About Author:Harshal Ashok Pawar, M. Pharm., PhD
(Pharmacy), MD (AM)
He is currently working as an Assistant
Professor with Dr. L. H. Hiranandani College of Pharmacy, Ulhasnagar,
(Affiliated to University of Mumbai, India). He has 15 years of teaching and
industry research experience. He also worked as a Head of Department of Quality
Assurance for six years. He worked with various pharmaceutical industries like
Medley, Charak and Alkem Research Centre, Mumbai. He has published more than 60
research and review articles in various national / international journals of
repute. He has also presented various research papers in national /
international conference, seminars, symposia and workshops. He has two Indian
and two international patents to his credit. He has received research grants
from University of Mumbai. He is on editorial board and reviewer of various National
/ International journals. He has guided 25 M. Pharmacy Research scholars in the
subject of Quality Assurance. He is also recognized PhD guide of University of
Mumbai. He has authored seven books in the field of Pharmaceutical sciences. He
is a life member of Association of Pharmaceutical Teachers of India (APTI).
About Book:
A Textbook of Pharmaceutical Quality Assurance is an
outcome of sincere efforts made by author to collect, compile and simplify
various aspects of Quality assurance keeping in view the level and learning objectives
of Pharmacy students at undergraduate level. This book is prepared according to
new syllabus of B. Pharmacy, introduced by Pharmacy Council of India (PCI). The
present efforts will help the students to understand the subject matter easily.
This book mainly covers
the syllabus in the subject of Pharmaceutical Quality Assurance at the
undergraduate level, implemented in most of the Indian and Foreign Universities.
The book provides an overview about quality assurance, Good Manufacturing
Practice (GMP), validation, Good Laboratory Practices (GLP) and documentation
practice followed in industry. It is the most comprehensive book which deals
with the important aspects of
Quality assurance like cGMP, Quality control tests on packaging material, Pharmaceutical
documentation, Quality certifications and Regulatory affairs. The principles of
GMP and GLP are discussed which are expected to guide the manufacturer and the regulator
for maintaining high scientific and professional standards for ensuring only
drugs and pharmaceuticals of highest quality are produced and marketed.
The present book is
divided in to five units. The unique
feature of this book is the presentation of fundamental concepts in a simple,
lucid and self-explanatory form. Each unit includes learning objectives,
general introduction to the topics covered, discussion on various regulatory aspects
considering current regulatory guidelines and Pharmacopoeial requirements. At
the end of each unit a list of probable questions to be asked in semester
examination is provided so as to help the student to evaluate themselves. Every
effort is taken to provide most authenticated and precise information and
views, but readers are advised to refer the latest guidelines and cited
references for more details.
BOOK CONTENTS
1. QUALITY ASSURANCE AND QUALITY MANAGEMENT CONCEPTS...... 1
1. Introduction..................................................................................................... 1
1.1. Definition of
Quality................................................................................. 2
1.2 Quality of a Pharmaceutical Product...................................................... 2
2. Concept Of
Quality Assurance.................................................................... 3
2.1 Objectives of
Quality Assurance.............................................................. 4
2.2 Requirements of Quality
Assurance System as per WHO.................. 4
2.3 Quality Assurance Methods..................................................................... 5
3. Good Manufacturing Practices (GMP) For
Pharmaceutical Products...... 6
3.1 What is Good
Manufacturing Practice (GMP)?..................................... 6
3.2 What GMP covers?..................................................................................... 7
4. Quality Control............................................................................ 8
4.1 Objectives of
Quality Control................................................................... 8
4.2 Basic Requirements of Quality Control.................................................. 9
4.3 Tools /Methods /Techniques of Quality Control............................... 10
5. Comparison Of Quality Assurance and Quality Control................... 10
2. TOTAL QUALITY
MANAGEMENT (TQM).................................................... 12
1. Introduction.................................................................................................. 12
2. Quality Management
Philosophies.............................................. 14
3. Definitions Of
TQM..................................................................................... 17
4. Benefits Of TQM........................................................................................... 17
5. Disadvantages /
Limitations of TQM.......................................... 18
6. Characteristics Of
TQM.............................................................................. 18
7. Total Quality
Management Principles................................................... 18
8. Elements Of TQM....................................................................... 18
9. TQM In Pharmaceutical
Industry............................................................ 22
9.1 Application of TQM in Pharmaceutical Industry................................ 23
10. Reasons of Failures
in Implementation of TQM Approach............. 25
3. ICH GUIDELINES.......................................................................... 28
1. Introduction.................................................................................................. 28
1.1 Mission of ICH.......................................................................................... 29
1.2 The Need to
Harmonise........................................................................... 30
1.3 Process of
Harmonization....................................................................... 31
2. Organization of ICH................................................................... 33
3. Classification of ICH Guidelines.............................................................. 35
4. Stability Testing Guidelines (Q1A - Q1F)*............................................ 38
4.1. Stability Testing Guidelines for New Drug Substance..................... 41
4.2. New Drug Product.................................................................................. 47
4.3 Photostability Testing (Q1B Guidelines).............................................. 56
4. QUALITY BY DESIGN (QBD)......................................................................... 59
1. Introduction.................................................................................................. 59
1.1 QbD in Pharmaceutical Development................................................. 61
1.2 Definitions of
Quality by Design........................................................... 63
1.3 Objectives of Pharmaceutical QbD....................................................... 63
1.4 Comparison of Traditional and QbD Approach of
Pharmaceutical
Development................................................................................................................... 63
1.5 Benefits of
QbD to Industry................................................................... 65
1.6 Opportunities........................................................................................... 66
2. Important Definitions................................................................................ 67
3. Elements / Components of QbD................................................. 68
4. Tools of QbD.............................................................................. 75
4.1 Prior Knowledge....................................................................................... 75
4.2 Risk Assessment..................................................................................... 76
4.3 Mechanistic Model, Design of
Experiments, and Data Analysis......... 77
4.4 Process Analytical Technology (PAT).................................................... 78
5. 
Steps For Pharmaceutical Qbd Implementation................................ 81
5. ISO 9000 AND ISO 14000............................................................. 84
1. Introduction.................................................................................................. 85
2. History And Revisions: Iso 9000:2000, 2008,
2015.................... 86
3. ISO 9000.................................................................................... 86
3.1 Objectives of ISO 9000............................................................................ 87
3.2 Benefits of ISO 9000 (Why to adopt ISO 9000?)................................ 87
3.3 ISO 9000 Series standards.................................................................... 88
3.4 ISO 9000:2000.......................................................................................... 89
3.5 ISO 9004.................................................................................................... 89
4. Elements Of ISO 9000 Quality
Management Systems................. 90
5. ISO9000 Principles Of Quality
Management...................................... 93
6. Advantages Of ISO 9000............................................................ 94
7. Disadvantages Of ISO 9000........................................................ 96
8. ISO 14000................................................................................. 97
9. Components Of ISO 14000 Series.............................................. 97
10. Benefits Of
ISO 14000 (Why To
Adopt The ISO 14000 Standard?)..... 99
11. Registration Process - Steps To Follow............................................. 100
6. NABL ACCREDITATION.............................................................. 103
1. Introduction............................................................................................... 103
2. Why Laboratory Accreditation?............................................................ 106
2.1 Benefits of
Accreditation...................................................................... 106
2.2 Scope of
Accreditation.......................................................................... 108
3. Preparation And Eligibility For Accreditation.................................. 108
4. Process Of
Accreditation......................................................................... 110
7. ORGANIZATION AND PERSONNEL.............................................. 114
1. Introduction................................................................................................ 114
2. Personnel (Who
Guidelines).................................................................... 116
2.1 Principle.................................................................................................. 116
2.2 General requirements........................................................................... 116
2.3 Key personnel......................................................................................... 117
3. Training
3.1 Types of
training.................................................................................... 121
3.2 Training as per WHO guidelines......................................................... 122
4. Personal Hygiene
(WHO guidelines)..................................................... 123
5. Personnel Records..................................................................................... 124
8. PREMISES.................................................................................. 126
1. Introduction................................................................................................ 126
1.1 Essentials /
Elements (General Requirements of
Quality Premises)....... 127
2. Location....................................................................................................... 127
3. Pharmaceutical Plant Layout................................................................. 128
3.1 What is a pharmaceutical plant layout?........................................... 128
3.2 Features of a good pharmaceutical plant layout............................. 128
3.3 Advantages of a good pharmaceutical plant layout......................... 129
4. Design And Construction........................................................................ 129
4.1 Plan and Layout..................................................................................... 130
4.2 Design, Construction, And Validation Of Pharmaceutical Facilities.... 132
4.3 Premises.................................................................................................. 136
5. Maintenance............................................................................................... 141
6. Sanitation................................................................................ 141
6.1 Requirements as per WHO guidelines................................................. 142
6.2 Sanitation for sterile pharmaceutical products..................................... 142
7. Utilities And Sterile
Area......................................................... 143
7.1 Water systems........................................................................................ 143
7.2 Compressed gases and vacuum systems.............................................. 145
7.3 Cooling systems...................................................................................... 145
8. Aseptic Area And Parenteral Production............................................ 146
8.1 Areas in parenteral processing............................................................. 146
8.2 Requirements for
design of
aseptic area................................................ 148
9. Control Of Contamination........................................................ 151
9.1
Sources of
Contamination and
its Prevention....................................... 152
10. Environmental Control.......................................................... 154
9. EQUIPMENT’S AND RAW MATERIALS......................................... 157
1. Introduction............................................................................................... 157
2. Equipment’s............................................................................ 158
2.1 Types of Equipment’s........................................................................... 159
2.2 Life cycle of an Equipment.................................................................. 159
2.3 Management of Equipment’s in Pharmaceutical Plants as per International GMP
Literature...................................................................................................... 159
3. Equipment Selection................................................................................ 160
3.1 Factors to be considered during
equipment selection................... 160
4. Purchasing.................................................................................................. 162
4.1 Stores and purchase
committee........................................................ 162
4.2 Purchase specifications....................................................................... 163
5. Maintenance Of Equipment’s................................................................ 164
5.1 Objectives of
Maintenance.................................................................. 164
5.2 Types of maintenance.......................................................................... 164
6. Requirements For Equipment
As Per Who Guidelines............... 165
7. Raw Materials.......................................................................... 166
7.1
Factors to
be considered while purchasing the materials................. 167
7.2 Purchase specification......................................................................... 167
7.3 General Specifications for Raw Materials (Contents of Raw
material
monograph)................................................................................... 168
7.4 Steps involved in purchase procedure.............................................. 169
7.5 Vendor selection and Certification.................................................... 169
8. Maintenance Of Stores............................................................................ 170
9. WHO Guidelines For Raw Materials........................................... 171
9.1 General requirements.......................................................................... 171
9.2 Starting materials................................................................................. 172
9.3 Packaging materials............................................................................. 173
9.4 Finished products................................................................................. 174
10. QUALITY CONTROL.................................................................. 176
1. Introduction............................................................................................... 176
1.1 Definitions.............................................................................................. 177
1.2 Types of Package................................................................................... 178
1.3 Associated Components...................................................................... 179
2.
Ideal Requirements of
Good Package / Container (Hazards Encountered
By Package)....................................................................................................... 179
3. Package Testing Procedure.................................................................... 180
3.1 Testing of material................................................................................ 180
3.2 Testing of Packages.............................................................................. 181
3.3 Instrumental Techniques used for Quality
control of Packaging
material.................................................................................... 181
4. Composition Of Package......................................................................... 181
5. Quality Control of Packaging Components....................................... 182
5.1 Containers............................................................................................. 182
5.2 Plastic Containers................................................................................. 194
5.3 Metal containers................................................................................... 198
6. Closures.................................................................................. 201
6.1 Types of closures................................................................................... 201
6.2 Materials used for making
closures.................................................. 201
6.3 Test for Closures................................................................................... 202
7. Secondary Packaging Components...................................................... 204
7.1 Paper, Paperboard and Cardboard.................................................... 205
7.2 Evaluation of Secondary Packaging Components........................... 205
11. GOOD LABORATORY PRACTICES............................................. 210
1. Introduction............................................................................................... 211
1.1 Aims / Goals of
GLP............................................................................. 211
1.2 Benefits of
GLP...................................................................................... 212
1.3 Fundamentals of GLP........................................................................... 213
1.4 Definition and Principles of GLP......................................................... 213
2. General Provisions................................................................... 218
2.1 Scope....................................................................................................... 218
2.2 Important Definitions.......................................................................... 218
2.3 Applicability to studies
performed under grants
and contracts... 220
2.4 Inspection of
a testing facility............................................................. 220
3. Organization And Personnel..................................................... 220
3.1 Personnel................................................................................................ 220
3.2 Testing facility management............................................................... 221
3.3 Study director........................................................................................ 222
3.4 Quality assurance unit........................................................................ 222
4. Facilities...................................................................................................... 224
4.1 General.................................................................................................... 224
4.2 Animal care
facilities............................................................................. 224
4.3 Animal supply
facilities........................................................................ 224
4.4 Facilities for handling
test and control
articles................................ 225
4.5 Laboratory operation
areas.................................................................. 225
4.6 Specimen and
data storage facilities.................................................. 225
5. Equipment............................................................................... 225
5.1 Equipment design.................................................................................. 225
5.2 Maintenance and
calibration of equipment...................................... 225
6. Testing Facilities Operation................................................................... 226
6.1 Standard operating procedures.......................................................... 226
6.2 Reagents and
solutions........................................................................ 227
6.3 Animal care............................................................................................. 227
7. Test And Control Articles....................................................................... 228
7.1 Test and
control article characterization........................................... 228
7.2 Test and
control article handling........................................................ 229
7.3 Mixtures of
articles with carriers........................................................ 229
8. Protocol For Conduct
Of A Nonclinical Laboratory Study.............. 230
8.1 Protocol.................................................................................................... 230
8.2 Conduct of a nonclinical laboratory study........................................ 231
9. Records And Reports................................................................................ 231
9.1 Reporting of nonclinical laboratory study results........................... 231
9.2 Storage and
retrieval of records and data......................................... 233
9.3 Retention of
records.............................................................................. 233
10. Disqualification Of Testing
Facilities................................................ 235
10.1 Purpose................................................................................................. 235
10.2 Grounds for
disqualification.............................................................. 235
10.3 Notice of and opportunity for
hearing on
proposed disqualification.... 235
10.4 Final order on disqualification.......................................................... 236
10.5 Actions upon disqualification............................................................ 236
10.6 Public disclosure of information regarding disqualification........ 237
10.7 Alternative or additional actions to disqualification..................... 237
10.8 Suspension or termination of a testing
facility by a sponsor...... 238
10.9 Reinstatement of a disqualified testing
facility.............................. 238
12. COMPLAINT, RETURN GOODS, RECALL AND WASTE DISPOSAL...... 240
1. Introduction................................................................................................ 240
2. Complaint................................................................................ 242
2.1 Need for
Complaint Handling System................................................ 242
2.2 Types of
complaint encountered......................................................... 242
3. Complaint Handling / Evaluation............................................. 243
3.1 Evaluation of
Complaint....................................................................... 244
3.2 Standard operating procedure
for handling complaint.................. 245
3.3 WHO Guidelines
for Review of Complaint......................................... 246
4. Handling Of Return
Goods........................................................ 247
4.1 Classification of
returned goods......................................................... 248
4.2 Record of
return goods......................................................................... 248
5. Product Recall / Withdrawal.................................................................. 248
5.1 Definitions............................................................................................... 248
5.2 Reasons for Recall
/ withdrawal of Product..................................... 249
5.3 Recall Classification.............................................................................. 249
5.4 Basic information
required for recall................................................. 249
5.5 Stages of
recall procedure...................................................... 250
5.6 Implementation of
recall communication.......................................... 251
5.7 Contents of
recall communication........................................... 251
5.8 WHO guidelines
for Recall................................................................... 251
6. Waste Disposal......................................................................... 252
6.1 Procedure for disposal
of pharmaceutical waste.............................. 252
13. DOCUMENT MAINTENANCE IN
PHARMACEUTICAL INDUSTRY..... 256
1. Introduction............................................................................................... 257
1.1 Purpose of
Documentation.................................................................. 257
2. General Requirements About Documentation (As
Per WHO Guidelines)..................................................................................... 258
3.
Batch Formula Record
(BFR) / Batch Production Record (BPR)
/ Batch Processing And Control Records
(BPCR) /
Batch Manufacturing Record (BMR)......................................................... 259
4.
Mater Formula Record
(MFR) / Master Production
Instructions / Master Production And Control Records
(MPCR) / Master Formula Card (MFC)...................................................... 262
5. Standard Operating Procedure
(SOP) And Other Documents....... 263
6. Quality Audit........................................................................... 266
6.1 Reasons for
auditing............................................................................. 267
6.2 Types of Audit......................................................................................... 267
6.3 Procedure for
conducting an audit..................................................... 267
6.4 Audit preparation.................................................................................. 268
6.5 Conducting of
audit.............................................................................. 268
6.6 Completing and
follow up of audit..................................................... 269
7. Product Quality
Review........................................................................... 269
8. Quality Documentation........................................................................... 270
9. Reports And Documents......................................................................... 271
10. Distribution Records.............................................................................. 272
14. CALIBRATION AND VALIDATION
1. Introduction................................................................................................ 276
2. Important Definitions.............................................................................. 276
3. Qualification Process............................................................................... 277
3.1 Qualification stages............................................................................... 278
4. What Is
Equipment Calibration?.......................................................... 281
4.1 Scope/ Purpose of Calibration............................................................ 281
4.2 When to
perform Calibration?............................................................. 282
4.3 Types of
Calibration.............................................................................. 282
5. Validation of Equipment.......................................................... 284
5.1 Need of
Equipment Validation............................................................. 284
6. Validation................................................................................ 285
6.1 Various Definitions
of Validation........................................................ 285
6.2 Reasons for
Validation.......................................................................... 285
6.3 Scope of
Validation................................................................................ 286
6.4 Types of
Validation................................................................................ 287
6.5 Validation Protocol................................................................................ 289
6.6 Validation Master Plan (VMP) / Master Validation Plans (MVP)....... 290
7. Calibration of PH Meter............................................................ 293
7.1 Construction of
pH meter..................................................................... 293
7.2 Calibration Procedure........................................................................... 294
8. Qualification Of UV-Visible Spectrophotometers............................. 295
8.1 Installation Qualification...................................................................... 296
8.2 Operational Qualification..................................................................... 296
8.3 Calibration of
UV-VIS spectrophotometer......................................... 297
8.4 Performance Qualification.................................................................... 299
9. General Principles Of Analytical Method
Validation...................... 301
9.1 Principle.................................................................................................. 301
9.2 General requirements........................................................................... 302
9.3 Analytical Method
Validation.............................................................. 303
15. WAREHOUSING AND MATERIALS MANAGEMENT...................... 312
1. Introduction................................................................................................ 312
2. Role /
Functions of Warehousing......................................................... 313
3. Types of Warehouses................................................................ 314
4. Warehouse Location................................................................................. 315
5. Why is Good Warehouse Practices (GWP) Important?.................... 315
6. Good Warehouse
Practices (GWP)......................................................... 316
6.1 Premises.................................................................................................. 316
6.2 Security................................................................................................... 316
6.3 Temperature and
Humidity Control................................................... 317
6.4 Equipment’s............................................................................................ 317
6.5 Personnel................................................................................................. 317
6.6 Sanitation................................................................................................ 318
6.7 Receipt of
incoming goods.................................................................... 318
6.8 Assembling orders
and issuing goods................................................ 318
6.9 Packing for
transportation................................................................... 319
6.10 Transport.............................................................................................. 319
6.11 Records.................................................................................................. 320
7. Material Management............................................................................ 321
7.1 Objectives................................................................................................ 322
7.2 Functions of
Material Management.................................................... 322
7.3 Purchasing.............................................................................................. 322
7.4 Stores Management............................................................................... 325
7.5 Salvaging and disposal
of scrap and surplus................................... 326
8. Materials Management for API
(As per US FDA - Q7A -
GMP guidance for API).................................................................................. 326
8.1 General Controls.................................................................................... 326
8.2 Receipt and
Quarantine....................................................................... 326
8.3 Sampling and Testing
of Incoming Production Materials............... 327
8.4 Storage..................................................................................................... 328
8.5 Re-evaluation......................................................................................... 328
ANNEXURES.................................................................................. 330
MODEL QUESTION PAPERS............................................................ 403
BIBLIOGRAPHY.............................................................................. 404
KEY WORD INDEX.......................................................................... 408
Publishers Note:
Everest's New Arrival for Semester VI B.Pharm All India Colleges
A Textbook of Pharmaceutical Quality Assurance
by
Dr. Harshal Ashok Pawar
As per PCI Syllabus Guidelines
The Book has been foreworded and recommended by Shri Jagannath Shinde who is the President, Chairman, MD of a number of Chemists, Druggists & Distributors Associations of India, member of various Regulatory Bodies of India such as PCI, Maharashtra State Pharmacy Council etc. as well as Member of Maharashtra Legislative Council.
Make the most use of the book by increasing the educative beauty of your Library.
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