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John Geigert

The Challenge of CMC


Regulatory Compliance
for Biopharmaceuticals
Fourth Edition
The Challenge of CMC Regulatory Compliance
for Biopharmaceuticals
John Geigert

The Challenge of CMC


Regulatory Compliance
for Biopharmaceuticals
Fourth Edition
John Geigert
BioPharmaceutical Quality Solutions
Carlsbad, CA, USA

ISBN 978-3-031-31908-2    ISBN 978-3-031-31909-9 (eBook)


https://doi.org/10.1007/978-3-031-31909-9

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2004, 2013, 2019, 2023
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by similar
or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any
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claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Preface

Preparing the fourth edition of my book was again a most humbling experience for
me. My primary purpose for updating the previous edition was to continue to pro-
vide relevant insight and practical suggestions for a common sense, cost-effective,
risk-managed approach to meeting the Chemistry, Manufacturing and Controls
(CMC) regulatory compliance requirements and expectations for biopharmaceuti-
cals as human medicinal products. But the scope of this approach was almost over-
whelming as there was so much that could not be included in this latest updated
edition. I trust that my choices will be of the most benefit to the upcoming next
generation of Project Management, Process Development, Manufacturing,
Analytical Development, Quality Control, Quality Assurance, and Regulatory
Affairs staff who take responsibility for ensuring the quality, efficacy, and safety of
these biopharmaceutical medicines for patients.
So many changes continue in the advancement of the protein-based biopharma-
ceuticals. Over 250 recombinant proteins, monoclonal antibodies, bispecific anti-
bodies, fusion proteins, antibody Fab and Fc fragments, antibody-drug conjugates
(ADCs) are now in the marketplace in both the United States of America (USA) and
European Union (EU). And not to forget that over 80 biosimilars are also now avail-
able across all major classes of off-patent recombinant proteins and monoclonal
antibodies.
The increasing entrance into the marketplace over the past 5 years of the gene
therapy-based biopharmaceuticals. Using genetically engineered viruses, genes
(DNA) are delivered either directly to the patient or to collected patient cells that
then get administered back to the patient, so that the patient becomes the “bioreac-
tor” producing the needed protein product. About 20 gene therapy-based biophar-
maceuticals are now market-approved, with an estimate of about 10 new therapies
to be approved every year going forward.
Another measure of the rapid degree of change occurring in the biopharmaceuti-
cal field is reflected in over 400 CMC regulatory compliance references listed in this
book that were either issued or updated since the release of the last edition.
I am indebted to two major regulatory authorities: the United States Food and
Drug Administration (FDA) and the European Medicines Agency (EMA). These

v
vi Preface

two regulatory authorities publish on their websites an abundance of CMC regula-


tory guidances (recommendations and expectations) to help the developing and
changing biopharmaceutical industry. In addition, they both upload (after a biophar-
maceutical medicine is market-approved) discussions, reviews, and meeting min-
utes during the biopharmaceutical review process, thus providing insights into how
the regulatory authority currently views the current application of manufacturer’s
biopharmaceutical CMC regulatory compliant strategy. Many of the references
listed in this book are from this information that is readily downloaded from their
websites. Thanks also goes to the International Council of Harmonisation (ICH), in
their harmonizing of consensus CMC guidelines. ICH has issued harmonized CMC
guidelines not only for the content to be included in biopharmaceutical submissions
seeking market approval (e.g., for viral safety evaluation, comparability of biophar-
maceuticals after a manufacturing process change, etc.) but also for the strategic
control for the complex biopharmaceutical manufacturing processes (e.g., for phar-
maceutical development, quality risk management, pharmaceutical quality system,
etc.). While the initial focus for ICH was on the protein-based biopharmaceuticals,
as their guidances are updated, aspects for the gene-therapy biopharmaceuticals are
being included. The ICH regulatory guidelines have driven the biopharmaceutical
industry to a higher standard of manufacturing excellence and quality control, intro-
ducing the principles of Quality by Design (QbD), Quality Risk Management
(QRM), Pharmaceutical Quality Systems (PQS), Knowledge Management (KM),
Established Conditions (EC), and Post-Approval Change Management Protocols
(PACMPs). It is for this reason that I have provided the FDA, EMA, and ICH web-
site locations (listed at the end of each chapter) for the many regulations, guidance
documents, and case examples that I have used in the preparation of this book.
Expediting clinical pathways have shortened the time in clinical development –
Breakthrough Therapy designation (BTD) and Regenerative Medicines Advanced
Therapy (RMAT) designation in the USA; PRIME (PRIority MEdicine) designa-
tion in the European Union. This shortening of the clinical study time from First-in-­
Human (FIH) entry studies to market approval (estimated to be at least a 2–3 year
savings) has placed great demands upon the CMC regulatory compliance strategy
with ever-decreasing time to complete all of the required development, optimiza-
tion, validation, site changes, etc. for the challenging biopharmaceutical manufac-
turing processes and complex products. 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. Discussion on how to effectively manage the CMC regulatory
compliance strategy under clinical expedited pathways is provided in this book.
Thanks also go to the companies who stumbled in their CMC regulatory compli-
ance 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 like a mystery. Sometimes this mystery is self-induced in our
companies, when the CMC team is not aware that an effective CMC regulatory
Preface vii

compliance strategy can be at hand. Through means of this fourth edition, I want to
show clearly the “good news” that CMC regulatory compliance no longer 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 information over-
load.” This is where this book becomes invaluable (along with the help of a good
CMC consultant of course) in sifting through all of the public guidance available to
determine which pieces are relevant for each specific biopharmaceutical manufac-
turing processes and product types. To reinforce that no commercial proprietary
information is revealed in this book, I have provided internet website addresses for
the comments on the various companies and their CMC biopharmaceutical issues,
mentioned in this book.
Throughout this book, I use the terms “biologic” or “biological” whenever I am
discussing CMC issues that apply across the board to pharmaceuticals that are (1)
derived from living organisms, (2) have challenging manufacturing processes, and
(3) are complex products. But, I use the terms “biopharmaceutical” or “recombinant
DNA-derived” whenever I am discussing CMC issues specific for biologics manu-
factured from genetically engineered living organisms.
In Chap. 1, defining the terminology used in CMC regulatory compliance of
biopharmaceuticals is paramount to being able to effectively communicate not only
throughout our industry but also with the regulatory authorities. Also, the increasing
diversity of biopharmaceutical product types is unveiled, with a discussion of the
four major “waves” of product types that have entered the marketplace from the
early 1990s through today. Today, there are the protein-based biopharmaceuticals
(the recombinant proteins and the monoclonal antibodies) and there are the ever-­
increasing number of gene therapy-based biopharmaceuticals (the viral vectors and
the genetically modified patient cells). In addition, a non-viral vector (mRNA) is
now being pursued in the clinic. Time will tell how abundant these human patient
“bioreactors” will become. In Chap. 2, the various regulatory pathways for initiat-
ing a clinical trial, for maintaining the clinical trial during its development and then
for seeking market approval for biopharmaceuticals, is examined, within the USA
and European Union regions. Differences in the regulatory pathways are discussed.
In Chap. 3, biopharmaceuticals are shown to be definitely different from chemical
drugs. This is not a perception, but a reality, and it is reflected by the statements on
regulatory authority websites and in the wording of the regulatory guidances that
they issue. Differences due to starting materials, differences due to the ability to
control the manufacturing process, and differences due to the molecular complexity
of the products are examined across four product types. Avoidance of the word “bio-­
generic” for biosimilars is discussed. In Chap. 4, why the risk-based approach is
absolutely necessary to effectively manage the minimum CMC regulatory compli-
ance continuum, due to the challenge in manufacturing and complexity of the result-
ing biopharmaceuticals, is examined. The ICH-recommended risk-based approach
for biopharmaceuticals – Quality by Design (QbD)/Quality Risk Management
(QRM) – is also discussed and shown to be an invaluable tool for establishing and
viii Preface

maintaining adequate and appropriate control for all biopharmaceutical types. In


Chap. 5, the four primary adventitious agents of concern for biopharmaceuticals are
examined in detail – prions, viruses, mycoplasma, bacteria/fungi. While each manu-
facturing process type has a different level of risk due to adventitious agent con-
tamination, there is no biopharmaceutical manufacturing process that carries no risk
of adventitious agent contamination. In Chap. 6, the significant differences between
the starting materials for the protein-based biopharmaceuticals (Master Cell Bank)
and the many starting materials for the gene therapy-based biopharmaceuticals (i.e.,
the viral vectors, transduced patient cells, mRNA non-viral vector) are evaluated. A
problem here can carry all the way through the manufacturing process to the final
administered biopharmaceutical product. In Chaps. 7 and 8, the risk-based require-
ments and expectations for an adequate and appropriate design and control of the
biopharmaceutical drug substance manufacturing stages are examined. Similarities
and differences between what is expected and what is doable for the drug substance
manufacture, across the four types of biopharmaceuticals (recombinant proteins and
monoclonal antibodies, viral and non-viral vectors, and genetically modified patient
cells), are compared and contrasted. In Chap. 9, the risk-based requirements and
expectations for an adequate and appropriate design and control of the biopharma-
ceutical drug product manufacturing stages – formulation, container closure, and
aseptic processing of filling/sealing – are examined. Sometimes between the puri-
fied drug substance and formulation, the drug substance is conjugated (e.g., anti-
body-drug conjugates, PEGylation). In Chaps. 10 and 11, compared to chemical
drugs, biopharmaceuticals have a large, complex biomolecular structure, seemingly
endless structural variants, and, in addition, a highly complex process-related impu-
rity profile, primarily due to the use of living systems involved in their manufactur-
ing process. The challenges for the physicochemical and functional characterization
of the different biopharmaceutical types – recombinant proteins, monoclonal anti-
bodies, genetically engineered viruses, genetically engineered cells, mRNA non-
viral vector – are examined, along with the use of a risk-based approach for
process-related impurity control (and hopefully reduction or removal through the
purification process). In Chap. 12, it is shown that because of the size and complex-
ity of a biopharmaceutical functional/therapeutic activity, assays are required for
strength/ potency measurement. In this chapter, the three types of functional activity
assays for measuring potency are examined: bioassay, surrogate, and assay matrix.
In Chap. 13, the seven major categories of Critical Quality Attributes (CQAs) are
explored. Specific testing to meet the requirements of each of these quality attri-
butes, for each biopharmaceutical type, is discussed. In Chap. 14, the art of specifi-
cation setting for biopharmaceuticals is examined – both for the release of batches
and for setting the shelf-life. The use of a risk-based approach to set the limits or
ranges through clinical development and into market approval for a
Preface ix

biopharmaceutical is discussed. The concept of an interim regulatory specification


for a to-be-marketed biopharmaceutical, especially when so few batches are avail-
able today to statistically set specifications, is explored. In Chap. 15, the three risk-
based concerns that need to be addressed by an effective comparability study are
examined. Demonstrating comparability for a biopharmaceutical after a manufac-
turing process change is no easy task, whether it be for a recombinant protein,
monoclonal antibody, viral vector, or genetically modified patient cells. In Chap. 16,
the critical importance of communicating with the regulatory authorities on the
CMC regulatory compliance strategy is 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.
CMC regulatory compliance strategy does not determine the direction of the
clinical development program; its primary purpose is to support it, but that does not
mean that we in CMC should avoid the tough decisions that scientists must make
when advancing the applications of genetic engineering toward human. Francis
S. Collins, the former Director of the United States National Institutes of Health
(NIH) and the Human Genome Project (HGP) laid out this thought for all to con-
sider [1]:
Is the science of genetics and genomics beginning to allow us to “play God”? That phrase
is the one most commonly used by those expressing concern about these advances, even
when the speaker is a nonbeliever. Clearly the concern would be lessened if we could count
on human beings to play God as God does, with infinite love and benevolence. Our track
record is not so good. Difficult decisions arise when a conflict appears between the mandate
to heal and the moral obligation to do no harm. But we have no alternative but to face those
dilemmas head-on, attempt to understand all of the nuances, include the perspectives of all
the stakeholders, and try to reach a consensus. The need to succeed at these endeavors is just
once more compelling reason why the current battles between the scientific and spiritual
worldviews need to be resolved – we desperately need both voices to be at the table, and not
to be shouting at each other.

Learning never ceases in the area of biopharmaceutical CMC regulatory compliance


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 constantly
amazed at the energy and creativity by my colleagues continually developing new
manufacturing process technologies and new product types, which demand chal-
lenging CMC strategies to effectively manage and ensure their regulatory compli-
ance. It is my sincere desire that this book will be of help to those who work in these
biopharmaceutical companies both today and for years to come. I encourage the
users of this book to seek to learn more on their own about CMC regulatory compli-
ance strategy for biopharmaceuticals.

Carlsbad, CA, USA John Geigert


x Preface

Reference

1. Collins FS. The language of god – a scientist presents evidence for belief. Free
Press/Simon & Schuster, Inc; 2007.

Photo courtesy of Nicki Geigert Photography


Acknowledgments

Many colleagues during my 50 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 sepa-
rate 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 biopharmaceutical
companies that I now serve as their consultant – for the many CMC regulatory com-
pliance 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 strong 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 genetic engineering on living cells to re-design them either to
over-produce recombinant proteins or monoclonal antibodies or to become a living
biopharmaceutical product itself such as a genetically engineered T-cell. As a scien-
tist who believes that God is the ultimate genetic engineer, I trust that scientists will
eventually comprehend and appreciate His original creative work.

Carlsbad, CA, USA John Geigert

xi
Contents

1 Biopharmaceutical Landscape����������������������������������������������������������������    1


1.1 Introduction��������������������������������������������������������������������������������������    1
1.2 What’s in a Name������������������������������������������������������������������������������    2
1.2.1 Terms: ‘Biologic’ and ‘Biological’��������������������������������������    2
1.2.2 Terms: ‘Biopharmaceutical’ and ‘rDNA-Derived’ ��������������    5
1.2.3 Terms: ‘ATMP’ and ‘CGTP’������������������������������������������������    7
1.3 Diversity of the Biopharmaceutical Product Landscape������������������    8
1.3.1 1st Wave – Recombinant Proteins����������������������������������������    8
1.3.2 2nd Wave – Monoclonal Antibodies ������������������������������������   10
1.3.3 3rd Wave – Biosimilars ��������������������������������������������������������   17
1.3.4 Transitioning to the ‘Fourth Wave’ of Biopharmaceuticals��   20
1.3.5 4th Wave – Gene Therapy-Based Biopharmaceuticals ��������   21
References��������������������������������������������������������������������������������������������������   28
2 
Regulatory Pathways Impacting Biopharmaceuticals ������������������������   31
2.1 Different Regulatory Pathways ��������������������������������������������������������   31
2.2 Navigating United States Regulation for Biopharmaceuticals ��������   32
2.2.1 Food, Drug, & Cosmetic (FD&C) Act����������������������������������   33
2.2.2 Public Health Services (PHS) Act����������������������������������������   35
2.2.3 Similarity in CMC Regulatory Requirements
Between the Two FDA Laws������������������������������������������������   37
2.2.4 Significant Differences in CMC Regulatory Requirements
Between the Two FDA Laws������������������������������������������������   40
2.2.5 CDER, CBER and CDRH����������������������������������������������������   47
2.3 Navigating the European Union Regulation for Biopharmaceuticals ���   48
2.3.1 NCA Review and Approval During Clinical Development��   49
2.3.2 EMA Review and Approval at Market Approval������������������   50
2.3.3 CMC Regulation Differences Between EMA and FDA
for Biopharmaceuticals ��������������������������������������������������������   51
2.4 Embrace the CMC Regulatory Compliance Complexity������������������   51
References��������������������������������������������������������������������������������������������������   53

xiii
xiv Contents

3 Differences in CMC Regulatory Compliance:


Biopharmaceuticals Versus Chemical Drugs����������������������������������������   57
3.1 Regulatory Authorities Agree ����������������������������������������������������������   57
3.2 Four Major CMC Regulatory Compliance Differences��������������������   60
3.2.1 Difference: Due to Type of Starting Material ����������������������   60
3.2.2 Difference: Due to Inconsistency of Manufactured Product   63
3.2.3 Difference: Due to Complexity of Molecular Structure ������   65
3.2.4 Difference: Biosimilars Are Not ‘Bio-Generics’������������������   69
3.3 The Times Are Changing������������������������������������������������������������������   74
References��������������������������������������������������������������������������������������������������   75
4 
Risk Management of the Minimum CMC Regulatory Compliance
Continuum������������������������������������������������������������������������������������������������   77
4.1 Strategic Risk Management Is Essential������������������������������������������   77
4.2 Minimum CMC Regulatory Compliance Continuum����������������������   78
4.3 Three Interactive CMC Regulatory Compliance Components ��������   79
4.3.1 CMC Regulatory������������������������������������������������������������������   80
4.3.2 cGMPs����������������������������������������������������������������������������������   86
4.3.3 Quality System����������������������������������������������������������������������   90
4.3.4 Industry Embracing the Three Interactive Regulatory
Components��������������������������������������������������������������������������   95
4.3.5 Consequences of Inadequate Senior Management
Support����������������������������������������������������������������������������������   97
4.4 QbD/QRM Risk-Based Approach���������������������������������������������������� 101
4.4.1 Quality Target Product Profile (QTPP) �������������������������������� 102
4.4.2 Critical Quality Attribute (CQA)������������������������������������������ 104
4.4.3 Critical Process Parameter (CPP) ���������������������������������������� 109
4.4.4 Control Strategy (CS) ���������������������������������������������������������� 112
4.4.5 Design Space for Biopharmaceuticals���������������������������������� 115
4.5 Limitations of Risk-Based CMC Regulatory Compliance �������������� 117
References�������������������������������������������������������������������������������������������������� 118
5 Ever-Present Threat of Adventitious Agent Contamination���������������� 121
5.1 Risk-Managing the Ever-Present Threat������������������������������������������ 122
5.2 Adventitious Prions�������������������������������������������������������������������������� 123
5.2.1 Prion Risk Assessment���������������������������������������������������������� 124
5.2.2 Prion Risk Control���������������������������������������������������������������� 125
5.2.3 Necessity of Ongoing Prion Risk Review���������������������������� 132
5.3 Adventitious Viruses ������������������������������������������������������������������������ 133
5.3.1 Virus Risk Assessment���������������������������������������������������������� 134
5.3.2 Virus Risk Control���������������������������������������������������������������� 135
5.3.3 No Room for Complacency with Adventitious Virus ���������� 152
5.4 Adventitious Mycoplasma���������������������������������������������������������������� 153
5.4.1 Mycoplasma Risk Assessment���������������������������������������������� 154
5.4.2 Mycoplasma Risk Control���������������������������������������������������� 155
5.4.3 CMC Strategy Tip: Improvements Sometimes Lead
to Other Problems ���������������������������������������������������������������� 161
Contents xv

5.5 Adventitious Bacteria/Fungi ������������������������������������������������������������ 162


5.5.1 Bacteria/Fungi Risk Assessment������������������������������������������ 162
5.5.2 Bacteria/Fungi Risk Control ������������������������������������������������ 163
5.5.3 CMC Strategy Tip: Not All Discoveries Have Been Made
Yet ���������������������������������������������������������������������������������������� 175
5.6 ‘Not Detected’ Is Not Confirmation of Absence������������������������������ 176
References�������������������������������������������������������������������������������������������������� 178
6 Starting Materials for Manufacturing the Biopharmaceutical
Drug Substance���������������������������������������������������������������������������������������� 183
6.1 In the Beginning�������������������������������������������������������������������������������� 183
6.2 Starting Material for Recombinant Proteins and Monoclonal
Antibodies ���������������������������������������������������������������������������������������� 185
6.2.1 Development Genetics – Steps Prior to Cell Banking���������� 185
6.2.2 Importance of Documenting Development Genetics������������ 188
6.2.3 Importance of the Single Clone�������������������������������������������� 192
6.2.4 CGMPs for Manufacture and Maintenance
of Cell Banks������������������������������������������������������������������������ 195
6.2.5 Characterization of Recombinant Cell Banks���������������������� 197
6.2.6 Recombinant Cell Bank Myth Busting �������������������������������� 201
6.2.7 Meeting CMC Regulatory Compliance for Cell Bank
Starting Materials������������������������������������������������������������������ 203
6.3 Starting Materials for Gene Therapy-Based Biopharmaceuticals���� 204
6.3.1 Development Genetics���������������������������������������������������������� 204
6.3.2 CGMPs Versus ‘Principles of GMP’������������������������������������ 205
6.3.3 CMC Information on Starting Materials in Regulatory
Submissions�������������������������������������������������������������������������� 207
6.3.4 Planning for the Logistical Challenges �������������������������������� 226
References�������������������������������������������������������������������������������������������������� 227
7 
Upstream Production of the Biopharmaceutical Drug Substance������ 231
7.1 At the Start of the DS Manufacturing Process���������������������������������� 231
7.2 Upstream Cell Culture Production of Recombinant Proteins
and Monoclonal Antibodies�������������������������������������������������������������� 233
7.2.1 Assembling the rProtein/mAb Upstream Production
Process���������������������������������������������������������������������������������� 234
7.2.2 Applying the Minimum CMC Regulatory Compliance
Continuum���������������������������������������������������������������������������� 240
7.2.3 Genetic Instability During Production of Protein-Based
Drug Substances������������������������������������������������������������������� 243
7.2.4 Meeting CMC Regulatory Compliance for Upstream
Production ���������������������������������������������������������������������������� 247
7.3 Upstream Cell Culture Production of Viral Vectors�������������������������� 249
7.3.1 Assembling the Viral Vector Production Process������������������ 249
7.3.2 Applying the Minimum CMC Regulatory Compliance
Continuum���������������������������������������������������������������������������� 253
7.3.3 Genetic Instability During Production of Viral Vectors�������� 256
xvi Contents

7.3.4 Meeting CMC Regulatory Compliance for Upstream


Production ���������������������������������������������������������������������������� 256
7.4 Upstream Production of Genetically Modified Patient Cells������������ 257
7.4.1 Assembling the Transduction Process���������������������������������� 257
7.4.2 Applying the Minimum CMC Regulatory Compliance
Continuum���������������������������������������������������������������������������� 261
7.4.3 Meeting CMC Regulatory Compliance for Upstream
Production ���������������������������������������������������������������������������� 264
7.5 Upstream IVT Production of Non-Viral Vector (mRNA)���������������� 265
7.5.1 Assembling the Non-Viral mRNA Production Process�������� 265
7.5.2 Meeting CMC Regulatory Compliance for Upstream
Production ���������������������������������������������������������������������������� 266
7.6 Looking into the Future�������������������������������������������������������������������� 267
References�������������������������������������������������������������������������������������������������� 268
8 Downstream Purification of the Biopharmaceutical
Drug Substance���������������������������������������������������������������������������������������� 271
8.1 At the End of the DS Manufacturing Process���������������������������������� 271
8.2 Downstream Purification of Recombinant Proteins
and Monoclonal Antibodies�������������������������������������������������������������� 273
8.2.1 Assembling the rProtein/mAb Downstream Purification
Process���������������������������������������������������������������������������������� 274
8.2.2 Applying the Minimum CMC Regulatory Compliance
Continuum���������������������������������������������������������������������������� 277
8.2.3 Value/Limitation of Reduced-Scale Purification Studies������ 282
8.2.4 Meeting CMC Regulatory Compliance for Downstream
Purification���������������������������������������������������������������������������� 285
8.3 Downstream Purification of Viral Vectors���������������������������������������� 286
8.3.1 Assembling the Viral Vector Downstream Purification
Process���������������������������������������������������������������������������������� 287
8.3.2 Applying the Minimum CMC Regulatory Compliance
Continuum���������������������������������������������������������������������������� 289
8.3.3 Value/Limitation of Reduced-Scale Purification Studies������ 291
8.4 Downstream Purification of Transduced Patient’s Cells������������������ 293
8.5 Downstream Purification of Non-viral mRNA �������������������������������� 294
8.5.1 Assembling the Non-viral Vector Downstream
Purification Process�������������������������������������������������������������� 294
8.5.2 Meeting CMC Regulatory Compliance for Downstream
Purification���������������������������������������������������������������������������� 295
8.6 Can We Speed Up Filling in the Knowledge Gap���������������������������� 296
References�������������������������������������������������������������������������������������������������� 296
9 
Manufacturing the Biopharmaceutical Drug Product ������������������������ 299
9.1 The Drug Product Manufacturing Process���������������������������������������� 299
9.2 Conjugation of the Purified Protein Drug Substance������������������������ 300
9.2.1 Antibody-Drug Conjugates (ADCs) ������������������������������������ 301
9.2.2 PEGylation���������������������������������������������������������������������������� 304
Contents xvii

9.3 Formulation�������������������������������������������������������������������������������������� 307


9.3.1 Formulation of Recombinant Proteins & Monoclonal
Antibodies ���������������������������������������������������������������������������� 308
9.3.2 Formulation of Gene Therapy Viral Vectors ������������������������ 311
9.3.3 Formulation of Genetically Modified Patient Cells�������������� 313
9.3.4 Formulation of mRNA Non-viral Vector������������������������������ 314
9.3.5 Formulation Changes – Tread Carefully������������������������������ 315
9.4 The Container Closure System �������������������������������������������������������� 316
9.4.1 Close Encounters Not Wanted: Product – Container-Closure
Interactions���������������������������������������������������������������������������� 317
9.4.2 Applying the Minimum CMC Regulatory Compliance
Continuum���������������������������������������������������������������������������� 318
9.4.3 Combination Products���������������������������������������������������������� 320
9.5 Stringent Aseptic Processing During the Filling/Sealing Process���� 321
9.5.1 Sterile Formulated Bulk Drug���������������������������������������������� 322
9.5.2 Aseptic Filling/Sealing Process Step������������������������������������ 323
9.6 Applying the Minimum CMC Regulatory Compliance
Continuum���������������������������������������������������������������������������������������� 326
9.7 Meeting CMC Regulatory Compliance for Drug Product
Manufacturing���������������������������������������������������������������������������������� 330
References�������������������������������������������������������������������������������������������������� 335
10 
Complex Process-Related Impurity Profiles ���������������������������������������� 339
10.1 Is It a Process-Related Impurity?���������������������������������������������������� 340
10.2 Process-Related Impurities Based on Manufacturing
Process Type ���������������������������������������������������������������������������������� 341
10.2.1 Recombinant Proteins and Monoclonal Antibodies���������� 342
10.2.2 Viral Vectors���������������������������������������������������������������������� 349
10.2.3 Genetically Modified Patient Cells������������������������������������ 353
10.2.4 mRNA Non-Viral Vector �������������������������������������������������� 357
10.3 Specific Process-Related Impurities ���������������������������������������������� 360
10.3.1 Residual DNA�������������������������������������������������������������������� 360
10.3.2 Residual Host Cell Proteins (HCPs)���������������������������������� 364
10.3.3 Residual Endotoxin – LAL and LER�������������������������������� 368
10.3.4 Leachables ������������������������������������������������������������������������ 370
10.4 Unknown Unknowns���������������������������������������������������������������������� 374
References�������������������������������������������������������������������������������������������������� 375
11 
Seemingly Endless Biomolecular Structural Variants�������������������������� 381
11.1 Is It a Biomolecular Structural Variant?������������������������������������������ 382
11.2 Recombinant Proteins and Monoclonal Antibodies������������������������ 384
11.2.1 Origin of the Protein Variants in the Manufacturing
Process������������������������������������������������������������������������������ 384
11.2.2 Structural Variants Due to the Nature of Proteins ������������ 387
11.2.3 Totality of Possible Biomolecular Structural Variants������ 388
11.2.4 Applying the Minimum CMC Regulatory Compliance
Continuum ������������������������������������������������������������������������ 390
xviii Contents

11.3 Viral Vectors������������������������������������������������������������������������������������ 393


11.3.1 Sources of Biomolecular Structural Variants�������������������� 393
11.3.2 Issue of Empty Capsids ���������������������������������������������������� 395
11.3.3 Applying the Minimum CMC Regulatory Compliance
Continuum ������������������������������������������������������������������������ 396
11.4 Genetically Modified Patient Cells ������������������������������������������������ 398
11.4.1 Sources of Biomolecular Structural Variants�������������������� 398
11.4.2 VCN – Not Too Much, Not Too Little������������������������������ 400
11.4.3 Applying the Minimum CMC Regulatory Compliance
Continuum ������������������������������������������������������������������������ 401
11.5 mRNA Non-Viral Vector���������������������������������������������������������������� 402
11.6 Variants – A Journey, Not a Destination ���������������������������������������� 403
References�������������������������������������������������������������������������������������������������� 404
12 Indispensable Potency (Biological Activity)������������������������������������������ 407
12.1 Is It Active? ������������������������������������������������������������������������������������ 408
12.2 Importance of the Potency Assay���������������������������������������������������� 409
12.2.1 Characterization���������������������������������������������������������������� 409
12.2.2 QC Batch-to-Batch Release���������������������������������������������� 411
12.2.3 QC Stability Program�������������������������������������������������������� 411
12.2.4 Product Comparability After Manufacturing Process
Changes ���������������������������������������������������������������������������� 412
12.2.5 Demonstration of Biosimilarity���������������������������������������� 413
12.3 Measurement of Biological Activity for Biopharmaceuticals�������� 413
12.3.1 Bioassay���������������������������������������������������������������������������� 414
12.3.2 Surrogate Assay ���������������������������������������������������������������� 417
12.3.3 Assay Matrix �������������������������������������������������������������������� 420
12.4 Applying the Minimum CMC Regulatory Compliance
Continuum�������������������������������������������������������������������������������������� 424
12.5 Missing the Target�������������������������������������������������������������������������� 427
References�������������������������������������������������������������������������������������������������� 428
13 Biopharmaceutical Critical Quality Attributes������������������������������������ 431
13.1 Appearance ������������������������������������������������������������������������������������ 432
13.1.1 Common Descriptors of Appearance�������������������������������� 432
13.1.2 Intrinsic Visible Particles �������������������������������������������������� 433
13.2 Identity�������������������������������������������������������������������������������������������� 435
13.2.1 Difference in Identity Between Chemical Drugs
and Biopharmaceuticals���������������������������������������������������� 435
13.2.2 Regulatory Guidance on Identity�������������������������������������� 436
13.2.3 Meeting the Criteria���������������������������������������������������������� 437
13.3 Purity/Impurities ���������������������������������������������������������������������������� 438
13.3.1 What Is Purity for a Biopharmaceutical?�������������������������� 438
13.3.2 Regulatory Guidance on Purity/Impurities������������������������ 438
13.4 Potency�������������������������������������������������������������������������������������������� 440
13.5 Quantity������������������������������������������������������������������������������������������ 441
13.5.1 Common Descriptors of Quantity ������������������������������������ 441
Contents xix

13.5.2 Regulatory Guidance on Quantity ������������������������������������ 442


13.5.3 Measurement of Quantity�������������������������������������������������� 442
13.6 Safety���������������������������������������������������������������������������������������������� 444
13.6.1 Safety from Adventitious Agents�������������������������������������� 444
13.6.2 Replication Competent Virus�������������������������������������������� 445
13.7 General�������������������������������������������������������������������������������������������� 447
13.8 Compiled Tables of CQAs for Different Biopharmaceutical
Types ���������������������������������������������������������������������������������������������� 447
13.8.1 FDA Released CQA Test Results�������������������������������������� 447
13.8.2 Project A-Gene������������������������������������������������������������������ 449
13.8.3 Project A-Cell�������������������������������������������������������������������� 452
13.8.4 mRNA (USP)�������������������������������������������������������������������� 454
References�������������������������������������������������������������������������������������������������� 455
14 The Art of Setting Biopharmaceutical Specifications – Release
and Shelf-Life ������������������������������������������������������������������������������������������ 459
14.1 What Is a Specification?������������������������������������������������������������������ 460
14.1.1 Connections Between Testing Categories ������������������������ 460
14.1.2 Specifications – Only as Reliable as the Test Method
Used���������������������������������������������������������������������������������� 462
14.2 Setting Release Specifications�������������������������������������������������������� 464
14.2.1 Spec Linkages�������������������������������������������������������������������� 464
14.2.2 Approaches to Setting Specs �������������������������������������������� 465
14.2.3 A Time for Everything – Including Statistics�������������������� 466
14.3 Setting Shelf-Life Specifications���������������������������������������������������� 468
14.3.1 Stability Assessment – A Regulatory Requirement���������� 469
14.3.2 Key Basics of the Stability Program���������������������������������� 470
14.4 In-Use Guidance for the Administered Drug���������������������������������� 472
14.5 Applying the Minimum CMC Regulatory Compliance
Continuum�������������������������������������������������������������������������������������� 473
14.5.1 Minimum … Continuum Applied to Release
Specifications�������������������������������������������������������������������� 474
14.5.2 Minimum … Continuum Applied to Shelf-Life
Specifications�������������������������������������������������������������������� 484
14.6 Release Specification Limits – Required Versus Recommended���� 491
14.6.1 Required Regulatory Release Specification Limits ���������� 491
14.6.2 Recommended Release Specification Limits�������������������� 493
14.7 Need to Get This Right the First Time�������������������������������������������� 495
References�������������������������������������������������������������������������������������������������� 496
15 
The Challenge of Demonstrating Biopharmaceutical Product
Comparability������������������������������������������������������������������������������������������ 499
15.1 Manufacturing Process Change Is Inevitable���������������������������������� 500
15.1.1 Process Change – Anytime and Anywhere������������������������ 500
15.1.2 Process Change – Should Be Value-Added ���������������������� 501
15.1.3 Process Change – ICH Q5E Adapted for all
Biopharmaceutical Types�������������������������������������������������� 502
xx Contents

15.1.4 The Comparability Study Must Address


Three Risk-Based Concerns���������������������������������������������� 503
15.2 Level of Risk Due to Stage of Clinical Development When
Change Is Planned�������������������������������������������������������������������������� 505
15.3 Level of Risk Due to Nature (Type, Extent, Location) of Planned
Process Change ������������������������������������������������������������������������������ 508
15.3.1 Assigning Risk Levels to Proposed Manufacturing
Process Changes���������������������������������������������������������������� 509
15.3.2 Risk Levels for Recombinant Proteins and Monoclonal
Antibodies�������������������������������������������������������������������������� 510
15.3.3 Risk Levels for Viral Vectors and Genetically
Modified Patient Cells ������������������������������������������������������ 514
15.3.4 Established Conditions (ECs)�������������������������������������������� 516
15.4 Level of Risk Due to Residual Uncertainty Still Remaining���������� 517
15.5 PACMPs – Comparability ‘Contracts’�������������������������������������������� 520
15.6 Clear Communication – Comparability Missteps Not Allowed ���� 523
References�������������������������������������������������������������������������������������������������� 525
16 
Strategic CMC-Focused Interactions with Regulatory Authorities���� 527
16.1 CMC Regulatory Compliance Strategy – Teamwork Required������ 528
16.2 Clinical Development Milestones – Opportunities
for CMC Strategy Discussions�������������������������������������������������������� 530
16.2.1 FDA’s Encouragement for Milestone Meetings���������������� 530
16.2.2 EMA’s Encouragement for Scientific Meetings���������������� 534
16.3 Expedited Clinical Development – Opportunities for Additional
Discussions ������������������������������������������������������������������������������������ 536
16.4 Securing a CMC Strategy-Focused Meeting���������������������������������� 539
16.4.1 PDUFA Meetings with FDA �������������������������������������������� 540
16.4.2 BsUFA Meetings with FDA���������������������������������������������� 542
16.4.3 Scientific Advice Meetings with EMA������������������������������ 543
16.5 Defending the CMC Strategy During the BLA/MAA Review������ 545
16.5.1 FDA BLA Review Process������������������������������������������������ 545
16.5.2 EMA MAA Review Process���������������������������������������������� 552
16.6 Why So Many Problems with Biopharmaceutical
CMC Strategy?�������������������������������������������������������������������������������� 558
16.7 Biopharmaceutical CMC Regulatory Compliance
Strategy Future�������������������������������������������������������������������������������� 560
References�������������������������������������������������������������������������������������������������� 561

Index������������������������������������������������������������������������������������������������������������������ 565
List of Figures

Fig. 1.1 Amino acid sequence for the 51 amino acid recombinant
human insulin������������������������������������������������������������������������������������������ 9
Fig. 1.2 Amino acid linear schematic for the 570 amino acid
recombinant human Xenpozyme���������������������������������������������������������� 10
Fig. 1.3 X-ray crystal 3-dimension structure of the 497 amino acid
recombinant human Vpriv�������������������������������������������������������������������� 10
Fig. 1.4 Two-dimensional schematic of the IgG monoclonal antibody ������������ 12
Fig. 1.5 Two-dimensional schematic of a bispecific antibody �������������������������� 14
Fig. 1.6 Molecular schematic of some market-approved engineered
antibody fragments�������������������������������������������������������������������������������� 16
Fig. 1.7 Molecular schematic of some commercial antibody-drug
conjugates (ADCs)�������������������������������������������������������������������������������� 17
Fig. 1.8 FDA’s description of a biosimilar �������������������������������������������������������� 19
Fig. 1.9 Manufacture of protein-based biopharmaceuticals
(waves 1, 2, 3) �������������������������������������������������������������������������������������� 21
Fig. 1.10 Manufacture of gene therapy-based biopharmaceuticals
(wave 4)������������������������������������������������������������������������������������������������ 22
Fig. 1.11 Two main approaches to inserting gene therapy-base
biopharmaceuticals into patients���������������������������������������������������������� 24
Fig. 1.12 Schematic illustrating the structure of a recombinant AAV
viral vector�������������������������������������������������������������������������������������������� 24
Fig. 1.13 Schematic illustrating the anti-CD19 CAR transduced
onto a T-cell������������������������������������������������������������������������������������������ 25
Fig. 2.1 The pharmaceutical regulatory system in the United States ���������������� 33
Fig. 2.2 Regulatory drug development pathways in the USA���������������������������� 33
Fig. 2.3 The pharmaceutical regulatory system in the European Union������������ 49
Fig. 2.4 Regulatory drug development pathway in the European Union ���������� 49
Fig. 3.1 Difference due to type of starting material across
the four product types �������������������������������������������������������������������������� 61
Fig. 3.2 Difference due to inconsistency of manufactured product
across the four product types���������������������������������������������������������������� 64
xxi
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SOUFFLÉS.

The admirable lightness[132] and delicacy of a well-made soufflé


render it generally a very favourite dish, and it is now a fashionable
one also. It may be greatly varied in its composition, but in all cases
must be served the very instant it is taken from the oven; and even in
passing to the dining-room it should, if possible, be prevented from
sinking by a heated iron or salamander held above it. A common
soufflé-pan may be purchased for four or five shillings, but those of
silver or plated metal, which are of the form shown at the
commencement of this chapter, are of course expensive; the part in
which the soufflé is baked is placed within the more ornamental dish
when it is drawn from the oven. A plain, round, cake-mould, with a
strip of writing paper six inches high, placed inside the rim, will
answer on an emergency to bake a soufflé in. The following receipt
will serve as a guide for the proper mode of making it: the process is
always the same whether the principal ingredient be whole rice
boiled very tender in milk and pressed through a sieve, bread-
crumbs soaked as for a pudding and worked through a sieve also,
arrow-root, potato-flour, or aught else of which light puddings in
general are made.
132. This is given to every description of soufflé in the same manner as to Savoy
or sponge-cakes, by mingling gently with the other ingredients the whites of
eggs whisked to a solid mass or snow froth,—that is to say, that no portion of
them must remain in a liquid state. For the proper mode of preparing them,
see commencement of the chapter of Cakes, page 540: soufflé-puddings are
rendered light in the same manner, and steamed instead of being boiled.

Take from a pint and a half of new milk or of cream sufficient to


mix four ounces of flour of rice to a perfectly smooth batter; put the
remainder into a very clean, well-tinned saucepan or stewpan, and
when it boils, stir the rice briskly to it; let it simmer, keeping it stirred
all the time, for ten minutes, or more should it not be very thick; then
mix well with it two ounces of fresh butter, one and a half of pounded
sugar, and the grated rind of a fine lemon (or let the sugar which is
used for it be well rubbed on the lemon before it is crushed to
powder); in two or three minutes take it from the fire, and beat
quickly and carefully to it by degrees the yolks of six eggs; whisk the
whites to a very firm solid froth, and when the pan is buttered, and all
else quite ready for the oven, stir them gently to the other
ingredients; pour the soufflé immediately into the pan and place it in
a moderate oven, of which keep the door closed for a quarter of an
hour at least. When the soufflé has risen very high, is of a fine
colour, and quite done in the centre, which it will be in from half to
three-quarters of an hour, send it instantly to table. The exact time
for baking it depends so much on the oven that it cannot be precisely
specified. We have known quite a small one not too much baked in
forty-five minutes in an iron oven; but generally less time will suffice
for them: the heat, however, should always be moderate.
New milk or cream, 1-1/2 pint; flour of rice, 4 oz.; fresh butter, 2
oz.; pounded sugar, 1-1/2 oz.; eggs, 6; grain of salt; rind, 1 lemon: 30
to 45 minutes.
Obs. 1.—The soufflé may be flavoured with vanilla, orange-
flowers, or aught else that is liked. Chocolate and coffee also may be
used for it with soaked bread: a very strong infusion of the last, and
an ounce or two of the other, melted with a little water, are to be
added to the milk and bread.
Obs. 2.—A soufflé is commonly served in a dinner of ceremony as
a remove of the second-course roast; but a good plan for this, as for
a fondu, is to have it quickly handed round, instead of being placed
upon the table.
LOUISE FRANKS’ CITRON SOUFFLÉ.

To obtain the flavour of the citron-rind for this celebrated Swedish


soufflé, take a lump of sugar which weighs two ounces and a half,
and rub it on the fruit to extract the essence, or should the citron not
be sufficiently fresh to yield it by this means, pare it off in the thinnest
possible strips and infuse it by the side of the fire in the cream of
which the soufflé is to be made. Should the first method be pursued,
crush the sugar to powder and dry it a little before it is added to the
other ingredients. Blend very smoothly two ounces of potato-flour
with a quarter of a pint of milk, and pour boiling to them a pint of
good cream; stir the mixture in a large basin or bowl until it thickens,
then throw in a grain of salt, two ounces of fresh butter just dissolved
in a small saucepan, and the sugar which has been rubbed on the
citron; or should the rind have been pared, the same weight some of
which is merely pounded. Add next, by degrees, the thoroughly
whisked yolks of six fresh eggs, or seven should they be very small.
Beat the whites lightly and quickly until they are sufficiently firm to
remain standing in points when dropped from the whisk; mix them
with the other ingredients at the mouth of the oven, but without
beating them; fill the soufflé-pan less than half full; set it instantly into
the oven, which should be gentle, but not exceedingly slow, close the
door immediately, and do not open it for fifteen or twenty minutes: in
from thirty to forty the soufflé will be ready for table unless the oven
should be very cool: a fierce degree of heat will have a most
unfavourable effect upon it.
Rind of half citron (that of a Seville orange may be substituted on
occasions); sugar, 2-1/2 oz.; cream, 1 pint; potato-flour, 2 oz.; milk,
1/4 pint; butter, 2 oz.; yolks and white of 6 large or of 7 small eggs:
30 to 40 minutes, or more in very slow oven.
Obs.—The fresh citron would appear to be brought as yet but very
sparingly into the English market, though it may sometimes be
procured of first-rate fruiterers. Nothing can well be finer than its
highly aromatic flavour, which is infinitely superior to that of any other
fruit of its species that we have ever tasted. We have had delicious
preparations made too from the young green citron when extremely
small, of which we may have occasion to speak elsewhere.
A FONDU, OR CHEESE SOUFFLÉ.

Mix to a smooth batter, with a quarter of a pint of new milk, two


ounces of potato-flour, arrow-root, or tous les mois; pour boiling to
them three-quarters of a pint more of milk, or of cream in preference:
stir them well together, and then throw in two ounces of butter cut
small. When this is melted, and well-beaten into the mixture, add the
well-whisked yolks of four large or of five small eggs, half a
teaspoonful of salt, something less of cayenne, and three ounces of
lightly-grated cheese, Parmesan or English, or equal parts of both.
Whisk the whites of the eggs to a quite firm and solid froth; then
proceed, as for a soufflé, to mix and bake the fondu.
20 minutes.
OBSERVATIONS ON OMLETS, FRITTERS, &C.

The composition and nature of a soufflé, as we have shown, are


altogether different, but there is no difficulty in making good omlets,
pancakes, or fritters; and as they may be expeditiously prepared and
served, they are often a very convenient resource when, on short
notice, an addition is required to a dinner. The eggs for all of them
should be well and lightly whisked; the lard for frying batter should be
extremely pure in flavour, and quite hot when the fritters are dropped
in; the batter itself should be smooth as cream, and it should be
briskly beaten the instant before it is used. All fried pastes should be
perfectly drained from the fat before they are served, and sent to
table promptly when they are ready. Eggs may be dressed in a
multiplicity of ways, but are seldom more relished in any form than in
a well-made and expeditiously served omlet. This may be plain, or
seasoned with minced herbs and a very little eschalot, when the last
is liked, and is then called an “Omlette aux fines herbes;” or it may
be mixed with minced ham, or grated cheese; in any case, it should
be light, thick, full-tasted, and fried only on one side; if turned in the
pan, as it frequently is in England, it will at once be flattened and
rendered tough. Should the slight rawness which is sometimes found
in the middle of the inside, when the omlet is made in the French
way, be objected to, a heated shovel, or a salamander, may be held
over it for an instant, before it is folded on the dish. The pan for frying
it should be quite small; for if it be composed of four or five eggs
only, and then put into a large one, it will necessarily spread over it
and be thin, which would render it more like a pancake than an
omlet; the only partial remedy for this, when a pan of proper size
cannot be had, is to raise the handle of it high, and to keep the
opposite side close down to the fire, which will confine the eggs into
a smaller space. No gravy should be poured into the dish with it, and
indeed, if properly made, it will require none. Lard is preferable to
butter for frying batter, as it renders it lighter; but it must not be used
for omlets.
A COMMON OMLET.

Six eggs are sufficient for an omlet of moderate size. Let them be
very fresh; break them singly and carefully; clear them in the way we
have already pointed out in the introduction to boiled puddings, or
when they are sufficiently whisked pour them through a sieve, and
resume the beating until they are very light. Add to them from half to
a whole teaspoonful of salt, and a seasoning of pepper. Dissolve in a
small frying-pan a couple of ounces of butter, pour in the eggs, and
as soon as the omlet is well risen and firm throughout, slide it on to a
hot dish, fold it together like a turnover, and serve it immediately;
from five to seven minutes will fry it.
For other varieties of the omlet, see the observations which
precede this.
Eggs, 5; butter, 2 oz.; seasoning of salt and pepper: 5 to 7
minutes.
AN OMLETTE SOUFFLÉ. SECOND COURSE REMOVE OF
ROAST.[133]
133. Served also as an entremets.

Separate, as they are broken, the whites from the yolks of six fine
fresh eggs; beat these last thoroughly, first by themselves and then
with four tablespoonsful of dry, white sifted sugar, and the rind of half
a lemon grated on a fine grater. Whisk the whites to a solid froth, and
just before the omlet is poured into the pan, mix them well, but
lightly, with the yolks. Put four ounces of fresh butter into a very
small delicately clean omlet or frying pan, and as soon as it is all
dissolved, add the eggs and stir them round that they may absorb it
entirely. When the under side is just set, turn the omlet into a well-
buttered dish, and send it to a tolerably brisk oven. From five to ten
minutes will bake it; and it must be served the instant it is taken out;
carried, indeed, as quickly as possible to table from the oven. It will
have risen to a great height, but will sink and become heavy in a
very short space of time: if sugar be sifted over it, let it be done with
the utmost expedition.
Eggs, 6; sugar, 4 tablespoonsful; rind, 1/2 lemon; butter, 4 oz.:
omlet baked, 5 to 10 minutes.
Obs.—This omlette may be served on a layer of apricot-
marmalade which must be spread over the dish in which it is to be
baked, and sent to table before the omlette is turned into it.
PLAIN COMMON FRITTERS.

Mix with three well-whisked eggs a quarter of a pint of milk, and


strain them through a fine sieve; add them gradually to three large
tablespoonsful of flour, and thin the batter with as much more milk as
will bring it to the consistence of cream; beat it up thoroughly at the
moment of using it, that the fritters may be light. Drop it in small
portions from a spouted jug or basin into boiling lard; when lightly
coloured on one side, turn the fritters, drain them well from the lard
as they are lifted out, and serve them very quickly. They are eaten
generally with fine sugar, and orange or lemon juice: the first of these
may be sifted quickly over them after they are dished, and the
oranges or lemons halved or quartered, and sent to table with them.
The lard used for frying them should be fresh and pure-flavoured: it
renders them more crisp and light than butter, and is, therefore,
better suited to the purpose. These fritters may be agreeably varied
by mingling with the batter just before it is used two or three ounces
of well cleaned and well dried currants, or three or four apples of a
good boiling kind not very finely minced. Double the quantity of
batter will be required for a large dish.
Eggs, 3; flour, 3 tablespoonsful; milk, 1/4 to 1/2 pint.
PANCAKES.

These may be made with the same batter as fritters, if it be


sufficiently thinned with an additional egg or two, or a little milk or
cream, to spread quickly over the pan: to fry them well, this ought to
be small. When the batter is ready, heat the pan over a clear fire and
rub it with butter in every part, then pour in sufficient batter to spread
over it entirely, and let the pancake be very thin: in this case it will
require no turning, but otherwise it must be tossed over with a
sudden jerk of the pan, in which the cook who is not somewhat
expert will not always succeed; therefore the safer plan is to make
them so thin that they will not require this. Keep them hot before the
fire or in the stove-oven until a sufficient number are ready to send to
table, then proceed with a second supply, as they should always be
quickly served. Either pile them one on the other with sugar strewed
between, or spread quickly over them, as they are done, some
apricot or other good preserve, and roll them up: in the latter case,
they may be neatly divided and dished in a circle. Clotted cream is
sometimes sent to table with them. A richer kind of pancake may be
made with a pint of cream, or of cream and new milk mixed, five
eggs or their yolks only, a couple of ounces of flour, a little pounded
cinnamon or lemon-rind rasped on sugar and scraped into them, with
two ounces more of pounded sugar, and two ounces of clarified
butter: a few ratifias rolled to powder may be added at pleasure, or
three or four macaroons.
From 4 to 5 minutes.
FRITTERS OF CAKE AND PUDDING.

Cut plain pound, or rice cake, or rich seed cake, into small square
slices half an inch thick; trim away the crust, fry them slowly a light
brown in a small quantity of fresh butter, and spread over them when
done a layer of apricot-jam, or of any other preserve, and serve them
immediately. These fritters are improved by being moistened with a
little good cream before they are fried: they must then be slightly
floured. Cold plum-pudding sliced down as thick as the cake, and
divided into portions of equal size and good form, then dipped into
French or English batter and gently fried, will also make an
agreeable variety of fritter. Orange marmalade and Devonshire
cream may be served in separate layers on the seed cake fritters.
The whole of the above may be cut of uniform size and shaped with
a round cake-cutter.
MINCEMEAT FRITTERS.

With half a pound of mincemeat mix two ounces of fine bread-


crumbs (or a tablespoonful of flour), two eggs well beaten, and the
strained juice of half a small lemon. Mix these well, and drop the
fritters with a dessertspoon into plenty of very pure lard or fresh
butter; fry them from seven to eight minutes, drain them on a napkin
or on white blotting paper, and send them very hot to table: they
should be quite small.
Mincemeat, 1/2 lb.; bread-crumbs, 2 oz. (or flour, 1 tablespoonful);
eggs, 2; juice of 1/2 lemon: 7 to 8 minutes.
VENETIAN FRITTERS.

(Very good.)
Wash and drain three ounces of whole rice, put it into a full pint of
cold milk, and bring it very slowly to boil; stir it often, and let it
simmer gently until it is quite thick and dry. When about three parts
done, add to it two ounces of pounded sugar, and one of fresh butter,
a grain of salt, and the grated rind of half a small lemon. Let it cool in
the saucepan, and when only just warm, mix with it thoroughly three
ounces of currants, four of apples chopped fine, a teaspoonful of
flour, and three large or four small well-beaten eggs. Drop the
mixture in small fritters, fry them in butter from five to seven minutes,
and let them become quite firm on one side before they are turned:
do this with a slice. Drain them as they are taken up, and sift white
sugar over them after they are dished.
Whole rice, 3 oz.; milk, 1 pint; sugar, 2 oz.; butter, 1 oz.; grated
rind of 1/2 lemon; currants, 3 oz.; minced apples, 4 oz.; flour, 1
teaspoonful; a little salt; eggs, 3 large, or 4 small: 5 to 7 minutes.
RHUBARB FRITTERS.

The rhubarb for these should be of a good sort, quickly grown, and
tender. Pare, cut it into equal lengths, and throw it into the French
batter of page 130; with a fork lift the stalks separately, and put them
into a pan of boiling lard or butter: in from five to six minutes they will
be done. Drain them well and dish them on a napkin, or pile them
high without one, and strew sifted sugar plentifully over them. They
should be of a very light brown, and quite dry and crisp. The young
stalks look well when left the length of the dish in which they are
served, and only slightly encrusted with the batter, through which
they should be merely drawn.
5 to 6 minutes.
APPLE, PEACH, APRICOT, OR ORANGE FRITTERS.

Pare and core without dividing the apples, slice them in rounds the
full size of the fruit, dip them into the same batter as that directed for
the preceding fritters, fry them a pale brown, and let them be very
dry. Serve them heaped high upon a folded napkin, and strew sifted
sugar over them. After having stripped the outer rind from the
oranges, remove carefully the white inner skin, and in slicing them
take out the pips; then dip them into the batter and proceed as for
the apple fritters. The peaches and apricots should be merely
skinned, halved, and stoned before they are drawn through the
batter, unless they should not be fully ripe, when they must first be
stewed tender in a thin syrup.
8 to 12 minutes
BRIOCHE FRITTERS.

The brioche-paste,[134] when good, makes very superior


cannelons and fritters: it is, we should say, better in this form than in
that of the bun or cake, in which it is seen so commonly abroad.
Make it, for the fritters, into very small balls; roll them quite thin, put a
teaspoonful or less of rich preserve into each, moisten the edges
and fold the paste together securely, or with a small tin shape cut as
many rounds of the brioche as are wanted, place some preserve in
the centre of one half of these, moisten the edges, lay the remainder
lightly over them, press them carefully together and restore them to a
good form with the tin-cutter, by trimming them with it to their original
size; glide them gently into a pan of boiling lard, and fry them from
four and a half to five minutes. Serve them very hot, crisp, and dry,
piled on a folded napkin. The cannelons are made like those of
paste, and are very good. They are sometimes filled with lemon-
cheesecake mixture, or with Madame Werner’s (see Chapter XVIII.)
134. For this see page 347.
Fritters, 4-1/2 to 5 minutes; cannelons, 5 to 6 minutes.
POTATO FRITTERS. (ENTREMETS.)

The same mixture as for potato puddings, Chapter XXI., if dropped


in small portions into boiling butter, and fried until brown on both
sides, will make potato-fritters. Half the proportion of ingredients will
be quite sufficient for a dish of these.
LEMON FRITTERS. (ENTREMETS.)

Mix with six ounces of very fine bread-crumbs four of beef suet
minced as small as possible, four ounces of pounded sugar, a small
tablespoonful of flour, four whole eggs well and lightly whisked, and
the grated rind of one large or of two small lemons, with half or the
whole of the juice, at choice; but before this last is stirred in, add a
spoonful or two of milk or cream if needed. Fry the mixture in small
fritters for five or six minutes.
CANNELONS. (ENTREMETS.)

Roll out very thin and evenly some


fine puff-paste into a long strip of from
three to four inches wide, moisten the
surface with a feather dipped in white
of egg, and cut it into bands of nearly
two inches wide; lay some apricot or
peach marmalade equally along
these, and fold the paste twice over it,
close the ends carefully, and when all
are ready, slide them gently into a pan of boiling lard;[135] as soon
as they begin to brown, raise the pan from the fire that they may not
take too much colour before the paste is done quite through. Five
minutes will fry them. Drain them well, and dry them on a soft cloth
before the fire; dish them on a napkin, and place one layer crossing
another, or merely pile them high in the centre. If well made, and
served of a light brown and very dry, these cannelons are excellent:
when lard is objected to butter may be used instead, but the paste
will then be somewhat less light. Only lard of the purest quality will
answer for the purpose.
135. Cannelons may be either baked or fried: if sent to the oven, they may first be
glazed with white of egg and sugar.

5 minutes.
CANNELONS OF BRIOCHE PASTE. (ENTREMETS.)

Proceed exactly as for the cannelons above, substituting the


brioche for the puff-paste, and rolling it as thin as possible, as it
swells very much in the pan. Fine sugar may be sifted over these
after they are dried and dished.
4 or 5 minutes.

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