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 Active Pharmaceutical
Ingredients
Development, Manufacturing, and Regulation

edited by

Stanley H. Nusim
S. H. Nusim Associates, Inc.
Aventura, Florida, U.S.A.

Boca Raton London New York Singapore

Published in 2005 by
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742

© 2005 by Taylor & Francis Group, LLC

No claim to original U.S. Government works
Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1
International Standard Book Number-10: 0-8247-0293-X (Hardcover)
International Standard Book Number-13: 978-0-8247-0293-9 (Hardcover)
This book contains information obtained from authentic and highly regarded sources. Reprinted material is
quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts
have been made to publish reliable data and information, but the author and the publisher cannot assume
responsibility for the validity of all materials or for the consequences of their use.
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Preface

Active pharmaceutical ingredients known today as ‘‘APIs’’ are

organic chemicals, generally synthetic, that are the subject of
this book. These ingredients are chemicals that will be used
in a final pharamaceutical dosage form. The manufacturing
of these chemicals is a subsection of fine chemical manufactur-
ing. This subsection of the chemical industry has undergone
very significant changes in much the same manner, but
perhaps trailing, the pharmaceutical industry that manufac-
tured the final dosage form.
The ‘‘pharmaceutical industry’’ at the turn of the 20th
century was essentially the local pharmacy (or ‘‘chemist’’ as
it was also known). The ‘‘bulk pharmaceutical chemical indus-
try’’ at that time was merely a provider of all those laboratory
chemicals, including solvents and excipients as well as APIs
needed by the local pharmacist to compound the prescribing
doctor’s formulation.
Over this past century, as with many industries, enor-
mous changes have occurred in the pharmaceutical industry,
causing equally significant changes for API suppliers. It is
these changes, many of which have accelerated in recent
decades, that suggested the need for a definitive reference
for this manufacturing activity.
iii
iv Preface

At one time following routine chemical manufacturing

practices would have been sufficient; however, this is no
longer the case. Not only has there been a significant shift
in the government regulations that control the redefined
‘‘quality’’ of the product, but a very intensive look at the devel-
opment of the process to be used as well as the manufacturing
activities required to make the API.
This focus is to ensure that the API is produced in an
environment that ensures it is free of contamination that
may be introduced from inherent process impurities but also
from the manufacturing environment itself. The latter is con-
trolled by the so-called ‘‘cGMPs’’ (current Good Manufacturing
Practices), while the former by the nature of the chemical pro-
cess and the level of quality assurance that the process pro-
vides; hence, a focus on the process development is essential.
It is the intent of this volume to focus on the three overall
activities that bring an API to market; the development of the
chemical process, the manufacturing activity utilizing that
process, and the governmental regulations that control the
approval of the product so that it may be commercially mar-
keted. This book brings together information into a single
source that will allow those in the field to be sure they are
up to date. In addition, it will provide to those organizations
that are planning to enter this field, the basic information
needed to think through, understand, and effectively plan
bulk manufacturing of an API.
The rapidly changing environment that has occurred in
the past decades shows no signs of easing; thus, this volume
will be a starting point. Ongoing continuing attention to all
aspects of these issues is an absolute necessity to ensure that
manufactured APIs will meet the newest standards in an
environment that has seen many changes in the market itself
as well as its regulation, product mix, and volume.
This text covers those three activities of development,
manufacturing, and regulation in its broadest sense. This will
include discussions on the process development cycle,
introduction of the process into factory design engineering,
regulatory matters that include the regulatory approval pro-
Preface v

cess, quality control=assurance, and validation as well as the

standard plant manufacturing operation activities including
materials management and planning and maintenance. In
addition, it will discuss other plant operational issues includ-
ing safety and environmental issues that are part of any che-
mical manufacturing operation.
I have chosen to exclude fermentation and other biologi-
cal processes from this book although products from those
processes continue to be an increasingly important source of
pharmaceutical actives in today’s world. This decision was
made because the chemical routes remain the largest source
of actives to the pharmaceutical industry. Actives supplied
by biological processes are no less important than chemically
generated actives but are sufficiently different to be worthy of
their own volume.
I wish to express my thanks to the publisher for its invi-
tation to assemble this book and particularly to Sandra
Beberman for bearing with me in the very long and tedious
development process for the book. Her advice and encourage-
ment throughout this process was a primary driving force to
ensure its completion.

Stanley H. Nusim
Contents

Preface . . . . iii
Contributors . . . . xiii

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Stanley H. Nusim
I. Consolidation and Integration . . . . 2
II. Quality . . . . 2
III. Potency . . . . 5
IV. Computer Control and Automation . . . . 6
V. Summary . . . . 7

2. Process Development . . . . . . . . . . . . . . . . . . . . . 9
Carlos B. Rosas
I. Introduction . . . . 9
II. The Bulk Drug Process as Part of the
Drug Development Program . . . . 13
III. From the Bench to the Pilot
Plant and Beyond . . . . 39
IV. The Physicochemical Attributes of the
Bulk Drug . . . . 61
V. The Process Body of Knowledge . . . . 65
VI. Processing Responsibility in Bulk Drug
Process Development . . . . 73
VII. Outsourcing in Bulk Drug
Process Development . . . . 89
vii
viii Contents

VIII. In Closing . . . . 89
References . . . . 90

3. Bulk Drugs: Process Design, Technology Transfer,

and First Manufacture . . . . . . . . . . . . . . . . . . . 93
Carlos B. Rosas
I. Introduction . . . . 93
II. The Process Design Task in Bulk
Drugs . . . . 96
III. Technology Transfer of the Bulk Drug
Process and First Manufacture . . . . 106
IV. In Closing—The Processing Technologies of
Bulk Drugs . . . . 123
References . . . . 125

4. Design and Construction of Facilities . . . . . . . 127

Steven Mongiardo and Eugene Bobrow
I. Introduction . . . . 127
II. Business Requirements . . . . 129
III. Developing the Preliminary Scope . . . . 132
IV. Utilities and Building Systems . . . . 137
V. Preliminary Scope Deliverables . . . . 138
VI. Design Development . . . . 142
VII. Utilities . . . . 147
VIII. Safety . . . . 150
IX. Current Good Manufacturing Practices
Requirements . . . . 150
X. Qualification Plan . . . . 151
XI. Expansion Capabilities . . . . 152
XII. Hazard and Operability Analysis . . . . 152
XIII. Execution Strategy and Planning . . . . 154
XIV. Procurement Strategy . . . . 156
XV. Construction Management . . . . 161
XVI. Start–Up Acceptance . . . . 162
XVII. Project Turnover and Installation
Qualification . . . . 163
XVIII. Conclusions . . . . 165
References . . . . 166
Contents ix

5. Regulatory Affairs . . . . . . . . . . . . . . . . . . . . . . . 167

John Curran
I. Introduction . . . . 167
II. Requirements for Submission of
Regulatory CMC Documents . . . . 169
III. Contents of Regulatory
Submissions—API Sections . . . . 173
IV. Registration Samples . . . . 191
V. The Review and Approval Process . . . . 192
VI. Preapproval Inspections . . . . 195
VII. Postapproval Change Evaluations . . . . 196
VIII. The Future . . . . 199
IX. Helpful References . . . . 200

6. Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
James Agalloco and Phil Desantis
I. History . . . . 203
II. Definition of Validation . . . . 205
III. Regulations . . . . 206
IV. Application of Validation . . . . 206
V. Life Cycle Model . . . . 206
VI. Validation of New Products . . . . 207
VII. Validation of Existing Products . . . . 208
VIII. Implementation . . . . 209
IX. Bulk Pharmaceutical Chemical
Validation . . . . 211
X. In-Process Controls . . . . 220
XI. Cleaning Validation . . . . 222
XII. Computerized Systems . . . . 225
XIII. Procedures and Personnel . . . . 225
XIV. Validation of Sterile Bulk Production . . . . 225
XV. Conclusion . . . . 231
References . . . . 231

7. Quality Assurance and Control . . . . . . . . . . . . 235

Michael C. VanderZwan
I. Introduction . . . . 235
II. Defining and Assuring the Quality of the Active
Pharmaceutical Ingredient . . . . 240
x Contents

III. The Regulations for Quality . . . . 245

IV. The Quality Control and Quality
Assurance Department . . . . 273
Appendix A . . . . 280

8. Plant Operations . . . . . . . . . . . . . . . . . . . . . . . . 285

Stanley H. Nusim
I. Plant Organization . . . . 285
II. Batch vs. Continuous . . . . 286
III. Dedicated vs. Shared Manufacturing
Facilities . . . . 288
IV. Shift Operations . . . . 288
V. Sterile Operations . . . . 291
VI. Clean Room . . . . 294
VII. Cost Control . . . . 296
VIII. Fixed Overhead Absorption . . . . 299
IX. Safety . . . . 300
X. Environmental . . . . 303

9. Materials Management . . . . . . . . . . . . . . . . . . . 305

Victor Catalano
I. Introduction . . . . 305
II. Production Planning . . . . 306
III. Inventory Management . . . . 307
IV. Purchasing=Supply Management . . . . 308
V. Distribution=Transportation . . . . 315
VI. Information Technology . . . . 316
VII. Quality Management . . . . 317
References . . . . 318

10. Plant Maintenance . . . . . . . . . . . . . . . . . . . . . . 323

Raymond J. Oliverson
I. Introduction . . . . 323
II. Strategic Plan . . . . 324
III. Reliability-Balanced Scorecards . . . . 325
IV. Maintenance Basics . . . . 327
V. Condition Monitoring . . . . 329
VI. Operator-Driven Reliability . . . . 330
Contents xi

VII. Reliability Engineering . . . . 331

VIII. Risk Management . . . . 333
IX. Summary . . . . 334

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Contributors

James Agalloco Agalloco & Associates, Inc., Belle Meade,

New Jersey, U.S.A.

Eugene Bobrow Merck & Co., Inc., Whitehouse Station,

New Jersey, U.S.A.

Victor Catalano Purchasing Group Inc. (PGI), Nutley,

New Jersey, U.S.A.

John Curran Merck & Co., Inc., Whitehouse Station,

New Jersey, U.S.A.

Phil Desantis Schering-Plough Corp., Kenilworth,

New Jersey, U.S.A.

Steven Mongiardo Merck & Co., Inc., Whitehouse Station,

New Jersey, U.S.A.

Stanley H. Nusim S. H. Nusim Associates Inc., Aventura,

Florida, U.S.A.

Raymond J. Oliverson HSB Reliability Technologies,

Kingwood, Texas, U.S.A.

xiii
xiv Contributors

Carlos B. Rosas Rutgers University, New Brunswick,

New Jersey, U.S.A.

Michael C. VanderZwan Pharmaceutical Technical,

Roche Pharmaceuticals, Basel, Switzerland
1
Introduction
STANLEY H. NUSIM

S. H. Nusim Associates Inc., Aventura, Florida, U.S.A.

I. Consolidation and Integration . . . . . . . . . . . . . . . . . . 2

II. Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
III. Potency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
IV. Computer Control and Automation . . . . . . . . . . . . . . . 6
V. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Pharmachemical manufacturing is that branch of fine chemi-

cal manufacturing that is directed to the manufacture of
chemicals whose ultimate use will be in a final pharmaceutical
dosage form, referred to as the active pharmaceutical ingredi-
ent (‘‘API’’). This industry segment has undergone very signif-
icant changes in much the same manner, but trailing, the
pharmaceutical industry itself, from the time it emerged early
in the 20th century.
Thus, we must examine what has happened in the phar-
maceutical industry over this period, in order to understand
the implications for API manufacturing. This will lead us to
the present time and to the goal of this book.
It is our objective to provide a reference book that speaks
to those issues that need to be addressed in order to assure that
an existing or proposed pharmachemical operation will meet
its objective of supplying an API to meet a medical=market
need efficiently and effectively.
1
2 Nusim

The changes are themselves a result of major changes

that have occurred both directly and indirectly, in and on,
the industry. These changes include company consolidations,
both backward and forward integration, the increased and
changed role of quality, the significant intensification of regu-
latory bodies worldwide, the impact of the greatly increased
potency of APIs, thereby reducing pharmachemical require-
ments and the broadening of the market worldwide.
These ideas will be discussed briefly here and touched on
in depth in the subsequent chapters.

I. CONSOLIDATION AND INTEGRATION

The ‘‘pharmaceutical industry’’ at the turn of the 20th century

was essentially the local pharmacy (or chemist as it was also
known outside of the United States). The objective of the phar-
machemical supplier to the local industry, at that time, was a
provider of all the chemicals, including APIs, as needed by the
pharmacist to compound the prescribing doctor’s prescription.
Thus, the great pharmaceutical titans of today, such as
Merck, were a fine chemical manufacturer providing a full vari-
ety of basic laboratory chemicals and solvents as well as the
actives of the day, in order to meet all of the formulating needs
of the pharmacist. This activity was common in those early
days, as well, to Pfizer, Bayer, and Sterling, among others.
The forward integration of these companies into provid-
ing the finished dosage form had by the middle of this past
century become the standard rather than the exception, as
the medical community shifted to writing prescriptions for
the local pharmacist to fill prescribing finished dosage forms
rather than their own formulations. This practice continues
today, as the determination of efficacy and safety of formu-
lated product has grown to very significant proportions.

II. QUALITY

An overriding driving force in this direction, although it may

never have been originally intended, has been the shift of
Introduction 3

governmental control that has been exercised by the U.S.

Food & Drug Administration (‘‘FDA’’). A brief discussion of
that change is now in order.
The initial purpose of the first Pure Food, Drug &
Cosmetics Act (Act) that was passed by Congress in the first
decade of the last century was one of safety. It began by the
regulation of those items of commerce that had the potential
of poisoning the individual who used it if the product was
contaminated. It is for this reason that the Act covered
those three specific items, all lumped together although each
being used for very different purposes.
The initial focus, at that time, for drugs as well as the
other two types of ingested or topically applied products,
was lack of contamination as determined by quality sampling
and testing. In addition, and extrapolating that issue to new
proposed pharmaceuticals, the key data required was the
toxicity data and its ratio to the proposed dose level, the ‘‘ther-
apeutic index.’’ However, no data or judgment on efficacy was
required for its proposed use. Its medical purpose and its
ultimate use remained in the hands of the physician and
the sponsoring company that promoted it.
In the middle 1950s, this changed dramatically when the
Act was amended significantly. The change, driven by
congressional hearings and the ‘‘Thalidomide affair,’’a
now required not only more significant safety data, beyond
simple toxicity, but also, more significantly, scientific proof

a
Thalidomide was an antinausea drug that at that time had
been approved in Europe and was before the FDA for
approval in the United States. Pregnant women who are nor-
mally prone to nausea became an instant market for the new
drug. However, very serious birth defects (missing limbs)
were experienced in babies born to many of those women
who had taken the drug. This precipitated a worldwide reac-
tion to review the new drug approval process. Needless to say
that the drug was not approved in the United States at that
time. (In recent years, it has been approved for limited special
use in leprosy.)
4 Nusim

of efficacy. This now placed a new burden on the sponsoring

company to provide unequivocal proof, to the government’s
satisfaction, that the addition of a new chemical entity at
the dose level recommended was worthwhile to the public.
The shift was due to the recognition that replacing a tried
and true medication, that was widely used and its side effects
well defined with a new compound with only limited experi-
ence in man, was in itself an unknown risk and, therefore,
must be shown to be worth the risk.
This greatly increased the cost and the risk associated
with the discovery and introduction of new chemical enti-
ties. This change was absorbed by the industry and set
the stage for the next major shift in policy that came in
the middle 1970s. This was the establishment of current
good manufacturing practices (cGMPs) for the manufacture
of pharmaceutical actives as well as the finished pharmaceu-
tical products.
This was the next step in the focus of the FDA on the
safety of the product. Up until this point, contamination (or
lack thereof) was defined by the presence (or absence) of
foreign impurities not specified in the analytical protocol for
the product. This was the case for either the pharmaceutical
product or the API that went into the finished product.
Although this could be a definitive test for a uniformly distrib-
uted contaminant, it would not necessarily find random
contamination that occurred in processing or extraneous
matter that could enter the system from dirty facilities or poor
operating practices.
Finished goods testing, today, as it was at that time always
depended upon the assumption of uniformity of product. It was
this presumption that permitted the approval and release of a
product based on the testing of 100 g of a 100 kg pharmachem-
ical batch or 30 tablets of a lot of 500,000 tablets.
The concept of current ‘‘cGMPs’’ and quality assurance
became the dominant theme, thereby pushing the analytical
testing (quality control) into the background.
In principle, one now had to show, in order to have a pro-
duct free of contamination, that the manufacturer produced
the product in contaminant-free equipment in a clean facility,
Introduction 5

within equipment designed and tested to show consistent and

reproducible product by people thoroughly trained and with
full knowledge of the process. Thus, in the United States, this
greatly shifted the emphasis to a more rigorous standard of
‘‘quality’’.
The most recent change implemented is the requirement
of formal ‘‘validation’’ of facilities, equipment and the process
itself. This is the ‘‘proof’’ that the process and the facility can
produce quality product on a consistent basis.
In a similar fashion, one can see the extension of the
tighter regulations as they apply in the United States, to
Japan and Western Europe. Through the EU, they have
implemented similar standards for the very same reason in
Europe; additionally, many of the ‘‘third world’’ nations have
already implemented their own GMP initiatives reemphasiz-
ing the growing uniformity in such requirements throughout
the world.
All these factors are discussed more thoroughly in the
appropriate chapters within this book.

III. POTENCY

A subtle change that has emerged in the methods of discover-

ing and developing new drugs in the past decades has had
significant impact on the pharmachemical industry.
In the early days, the key to drug discovery often was
screening programs, where laboratory-screening models were
used to test new chemical entities for efficacy against specific
disease candidates. Those that were effective, however, often
found much of their potency diminished as the active, gener-
ally formulated into a pill, was attacked by normal body
chemistry as it passed through the digestive system on its
way to be absorbed into the blood and transported to the dis-
ease site. Thus, only a fraction of the orally ingested drug
reached the drug target area. As a result, dose regimens for
most oral drugs were 100–500 mg.
These dosing levels generated needs for significant quan-
tities of actives in some cases into the millions of kilograms
6 Nusim

annually. (Five billion tablets at 200 mg dose require 1 million

kilograms of active.) This resulted in dedicated plants for each
drug active, particularly since the active was generally a com-
plex organic molecule requiring many chemical steps to
synthesize.
However, with the advent of the focus on biochemistry
and the new sophistication gained in understanding the
chemistry and biology of the body, today’s drugs are designed
so as to be more potent. In addition, they can be chemically
protected to limit the destruction of the drug as it passes
through the body on its way to the target site. Thus, normal
dosing of today’s ‘‘designer’’ drugs are 5–20 mg, 10 fold less
than in the past. This reduces the API need for ‘‘blockbuster’’
drugs by an order of magnitude (5 billion tablets at 10 mg dose
requires 50,000 kg of API). This also suggests that those les-
ser volume products would require very small quantities of
API making dedicated facilities for them very uneconomical.
These factors have refocused API manufacturing from
facilities dedicated to a single API product to multiproduct
manufacturing facilities. The added costs of a facility due to
the more rigorous cGMPs that now apply favor these kinds
of facilities, where the cost can be shared by many rather than
a single product.
This adds a very critical aspect to the operation because
the issues of equipment clean out and turnaround, particu-
larly as the issue of cleanliness to ensure that cross contami-
nation does not occur must be addressed.

IV. COMPUTER CONTROL AND

AUTOMATION

This industry, like nearly all others, has seen the positive
impact of the introduction of computers and automation in
the manufacturing facilities. The first impact was in the auto-
matic control systems that are used to maintain accurate and
reproducible operating conditions for reaction and isolation
systems. This was extended into the integration of multiple
operations under computer control often eliminating or at
least minimizing people intervention.
Introduction 7

This itself caused some concerns for the FDA, which, in

the past, depended upon manual documentation by operators
of batch procedures written and issued by people and people
observing and recording all data. This was transformed to
computer-recorded data and operating instructions being
maintained in computer files. This generated an entire series
of new issues that had to be dealt with by both the operation
and the FDA. First was security to be sure that the automated
instructions are safe from improper and unauthorized
changes to the issue of signatures, often electronic signatures,
a new concept that has become very common.

V. SUMMARY

The changes referred to above, and the changes that are to

occur, without doubt, in the future, drive the need to under-
stand where we are today and where we are going in the
future. We have chosen to address the various segments
and activities of a pharmachemical plant by having a focused
discussion on each in the subsequent chapters.
Again, I repeat a statement from the Preface. Each and
every topic covered in this volume has changed from the past
and will continue to change in the future; therefore, the
reader is being presented with a ‘‘starting point’’ from which
he or she must continue to follow the progress of in order to
keep current.
2
Process Development
CARLOS B. ROSAS

Rutgers University, New Brunswick, New Jersey, U.S.A.

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
II. The Bulk Drug Process as Part of the Drug Development
Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
III. From the Bench to the Pilot Plant and Beyond . . . . . . 39
IV. The Physicochemical Attributes of the Bulk Drug . . . . . 61
V. The Process Body of Knowledge . . . . . . . . . . . . . . . 65
VI. Processing Responsibility in Bulk Drug Process Development73
VII. Outsourcing in Bulk Drug Process Development . . . . . 89
VIII. In Closing . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

I. INTRODUCTION

The purposes of this chapter are few and rather ambitious.

First, to provide a sound perspective of bulk drug process work
to the uninitiated and the relatively new practitioner, hope-
fully without prejudice to the benefit that the approach herein
might afford to an experienced but still restless practitioner.
All work in a forest that is dense and rich in its variety; it
should be regarded from a vantage now and then, and it is
from such a deliberately selected vantage that the chapter
unfolds.
Then there is the promotion of the power that the purpo-
seful convergence of chemistry, microbiology, and chemical=

9
10 Rosas

biochemical engineering can bring to bear on the increasingly

difficult task at hand: the timely conception, development, and
reduction to practice at scale of a sound process for the manu-
facture of a bulk drug. In the 2000s, timely is shorthand for
swift, sound encompasses safety to the environment and to
people as well as amenable to various regulatory approvals,
and reduction to practice at scale means that the resulting
process can be used for reliable manufacture in whatever
context might be first required.
Chemistry, in the context at hand, is the aggregate of
synthetic, analytical, and physical chemistry fields
within what may be called the drug process chemistry
discipline at large. The latter, while practiced for dec-
ades, has truly come into being in the 1990s, spurred
mostly by the greater ascendance of the pharmaceutical
industry among chemistry practitioners and by the
enhanced role of the bulk drug process in the outcome
of drug development. Whereas toxicology or clinical
results were the exclusive causes for the demise of drug
candidates, the greater difficulty in making today’s more
complex structures in today’s regulatory milieu has for
some time raised the profile of their bulk process develop-
ment task as a factor in the overall outcome (1).
Although first manufacture of the bulk drug is the para-
mount objective of the technology transfer to manufac-
turing, the process body of knowledge should be sturdy
and complete enough to support expanded manufacture
for product growth, as well as provide at least a clear
sense of direction for process improvements or second-
generation processing.
The above definitions conveniently describe a complex
task, to which considerable skills need to be applied with
due deliberation and under constant managerial attention.
Indeed, successful bulk drug process development, as just
defined, requires that sufficient interdisciplinary and opera-
tional resources be brought together in a cohesive manner,
not unlike that required by a critical mass in nuclear fission.
Most often, having the resources is not enough, and their
cohesiveness makes a significant difference in the degree of
Process Development 11

success, sometimes making the ultimate difference: having or

not having a new drug available when needed.
Another sought perspective applies to the integration of
the bulk drug process development task with the simultaneous
drug development program at large: toxicology, dosage form
development, clinical development, and the assembly of the
regulatory submissions. The latter, leading to the desired
regulatory approvals as the culmination of the overall effort,
has in recent years become increasingly dependent on the scope
and execution of the process work for the bulk drug, which in
some of its aspects has now become fastidious and greatly
increased the burdens of the bulk process development task.
As the last objective, the methods of bulk drug process
development will be weaved discreetly, if not seamlessly,
throughout the chapter: (a) the principal issues that shape
the methods, (b) the most trenchant choices confronting the
process development team, and (c) some selected heuristics
(i.e., empirical rules that, although lacking proof, are useful
often enough) distilled from the author’s experience.

As a distinct and credible literature of process develop-

ment for bulk drugs and fine chemicals has come into
being and grows, statements of applicable empirical wis-
dom are appearing with a modicum of organization (2–6)
and the field should one day become amenable to indepen-
dent study (it is not currently taught formally anywhere).
In addition, a journal focused on the field has been
published since 1997 as a joint venture of the American
Chemical Society and the Royal Chemical Society (7).
Alas, the engineering scale-up of synthetic bulk drug pro-
cesses is still badly understated, as most contributors to
the new body of literature are synthetic chemists. For
compounds derived from biosynthesis, however, there is
a large body of biochemical engineering literature that
deals in depth with the scale-up of the biosyntheses and
the subsequent ‘‘downstream processing’’ technologies
(e.g., Refs. 8–10).
The application of the fruits of bulk drug process develop-
ment to process design, technology transfer, and first manufac-
ture will be addressed in the companion chapter 3, as those
12 Rosas

activities are carried out in a distinct context that overlaps

with the R&D activities. Such planes of contact will, of course,
be identified in this chapter and their discussion confined to
the minimum needed herein.
About the scope of the chapter, it is ambitious in its aim
to support the above objectives, yet modest in its depth of
descriptive material, since doing justice to the latter would
require a much larger volume. Instead, the author has chosen
to address the fundamentals along the said objectives, while
keeping the descriptive technical material spare and aimed
at selected targets of the bulk drug process development task:
e.g., seeking thermochemical safety, scaling-up, achieving the
desired physicochemical attributes of the bulk drug, captur-
ing and applying the process know-how.
As of this writing in 2004, the process development
milieu of the bulk drug industry is quite varied—from the
large drug company in which all the skills are represented
to the small virtual firm that contracts out the work, as well
as firms that do selected process development tasks as part
of their attempt to secure the eventual manufacturing busi-
ness from the owner of the drug candidate. The author has
not attempted to deal separately with these different environ-
ments lest the exposition of the target fundamentals get
obscured by the specifics of each case. Instead, the bulk drug
process development task is discussed within the continuum
of a large drug company and commentary that applies to
other contexts has been inserted, hopefully in a sparing and
incisive manner.
The reader should be alerted to an additional choice of
the author. Although the increased regulatory expectations
have deeply transformed the process development task, the
paramount stance for the practitioner remains intact: know
and understand your process, reduce it to practice soundly,
and operate it in a disciplined manner. Accordingly, this
and its companion chapter, aimed at the fundamentals, avoid
the spectrum of the current good manufacturing practices
subject (or cGMP), which seems to have soaked so much of
the energy of process practitioners throughout the bulk drug
industry. However, the issues associated with the assembly of
Process Development 13

regulatory submissions (IND, NDA and the like) and with the
expectations of the subsequent approval process will be
discussed as required to meet the objectives of the chapters.
Finally, the diligent reader of these two chapters, armed
with the perspectives provided herein, should find that
continued study of the literature can be quite fruitful. To
assist in that task, a selection of references is included, most
of which are cited throughout the text, with the rest cited
separately as suitable reading for the studious.

II. THE BULK DRUG PROCESS AS PART OF THE

DRUG DEVELOPMENT PROGRAM
A. The Chemical Process of a Bulk Drug
In the context of this chapter, a bulk drug or a bulk drug
substance is a material—a single chemical compound with
the desired biological activity—obtained in bulk form and des-
tined for the preparation of dosage forms. The latter, when
administered in a prescribed manner to the target patient,
animal or plant, delivers the drug so as to elicit a desired
physiological response and, in due course, the intended thera-
peutic or protective result. More recently, terms such as active
pharmaceutical ingredient (API) or bulk pharmaceutical chem-
ical (BPC) seem to have overtaken the usage, seemingly as the
result of their adoption by regulators in the United States.
Herein we will use the original term bulk drug (or bulk), as it
most aptly describes the material—a drug that is obtained
and characterized in bulk form. However, we will confine our
scope to those compounds commonly known as chemical enti-
ties—drugs of relatively small molecular weight that can be
characterized well by current methods of chemical and physico-
chemical analysis. In doing so, we are excluding those macromo-
lecules, substances, and preparations of biosynthetic origin that
are collectively known as biologicals. The processing methods
used in biologicals, albeit based on the same fundamentals,
are significantly different from those applied to chemical enti-
ties, and their process development, registration, and manufac-
ture also take place in a rather different environment. In
14 Rosas

addition, organic compounds categorized as nutritionals and

fine chemicals at large are not within this scope, their proces-
sing similarities with bulk drugs notwithstanding.
Bulk drugs are obtained through three chemical proces-
sing routes:
a. Extraction, recovery, and purification of the drug
from biomasses of natural origin or from fermentation
(Fig. 1): (1) paclitaxel is extracted from various Taxus
plants; (2) lovastatin is biosynthesized in the fermen-
tation of nutrients by Aspergillus terreus.
b. Semisynthesis, in which a precursor compound
from a natural source or a fermentation is converted
to the target drug by synthetic chemical modifica-
tion: (1) fermentation penicillin G is converted to
6-aminopenicillanic acid, which in turn is reacted
with an acyl chloride to afford ampicillin; (2) natural
morphine is methylated to codeine (Fig. 2).
Both routes to bulk drugs take advantage of the diversity
and richness of molecular structures found in natural
sources, where many important biological activities are
also found.

Figure 1 Bulk drugs from natural sources: Paclitaxel (antileuke-

mic and antitumor) and lovastatin (inhibitor of cholesterol bio-
synthesis) are examples of the diverse and complex structures
made by plant and microbial cell biosyntheses, respectively. In most
instances of such compounds having desirable biological activities,
their structural and chiral complexities make chemical synthesis
not competitive with isolation from biosynthesis.
Process Development 15

Figure 2 Semisynthetic bulk drugs: Ampicillin (antibacterial)

from penicillin G. Modifications of biosynthetic structures are often
created to improve the in vivo attributes of the original compound,
utilizing the biosynthesis product as the starting material contain-
ing most, if not all, of the structural complexity that provides the
basic biological activity. Similarly, codeine (analgesic), although
found in opium from Papaver plants, is most economically made
by methylation of morphine, which is more efficiently isolated from
opium.

c. Total synthesis from simple starting materials or

less simple intermediate compounds (Fig. 3): (1)
fosfomycin from commodity chemicals, (2) lobetalol
from 5-bromoacetyl salicylamide.
In either total synthesis or semisynthesis processing,
sometimes a desired synthetic transformation is best
done by an enzyme. Such synthesis step, whether using
a preparation of the enzyme or the host microorganism,
will be considered a chemical synthesis step (a biotrans-
formation or a biocatalytic step) and not a fermentation
for biosynthesis.

Whichever of these routes is used to obtain a bulk drug consti-

tutes the chemical process. Further processing of the bulk
drug to obtain the dosage form constitutes the pharmaceuti-
cal process. This distinction is depicted in Fig. 4, where simple
16 Rosas

Figure 3 Drugs by total synthesis: Fosfomycin (antibacterial) is a

good example of the manufacture of a bulk drug by total synthesis
from basic chemicals, albeit the compound is of biosynthesis origin.
Alternatively, and more frequently, the manufacturing process is
simplified by tapping on commercially available compounds of
greater structural complexity (intermediates), such as 5-bromoacetyl
salicylamide as the starting material for lobetalol (antihypertensive).
Even if the intermediate is custom made by others, the process
development and manufacturing task for the drug developer is
greatly simplified relative to the use of basic or building block
chemicals.

graphical means are used in an attempt to differentiate the

bulk character of the product of the chemical process, in con-
trast to the discrete character of the product of the pharma-
ceutical (or dosage form or secondary manufacturing)
process. The distinction also reflects their very different tech-
nology, manufacturing, and regulatory environments.
In the current pharmaceutical parlance, the term API is
used most often as descriptive of the biological activity
contribution. Herein, however, the term bulk drug is
used instead as descriptive of the physical and chemical
character of the subject material, with its biological activ-
ity taken as obvious. Indeed, the conventional term for
Process Development 17

Figure 4 The domains of chemical (bulk drug) and pharmaceuti-

cal (dosage form) processing, with the chemical processing domain
defined by the shaded area of the diagram.

the other ingredients added to formulate the dosage form

is still inactive pharmaceutical ingredients.
As we proceed, unavoidably some other terms will be used
that may not be familiar to all readers. Accordingly, an
effort will be made to define such terms at the point of first
use, as well as to use them sparsely. For example, unit
operations are those methods that can be found repeatedly
used in chemical processing and that have a common
phenomena root, their many variations notwithstand-
ing—filtration to separate solids from an accompanying
liquid, distillation to separate volatile components from a
mixture, or milling to reduce the particle size of particu-
late solids. The organization of chemical processing on
the basis of such unit operations was crucial to the
development of organic chemical technology, which was
18 Rosas

originally arranged on the chemistry basis of unit pro-

cesses, such as nitration, sulfonation, or esterification.
Whereas the latter organized knowledge on a strictly
descriptive basis, the unit operations approach made possi-
ble the study of processing phenomena on the basis of gen-
eralized principles from physics, chemistry, kinetics, and
thermodynamics, which could then be used to undergird
methods applicable in the context of any chemical process
and over a wide range of scale and circumstances. Hence,
the keystone role that unit operations played in the advent
of chemical engineering as a discipline, with a practice
quite distinct from that of the earlier industrial chemistry.

B. A Perspective
Process development of a bulk drug consists of three distinct
tasks:
a. Preparation of bulk drug as needed by the overall
development effort—the preparative task. The scope
of this task varies over a wide range, as shown in
Table 1.
b. Definition and achievement of the desired physico-
chemical attributes of the bulk drug as needed by
the dosage form development—the bulk drug defini-
tion task.
c. Acquisition and organization of a body of knowledge
that describes a sound process for regulatory submis-
sions and technology transfer to first manufacture at
scale—the body of knowledge task.

However, these tasks cannot be directed to successful

and timely completion unless viewed and managed as a veri-
table trinity, their differing demands and instantaneous
urgencies notwithstanding. Drug development is a fast paced
and difficult enterprise; it presents frequent junctures at
which the need to focus on the most compelling task needs
to be artfully balanced with other needs lest the aggregate
task be compromised—all three tasks need to be completed
Table 1 Bulk Drug Demands of the Various Drug Development Phases

Preclinical phase—Initial toxicology, probes on drug bioavailability, Supplies to be delivered Total
5–50 kg
data gathering for the IND, additional animal studies, etc. over 2–6 months
Phase I—Use in humans (20–80 mostly healthy Supplies to be delivered Total
20–100 kg
subjects) for pharmacokinetic, pharmacological, routes of over 6–12 months
administration, dose ranging, and tolerance studies. Continuing
toxicology and dosage form development. All aimed at the design
Process Development

of Phase II=III studies and defining the target dosage forms

Phase II=III—Increasingly large number of patients (up to thousands) Supplies to be delivered Total
300 to
in studies for therapeutic effectiveness (initial and confirmatory), over 18–48 months > 2000 kg.
dose and regimen determination, evaluation of target populations
for safety and efficacy, support of desired claims, market-specific
and dosage form-specific studies, etc. Continuing toxicology and
dosage form development, stability studies. All aimed at the
assembly of the dossier
Phase IV—Postapproval studies for optimization of drug use, These studies are
pharmacoeconomic data, morbidity and mortality data, generally supplied from
head-to-head and concomitant drug uses, etc. bulk drug made in the
manufacturing operation.

Notes:
1. IND (investigational new drug) is the submission requesting USFDA’s exemption from drug shipping in interstate commerce, thus
signaling the intent to initiate study in humans (or target species if a veterinary drug). Dossier is a term often used to describe the total
body of knowledge on the drug candidate, from which individual submissions are assembled for filing with the various agencies; e.g., the
new drug application (NDA) to the USFDA.
2. The ranges of bulk drug totals reflect the wide differences among drug candidates and their programs. Issues such as drug potency and
dosage regimens, low animal toxicity, length of treatment to the clinical endpoint, relative difficulty of dosage form development, number
of dosage forms developed and scope of the clinical studies are the principal factors determining the demands for bulk drug. Obviously,
19

relatively infrequent extremes exist on both ends: from a low end for drugs such as dizocilpine, paclitaxel, and some experimental
oligonucleotides to a high end for HIV protease inhibitors (high doses) and some cardiovascular drugs (clinical studies of very large scope).
Source: Author’s observations from involvement in numerous drug development programs.
20 Rosas

at the same time for timely and successful product launch.

Selected instances of such balancing, in which some risk is
often inevitable, are discussed throughout the rest of the
chapter; therein lies the crucial need for overall coordination
of each drug’s development program.
Although various models exist, today’s drug development
is generally facilitated by a coordination mechanism and
forum, usually in the form of a cross-functional team that
drives and manages a drug candidate. The principal
objectives are to have and execute: (a) a drug develop-
ment plan, (b) rigorous means to closely track its execu-
tion, and (c) mechanisms to effectively respond to events
and findings that invariably arise in spite of the plan.
Indeed, the development of a new drug encompasses a
myriad activities and objectives that are extremely
cross-linked among the various disciplines contributing
to the effort. Clearly, the bulk process development team
needs to be well represented in the cross-functional forum
throughout the drug development cycle.
Success in development coordination means that, no
matter which coordination model is used, there must be
prompt and effective resolution of most issues and difficul-
ties, say > 90%, at the team level, with the rest going up to
a broader and more senior team of the R&D organization
(i.e., the heads of the disciplines, functions, and those
above). Indeed, the direction and operation of such teams
have become a distinct function (it will be referred herein
as drug coordination), with its own set of skills and not
unlike the distinct set of skills in new drug submissions
and approval—the regulatory affairs function.
The relationships of the three basic tasks with the over-
all drug development program are depicted in Fig. 5 in rather
simple terms, whereas the specifics of each relationship will
be discussed under the heading of each task. The arrows indi-
cate the flow of materials from the preparative task and the
flow of information and know-how from each task to the
others and to the drug development at large.
It is also useful to depict the bulk drug process develop-
ment cycle on a Cartesian coordinate plane (Fig. 6). The
Process Development 21

Figure 5 The three basic tasks of bulk drug process development.

These tasks exist concurrently throughout most of the development
cycle, albeit their burdens vary through the cycle. Nevertheless,
managing well all three tasks as inseparable parts of a single
overall endeavor is the principal managerial challenge in bulk drug
process development.

abscissa axis represents progress since the onset of develop-

ment of a compound and, although progress along well-
defined milestones is used, one might also look at the abscissa
as measuring the applied technical effort or, less precisely,
the extent to which the bulk drug process has been reduced
to practice (e.g., kilos of bulk drug made, batches made, or
versions of the process piloted). Inevitably, the abscissa scale
shown herein is arbitrary, albeit deliberately selected; the
experienced reader will probably readily think of an example
with a more apt progress scale. Thus, the need to deal with
the latter in terms of more distinct stages, which Fig. 6
attempts to depict.
Were elapsed time to be used, the distance between
Phase II=III start and the Dossier filing milestones would be
quite variable from drug to drug, as that interval depends
on the scope of the clinical program and on the therapeutic
target. Whereas osteoporosis, diabetes, or depression require
22 Rosas

Figure 6 The process know-how vs. applied effort plane, includ-

ing the major milestones of bulk drug process development. As
defined herein, 100% know-how describes the body of knowledge
needed for registration and reliable first manufacture for product
launch, whereas additional know-how accumulates with manufac-
turing experience and follow-up work that might be done for process
improvements or a second generation process.

considerable time to reach their efficacy endpoints, those for

bacterial infection or pain relief, for example, arrive much
sooner. For this, and for other reasons related to the intended
scope of the drug development (e.g., claims structure, schedule
of filings, multiple routes of administration, etc.), the elapsed
time scale is unsuitable for the process know-how purposes
of Fig. 6. Instead, applied effort or extent of reduction to
practice of the process relate directly, if not strictly in direct
proportion, to the acquisition of the process know-how.
Although the biobatch and preapproval inspection prere-
quisites are specific to USFDA approvals, analogous expecta-
tions are arising in other drug agencies in the major markets
(more on this in Chapter 3). The biobatch is a distinct marker
in dosage form development in that it serves as the bioavail-
ability=bioequivalence bridge to pivotal clinical studies, as well
as the bioavailability=bioequivalence reference for all subse-
quent dosage form output. As such, the biobatch reflects the
Process Development 23

process that goes into the dossier, uses representative bulk drug
and excipients, and its size is no less than 10% of the intended
manufacturing scale. Preapproval inspection is a methodology
employed by the USFDA to ascertain, at its discretion, that
the intended manufacture of dosage form and bulk drug
correspond to the processes used in the pivotal clinical studies
and described in the NDA or other new drug submissions.
The ordinate axis, on the other hand, is straightforward,
as it measures the fractional bulk process know-how relative
to that required for regulatory approvals and for sound first
manufacture. Note, therefore, that it is not being suggested
that at 100% on the ordinate axis there is nothing else to be
learned about the process; instead, the 100% ordinate value
merely describes the knowledge required to fulfill the said pro-
cess development objectives. Indeed, further gains in process
know-how are always realized with manufacturing experi-
ence, and mature processes often differ appreciably from their
first manufacture versions, by virtue of gradual improve-
ment or from significant step changes (second-generation
processes), although most often the seeds for such later devel-
opments are planted in the original development body of
knowledge. Thus, the curve in Fig. 6 describes the accumula-
tion of know-how during four distinct phases of the process
development effort:
a. The preparative stage, during which the effort is
focused on making available kilogram amounts of
the bulk drug to the preclinical, toxicology, and
Phase I work, usually not based on the eventual
synthesis route, let alone the eventual process.
Whereas the synthesis route (or scheme) describes the
intermediate chemical structures sought to arrive at the
final compound (starting materials, synthesis approach,
and probable chemical reactions to use), the process
describes how the route is implemented at a much higher
level of detail. (solvents, catalysts, purifications, isola-
tions vs. straight-through, etc.).
b. The development stage, in which the preparative
work is scaled up and the synthesis effort goes into
24 Rosas

high gear, aimed at the manufacturing route and

process. It is in this stage that the chemical engi-
neering effort is applied in earnest, first to support
the scaled-up preparative work and then to address
the scale-up issues of the manufacturing route.
Ideally, the chemical engineering contribution starts
early, so as to appropriately influence the seminal choices
being made by the process chemists as to route. This
influence is reasonably apparent with respect to issues
of thermochemical safety and probable environmental
impact; yet, there is across-the-board synergy that a che-
mistry=engineering dialogue can exploit. The latter is
particularly true in those instances when the chemists
perceive a desirable approach as not being feasible on
grounds of scale-up difficulty or, more simply, because
of lack of experience with some demanding processing
conditions.
c. The consolidation stage, in which the synthesis route
is fully settled and the specific process for it is defined
at the level of detail that permits process design for
the manufacturing plant, definition of the bulk drug
attributes and the assembly of the dossier. Also dur-
ing this phase all the preliminaries for technology
transfer are carried out and the stage set for first
manufacture.
d. The technology transfer stage, in which the process is
run in its first manufacturing venue, its performance
established, and the bulk drug needed for product
launch is produced. Also during this phase, the manu-
facturing scheme receives approval within the
approval of the dossier, often after plant inspection
by the approving agencies.

From the above definitions, a discussion of the specifics of

each stage is now possible, also based on the depiction of the
bulk drug process development cycle on the know-how vs.
applied effort plane introduced in Fig. 6. During these
stage-specific discussions, the three bulk development tasks
will serve as the basis and along the lines of Fig. 5.
Process Development 25

C. The Stages of Bulk Drug Process Development

1. The Preparative Stage
Although preparative work takes place throughout the pro-
cess development cycle, this first stage is most aptly described
as the preparative stage. Its focus, although not exclusively, is
the preparation of limited amounts of bulk drug for assorted
preclinical purposes, then followed by first scale-up to support
Phase I activities, which include testing the drug in healthy
subjects (humans or the target animals if a veterinary drug).
Starting with bench scale equipment (up to 100 L in the
so-called kilo lab) or pilot scale fermentors (up to 5000 L when
titer is low), this early preparative work uses whatever syn-
thetic method or fermentation conditions (the microorganism
and the nutrients) are immediately available. In most cases of
synthesis, the route may be a somewhat streamlined version
of the discovery route or a temporary route that may or may
not include parts of synthesis schemes being considered for
eventual development. In most cases of biosynthesis, the
microorganism is that from the discovery stage, but taken
from whatever stage of microbial strain improvement is
amenable to scale up from shake flasks or bench scale
fermentors.
Fermentation processes at this stage are generally of
very low productivity (final concentrations of the target
compound of < 1g=L), making access to relatively large
fermentors most helpful, including, in cases of dire need,
the use of manufacturing scale units (up to 75,000 L), the
poor scaled-up performance of the early stage notwith-
standing. The analogy for chemical synthesis is the ardu-
ous operation of lengthy procedures in the kilo lab, the
low yields notwithstanding.
Although the kilo lab will be described more fully later
on, it may be said at this point that the kilo lab is a larger
scale lab, traditionally used for running preparative
procedures than for experimentation.
Preclinical and Phase I development work is crucial
in that it determines the merit of further development or,
26 Rosas

hopefully, the adjustments that need to be made to move

the compound forward. Thus, the importance of providing
the required material on time to get those answers as soon
as possible. This reflects on the need for capital investment
in facilities such as kilo lab or pilot plant, and we will discuss
elsewhere in this chapter the challenges of this stage of
development when the preparative stage depends on outsour-
cing (the reliance on outside suppliers). Indeed, sufficient
internal resources for the preparative stage is a clear compe-
titive advantage, with the optimal setting providing the
means—hardware and engineering skills—to swiftly overlap
the kilo lab work with pilot plant work-up to, say, 1000 L
vessels and the appropriate auxiliaries and operating envir-
onment (safety, industrial hygiene, and pollution abatement).
Figure 7 depicts this preparative environment, whereas

Figure 7 The resources for the preparative task. The need to

engage larger-scale resources depends on the scope of the prepara-
tive task, which can vary widely (Table 1 and Fig. 8).
Process Development 27

Figure 8 The scope of the preparative task. Some examples to

illustrate the dependence of the preparative effort on drug potency,
therapeutic target, and scope of the clinical effort.

Fig. 8 complements the range of preparative scopes pre-

sented in Table 1.
Also depending on the resources of the organization,
synthesis bench work may take place in search of routes that
can support a manufacturing process, as the routes used dur-
ing the discovery phase are largely unsuitable on the basis of
projected cost, length of the synthesis cycle, commercial una-
vailability of starting materials or simply because of their per-
ceived inferiority relative to what the process chemists foresee
as attractive alternatives. Clearly, the compelling wisdom of
such early synthesis work needs to be balanced against the
resources available and, most of all, against the empirical
probability of less than 20% that a drug candidate at that
stage will reach the market, as indicated by Table 2.
Whereas medicinal chemists practice organic synthesis as
an indispensable tool and are largely oriented upstream
(towards the domain of biological and pharmaceutical
attributes of the compounds they work with), process
28 Rosas

Table 2 Best Practices Probabilities of a Drug Candidate

Reaching the Market

Drug candidates in the preclinical phase 5–10%

In Phase I 10–20%
In Phase II 30–60%
In Phase III 60–80%
Post NDA filing > 95%

Notes: ‘‘Best practices’’ refers to drug development organizations with established

good records of bringing drugs to market. In particular, best practices include a high
hurdle for a drug candidate to enter development or Phase I.
Source: Author’s assessment from assorted estimates, including those from the
PhRMA Annual Report—online edition, 1997. While the figures from total
compounds synthesized (or total number of biologically active compounds) have
increased as the methods for generating actives improve their total output, the above
figures after entry into development have remained largely unchanged. The above
ranges probably reflect the adequacy of the tools used to assess the merit of
developing an active compound and the rigor of the criteria for moving a compound
forward.

chemists in the drug industry practice synthetic chemis-

try as their profession and are oriented downstream
(towards the reduction to practice beyond their lab
bench), thus the usual discontinuity in synthetic route
at the discovery=development boundary.
Although sometimes much is made about smoothing
and simplifying the discovery synthetic route (eliminating
isolations and purification, shortening the processing cycle,
and using less expensive materials), the most desirable
contribution of the process chemist is the conception of a
distinctly advantageous synthesis route that can then be
developed and engineered into a sound manufacturing pro-
cess. Such a route would bring the advantages of fewer steps
from reasonably available starting materials, environmental
benevolence (or, preferably, green chemistry), parallel moi-
eties that can converge into shorter synthesis cycles, stereose-
lectivity, and similarly decisive gains.
As a summary, Fig. 9 focuses on the preparative stage
and the rest of the preparative effort on the know-how vs.
applied effort plane, whereas Fig. 10 depicts the materials
flow from the bulk drug preparative effort at large.
Process Development 29

Figure 9 The preparative effort in the know-how vs. applied

effort plane. The principal preparative milestones are shown.

Figure 10 Materials flow from the bulk drug preparative effort.

The width of the arrows approximately indicates the relative
amounts of bulk drug going to the users in the overall drug develop-
ment program. Examination of this figure and Fig. 9 provides an
equally approximate description of the bulk drug usage as a func-
tion of the development cycle.
30 Rosas

2. The Development Stage

As made clear by the slope of the curve in the know-how vs.
applied effort plane (Fig. 6), the development stage comprises
the most productive development effort:
(a) Synthesis work at the bench scale seeks the even-
tual manufacturing route in earnest, preferably on more
than one approach, with all promising a substantial, if
not overwhelming, advantage over the current preparative
procedures.
In chemical synthesis, the route is basically driven by the
structure of the target compound. Within that logic, however,
the creativity of the process chemist is bounded only by the
realities of starting materials availability. However, examples
of bulk drugs made from commodity chemicals are now few
and rapidly disappearing (thiabendazole and l-methyldopa,
for example), as the more complex structures of today’s med-
icinal chemistry preclude synthesis from basic raw materials.
Instead, today’s process chemist must be very alert to what
the fine chemicals industry offers (or could be induced to offer)
by way of suitable building blocks or intermediates and the
corresponding manufacturing capabilities. Such alertness,
combined with creative synthesis skills, is the key to truly
advantageous routes. This theme is discussed amply and in
depth in some of the previous references (2–5), as well as in
Saunders’s (11) compendium of selected major drugs. In the
extreme, the total synthesis of structurally rich natural
products, although rarely aimed at a manufacturing process,
offers leads and inspiration to the process chemist, as well
as blazes the trail with new reactions, some of which are
eventually used in bulk drug syntheses (e.g., Ref. 12).
In celebrating the opportunities for the creative process
chemist, we should not neglect factors such as the increas-
ing desire for environmentally benevolent chemistry
(green chemistry) or the prevailing business model in the
bulk drug industry, by which the range and scope of
chemical processing has been narrowed in favor of con-
tracting out (outsourcing). There is also, on management’s
part, the reluctance to practice hazardous chemistry
Exploring the Variety of Random
Documents with Different Content
 DON CAMILLO
Nossignori! Nient'affatto! Io gli scrissi a Merate per il mio ministero di
sacerdote, appena ricevuta la confessione.

ROGHI
Ah, quando la signora si tirò?

DON CAMILLO
Precisamente. Volle confessarsi. Per morire in pace con tutti, chiese
per mio mezzo al marito il perdono de' suoi trascorsi. Ora il
professore poteva rispondere alla mia lettera con un'altra lettera.
Nossignori. Per sua bontà, preferì venire ad accordar di presenza il
perdono.

ROGHI
E trovò qui quell'altro?

DON CAMILLO
Che c'era piombato da Perugia all'alba, poche ore dopo che la
signora s'era ferita. Nel trambusto, in principio, non ce n'eravamo
neanche accorti.

GIUDITTA
Non sapevamo chi fosse la signora...

DON CAMILLO
Si vide lui attorno al letto, che piangeva, piangeva, come non ho mai
visto nessuno!

ROGHI
Eh, l'amante!

LA NÀCCHERI
Sì, amante... Che amante! — Uno dei tanti. — L'ultimo.

ROGHI
Ah, perchè la signora... Sì, dico, — andata proprio a male?

LA NÀCCHERI
Ma sì, roba... roba da guerra!

GIUDITTA
Piano, per carità!

LA NÀCCHERI
Ih che scrupoli! Non c'è poi mica d'aver tanti riguardi!

DON CAMILLO
Ma almeno per il professore!

LA NÀCCHERI
Sì — che vi pagherà le spese. Il fastidio, intanto, non ve lo paga, di
sicuro! Di due mesi a momenti.

DON CAMILLO
Oh che discorsi! (Poi, ipocritamente al Roghi) La signora aveva
abbandonato da tredici anni il tetto coniugale, e... (abbandona la
frase, socchiudendo gli occhi, a un indulgente gesto delle mani).

LA NÀCCHERI
(rifacendo smorfiosamente con aria compunta il gesto del cognato)
E... e... (Subito, staccando) Qua, dietro l'esempio, caro lei, una
voglia abbiamo tutti, ma una voglia di farci male con la indulgenza e
la sopportazione, che Dio, si spera, ne vorrà tener conto lassù,
perchè quaggiù, quanto agli uomini, non si fa che rider di noi,
gliel'assicuro io!
 DON CAMILLO
Ma non è vero!

LA NÀCCHERI
(staccando ancora) Oh, ce n'è, dico, di paesi, in Valdichiana; e di
pensioni qua, per la cura delle acque, dico, non c'è soltanto la mia!
Ebbene: proprio qua doveva capitare codesta signora, e proprio da
noi! Ma colpa sua, veh! (indica il cognato) Sua, e di quella lì! (indica
la figlia).

GIUDITTA
Son io sempre la colpa di tutto...

LA NÀCCHERI
Se per te non fosse vangelo, sempre, tutto ciò che dice e fa tuo zio!
— E così, m'intende, tutti i malanni, alla fine, mi si rammucchiano
qui! — Ah, che! Non si maturerà mai nulla qui: (cantarellando) c'è
troppe frasche!

DON CAMILLO
La vidi arrivar di sera, in legno! giusto con Dodo. Sola, mogia mogia,
con una valigina... Io ritornavo da scuola...

LA NÀCCHERI
Non c'ero, io!

GIUDITTA
Ma noi si disse bene, mamma, che la pensione non era ancora
aperta ai forestieri.

LA NÀCCHERI
E dunque, non si doveva pigliare!

DON CAMILLO
Di bujo, una signora sola... Insistette, chiedendoci posto almeno per
la notte...

GIUDITTA
(scotendo in aria le mani) E la notte...

LA NÀCCHERI
Un botto, caro lei, nel silenzio della casa, che mi fece springar un
palmo su dal letto!

ROGHI
Ma si tirò proprio al ventre?

DON CAMILLO
Che! Al cuore aveva mirato.

LA NÀCCHERI
Lo suppone lui!

DON CAMILLO
Ma sì! Mano di donna... Premendo il grilletto, la canna — voi capite
— s'abbassò. Si ferì al ventre.

GIUDITTA
Accorremmo tutti. Poverina, sul letto...

LA NÀCCHERI
Poverina, già!

ROGHI
Eh via, in quello stato...

DON CAMILLO
Bianca come un cencio, sorrideva come a chiederci scusa, e diceva
che non era nulla... — Lei scappò per il medico (indica Giuditta).

ROGHI
Il dottor Balla?

DON CAMILLO
Sapete com'è!

ROGHI
Se lo so! Mi sta lasciando finir così la mia povera figliuola!

DON CAMILLO
E anche qui difatti disse che non c'era più da far nulla; quando
invece, venuto il professore, si vide che a operarla in tempo non ci
sarebbe stato rischio di sorta; mentre, quando poi la operò lui, il
marito, dopo quattro giorni, già tutta infetta, capirete, agonizzante, il
caso s'era fatto disperato.

GIUDITTA
E quel matto lì che non voleva! non voleva!

ROGHI
Ah sì? — L'amante? Oh bella! Non voleva che il marito la operasse?

DON CAMILLO
Che! Fece il diavolo a quattro! Se la voleva caricar su le braccia e
portar via, così moribonda, per non fargliela toccare!

ROGHI
Oh bella!

DON CAMILLO
Perchè diceva che, se il marito la salvava, era perduta per lui!

GIUDITTA
Ed era più contento che morisse!

ROGHI
E il marito? o come fece a sopportarselo davanti, e così accanto alla
moglie?

DON CAMILLO
Se la prese con me!

LA NÀCCHERI
Che gusto!

DON CAMILLO
Già, come se non avessi fatto di tutto, io, per farlo andar via, prima
ch'egli arrivasse. Non ci fu verso! — Tanto vero che non se ne volle
andare, neppur quando arrivò lui, che dopo tutto, ohè, dico, era il
marito!

Giuditta a questo punto, si recherà di nuovo in fondo a

guardare, se si scorgano le vetture di ritorno.

LA NÀCCHERI
E come gli tenne testa! Bisognava vedere!

ROGHI
Sì, eh?

DON CAMILLO
Col pretesto, capite? che in punto di morte non c'è più gelosie, e che
il marito non poteva, dice, adontarsi di lui, dopo tredici anni e dopo
ciò ch'era passato. Si dovette mandarlo via con le guardie.
 GIUDITTA
(dal pianerottolo della saletta in fondo, annunziando) Ecco, ecco,
ritornano le vetture!

La Nàccheri accorre come una papera.

DON CAMILLO
Oh finalmente!

GIUDITTA
(con un grido di spavento) Oh Dio! Ma è lui! Lui, di nuovo qua!

ROGHI
Chi lui?

DON CAMILLO
Il matto? Di nuovo qua?

LA NÀCCHERI
Lui! sì! lui! lui! — Rièccoci daccapo!

DON CAMILLO
Ma come! Che altro, ora, vorrà qua?

GIUDITTA
(ritirandosi impaurita) Vien su di corsa! ha scavalcato il murello
dell'orto!

ROGHI
È una bella sfrontatezza!

DON CAMILLO
E di nuovo in assenza del signor professore! Se lo ritroverà qui tra i
piedi!

LA NÀCCHERI
E come giulivo! Fa i gesti, oh, così... così... (agita in aria le braccia).

ROGHI
Dateci man forte per carità, caro Roghi! Non bisogna farlo entrar qua
dalla signora! — Andiamo, andiamo via tutti di là! (indica la saletta
d'ingresso e s'avvia spingendo fuori gli altri) Chiudiamo quest'uscio!
Chiudiamo quest'uscio!

Richiude l'uscio a vetri, andando via col Roghi, con la

Nàccheri e Giuditta.
Quasi contemporaneamente s'apre l'uscio a destra e
appare FULVIA GELLI, incerta, sgomenta, pallidissima,
come una che sia stata or ora strappata dalle mani
della morte. Ha tuttavia negli occhi un che di fosco; e il
volto è come indurito, sassificato in una disperazione
squallida e atroce.
Venuta qui per morire, sprovvista di tutto, levandosi
ora di letto, ha indossato — in mancanza d'altro — il
suo abito di viandante perduta, che stride, in contrasto
con quella disperazione del volto. Stridono ancor più i
voluminosi magnifici capelli in disordine,
sfacciatamente ritinti d'un color fulvo acceso, che le
avviluppano come in una fiamma lingueggiante il volto
disperato. Non ha avuto forza d'agganciarsi il busto sul
seno, che è quasi scoperto, e pròvoca, ma
frigidamente, poichè ella ha un evidente sdegno e un
vero intimo odio per la sua bella persona, come se da
un pezzo non le appartenesse più, e non sapesse più
neppure com'esso è, non avendo mai, se non con
 feroce ribrezzo, condiviso la gioja che gli altri ne han
preso.
Muove alcuni passi per la sala, verso l'uscio a vetri
chiuso, attraverso al quale giungono le voci concitate
delle due donne, di don Camillo e del Roghi, che
cercano d'impedire il passo a MARCO MAURI. A un
tratto, però, questi, sbarazzandosi di tutti con uno
strappo violento, irrompe spalancando l'uscio e si
precipita su Fulvia (ch'egli chiama Flora)
abbracciandola, stringendola a sè freneticamente. È
sulla quarantina, bruno, magro, con lucidi occhi
sfuggenti, da matto: quasi ìlari, pur nella più fiera
esagitazione, ìlari e parlanti. Fronte rotonda,
specchiante. Capelli da negro, crespi e gremiti, ma già
in parte grigi, spartiti nel mezzo. Sopracciglia
foltissime. Parla e gestisce con quella certa teatralità
che è propria della passione esaltata: teatralità calda e
sincera, ma che pure, a tratti, quasi vede sè stessa, e
scatta allora per rimorso in gesti irosi, o scade, quasi in
compenso, improvvisamente, in toni confidenziali, che
fanno, per contrasto e così senza trapasso, un
curiosissimo effetto.
Fulvia tenta dapprima di respingere, quasi
odiosamente, l'abbraccio; ma poi, investita, soffocata
da quella frenesia, nello smarrimento della debolezza
che il male recente le ha lasciato, vien meno e
s'abbandona come morta tra le braccia di lui.

MAURI
(liberandosi e spalancando l'uscio) Via tutti, vi dico! (precipitandosi
su Fulvia e abbracciandola c. s.) Flora! Flora mia! Flora! Flora! —
Libero! Sono libero! Ritorno a te, liberato! — Mi son liberato di tutto
e di tutti! (Notando che ella gli s'abbandona tra le braccia, riversa)
Flora mia!

À
 A questo grido, don CAMILLO, il ROGHI, la NÀCCHERI
e GIUDITTA, che sono entrati nella sala dietro il Mauri
e, sopraffatti dalla violenza, son rimasti sgomenti e
sospesi a mirare il frenetico abbraccio, accorrono
premurosi e minacciosi gridando insieme.

ROGHI
Ma non vede, perdio, che non si regge!

DON CAMILLO
Che violenze son codeste?

GIUDITTA
È svenuta! è svenuta!

MAURI
Svenuta? No! no! — Flora!

DON CAMILLO
(aggressivo) La lasci! via! — La lasci, e vada via subito di qua!

MAURI
(senza dargli ascolto, sorreggendo Fulvia) Flora mia... Flora... Flora...

DON CAMILLO
(alle donne) Ma levategliela dalle mani!

Giuditta e la Nàccheri si fanno avanti.

GIUDITTA
Dia qua... dia qua...

MAURI
(gridando minaccioso) Non me la tocchi nessuno!

DON CAMILLO
Non appartiene mica a lei!

MAURI
Appartiene a me! a me!

DON CAMILLO
Ah, nossignori! — C'è qua il marito!

MAURI
E venga! — Dov'è? — Me la strappi dalle braccia, se è buono!

ROGHI
(vedendo Fulvia tra le braccia di lui, così abbandonata, che quasi sta
per cadere) Ma la adagi almeno qua, per ora, in nome di Dio! (indica
il canapè).

GIUDITTA
(accorrendo e ajutandolo a sorregger Fulvia) Qua, venga qua — qua:
l'ajuto io!

MAURI
(trasportando Fulvia sul canapè) Non è niente, vi dico! Ora rinviene!

GIUDITTA
Vado a prendere i sali! (corre via per l'uscio a sinistra; rientrerà poco
dopo).

LA NÀCCHERI
(al cognato) Ma che siete voi qua? Siete o no il padrone?
 ROGHI
(a don Camillo) Questa infine è casa vostra!

MAURI
(subito rizzandosi con gli occhi spiritati, grida sillabando) Nossignori:
— Al-ber-go!

DON CAMILLO
(investendolo) Che? dove? quando? Chi gliel'ha detto, albergo? dove
sta scritto?

MAURI
Sulla porta, giù: — Pensione Zonchi!

DON CAMILLO
Sissignore — ma d'estate! — Ora non è stagione, capisce? ed è casa
mia soltanto; e vi ricevo chi mi pare e piace!

MAURI
(gridando) Non strillate così!

DON CAMILLO
(restando, quasi sbalordito) Ah senti: strillo io!

MAURI
Tanto è inutile: non me ne vado!

DON CAMILLO
Lei andrà via, andrà via, perchè...

LA NÀCCHERI
(intromettendosi e terminando la frase) Questa non è casa vostra!
 DON CAMILLO
(seguitando) E non ha più nulla a far qui! Inteso?

Il Mauri, per tutta risposta, poichè Giuditta ritorna coi

sali, si china su Fulvia per farglieli odorare.

MAURI
(a Giuditta) — Dia qua! dia qua!

DON CAMILLO
(al Roghi, indicandoglielo) — Là — vedete come intende lui?

MAURI
(chino su Fulvia) Flora mia, son qua io... — Su, via... Sei salva,
guarita... E io, libero — libero, sai? E ora ti porto via con me!

DON CAMILLO
(rifacendosi avanti, risoluto) Ah no, sa! Per questo, può star sicuro:
— lei non porta via nessuno!

MAURI
Me l'impedirete voi?

ROGHI
(facendosi avanti anche lui) Potrei, a un bisogno, impedirglielo
anch'io!

DON CAMILLO
Ma no: c'è il marito, caro Roghi, che sarà qui a momenti.

MAURI
E io son venuto per parlare con lui!
 DON CAMILLO
Vi farà cacciar di nuovo!

MAURI
Vorrò vederlo! — Non s'era mica uccisa per lui, questa donna! — Per
me, per me s'era uccisa!... E io, per lei — io, Marco Mauri — ho
abbandonato il mio posto, la mia famiglia, mia moglie, i miei figli!
(Guardando tutti in giro; poi rivolto al Roghi) Veda un po' se è
possibile, che qualcuno ora mi stacchi da lei!

DON CAMILLO
(vedendo che Fulvia, sorretta da Giuditta, comincia a riaversi e
guarda come smarrita) Ma sarà lei... ecco, ora... sarà lei stessa, la
signora!

MAURI
(subito voltandosi e accorrendo a lei) Tu, Flora? Mi scaccerai anche
tu?

Fulvia leva una mano per tenerlo discosto e si volta

verso don Camillo, ancora stordita, ma già fosca.

DON CAMILLO
Io la prego di credere, signora, che è entrato a forza, approfittando
dell'assenza del signor professore!

FULVIA
(alzandosi) Che volete ancora da me — voi?

DON CAMILLO
Ecco! Come gli ho detto io!

MAURI
(quasi trasecolato) Flora!... Oh Dio... Mi dài del voi?
 FULVIA
(seccata, scrollandosi) Ma se vi conosco appena!

DON CAMILLO
E voi l'avete ingannata, codesta signora: — Io lo so!

MAURI
(violentissimo) Statevi zitto, voi!

DON CAMILLO
Ingannata! ingannata! me l'ha detto lei!

MAURI
(a Fulvia) Come! Tu mi conosci appena? Me, Flora? me, che t'ho
dato tutta la mia vita?

FULVIA
(con nausea) Ma finite una buona volta di parlare così!

MAURI
(c. s. smorendo) Oh Dio... Come parlo? — Ma tu piuttosto, Flora...

FULVIA
Io non mi chiamo Flora.

MAURI
Fulvia, sì, Fulvia, lo so! Ma se volesti tu stessa, che ti chiamassi
Flora...

FULVIA
(con crudezza, sdegnosa) E volete dire anche come fu, davanti a
codesti signori?
 MAURI
(ferito) No! — Io? — Ah! — Ma allora veramente tu mi disprezzi?

FULVIA
(rimettendosi a sedere, tutta assorta in sè, cupa, mormora, seccata)
Non disprezzo nessuno, io.

MAURI
(insistendo) — Perchè t'ingannai?

FULVIA
Ma no, vi dico! (esasperatamente).

MAURI
(rivolgendosi a don Camillo) Me lo rinfacciate? Ma se lo gridai io
stesso a tutti, qua, che avevo dentro di me lo strazio d'un doppio
rimorso! Anche davanti a tuo marito lo gridai! — Testimoni tutti qua!
— Dite, dite se non gli gridai ch'era un impostore!... Impostore, sì,
impostore! Perchè era «venuto a perdonare»! Lui: a perdonare!
Quando avrebbe dovuto invece buttarsi in ginocchio, qua, davanti a
te, e farsi lui perdonare — come me! come me! — qua, così, ecco!
(Le casca davanti in ginocchio e grida) Perchè tutti l'abbiamo
ingannata, questa donna!

FULVIA
(si leva da sedere senza scatto e dice piano, frigidamente, con
disperata stanchezza) Dio mio, ancora codesto teatro... Che nausea!

MAURI
(come se si vedesse con gli occhi di lei; lì in ginocchio, ma tuttavia
non riuscendo a rialzarsi) Ah sì! nausea, sì! Hai ragione. Mi vedo; me
n'accorgo io stesso! (Si copre la faccia con le mani, e dice
piangendo) Ma non sono io; è la mia passione, Flora! Non grido io:
grida lei! Faccio nausea a me stesso, a sentirmi gridare così: ma non
posso farne a meno! Non vorrei gridare, e grido! (Si alza infine
risolutamente, come se d'improvviso, a forza, si riprendesse) Sono
venuto qua però per dimostrarti, che non t'ho mentito, io, sai? La
verità ti dissi: quella ch'era la verità per me; perchè non ho avuto
mai nessuno io nella vita, veramente per me; — tranne te, per pochi
giorni! — Venti — quanti sono stati? — non più di venti, in tutta una
vita!

FULVIA
Sì, va bene. Venti. Sono finiti. E dunque, basta.

MAURI
No! Come basta? No! — Adesso, Flora? Adesso che è finito invece
l'inganno?

FULVIA
Ma che inganno? di che inganno mi parlate?

MAURI
Del mio! di quello che ti feci! — È finito! finito! — Mi sono liberato!
sono libero ora!

FULVIA
(fissandolo fosca, come se cominci a prestarle attenzione solo ora,
per qualche idea che già le si matura dentro) Di che siete libero?

MAURI
Di disporre di me! Ho lasciato tutto! Il posto. Mi son dimesso. E mia
moglie, sai? lei stessa, mi ha aperto la porta: — «Vattene!» —
Felicissima.

LA NÀCCHERI
Oh guarda!
 MAURI
(voltandosi a lei, pronto) Non mi ha mai amato! Non ha mai saputo
che farsi di me! Vive per conto suo; ricca, con case e poderi. — Solo
per un malvagio istinto andò a scovar lei (indica Fulvia) là, a Perugia
— e le disse — (si volta verso Fulvia, che si è di nuovo seduta, ma
come assente, ancora assorta in sè) che ti disse? che ti disse? — Io
ancora non lo so! (E poichè Fulvia non risponde seguita rivolto agli
altri) Forse lei, capite? lusingandosi di ridar la pace a una famiglia, se
ne venne qua per levarsi di mezzo. (Riaccostandosi a Fulvia, allegro,
e lanciandosi a dire una cosa, che a un certo punto non gli par più
facile a dire; tuttavia la dice, facendosi coraggio, con una
sfrontatezza, che un po' fa pena, un po' fa ridere) Ma ora l'inganno è
finito! Figurati che... ma sì, non ho vergogna a dirlo... — lei stessa,
con le sue mani, mi... mi diede.... sì, un po' di denaro, per farmene
andar via.

FULVIA
(levando il capo, subito, per impedire che altri ne faccia le
meraviglie) E poi?

MAURI
(stordito dalla domanda inopinata) E poi? Che vuoi dire?

FULVIA
Che farete poi?

MAURI
Che farò? — Oh! — Che farò poi? — Ma se ho te, ho tutto! Farò di
tutto! Mi metterò a dar concerti... Posso — non nelle grandi città,
s'intende.

FULVIA
(freddamente e stranamente, alzandosi) Mi farete il piacere di dire a
lui tutto questo, appena sarà di ritorno.
 MAURI
(con gioja impetuosa, mentre gli altri restano come basiti) Io? a lui?
Sì? Vuoi che gli dica questo?

FULVIA
(per troncare, più che mai fredda, rivolgendosi a don Camillo)
Dovrebbe già esser qui...

DON CAMILLO
Già... io non so... questo ritardo...

MAURI
E allegramente, sai? allegramente glielo dirò... Eh, ora che tu... Sono
felice!

FULVIA
(infastidita) Vi prego... vi prego...

MAURI
Ma non sono stato mai io, Flora! Tu, invece — devi convenirne: sei
stata tu a voler prender la cosa così sul serio! Fare quello che hai
fatto, scusa!... Ma sì, via! — Per quel vecchio cammello là!

ROGHI
(non potendo tenersi dal ridere) Ah senti!

LA NÀCCHERI
(contemporaneamente, gargarizzando) Ah! ah! ah! ah! La moglie?
cammello?

DON CAMILLO
(contemporaneamente anche lui) Ma non ve lo dico, che è matto?
 MAURI
(con perfetta serietà) Un vecchio cammello, vi assicuro, signori. —
Nove anni più di me. — Zotica! Contadina... Lei l'ha veduta! (indica
Flora) — La sposai perchè aveva un pianoforte.

LA NÀCCHERI
(c. s. più forte, irrefrenabilmente) Ah! ah! ah! ah!

Il riso si comunica per contagio al Roghi e a Giuditta.

MAURI
(c. s. irritato un po') — Scusi, signora, se le dico che in questo,
veramente, non c'è niente da ridere.

ROGHI
(ridendo ancora) Ma come no, abbiate pazienza!

MAURI
Perchè non capite che cosa voglia dire capitare a venticinque anni,
pieno di sogni in un paesucolo più piccolo, più brutto — scusate — di
questo vostro, e marcirvi quattro, cinque, dieci eterni anni, pretore!

ROGHI
(a don Camillo) Ah, ecco dunque, è giudice davvero!

DON CAMILLO
(con forza convinta) È matto!

MAURI
(subito, serio) Mi sono dimesso. — Una vita che non si può figurare!
come nessuno di voi, che vi marcite dentro qua, può conoscere! —
Neanche tu, sai, Flora; che pure hai conosciuti tutti gli orrori della
vita! Ma, Dio mio, sono orrori almeno! — Non una vita fatta di
niente. — Niente! — Ombra. — Silenzio d'un tempo che non passa
mai. — Neanche acqua da bere. — Acqua di cisterna, amara,
renosiccia... — Ma non sarebbe nulla! È quel silenzio! quel silenzio!
Figuratevi che vi si sente anche un soffio di vento, quando scuote la
fune della cisterna giù in piazza, e la carrucola che ne stride; mentre
voi, dentro... — Ah! Un piano di vecchio tavolino, unto, polveroso,
ingombro di carte giudiziarie — e una mosca che vi scorre a tratti,
sopra. E tutta la vita lì, in quella mosca che voi state a guardare per
ore e ore. — Ebbene, immaginate di sentire un giorno, in quel
silenzio, il suono d'un pianoforte: l'unico del paese. Vi corsi incontro
come un assetato! E sissignori, sposai quella donna più vecchia di
me, che mi parve bellissima e intelligentissima, solo perchè aveva
quel pianoforte. — Perchè musica, musica io ho studiato, capite? non
ho mai studiato legge io. — Sono un musicista, io! — E quella —
dacchè la sposai — m'ha chiamato sempre pretore. Sì, sì, e anche i
figli! — Quattro — cresciuti con lei in campagna — a-nal-fa-be-ti. —
Anch'essi, anch'essi — non mi chiamano mica papà! pretore mi
chiamano! anzi: — Preto'!, come la madre. — È in casa il Preto'? —
No, è alla pretura, il Preto'!

Scoppiano a ridere tutti, tranne Fulvia.

ROGHI
(tra le risa) Oh bella! oh bella!

MAURI
Ridete, sì, ridete! Voglio riderne anch'io, ora! — Me ne sono liberato,
vivaddio! — D'amore e d'accordo — sì! Con qualche carezza, anche.
— E l'avrei strozzata, v'assicuro!

DON CAMILLO
(vedendo apparire dalla porticina dell'orto, in fondo, Silvio Gelli, che
viene avanti tra quelle risa, costernato) Oh, Dio sia lodato, ecco qua
finalmente il signor professore!
Alto di statura, SILVIO GELLI, di circa cinquant'anni,
ossuto, poderoso, porta occhiali a staffa, cerchiati
d'oro. Non ha barba nè baffi. Quasi calva la sommità
del capo; ma lunghe ciocche di capelli biondastri,
scoloriti, gli scendono scompostamente su la fronte e
su le tempie. Egli se le rialza di tanto in tanto, e si
tiene allora, per un tratto, le mani sul capo, come per
un gesto di meditazione, che gli è abituale. Ha l'aria tra
stordita e aggrondata d'un uomo che attraversi una
grave crisi di coscienza. Ma vuol dissimularla. Per cui,
spesso, resta quasi ottusamente inerte, con un sorriso
freddo e vano, rassegato sulle labbra: espressione
involontaria d'un che di beffardo, che è nella sua
natura, e che quasi affiora a sua insaputa da antiche,
maligne passioni, non ancora spente in lui, sebbene
già da un pezzo domate. A urtarlo un po' in queste
pause di ottusa inerzia, che sono in lui come ambigui
arresti di difesa morale, egli s'intorbida: quel sorriso
vano gli si scompone in una contratta smorfia di
dolore, come se gli bisognasse che il dolore gli
diventasse anche fisico, per poterlo sentire. Da queste
contrazioni la sua fisonomia riassomma poi ricomposta,
o meglio, quasi impostata in una grave e stanca aria di
probità, che vorrebbe apparire da gran tempo serena,
come lontanissima ormai da quelle passioni che pure
or ora, in tempestoso fermento, lo hanno travagliato.
Al suo entrare Fulvia si rizza in piedi felinamente, con
lo stesso animo che, tredici anni addietro, la condusse
alla perdizione. Ê per lei, questo, il momento d'una
prova suprema. E in tutto il suo aspetto sarà dunque la
risoluzione ferma d'affrontar questa prova, già
meditata e preparata oscuramente nella scena
antecedente, a costo di qualunque crudezza, mettendo
a nudo come un vivo lacerto la sua coscienza e quella
 di lui, con la più brutale sincerità, avvalendosi anche
della presenza di quel suo pazzo amante.

SILVIO
(notando la presenza del Mauri, ìlare tra la ilarità degli altri, e l'aria di
sfida della moglie) Ah, di nuovo qua?

MAURI
(irrompente) — Sissignore. E son venuto per...

FULVIA
(pronta, troncando, imperiosa) Lasciate parlar me! (Al marito,
recisamente) Qua di nuovo, sì. — Prega tutti questi signori di
lasciarci soli.

DON CAMILLO
Oh, subito, signora. Soltanto tengo a dichiarare al signor
professore...

FULVIA
(interrompendo di nuovo, per troncare) Che questo signore è entrato
a forza. — Va bene!

MAURI
(a don Camillo, accennando a Fulvia) Ma se siamo già d'accordo!

LA NÀCCHERI
(al cognato) Se son d'accordo! Che storie!

SILVIO
(a Fulvia) L'hai forse chiamato tu?

FULVIA
Non l'ho chiamato io. — Dobbiamo parlar di questo.

SILVIO
Sento che c'è un accordo...

FULVIA
Nessun accordo. Non è vero!

MAURI
Io son venuto da me.

FULVIA
(c. s.) Aspettate a parlare!

DON CAMILLO
E su, su, andiamo noi, andiamo via! (invitando col gesto a uscire il
Roghi, Giuditta, e la Nàccheri).

LA NÀCCHERI
(rivoltandoglisi) Ecco, ecco... Ma diciamo anche noi, a nostra volta, al
signore e alla signora, che noi qua...

DON CAMILLO
(sulle spine) Ma no, via, Marianna, che dite?

LA NÀCCHERI
Dico che siamo alla fine d'aprile, ohè! e che col maggio, voi sapete
bene, cominciano a venire i forestieri per la cura delle acque.

SILVIO
Conto, per me, di ripartire prestissimo, signora.

LA NÀCCHERI
La prescriverà, m'immagino, anche lei ai suoi ammalati, signor
professore! Ora, noi, qua, dobbiamo ancora rimettere in ordine la
pensione, ecco!

DON CAMILLO
Ma non vorrei che il signor professore credesse...

SILVIO
Lei sa bene che ho ragioni impellenti d'andar via al più presto.

ROGHI
Ma se non dovesse oggi, signor professore — ecco, io vorrei...

SILVIO
(accennando alla moglie) Vi prego...

ROGHI
Sì, sì, attenda, attenda con comodo, signor professore! Io posso
aspettare... aspetterò, ritornerò...

DON CAMILLO
Ritiriamoci, ritiriamoci adesso...

Spinge fuori il Roghi, la Nàccheri, Giuditta ed esce per

ultimo, inchinandosi e richiudendo l'uscio a vetri.

FULVIA
(subito, nervosamente) Ecco, Silvio. Questo signore, che conosco
appena...

MAURI
(ferito, protestando) Ma no, Flora!

FULVIA
Vi ho detto di lasciare parlar me!

MAURI
Ma se gli dici così, scusa!

FULVIA
Che volete che significhi, per una come me, conoscere uno da poco
o da molto? (Voltandosi verso il marito) «Flora» hai sentito? — Mi
chiama Flora!

MAURI
(in tono di rimprovero) Fulvia!

FULVIA
(precipitosamente) No, no, Flora, Flora — sono Flora. — (Di nuovo al
marito) Mi si chiama subito per nome, e mi si dà del tu.

SILVIO
A me premerebbe ora di sapere, come e perchè — dopo quanto è
avvenuto — si trovi qua di nuovo codesto signore.

FULVIA
Ecco, sì. — Questo signore, Silvio, crede sinceramente ch'io abbia
voluto uccidermi per lui. E non è vero!

MAURI
Ah, non è vero?

FULVIA
Non è vero. L'ho fatto per me. Ditegli come e dove m'avete
conosciuta. Basterà per farglielo comprendere.

SILVIO
Ma io non voglio saperlo!

FULVIA
Ero arrestata.

MAURI
(subito protestando) No! Che arrestata! Che dici!

FULVIA
Con un mandato di comparizione, sì. Complicata in un volgarissimo
delitto.

MAURI
(c. s.) Ma che! Non creda! Prosciolta in Camera di Consiglio!

SILVIO
Vi dico che non voglio saperlo!

MAURI
(seguitando con foga) Venuta soltanto per deporre. Lo so io! Fu a
Perugia, guardi, un mese appena dopo il mio trasferimento colà.
C'era io nella sala del giudice istruttore, mio collega. Fu nel processo
per l'assassinio d'un tal Gamba.

FULVIA
Con cui ero andata a Perugia.

MAURI
Sì, un pittore...

FULVIA
Ma che pittore! Un miserabile applicatore mosaicista della fabbrica di
Murano.
 MAURI
Già... venuto per restaurare non so che mosaico...

FULVIA
Un mascalzone che s'ubriacava tutti i giorni.

MAURI
E la picchiava! la picchiava!

FULVIA
Fu trovato morto, una notte, sulla strada, con la testa spaccata.

Silvio Gelli si rialza i capelli sul capo e vi trattiene le

mani.

MAURI
(scattando al gesto di Silvio Gelli) Orrore, eh? «Fin dov'era caduta!»
eh? — Ma mi faccia il piacere! lasci andare!

FULVIA
(subito, forte) Non declamate, al vostro solito!

MAURI
(senza darle retta, seguitando, ma in tono più basso, rivolto a Silvio)
Lei m'insegna che tutto sta nel togliersi d'addosso, una prima volta,
sotto gli occhi di tutti, l'abito, che ci ha imposto la società. Si provi,
lei che sorride...

SILVIO
Ma io non sorrido.

MAURI
Ha sorriso! — Si provi, si provi a rubare una volta cinque lire e faccia
che venga scoperto nell'atto di rubare. Me ne saprà dire qualche
cosa! — Ma lei non ruba... Grazie! — E questa disgraziata avrebbe
fatto quello che fece, se lei, suo marito...

FULVIA
(troncando, fierissima) Basta! Vi proibisco di seguitare!

SILVIO
(piano, calmo) Io sono venuto qua...

MAURI
Per perdonare, lo sappiamo!

SILVIO
(pronto, fermo, grave) No! — Per riconoscere il danno degli antichi
miei torti verso questa donna. Non m'aspettavo però che altri qua,
oltre lei, potesse arrogarsi di rinfacciarmeli.

MAURI
(subito, a sfida) E riparare?

FULVIA
(c. s.) Aspettate! Non sapete ciò che vi dite!

MAURI
No, io dico riparare, Flora! E lo dico davanti a lui! Perchè ho anch'io il
mio torto verso di te. Tu mi hai perdonato, ma io sono qua per
riparare, per riparare!

FULVIA
(col piglio di chi non vuol discutere) Dunque — sta bene — ecco —
io ti volevo dir questo, Silvio: — che egli è pronto...
 MAURI
(insistendo, pigiando, sfidando) A riparare, sì, a riparare!

FULVIA
(esasperatamente, sdegnata, gridando) Ma non dite a riparare —
fate ridere — se io non vi riconosco il torto, di cui volete accusarvi!
— Oh quest'è bella! — Avete mentito con me — come tanti... Che
volete che me n'importi? (Rivolgendosi di scatto al marito) Senti
forse anche tu qualche dovere verso me per avermi salvata? — No,
niente, caro! Grazie!

SILVIO
(stordito) Come! Io...

FULVIA
(subito incalzando, ma col tono di chi vuol ragionare) Sei forse
venuto qua come medico, per operarmi?

SILVIO
No.

FULVIA
(c. s.) Ma anche operandomi — (cosa che nessuno però ti chiese di
fare).

MAURI
Io m'opposi! io m'opposi!

FULVIA
(c. s. senza badare al Mauri) Io, per me certo, non te lo chiesi — è
vero?

SILVIO
(impacciato, come sopraffatto, non sapendo a che cosa tenda
quell'interrogatorio) No... — io lo feci...

FULVIA
(subito, venendogli in a ajuto, con uno strano lustro negli occhi)
Quasi irresistibilmente, è vero?

SILVIO
Vendendoti in quello stato...

FULVIA
E dunque! — Ero come morta. Fu un miracolo anche per te! — Se
sapessi come credo adesso ai miracoli!

SILVIO
Che vuoi, insomma, concludere?

FULVIA
Niente. Questo. Che non devi credere neanche tu d'aver adesso
verso di me qualche dovere per avermi così... diciamo «restituito alla
vita». — Nessun dovere, nessun dovere. Non ne accetto! — Nè da
te, nè da altri. Nè doveri, nè riparazioni.

SILVIO
E che intendi di fare allora?

MAURI
Se ne viene con me!

FULVIA
Sono qua. Vedete voi... Giacchè mi trovo tra un dovere che riconosco
insussistente, e un rimorso che dichiaro immaginario...

SILVIO
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