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Full download The Challenge of CMC Regulatory Compliance for Biopharmaceuticals, 4th 4th Edition John Geigert file pdf all chapter on 2024
Full download The Challenge of CMC Regulatory Compliance for Biopharmaceuticals, 4th 4th Edition John Geigert file pdf all chapter on 2024
Full download The Challenge of CMC Regulatory Compliance for Biopharmaceuticals, 4th 4th Edition John Geigert file pdf all chapter on 2024
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John Geigert
© 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
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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
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
Reference
1. Collins FS. The language of god – a scientist presents evidence for belief. Free
Press/Simon & Schuster, Inc; 2007.
xi
Contents
xiii
xiv Contents
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.
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.
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.
(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.
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.)
5 minutes.
CANNELONS OF BRIOCHE PASTE. (ENTREMETS.)