIME (priority medicines) designation in
Europe. This shortening of the time from entry into first-in-human (FIH) studies to
market approval (estimated to be at least a 2-year savings) has placed great demands
upon the CMC regulatory compliance strategy with ever-decreasing time to com-
plete all of the required development, optimization, and validation for the challeng-
ing biopharmaceutical manufacturing processes. This enhanced pressure on the
CMC teams has not gone unnoticed by the regulatory authorities, and they are
keenly aware of the potential delays in biopharmaceutical product market approval
that now can be due to CMC issues.
Thanks also go to the companies who stumbled in their CMC regulatory strategy,
resulting in delay or rejection of their biopharmaceutical, so that we can learn from
their mistakes. At times, an effective CMC regulatory compliance strategy can seem
Preface vii
like a mystery. Sometimes this mystery is self-induced in our companies – (1) job
security, especially for regulatory affairs personnel and project managers who mas-
ter the CMC strategy or (2) the infamous proprietary defense – divulging this CMC
regulatory strategy only to limited members within one’s own company or group,
that is, the initiated. Sometimes, the mystery is due to the staff not being aware that
an effective CMC regulatory compliance strategy can be at hand. Through this third
edition, I want to reveal the “good news” that CMC regulatory compliance no lon-
ger has to be a mystery. But I also want to caution against the “bad news” that there
can be too much CMC regulatory compliance information available, “an informa-
tion overload.” This is where this book becomes invaluable (along with the help of
a good consultant of course) in sifting through all of the public guidance available
to determine which pieces are relevant for specific biopharmaceutical manufactur-
ing processes and product types. To reinforce that no proprietary information is used
in this book, I have provided Internet website locators for the public communication
of the information that has been used.
Throughout this book, I use the terms “biopharmaceutical” or “biotechnology-
derived” or “rDNA-derived” or “recombinant” whenever I am discussing CMC
issues specific for genetically engineered products. On the other hand, I use the
terms “biologic” or “biological” whenever I am discussing CMC issues that apply
to both natural-sourced and genetically engineered products.
In Chap. 1, the complexity of biologic CMC regulatory compliance is unveiled.
The multiple pathways for regulatory approval both within the United States and the
European Union can appear confusing for biopharmaceuticals and place pressure on
the regulatory affairs group within a company, especially in explaining to those in
their company why a biopharmaceutical is treated under one pathway and not
another. In Chap. 2, biopharmaceuticals will be shown to be definitely different from
chemical drugs. This is not a perception but a reality, and it is reflected by the state-
ments on regulatory authority websites and in the wording of the regulatory guid-
ances that they issue. The four major differences between biopharmaceuticals and
chemical drugs are discussed. In Chap. 3, the two major forces that shape the corpo-
rate CMC regulatory compliance strategy for biopharmaceuticals are examined.
Also, the five key design elements that comprise an effective corporate CMC regula-
tory compliance strategy for biopharmaceuticals are discussed. In Chap. 4, the four
primary adventitious agents of concern for biopharmaceuticals are examined in
detail, and the three complementary core risk control procedures for these contami-
nating agents are discussed. In addition, lessons learned from previously reported
infectious agent contaminations of biopharmaceuticals are reviewed. In Chap. 5, the
significant differences between source materials for chemical drugs and biopharma-
ceuticals are evaluated. Three myths about biopharmaceutical cell banks will be
debunked. In Chap. 6, the risk-based requirements and expectations for an adequate
and appropriate control of the biopharmaceutical API manufacturing process, across
the life cycle of the product, are explored. The manufacturing of the different bio-
pharmaceutical types – recombinant proteins, monoclonal antibodies, genetically
engineered viruses and cells – will be compared and contrasted. In Chap. 7, the
impact on the manufacture of the biopharmaceutical final product, from the design
of the formulation, coupled with the choice for an appropriate product-c ompatible
viii Preface
container closure system, and the challenge of aseptic processing control on CMC
regulatory compliance are examined. In addition, the regulatory and safety concerns
around manufacture of an antibody-drug conjugate (ADC) are examined. In Chap.
8, it will be shown that, compared to chemical drugs, biopharmaceuticals have a
much more complex process-related impurity profile, primarily due to the use of
living systems involved in the manufacturing process. A risk-based approach is
essential for their control (and hopefully reduction or removal from the process)
through the life cycle of the biopharmaceutical. In Chap. 9, the importance of the
physicochemical and functional characterization of the different biopharmaceutical
types  – recombinant proteins, monoclonal antibodies, genetically engineered
viruses, and genetically engineered cells – is examined. Characterization is a jour-
ney with new test methods providing more depth of knowledge about our products.
In Chap. 10, it will be shown that because of the size and complexity of a biophar-
maceutical, functional/therapeutic activity assays are required for strength/potency
measurement. In this chapter, the three types of functional activity assays for mea-
suring potency will be examined: bioassay, surrogate, and assay matrix. In Chap. 11,
the seven major categories of quality attributes will be explored. Specific testing to
meet the requirements of each of these quality attributes, for each biopharmaceutical
type, will be discussed. In Chap. 12, the proper design of a biopharmaceutical stabil-
ity program, and the appropriate interpretation of the stability data, in order to cor-
rectly assign the shelf life for a biopharmaceutical, is discussed. In Chap. 13, the art
of specification setting for biopharmaceuticals is examined. The use of a risk-based
approach to set the limits or ranges through clinical development and into market
approval for a biopharmaceutical is discussed. The concept of an interim regulatory
specification for a to-be-marketed biopharmaceutical, especially when so few
batches are available today to statistically set specifications, is explored. In Chap.
14, the three key elements of an effective comparability study for a biopharmaceuti-
cal after a manufacturing process change will be examined. The challenge of con-
firming analytical biosimilarity for a biosimilar will be discussed. In Chap. 15, the
critical importance of communicating with the regulatory authorities on the CMC
regulatory compliance strategy will be stressed. Finally, in this chapter, an encour-
agement is given to senior management to take advantage of CMC-focused meet-
ings available with the regulatory authorities.
Learning never ceases in the area of biopharmaceutical CMC regulatory compli-
ance strategy. After 40 years in the biopharmaceutical industry, I would have thought
by now that there would be “nothing new under the sun” to learn. But I am con-
stantly amazed at the energy and creativity by my colleagues continually develop-
ing new manufacturing process technologies and new product types, which demand
challenging CMC strategies to effectively manage and ensure their regulatory com-
pliance. It is my sincere desire that this book will be of help to those who work in
these biopharmaceutical companies both today and for many years to come. I
encourage the users of this book to seek to learn more on their own about CMC
regulatory compliance strategy for biopharmaceuticals.
Carlsbad, CA, USA John Geigert
Acknowledgments
Many colleagues over my 40 years of service in the biopharmaceutical industry
have impacted my understanding of CMC regulatory compliance strategy and have
indirectly contributed to the writing of this book. I would like to especially acknowl-
edge my friends and colleagues at my former companies (all of which now have
been acquired by larger biopharmaceutical companies and no longer exist as
separate entities)  – Cetus Corporation, Immunex Corporation, and IDEC
Pharmaceuticals – for the insights and experiences that we shared. I would also like
to acknowledge my new friends and colleagues in the many companies that I now
serve as their consultant – for the many CMC regulatory compliance strategies that
we wrestle with.
A special expression of appreciation goes to my wife, Nicki, who understood the
time commitment and mental exhaustion that comes along with trying to update a
book of this magnitude and for her patient support and encouragement again
throughout this entire lengthy process.
Quoting from Albert Einstein, Nobel laureate in Physics, “The most beautiful
thing we can experience is the mysterious. It is the source of all art and science. He
to whom this emotion is a stranger, who can no longer pause to wonder and stand
rapt in awe, is as good as dead; his eyes are closed.” I have been in awe watching
my fellow scientists unravel the ever-increasing intricate complexity and design of
life – carrying out their genetic engineering on living cells to redesign them either
to overproduce recombinant proteins or monoclonal antibodies or to become a liv-
ing biopharmaceutical product itself such as a genetically engineered T cell. As a
scientist who believes that God is the ultimate genetic engineer, I wonder how much
scientists will eventually comprehend and appreciate His original creative work.
Carlsbad, CA, USA John Geigert
ix
Contents
1 C omplexity of Biologics CMC Regulation . . . . . . . . . . . . . . . . . . . . . . 1
1.1 What’s in a Name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.1.1 Terms: “Biologic” and “Biological” . . . . . . . . . . . . . . . . . . 2
1.1.2 Terms: “Biotechnology-Derived”
and “Biopharmaceutical” . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.1.3 Terms: “Biosimilar” and “Similar Biotherapeutic
Product” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.1.4 Terms: “CGTP” and “ATMP” . . . . . . . . . . . . . . . . . . . . . . . 7
1.2 Navigating United States Biologic Regulation . . . . . . . . . . . . . . . . 9
1.2.1 Food, Drug, & Cosmetic (FD&C) Act . . . . . . . . . . . . . . . . 10
1.2.2 Public Health Service (PHS) Act . . . . . . . . . . . . . . . . . . . . 11
1.2.3 Confusion About Which Law Applies to Proteins . . . . . . . 12
1.2.4 Significant CMC Regulatory Differences
Between the Two Laws . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.2.5 Two FDA Centers to Execute
Two Pharmaceutical Laws . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.3 Navigating the European Union Biologic Regulation . . . . . . . . . . 21
1.3.1 Legal Definition of “Biological” in the EU . . . . . . . . . . . . 22
1.3.2 Biologic Regulation During Clinical Development . . . . . . 22
1.3.3 Biologic Regulation at Market Approval . . . . . . . . . . . . . . 23
1.4 Navigating Other Country Biologic Regulation . . . . . . . . . . . . . . . 24
1.5 Embrace the CMC Complexity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2 B iopharmaceuticals Are Not Chemical Drugs . . . . . . . . . . . . . . . . . . . 33
2.1 Regulatory Authorities Agree . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2.2 I CH Responds to CMC Differences. . . . . . . . . . . . . . . . . . . . . . . . . 35
2.3 Four Major CMC Differences of Biopharmaceuticals . . . . . . . . . . . 36
2.3.1 Synthesis of the Product. . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.3.2 Impact of the Manufacturing Process on the Product . . . . . 38
2.3.3 Complexity of the Manufactured Product . . . . . . . . . . . . . . 43
xi