Active Pharmaceutical Ingredients - Devel., Mfg, Regul.

355 Pages·2005·3.181 MB·English

by  S. Nusim

DK2287_half-series-title.qxd 4/14/05 12:35 PM Page i
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
DK2287_Discl.fm Page 1 Tuesday, April 12, 2005 2:45 PM
Published in 2005 by
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Preface
Activepharmaceuticalingredientsknowntodayas‘‘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
ofthesechemicalsisasubsectionoffinechemicalmanufactur-
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-
turedthefinaldosageform.
The ‘‘pharmaceutical industry’’ at the turn of the 20th
century was essentially the local pharmacy (or ‘‘chemist’’ as
itwasalsoknown).The‘‘bulkpharmaceuticalchemicalindus-
try’’atthattimewasmerelyaproviderofallthoselaboratory
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’’oftheproduct,butaveryintensivelookatthedevel-
opmentoftheprocesstobeusedaswellasthemanufacturing
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-
trolledbytheso-called‘‘cGMPs’’(currentGoodManufacturing
Practices),whiletheformerbythenatureofthechemicalpro-
cess and the level of quality assurance that the process pro-
vides; hence, a focus on the process development is essential.
Itistheintentofthisvolumetofocusonthethreeoverall
activitiesthatbringanAPItomarket;thedevelopmentofthe
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
environmentthathasseenmanychangesin themarketitself
as well as its regulation, product mix, and volume.
This text covers those three activities of development,
manufacturing,andregulationinitsbroadestsense.Thiswill
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
generatedactivesbutaresufficientlydifferenttobeworthyof
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. ProjectTurnoverandInstallation
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