Foodtech Network - Quality Assurance

I
OUALITY
ASSURANCE
. .
QUALITY ASSURANCE
B . Pharm, Sixth Semester
According to the syllabus based on ‘ Pharmacy Council of India '
Dr. R. Sundhararajan
M.Pharm, Ph.D.
Principal
Mohamed Sathak A.J . College of Pharmacy, Chennai
Dr. M .V . Kumudhavalli
M.Pharm, Ph.D.
Professor
Vinayaka Missions College of Pharmacy, Tamil Nadu
Dr. Minal T Harde

M . Pharm, Ph .D.
Assistant Professor
Modern College of Pharmacy , Pune
THAKUR PUBLICATION PVT. LTD., LUCKNOW

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Quality Assurance
- Dr.. R..VSundhararajan
- Dr M . Kumudhavalli
- Dr. Mittal T Harde
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ISBN No. 978-93-89627 -90-9

First Edition 2020
Reprint 2021
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“ Dedicated
to
my Dear Parents
and
Family "
- Dr . R . Sundhararcyan
“Dedicated
to
my entire work
to God Almighty for his endless mercy”
- DR . M .V . Kumudhavalli
“Dedicated
to
my Family ”
- Dr . MinalT Harde
Preface
It gives us immense pleasure to place before the B.Pharm Sixth Semester
pharmacy students the book on “ Quality Assurance”.
This book has been written strictly in accordance with the current syllabus
prescribed by Pharmacy Council of India, for B. Pharm students. Keeping in view
the requirements of students and teachers, this book has been written to cover all
the topics in an easy -to-comprehend manner within desired limits of the
prescribed syllabus, and it provides the students concepts of quality assurance
and quality management , TQM , QbD, ICH guidelines, ISO 9000 and 14000, etc.
which are required by them during their pharmaceutical career.
All efforts have been made to keep the text error-free and to present the subject
in a student friendly and easy to understand. However, any suggestions and
constructive comments would be highly appreciated and incorporated in the
future edition .
Please e-mail us at , thakurpublication @ gmail.com
Website, www.tppl.org.in
Acknowledgement
I wish to express my deep appreciations and warmest thanks to the team of
Thakur Publication Pvt. Ltd. for giving me this opportunity to pen this book. I
thank the Management of Mohamed Sathak A. J. College of Pharmacy,
Sholinganallur, Chennai , for providing me suitable working environment to
carry out my work in a smooth and efficient manner. I also express my sincere
thanks to all authors whom I referred while preparing the book. I am extremely
grateful to bestow my honor and respect to all my Teachers who have guided me
throughout my career.
I also thank Dr. N.B. Santha Sheela. M.Pharm, Ph.D., Professor and Head
Department of Pharmaceutics and Mrs. G. Rajalakshmi, M. Pharm, ( Ph.D ) , .
Associate Professor, Department of Pharmaceutics, Mohamed Sathak A. J .
College of Pharmacy, Sholinganallur, Chennai for sharing their suitable
suggestions. I would like express my gratitude to all people who have served as a
backbone in successful completion this book.
Above all I thank God for providing me this opportunity and helping me to overcome
all hindrances and obstacles to reach my goal in a smooth and efficient manner.
- Dr . R . Sundhararajan
We are greatful to the Almighty, whose love, merciful, Blessings and Patience
that carried me through my endeavor and finally made this book a grant success.
I gratefully acknowledge the suggestions of colleagues and mentors for their
grateful assistance, enthusiastic encouragement for their grateful assistance in the
preparation of this manuscript. I express my heart full thanks to our
Management of Vinayaka Missions Research Foundation ( deemed to be
University ) , which accomplish a successful completion of this task.
I shall remain thankful to Principal and my mentors of Vinayaka Missions

College of Pharmacy, Salem, Tamil Nadu for encouraging this book. I express
my heart full thanks to my lovable husband and kids for their endless affections
showered on me. Above all , I would like to thank our energetic and Dynamic
Publishers for bringing out this quality based theory book.
- DR . M .V . Kumudhavalli
. .
I am grateful to my publisher Thakur Publication Pvt Ltd house who have
rendered all possible assistance in bringing out this book. I wish to acknowledge
my deep gratitude to staff who have assisted and helped me in preparing this
book. I also thankful to all my colleagues & family members for encouragement
& support. I ' ll consider my efforts amply rewarded in case the book proves
useful to the students.
- Dr . Minal THarde
-6-
Syllabus
Module 01 10 Hours
Quality Assurance and Quality Management Concepts
• Definition and concept of Quality control , Quality assurance and GMP.
Total Quality Management ( TQM )
• Definition, elements, philosophies.
ICH Guidelines
.
• Purpose, participants, process of harmonization Brief overview of QSEM, with special
emphasis on Q-series guidelines, ICH stability testing guidelines.
Quality by Design ( QhD )
• Definition , overview, elements of QbD program, tools.
ISO 9000 & ISO14000
• Overview, Benefits, Elements, steps for registration.
NABL Accreditation
• Principles and procedures.
Module 02 10 Hours
Organization and Personnel
• Personnel responsibilities, training, hygiene and personal records.
Premises
• Design, construction and plant layout, maintenance, sanitation, environmental control,
utilities and maintenance of sterile areas, control of contamination.
Equipments and Raw Materials
• Equipment selection, purchase specifications, maintenance, purchase specifications
and maintenance of stores for raw materials.
Module 03 10 Hours
Quality Control
• Quality control test for containers, rubber closures and secondary packing materials.
Good Laboratory Practices
• General Provisions, Organization and Personnel, Facilities, Equipment, Testing
Facilities Operation.
• Test and Control Articles.
• Protocol for Conduct of a Nonclinical Laboratory Study.
• Records and Reports.
• Disqualification of Testing Facilities.
Module 04 08 Hours
Complaints
.
• Complaints and evaluation of complaints Handling of return good, recalling and
waste disposal.
Document Maintenance in Pharmaceutical Industry
. .
• Batch Formula Record Master Formula Record, SOP, Quality audit Quality Review and
.
Quality documentation Reports and documents, distribution records.
Module 05 07 Hours
Calibration and Validation
• Introduction, definition and general principles of calibration, qualification and validation,
importance and scope of validation, types of validation, validation master plan .
.
• Calibration of pH meter Qualification of UV -Visible spectrophotometer General .
principles of Analytical method Validation.
Warehousing
• Good warehousing practice, materials management .
-7-
Contents
Chapter 1: Quality Assurance 2.1.3.4. Quality Tools 42
and Quality Management 2.1.4. Advantages 44
1.1. Quality Assurance and 11 2.1.5. Disadvantages 44
Quality Management 2.2. Summary 45
Concepts 2.3. Exercise 46
1.1 . 1 . Introduction 11 Chapter 3: ICH Guidelines
1.1.2. Definition and Concept of 11 3.1. ICH Guidelines 47
Quality Control 3.1.1. Introduction 4'
"
1.1.3. Definition and Concept of 12 3.1.2. Purpose 47

"
Quality Assurance 3.1.3. Participants 47

1.2. Definition and Concept 13 3.1.4. Process of Harmonization 48
of GMP 3.1.4.1. Formal ICH Procedure 48
1.2.1. Introduction 13 3.1.4.2. Questions and Answers 50
1.2.2. Personnel 14 Procedure
1.2.3. Buildings and Infrastructure 16 3.1.4.3. Revision Procedure 50
1.2.4. Process Equipment 18 3.1.4.4. Maintenance Procedure 50
1.2.5. Documentation and Records 20 3.1.5. Overview of QSEM 51
1.2.6. Materials Management 22 3.1.5.1. Q-Series Guidelines 51
1.2.7. Production and In -Process 24 3.1.5.2. S-Series Guidelines 52
Controls 3.1.5.3. E-Series Guidelines 52
1.2.8. Packaging and 26 3.1.5.4. M -Series Guidelines 53
Identification Labelling of 3.2. ICH Stability Testing 53
APIs and Intermediates
Guidelines
1.2.9. Storage and Distribution 27 3.2.1. Introduction 53
1.2. 10. Laboratory Controls 27 3.2.2. Climatic Zones for 53
1.2.11. Validation 30 Stability Testing
1.2.12. Change Control 32 3.2.3. Protocol for Stability 54
1.2.13. Rejection and Re- Use of 33 Testing
Materials 3.3. Summary 57
1.2.14. Complaints and Recalls 33 3.4. Exercise 58
1.3 . Summary 33
1.4. Exercise 36 Chapter 4: Quality bv Design
( QbD )
Chapter 2: Total Quality 4.1. Quality by Design ( QbD ) 59
Management 4.1. 1 . Definition and Overview 59
2.1 . Total Quality 37 4.1.2. Elements of QbD Program 59
Management TQM )
( 4.1.2.1. Quality Target Product 60
2.1.1. Introduction and 37 Profile ( QTPP)
Definition 4.1.2.2. Critical Quality Attributes 60
2.1 .2. Elements 37 ( CQAs )
2.1 .2.1 . Foundation 37 4.1.2.3. Quality Risk Management 61
2.1 .2.2. Building Bricks 38 ( QRM )
2.1.2.3. Binding Mortar 38 4.1.2.4. Determination of Critical 63
( Communication ) Process Parameters ( CPPs)
2.1.2.4. Roof ( Recognition ) 39 4.1.2.5. Design Space 64
2.1.3. Philosophies 39 4.1.2.6. Control Strategy 65
2.1.3.1. Quality Circle 39 4.1.3. Tools 65
2.1.3.2. Customer Focus 41 4.2. Summary 67
2.1.3.3. Continuous Improvement 41 4.3. Exercise 68
-8-
Chapter 5: ISO 9000 & ISO 8.1.3. Design and Construction 94

14000 8.1.4. Plant Layout 96
5.1. ISO 9000 69 8.1.5. Sanitation 98
5.1.1 . Introduction and Overview 69 8.1 .6. Maintenance 98
5.1.2. Benefits 71 8.1.7. Environmental Control 98
5.1.3. Elements 72 8.1 .8. Utilities of Sterile Area 99
5.1.4. Steps for Registration 73 8.1.9. Maintenance of Sterile Area 100
5.2. ISO 14000 75 8.1.9.1. Cleaning Agents and 100
5.2.1. Introduction and Overview 75 Disinfectants
5.2.2. Benefits 76 8.1.9.2. Validation of Disinfection 101
Procedures
5.2.3. Elements 77
5.2.4. Steps for Registration 78 8.1 .9.3. Monitoring of Adequacy 101
5.3 . Summary 79 and Efficacy of Cleaning
5.4 . Exercise 81 and
Procedures
Disinfection
8.1 . 10. Control of Contamination 102

Chapter 6: NABL Accreditation 8.1 .10.1. Cleanrooms and Cross 102 -
6.1 . NABL ( National 82
Contamination
Accreditation Board for 8.1.10.2. Main Sources of 102
Testing and Calibration Contamination
Laboratories ) 8.1.10.3. Contamination Control 103
6.1 . 1 . Introduction 82 8.1.10.4. Raw Materials Store 103
6.1.2. Benefits and Scope of 82 8.1.10.5. Control Over Incoming 103
NABL Accreditation Goods
6.1.3. Procedures 83 8.1.10.6. Use of Computer Systems 103
6.2. Summary 84 8.1.10.7. Maintenance Department 103
6.3. Exercise 85 8.1.10.8. Dispensary 104
8.1.10.9. Filling Department 104
Chapter 7: Organisation and 8.1.10.10. Contamination by 104
Personnel Machinery
7.1 . Organisation and 86 8.1.10.11. Control of Air Quality 105
Personnel 8.1.10.12. Packaging Department 105
7.1.1 . Introduction 86 8.1.10.13. Contamination by People 105
7.1.2. Responsibilities of QC 86 8.1.10.14. Cleanroom Air Control 106
Unit 8.1.10.15. Airflow Patterns and 106
7.1.3. Personnel Qualifications 87 Contamination Control
7.1.4. Personnel Responsibilities 87 8.1.10.16. Positive Pressure Rooms 106
7.1.5. Personnel Training 88 8.1.10.17. Negative Pressure Rooms 106
7.1.5.1. Training System 88 8.1.10.18. Airflow Patterns 107
7.1.5.2. Training Requirements 89 8.2. Summary 107
7.1.5.3. Training Plan 89 8.3 . Exercise 109
7.1.5.4. Levels of Training 89
7.1.5.5. Training Materials 90 Chapter 9: Equipments and
7.1.5.6. Personal Records 91 Raw Materials
7.1.6. Personnel Hygiene 91 9.1 . Equipments and Raw 110
7.2. Summary 92 Materials
7.3 . Exercise 93 9.1. 1 . Introduction 110
9.1.2. Equipment Selection 110
Chapter 8: Premises 9.1.3. Purchase Specifications 111
8.1. Premises 94 for Equipment
8.1 . 1 . Introduction 94 9.1.4. Maintenance of 111
8.1.2. Location 94 Equipment
-9-
9.1.5. Purchase Specifications 112 11.1.10.3. Final Order on 142
for Raw Materials Disqualification
9.1 .6. Maintenance of Stores for 114 11.1.10.4. Actions upon 142
Raw Materials Disqualification
9.2. Summary 115 11.1.10.5. Public Disclosure of 143
9.3. Exercise 115 Information Regarding
Disqualification
Chapter 10: Quality Control 11.1.10.6. Alternative or Additional 143
10.1 . Quality Control 116 Actions to Disqualification
10.1. 1. Introduction 116 11.1.10.7. Suspension or Termination 144
10.1 .2. Quality Control Test for 116 of a Testing Facility by a
Containers Sponsor
10.1.2.1. Glass Containers 117 11.1.10.8. Reinstatement of a 144
10.1.2.2. Plastic Containers 120 Disqualified Testing Facility
10.1.3. Quality Control Test for 121 11.2. Summary 144
Rubber Closures 11.3. Exercise 146
10.1.4. Quality Control Test for 122
Secondary Packing Chapter 12: Complaints
Materials 12.1. Complaints 147
10.2. Summary 124 12.1.1. Introduction 147
10.3 . Exercise 126 12.1.2. Complaints and 147
Evaluation of Complaints
Chapter 11: Good Laboratory 12.1.3. Handling of Return Good 148
12.1.4. Recalling 148
Practices 12.1.4.1. Primary Reasons for a 149
11.1. Good Laboratory 127
Product Recall
Practices
12.1.4.2. Goals of a Product Recall 150
11.1. 1. Introduction 127
12.1.4.3. Product Recall Procedure 150
11.1.2. General Provisions 127
12.1.4.4. Recall Triggers 150
11.1.3. Organisation and Personnel 130
12.1.5. Waste Disposal 151
11.1.4. Facilities 130
11.1.5. Equipment 132
12.2. Summary 152
11.1.6. Testing Facilities 134
12.3. Exercise 152
Operations
11.1.7. Test and Control Articles 136 Chapter 13: Document
11.1 .8. Protocol for Conduct of a 137 Maintenance in Pharmaceutical
Non -Clinical Laboratory Industry
Study 13.1. Document Maintenance 153
11.1.8.1. Study Plan or Protocol 137 in Pharmaceutical
11.1.8.2. Content of the Protocol 137 Industry
11.1.9. Records and Reports 139 13.1.1. Introduction 153
11.1.9.1. Carrying out Procedures & 139 13.1.2. Batch Formula Record 153
Recording Observations 13.1.3. Master Formula Record 154
11.1.9.2. Records and Recording 139 13.1.4. SOP 155
11.1.9.3. Storage and Retrieval of 141 13.1.4.1. Benefits of SOP 156
Records and Data 13.1.4.2. Guidelines to Prepare 157
11.1.10. Disqualification of Testing 141 SOPs
Facilities 13.1.4.3. SOPs for Receipt of 157
11.1.10.1. Grounds for 142 Materials
Disqualification 13.1.4.4. SOPs for Sampling 157
11.1.10.2. Notice of and Opportunity 142 13.1.4.5. SOPs for Batch 158
for Hearing on Proposed Numbering
Disqualification 13.1.4.6. SOPs for Testing 158
- 10 -
13.1.5. Quality Audit 158 14.2. General Principles of 178
13.1.5.1. Procedure for Conducting 158 Analytical Method of
an Audit Validation
13.1.5.2. Audit Preparation 159 14.2.1. Introduction 178
13.1.5.3. Conducting of Audit 159 14.2.2. Need to Validate an 178
13.1.5.4. Completing and Follow- 159 Analytical Method
Up of Audit 14.2.3. Validation Protocol 180
13.1.6. Quality Review and 159 14.2.4. Types of Analytical 180
Quality Documentation Procedures to be Validated
13.1.7. Reports and Documents 160 14.2.5. Validation Characteristics 181
13.1.8. Distribution Records 162 14.2.5.1 . Specificity 181
13.2. Summary 162 14.2.5.2. Linearity 183
13.3. Exercise 163 14.2.5.3. Range 183
14.2.5.4. Accuracy 184
Chapter 14: Calibration and 14.2.5.5. Precision 185
Validation 14.2.5.6. Detection Limit 185
14.2.5.7. Quantitation Limit 186
14.1. Calibration and Validation 164
14.1.1. Introduction 164 14.2.5.8. Robustness 187
14.1.2. Definition and General 164 14.2.5.9. System Suitability Testing 187
Principles of Calibration 14.2.6. Steps in Method 187
14.1.2.1. Reason for Calibration of 165 Validation
an Instrument 14.2.7. Validation Report 188
14.1.2.2. Frequency of Calibration 165 143. Summary 188
14.4. Exercise 191
14.1.2.3. Common Terms used in 165
Instrument Calibration Chapter 15: Warehousing
14.1.3. Definition and General 168 15.1. Warehousing 191
Principles of Qualification 15.1.1. Introduction 191
14.1.3.1 . Design Qualification ( DQ ) 168 15.1.2. Good Warehousing 191
14.1.3.2. Installation Qualification 169 Practice
( IQ )
15.1.2.1. Personnel 191
14.1.3.3. Operational Qualification 169 15.1.2.2. Premises 191
( OQ )
15.1.2.3. Sanitation 192
14.1.3.4. Performance Qualification 170 15.1.2.4. Temperature and 193
( PQ )
Environment Control
14.1 .4. Definition and General 170 15.1.2.5. Equipment 193
Principles of Validation 15.1.2.6. Materials Management 193
14.1.4.1. Importance and Scope of 171 15.1.2.7. Packing for Transportation 195
Validation 15.1.2.8. Dispatch and Transport 195
14.1.4.2. Types of Validation 171 15.1.2.9. Documentation and Records 196
14.1.4.3. Validation Master Plan 172 15.1.2.10. Returned Goods 196
14.1.5. Calibration of pH Meter 173 15.1.2.11. Product Recalls 196
14.1.6. Qualification of UV- 175 15.1.2.12. Complaints 197
Visible Spectrophotometer 15.1.2.13. Disposal of Unsaleable 197
14.1.6.1. Operational Qualification 175 Goods
( OQ )
15.1.2.14. Repacking and Labelling 197
14.1.6.2. Performance Qualification 176 15.2. Summary 197
( PQ )
15.3. Exercise 198
Quality Assurance and Quality Management Concepts ( Chapter 1 ) 11
CHAPTER Quality Assurance and Quality

1 Management Concepts
1.1. QUALITY ASSURANCE AND QUALITY

MANAGEMENT CONCEPTS
1.1.1. Introduction
A management technique used for communicating to employees what is required
to produce the desired quality of products and services and to influence employee
actions to complete tasks according to the quality specifications is termed
Quality Management System ( QMS ).
QMS is a set of policies, processes, and procedures required for planning and
execution ( production, development , or service ) in the core business area of an
organisation ( i .e., area that can impact the organisation’s ability to meet customer
requirements). An example of a QMS is ISO 9001.
A QMS integrates various internal processes in an organisation and provides
a process approach for project execution . With a process-based QMS, an
organisation can identify , measure, control, and improve the various core
business processes that improve the business performance.
Quality management is the act of supervising all the activities required for
maintaining a desired level of quality. The activities include determination of a
quality policy, creating and implementing quality planning and assurance, quality
control , and quality improvement.
1.1.2. Definition and Concept of Quality Control

The word quality generally has different meanings. Quality can be defined as “fitness
for use,” “customer satisfaction,” “doing things right the first time,” or “zero defects.”
These definitions are accepted as quality that refers to degrees of excellence. Quality
is defined as “an inherent characteristic, property or attribute”. Quality control is
the science that keeps these characteristics or qualities within the limit range.
The term quality control includes various techniques and activities of an
organisation that are involved in monitoring and improving the business so that the
products, processes or services meet the standard specifications. Quality control also
involves reviewing the processes and specifications and make recommendations for
their improvement. It aims to identify and eliminate the causes of sub-standard
performance by removing or reducing the variation sources. The quality control
program works on the objective to define a system in which the products meet the
design requirements and checks and feedback for corrective actions and process
improvements. Quality control also includes selecting and rating of suppliers to make
sure that the purchased products meet the quality requirements.
12 ( tppl .org . in ) Quality Assurance
In a manufacturing or service environment, quality of design and quality of

conformance are the two major categories of quality. If a product is not designed
properly, it will not function appropriately even if it complies with all the standard
specifications. On the other hand, if a product does not conform to excellent design
specifications, it will not perform its intended function in a proper way.
Quality of Design
It refers to the level of characteristics that the designers specify for a product.
High-grade materials, tight tolerances, special features, and high performance are
the characteristics related to the high quality product.
Quality of Conformance
After determining the quality of design , the product characteristics are formed
into drawings and specifications, which are used by the manufacturing
engineers to develop manufacturing standards and design the operations as
required for production . The standards and design include the floor layout ,
machinery, test sets, tools and other equipment , and a plan for the number of
employees required .
The quality and the manufacturing engineers work together to make the quality
system and maintenance of conformance quality an integral part of the
manufacturing process. Any product checks, process checks, or quality improvement
activities are an inherent part of the process. Conformance quality is the degree of
adherence of the product characteristics to the design drawings and specifications.
The objective of a quality program is to have a system that economically measures
and controls the degree of product and process conformance.
The quality engineer determines what product or process characteristics are to be
checked, and the type of data to be collected , the required corrective actions, and
the statistical tools or other techniques to be used.
1.1 .3. Definition and Concept of Quality Assurance

The term quality assurance includes all the planned and systematic activities ( in
the form of an independent final inspection ) required for assuring that a product
or service will meet the specifications. The difference between quality control
and quality assurance is that the former makes quality product and the latter
assures the same. Quality assurance function should represent the customers and
should not depend on the quality control function that forms an integral part of
the manufacturing operation.
Quality assurance is a wide-ranging concept covering all matters that individually
or collectively influence the product quality. It is the totality of the arrangements
made with the object of ensuring that pharmaceutical products are of the quality
required for their intended use.
The system of quality assurance appropriate to the manufacture of
pharmaceutical products should ensure that:
1 ) Pharmaceutical products are designed and developed in a way that takes
account of the GMP requirements and other associated codes such as those of
Good Laboratory Practice (GLP) and Good Clinical Practice ( GCP).
2) Production and control operations are clearly specified in a written form and
GMP requirements are adopted.
3) Managerial responsibilities are clearly specified in job descriptions.
4 ) Arrangements are made for the manufacture, supply and use of the correct
starting and packaging materials.
5 ) All necessary controls on starting materials, intermediate products, and bulk
products and other in -process controls, calibrations, and validations are
carried out.
6) The finished product is correctly processed and checked, according to the
defined procedures.
7) Pharmaceutical products are not sold or supplied before the authorised
persons have certified that each production batch has been produced and
controlled in accordance with the requirements of the marketing
authorisation and any other regulations relevant to the production, control
and release of pharmaceutical products.
8) Satisfactory arrangements exist to ensure that the pharmaceutical products
are stored by the manufacturer, distributed , and subsequently handled so that
quality is maintained throughout their shelf -life.
9) There is a procedure for self -inspection and/or quality audit that regularly
appraises the effectiveness and applicability of the quality assurance system.
10) Deviations are reported , investigated and recorded .
11 ) There is a system for approving changes that may impact product quality.
12) Regular evaluations of the quality of pharmaceutical products should be
conducted with the objective of verifying the consistency of the process and
ensuring its continuous improvement.
The manufacturer must assume responsibility for the quality of pharmaceutical
products to ensure that they are fit for their intended use, comply with the
requirements of the marketing authorisation and do not place patients at risk due
to inadequate safety, quality, or efficacy. Attainment of this quality objective is
the responsibility of senior management and requires the participation and
commitment of staff in many different departments, the company ’s suppliers, and
the distributors. To achieve the quality objective, there should be a
comprehensively designed and correctly implemented system of quality
assurance incorporating GMP and quality control. All parts of the quality
assurance system should be adequately staffed with competent personnel , and
should have suitable and sufficient premises, equipment , and facilities.
1.2. DEFINITION AND CONCEPT OF GMP

1.2.1. Introduction
GMP is a part of quality management that ensures that products are consistently
manufactured and analysed as per the quality standards appropriate for use and as
required by the marketing authorisation, clinical trial authorisation , or product
specification . GMP should be followed by the production department as well as
14 ( tppl.org.in ) Quality Assurance
by the quality control unit. GMP is mainly concerned with the management and
minimisation of the inherited risks in pharmaceutical manufacturing, thus ensures
the quality , safety and efficacy of products.
Under GMP:
1 ) All the processes involved in manufacturing of pharmaceutical products are
clearly defined , systematically reviewed for associated risks according to the
scientific knowledge and experience. Thus, GMP also ensures that current
manufacturing process is capable of manufacturing pharmaceutical products
of required quality that comply with their specifications.
2) Qualification and validation of the product is performed.
3) All required resources are provided, including:
i) A qualified and trained personnel,
ii ) Sufficient space and adequate premises,
iii ) Required equipment and services,
iv ) Appropriate materials, containers, and labels,
v) Approved procedures and instructions,
vi) Suitable storage and transport, and
vii ) Sufficient personnel , laboratories and equipment for in -process controls.
4 ) All instructions, procedures and facilities to be provided are given in clear
and unmistakable language.
5) The personnel are trained to carry out all the manufacturing processes correctly.
6) During manufacturing processes, records are either made manually or by
recording instruments to describe that the steps taken are as per the defined
procedures and instructions, and even the quantity and quality of the product
are as expected.
7 ) Any significant deviations are recorded and investigated with their root
cause. Along with this, appropriate corrective and preventive measures are
implemented.
8) Records of manufacturing and distribution are maintained in an accessible
form so that the complete history of a batch can be traced.
9) Proper storage conditions and distribution of the products reduce any risk to
their quality and takes account of Good Distribution Practices ( GDP).
10) A system is available to recall any batch of product from sale or supply.
11 ) All the complaints related to the marketed products are examined, the causes
of quality defects are identified , and required corrective steps are taken in
respect of the defective products to prevent recurrence.
1.2. 2. Personnel
It is the personnel on which the establishment and maintenance of a satisfactory
system of QA and the correct manufacturing processes depend. Quality of
pharmaceutical products and active ingredients rely upon the people. Due to
these reasons, appropriately qualified personnel should be appointed to carry out
all the tasks for which the manufacturer is responsible. Individual responsibilities
should be clearly defined and described by the concerned persons and recorded in
written form. All the personnel should have knowledge of GMP principles.
Therefore, initial and continuing training should be given to everyone, including
hygiene instruction , relevant to their needs. All personnel should be motivated to
support the establishment and maintenance of high quality standards.
Personnel Qualification
The key personnel who supervise the production and quality unit(s ) for
pharmaceutical products should possess the qualifications of a scientific
education and practical experience as described by national legislation. He /she
should be qualified with an appropriate combination of :
1 ) Chemistry ( analytical or organic ) or biochemistry,
2) Chemical engineering,
3) Microbiology,
4 ) Pharmaceutical sciences and technology ,
5 ) Pharmacology and toxicology,
6) Physiology, and
7) Other related sciences.
Personnel Training
A training programme should be designed by the manufacturer according to a
written programme for all personnel appointed into manufacturing areas or
control laboratories ( including the technical, maintenance and cleaning
personnel ) and for other personnel as required . Along with the basic training on
theory and practice of GMP, newly recruited personnel should also be given
training according to the duties assigned to them .
A continuous training programme should also be provided by the
manufacturer, and its practicality and effectiveness should be assessed
periodically . The training records should be maintained by the manufacturer.
Personnel working in contaminated areas, such as cleanness areas or areas
where highly active, toxic, infectious or sensitising materials are handled ,
should be given specific training.
Personnel Hygiene
All personnel should undergo proper health examinations before and during
employment. A periodic eye examination should also be carried out for the personnel
appointed for visual inspections. A high level of personal hygiene should be
observed by all those concerned with manufacturing processes, therefore personal
hygiene training should be provided to all the personnel of the manufacturing and
quality control unit. Instructions regarding washing of hands should be posted within
the premises for the personnel before entering the production areas.
If a person shows any symptom of an apparent illness or has open lesions that
may affect the product quality , he should not be allowed to handle the starting
materials, packaging materials, in - process materials, or medicines till the
condition is improved and poses no more risk . Such practices should be
followed for the safeguard of both the employee and the manufacturing
product.
Healthy habits and good sanitation practices should be followed by all the
employees. For manufacturing activity, clean clothing should be worn by the
personnel in manufacturing unit , and additional clothing such as protective
apparel including coverings for head , face, hands, arms, etc. should be worn by
the manufacturer to protect the intermediates and APIs from contamination. This
clothing should be changed whenever required. Smoking, eating, drinking,
chewing, and food storage area should be separated from the manufacturing area.
1.2.3. Buildings and Infrastructure

The location, design , and construction of the premises should be such that the
operations are suitably carried out within the manufacturing unit. The layout and
design of premises should be such that it minimises the risk of errors and allow
effective cleaning and maintenance to prevent cross-contamination, accumulation
of dust or dirt, and any adverse effect on the quality of products.
It is the responsibility of the manufacturer to maintain the premises and to
ensure that any repair and maintenance process should not cause any hazard
to the product quality . Cleanness and hygiene level of the premises should be
maintained and disinfected as per the standards and detailed written
procedures. All the records of cleanness and hygiene of the premises should
be maintained .
Design and Construction
Adequate space should be present within the premises so that the equipment can
be arranged orderly and mixing and contamination of the materials can be
avoided. Equipment ( e.g., closed or contained systems ) which itself provide
adequate protection of the material should be placed outdoors. The flow of
materials and personnel through the building or facilities should be designed such
a way that mix-ups or contamination can be avoided.
A separate area should be allotted for the following activities:
1 ) Receipt, identification , sampling, and quarantine of incoming materials,
pending release or rejection,
2 ) Quarantine before release or rejection of intermediates and APIs,
3) Sampling of intermediates and APIs,
.
4 ) Holding rejected materials before further disposition ( e g., return,
reprocessing, or destruction ),
5) Storing released materials,
6) For production related operations,
7) For packaging and labelling operations, and
8) For operations performed in laboratory.
There should be adequate and clean washing and toilet facilities for personnel
within the premises. The washing area should be equipped with hot and cold
water facilities, soap or detergent dispenser, air drier, or single use towels. The
washing and toilet areas should be located away from, but easily accessible to
manufacturing areas. An area for showering and/or changing clothes should also be
provided.
Utilities
..
All utilities affecting the product quality [e g , steam, gases, compressed air, and
Heating, Ventilation and Air Conditioning ( HVAC)] should be analysed and
appropriately monitored prior to their use and appropriate action should be taken if
acceptable limits are exceeded. Drawings for these utility systems should be available.
Facilities for adequate ventilation , air filtration and exhaust systems should be
provided , where required . These systems should be installed such that the risks of
contamination and cross-contamination can be minimised. Equipment for control
of air pressure, microorganisms, dust, humidity , and temperature should also be
installed where needed in the manufacturing stage. Special attention should be
given to areas where APIs are exposed to the environment.
Water
Water used in API manufacture should be demonstrated to be suitable prior to use.
Unless otherwise specified, the process water should be as per the WHO guidelines
for drinking ( potable ) water quality. If this water is not sufficient to assure API
quality and more strict chemical and/or microbiological water quality
specifications are necessary, specifications for physical/chemical properties, total
microbial counts, objectionable organisms and/or endotoxins should be described.
If a manufacturer is using treated water, it is necessary to achieve the required
quality of the water and also the treatment process should be validated and
monitored with appropriate action limits. In the final isolation and purification
steps, water should be monitored and controlled for total microbial counts,
objectionable organisms, and endotoxins, in case the manufacturer of a non -
sterile API either intends or claims that such water is suitable for use in further
processing to produce a sterile drug ( medicinal ) product.
Containment
..
For the production of sterile and sensitive materials (e g , penicillins, cephalosporins,
etc.), separate production areas, including facilities like air handling equipment
and/or process equipment, should be employed. Separate production areas should
also be provided for manufacturing agents of infectious nature or high
..
pharmacological activity or toxicity ( e g , certain steroids or cytotoxic anti-cancer
agents) till the establishment of validated inactivation and/or cleaning procedures.
Sufficient measures should be designed and taken to prevent cross-contamination
from personnel, materials, etc. moving from one area to another.
Lighting
All the areas should have proper lighting to facilitate cleaning, maintenance, and
proper operations. Electrical supply , lighting, temperature, humidity , and
ventilation should be proper and should not produce any direct or indirect
adverse effect either on the pharmaceutical products during their manufacture
and storage, or on the accurate functioning of equipment .
Sewage and Refuse
Safe and timely disposition of sewage, refuse, and other wastes (e.g., solids,
liquids, or gaseous by-products from manufacturing ) in and from the buildings and
immediate surrounding area should be performed in a sanitary manner. Containers
and/or pipes used for disposal of waste material should be clearly identified.
Sanitation and Maintenance

Manufacturing areas of intermediates and APIs should be well -cleaned,
maintained and repaired. The cleaning procedures should be retained in written
form and sanitation responsibilities should be assigned by describing the cleaning
schedules, methods, equipment , and materials to be used in cleaning buildings
and facilities. For the use of suitable rodenticides, insecticides, fungicides,
fumigating agents, and cleaning and sanitising agents, written procedures should
be established so that the equipment, raw materials, packaging/labelling
materials, intermediates and APIs can be prevented from contaminations.
Ancillary Areas
Areas for rest and refreshment should be separated from the manufacturing and
control areas. There should be sufficient numbers of and easily accessible
changing rooms and areas for storing clothes, for washing and toilet purposes.
Toilets and maintenance workshops should be separated from the production or
storage areas. A separate room and locker should be there to store the various
machinery parts and tools in the production area. Animal houses should have
separate entrance ( for animal access ) and air-handling facilities, and should also
be isolated from other areas.
1.2.4. Process Equipment

Equipment should be located, designed, constructed , adapted and maintained as
per the need of the operations to be carried out. The layout and design of
equipment should be such that they reduce the chances of errors and allow easy
and effective cleaning and maintenance. Such arrangement or design helps to
eradicate cross-contamination, accumulation of dust or dirt , and adverse effect on
product quality.
All service pipework and devices should be adequately marked. Special attention
should be given to the non-interchangeable connections or adaptors for
dangerous gases and liquids. Measuring equipment (such as balances and scales,
etc.) of a fixed range and precision should be always present within the
production area and quality control area. All the measuring equipments should be
calibrated previously according to a fixed schedule. Equipment used in the
production area should be cleaned properly according to a fixed schedule.
Laboratory equipment and instruments should follow the testing procedures.

Equipment for washing, cleaning and drying should be selected and used so as
not to be a source of contamination.
Design and Construction

For manufacturing of intermediates and APIs, equipment of appropriate design
and size should be selected. These equipment should be suitably located for its
intended use, cleaning, sanitisation ( where appropriate ), and maintenance. The
construction material used for the equipment should be non -reactive so that
contact raw materials, intermediates, or APIs do not alter the quality of the
intermediates and APIs beyond the official or other established specifications.
Production equipment should be used within its qualified operating range.
Quality Assurance and Quality Management Concepts ( Chapter I ) 19
Both open and closed or contained equipment can be used wherever required. Where
open equipment is used or equipment is opened, appropriate precautions should be
..
taken to reduce the contamination risk. For equipment and critical installations ( e g ,
instrumentation and utility systems), a set of current drawings should be maintained.
Maintenance and Cleaning
For cleaning of equipment and its subsequent release for further use in the
manufacture of intermediates and APIs, a written procedure should be
established. The cleansing procedure should be detailed so that it enables the
operators to clean each type of equipment in a reproducible and effective manner.
The cleansing procedures should include:
1) Assigning responsibility for equipment cleaning,
2) Cleaning and sanitising schedules,
3) A complete description of the methods and materials, including dilution of
cleaning agents used to clean equipment,
4 ) Instructions for disassembling and reassembling each article to enable proper
cleaning,
5 ) Instructions for the removal or obliteration of previous batch identification ,
6) Instructions for the protection of clean equipment from contamination before
their use,
7 Inspection of equipment for cleanliness prior to use, and
)
8) Establishing the maximum time that may lapse between the completion of
processing and equipment cleaning.
Calibration
Written procedures and established schedules should be followed for the calibration
of control, weighing, measuring, monitoring and test equipment required for assuring
the quality of intermediates or APIs. If possible, equipment calibrations should be
performed as per the standards, which are traceable to the existing certified standards.
Records of these calibrations should also be maintained. The current calibration
status of critical equipment should be known and verified. Use of instruments that
do not meet the calibration criteria should be restricted. If any deviation from
approved standards of calibration on critical instruments is identified, investigation
should be carried out to determine its effect on the quality of intermediate( s) or
API( s ) produced using this equipment after the last successful calibration.
Computerised Systems
The computerised systems to be used for GMP should be validated . The
validation criteria of the computerised system depend on the diversity,
complexity and criticality of the computer software used. The suitability of
computer hardware and software of performing an assigning task can be
demonstrated by the installation qualification and operational qualification .
However, already qualified commercially available software does not require the
same testing procedure. By using the required documents, a retrospective
validation can be conducted if an existing system was not validated at the time of
installation. For smooth operation and maintenance of computerised system,
written procedures should be available. An additional check on the accuracy of
the entry should be made, where critical data are being entered manually that can
be performed by a second operator or by the system itself.
1.2.5. Documentation and Records

Good documentation forms a critical part of quality assurance system, and should
exist for all aspects of GMP.
The objectives are:
1 ) To define the specifications and procedures for all materials, manufacture
methods, and control methods,
2 ) To ensure that all personnel in manufacturing Field know what to do and
when to do,
3) To ensure that the authorised personnel have necessary information to decide
whether or not to release a batch of a medicine for sale,
4 ) To ensure the existence of documented evidence and traceability, and
5 ) To provide records and an audit trail to allow investigation.
Records of Equipment Cleaning and Use
Records of use, cleaning, sanitisation , sterilisation and maintenance of equipment
should present the date, time, product , batch number of each batch processed in
the equipment , and the person who performed the cleaning and maintenance of
equipment. If an equipment is meant for manufacturing one intermediate or API,
individual equipment records are not required if batches of the intermediate or
API follow the traceable sequence. On the other hand, if specialised equipment is
used, the records of cleaning, maintenance, and use should be maintained
separately or kept as a part of batch record.
Records of Raw Materials, Intermediates, API Labelling, and Packaging
Materials
Records of raw materials, intermediates, API labelling, and packaging materials
should include:
1 ) The manufacturer 's name,
2) Identity and quantity of each shipment of each batch of raw materials,
intermediates or API labelling, and packaging materials,
3) The supplier’s name, control number( s ) ( if known ), or other identification
number,
4 ) The number allocated on receipt , and the date of receipt ,
5 ) The results and conclusions derived from any test or examination performed,
6 ) The records of tracing the use of materials,
7) Documentation of the examination and review of API labelling and
packaging materials to abide by the established specifications, and
8) The final decision regarding the rejected raw materials, intermediates or API
labelling and packaging materials.
Master ( approved ) labels should be maintained for comparing with issued labels.
Master Production Instructions ( Master Production and Control Records )
Master production instructions for each intermediate and API should be maintained,
dated, and signed by one person and independently checked, dated, and signed by a
person in the quality unit(s). This ensures batch-to-batch uniformity.
Master production instructions should include:

1 ) Name of the intermediate or API being manufactured and an identifying
document reference code,
2) List of raw materials and intermediates along with their specific names or
codes that help in identifying their special characteristics,
3) An accurate statement of the quantity or ratio along with the unit of measure
of each raw material or intermediate to be used. If the quantity is not fixed,
the calculation for each batch size or production rate should be included . Any
variations to quantities should also be included,
4 ) Production location and major production equipment to be used,
5 ) Detailed instructions for production , including:
i) The sequences to be followed,
ii ) Ranges of process parameters to be used,
iii ) Sampling instructions and in-process controls along with their
acceptance criteria,
iv ) Time limits for completing individual processing steps and/or the entire
process, and
v) Expected ranges of yield at appropriate phases of processing or time.
6) Special notations and precautions to be followed or cross-references to these, and
7 ) Instructions for storage of intermediate or API (to assure that it is suitable to
use ), labelling and packaging of materials, and special storage conditions
with time limits.
Batch Production Records ( Batch Production and Control Records )
Batch production records should be prepared for each intermediate and API. They
should include complete information on the production and control of each batch.
Before being issued they should be checked to assure that they are the correct version
and accurately produced from the master production instruction. If the batch
production record is produced from a separate part of master document, that document
should include a reference to the master production instruction currently in use.
These records should hold a unique batch or identification number, and should be
dated and signed while being issued. In case of continuous production, the
product code, date and time together serve as the unique identifier until the final
number is allocated.
Documentation of completion of each significant step in batch production records
should include :
1 ) Dates and times,
2) Identity of the major equipment ( e.g., reactors, driers, mills, etc.) used,
3) Weights, measures, and batch numbers of each batch of raw materials,
intermediates, or any reprocessed materials used during manufacturing for
their specific identification,
4) The results recorded for critical process parameters,
5) Sampling ( if performed ),
6) Signatures of the personnel who performed and supervised each critical step
in the operation,
22 ( tppl .org.in ) Quality Assurance
7) Results of in-process and laboratory test ,

8) The yield ranges at appropriate phases or times,
9) Description of packaging and labelling for intermediates or APIs,
10) Representative label of API or intermediate ( if commercially available ),
11 ) Any deviation noted, its evaluation , investigation conducted, or reference to
that investigation , and
12) Results of release testing.
Written procedures should be established and followed for investigating critical
deviations or the failure of a batch of intermediate or API to meet specifications.
Laboratory Control Records
Laboratory control records should include the data obtained from all the tests ( to
ensure compliance with established specifications and standards ), examinations
and assays performed:
1 ) A description of samples received for testing, the raw materials’ name,
source, batch number, or distinctive code ( if any ), and the quantity and date
when the sample was received for testing,
2 ) A statement of or reference to the test method(s ) used,
3) A statement of the weight or measure of sample used for each test method,
4 ) Data on or cross-reference to the preparation and testing of reference
standards, reagents, and standard solutions,
5 ) A record of all raw data derived from each test, including graphs, charts, and
spectra from laboratory instrumentation, properly identified to show the
specific material and batch tested,
6) A record of all calculations performed during the test, including the units of
measure, conversion factors, and equivalency factors,
7) A statement of the test results and their comparison with the established
acceptance criteria,
8) Signature of a person who performed the tests and the date( s) on which tests
were performed ,
9 ) Date and signature of a second person showing that the original records have
been reviewed for accuracy, completeness, and conformity with the
established standards, and
10) Complete records for:
i ) Any changes made to an established analytical method,
ii ) Periodic calibration of laboratory instruments, apparatus, gauges, and
recording devices,
iii ) Stability tests performed on APIs, and
iv ) Out-Of -Specification ( OOS ) investigations.
1.2.6. Materials Management

Materials include starting materials, packaging materials, gases, solvents, process
aids, reagents, and labelling materials. The materials used for cleaning, lubrication of
equipment, and pest control should not come into direct contact with the product.
These materials should be of a suitable grade ( e.g., food grade ) to reduce health risks.
The incoming materials and finished products should be immediately quarantined

after receiving or processing before their release for use or distribution . All the
materials and products should be stored under the conditions established by the
manufacturer. They should be stocked in an orderly manner to aid batch
segregation and stock rotation by first-expire, first-out rule.
General Controls
Written procedures describing the receipt, identification, quarantine, storage,
handling, sampling, testing, and approval or rejection of materials should be
maintained . The manufacturers of intermediates and/or APIs should have a system
for evaluating the suppliers of critical materials. The materials should be purchased
from a supplier( s ) approved by the quality unit(s) against an agreed specification.
If the person supplying a critical material is not the manufacturer of that material ,
the manufacturer’s name and address should be known by the manufacturer of
the intermediate and/or API.
Receipt and Quarantine
On receiving and before accepting, each container or group of containers of
materials should be visually examined for correct labelling ( correlation between
the supplier name and the in-house name, if they are different ), container
damage, broken seals, tampering, and contamination . Materials should be
quarantined before they are sampled , examined, tested, and released for use.
..
Before mixing the incoming materials with the existing ones (e g , solvents or
stocks in silos), the former materials should be identified as correct, tested , and
released. Procedures should be available to prevent the incoming materials from
being wrongly discharged into the existing stocks.
If bulk deliveries are made in non -dedicated tankers, it should be ensured that
there is no cross-contamination from the tanker. Means of providing this
assurance could include one or more of the following:
1 ) Certificate of cleaning,
2) Testing for trace impurities, and
3) Audit of the supplier.
Sampling and Testing of Incoming Production Materials
Instead of performing other tests, the Certificate of Analysis of a supplier can be
used, only if the manufacturer has a system to evaluate suppliers. For supplier
approval , an evaluation should be carried out to make available sufficient
..
evidence ( e g , past quality history ) that the manufacturer can provide material
before reducing in-house testing. However, a full analysis should be performed at
appropriate intervals and compared with the Certificates of Analysis. Reliability
of these certificates should be checked at regular intervals.
There is no need to test the processing aids, hazardous or highly toxic raw materials,
other special materials, or materials transferred to another unit ( within the company ’s
control ) if the manufacturer s Certificate of Analysis shows that these materials abide
'
by the established specifications. Visual examination of containers and labels and

keeping record of batch numbers help in establishing the identity of these materials.
The lack of on-site testing for these materials should be justified and documented.
24 ( tppl . org . in ) Quality Assurance
Samples should represent the batch of material from which they have been
withdrawn. Sampling methods should specify the number of containers to be
sampled, the part of container to be sampled, and the amount of material to be
taken from each container.
Storage
Degradation , contamination , and cross-contamination of the materials can be
prevented by their proper handling and storage. Materials stored in fibre drums,
bags, or boxes should be stored off the floor, with adequate space in between
each, to ease cleaning and inspection. Materials should be stored under such
conditions and for such a time period that their quality is not adversely affected.
The materials should be arranged such that the oldest stock is used first.
Some materials can be stored in outdoor areas, provided identifying labels remain
legible and containers are properly cleaned prior to their usage. Rejected
materials should be identified and controlled under a quarantine system so that
they are no more used in manufacturing.
-
Re evaluation
If required, the materials should be re-evaluated to determine their suitability for
..
use ( e g , after prolonged storage or exposure to heat or humidity ).
1.2.7. Production and In -Proccss Controls

In-Process Controls ( IPC ) are checks carried out before completing the
manufacturing process. Function of IPC is monitoring and adaptation of the
manufacturing process to conform to the specifications, and also controlling
equipment and environment. Identity , strength , quality and purity of the in-
process materials should be tested and approved or rejected by the QC unit
during production. The rejected in-process materials should be identified and
controlled under a quarantine system so that they are not used in manufacturing.
In-process controls can be performed at regular intervals during a process step
( e.g., tableting, encapsulation ) or at the end of a process step ( e.g., granulation,
blending ). The objectives of in-process control are quality control as well as
process control.
Production Operations
If a material is sub-divided for later use in production, the container receiving the
material should be suitably identified to assure that it bears the following
information:
1 ) Name and/or item code of the material ,
2) Receiving or control number,
3) Weight or measure of the material in the new container, and
4 ) A date for re-evaluation or re-test ( if needed ).
Operations of weighing, measuring, or sub-dividing should be subjected to an

equivalent control. Before using the materials, the production personnel should
verify that the materials are specified in the batch record for the intended
intermediate or API. Actual yields should be compared with the expected yields
at designated steps during production . Expected yields with appropriate ranges

should be established based on previous laboratory , pilot scale, or manufacturing
data. Any deviations in yields related to the critical process steps should be
studied to evaluate their effect on quality of the affected batches.
Time Limits
Time limits are one of the indications for product quality. Time limits specified
in master production instruction should be met to ensure the quality of
intermediates and APIs. Any deviations from specified time limits should be
evaluated and documented. Completion of reactions or processing steps is
determined by in-process sampling and testing, thus time limits may be
inappropriate when processing to a target value ( e.g., pH adjustment, drying to
predetermined specification ). Intermediates for further processing should be
stored under appropriate conditions to assure that they can be suitably used.
-
In Process Sampling and Controls
The progress and performance of processing steps that alter the quality
characteristics of intermediates and APIs can be monitored and controlled by
establishing written procedures. In - process controls and their acceptance criteria
should be defined based on the information obtained during the development
stage or historical data. The nature of intermediate or API being manufactured,
the reaction or process step being conducted, and the degree to which the process
introduces variability in the product’s quality influence the acceptance criteria,
and type and extent of testing. Less strict in -process controls are suitable for early
processing steps, while the more strict ones are appropriate in the later processing
steps ( e.g., isolation and purification steps). Critical in-process controls ( and
critical process monitoring ), including the control points and methods, should be
stated in writing and approved by the quality unit(s ). All the tests and their results
should be documented as part of the batch record.
Written procedures that describe the sampling methods for in -process materials,
intermediates, and APIs should be established. Sampling plans and procedures
should be based on scientifically-proven sampling practices. Procedures should
be established to maintain the integrity of samples after collection . Out -Of -
Specification ( OOS ) investigations are not required for in -process tests
performed for monitoring and/or adjusting the process.
Contamination Control
Residual materials can be carried over into successive batches of the same
intermediate or API if adequately controlled. For example, residue adhering to
the wall of a microniser, residual layer of damp crystals in a centrifuge bowl after
discharge, and incomplete discharge of fluids or crystals from a processing vessel
on transferring the material to the next step in the process. Such carryover should
not result in the carryover of degradants or microbial contamination, which may
adversely alter the established API impurity profile.
Production operations should be conducted in such a manner that contamination
of intermediates or APIs by other materials is prevented . Precautions should be
taken to avoid contamination when handling APIs after purification.
26 ( tppl .org.in) Quality Assurance
1.2.8. Packaging and Identification Labelling of APIs and

Intermediates
Written procedures that describe the receipt, identification , quarantine, sampling,
examination, testing and release, and handling of packaging and labelling
materials should be established. Packaging and labelling materials should meet
the standard specifications, and those that do not should be rejected. Records for
each shipment of labels and packaging materials, including their receipt,
examination , testing, and whether accepted or rejected , should be maintained.
Packaging Materials
Containers should provide protection against contamination or deterioration of
the intermediate or API ( may occur during transportation and storage ). Cleaning
and sanitisation of containers should be done to make them suitable for their
intended use. Containers should be non -reactive, non -additive, or non -absorptive ,
or else they may alter the quality of the intermediate or API beyond the specified
limits. Before re-using the containers, they should be cleaned as per the
documented procedures and the previous labels should be removed or destroyed.
Label Issuance and Control
Only the authorised personnel should be allowed to enter the label storage areas.
Procedures to reconcile the quantities of labels issued , used, and returned, and
procedures to evaluate differences between the number of labelled containers and
the number of labels issued should be followed. Such differences should be
examined, and the results should be approved by the quality control unit(s).
All the additional labels with batch numbers or other batch -related printing, and
the obsolete and out -dated labels should be destroyed. Returned labels should be
maintained and stored appropriately to prevent mix-ups and allow proper
identification. Printed labels issued for a batch should be investigated for proper
identity and conformity to specifications in the master production record . Results
of this investigation should be documented. A printed label representative of
those used should be included in the batch production record.
Packaging and Labelling Operations
Documented procedures should be established to ensure that suitable packaging
materials and labels are used . Labelling operations should be devised to prevent
mix -ups. There should be physical or spatial separation from operations
involving other intermediates or APIs. Labels on containers of intermediates or
APIs should bear the name or identifying code, the product batch number, and
storage conditions, if such information assures the quality of intermediate or API.
Packaging and labelling facilities should be examined prior to use to make sure
that the materials not required for the next packaging operation have been
removed. This examination should be documented in the batch production
record, the facility log, or other documentation system. Packaged and labelled
intermediates or APIs should be examined to make sure that the containers and
packages in the batch bear the correct label . This examination should be a part of
the packaging operation , and the results should be recorded in the batch
production or control records.
1.2.9. Storage and Distribution

Distribution forms a significant part of the integrated supply-chain management
of pharmaceutical products. Various individuals and entities involve in the
handling, storage and distribution of such products. However, sometimes, an
individual or entity is only involved in certain elements of the distribution
process. Various companies, institutions and individuals are involved in the
storage, sale and distribution of pharmaceutical products.
Warehousing Procedures
Facilities should be provided for storage of materials under proper conditions
.
( e g., controlled temperature and humidity ). Records of these conditions should
be maintained if they are critical for the maintenance of material characteristics.
Separate storage areas should be provided for temporary storage of quarantined ,
rejected, returned, or recalled materials until and unless an alternative system is
designed to prevent their unintentional or unauthorised use and a decision is
made regarding their future use.
Distribution Procedures
APIs and intermediates should be released for distribution to third parties only
when they have been released by the quality control unit( s ). APIs and
intermediates can be transferred under quarantine to another unit within the
company’s control when authorised by the quality unit( s) and controls and
documentation are in place. APIs and intermediates should be transported such
that their quality remains unaffected.
Special conditions for transport or storage of an API or intermediate should be
mentioned on the label . The manufacturer should make sure that the contractor
( contract acceptor ) for transportation of the API or intermediate is aware of and
also follows the specific transport and storage conditions. A system should be
devised by which the distribution of each batch of intermediate and /or API can
be determined to permit its recall.
1.2. 10. Laboratory Controls

The independent quality unit(s ) should have suitable laboratory facilities.
Documented procedures to describe sampling, testing, approval or rejection of
materials, and recording and storage of laboratory data should be established. All
specifications, sampling plans, and test procedures should be scientifically -
proven and sufficient enough to confirm that raw materials, intermediates, APIs,
and labels and packaging materials meet the standards of quality and/or purity.
Specifications and test procedures should be dependable on those included in the
registration/filing.
Laboratory controls should be followed and documented during performance.
Deviations ( if any ) from the established standard procedures should be
documented and justified . Any out-of -specification result obtained should be
investigated and documented according to a procedure, involving data analysis,
evaluating whether or not a significant problem exists, and division of tasks for
remedial actions and conclusions. Any resampling and/or retesting after out -of -
specification results should also be performed as per the documented procedure.
Primary reference standards for manufacturing APIs should be obtained, and

the source of each should be documented. Records for the storage and use of
each primary reference standard should be maintained as per the supplier’s
recommendations. Primary reference standards obtained from an officially
recognised source are used without testing if stored under conditions consistent
with the supplier's recommendations. In case of unavailability of a primary
-
reference standard from an officially recognised source, an in house primary
standard should be designed , and properly tested to establish its identity and
purity. The testing procedure should also be documented.
Secondary reference standards should be prepared, identified, tested, approved,
and stored. The suitability of each batch of secondary reference standard should
be determined prior to first use by comparing against a primary reference
standard. Each batch of secondary reference standard should be periodically re -
qualified in accordance with a written protocol.
Testing of Intermediates and APIs
Appropriate laboratory tests should be performed for each batch of intermediate
and API to ensure that they conform to the specifications. An impurity profile
describing the identified and unidentified impurities that may be present in a
typical batch produced by a specific controlled production process should be
established for each API. This impurity profile should also include the identity or
.
some qualitative analytical designation (e gM retention time ), the range of each
impurity, and classification of each identified impurity ( e.g., inorganic and
organic solvent ). The impurity profile depends on the production process and
origin of API. There is no necessity to maintain impurity profiles for APIs
derived from herbal or animal tissue origin.
The impurity profile at specific intervals should be compared with the impurity
profile in the regulatory submission or with the historical data. This helps in
detecting the changes an API undergoes due to alterations in raw materials,
equipment operating parameters, or the production process. Appropriate
microbiological tests for each batch of intermediate and API should be performed
where microbial quality is specified.
Certificates of Analysis
Authentic Certificates of Analysis should be issued on request for each batch of
intermediate or API. The label and/or certificates should carry the name of the
intermediate or API, its grade, batch number, the date of release, the expiry date
( if any ), and the retest date ( if any ).
The Certificate should carry a list of all the tests performed ( according to the
compendial or customer requirements ), the acceptance limits, and the numerical
results obtained ( only if the test results are numerical ). The authorised personnel
of the quality control unit( s ) should sign and date the certificates. The name,
address and telephone number of the original manufacturer should also be
mentioned. If analysis has been conducted by a re-packer or re-processor, the
name, address and telephone number of the re- packer/ re- processor and a
reference to the name of the original manufacturer should be stated on the
Certificate of Analysis.
If new Certificates are issued by or on behalf of re -packers/re-processors, agents

or brokers, the Certificates should have the name, address and telephone number
of the laboratory where the analysis was performed. A reference to the name and
address of the original manufacturer and a reference to the original batch
Certificate, a copy of which should be attached, should also be present.
Stability Monitoring of APIs
A documented , on -going testing program should be designed to monitor the
stability characteristics of APIs, and the results should be observed to confirm
appropriate storage conditions and retest or expiry dates. The test procedures of
stability testing should be validated and should be stability indicating. Stability
samples should be stored in containers that simulate the market container. For
example, if the API is marketed in bags within fibre drums, stability samples can
be packaged in bags of the same material and in drums of material composition
similar to that of the market drums.
The first three commercial production batches should be placed on the stability
monitoring program to confirm the retest or expiry date. However, less than three
batches can be used in cases when data from previous studies show that the API is
expected to remain stable for minimum two years. Subsequently, at least one batch
per year of API manufactured ( unless none is produced that year ) should be added
to the stability monitoring program and tested annually to confirm the stability.
Date of Expiry and Retest
When an intermediate is to be transferred outside the control of the manufacturer’s
material management system and an expiry or retest date is assigned, sufficient
..
stability information should be available ( e g , published data and test results). An
API expiry or retest date should rely on evaluation of data obtained from stability
studies. A common practice is to use a retest date instead of an expiration date.
Preliminary API expiry or retest dates can be based on pilot scale batches if:
1 ) The pilot batches use such a manufacture method that simulates the final
process to be used on a commercial manufacturing scale, and
2) The API quality represents the material to be made on a commercial scale. A
representative sample should be taken for performing a retest.
Reserve/Retention Samples
The packaging and holding of reserve samples is done for the potential future
evaluation of the quality of API batches and not for future stability testing
purposes. Suitably identified reserve samples of each API batch should be
retained either for a year after the expiry date of the batch assigned by the
manufacturer, or for three years after the distribution of batch ( whichever is the
longer ). For APIs with retest dates, similar reserve samples should be retained for
three years after the manufacturer has completely distributed the batch .
The reserve sample should be stored in the same packaging system in which the
API is stored or in a packaging system that is identical to or more protective than
the packaging system in the market . The reserve samples should be retained in
sufficient quantities to conduct two full compendial analyses, or two full
specification analyses when there is no Pharmacopoeial monograph.
1.2.11. Validation
Validation should establish and provide documentary evidences that:
1 ) The premises, supporting utilities, equipment, and processes have been
designed as per the requirements for GMP ( Design Qualification or DQ ),
2) The premises, supporting utilities, and equipment have been built and installed
according to their design specifications ( Installation Qualification or IQ),
3) The premises, supporting utilities, and equipment operate according to their
design specifications ( Operational Qualification or OQ ), and
4 ) A specific process will constantly produce a product that abides by its
predetermined specifications and quality attributes ( Process Validation or
PV , also called Performance Qualification or PQ ).
Any aspect of operation , and significant changes to the premises, facilities,
equipment or processes, that may directly or indirectly affect the product quality,
should be qualified and validated.
Validation Policy
The company’s policy, intentions and approach to validation, including the
validation of production processes, cleaning procedures, analytical methods, in -
process control test procedures, computerised systems, and individuals
responsible for design, review, approval and documentation of each validation
phase, should be documented .
The critical parameters/attributes should be identified during the development
stage or from historical data, and the ranges necessary for reproducible operation
should be defined, including:
1 ) Defining the API in terms of its critical product attributes,
2) Identifying process parameters that could affect the critical quality attributes
of the API, and
3) Determining the range for each critical process parameter to be used during
routine manufacturing and process control.
Validation Documentation
A written validation protocol describing how to conduct validation of a particular
process should be established , and reviewed and approved by the quality control
and other selected units. All the essential process steps and acceptance criteria,
..
the type of validation to be conducted ( e g , retrospective, prospective, or
concurrent ), and the number of times the process is to be repeated should be
specified in the protocol.
A validation report to cross-reference the validation protocol should be prepared
having a summary of the obtained results, comments on observed deviations ( if
any ), appropriate conclusions, and recommendations on correcting the
deficiencies. Any variations from the validation protocol should be documented
and justified.
Approaches to Process Validation
Process Validation ( PV ) is the documented evidence that the process has been
operated within the specified parameters and can effectively and reproducibly
produce an intermediate or API that conforms to its predetermined specifications

and quality attributes. There are three approaches to validation :
1 ) Prospective Validation: This is performed on an API process and should be
completed before the final drug product manufactured from that API is
commercially distributed.
2) Concurrent Validation: This can be performed when no data is available from
replicate production runs because only a limited number of API batches have
been produced, API batches are produced infrequently or by a validated process
that has been modified. Before the concurrent validation process is completed, the
batches can be released and used in final drug product for commercial distribution
after monitoring and testing the API batches.
3) Retrospective Validation: This is a well -established process that does not
alter the API quality due to changes in raw materials, equipment, systems,
facilities, or the production process.
Prospective validation is the preferred approach; however , there are exceptions
where the other two approaches can be used.
Process Validation Programme
The number of process runs for validation should depend on the process
complexity or the magnitude of process change being considered. Three
consecutive successful production batches should be used as a guide for
prospective and concurrent validation, but in some cases additional process runs
..
are warranted to prove consistency of the process ( e g , complex API processes
or API processes with prolonged completion times ). For retrospective validation,
data from 10-30 consecutive batches should be examined to assess process
consistency, but fewer batches can be examined if justified.
During process validation studies some critical process parameters should be
controlled and monitored. However, process parameters not related to quality, such
as variables controlled to reduce energy consumption or equipment use, are not
required to be included. Process validation should confirm that the impurity profile
for each API is within the limits specified. The impurity profile should be either
equivalent to or better than the past data and the profile determined during process
development or for batches used for pivotal clinical and toxicological studies.
Periodic Review of Validated Systems
Periodic evaluation of the systems and processes is required to verify that they
are operating in a valid manner. Revalidation is not required if no significant
changes have been made to the system or process, and if it is confirmed from a
quality review that the system or process is consistently producing material that
abides by its specifications.
Cleaning Validation
Cleaning procedures should be validated . Cleaning validation should be
directed to process steps where API quality is at great risk due to
contamination or carryover materials. For example , during early production ,
validating the cleaning procedures for equipment is not required as the
residues are removed by subsequent purification steps. Validation of cleaning
procedures should reflect actual equipment usage patterns. If different APIs

or intermediates are manufactured in the same equipment and the equipment
is cleaned by the same process, a representative intermediate or API should
be selected for cleaning validation based on the solubility and difficulty of
cleaning and the calculation of residue limits based on potency , toxicity, and
stability.
The equipment to be cleaned , procedures, materials, acceptable cleaning levels,
parameters to be monitored and controlled, and analytical methods should be
specified in the cleaning validation protocol . The type of samples to be obtained ,
their collection and labelling should also be presented in the protocol. Sampling
..
should include swabbing, rinsing, or alternative methods ( e g , direct extraction )
to detect insoluble and soluble residues.
Validation of Analytical Methods

Analytical methods should be validated till the used method is included in the relevant
Pharmacopoeia or other recognised standard reference. Suitability of all testing
methods used should be verified under actual conditions of use and documented.
Methods should be validated to include consideration of characteristics in the
ICH guidelines on validation of analytical methods. The degree of analytical
validation performed should reflect the purpose of analysis and the stage of API
production process. Appropriate qualification of analytical equipment should be
considered before validating the analytical methods.
Records should be maintained if any modification has been made in the validated
analytical method . The reason for the modification and necessary data to justify
that the after-effects of modification are as accurate and reliable as the
established method should also be mentioned in the records.
1.2. 12. Change Control

A change control system evaluating all changes that may affect the production
and control of the intermediate or API should be devised. Written procedures for
identification , documentation, review and approval of changes in raw materials,
specifications, analytical methods, facilities, support systems, equipment
( including computer hardware ), processing steps, labelling and packaging
materials, and computer software, should be established.
Any proposals for making relevant GMP changes should be drafted ,
reviewed , and approved by the concerned organisational units, and reviewed
and approved by the quality control unit ( s). How this proposed change is
affecting the intermediate or API quality should be evaluated . A classification
procedure should be designed to determine the level of testing, validation ,
and documentation required for justifying the changes made in a validated
process.
Depending on the nature and extent of changes, and their effect on the process,
the changes can be classified as minor or major. Scientific judgement should
determine what additional testing and validation studies should be conducted to
justify the change made in a validated process.
1.2. 13. Rejection and Re- Use of Materials

Rejected materials and products should be clearly marked and separately stored
in restricted areas. They should either be returned to the suppliers or reprocessed
( if possible) or destroyed timely only after proper approval from the authorised
personnel and recorded.
Recalled products should be identified and separately stored in a secure area, and
a decision related to them should be made as soon as possible.
There are exceptional cases of reworking or recovery of rejected products. This is
allowed only if the final product quality remains unaffected, if the specifications
are fulfilled , and if it is done as per the defined and authorised procedure after
evaluating the involved risks. A record should be maintained for the same (i.e.,
reworking or recovery rejected products ). A new batch number should be
assigned to the reworked batch.
1.2. 14. Complaints and Recalls

The complaints regarding quality , whether received orally or in writing, should
be recorded and investigated as per the written procedure. Complaint records
should include:
1 ) The complainant s name and address,
2) Name and phone number of the individual submitting the complaint ,
3) The nature of complaint, and the name and batch number of the API,
4 ) The date on which complaint is received,
5 ) Action taken initially, and the dates and identity of the individual taking the
action,
6) Follow - up action taken ( if any ),
7) Response provided to the originator of complaint , and the date of sending the
response, and
8) Final decision made on the intermediate or API batch.
Records of complaints should be maintained to evaluate trends, product -related
frequencies, and the urgency to take additional corrective actions. A written
procedure should be established to define the conditions under which an
intermediate or API should be recalled.
The recall procedure should designate an individual who should evaluate the
information , initiate a recall, and should be informed about the recall. In case of a
potentially life-threatening situation, the local, national , and/or international
authorities should be informed and their advice should be taken.
1.3. SUMMARY
The details given in this chapter can be summarised as follows:
l ) QMS is a set of policies, processes, and procedures required for planning and
execution ( production, development, or service ) in the core business area of
an organisation ( i .e., area that can impact the organisation ’s ability to meet
customer requirements).
2) An example of a QMS is ISO 9001.
3) Quality is defined as an inherent characteristic, property or attribute .
4 ) Quality control is the science that keeps these characteristics or qualities
within the limit range.
5) Quality of design refers to the level of characteristics that the designers
specify for a product.
6 ) Conformance quality is the degree of adherence of the product
characteristics to the design drawings and specifications.
7 ) The term quality assurance includes all the planned and systematic
activities ( in the form of an independent final inspection ) required for
assuring that a product or service will meet the specifications.
8) GMP is a part of quality management that ensures that products are
consistently manufactured and analysed as per the quality standards
appropriate for use and as required by the marketing authorisation, clinical
trial authorisation , or product specification .
9) The key personnel who supervise the production and quality unit ( s ) for
pharmaceutical products should possess the qualifications of a scientific
education and practical experience as described by national legislation.
10 ) A training programme should be designed by the manufacturer according to a
written programme for all personnel appointed into manufacturing areas or
control laboratories ( including the technical , maintenance and cleaning
personnel ) and for other personnel as required.
11 ) All personnel should undergo proper health examinations before and during
employment.
12 ) The location , design , and construction of the premises should be such that the
operations are suitably carried out within the manufacturing unit.
13) Adequate space should be present within the premises so that the equipment
can be arranged orderly and mixing and contamination of the materials can
be avoided.
14 ) All utilities affecting the product quality [ e.g., steam, gases, compressed air,
and Heating, Ventilation and Air Conditioning ( HVAC ) ] should be analysed
and appropriately monitored prior to their use and appropriate action should
be taken if acceptable limits are exceeded.
15 ) Water used in API manufacture should be demonstrated to be suitable prior to use.
16) For the production of sterile and sensitive material ( e.g., penicillins,
cephalosporins, etc.), separate production areas including facilities like air
handling equipment and/or process equipment , should be employed.
17 ) All the areas should have proper lighting to facilitate cleaning, maintenance,
and proper operations.
18) Safe and timely disposition of sewage, refuse, and other wastes ( e.g., solids,
liquids, or gaseous by -products from manufacturing) in and from the buildings
and immediate surrounding area should be performed in a sanitary manner.
19) Manufacturing areas of intermediates and APIs should be well -cleaned,
maintained and repaired .
20) Areas for rest and refreshment should be located separate from the
manufacturing and control areas.
21 ) Written procedures that describe the receipt, identification , quarantine,
sampling, examination , testing and release, and handling of packaging and
labelling materials should be established.
22) Distribution forms a significant part of the integrated supply -chain
management of pharmaceutical products.
23) The independent quality unit( s ) should have suitable laboratory facilities.
24 ) Primary reference standards for manufacturing APIs should be obtained ,
and the source of each should be documented.
25) In case of unavailability of a primary reference standard from an officially
-
recognised source, an in house primary standard should be designed, and
properly tested to establish its identity and purity.
26 ) Secondary reference standards should be prepared , identified, tested,
approved , and stored.
27 ) Appropriate laboratory tests should be performed for each batch of
intermediate and API to ensure that they conform to the specifications.
28) Authentic Certificates of Analysis should be issued on request for each batch
of intermediate or API.
29) An API expiry or retest date should rely on evaluation of data obtained from
stability studies.
30) A written validation protocol describing how to conduct validation of a
particular process should be established , and reviewed and approved by the
quality control and other selected units.
31 ) Prospective validation is performed on an API process and should be
completed before the final drug product manufactured from that API is
commercially distributed.
32 ) Concurrent validation can be performed when no data is available from
replicate production runs because only a limited number of API batches have
been produced, API batches are produced infrequently, or API batches are
produced by a validated process that has been modified.
33 ) Retrospective validation is a well -established process that does not alter the
API quality due to changes in raw materials, equipment, systems, facilities,
or the production process.
34 ) A change control system evaluating all changes that may affect the
production and control of the intermediate or API should be devised.
35 ) Rejected materials and products should be clearly marked and separately

stored in restricted areas.
36) Recalled products should be identified and separately stored in a secure area ,
and a decision related to them should be made as soon as possible .
37 ) The complaints regarding quality , whether received orally or in writing,
should be recorded and investigated as per the written procedure .
38) Records of complaints should be maintained to evaluate trends, product -
related frequencies , and the urgency to take additional corrective actions.
39) The recall procedure should designate an individual who should evaluate the
information, initiate a recall , and should be informed about the recall .
1.4. EXERCISE
1.4. 1 . Very Short Answer Type Questions
1) What is quality control and quality assurance?
2) Define conformance quality.
3) What personnel qualification is required as per GMP?
4) What lighting conditions should be maintained as per GMP?
5) Write about the design and construction of process equipment as per GMP.
6) What packaging materials are used for APIs and intermediates as per GMP?
7) Define prospective validation.
8) How rejected materials are handled ?
1.4. 2. Short Answer Type Questions

1) Write a note on the concept of quality control .
2) Write about the buildings and infrastructure as per GMP.
3) Discuss the cleansing and calibration of process equipment as per GMP.
4) Write a note on master production and laboratory records.
5) Discuss the sampling, testing and storage of incoming materials.
6) Discuss the storage and distribution of pharmaceutical products as per GMP.
1.4.3. Long Answer Type Questions

1) Write an exhaustive note on the concept of quality control and quality assurance .
2) Give a brief review on the concept of GMP.
3) Write a detailed note on documentation and record maintenance as per GMP.
4) Give a descriptive note on laboratory controls as per GMP.
Total Quality Management ( Chapter 2) 37
CHAPTER
Total Quality Management
2
2.1, TOTAL QUALITY MANAGEMENT (TQM)

2.1.1. Introduction and Definition
An integrated organisational effort to improve the product quality at every level
is referred to as Total Quality Management (TQM ).
TQM involves the management methods used for improving the quality and
productivity of business in an organisation. It is a comprehensive management
approach that works parallelly with the organisation , involving all departments
and employees and extending backward and forward to include both suppliers
and clients or customers.
Besides TQM, there are many other abbreviations used to label management systems
focusing on quality, such as CQI (Continuous Quality Improvement ), SQC
(Statistical Quality Control ), QFD (Quality Function Deployment ), QIDW ( Quality
In Daily Work), TQC (Total Quality Control ), etc. Alike these systems, TQM
provides a basis for implementing effective quality and productivity initiatives so that
the productivity and competitiveness of the organisations can be increased.
TQM allows the employees to focus on quality ( instead of quantity ) and strive
hard to give their best in whatever they do. According to TQM , the views and
expectations of customers are essential when new strategies are to be framed and
implemented for delivering products that are superior to those of competitors,
thereby yielding higher profits for the organisation.
2.1.2. Elements
According to their function , the TQM elements can be categorised into:
1 ) Foundation: It involves ethics, integrity, and trust.
2 ) Building Bricks: It involves training, teamwork, and leadership.
3) Binding Mortar: It involves communication .
4 ) Roof : It involves recognition.
The term TQM is used to define a philosophy that includes quality as the driving
force behind leadership, design, planning, and improvement initiatives.
....
2I2I Foundation
Foundation of the TQM involves the following factors:
1) Ethics: It is the discipline related to good and bad deeds under any
circumstances. It is a two-faceted subject, including organisation ethics and
individual ethics. Organisation ethics refers to a business code of ethics that
set up guidelines which the employees follow while performing their work ;
while, individual ethics refers to the personal rights or wrongs.
38 Quality Assurance
2) Integrity: It refers to some characteristic traits like honesty, morals, values,

fairness, and adherence to the fact and sincerity. These characteristics define
what internal or external customers expect and what they deserve to receive.
The opposite of integrity is duplicity , and TQM does not work under
duplicity conditions.
3) Trust: It is the by -product of integrity and ethical conduct, and builds the
framework of TQM . Trust results from the above two features. Trust ensures
participation of all the members and allows empowerment that influences
pride ownership and commitment for the task to be performed.
2.1.2.2. Building Bricks

Once a strong foundation structured by the trust, ethics, and integrity has been
established, bricks are placed to reach the roof of recognition. Under the bricks,
the following factors are included:
1) Training: It makes employees more productive. Training provided to the
employees includes interpersonal skills, decision making, job management,
performance analysis, problem-solving ability, business economics, and technical
skills. Training is generally provided by the supervisors so that they can implement
TQM as per the requirements of their department and guide their subordinates.
2) Teamwork : For a successful business, teamwork is one of the important
components and therefore is categorised as a key element of TQM . Teamwork
provides quicker and better solutions to problems in business. A team also
provides more permanent improvement in processes and operations.
Following three types of teams can be adopted by a TQM organisation:
i ) Quality Improvement Teams ( QITs ) or Excellence Teams: These
temporary teams are set up for 3-12 months to deal with frequently
occurring specific problems.
ii ) Problem Solving Teams ( PSTs): These temporary teams are set up for a
week to three months to identify the cause of certain problems and
provide solutions.
iii ) Natural Work Teams ( NWTs ): These teams are set up for 1-2 hours a
week and involve small groups of skilled workers, who share task and
responsibilities. The concept of these teams is based on employee
involvement teams, self -managing teams and circles.
3) Leadership: It is the most important TQM element that can be seen
everywhere in an organisation. In TQM , leadership requires the manager to
provide an inspiring vision, to make strategic directions which can be
understood by all , and to provide guidelines for the employees. TQM can be
successfully maintained in a business if the supervisor leads his subordinates
by understanding TQM, and demonstrating its facts through daily practices.
2.1.2.3. Binding Mortar (Communication )

Communication acts as a binding mortar to bind bricks and other elements of
TQM together. Starting from the roof of TQM house, everything is bound
together via strong mortar of communication, thus it can be said that it acts as a
vital link between all the TQM elements.
Communication is defined as a common understanding of ideas between the

sender and the receiver. For the success of TQM , proper communication between
all the organisation members, suppliers and customers should be maintained.
Therefore, the supervisor should keep an open airway where employee can send
and receive information about the TQM process.
Following are the different ways of communication:
1 ) Downward Communication: This is the most common form of
communication in an organisation, and presentation and discussion are its
two basic factors. Using this type of communication method, the supervisors
demonstrate the facts and details of TQM to the employees.
2 ) Upward Communication: By this form of communication , the lower level
employees convey their suggestions or ideas to the upper management of the
effects of TQM. The supervisors should listen to the insight and constructive
criticism provided by the employees to correct the situation that results
through the use of TQM . In this way, a bond builds up between the
supervisors and employees.
3) Sideways Communication: This form of communication is essential as it
breaks down the barrier between the departments. This type of communication
also permits easy and a more professional dealing with customers and suppliers.
2. I .2.4. Roof ( Recognition )

Recognition is the last element of TQM , and forms the roof of the entire system.
It should be provided for suggestions as well as for achievements for teams and
for individuals. Within an organisation , employees are striving to receive
recognition for themselves and their teams. It is the responsibility of a supervisor
to find and recognise the contributors. Such recognition significantly changes the
self-esteem, productivity, quality and efforts of an employee. Recognition should
immediately follow an action or task performed by an employee.
Recognition may come in different ways, places, and time as follows:
1 ) Ways: Recognition may be in the form of personal letter from top
management or in the form of award banquets, plaques, trophies, etc.
2) Places: Good performers can be recognised in front of departments, on
performance boards, or in the presence of top management.
3 Time: Recognition can be given in a staff meeting, annual award banquets, etc.
)
2.1 .3. Philosophies

The main characteristic of TQM is to focus on determining the root causes of
quality problems and overcoming them at the source, as opposed to inspecting
the product after it has been made. TQM includes the whole organisation as well
as stresses that quality is customer-driven.
2.13.1. Quality' Circle

Use of quality circle is successfully implemented by some organisations as part of an
on-going improvement programme. While some organisations experimented with
quality circles with the best intentions and faced many obstacles. But the fact is that
this type of participatory management gives many benefits to all concerned.
Objectives
1 ) Improvement of the quality and productivity so that enterprise can be
improved and developed.
2) Reduction of the cost of products or services by reducing the waste, by effective
utilisation of resources, and by avoiding unnecessary errors and defects.
3) Identification of work-related problems that hinder with production and their
correction.
4 ) Optimum use of human resources and identification of creative intelligence
of the people working in the organisation.
5 ) Providing required training to the employees to develop and use greater
amount of knowledge and skills.
6) Motivating the employees for performing a wide range of challenging tasks.
7 ) Improvement of communication within the organisation.
8) Developing within the employees the sentiment of loyalty and commitment
towards the organisation and its goals.
9 ) Respect for humanity and building a happy workplace environment.
10) Increase human capability, confidence, morale, attitude, and relationship.
11 ) To develop a sense of security for human needs of recognition, achievement
and self -development.
Advantages
1 ) Develops a high level of productivity and quality-mindedness,
2) Self and mutual development of employees,
3) Builds up team spirit and unity of action,
4 ) Develops in the employees the sense of motivation, job satisfaction , and
pride for their work,
5 ) Increases the work efficiency of employees,
6) Reduces the number of absentees and labour turnover,
7) Develops in the employees the sense of belongingness towards the organisation,
8) Reduces waste and cost,
9) Improves communication,
10) Improves safety,
11 ) Increases the utilisation of human resource potential ,
12) Increases the consciousness and morale of employees through recognition of
their activities,
13) Develops leadership skills, and
14) Trains the staff.
Function
Quality circle ( also known as work improvement or quality teams ) is defined
as a small group of employees who voluntarily meet at regular times so that they
can identify, analyse, and solve quality and other problems related to their work
environment or organisation. Quality circles make recommendations and
implementations to improve strategies and to provide a reservoir for new ideas.
2. I .3.2. Customer Focus

Organisations depend on their customers and therefore should understand current
and future customer needs, meet customer requirements and strive to exceed
customer expectations.
Steps in the application of this principle are:

1 ) Understand customer needs and expectations for products, delivery, price,
dependability, etc.,
2) Ensure a balanced approach among customers and other stakeholders
( owners, people, suppliers, local communities, and society at large ) needs
and expectations,
3) Communicate these needs and expectations throughout the organisation .
4 ) Measure customer satisfaction and act on results, and
5) Manage customer relationships.
2. I .3.3. Continuous Improvement

Continual improvement should be a permanent objective of the organisation .
Steps in the application of this principle are:

1) Make continual improvement of products, processes, and systems an
objective for every individual in the organisation,
2) Apply the basic improvement concepts of incremental improvement and
breakthrough improvement ,
3) Use periodic assessments against established criteria of excellence to identify
areas for potential improvement,
4 ) Continually improve the efficiency and effectiveness of all processes,
5 ) Promote prevention-based activities,
6) Provide every member of the organisation with appropriate education and training
on the methods and tools of continual improvement such as the Plan-Do-Check-
Act cycle, problem-solving, process re-engineering, and process innovation,
7 ) Establish measures and goals to guide and track improvements, and
8) Recognise improvements.
The Plan - Do-Study -Act ( PDSA ) Cycle

The PDSA cycle is a set of activities that a company performs to incorporate
continuous improvement in its operation:
1 ) Plan: The first step of the PDSA cycle is to plan (or planning ). During planning,
the process managers should evaluate the current process and make plans based
on the problems they recognise. They should document all the current
procedures, collect data, and identify problems. Thereafter, the documented
information should be analysed and utilised for developing a plan for betterment,
and also specific measures should be taken to evaluate performance.
2) Do: The second step of the PDSA cycle is implementation of the plan ( do ).
During this process, the process managers should document all the changes
made and collect data for further evaluation.
3) Study: The third step of the PDSA cycle is to study the data collected in the
previous step. In this phase, the collected data is evaluated to see whether the
plan is reaching to the goals established in the first step ( plan ).
4 ) Act: The fourth and the last step of the PDSA cycle is to act depending on
the results of the first three phases. This step can be performed by
communicating the results to other members of the organisation and then
implementing the new procedure if it has been successful.
Here it is important to note that since it is a cycle, the next step is to plan again
because once the act has been performed, other steps continue evaluating the
process, planning, and repeating the cycle again.
Plan
Act 1) Objective
1) What chranges are 2) Questions and
to be mad
de? predictions ( why?)
2) Next cycle? 3) Plan to carry out the cycle
( who. what, where, when )
4) Plan for data collection
Study Do
1) Complete the analysis 1 ) Carry out the plan
of the data 2) Document problems and
2) Compare data to unexpected observations
predictions 3) Begin analysis of the
3) Summarise what was il. u . i
\ learned
Figure 2.1: Plan - Do -Study - Act Cycle

Benchmarking
Benchmarking is defined as the study of the business practices of other
companies for making comparisons. The other way under benchmarking by
which the organisations perform continuous implementation for improvement is
to study business practices of the organisations considered best in class. Thus, the
important part of continuous improvement in an organisation is the ability to
learn and study how others do things. It is not mandatory that the benchmark
company have to be in the same business, as long as it excels at something that
the company doing the study wishes to follow.
2. I .3.4. Quality Tools

TQM puts a great deal of responsibility on all the employees. If they have been
assigned the job to identify and overcome quality problems, they should be provided
proper training, and should be made aware of how to evaluate quality by using
various quality control tools, how to interpret findings, and how to rectify problems.
There are seven different quality tools, which are also called the seven tools of
quality control:
- -
1 ) Cause and Effect Diagrams: These are charts used to identify potential
causes for particular quality problems. They are also termed as fishbone
diagrams as they look like fish bones. In a cause-and-effect diagram ( figure

2.2), the head of the fish is the quality problem, such as damaged zippers on
a garment or broken valves on a tire; while, the spine of the fish connects the
head to the possible causes of the problem related to machines, workers,
measurement, suppliers, materials, and other aspects of production.
Surroundings Suppliers
Detail Detail
Detail Mail
Mail Detail
The Problem
ail
Detail
Mail tail
Systems Skill
Figure 2.2: Cause-and-Effeet Diagram

Cause-and-effect diagrams are problem-solving tools, and thus are used by
the quality control teams. For drawing a cause-and-effect diagram , the team
needs to think through all the possible causes of poor quality.
2 ) Flowcharts: These are schematic diagrams of the sequence of steps
involved in a process. Flowchart provides a visual tool that can be easily
used and understood. By observing the steps involved in a process, a clear
picture of how the process works and where problems can arise develops
in the mind.
3) Checklists: These are lists of common defects and the number of observed
occurrences of these defects. Checklist is a simple and effective fact-finding
tool using which the worker collects specific information regarding the
observed defects. If a defect is frequently observed , a checklist measuring the
number of occurrences per shift , per machine, or per operator is developed .
In this way, the location of the particular defect can be identified and then the
problem can be rectified.
4 ) Control Charts: These important quality control tools are charts used for
evaluating whether or not a process is working within the expectations
related to some measured value such as weight , width , or volume. For
example, the weight of a sack of flour, the width of a tire, or the volume of a
bottle of soft drink can be measured. If the production process is operating
within the expectations, it is said to be in control.
By measuring the variable of interest and plotting it on a control chart , it can
be evaluated whether or not a process is in control. In the chart , a line present
in the centre represents the average value of the variable being measured .
The lines above and below the centre line are called the Upper Control Limit
( UCL ) and the Lower Control Limit ( LCL ), respectively. If the observed
values lie within the upper and lower control limits, the process is said to be
in control and there is no problem with quality. However, if a measured
observation falls outside these limits, there is a problem in quality.
5 ) Scatter Diagrams: These are graphs that represent the relationship between
two variables. Scatter diagrams are used to detect the amount of correlation
or the degree of linear relationship between two variables. Greater the degree
of correlation, more linear will be the observations in the scatter diagram. On
the other hand, more scattered the observations in the diagram, less
correlation exists between the variables.
6) Pareto Analysis: It is a technique used for identifying quality problems
based on their degree of importance. As per this analysis, only a few quality
problems are important and many others are not critical.
Pareto analysis can be used by developing a chart in which the causes of poor
quality are ranked in decreasing order based on the percentage of defects
caused by each. For example, a tally of the number of defects resulting from
different causes ( such as operator error, defective parts, or inaccurate
machine calibrations ) can be made.
7 ) Histograms: These are charts that represent the frequency distribution of
observed values of a variable. The plot indicates the type of distribution a
particular variable displays, such as whether it has a normal distribution or a
symmetrical distribution .
2.1.4. Advantages
Following are the advantages of TQM :
1 ) It strengthens a competitive position.
2) It improves the adaptability to changing or emerging market conditions and
to environmental and other government regulations.
3) It increases productivity.
4 ) It enhances the market image.
5 ) It eliminates defects and waste.
6) It reduces costs and better cost management.
7 ) It increases profitability.
8) It improves customer focus and satisfaction.
9) It increases customer loyalty and retention.
10) It increases job security.
11 ) It improves employee morale.
12) It enhances shareholder and stakeholder value.
13) It results in improved and innovative processes.
2.1.5. Disadvantages
Following are the disadvantages of TQM:
1 ) Initial introduction costs- training workers and disrupting current production
whilst being implemented.
2 ) Benefits may not be seen for several years.
3) Workers may be resistant to change and may feel less secure in jobs.
4 ) It is a long-term process that shows results only after years have passed.
Total Quality Management (Chapter 2) 45
2.2. SUMMARY
1) An integrated organisational effort to improve the product quality at every
level is referred to as Total Quality Management (TQM ).
2) Foundation involves ethics, integrity, and trust.
3) Building bricks involves training, teamwork, and leadership.
4) Binding mortar involves communication .
5 ) Roof involves recognition.
6) The term TQM is used to define a philosophy that includes quality as the
driving force behind leadership, design, planning, and improvement initiatives.
7 ) Ethics is the discipline related to good and bad deeds under any circumstances.
8) Organisation ethics refers to a business code of ethics that set up guidelines
which the employees follow while performing their work; while, individual
ethics refers to the personal rights or wrongs.
9) Integrity refers to some characteristic traits like honesty, morals, values,
fairness, and adherence to the fact and sincerity.
10 ) Trust is the by -product of integrity and ethical conduct , and builds the
framework of TQM .
11 ) Once a strong foundation structured by the trust , ethics, and integrity has
been established , bricks are placed to reach the roof of recognition.
12 ) Quality Improvement Teams ( QITs ) or excellence teams are set up for 3-
12 months to deal with frequently occurring specific problems.
13) Problem Solving Teams ( PSTs) are set up for a week to three months to
identify the cause of certain problems and provide solutions.
14 ) Natural Work Teams ( NWTs ) are set up for 1 -2 hours a week and involve
small groups of skilled workers, who share task and responsibilities.
15 ) Leadership is the most important TQM element that can be seen everywhere
in an organisation.
16 ) Communication acts as a binding mortar to bind bricks and other elements
of TQM together.
17 ) Downward communication is the most common form of communication in
an organisation , and presentation and discussion are its two basic factors.
18) By upward communication , the lower level employees convey their
suggestions or ideas to the upper management of the effects of TQM .
19) Sideways communication is essential as it breaks down the barrier between
the departments.
20 ) Recognition is the last element of TQM, and forms the roof of the entire system.
21 ) Use of quality circle is successfully implemented by some organisations as
part of an on-going improvement programme.
22) The PDSA cycle is a set of activities that a company performs to incorporate
continuous improvement in its operation.
23) The first step of the PDSA cycle is to plan (or planning ).
24) The second step of the PDSA cycle is implementation of the plan ( do).
25) The third step of the PDSA cycle is to study the data collected in the
previous step.
26) The fourth and the last step of the PDSA cycle is to act depending on results
of the first three phases.
27 ) Benchmarking is defined as the study of the business practices of other
companies for making comparisons.
28 ) Cause-and-effect diagrams are charts used to identify potential causes for
particular quality problems. They are also termed as fishbone diagrams as
they look like fish bones.
29 ) Flowcharts are schematic diagrams of the sequence of steps involved in a
process.
30 ) Checklists are lists of common defects and the number of observed
occurrences of these defects.
31 ) Control charts are used for evaluating whether or not a process is working
within the expectations related to some measured value such as weight ,
width, or volume.
32 ) Scatter diagrams are graphs that represent the relationship between two
variables.
33 ) Pareto analysis is a technique used for identifying quality problems based
on their degree of importance.
34 ) Histograms are charts that represent the frequency distribution of observed
values of a variable.
2.3. EXERCISE
1) What is TQM?
2) Enlist the elements of TQM .
3) What is ethics and integrity of TQM ?
4) Write about two ways of recognition in TQM .
5) What is the function of quality circle?
6) Draw a cause and effect diagram.
7) What are the advantages of TQM ?
2.3.2. Short Answer Type Questions

1 ) Write a note on the bricks of TQM .
2 ) Write about the buildings and infrastructure as per GMP .
3 ) Discuss the binding mortar of TQM .
4 ) Write a note on quality circles .
5 ) Discuss the tools of quality control in TQM .

1 ) Write an exhaustive note on the elements of TQM .
2 ) Give a brief review on the philosophies of TQM .
ICH Guidelines ( Chapter 3 ) 47
CHAPTER
ICH Guidelines
3
3.1. ICH GUIDELINES

3.1. 1 . Introduction
ICH stands for International Conference on Harmonisation of technical
requirements for registration of pharmaceuticals for human use. ICH is a joint
initiative in which regulators as well as research-based industry initiatives of
Europe, Japan , and U.S. involve in scientific and technical discussions regarding
the testing procedures and their evaluation to ensure safety , quality and efficacy
of the medicines. In 1980, the European Union took the initiative of
harmonisation of regulatory requirements.
In 1989 in Paris, bilateral discussions took place between Europe, Japan, and
U.S. on possibilities for harmonisation at WHO conference of drug regulatory
authorities to materialise specific action plans. Authorities approached the
IFPMA ( International Federation of Pharmaceutical Manufacturers and
Associations ) and discussed on joint regulatory -industry initiative on
international harmonisation , and thus ICH was perceived. ICH was originated in
April 1990 at a meeting hosted by the EFPIA ( European Federation of
Pharmaceutical Industries and Association ) in Brussels.
3.1 .2. Purpose
The year 1990 marked the establishment of ICH as a joint regulatory /industry
project to improve the efficiency of the process for developing and registering
new medicinal products in Europe, Japan and U.S. and to make them available to
the patients with minimum delay through harmonisation. The ICH serves the
following purposes:
1 ) It monitors, updates, and increases the international harmonisation of
technical requirements.
2 ) It ensures safety, efficacy and quality of medicines that should be developed
and registered in an efficient and cost-effective manner.
3) It promotes and protects public health from an international perspective.
4) It prevents unnecessary duplication of clinical trials in humans.
5 ) It reduces animal testing without compromising the safety and effectiveness.
6) It improves the efficiency of global drug development .
3.1 .3. Participants
The ICH steering committee and its sub-groups comprise of representatives from
six parties, representing the regulatory bodies and research-based industries in the
U.S.A., Japan , and the European Union. The ICH observers have been allied with
the ICH process from the starting to link the non-ICH countries. The European
Free Trade Association (EFTA ), World Health Organisation ( WHO), and Canada
are these non-voting members of the ICH steering committee and its sub-group.
Tahle 3.1: Regulatory Bodies and Research - Based Industries

Regions Regulatory Bodies Research- Based Industries
Japan MHLW - Ministry of Health, JPMA Japan Pharmaceutical
Labour and Welfare . Manufacturers Association .
Europe EU - European Union. EFPIA European Federation of
Pharmaceutical Industries and Associations .
USA FDA - Food and Drug PhRMA - Pharmaceutical Research and
Administration . Manufacturer of America.
ICH Expert Working Groups ( EWGs)/Implementation Working Groups ( IWGs)

Each of the six official ICH members (namely, EFPIA, EU. MHLW, JPMA, PhRMA,
and FDA) and the ICH observers ( namely, WHO, EFTA, and Health Canada ) appoint
official representatives to each ICH working group. The official membership of ICH
expert working groups should comprise of a topic leader and a deputy topic leader
for ICH members and one Steering Committee
representative for each ICH
observer ( EFTA Health Canada, and
Global MedDRA
WHO). Experts are constituted by the Cooperation Group Management
ICH regional coordinators. Depending
on the subject under harmonisation, Secretariat Coordinators
sometimes the ICH steering committee
also invites other specialists to ICH Working Groups
Q. S. E. M
nominate one representative to be a
part of the ICH working group. Figure 3.1: ICH Organisational Structure
If the steering committee permits, one expert can be called from ICH Regional
Pharmacopeias, ICH Interested members [ World Self Medication Industry
( WSMI ), International Generic Pharmaceutical Alliance ( IGPA ), International
Pharmaceutical Excipients Council ( IPEC ), Biotechnology Industry and Active
Pharmaceutical Ingredient Industry], Regional Harmonisation Initiatives
( RHIs ). Individual Drug Regulatory Authorities ( DRAs ), and Department of
Health ( DoH ) from non -ICH member countries.
3.1.4. Process of Harmonization
The ICH steering committee is responsible for the ICH administration, including
determining the adoption of every ICH project, whether a new issue,
maintenance of an existing guideline, or a specific implementation work.
Each harmonisation action is started with a concept paper which includes a short
summary of the proposal. A business plan may also be needed as per the category
of harmonisation activity. Any ICH member or observer can offer a proposal for
a new ICH implementation activity. The ICH steering committee determines the
adoption of every ICH task and supports the creation of a EWG/IWG. The ICH
harmonisation activities are categorised into formal ICH procedure, questions
and answers procedure, revision procedure, and maintenance procedure.
3.1 .4.1 .Formal ICH Procedure
A formal ICH procedure is started with the steering committee’s approval of a
concept paper and business plan. An Expert Working Group ( EWG ) with
membership as specified by the concept paper is established. At the same time, the
steering committee officially assigns a rapporteur and co-rapporteur. A regulatory

chair is also officially assigned to the three regulatory parties of the steering
committee. The EWG develops a draft guideline and develops it through the steps
given below and implement it in the ICH regions of a harmonised tripartite guideline.
Step 1: Consensus Building
The unanimity process begins when the steering committee obtains a concept paper
as a new topic. This step is begun when the EWG start preparing a unanimity draft of
the technical document, depending on the objectives set out in the concept paper.
Work is conducted via e-mails, telephonic conferences, and web conferences. If
supported by the steering committee, the EWG also meets head-on at the 2 years
steering committee meetings. Meanwhile reports are made to the steering committee
at regular intervals on the progress of the draft technical document. When consensus
is reached among all six EWG members, the EWG signs the Step 1 experts sheet.
This Step 1 technical document bearing EWG signature is presented to the steering
committee to request acceptance under Step 2a of the ICH process.
-
Step 2a: Confirmation of Six Party Unanimity on the Technical Document
Step 2a arrives when the steering committee, based on the EWG report , accepts
that there are sufficient scientific consensuses on the technical issues for the
technical document to proceed to the next stage of regulatory consultation. The
unanimity text approved by the Steering Committee is signed -off by the
Steering Committee as the Step 2a Final Technical Document .
Step 2b: Espousal of the Draft Guideline
Based on the technical document, the three ICH regulatory members take the
actions they believe to be essential for developing the draft guideline. The
unanimity text approved by the three regulatory ICH members is signed by the
three regulatory ICH members as Step 2b draft guideline.
Step 3: Regulator Consultation and Discussion
This Step occurs in the following three stages:
1) Stage I: Regional Regulatory Consultation: The guideline being the
scientific unanimity leaves the ICH process and becomes the subject of
normal varied regulatory consultation in three regions ( European Union,
Japan , and U.S.A.). In European Union , it is published as a draft Committee
for Medicinal Products for Human Use ( CHMP) Guideline. In Japan, it is
published and issued by MHLW for internal and external consultation. In the
U.S.A., it is issued as draft guidance in the federal register. Regulatory
authorities and industry associations in non -ICH areas may also annotate on
the draft consultation documents by providing their comments to the ICH
secretariat.
2) Stage II: Discussion of Regional Consultation Comments: The EWG on
receiving all the comments from the consultation process, handles the
comments and reach unanimity on Step 3 experts draft guideline. If the
rapporteur was from an industry member, a new rapporteur is appointed from
a regulatory party ( if possible from the same area as the previous rapporteur )
until Step 2b. The procedure of Step 1 is followed to address the consultation
results. The draft document to be formulated as a result of Step 3 phase is
called Step 3 experts draft guideline.
3) Stage III : Finalisation of Step 3 Experts Draft Guideline: After

considering the consultation results, the EWG reaches unanimity amongst
the experts from the three regulatory ICH members on a revised version of
the Step 2b Final draft guideline, and the Step 3 experts draft guideline is
signed by the EWG experts of the three regulatory ICH members. The Step 3
document bearing the regulatory EWG signature is presented to the steering
committee to request acceptance as Step 4 of the ICH process.
Step 4: Acceptance of an ICH Harmonised Tripartite Guideline
Step 4 is completed when the steering committee, based on the report from the
regulatory chair and the regulatory rapporteur of the EWG, accepts that there is
sufficient unanimity on the draft guideline. Step 4 is reached when the Step 4 final
document is signed by the steering committee signatories for the regulatory members
of ICH as an ICH harmonised tripartite guideline at Step 4 of the ICH procedure.
Step 5: Implementation
After the completion of Step 4, the harmonised tripartite guideline reaches the
final step, i.e., the regulatory execution or Step 5. Step 5 is accomplished
according to the national/ regional procedures that are applied to other regional
regulatory requirements, in the U .S.A., Japan , and the European Union.
3.1 . 4.2. Questions and Answers Procedure
The Q& As procedure is followed when additional guidance is required to
help interpreting certain ICH guidelines and ensure uniform implementation in
and outside the ICH regions. The implementation working group works, reaches
unanimity on a draft Q& A document , and recommends the steering committee
( based on the level of data provided by the answers) that whether the document
should be a Step 2b or a Step 4. Then the document follows the normal way of a
Step 2b/Step 4 Document as per the formal ICH process.
3.1.4.3. Revision Procedure
The revision procedure is compiled either when the scientific/technical content of
an existing ICH guideline is invalid or when a new data is to be added with no
amendments to the existing ICH guideline needed . In the latter case, the new data
can be added to the guideline in question either in the form of an addendum or as
an annexure. The procedure is started with the endorsement of a concept paper by
the steering committee. A business plan is not required for revisions. An EWG
with membership as specified by the concept paper is established.
The revision process is somewhat similar to the formal ICH procedure of five ICH
steps, with the only difference that the final result is a revised version of a present
guideline than a new guideline. The revision of a guideline is contrived by the letter
R 1 after the usual denomination of the guideline. When a guideline is revised
multiple times, the document is named as R2, R3, R4, etc. at each new revision. If an
addendum or annexure has been developed, on reaching Step 4 the addendum or
annexure is added to the existing guideline to form a revised guideline.
3.1 . 4.4. Maintenance Procedure
The maintenance procedure is applicable only for alterations to the Q3C
guideline on impurities: residual solvents. This process is used when new
information is to be added or the technical content is invalid.
ICH Guidelines (Chapter 3) 51
3.1.5. Overview of QSEM

ICH guidelines are mainly categorised into four types:
1 ) Q - Quality guidelines, 2) S - Safety guidelines,
3) E - Efficacy guidelines, and 4) M - Multidisciplinary guidelines.
3.1.5.1. Q-Series Guidelines
Attainment of harmonisation in the quality area include important milestones,
such as carrying stability studies, determining relevant thresholds for impurities
testing, and following a more flexible approach to pharmaceutical quality based
on GMP risk management.
S.
-
Table 3.2: Quality or Q Series Guidelines
Guidelines
No.
1) Q1A -Q1F ( Stability ):
Q1A: Stability testing of new substances and products.
Q1B: Photostability testing of new drug substances and products.
QIC: Stability testing for new dosage forms.
Q1D: Bracketing and matrixing designs of stability testing of new drug substances
and products.
Q1E: Evaluation of stability data.
Q1F: Stability data package for registration application in climatic zones III and IV.
2 ) Q2 ( Analytical Validation ): Validation of analytical procedures.
-
3) Q3A Q3D ( Impurities ):
Q3A: Impurities in new drug substances.
Q3B: Impurities in new drug products.
Q3C: Impurities - guidelines for residual solvents.
Q3D: Impurities - guidelines for elemental impurities.
-
4) Q4 A Q4B ( Pharmacopoeias ):
Q4A: Pharmacopoeial harmonisation.
Q4B: Evaluation and recommendation of Pharmacopoeial texts for use in the ICH
regions.
-
5 ) Q5A Q5E ( Quality of Biotechnological Products ):
Q5A: Viral safety evaluation of biotechnology products derived from cell lines of
human or animal origin.
Q5B: Analysis of expression construct in cells for production of r - DNA derived
protein products.
Q5C: Stability testing of biotechnological/biological products.
Q5D: Derivation and characterisation of cell substrates used for production of
biotechnological/biological products.
Q5E: Comparability of biotechnological/biological products subject to changes in
their manufacturing process.
-
6 ) Q6A Q6B ( Specifications ):
Q6A: Test procedures and acceptance criteria for new drug substances and new
drug products - Chemical substances.
Q6B: Test procedures and acceptance criteria for biotechnological/biological products.
7) Q7: Good manufacturing practices for active pharmaceutical ingredients.
8 ) Q8: Pharmaceutical development.
91 Q9: Quality risk management .
10 ) Q10: Pharmaceutical quality systems.
ID Qll: Development and manufacture of drug substances ( chemical entities and
biological entities ).
3.1.5.2. S-Series Guidelines

ICH prepared a complete set of safety guidelines to determine potential risks of
carcinogenicity , reprotoxicity , and genotoxicity . A recent finding is a non-clinical
testing scheme for determining the QT- interval prolongation liability .
Tables 3.3: Safety or S -Series Guidelines
S. No. ( Guidelines
1 ) S 1A - 1C
S ( Carcinogenicity Studies ) :
SI: Rodent carcinogenicity studies for human pharmaceuticals.
S1A: Need for carcinogenicity studies of pharmaceuticals.
SIB: Testing for carcinogenicity of pharmaceuticals.
2) S2 ( Genotoxicity Studies ) : S2 ( R l ) Guidance on genotoxicity testing and data
interpretation for pharmaceuticals intended for human use.
3) S3A -S3B ( Toxicokinetics and Pharmacokinetics ) :
S3A: Note for Guidance on Toxicokinetics: Assessment of systemic exposure in
toxicity studies.
S3B: Pharmacokinetics: Guidance for repeated dose tissue distribution studies.
4) S4 (Toxicity Testing ): Duration of chronic testing in animals ( rodent and not - rodent
toxicity testing ) .
5) S5 ( Reproductive Toxicology ): Detection of toxicity to reproduction for medicinal
products and toxicity to male fertility.
6) S6 ( Biotechnological Products ): Preclinical safety evaluation of biotechnology
derived pharmaceuticals.
7) S7 A -S7B ( Pharmacology Studies ):
S7A: Safety pharmacology studies for human pharmaceuticals.
S7B: Non -clinical evaluation of the potential for delayed ventricular repolarisation by
human pharmaceuticals.
8 ) S 8 ( Immunological Studies ) : Immunotoxieity studies for human pharmaceuticals.
21 S9: Non-clinical evaluation for anticancer pharmaceuticals.
10) S10: Photosafety evaluation of pharmaceuticals.
3.1.5.3. E-Series Guidelines

The efficacy guidelines are related to the design, carrying, safety, and reporting
of clinical trials . These guidelines also provide information on novel types of
medicines obtained by biotechnological methods and use of pharmacogenomic
techniques to produce a better-targeted drug.
Table 3.4: Efficacy or E-Series Guidelines
S. No Guidelines
1) El: Clinical safety for drugs used in long term treatment.
2) E2A -E2F: Pharmacovigilance.
21 E3: Clinical study reports.
4) E4: Dose response studies.
5) E5: Ethnic factors.
61 E6: Good clinical practice.
21 E7: Clinical trials in geriatric population .
81 E8: General consideration for clinical trials.
9) E9: Statistical principles for clinical trials.
10 ) E10: Choice of control group in clinical trials.
Ill Ell: Clinical trials in paediatric population .
ill E12: Clinical evaluation by therapeutic category.
ill E14: Clinical evaluation.
ill E15: Definitions in pharmacogenetics/ pharmacogenomics.
151 E16: Qualification of genomic biomarkers.

M E17; Multi - regional clinical trials.
121 E18: Genomic sampling methodologies.
3.1.5.4. M-Series Guidelines

These guidelines cover unique topics which do not fit into any of the quality, safety and
efficacy guidelines category. Multidisciplinary guidelines describe about Common
Technical Document ( CTD), medical terminology ( MedDRA ), and the development of
Electronic Standards for the Transfer of Regulatory Information ( ESTRI).
Table 3.5: Multidisciplinary or M -Series Guidelines
S.No. Guidelines
1) Ml: MedDRA ( Medical Dictionary for Regulatory Activities ) terminology .
21 M2: Electronic standards.
21 M 3: Non-clinical safety studies.
il M 4: Common technical document .
21 M 5: Data elements and standards for drug dictionaries.
21 M6: Gene therapy.
7) M7: Gcnotoxic impurities.
21 M8: electronic Common Technical Document ( eCTD ).
3.2 . ICH STABILITY TESTING GUIDELINES
3.2. 1 . Introduction
Stability studies include testing of those features of a drug substance that may
change during storage and influence quality, safety, and/or efficacy.
3.2.2. Climatic Zones for Stability Testing
For stability testing, the world has been divided into four zones ( i.e., I-IV )
depending on the environmental conditions to which the pharmaceutical products
are subjected during storage. These conditions have been derived based on the
mean annual temperature and relative humidity data in these four regions. This
data helps in deriving the long-term or real -time stability testing conditions and
accelerated stability testing conditions. Table 3.6 represents the standard climatic
zones to be used in pharmaceutical product stability studies, the division of
environmental conditions in each zone, and the derived long - term stability test
storage conditions (as given by the WHO ). The stability conditions have also
been harmonised and adjusted to enhance their practical use in industries.
Table 3.6: ICH Climatic Zones and Long Term Stability Conditions
Climate Climate Major Countries/ MAT*/Mean Annual Partial -
Long Term
Zones Regions Water Vapour Pressure Testing Conditions
I) Temperate United Kingdom. <; l 5°C / <; ilhPa 21°C/45% RH
Northern Europe .
Russia, and United
States
II ) Subtropical and Japan and Southern >15-22°C / > 11 - 18 hPa 25°C/60% RH
Mediterranean Europe 30°C/35% RH
HI ) Hot and Dry Iraq and India >22°C / <15 / >22°C / >15-27
hPa
IV a ) Hot and humid Iran and Egypt >22°C / > 27hPa 30°C/65% RH
IV b ) Hot and very Brazil and Singapore 30°C/75% RH
humid
*MAT- Mean Annual Temperature measured in open air.
3.2.3. Protocol for Stability Testing

The protocol for stability testing is an essential requirement before starting the
stability testing and is a written document containing the key components of a
regulated and well-controlled stability study. The testing condition relies on
inherent stability of the compound , the type of dosage form , and the proposed
container-closure system. Thus, the protocol depends on the type of drug
substance or product , and also on whether the drug is new or is already in the
market. The protocol should represent the regions where the product is planned
to be marketed ; for example, the stability program should include I -III, IVa and
IVb climatic zones if the product is proposed to be used in all these zones.
A well-designed stability protocol should bear the information discussed below.
Batches
At developmental stages, a single batch is subjected to stability studies; first three
production batches are subjected to studies proposed for registration of new
product or unstable established product; and stable and well-established batches
are subjected to both the studies. The first three batches of drug product
manufactured after approval should be subjected to long -term studies using the
same protocol as in approved drug application. This is done if the initial data is
not on a full scale production batch. The laboratory scale batches data obtained
during development of pharmaceuticals are not accepted as primary stability data
but constitute supportive information. Selection of batches should be done by
taking a random sample from the population of pilot or production batches.
Containers and Closures
The product is tested in immediate containers and closures intended for marketing.
The packaging materials include aluminium strip packs, blister packs, Alu -Alu
packs, HDPE bottles, secondary packs, etc. Products in different types of
containers/closures, either meant for distribution or for physician and promotional
samples, should be separately tested. However, testing for bulk containers should
be done in prototype containers if it simulates the actual packaging.
Orientation of Storage of Containers
Samples collected from solutions, dispersed systems and semisolid drug products
for conducting stability studies should be kept upright either inverted or on the
side to allow interaction between the product and the container -closure. Through
this orientation , it can be determined that the drug product or solvent and the
closure in contact causes extraction of chemical substances from the closure
components or adsorption of product components into the container-closure.
Sampling Time Points
Testing should be done so frequently that the stability profile of the new drug
substance can be established adequately. The products with a proposed shelf -life
of minimum 12 months should be tested at the long-term storage condition in
every 3 months over the first year, every 6 months over the second year, and then
annually throughout the proposed shelf -life, i.e., till the products expire.
In case of accelerated storage conditions, at least three time points, including the
initial and end points ( such as 0, 3 and 6 months ), are recommended . When the
test is conducted at the intermediate storage condition as a result of significant
ICH Guidelines ( Chapter 3) 55
change at the accelerated storage condition , at least four time points, including
the initial and end points ( such as 0, 6, 9 and 12 months ), are recommended .
Table 3.7 presents the test schedule for stability testing of a new product.
Table 3.7: Test Schedule for Stability Testing of New Products
Environment Sampling Time Points Method and Climatic Zones
( Months )
25°C/60% RH 3, 6, 9, 12, 18, 24, 36 Long -term for zones 1 and IV .
30°C/35% RH 3, 6, 9, 12, 18, 24, 36 Long -term for zones 111.
30°C/65% RH 3, 6, 9, 12, 18, 24, 36 Long -term for zone IVa or intermediate
condition for zones I and II.
30°C/75% RH 3, 6, 9, 12, 18, 24, 36 Long -term for zone IVa or intermediate
condition for zones I and II.
40°C/75% RH 3, 6 Accelerated condition for all zones.
If the same product of different strengths, multiple sizes, etc. is to be tested,

reduced stability testing plans, involving less number of test points, can be made
based on bracketing and matrixing statistical designs.
Bracketing is a stability schedule design in which only samples on the extremes of
..
certain design factors ( e g , strength and package size) are tested at all-time points
as in a full design. Matrixing on the contrary is a stability schedule design in
which a subset of the total number of possible samples for all combinations is
tested at a specific time point. Consequently, another subset of samples for all
factor combinations is tested. Batches, strengths with identical formulation,
container sizes, fill sizes, and intermediate time points are the factors that can be
matrixed.
Sampling Plan
Sampling plan for stability testing involves planning for the samples to be
charged to the stability chambers and sampling out of the charged batch to cover
the entire study. The entire process of sampling plan should involve development
of sampling time points followed by the number of samples to be collected at
each pull point for evaluation of all the test parameters and lastly summing up all
the samples to get the total number. For example, there would be a requirement
of 100 tablets per pull out in a long-term or accelerated stability studies including
10 each for assay, hardness and moisture determination , 6 each for dissolution
and disintegration , and 50 for friability ; this is multiplied with the total number of
pull outs to get the total number of tablets required for a study , and is followed
by the development of a sampling plan , which includes selection of the
containers representing the batch as a whole.
A stratification plan in which from a random starting point every nth container is
taken from the filling or packaging line ( n is chosen such that the sample is
spread over the whole batch ) has been suggested.
Test Storage Conditions
The test storage conditions to be selected depend on the climatic zone in which
the product is proposed to be marketed or for which the product is proposed to be
filed for regulatory approval. Table 3.8 presents the abridged/indicative ICH and
WHO storage conditions for drug products.
Table 3.8: Stability Test Storage Conditions for Drug Products

Intended Stability Test ICH Test Temperatures WHO Test Temperature
Storage Methods and Humidity and Humidity
Conditions ( Period in Months ) ( Period in Months )
Room Long term 25±2°C/60±5% RH ( 12 ) 25±2°C/60±5% RH or
temperature 30±2 C/65 ±5% RH
°
30±2°C/75±5% RH ( 12)
Intermediate 30± 2°C/65 ±5% RH ( 6 ) 30±2°C/65 ±5% RH ( 6 )
Accelerated 40± 2°C/75 ±5% RH ( 6 ) 40±2°/75 ±5% RH ( 6 )
Refrigerated Long -term 5 °C/ambient ( 12 ) 5 ±3°C
Accelerated 25±2°C/60±5% RH ( 6 ) 25 ±2°C/60±5% RH or
30±2°C/65±5% RH
Freezer Long - term -20 C/ambient ( 12 )
° -20°C±5 °C
Test Parameters
The test parameters to be used for evaluating the stability samples should be
described in the stability test protocol. The tests monitoring the quality, purity,
potency, and identity of the drug substance or product, which might change on
storage, are selected as stability tests. Thus, the tests for appearance, assay,
degradation , microbiological attributes (such as sterility, preservative efficacy, and
microbial count, e.g., for liquid injectable preparations), dissolution, and moisture
are considered standard and performed on stability test samples. The batches for
stability study should meet all the testing requirements including heavy metals,
residue on ignition, residual solvents, etc. Some of these are required at the time of
product release, but not required to be repeated during stability testing.
Test Methodology
The procedures given in the official compendia should always be followed so
that the results obtained from the official tests find better acceptance. If using
alternate methods, they should be appropriately validated. However, the drug
-
should be assayed by a stability indicating method, established by carrying out
stress tests on the drug under forced decomposition conditions. The specificity ,
accuracy, precision , and linearity in the range to which the drug is expected to
fall during stability studies should be validated for this method. The limits of
detection/quantification should also be included in the validated method for the
assay of degradation products. The methods reported in literature should be used
after confirming reproducibility and validating the linearity, range, etc. A
Standard Test Protocol (STP) for each test should always be prepared.
Acceptance Criteria
All the analytical methods should be validated, and the acceptance criteria for the
analytical results and for the presence of degradation products should also be
fixed prior to the stability studies. The acceptance criteria for each stability test
..
are fixed in the form of numerical limits for the results of quantitative tests, e g ,
moisture pick -up, viscosity, particle size, assay, degradation products, etc. and as
..
pass or fail for the results of qualitative tests, e g , odour, colour, appearance,
cracking, microbial growth, etc. The individual and total upper limits for
degradation products should also be included in these acceptance criteria.
ICH guideline Q3B( R2) related to impurities in new drug products addresses
degradation products in new drug formulations. The degradation products of
active or interaction products from the active ingredients and excipients and/or
active and container component should be reported , identified , and/or qualified
when the proposed thresholds are exceeded. The reporting threshold of impurities
relies on the intended dose. If the maximum daily dose is
less than or equal to lgm, the limit is 0.1% ; while, if the maximum daily dose is
greater than 1 , the limit is 0.05% . For maximum daily dose ranging between lmg
and 2gm, the identification threshold of impurities lies between 1.0-0.1 % .
3.3. SUMMARY
1 ) ICH stands for International Conference on Harmonisation of technical
requirements for registration of pharmaceuticals for human use.
2) The ICH steering committee and its sub-groups comprise of representatives
from six parties, representing the regulatory bodies and research -based
industries in the U.S.A., Japan , and the European Union .
3) The official membership of ICH expert working groups should comprise of a
topic leader and a deputy topic leader for ICH members and one
representative for each ICH observer ( EFTA, Health Canada, and WHO ).
4) The ICH harmonisation activities are categorised into formal ICH
procedure, questions and answers procedure, revision procedure, and
maintenance procedure.
5) A formal ICH procedure is started with the steering committee’s
approval of a concept paper and business plan .
6) The Q& As procedure is followed when additional guidance is required
to help interpreting certain ICH guidelines and ensure uniform
implementation in and outside the ICH regions.
7 ) The revision procedure is compiled either when the scientific/technical
content of an existing ICH guideline is invalid or when a new data is to be
added with no amendments to the existing ICH guideline needed.
8) The maintenance procedure is applicable only for alterations to the Q3C
guideline on impurities: residual solvents.
9) Stability studies include testing those features of a drug substance that may
change during storage and influence quality , safety, and/or efficacy .
10) For stability testing, the world has been divided into four zones ( i.e., I-IV )
depending on the environmental conditions to which the pharmaceutical
products are subjected during storage.
11 ) The protocol for stability testing is an essential requirement before starting
the stability testing and is a written document containing the key components
of a regulated and well-controlled stability study.
12) At developmental stages, a single batch is subjected to stability studies; first
three production batches are subjected to studies proposed for registration of
new product or unstable established product; and stable and well -established
batches are subjected to both the studies.
13) The product is tested in immediate containers and closures intended for
marketing.
14 ) Samples collected from solutions, dispersed systems and semisolid drug
products for conducting stability studies should be kept upright either
inverted or on the side to allow interaction between the product and the
container-closure.
15 ) Testing should be done so frequently that the stability profile of the new drug
substance can be established adequately.
16 ) Bracketing is a stability schedule design in which only samples on the
extremes of certain design factors ( e.g., strength and package size ) are tested
at all-time points as in a full design.
17 ) Matrixing on the contrary is a stability schedule design in which a subset of
the total number of possible samples for all combinations is tested at a
specific time point.
18) Sampling plan for stability testing involves planning for the samples to be
charged to the stability chambers and sampling out of the charged batch to
cover the entire study.
19) A stratification plan in which from a random starting point every n *11
container is taken from the filling or packaging line ( n is chosen such that the
sample is spread over the whole batch ) has been suggested.
20 ) The test storage conditions to be selected depend on the climatic zone in
which the product is proposed to be marketed or for which the product is
proposed to be filed for regulatory approval .
21 ) The test parameters to be used for evaluating the stability samples should
be described in the stability test protocol.
22 ) All the analytical methods should be validated , and the acceptance criteria
for the analytical results and for the presence of degradation products should
also be fixed prior to the stability studies.
3.4 . EXERCISE
1 ) What does ICH stand for?
2) What purposes does ICH serve?
3 ) Name the regulatory bodies of ICH .
4) Define the Q - series guidelines.
5 ) Enlist the M -series guidelines.
6 ) Give the climatic zones for ICH stability testing .

1) Write a note on the participants of ICH .
2) Write about the questions and answers and revision procedure of ICH .
3) Discuss the Q- and S -series guidelines .
4) Write a note on E- and M -series guidelines .
5) Discuss the protocol for ICH stability testing .

1 ) Write an exhaustive note on the process of harmonisation .
2) Give a brief review on the ICH stability testing guidelines.
Quality by Design ( QbD ) ( Chapter 4 ) 59
CHAPTER Quality by Design (QbD )

4
4.1 . QUALITY BY DESIGN ( QBD)

4.1 . 1 . Definition and Overview
A systematic approach for development of pharmaceutical products that begins
with predefined objectives and emphasises product and process understanding
and process control, based on sound science and quality risk management is
defined as Quality by Design ( QbD ).
The concept of QbD was developed by Dr. Joseph M. Juran , who believed that
quality should be designed into a product, and most quality problems are related
to the way in which a product was designed . Woodcock defined a high-quality
drug product as a contamination-free product that reliably produces the expected
therapeutic benefit to the consumer. The USFDA encourages risk-based
approaches and implementation of QbD principles in development ,
manufacturing, and regulation of drug product . FDA started emphasising on the
acceptance of QbD with the recognition that increased testing does not improve
product quality, and it should be built into the product.
QbD involves designing and developing
formulations and manufacturing processes that Labelled use safety and efficacy
ensure predefined product specifications. This
concept has been lately adopted in the
pharmaceutical industries through several
| Define quality target product profile
..
initiatives [e g , ICH Q81, Q92 and Q103, new Design formulation and process
.
regulatory documents Process Analytical
.
Technology ( PAT) FDAs cGMP for the 21st
Identify critical material attributes
Century ]. It aims to shift from the concept of and critical process parameters
Quality by Testing ( QbT, that was previously
implemented in the pharmaceutical industry )
Control materials and process
to a development that improves the
understanding of the processes and the Target Design - Implementation
products, and hence the product quality, Figure 4.1: Overview of QbD
process efficiency and regulatory flexibility.
4.1 . 2. Elements of QbD Program

In QbD approach to product development, an applicant identifies the desired
characteristics of quality from the patient’s viewpoint, and translates them into
the drug product Critical Quality Attributes (CQAs ). Then the applicant links the
formulation/ manufacturing variables with the CQAs to offer a drug product with
such CQAs to the patient.
QbD consists of the following elements:

1 ) Defining the quality target product profile,
2) Identifying the quality attributes,
3) Performing a risk ( assessment ) analysis,
4) Determining the critical quality attributes and critical process parameters,
5) Determining the design space, and
6) Identifying a control strategy.
4.1.2.1. Quality Target Product Profile ( QTPP)

According to ICH Q8( R2) guideline, QTPP is described as a prospective summary
of the quality characteristics of a drug product that ideally will be achieved to
ensure the desired quality, taking into account safety and efficacy of the drug
product . QTPP is a method used to establish the strategy for drug development.
Currently, it is used for planning, making clinical and commercial decisions,
interacting with regulatory agencies, and for risk management.
QTPP defines the properties of drug product that are essential to deliver
therapeutic benefits mentioned in the label. Under QTPP guidelines, formulation
strategies are established by the scientists to keep the formulation effort focused
and efficient. For example, QTPP of an immediate release solid oral dosage
form consists of the following:
1 ) Tablet characteristics, 2) Identity, 3) Assay and uniformity,
4 ) Purity or impurity, 5) Stability, and 6) Dissolution .
It is important to notice that under QTPP product performance elements that are
relevant to the patients should only be included. Other formulation related
properties ( e.g., tablet density, hardness, etc.) may be included as a specification
for process monitoring but not in QTPP. The QTPP should include dissolution but
not particle size, if particle size is critical to the dissolution of a solid oral product.
4.1.2.2. Critical Quality Attributes ( CQAs)

The next step after QTPP identification is the identification of relevant CQAs. A
CQA is defined as a physical , chemical , biological or microbiological
property or characteristic that should be within an appropriate limit, range,
or distribution to ensure the desired product quality .
[ Start
Prior Potential quality

knowledge attributes I QTPP I
Quality attribute No Is this a CQA ( from 1

I ' nsure Experimental work to
not a CQA patient perspective) increase knowledge
Yes
Apply suitable tool to
rank CQAs
Listof CQAs
Figure 4.2: Decision Tree to Decide CQAs
.
In general , CQAs are related to raw materials ( e g., drug substances and
.
excipients ), intermediates (e.g , in-process materials), and drug products. CQAs
of drug product are the properties that are important for product performance,
such as the desired quality, safety, and efficacy ( figure 4.2). Thus, CQAs are
subsets of QTPP that can be altered by changing the formulation or process
variables. For example, quality attributes of the drug product including strength
and dosage form are included in the QTPP but not included in CQA as they
cannot be changed during drug development process. However, quality attributes
of the drug product including assay, content uniformity, dissolution , and
permeation flux are included in both QTPP and CQA as they can be altered by
formulation or process variables. Some examples of the CQAs of drug
substances and drug products are enlisted in table 4.1.
Table 4.1 : Typical CQAs for Drug Substances and Drug Products
For Drug Substances ( Chemical ) For Drug Products ( Tablet )
Appearance Appearance
Particle size Identification
Morphic forms Hardness
Water content Dosage uniformity
Residual solvents Physical form
Organic impurities Dissolution
Inorganic impurities Degradation products
Heavy metals Water content
Residue on ignition Assay
Assay Microbiological limits
CQAs for a formulation are identified through risk assessment according to the ICH
guideline Q9. These risk assessments are made by prior product knowledge, such as
the accumulated laboratory, non-clinical and clinical experience with a specific
product-quality attribute. This knowledge may also include relevant data from
similar molecules and data from literature references. This information provides a
foundation to establish a relation between the CQA to product safety and efficacy.
4. I .2.3.Quality Risk Management ( QRM )

According to FDA, risk management is a strategic safety program designed to
reduce product risk by using one or more interventions or tools. QRM is a
systematic process designed to assess, control , communicate , and review the
risks related to the quality of the drug product during the product lifecycle. A
process for a typical quality risk management is briefly given in figure 4.3.
As per the ICH Q9 guideline, QRM provides a structure to start and follow a risk
management process. Following are the important tools of QRM :
1 ) Failure Mode Effects Analysis ( FMEA ): It is one of the most common tools of
risk-assessment used in pharmaceutical industries. This systematic and proactive
method is used to identify and mitigate the possible failure in the process. Failure
mode indicates any errors or defects that may occur in a process, material,
design, or equipment. If failure modes are established, FMEA tool recognises the
effect of these failures and enlist them accordingly. By performing critical
studies of the consequences and by providing clear indication of the situation,
advancement can be made in the FMEA tool.
initiate Quality Risk Management "'"'
Process
Risk Assessment
| Risk Identification ]
Risk Analysis
[ Risk Evaluation ]
Unacceptable
Risk Control
Risk Reduction
Risk Acceptance
Output Result of the Quality Risk

Management Process
Risk Review
r Review Events ]
Figure 4.3: Overview of a Typical Quality Risk Management
2) Failure Mode, Effects and Criticality Analysis ( FMECA ): It is the

extended form of FMEA tool that can be used for investigating the degree of
severity of consequences, their chances of occurrence, and their detectability.
In FMECA tool, failure modes of the products are identified and their
criticality is evaluated, which is then translated into a risk. Corrective actions
are taken in case of unacceptable levels of risk. The results are further used to
assess failures and risks associated with manufacturing processes. FMECA
tool can also be used to establish and optimise maintenance plans
for repairable systems and/or to control plans and other quality assurance
procedures.
3) Fault Tree Analysis ( FTA ): It is used to deal with failure of the functionality of
a product or process. The obtained results are pictorially represented in the form
of a tree of fault modes, which are then used for investigating complaints or
deviation to identify their cause and to ensure that the improvement made will
overcome the issues and will not cause any further problem.
4 ) Hazard Analysis and Critical Control Points ( HACCP): It is used for
providing elaborated documentation for any process or product understanding
through identifying parameters to control and monitor. Hazard analysis is
useful for both safety and quality of a process or product. HACCP tool
includes hazard analysis, determination of critical control point , establishment
of critical limit, installation of a system to monitor critical control point, and
establishment of a record-keeping system. It is done to identify and manage
risks associated to physical, chemical and biological hazards.
A combination of quantitative and qualitative estimation of risk is obtained
as the output of a risk assessment. As part of FMEA, a risk score or Risk
Priority Number ( RPN ) may be allotted to the deviation or to the affected
stage of the process; this helps in categorising the deviation .
For the calculation of RPN, Probability ( P), Detectability ( D), and

Severity (S), which are individually categorised and scored, are multiplied.
Rating scales usually range from 1 to 5.
RPN = Probability score x Severity score x Detectability score
Where, the score was defined prior to the risk analysis stage:
RPN is < 40 = Low risk
RPN is 40-99 = Intermediate risk
RPN is > 100 = High risk
4. I .2.4. Determination of Critical Process Parameters ( CPPs )

Any measurable input (such as input material attribute or operating parameter ) or
output ( process state variable or output material attribute ) of a process step that
needs to be controlled to achieve the desired product quality and process
consistency is stated as a critical process parameter.
A parameter is important when any alteration in it may cause the product to fail
to meet the QTPP. Therefore, whether or not a parameter is critical depends on
the changes made in them or how many changes one is willing to consider.
During the parameter classification, the first step is to establish the range of
interest which is called as Potential Operating Space ( POS ) . It indicates the
region between the maximum and minimum value of interest for each process
parameter. Thus, the criteria for identification of critical and non -critical
parameters are the following two:
1 ) A parameter is considered critical when there is a trend to failure within the
POS, and
2) A parameter is critical when there is evidence of interactions within the
Proven Acceptable Range ( PAR , the range of experimental observations that
establish an acceptable quality ).
The CCPs which are considered during tablet manufacturing along with CQAs
are given in table 4.2:
Table 4.2: Different Critical Process Parameters with Critical Quality Attributes
During Tahleting
Operations during Tableting Critical Process Critical Quality' Attributes
Parameters
Wet Granulation 1 ) Mixing time 1 ) Blend uniformity
2) Impeller speed 2) Granule size and distribution
3 ) Binder fluid addition 3 ) Moisture content
rate and time
4) Method of binder addition
5 ) Temperature
Drying 1 ) Drying time 1 ) Bulk/tapped density
2 ) Inlet air flow 2) Moisture content
3 ) Exhaust air temperature 3) Granules strength and
and flow uniformity
Milling 1 ) Milling speed 1 ) Flow properties
2) Screen size 2) Particle size distribution
3 ) Feeding rate 3 ) Bulk/tapped density
Quality Assurance
64
Mixing 1) Mixer type

2) Mixing time Blend uniformity
3) Order of addition
Compression 1) Pre-compression force I ) Weight variation
2) Main compression force 2) Hardness
3) Dwell time 3) Friability
4) Hopper design 4) Content uniformity
5) Punch penetration depth 5) Assay
6) Roller type 6) Dissolution
7) Auger screw rate 7) Disintegration
8) Ejection force
Coating 1) Inlet air flow 1 ) Thickness
2) Time 2) Hardness
3) Temperature 3) % of Weight gain
4 ) Spray pattern and rate 4 ) Appearance
Surveillance Visit After certification, routine surveillance is carried out on a
6-12 month basis. The final visit in the certification cycle
is termed a renewal visit.
Renewal Assessment A recommendation is made from this review on certificate
renewal, along with any adjustment required to the on -
going surveillance plan. The renewal package is then
reviewed independently and if found satisfactory the
certification is renewed for another 3 year.
4. I .2.5. Design Space

According to the ICH Q8( R 2 ) guideline, design space is defined as the
multidimensional combination and interaction of input variables (e.g.,
material attributes ) and process parameters established to provide quality
assurance . Working within the design space is not included in a change, while
movement out of the design space is regarded as a change and would generally
start a regulatory post -approval change process. An applicant proposes the design
space and it is subjected to regulatory assessment and approval.
Design space may be established for a single unit operation, multiple unit operations,
or the entire process. But as per the FDA guideline, defining design space is not an
essential condition because the product and process understanding can be established
without a formal design space; however, such an approach regarding the design
space can be helpful for better understanding and overall control of a system.
Design space is criticality related to the results of risk assessment , which
determine the associated CQAs and CPPs. It includes the multivariate functional
relationships between CQAs and CPPs that impact them, and should include their
relation to or across unit operations. These relationships can be identified by
application of risk assessment, experimental design , modelling, and by using
literature and prior experience.
Design space can be determined by the following methods:
1 ) One-variable-at -a -time experiments,
2 ) Statistically designed experiments, and
3) Modelling approaches.
The design space can be represented by graphs ( surface-response curves and

contour plots), linear combination of parameter ranges, equations, and models,
while the design space can be mathematically represented through equations
describing relationships between parameters for successful operation .
4. I .2.6.Control Strategy
According to the ICH Q10 guideline, a control strategy is defined as a planned
set of controls derived from current product and process understanding that
assures process performance and product quality . The controls include
parameters and attributes related to drug substances, drug product materials and
components, facility and equipment operating conditions, in -process controls,
finished product specifications , and the associated methods and frequency of
monitoring and control.
Input material controls, process controls and monitoring, design space around
individual or multiple unit operations, and/or final product specifications used to
ensure consistent quality are the factors included under control strategy. The
quality of finished drug products is tested by evaluating whether or not they meet
the specifications. Generally, it is expected that extensive in - process tests ( blend
uniformity or tablet hardness ) should be performed by the manufacturers.
In figure 4.4. a QbD-based control strategy for blending process is given. To
ensure the quality of a finished pharmaceutical product , it is essential to
understand and control formulation and manufacturing variables. The overall
quality of the product can be confirmed by testing the end product.
Start |
Prior Potential quality

knowledge attributes
|
Quality attribute No a CQA ( from Unsure Experimental work to

not a CQA patient perspective increase knowledge
Yes
Apply suitable tool to
rank CQAs
List of CQA
Figure 4.4: Example of Control Strategy for QbD Process
4.1.3. Tools
The tools for QbD include the following:
1 ) Prior Knowledge: The term prior knowledge has been widely used in
workshops, seminars, and presentations. In regulatory submissions, the
applicants attempt to use prior knowledge as an authentic reason for
substitution of scientific justifications or conducting necessary scientific
studies . Knowledge is defined as an awareness of someone or something
that can include information , facts, descriptions, and/or skills attained
through experience or education . The word prior in the term prior
knowledge indicates previous and also associates with ownership,

confidentiality , and not available to the public. Knowledge gained through
education or public literature is termed public knowledge. Prior knowledge
is the exclusive information, understanding, or skill that applicants acquire
through previous studies.
2) Design of Experiments ( DOE ): It is a structured and organised method of
determining relationship between the factors influencing process
outputs. DOE can offer returns that are four to eight times greater than the
cost of running the experiments in a fraction of time. Use of DOE in QbD
helps in achieving maximum information from a minimum number of
experiments. When DOE is applied to a pharmaceutical process, factors like
.
raw material attributes ( e.g., particle size), process parameters ( e g., speed
and time), and outputs are the CQAs such as blend uniformity, tablet
hardness, thickness, and friability. Each unit operation has many input and
output variables and process parameters, thus experimental investigation of
all of them is not possible. The results of DOE help in identifying optimal
conditions, critical factors influencing and not influencing CQAs, and the
existence of interactions and synergies between factors.
3) Process Analytical Technology ( PAT): It is defined as a system for
designing, analysing, and controlling manufacturing through
measurements, during processing of CQAs of raw and in process -
materials and processes, to ensure the final product quality . The PAT
aims to enhance understanding and control the manufacturing process, which
is consistent with our current drug quality system. Design space is the key
and critical process parameter ( primary focus of on-, in- or at-line PAT
applications ) identified from process characterisation studies and their
acceptable ranges. Principally , real -time PAT assessments provide the basis
for continuous feedback and improve process robustness. NIR is a tool for
PAT and is useful in Real Time Release Testing ( RTRT ) as it monitors the
particle size, blend uniformity, granulation , content uniformity,
polymorphism, dissolution and monitoring the process online, at the line and
offline, thus reducing the release testing of the product.
4) Risk Management Methodology: Quality risk management is defined as a
systematic process for the assessment, control, communication and
review of risks to the quality of the drug product across the product
lifecycle. Risk assessment tools are used based on prior knowledge and
.
primary experimental data for identifying parameters ( e g., process,
equipment , and input materials ) that can affect the product quality. The initial
list of potential parameters can be long, but can be modified and prioritised
through a combination of DOEs and mechanistic models. After identifying
the significant parameters, they are further studied through a combination of
DOEs, mathematical models, or studies that lead to mechanistic
understanding. This is done to achieve a higher level of process
understanding.
The pharmaceutical industry and regulators, with the help of the following
risk management tools and/or internal procedures , such as basic risk
management facilitation methods ( flowcharts, check sheets, etc.), evaluate

and manage risks:
i ) Failure Mode Effects Analysis ( FMEA ),
ii ) Failure Mode, Effects and Criticality Analysis ( FMECA ),
iii) Fault Tree Analysis ( FTA ),
iv) Hazard Analysis and Critical Control Points ( HACCP ),
v) Preliminary Hazard Analysis ( PHA ), and
vi ) Risk ranking and filtering.
4.2. SUMMARY
1 ) A systematic approach for development of pharmaceutical products that
begins with predefined objectives and emphasises product and process
understanding and process control, based on sound science and quality risk
management is defined as Quality by Design ( QbD ).
. .
2 ) The concept of QbD was developed by Dr Joseph M Juran, who believed
that quality should be designed into a product, and most quality problems are
related to the way in which a product was designed.
3) According to ICH Q8( R 2 ) guideline , QTPP is described as a prospective
summary of the quality characteristics of a drug product that ideally will be
achieved to ensure the desired quality, taking into account safety and efficacy
of the drug product .
4 ) A CQA is defined as a physical, chemical, biological or microbiological
property or characteristic that should be within an appropriate limit, range, or
distribution to ensure the desired product quality.
5) Failure Mode Effects Analysis ( FMEA ) is one of the most common tools
of risk-assessment used in pharmaceutical industries and is used to identify
and mitigate the possible failure in the process.
6) Failure Mode, Effects and Criticality Analysis ( FMECA ) is the extended
form of FMEA tool that can be used for investigating the degree of severity
of consequences, their chances of occurrence, and their detectability.
7) Fault Tree Analysis ( FTA ) is used to deal with failure of the functionality
of a product or process.
8) Hazard Analysis and Critical Control Points ( HACCP) is used for
providing elaborated documentation for any process or product
understanding through identifying parameters to control and monitor.
9) As part of FMEA, a risk score or Risk Priority Number ( RPN ) may be
allotted to the deviation or to the affected stage of the process; this helps in
categorising the deviation.
10) For the calculation of RPN, Probability ( P), Detectability ( D), and
Severity (S), which are individually categorised and scored, are multiplied.
11 ) During the parameter classification , the first step is to establish the range of
interest which is called as Potential Operating Space ( POS). It indicates the
region between the maximum and minimum value of interest for each
process parameter.
12) According to the ICH Q8( R2 ). design space is defined as the multidimensional
..
combination and interaction of input variables (e g , material attributes ) and
process parameters established to provide quality assurance.
13) According to the ICH Q 10, a control strategy is defined as a planned set of
controls derived from current product and process understanding that assures
process performance and product quality.
14 ) The term prior knowledge has been widely used in workshops, seminars,
and presentations.
15 ) Knowledge is defined as an awareness of someone or something that can
include information , facts, descriptions, and/or skills attained through
experience or education.
16) The word prior in the term prior knowledge indicates previous and also
associates with ownership, confidentiality, and not available to the public.
17 ) Knowledge gained through education or public literature is termed public
knowledge.
18 ) Design of Experiments ( DOE) is a structured and organised method of
determining relationship between the factors influencing process outputs.
19 ) Process Analytical Technology ( PAT) is defined as a system for designing,
analysing, and controlling manufacturing through measurements, during
processing of CQAs of raw and in-process materials and processes, to ensure
the final product quality.
20 ) Quality risk management is defined as a systematic process for the
assessment , control , communication and review of risks to the quality of the
drug product across the product lifecycle.
4.3 . EXERCISE
1) What is QbD?
2) Give the overview of QbD .
3) Enlist the elements of QbD .
4) Define QTPP .
5) What are CQAs?
6) What is fault tree analysis?
7) Give the definition of design space .

1) Write a note on critical quality attributes .
2) Write about the tools of QRM .
3) Discuss how critical process parameters are determined .
4) Write a note on control strategy .
5) Give a short review on the tools of QbD .
4.3.3. Long Answer Type Question

1 ) Write an exhaustive note on the elements of QbD program.
ISO 9000 & ISO 14000 (Chapter 5 ) 69
CHAPTER
5 ISO 9000 & ISO 14000
5.1. ISO 9000

5.1.1. Introduction and Overview
ISO refers to International Organisation for Standardisation . ISO 9000 is a
set of international standards on quality management and quality assurance . It has
been developed to help the companies in effectively documenting the quality
system elements to be implemented so that an efficient quality system can be
maintained . They are not specific to any one industry and can be applied to any
big or small organisations .
ISO 9000 helps a company to satisfy its customers, meet regulatory
requirements , and achieve constant improvement . However, it is only considered
as the first step or the base level of a quality system, and not a complete
guarantee of quality .
ISO 9000 is widely recognised in the world . It aims to implant a quality

management system in an organisation for increasing productivity , reducing
unnecessary costs, and ensuring quality of processes and products. Table 5.1
describes the standards and guidelines of ISO 9000, along with their purposes:
Table 5.1: Brief Description on the Standards and Guidelines of ISO 9000 Series
Standards and Guidelines Purposes
ISO 8402: Quality management and Defines the fundamental terms used in the
quality assurance - Vocabulary. ISO 9000 family, which should be known
to avoid internal and external
misunderstandings.
-
ISO 9000 1: Quality management and Establishes a starting point for
quality assurance standards Part 1 : understanding and selecting the standards
-
Guidelines for selection and use. appropriate to needs.
-
ISO 9000 2: Quality management and Assists in interpretation and application of
quality assurance standards - Part 2: ISO 9001 , ISO 9002, and ISO 9003.
Generic guidelines for the application
of ISO 9001 , ISO 9002, and ISO 9003.
-
ISO 9000 3: Quality management and Provides specific interpretation of the
quality assurance standards - Part 3: requirements of ISO 9001 for computer
Guidelines for the application of ISO software development applications.
9001:1994 in the development, supply,
installation and maintenance of
computer software.
-
ISO 9000 4: Quality management and Provides guidance on how to plan, organise
quality assurance standards - Part 4: and control resources to produce reliable
Guide to dependability programme and maintainable products.
management .
ISO 9001: Quality systems - Model Requirement standard used to demonstrate

for quality assurance in design, capability for design/development of the
development, production, installation , product or service, and also for production,
and servicing . installation , and servicing .
for quality assurance in production, capability for production, installation , and
installation, and servicing. servicing ( identical to ISO 9001 except for
design control requirement ).
for quality assurance in final capability to control the product or service
inspection and test. by final inspection and test.
ISO 9004-1: Quality management and Requirement standard that provides
quality system elements - Part 1 : guidelines to implement a quality system to
Guidelines. satisfy the customers and fulfil the
organisation 's needs
-
ISO 9004 2: Quality management and This standard is made up in a similar way
quality system elements - Part 2: as ISO 9004- 1 , but the guidelines are
Guidelines for services. designed with special regard to the
conditions pertinent to the service sector .
ISO 9004-3: Quality management and This standard provides quality management
quality system elements - Part 3: guidelines applicable to a producer of
Guidelines for processed materials . processed materials, which are provided in
bulk.
-
ISO 9004 4: Quality management and Provides guidelines for implementing
quality system elements - Part 4: continuous quality improvement within an
Guidelines for quality improvement . organisation using tools and techniques
based on data collection and analysis.
ISO 10005: Quality management - Provides guidance on how to prepare
Guidelines for quality plans. quality plans for the control of specific
products, projects, or contracts.
ISO 10006: Guidelines for quality in Provides guidelines to ensure the quality of
project management. the project processes and the project product.
ISO 10007: Quality management - Provides guidelines to ensure that a
Guidelines for configuration complex product continues to function
management. when components are changed
individually.
ISO 10011-1: Guidelines for auditing Provides guidelines for auditing a quality
quality systems - Part 1 : Auditing. system, and for verifying the system’s
ability to achieve the defined quality
objectives.
-
ISO 10011 2: Guidelines for auditing Provides guidance on education, training,
quality systems - Part 2: Qualification experience, personal attributes and
criteria for quality systems auditors. management capabilities required to carry
out an audit.
-
ISO 10011 3: Guidelines for auditing Provides basic guidelines for managing
quality systems - Part 3: Management quality system audit programmes.
of audit programmes.
ISO 10012-1: Quality assurance Provides guidelines on the main features of
requirements for measuring equipment a calibration system to ensure that
- Part 1: Metrological confirmation measurements are made with intended
system for measuring equipment . accuracy.
ISO 9000 & ISO 14000 ( Chapter 5 ) 71
-
ISO 10012 2: Quality assurance for Provides supplementary guidance on the
measuring equipment Part 2: application of statistical process control
Guidelines for control of measurement when this is appropriate for achieving the
processes . objectives of Part 1 .
ISO 10013: Guidelines for developing Provides guidelines for the development ,
quality manuals. preparation and control of quality manuals
tailored to specific needs.
Table 5.2 describes other ISO 9000 publications along with their purposes:
Table 5.2 Description of other ISO 9000 Publications and their Purposes
Publications Purposes
ISO 9000 for Small Provides guidelines and practical examples of how to
Businesses implement a simple and effective quality system in a
small business environment ( also includes full text of
ISO 9001 translated into other languages by ISO
members ).
ISO 9000 News This journal has been published 6 times a year in
separate English and French editions, and includes
updates on ISO 9000 family of quality management and
quality assurance standards, news on their
implementation around the world, and related
developments such as ISO 9000 certification.
Publicising ISO 9000 or This brochure provides guidelines to help certificate
ISO 14000 certification holders avoid the pitfalls of false, misleading or
confusing claims related to ISO 9000 and ISO 14000
certification in advertisements and all forms of
promotional material.
Table of Worldwide This table shows the state of worldwide adoption of
Equivalence of ISO 9000 ISO 9000 in ISO member countries.
Series of Standards
5.1.2. Benefits
The software development organisations are in competition with each other to
obtain ISO certification due to the benefits it offers. Some of these benefits that
an organisation acquires by obtaining ISO certification are:
1 ) The organisation gains customer’s confidence when it gets ISO certified .
2) ISO 9000 requires a well -documented software production process that
contributes to repeatable and higher quality of the developed software .
3 ) ISO 9000 makes the development process focused, efficient, and cost effective.
4 ) ISO 9000 certification recognises the weaknesses of an organisation and
recommends corrective measures .
5 ISO 9000 sets the basic framework for developing an optimal process and
)
Total Quality Management ( TQM ) .
The importance of ISO 9000 is the importance of quality . Many companies offer
products and services, but those efficiently delivering the best products and
services are successful . With ISO 9000, an organisation can recognise the cause
of problem, and find a remedial solution. An organisation can maximise its
profit , by improving its efficiency .
Since a wide range of companies implement the ISO 9000 standards, a supply
chain with integrity is created. Each company participating in the process of
developing, manufacturing, and marketing a product knows that it is part of an
internationally known, reliable system. Different businesses and even the
customers recognise the importance of ISO 9000 and quality. And since
consumer is most important to a company, ISO 9000 focuses on the customer.
5.1 .3. Elements

Given below are the major elements of ISO 9000:
1 ) Management Responsibility: It is the responsibility of the management to
set the company ’s quality policy and implement it by providing resources,
personnel, and training.
2 ) Quality System: This system comprises of a quality manual in which
supporting procedures are created and maintained.
3) Contract Review: Contracts represent the needs and expectations of
customers, which should be met by the products and services provided.
4 ) Design Control : Engineering drawings and design changes are documented
to ensure that the customers have fully coordinated and approved the changes.
5 ) Document Control: The documents supporting the quality system should
be created and modified under the strict control of ISO 9001 procedures.
6) Purchasing: The procedures for purchasing describe supplier requirements
and the system to ensure these standards are being met.
7 ) Handling of Purchaser Supplied Product : Procedures for the methods of
handling and safekeeping of products supplied by the customer should be
created.
8) Product Identification and Traceability: Methods need to be established
for tracking date and lot codes of product and raw materials from start to
finish guarantee traceability.
9) Process Control: Work instructions, quality plans, and workmanship
standards verify the accuracy of each job.
10 ) Inspection and Testing: Inspection and testing should be conducted at
receiving, in-process and final inspection areas to ensure quality. Test and
inspection records are maintained as part of the quality system.
11 ) Inspection, Measuring, and Test Equipment : Instruments and measuring
tools are regularly calibrated and related records are maintained .
12 ) Inspection and Test Status: Only inspected materials can be used for
further processing. Inspected products are always identified .
13 ) Control of Non-Conforming Product: Materials or products that do not
comply with the specifications are rejected and separated from normal
production. The concerned authorities can decide whether the rejected
materials will be used , reworked , or returned to the supplier.
14 ) Corrective Action: This system identifies the cause of quality concerns and
takes the desired corrective actions.
ISO 9000 & ISO 14000 ( Chapter 5 ) 73
15 ) Handling, Storage, Packaging, and Delivery: Procedures indicating the

practices to protect products from damage during manufacturing and
shipping are established .
16 ) Quality Records: These records provide an audit trail for internal and
external auditors.
17 ) Internal Quality Audits: Specially trained teams verify that the quality
system is evaluating the same 20 elements required by the external auditors,
on an on -going basis.
18) Training: Training records are maintained for each employee showing their
levels of proficiency.
19 ) Servicing: If servicing is mentioned in the contract, procedures are
established for verifying that servicing meets the indicated requirements.
20 ) Statistical Techniques: Control charts, graphs, and other analysis methods
determine the working of a process and facilitate its continuous improvement.
5.1.4. Steps for Registration

For being ISO 9001 certified , an organisation or a company should demonstrate
the following:
1 ) It should follow the guidelines within the ISO 9001 standards,
2) It should meet its own requirements,
3) It should fulfill its customers’ requirements, and statutory and regulatory
requirements, and
4 ) It should maintain necessary documentation of its performance.
An organisation s credibility improves on receiving an ISO 9001 certification as

'
it indicates that the products and services of that organisation meet the quality
expectations of customers. In some cases, an ISO 9001 certification is required or
is legally directed for businesses in some industries.
The following steps are included in the process of an organisation ’s ISO 9001
audit :
1 ) For receiving ISO 9001 certification, an organisation needs to implement
ISO 9001:2015 requirements.
2) After implementation , the organisation should complete registrar’s audit to
confirm that the organisation system meets all the specified requirements.
3) The auditor then interviews the management and staff of the organisation to
ensure whether they are aware of their roles and responsibilities in complying
with the ISO 9001 standards.
4 ) The auditor also examines the organisation ’s documentation to validate
compliance with the ISO 9001 requirements.
5 ) Thereafter, the auditor prepares a detailed report mentioning the standards
not fulfilled by the organisation.
6) The organisation settles to correct the problems within the specified time
limit.
7) It takes corrective actions to make sure all the problems are fixed.
8) The auditor rechecks and gives confirmation if the mentioned standards have
been met.
9 ) Then the organisation gets certified.
10) For maintaining the ISO 9001 certification , the organisation should conduct
regular inspection and recertification audits.
After successfully completing an organisation’s ISO 9001 audit, the ISO

registration process is continued , which involves the following essential steps:
1 ) Selecting the Type of ISO Certification: The type of ISO certification
required for a particular business is selected. The available types of ISO
certification are:
i ) ISO 9001:2008 - Quality management
ii) ISO 14001 Environmental management
iii ) ISO 27001 Information security management
iv) ISO 22008 Food safety management , and so on.
2) Selecting an ISO Certification Body ( CB ): It is not the ISO that provides
certification to the organisations, rather it is done by external bodies.
Therefore, a recognised and credible certification body should be selected.
One should consider the following points when choosing the ISO registrar:
i ) One should evaluate some ISO certification service providers.
ii ) One should check if the service providers follow the standards put forth
by CASCO ( ISO committee working on issues related to conformity
evaluation ).
iii ) One should check if the service providers are accredited or not
(accreditation is not obligatory but the requirements of ISO accreditation
bodies should be met ).
3) Creating an Application/Contract: The applicant and the registrar should
agree on a contract that defines the rights and obligations of both the parties
and includes liability issues, confidentiality, and access rights.
4 ) Quality Documents Review: The ISO auditor reviews all the quality
manuals and documents of various policies and procedures followed in the
organisation. This helps the ISO auditor to identify the parts which fail to
meet the requirements specified in the ISO standards.
5) Making an Action Plan: Then the ISO auditor conveys the existing
problems to the organisation. After which the applicant should prepare an
action plan to remove these problems. The applicant should prepare a list of
the tasks to be performed to make required changes in the organisation. The
applicant can give training to the employees to work efficiently and can also
adapt new procedures. All the employees should know the ISO standards in
terms of work efficiency and quality standards.
6) Initial Certification Audit: This step is divided into two stages:
i ) Stage 1: The changes made by the applicant in the organisation are
audited by the ISO auditor , who again identifies the possible parts in the
systems and procedures that do not conform to the desired quality
management system. The auditor divides these non -conformities into
ISO 9000 & ISO 14000 ( Chapter 5 ) 75
minor and major. The applicant should carefully examine these non -
conformities and arrange them as per the desired quality standards by
modifying the techniques and processes used by the organisation.
ii ) Stage 2: After making the required changes in the organisation , the ISO
auditor does the final auditing, and checks that all the non -conformities
have been removed. On confirming that the system meets all the required
ISO standards, the auditor prepares the final ISO audit report and
forwards it to the registrar.
7 ) Completing the ISO Certification: After all the non -conformities are
addressed and all the findings are put in the ISO audit report , the registrar
grants ISO certification to the applicant.
8) Surveillance Audits: Surveillance audit should be conducted at regular
intervals to ensure that an organisation maintains the ISO quality standards.
5.2. ISO 14000

5.2.1. Introduction and Overview
ISO 14000 is a series of international environmental management standards,
guides, and technical reports. These standards specify the requirements for
establishing an environmental management policy, determining environmental
impacts of products or services, planning environmental objectives,
implementing programs to meet objectives, and conducting corrective action and
management review. ISO 14001:2015 and its supporting standards, such as ISO
14006:2011, focus on environmental systems to achieve this. The other standards
of ISO 14000 focus on audits, communications, labelling, life cycle analysis, and
environmental challenges such as climate change.
The ISO 14000 family of standards is developed by ISO Technical Committee
( ISO/TC ) 207 and its various sub-committees. Some of the most notable
standards in the ISO 14000 series are:
1 ) ISO 14004 - General guidelines on principles, systems, and support
techniques,
2 ) ISO 14006 - Guidelines for incorporating ecodesign ,
3) ISO 14015 - Environmental Assessment of Sites and Organisations (EASO),
4 ) ISO 14020 - Environmental labels and declarations,
5) ISO 14031 - Environmental performance evaluation ,
6) ISO 14040 - Life cycle assessment ,
7) ISO 14050 - Vocabulary,
8) ISO 14063 - Environmental communication,
9 ) ISO 14064 - Greenhouse gases, and
10) ISO 19011 - Guidelines for auditing management systems.
History
Since 1947, the ISO has been developing voluntary technical standards for all
sectors of business, industry , and technology. The majority of ISO standards are
highly specific to a particular product , material , or process.
ISO 14000 is different from most of the other ISO standards. It is a generic
management system standard. Generic indicates that the same standard can be
applied to any large or small organisation, whatever product or service it
provides, in any sector of activity, and whether it is a business enterprise, public
administration , or government department. Management system indicates the
actions taken by an organisation to manage its processes or activities. ISO 14000
is concerned with the way an organisation goes about its work, and not directly
with the results of this work. The focus is on processes and not on products.
ISO 14000 grew out of ISO's commitment to support sustainable development as
discussed at the United Nations Conference on Environment and Development in
Rio de Janeiro in 1992. Conversations among 20 countries, 11 international
organisations, and more than 100 environmental experts began in 1991 to define
the basic requirements of a new approach to environment -related standards. The
first standards, i.e., ISO 14004 and ISO 14001, were published in 1996 in the
months of September and October, respectively. The ISO 14000 family of
standards and guidelines are related to environmental management systems and
support standards on terminology and specific tools, such as auditing. The
standards are concerned with the ways in which an organisation reduces the
harmful effects on environment caused by its activities, either during production
or disposal , either by pollution or by depleting natural resources.
5.2.2. Benefits
ISO 14000 certification is achieved either when a qualified auditor verifies that
all the requirements have been fulfilled or when a company self -declares so.
Obtaining ISO 14000 certification is considered as a sign of commitment to the
environment, which can be used as a marketing tool for companies. This
certification also helps the companies to meet some environmental regulations.
Other benefits of certification are that the company is permitted to sell products
to other companies using ISO 14000 certified suppliers. Companies and
customers also pay more for environmental -friendly products. If the ISO 14000
standards are met, the product cost is reduced, as it encourages the efficient use
of resources and waste limitation . This leads to ways of recycling products or
new uses for previously disposed by-products.
There are various benefits of obtaining ISO certification. If a company adheres to
the ISO 14000 standards it results in better conformance to environmental
regulations, greater marketability, better use of resources, higher quality goods
and services, increased levels of safety, improved image, and increased profits.
Environmental awareness and documents required by the ISO 14000 standards
help a company to abide by the environmental regulations. Thus, by adhering to
the standards a company will not violate the environmental regulations and will
always be ready for inspection by a regulatory agency. Certification and
documentation also assist a company in gaining funds, in guarding itself during
environmental litigation , and in receiving insurance or permits. Certification
results in a wider market for the goods and services of a company. Many
corporations and governments look for ISO 14000 certified suppliers to maintain
their own certification and reputation of environment -friendly in market. If ISO
ISO 9000 & ISO 14000 ( Chapter 5 ) 77
14000 becomes successful, the already ISO 14000 certified companies will have
an advantage in global markets. The producers of consumer goods will realise
that many consumers purchase goods from environment -friendly companies, and
also spend more if they feel they are helping the environment . For acquiring this
benefit, a company makes their environmental efforts acknowledged through
advertisements and labelling.
The process analyses that following ISO 14000 certification results in
rationalisation processes and efficient use of resources and raw materials, thereby
reducing a company’s costs. Finding ways to capture emissions or recycle the
products may reduce the amount of raw materials and utilities used. If the amount
of potentially dangerous substances in an end product is reduced, dangerous
chemicals will be less used in a plant, thus leading to a safer internal environment
for employees and reducing insurance premiums. The employee morale improves
when they feel their workplace is safe and their work contributes to the
environmental effort.
5.2.3. Elements
Given below are the major elements of ISO 14000:
1 ) Environmental Policy: This is a written statement describing the objectives and
targets of a business with respect to environmental policy. Principles on
environmental sustainability and performance indicators related to the EMS
( Environmental Management System ) are included in this policy. Environmental
policy should be internally and externally communicated and fully implemented.
2) Planning: Organisations can evaluate the environmental impact of all
operations with clear and thorough planning. This helps in developing a
process to identify compliance requirements, document targets and
objectives, and create a deployment plan.
3) Implementation: This step involves implementation of the developed plans,
incorporation of adjustments, and developing new processes to acclimate the
changing requirements. The organisations need to clearly define, document,
and communicate their implementation procedures for training and
compliance as well-documented processes aid in improving those processes.
This step also includes emergency response planning and awareness.
4 ) Study and Correct: After implementing the basic EMS, its functions are
monitored and necessary corrections or optimisations are made . This step
involves the management of new and existing procedures to make sure KPIs
( Key Performance Indicators ) are hit and EMS is functioning properly .
Organisations will be benefited if they establish a system for documentation
and for conducting audits of the EMS.
5) Management Review: A distinguished review of the EMS is conducted by
the management to ensure that everything is functioning within the scope of
successful performance. Management will be best positioned to evaluate this
kind of effectiveness.
6 ) Continuous Improvement: Every EMS utilises the principles of continuous
improvement to allow the organisations to optimise all aspects of the system.
5.2.4. Steps for Registration

The following documents should be maintained for acquiring ISO 14000
certification:
1) Environmental management system scope,
2) Environmental policy,
3) Environmental objectives and environmental management program,
4 ) Environmental procedures,
5 ) Legal compliance document,
6 ) Environmental aspect and environmental impact document ,
7 ) Emergency preparedness plan , and
8) Instrument calibration.
There are other documents also which should be maintained as per the
requirement of ISO 14001 environmental management system standard. The
steps involved in ISO 14001 certification are as follows:
1 ) Selecting Certification Body: Some CBs first visit the clients to explain the
certification process and to understand the activities of potential clients’ to
provide them with an accurate quotation for the certification.
2 ) Complete Questionnaire and Establish Contract: When applying for ISO
14001 certification , a questionnaire should be completed so that the CB can
evaluate the nature, scale and complexity of the organisation. This
determines the skill and time required for a comprehensive and efficient
evaluation . The quotation helps in confirming the cost of certification , on -
going surveillance, and re-assessment. After the acceptance of the quotation,
the CB will arrange a certification schedule for the organisation.
3) Document Review: The CB asks the applicant to present organisation’s
EMS document for auditor review. Document review ensures that the
documented EMS reflects all the essential requirements and delivers full
compliance with ISO 14001.
4) First Stage Assessment ( FSA ): This involves a site tour and system overview
to establish that the organisation’s EMS is related to the environmental
aspects. A detailed plan is provided prior to the visit and a full report
produced on -site, along with a plan for the certification assessment. Any non-
conformity identified will need to be corrected by a remedial action plan .
5) Certification Assessment: This step is conducted approximately one month
after the FSA. Certification assessment involves reviewing the efficiency of
the implemented EMS against ISO 14001 standards and the organisation’s
own requirements. A complete report, prepared after the audit , is reviewed
with the applicant at a closing meeting, and if no major non -conformity is
identified, a recommendation for registration is made. If necessary, the
applicant is asked to provide a corrective and preventive action plan or
follow-up visit before making the recommendation for registration.
6) Award Certification: If satisfactory , an independent review is conducted on
the report, after which the CB awards certification. These certificates are
valid for three years, subject to satisfactory surveillance visits.
ISO 9000 & ISO 14000 ( Chapter 5 ) 79
7) Surveillance Visit: After granting certification, routine surveillance is

conducted in every 6 months for a year. The final visit in the certification
cycle is termed a renewal visit .
8) Renewal Assessment: From this review on certificate renewal , a
recommendation is made, along with any adjustment required to be made in
the on-going surveillance plan. Then the renewal package is independently
reviewed, and if found satisfactory, the certification is renewed for the next 3
years.
Enquiry
Complete Questionnaire
Proposal
Confirm Application and Schedule
A
First Stage Assessment
Document Review
Certification Assessment
Yes
Corrective Actions Major Non-conformance
Follow Up
A No
Effective? I Recommendation for Registration

Yes
A
Certificate Awarded
Surveillance Assessment
( Every 6 months or annually )
A
Renewal Assessment
(Every 3 years )
Figure 5.1: ISO 14001 Certification Process
SUMMARY
1 ) ISO refers to International Organisation for Standardisation .
2) ISO 9000 is a set of international standards on quality management and
quality assurance.
3) It is the responsibility of the management to set the company’s quality policy
and implement it by providing resources, personnel, and training.
4) Quality system comprises of a quality manual in which supporting
procedures are created and maintained .
5) Contracts represent the needs and expectations of customers, which should

be met by the products and services provided.
6) Engineering drawings and design changes are documented to ensure that the
customers have fully coordinated and approved the changes.
7 ) The documents supporting the quality system should be created and modified
under the strict control of ISO 9001 procedures.
8) The procedures for purchasing describe supplier requirements and the system
to ensure these standards are being met.
9) Procedures for the methods of handling and safekeeping of products supplied
by the customer should be created.
10 ) Methods need to be established for tracking date and lot codes of product and
raw materials from start to finish guarantee traceability.
11 ) Work instructions, quality plans, and workmanship standards verify the
accuracy of each job.
12 ) Inspection and testing should be conducted at receiving, in -process and final
inspection areas to ensure quality.
13) Instruments and measuring tools are regularly calibrated and related records
are maintained.
14) Materials or products that do not comply with the specifications are rejected
and separated from normal production.
15) Procedures indicating the practices to protect products from damage during
manufacturing and shipping are established.
16 ) Quality records provide an audit trail for internal and external auditors.
17) Control charts, graphs, and other analysis methods determine the working of
a process and facilitate its continuous improvement.
18) If servicing is mentioned in the contract , procedures are established for
verifying that servicing meets the indicated requirements.
19) Training records are maintained for each employee showing their levels of
proficiency.
20 ) Surveillance audit should be conducted at regular intervals to ensure that an
organisation maintains the ISO quality standards.
21 ) ISO 14000 is a series of international environmental management standards,
guides, and technical reports.
22 ) Environmental policy is a written statement describing the objectives and
targets of a business with respect to environmental policy.
23) Organisations can evaluate the environmental impact of all operations with
clear and thorough planning.
24 ) First Stage Assessment ( FSA ) involves a site tour and system overview to
establish that the organisation’s EMS is related to the environmental aspects.
25 ) Certification assessment is conducted approximately one month after the
FSA.
ISO 9000 & ISO 14000 ( Chapter 5) 81
5.4 . EXERCISE
1) What is ISO 9000?
2) Give the benefits of obtaining ISO 9000 certification.
3) How the type of ISO certification is selected under ISO 9000 process?
4) Define ISO 14000.
5) Enlist four standards of ISO 14000 series.
6 ) What documents are required for obtaining ISO 14000 certification?
7 ) What is first stage assessment ?

1) Write the standards and guidelines of ISO 9000 series.
2) Write about the elements of ISO 9000.
3) Discuss the steps involved in ISO certification 9000 process.
4) Write a note on the benefits of ISO 14000 certification .
5) Give a short review on the elements of ISO 14000.
6) Discuss the steps for registration for ISO 14000 certification .

1) Write an exhaustive note on the registration steps of ISO 9000.
2) Give a brief review on ISO 14000.
CHAPTER NABL Accreditation

6
6.1. NABL (NATIONAL ACCREDITATION

BOARD FOR TESTING AND CALIBRATION
LABORATORIES)
6.1.1. Introduction
Accreditation is the formal recognition , authorisation and registration of a
laboratory that has demonstrated its capability , competence and credibility to
perform the tasks it claims to be able to do. It provides feedback to
laboratories regarding whether or not they are carrying out their tasks as per
the international criteria for technical competence. Laboratory accreditation
concept was developed to provide third - party certification to a laboratory that
is capable of performing the specific test or type of tests. Through laboratory
accreditation , customer confidence in the test reports issued by the laboratory
is build -up so that the clinicians and their patients accept the reports with
confidence.
NABL is an autonomous body under the Department of Science & Technology,
Government of India, and registered under the Societies Act. It was initially
established to provide accreditation to testing and calibration laboratories; but,
later its services were extended to the clinical laboratories in India.
NABL has been authorised by the Indian Government as the accreditation body
for testing and calibration laboratories. It aims to provide third-party assessment
of quality and technical competence. Years ago, NABL accredited laboratories
linked with international bodies, like Asia Pacific Laboratory Accreditation
Cooperation and International Laboratory Accreditation Cooperation , and thus
got international recognition. The international standard currently followed by
NABL is ISO 15189, which is specific for medical laboratories.
6.1.2. Benefits and Scope of NABL Accreditation

NABL accreditation of drug testing laboratories has the following advantages:
1 ) Due to accreditation status, customer confidence in testing and calibration
reports issued by the laboratory has increased .
2) Due to enhanced customer confidence and satisfaction , the business of
laboratory has also increased.
3) Accreditation provides better control over the laboratory operations.
4 ) Laboratories get feedback about their technical capability and quality
assurance system.
NABL Accreditation ( Chapter 6 ) 83
5 ) Database or directory of NABL accredited laboratories is made available

both online and offline. Customers can easily access NABL accredited
laboratories for their specific requirements.
6) NABL accreditation results in time and money saving as the need for re-
testing of the products is reduced or eliminated.
Scope of NABL Accreditation

NABL provides accreditation in the following fields and disciplines:
1 ) Testing laboratories, 2) Medical laboratories,
3) Calibration laboratories, 4) Proficiency testing providers, and
5 ) Reference material producers.
The following fields/disciplines related to biopharmaceuticals are covered under

the scope of NABL accreditation:
1) Drugs and pharmaceuticals,
2 ) Cosmetics and essential oils,
3) Ayush products,
4) Plants and plant materials,
5) Cell culture,
6) Molecular analysis,
7 ) Resistance to microbial attack,
8) Toxicology,
9) Veterinary testing,
10 ) Biologicals derived pharmaceuticals,
11 ) Nutraceuticals,
12 ) Medical accessories and surgical products ,
13) Medical laboratories including microbiology and serology, clinical
biochemistry, histopathology, cytopathology, clinical pathology,
haematology and immunohaematology genetics, and nuclear medicine ( in
, -
vitro tests only ), and
14 ) Inorganic and organic reference materials.
6.1.3. Procedures
Various steps to be followed in NABL accreditation process are discussed below:
1 ) Application for NABL Accreditation: The laboratory that desires to get
NABL accreditation submits an application in the prescribed form ( NABL
Form 151 for testing laboratories; NABL Form 152 for calibration
laboratories; NABL Form 153 for medical laboratories; NABL Form 180 for
proficiency testing providers; and NABL Form 190 for reference material
producers ) along with its quality manual and prescribed fees.
2) Acknowledgement of Application: The NABL secretariat , on receiving the
application in the prescribed format, issues an acknowledgement and assigns
a unique ID number to it.
3) Review' by Lead Assessor: The NABL secretariat appoints a lead assessor to
evaluate the application and quality manual, and submit its report to NABL
secretariat . The lead assessor thoroughly reviews the quality manual submitted
by the laboratory and if finds any insufficiency, asks the laboratory to amend it.
4) -
Pre Assessment: The lead assessor visits the laboratory for a pre-assessment
of the degree of vigilance of the laboratory for evaluating any non -
conformity in the implementation of the quality system and for determining
the number of assessor( s) required , key location to be visited, etc.
5) Assessment: NABL makes an assessment team, including the lead assessor,
technical assessor(s )/expert(s ), and an observer, after consulting the laboratory
that has applied for NABL accreditation . NABL then consults the laboratory
and the assessment team to fix dates for on-site assessment. Thereafter, the
assessment team carries out on -site assessment of the laboratory and reviews
and verifies its documented management system, work instructions, SOPs, test
methods, technical competence to perform specific tasks, etc. After finishing
the assessment, the team submits its report to NABL.
6) Scrutiny of Assessment Report: The NABL secretariat examines the
assessment report. If any insufficiency is found in the report, the laboratory
takes corrective actions as suggested by the assessment team.
7) Accreditation Committee: This committee examines the assessment report
and also the report the laboratory has submitted regarding the corrective
actions taken by it . The committee after evaluating the reports makes
appropriate recommendations to the NABL Chairman regarding the
accreditation of laboratory.
8) Issue of Accreditation Certificate: If the recommendation of the
accreditation committee is positive, the laboratory is granted accreditation
and is also issued an accreditation certificate by NABL. This certificate bears
a unique accreditation number, NABL hologram , date of validity , discipline,
and scope of accreditation.
6.2. SUMMARY
1 ) Accreditation is the formal recognition , authorisation and registration of a
laboratory that has demonstrated its capability , competence and credibility to
perform the tasks it claims to be able to do.
2 ) NABL is an autonomous body under the Dept of Science & Technology,
,
Government of India, and registered under the Societies Act.

3) NABL has been authorised by the Indian Government as the accreditation
body for testing and calibration laboratories.
4 ) The laboratory that desires to get NABL accreditation submits an application
in the prescribed form along with its quality manual and prescribed fees.
5) The NABL secretariat, on receiving the application in the prescribed format,
issues an acknowledgement and assigns a unique ID number to it.
6) The NABL secretariat appoints a lead assessor to evaluate the application
and quality manual, and submit its report to NABL secretariat.
NABL Accreditation (Chapter 6 ) 85
7) The lead assessor visits the laboratory for a pre -assessment of the degree of
vigilance of the laboratory for evaluating any non -conformity in the
implementation of the quality system and for determining the number of
assessor(s) required, key location to be visited , etc.
8) NABL makes an assessment team, including the lead assessor, technical
assessor(s)/expert(s), and an observer, after consulting the laboratory that has
applied for NABL accreditation .
9 ) The NABL secretariat examines the assessment report.
10 ) Accreditation committee examines the assessment report and also the report
the laboratory has submitted regarding the corrective actions taken by it .
11 ) If the recommendation of the accreditation committee is positive, the
laboratory is granted accreditation and is also issued an accreditation
certificate by NABL.
6.3 . EXERCISE
1) What is NABL?
2) Give the benefits of NABL accreditation .
3) What is the role of lead assessor in NABL accreditation?
4) What the accreditation committee does?

1 ) Give the benefits and scope of NABL accreditation .
2) Write about the procedure of NABL accreditation .

1 ) Write an exhaustive note on NABL.
CHAPTER Organisation and

7 Personnel
7.1 . ORGANISATION AND PERSONNEL

7.1 . 1 . Introduction
Establishment and maintenance of a suitable quality assurance system for
pharmaceutical products depend on the people. Sufficient number of qualified
personnel should be present for conducting various tasks in the manufacturing unit.
Individual responsibilities should be clearly understood by the concerned person and
should be recorded. The personnel should be aware of the GMPs, which if not
followed will affect the manufactured product; therefore, the personnel should
continuously receive training, including hygiene instructions relevant to their needs.
7.1 .2. Responsibilities of QC Unit

Some regulations are assigned to the personnel in QC units for approval or
rejection of components, in-process materials, and products. There was a time
when achievement of quality standards was solely dependent on testing and
inspection by quality control, i.e., quality was inspected into components and
products. Quality control testing is done after manufacturing the product and also
relies on the evaluation of a relatively small sample; thus, this approach is
considered as ineffective as well as inefficient by some. It also tends to separate
accountability for production and quality.
Since 1978, there have been progressive regulations and standards such as the
Device GMPs ( CFR 820), EC GMPs, ISO, and ICH standards; still the Current
Good Manufacturing Practices (CGMPs) focus most responsibility for quality on
the QC unit. The QC unit is responsible for all Quality Assurance ( QA ) aspects.
The responsibility for quality should be a collaborative and functional
responsibility between the quality groups and the functional areas
( manufacturing, engineering, logistics, etc.). The new inspectional approach by
the quality systems of Food and Drug Administration ( FDA ) increases the
recognition of the functional area quality responsibility.
For the QC unit, the FDA emphasises on release and/or rejection authority. The
regulations ignore the increasing importance of other activities by QC/QA that
affect the quality in a positive way. These include building -up quality awareness,
product designing and development , designing and providing quality training,
facilitating quality improvement, analysing quality trend data for identifying
needs and opportunities of improvement , identifying quality metrics, and
collecting and distributing quality benchmark data. All these activities enhance
the awareness of senior management and also demands their involvement to
ensure greater emphasis and focus on QC.
Organisation and Personnel ( Chapter 7 ) 87
The quality professional should be highly knowledgable, and should have a high
level of skills and experience. Only then , he can effectively monitor and virtually
control till the GMP documents or activities in a facility. The knowledge and skills
required for high-level quality professional in the 21 st century are as follows:
1) There should be a QC unit for approving or rejecting all components, drug
product containers, closures, in-process materials, packaging materials,
labelling, and drug products.
2) The QC unit should also have the authority to review production records for
ensuring that there are no errors, or if any they have been fully investigated.
The unit should approve or reject the drug products manufactured, processed,
packed , or held under contract by another company.
3) The QC unit should be provided with adequate laboratory facilities for
testing, approval or rejection of components, drug product containers,
closures, packaging materials, in -process materials, and drug products.
4 ) The QC unit should have the responsibility for approving or rejecting all
procedures or specifications affecting the identity, strength, quality, and
purity of the drug product .
The responsibilities and procedures to be followed by the QC unit should be
provided in written format .
7.1 .3. Personnel Qualifications

A person responsible for manufacturing, processing, packaging, and handling of
drug products should be provided with adequate education, training, and
experience, or their combination so that the person can perform the assigned tasks
efficiently. The person should be provided training on the particular task assigned
to him. Frequent training sessions on CGMP should also be conducted by qualified
personnel to make the individuals aware of the CGMP applicable requirements.
Sufficient number of qualified personnel should be present to supervise the
manufacturing, processing, packaging, and handling of drug products. The
individual who has been assigned for this task should be provided with adequate
education , training, and experience, or their combination so that the person can
perform the assigned tasks in a way to ensure that the product has the claimed
safety, identity, strength, quality, and purity.
Personnel are the most significant part of a manufacturing system. Thus, they
should be provided with standardised training to maintain a high level of
proficiency and competency in the work area. A defined training system should
be established so that it produces qualified individuals.
7.1.4. Personnel Responsibilities

Given below are the guidelines for personnel responsibilities in the work area:
1) Personnel involved in aseptic manufacturing, processing, packaging, and
handling of drug products should wear clean clothing or uniform. They
should wear protective apparels, such as coverings for head, face, hands, and
arms to prevent contamination of the drug products. The company should
provide appropriate uniforms or protective clothing to the personnel. If
protective clothing is needed, personnel should be trained in donning or

removing the protective clothing.
2 ) Personnel should follow good sanitisation and healthy habits.
3) Personnel should not wear any jewellery or make-up in production or quality
control areas because it can result in a safety hazard and a contamination issue.
4) Eating, drinking, chewing, smoking, and storing food, alcohol, cigarettes, or
personal medication in the production and storage areas should not be allowed.
5 ) Only authorised and suitable trained personnel should enter the areas with
limited access. If a contractor, service technician, or personnel who are not
the employee of company need to enter these areas, they should receive
minimum training required to perform their job and should also be
accompanied by the company personnel.
6 ) The personnel should be physically fit to work. A pre -employment physical
test should be conducted based on the company’s requirements.
7 ) If an individual is found, either by medical examination or supervisory
observation, to have an apparent illness or open lesions that may adversely
affect the safety or quality of drug products, he should be barred from
touching the components, drug product containers, closures, in-process
materials, and drug products until his medical condition is corrected or it is
determined by a competent medical personnel that the condition will not
hamper the safety or quality of drug products.
8) All the personnel should be instructed to report to supervisory personnel
regarding any health condition that may adversely affect the drug products.
9) An employee who was not present due to illness should report to the
company 's medical facility before reporting to work in their functional area.
10) In case of an equipment malfunction or process deviation, the personnel
should immediately report it to the supervisor.
7.1 .5. Personnel Training

Personnel are the most significant part of a manufacturing system. Thus, they
should be provided with standardised training to maintain a high level of
proficiency and competency in the work area. A person responsible for
manufacturing , processing, packaging, and handling of drug products should be
provided with adequate education, training, and experience, or their combination
so that the person can perform the assigned tasks efficiently.
7.1 .5.1 . Training System

The product quality is directly affected by the actions of personnel taken in their
jobs. Thus, they should be provided proper training, which is possible by having
a robust, compliant, and sustainable training system that is able to produce
qualified individuals.
The following elements are needed in a strong training system:
1 ) An accurate description of the job or role,
2) Specific training requirements for each job or role,
3) Training plan to complete the training,
Organisation and Personnel (Chapter 7 ) 89
4) Training materials applicable to each type of training,

5) Qualified trainers to provide training,
6) Evaluations to measure the effectiveness of training system, and
7) A documentation and record -keeping system for storage and retrieval of
training records and materials.
7. I .5.2. Training Requirements

Training requirements can be defined when a job description has been created
and approved by Human Resources ( HR ) as well as the functional areas. The
knowledge and skills individuals need to successfully perform the job should be
identified. The desired skills and knowledge are compared against the
individual ’s skills and knowledge when entering the position to identify the gaps .
The training requirements are derived from the identified gaps.
Training requirements should be updated periodically. The training requirements
should be reviewed when new processes and new equipment are introduced ,
regulations are changed, and job responsibilities and duties are changed. Training
requirements should be established within the organisation for all levels.
7.1 .5.3. Training Plan

An individual training plan should be designed and established so that each
individual receives proper training at the right time. A training plan should
include the following (figure 7.1):
1 ) The employee’s curriculum or training topics or courses,
2) The manner in which the training will be performed ,
3) The sequence of training,
4 ) The approximate time of training, and
5 ) An indication of when the employee will be completely qualified.
The curriculum for each employee should include procedural (knowledge )
training, usually SOPs, and competency-based skills training ( On -the-Job
Training or OJT). These types of training should be standardised with the
training material used for all the trainees.
7.1 .5.4. Levels of Training

The employee’s curriculum includes three different levels of training. The first
level of training is an overview or general training conducted by the site HR or
corporate training group as part of a new hire or induction training. The second
level of training is held within the functional area. The third level of training is
most specific to the employee and involves one-on-one training.
The manner in which employees will receive the training, i.e., self -study by
reading, classroom training, computer-based training, or one-on -one OJT, should
also be mentioned in the training plan.
The sequence of training should also be clearly mentioned. For example , if an
employee has to learn about equipment, he will start from the equipment’s
assembly , operation, disassembly , and lastly cleaning. In functional areas, the
personnel are provided proper training on specific equipment. By defining a
proper training sequence, the trainee as well as the supervisor can determine
where the trainee is in the training plan and can estimate when the training will
complete and the trainee will become fully qualified.
Broad general knowledge
Level 1 introduction to GMP sections
Application of specific GMPs,
Level 2 \ to the functional area /
Application of
Level 3 GMPs to a
Vpedfic job /
Evaluation
Job Training Individual Appropriate

" Documentation
Description Requirements
Plan Event
Qualified Approved and Accurate

Trainers Training Material
Knowledgeable
Training Designers
Figure 7.1 : Training System
An approximate time for training should be mentioned in the training plan.

Training should be periodically monitored to check whether or not it is going as
per the plan. This helps in early identification of problems in the training process
and make suitable corrections. An agreement should be made within the
company and functional area as to what constitutes qualification. It can be either
a document presenting a structured training programme that is entered into the
record-keeping system or a series of courses completed by the individual.
The site of training should also have an annual or semi -annual training plan to
define what GMP training is and when it should be given to the employees in
functional areas.
7.1 .5.5. Training Materials

Clear and well-organised training materials should be designed and developed,
and the information within should be same whether the training is given once or
multiple times. Training materials should contain the stated objectives. Apart
from the content being trained, the reason behind the training should also be
explained. If training GMPs, the impact of the particular training on the
production of the product should be explained.
The design of training materials should be as important as the content. The design
should be such that it optimises maximum retention by the employee. The designer
should understand that the retention rates vary with the delivery method, and this can
be explained with a Learning Pyramid , as defined by the National Training
Laboratories in Bethel, Maine based on Edgar Dale’s “Cone of Learning”, found the
following average retention rates for different training and teaching methods:
1) 5% Lecturing, 2) 10% Reading, 3) 20% Audiovisual,
4 ) 30% Demonstration , 5 ) 50% Discussion , 6) 75% Practice by doing, and
7) 90% Teaching others.
GMP training should be designed by someone who knows about adult learning
theory. The learning capability of adults is different than that of children because
of their experience and knowledge. After choosing the training method, a
template should be developed for designing the training materials to standardise
them and provide consistency. Training materials of approved quality should be
used for GMP training.
Training materials should be version-controlled, and if developed along with an
SOP, they should be reviewed and updated when the SOP is reviewed or updated.
7.1.5.6. Personal Records

The training system and processes should be documented in an SOP, and its working
and the type of training included in the training system should be mentioned.
Training records should be retained in a documentation system. A method to ensure
the availability of latest training curricula and training requirements if an individual
transfers to another job within the company should be established. Any changes
made in the curricula should be documented and approved.
Training documentation should be easy to retrieve. The FDA or other regulators
often request an employee 's training record . In such a case, the record should be
presented to them within a short time period after their request. Performance
evaluations should also be retained.
7.1 .6. Personnel Hygiene

Given below are the requirements for maintaining personnel hygiene:
1 ) The personnel employed for handling P-lactam antibiotics should be tested
for penicillin sensitivity and those employed for handling cytotoxic
substances and other potent drugs should be regularly examined for adverse
effects. Such personnel should be moved out of these sections on rotation
basis as a health safeguard.
2 ) Before employment, the personnel should be medically examined including
eye and communicable or contagious disease testing.
3) The personnel should regularly undergo medical examination once a year
and proper records thereof should be maintained .
4 ) It is the duty of the licensee to provide services of a qualified physician who
will examine the health status of personnel involved in manufacturing of
pharmaceutical products.
5) All the personnel engaged in the manufacturing processes should be provided
training to follow healthy habits for maintaining personal hygiene and sanitation.
6) The personnel should not be allowed to handle starting materials, packaging
materials, in-process materials, and drug products if they are suffering from
apparent illness or having open lesions that may adversely affect the quality
of products until their condition improves.
7 ) The personnel should inform about their illness to their immediate supervisor
so that appropriate actions can be taken.
8) Direct contact between the unprotected hands of personnel and raw materials,
intermediate or finished products should be avoided.
9) The personnel should wear clean body coverings during the duties they
perform in manufacturing areas. Additional protective coverings for head ,
face, hands, and arms should be worn to protect the intermediates and APIs
from contamination.
10 ) Before entering the manufacturing area, separate changing rooms for men
and women with proper facilities for personal cleanliness like washbasin
with running water, clean towels, hand dryers, soaps, disinfectants, etc.
should be present. The changing rooms should also have cabinets for the
personnel to store their belongings.
11 ) If the used clothes are reusable, they should be stored in separate closed
containers until they are properly dry -cleaned and should be regularly
disinfected or sterilised.
12) Smoking, eating, drinking, and chewing should be strictly prohibited in the
production and testing areas.
7.2. SUMMARY
1 ) Some regulations are assigned to the personnel in QC units for approval or
rejection of components, in-process materials, and products.
2 ) A person responsible for manufacturing, processing, packaging, and handling
of drug products should be provided with adequate education, training, and
experience, or their combination so that the person can perform the assigned
tasks efficiently.
3) Personnel are the most significant part of a manufacturing system.
4 ) The product quality is directly affected by the actions of personnel taken in
their jobs.
5 ) Training requirements can be defined when a job description has been created
and approved by Human Resources ( HR ) as well as the functional areas.
6 ) An individual training plan should be designed and established so that each
individual receives proper training at the right rime.
7) The first level of training is an overview or general training conducted by the
site HR or corporate training group as part of a new hire or induction training.
8) The second level of training is held within the functional area.
9) The third level of training is most specific to the employee and involves one-
on-one training.
10) Clear and well -organised training materials should be designed and
developed, and the information within should be same whether the training is
given once or multiple times. Training materials should contain the stated
objectives.
11 ) GMP training should be designed by someone who knows about adult
learning theory.
12) Traning materials should be version-controlled, and if developed along with an
SOP, they should be reviewed and updated when the SOP is reviewed or updated.
7.3. EXERCISE
1) What personnel qualifications are required in a QC unit ?
2) Give two responsibilities of the personnel in work area.
3) What elements are required in a training system ?
4) Give the training plan for personnel.
5) Write about personal records.

1) Write the responsibilities of QC unit.
2) Write about the training levels for personnel .
3) Discuss the materials used for providing training to personnel .
4) Discuss the hygiene practices for personnel in QC unit.

1) Write an exhaustive note on personnel training.
CHAPTER
8 Premises
8.1 . PREMISES
8.1.1. Introduction
The location, environment, plant layout, design and construction of premises
directly or indirectly affect the quality of pharmaceuticals, thus play a significant
role in pharmaceuticals. Therefore, a thorough analysis of the conditions for
selection of location of premises, environment , plant layout, design and
construction of premises should be done.
8.1.2. Location
The location for the construction of a pharmaceutical plant should be
appropriately selected as it determines the balancing of investment and profit .
While selecting the location of premises, one should consider both the external
and the internal environment.
The following factors should be taken into consideration before purchasing,

constructing, or making changes in the existing facilities:
1 ) Availability of water, power, fuel , sewage, and waste-stream removal ,
2) Applicable laws,
3) Proper space for future expansion ,
4) Accessibility for employees, materials, and visitors,
5) Environmental issues, like water and air quality, etc.,
6) Nearness of undesirable activities that can pollute or act as a source of
microbial contamination,
7) Availability of suitable labour force,
8) Availability of proper security arrangements,
9 ) Accessibility to inter-related operations of the company, and
10) Political situations like government stability, trade policies and taxation,
financial incentives, etc.
8.1. 3. Design and Construction

The premises to be used for the manufacturing, processing, packing or holding of
drug products should be of suitable size, design , construction and location. This
reduces the risk of errors and allows effective cleaning and maintenance to
prevent cross-contamination, accumulation of dust or dirt , and any adverse effect
on the product quality . The premises should also abide by the conditions laid
down in the Factories Act, 1948.
Premises ( Chapter 8 ) 95
A site development plan addressing the following should be prepared:

1 ) Site resources and infrastructure, like green spaces, parking, road and rail
access, etc.,
2) Storm water and waste management ,
3) Compliance with appropriate laws and regulations,
4) Site security and access, like installation of fences, guard posts, cameras, etc.,
5) Layout, usage and possible expansion of buildings,
6) Utilities, like design , layout, and electricity backups,
7) Equipment , like design , layout, spares, and capacity,
8) Pedestrian and vehicular traffic flow,
9 ) Safety for personnel and equipment ,
10 ) External architecture to consider the local environmental conditions,
11 ) Ease of maintenance and cleaning,
12) Selection and use of experienced contractors,
13) Identification of project management responsibility,
14 ) Validation plans and an effective change control procedure, and
15) Construction materials.
The following guidelines should be followed during plant design and construction:
1 ) Walls: The walls should be positioned such that they enable orderly movement
of materials and personnel. Noise levels should be kept to minimum to
maintain suitable working conditions. The inter-relationship of different
operations should minimise cross-contamination and for component mix-up
during storage and inter-departmental shipping. High-quality concrete blocks
or gypsum board with plaster finish should be used for making walls in
corridors, manufacturing and packaging areas. The finish of these walls should
be smooth and with enamel or epoxy paint. Pre-fabricated partitions should be
used in packaging areas where flexibility of layout is required .
2) Floors: Floor coverings should be such that they are durable, easily cleanable,
and resistance to the chemicals with which it would come into contact. Flooring
should be washable, smooth, without cracks and crevices, and should not allow
dust accumulation. Given below are some commonly used coverings:
i) Terrazzo: It provides a hard-wearing finish. It is available in tiles as well
as poured-in-place finishes. The latter is preferred for manufacturing. Tiles
should be used carefully to ensure that they are effectively sealed, or else
dirt and microorganisms can accumulate in the gaps between two tiles.
ii ) Ceramic and Vinyl Tiles: They are not recommended for production areas.
iii) Welded Vinyl Sheeting: It provides a smooth and easily cleanable
surface. It is preferred in production areas, especially for injectables
because lack of joints improves the ease of cleaning and sanitation.
iv ) Epoxy Flooring: It provides durability and cleanability to the surface.
3) Ceilings: Office areas, laboratories, toilets, and cafeterias consisting of lay in
acoustical panels of non -brittle, non -friable, non -asbestos, and non -
combustible material should have suspended ceilings. In the manufacturing
areas, the ceilings should be of seamless plaster or gypsum board with a
smooth finish. All ceiling fixtures, like light fittings, air outlets and returns,
and sprinkler heads should be so designed that they permit cleaning and
reduce dust accumulation.
4 ) Services: Adequate provisions should be made for drainage, water, steam,
electricity, and other services for easy maintenance of the buildings. The
design and facilities of buildings should be such that they have sufficient
space for orderly arrangement of equipment and materials so that any mix -
ups and contamination do not occur. Adequate cleaning, washing and toilet
facilities should also be provided for the personnel .
5 ) Lighting: Adequate amount of light ( lux or foot -candles) should reach the
working surface of each area involved in the production of pharmaceuticals.
There are public standards for some types of work. Normally, range of 30 to
50 foot-candles is suitable to provide work comfort and ability to
perform efficiently and effectively ; however, some areas demand 100 foot-
candles along with special lighting for some operations, such as inspection of
filled vials.
After defining the light levels, they should be measured periodically to
record the results. The specifications should demand either replacement of
light sources when they have reached some level above the established
minimum or routine replacements of light sources on scheduled time to
ensure that light levels do not reach below the established minimum.
8.1 .4. Plant Layout

Plant layout is the area within the factory building where physical facilities
like machinery, equipment , furniture, etc., are arranged such to permit quick
flow of material at lowest cost and with the least amount of handling in
processing the product from the receipt of material to the shipment of finished
product.
A proper layout can be produced by arrangement of processing, storage and
handling areas in efficient coordination. An appropriate layout can be designed if
information on dimensions of work places, sequence of operations, flow pattern
of materials, storage space for raw materials, in-process inventory and finished
goods, space for offices, aisles, toilets, etc. are available.
Importance of Plant Layout
1) It provides optimum relationship among output, floor area, and
manufacturing process,
2 ) It allows easy production flow,
3) It provides flexibility of operation,
4 ) It makes economic use of building,
5 ) It promotes effective utilisation of manpower,
6 ) It provides employee’s convenience,
7 ) It provides safety,
8) It provides comfort at work, and
9) It provides maximum exposure to natural light and ventilation.
Types of Plant Layout

Manufacturing unit plant layout is of the following four types:
1 ) Product or Line Layout : In this layout, all the equipment, machines, tools,
and other items required for the processing are arranged as per the sequence
in which the operations including production, testing, packaging, etc., are
carried out. Product or line layout is called as one line layout as it is meant
for the processing of one specific product . While designing this layout , one
line should not cross the other line.
Advantages
i) Low cost of material handling.
ii) Continuous work flow.
iii) Lesser investment in inventory and work-in-progress.
iv ) Optimum use of floor space.
v ) Shorter processing time or quicker output.
vi) Lower cost of manufacturing per unit.
Disadvantages
i ) High initial capital investment .
ii) Heavy overhead charges.
iii) Breakdown of one machine stops the entire production process.
iv) Suitability.
v) Mass production of standardised products.
2) Process Layout: In this layout, all the equipment, machines, etc. are not
arranged as per the sequence of operations; but, a specific operation like
granulation, coating, mixing, etc., for all the products is carried out at a particular
work station or department. The departments should be located at minimum
distance to avoid long distance movement of materials. The departments should
be arranged as per the convenience for inspection and supervision.
Advantages
i) Lower initial capital investment.
ii) Effective supervision.
iii) Breakdown of one machine does not stop the whole production process.
iv) Flexibility of expansion.
Disadvantages
i ) Material handling costs are high due to back-tracking.
ii) Work-in-progress inventory is high.
iii) Higher cost due to requirement of skilled labour.
iv) Frequent inspection results in costly supervision .
v ) Greater storage space.
3) Fixed Position or Location Layout: In this layout, a complete product or a
major part of it is produced at a fixed location. The facilities required are
arranged around the particular work centre/location .
Advantages
i) Time and cost saving.
ii) Adjustments can be made.
iii ) Flexible layout.
Disadvantages
i ) Heavy capital investment.
ii ) Very long production period .
iii ) A large space is required for storage of material and equipment .
iv) Possibility of confusion and conflicts.
4 ) Combined Layout: This layout is a combination of product and process
layouts to take the advantages of both.
8.1.5. Sanitation
Buildings used for manufacturing, processing, packing, or storing of drug
products should be maintained under clean and sanitary conditions and should
not be infested with rodents, birds, insects, and other vermin. Scrap and waste
materials should be collected and disposed timely in a sanitary manner. Spilled
materials that might attract creatures should be removed immediately. Cleaning
and sanitation programmes should be conducted to fulfil the specific needs of
each facility. The cleaning procedures should be written and validated suitably.
A routine sanitation programme should be conducted, properly recorded, and
should indicate the following:
1 ) Specific areas to be cleaned and cleaning intervals,
2) Cleaning procedure to be followed, including equipment and materials to be
used for cleaning, and
3) Personnel assigned for the cleaning operation .
8.1.6. Maintenance
Buildings used in the manufacturing, packaging or warehousing of drug
products should be properly maintained. A deteriorated building presents a
poor image of the facility and also affects the product quality. Any cracks or
holes in the walls, floors, or ceilings of warehouse can provide entry for
insects, birds, rodents, dirt , or microorganisms. The cracks or holes also
hinders the process of cleaning and sanitation , and thus increased the risks for
cross-contamination and microbial growth. Floor cracks can become a safety
hazard for people or even dislodge materials from trucks during material
transfer. Water leaking from the cracked roofs significantly damages the
stored materials and equipment , and can also cause electrical failures and
fires that further damage the basic building structure. Birds may form nests in
the holes in buildings and thus result in contamination .
Written procedures for the use of suitable cleaning and sanitising agents,
fumigating agents, rodenticides, insecticides, fungicides, etc. should be
established. Rodenticides, insecticides, and fungicides should be used as per the
applicable laws.
8.1.7. Environmental Control

Environment indicates the entire surrounding. It includes the biological , physical
and social things present on the earth around the mankind. Pharmaceutical
manufacturing plants produce large amount of waste materials that pollute the
environment. Every pharmaceutical manufacturer should take appropriate steps
Premises (Chapter 8 ) 99
to reduce the generation of waste materials, to recycle the waste to increase the
product yield , to reduce the consumption of raw materials, and to fulfil the duties
of hazardous waste management and environmental control.
In the premises, the product and its residues and waste should neither be allowed to
escape into the atmosphere nor be discharged directly into the normal drainage
systems. The external environment and the public in the surrounding facility
should be protected from hazardous substances. Liquid effluent , that poses safety
or contamination risk should be treated before discharging into the municipal drain.
The pharmaceutical company should have written procedures to ensure the
environment quality by continuous monitoring the environmental conditions as
well as the temperature and humidity within the drug manufacturing facility.
Effective air extraction system equipped with air filters should be installed for
retaining dust and protecting the factory and local environment.
The facilities providing special environmental conditions of pressure differentials
between rooms should be monitored regularly. Manufacturing areas for oral solid
dosage forms should have double door airlock facility for entry, and the
manufacturing areas for topical products should have a suitable airlock facility
for entry. Insect-outros should be installed in these areas. Air entering these areas
should be filtered through minimum 20 air filters and should also be air-
conditioned . These manufacturing areas should be ventilated and fitted with an
exhaust system for removing vapours, fumes, smoke, and floating dust particles.
The temperature and humidity requirements in manufacturing areas of metered
dose inhalers depend on the type of product and propellants being handled. There
should be a difference of atleast 15 Pascal in room pressure between the
manufacturing areas and the support areas. For air supplies to bulk drug
manufacturing areas, air filtration systems including pre-filters and particulate
matter retention air filters should be used.
8.1.8. Utilities of Sterile Area

Suitable Heating, Ventilation, and Air Conditioning ( HVAC) systems should be
designed, installed, and observed for controlling air in clean areas and also for
maintaining the atmospheric conditions at appropriate levels. HVAC systems
should be managed to ensure constant and secure operations against temporal
variations due to operational activities (such as door opening and closing and
facility equipment operation ) and sustained variations due to non -operational
activities (such as seasonal changes in outdoor conditions and deterioration of
equipment and apparatuses over time ). The basic elements of HVAC systems and
their management programs include temperature, relative humidity, air flow
volume, air exchange rate, unidirectional air flow, pressure difference relative to
adjacent rooms, HEPA filter integrity, airborne particle count, and microbial count.
Temperature and Relative Humidity
Temperature and relative humidity can directly affect the materials and products,
comfort of personnel, and potential for microbial contamination in processing
areas. Thus, the temperature and relative humidity level should be appropriately
established , controlled , monitored , and maintained throughout processing.
Air
It is critical to secure constant airflow from an area of higher cleanliness level to
an area of lower cleanliness level to maintain the environmental conditions of
clean areas at appropriate levels.
Pressure difference between areas of different cleanliness levels should be
defined, monitored, and controlled. If pressure difference is one of the most
important factors for controlling bioburden before sterilisation , pressure
difference between areas should be continuously monitored and an alarm system
should be installed to enable prompt detection of abnormal pressure difference.
If the areas of different cleanliness levels ( e.g., Grades A and B ) are located in a
facility, the air control measure should meet the applicable requirements
specified in the Guidance on the Manufacture of Sterile Pharmaceutical Products
by Aseptic Processing.
8.1.9. Maintenance of Sterile Area

The manufacturing areas for sterile pharmaceutical products should be cleaned
and disinfected as per the applicable SOPs, and such activities should be
recorded in writing and retained in archive.
8.1 .9.1 . Cleaning Agents and Disinfectants

1 ) The cleaning agents and disinfectants to be used should be evaluated and
confirmed by the QC unit to confirm their suitability and reliability in
removing contaminants. The efficacy of disinfectants should be monitored
and validated based on the type and count of microorganisms characterised
by periodic environmental monitoring.
2) SOPs should be established for the application of cleaning agents and
disinfectants, schedules of cleaning and disinfection, cleaning following
disinfection where necessary, precautions for cleaning staff to ensure their
safety, and for caring and storage of cleaning tools. Cleaning agents and
disinfectants to be used in Grade A or B areas should be filtered or treated by
other means to ensure their sterility before use and should be controlled to
prevent internal microbial contamination until use.
3) In -house prepared cleaning agents and disinfectants should be prepared as per
the applicable SOPs, and preparation records should be prepared and retained.
When commercial cleaning agents and disinfectants are used after dilution , the
details of dilution procedure, such as diluents, dilution ratio, expiration date,
storage conditions, and sterilisation methods should be recorded in writing.
4 ) After the process of cleaning and disinfection, the surfaces and equipment
that may come into direct contact with pharmaceutical products should be
made free of cleaning agents or disinfectants by appropriate methods.
5 ) Expiration dates for individual disinfectants should be established , and such
agents should be used before the expiry dates.
6) The manufacturing environment should not be disinfected before the
cleaning procedure. If residues of cleaning agents remain at any locations in
the environment after cleaning, steps should be taken to make sure that these
residues do not impair the efficiency of disinfectants.
7 ) Disinfectant containers should not be refilled with disinfectants.

8) The following should be considered while selecting and using disinfectants:
i ) The storage and usage of disinfectants should be done as per the
supplier 's instructions.
ii) Disinfectants and disinfection procedures should be selected based on the
safety of the personnel involved in disinfection work.
iii ) If selected disinfectants are suspected of being ineffective against
microorganisms isolated from the environment , their efficacy should be
re-evaluated, and different disinfectants should be used as alternative.
iv) If environmental monitoring data suggest the presence of spore-forming
bacteria or fungi, effective sporicides or fungicides should be used for
disinfection.
v) The directions for using disinfectants should include the disinfection
method , application sites, and duration of use required for obtaining the
desirable effects.
vi) The chemical properties of cleaning agents and disinfectants, in terms of
their effects ( e.g., corrosiveness ) on facility and equipment surfaces,
should be evaluated before the selection of such agents.
9 ) If sporicides or fungicides are to be used in areas for processing sterile
pharmaceutical products by terminal sterilisation procedures, their type,
concentrations, usage, and procedures for confirming efficacy should be
predetermined and specified in writing.
10) Cleaning agents, disinfectants, and cleaning utensils should not be stored in
critical areas. Materials necessary for operations in critical areas (such as
hand sprays for sanitising gloves ) should be stored in well-controlled critical
areas. Control procedures for the cleaning agents and disinfectants to be
stored in critical areas should be defined in writing.
8.1 .9.2. Validation of Disinfection Procedures

1 ) The reliability and frequency of disinfection procedures should be
established through environmental monitoring program.
2) Disinfectants to be used should be microbiologically evaluated in individual
facilities, and appropriate control procedures should be instituted for such facilities.
3) The efficacy of disinfectants should be evaluated to ensure that they keep the
microorganism counts below the count predetermined based on the type and
count of isolates collected from various surfaces through environmental
monitoring program.
8.1 .9.3. Monitoring of Adequacy and Efficacy of Cleaning and

Disinfection Procedures
1 ) The adequacy and efficacy of cleaning and disinfection processes should be
established through the environmental monitoring program.
2 ) Microorganism counts on the surfaces of equipment and facilities should be
obtained by environmental monitoring and analysed to detect occurrence and
proliferation. The causes of abnormalities when the microbial count exceeds
the action level, when the species ratio of microorganisms is different from
that routinely reported , or when abnormalities in the count or species ratio

continue for an extended period of time should be determined. Corrective
and preventive steps should be taken whenever necessary.
3) If the established disinfection procedure of certain types or concentrations of
disinfectants is not effective, their reliability should be re-evaluated with
different disinfectants interchangeably or replacing them with other
disinfectants.
8.1 . 10. Control of Contamination

Contamination is the presence of any foreign substance in the products. It may be:
1 ) Physical: Hair, foreign objects, dirt , dust , and pollens.
2) Chemical: Cleaning agents, lubricants, and other products.
3) Microbiological: Bacteria, moulds, spores, and yeasts.
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Cross contamination of any product is caused by:
1 ) Contamination of a batch with a previous batch of the same product ,
2) Contamination with a different product through carryover or proximity of
production lines, or
3) Contamination by a foreign starting material of the dispensary or in the store.
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Prevention of cross contamination requires:
1 ) Proper sealing, separation, and storage of raw materials,
2 ) Care in management of the dispensary to exclude the opening of different
lots of containers in close proximity,
3) Proper cleaning of all equipment, utensils, transfer lines, extraction systems,
and vessels after use.
4 ) Re-inspection of equipment before use and line clearances at all stages of
manufacture.
5) Ensuring that all air conditioning systems are serviced and maintained properly.
8.1 . 10.1 . Cleanrooms and Cross- Contamination

Cross-contamination during processing can be prevented by using positive air
barriers ( to exclude other products), dust extractors, and containment hoods ( to trap
and remove dust ). Cleanrooms are designed such that the air flow patterns and room
pressures protect the product, if is very important to maintain this protection by:
1) Keeping doors closed to prevent pressure loss,
2 ) Keeping air returns clear to maintain air sweeping,
3) Cleaning extractors and filters for efficient operation ,
4 ) Checking room monitors to verify set pressures, and
5 ) Regularly maintaining/servicing the air handling units.
8.1 . 10.2. Main Sources of C ontamination

Following are the major sources of contamination :
1 ) Environment in which the product is formulated and filled,
2) Equipment used in formulation and filling,
3) Operators,
4 ) Raw materials and packaging materials, and
5) Other products that may cause cross-contamination.
8.1 . 10.3. Contamination Control

Since all contaminants are not visible to naked eyes, e.g., bacterial contaminants,
therefore strict controls are needed to prevent contamination . The personnel
should know and follow the company ’s procedures.
If contamination has been suspected to occur, a note on the batch records should
be made and the supervisor should be informed . In this way , the contaminants
can be detected easily.
8.1. 10.4. Raw Materials Store

Poor housekeeping in the store can lead to product mix -ups and cross-
contamination. Therefore,
1) Doors should be kept closed to prevent the entry of dust and pests,
2) Materials should not be stored on the floor to prevent damage or contamination,
3) Spills should be immediately cleaned up,
4) The materials and products should be clearly labelled to prevent mix - ups,
5) A separate storage area for quarantined goods and a locked area for rejected
materials should be available,
6) The open containers are prone to contamination from humidity or other
microbial agents in the environment , thus should be kept closed, and
7 ) Personnel should wear protective clothing.
8.1 . 10.5. Control Over Incoming Goods

Incoming goods should be controlled. Each lot of material should be assigned a
unique identification number to ensure traceability and checked for possible
transit damage and contamination.
After receiving these materials into the facility , they should be stored such that
contamination is minimised.
Before use, these materials should be checked for correct identity, cleanliness,
integrity of the storage container or protective wrapping, and suitability for use in
the manufacturing process. After these checks, only the operators confirm that
the materials have not been contaminated during storage and are suitable for use.
8.1 . 10.6. Use of Computer Systems

Computer systems are often used to control inspection and test status if materials and
products do not have physical status labels. Such systems should be validated and
thoroughly documented. All the operators should be trained in using these systems.
8.1 . 10.7. Maintenance Department

Poor housekeeping practices by maintenance personnel can cause problems in
manufacturing, therefore:
1 ) Operators should wear clean working gowns,
2) Doors should be kept closed to prevent the entry of dust and pests,
3) Proper cleaning and hygiene practices should be maintained to prevent
product contamination,
4) Product bottles for lubricants or other supplies should not be used,

5) Bottles should be clearly labelled to prevent mix -ups,
6) Spills should be cleaned up immediately, and
7) Pest control programmes should be practiced in the entire facility.
8, 1.10.8. Dispensary
Dispensing areas should be designed to minimise the risk of contamination and
mix-ups. Only raw materials should be dispensed by the authorised personnel by
following the standard procedures:
1 ) The operators should wear clean working gowns,
2 ) Doors should be kept closed to prevent the entry of dust and pests,
3) Two doors should never be opened at the same time,
4) Exhaust fans should be installed to prevent dust generation ; exhaust fans are
effective only if they are well-maintained and switched on , and
5 ) Cleaning procedures should specify the methods for cleaning exhaust ducts,
grills, flues, and fan blades as dirty equipment can be a contamination source.
8.1 . 10.9. Filling Department

Poor contamination control in the filling department can lead to disastrous
consequences, therefore:
2) The operators should wear clean working gowns,
3) Specified work garments should be worn to prevent cross-contamination ,
4 ) Air handling units should be installed, operated, and maintained to ensure
clean air supply,
5) Product bottles should not be used for lubricants,
6) Bottles should be clearly labelled to prevent mix-ups,
7) The equipment and machine set ups should be well-maintained or else it may
damage the product containers, and
8) Dropped product should never be returned to the line.
8.1 . 10.10. Contamination by Machinery

The machinery used for manufacturing a product is a possible source of
contamination and is often overlooked. The possible contaminants are lubricating
fluids, wearing parts that generate metal particulates, remnants of previous
product due to improper cleaning, and malfunctioning equipment that smash
containers or have inefficient extraction devices fitted .
The operator using these machines can ensure that product contamination does not
occur if the machines are properly cleaned after use and examined for cleanliness
prior to use. While operating the machines, the operator should be familiar with the
fact that the product may get contaminated due to malfunctioning machine, and thus
be alert for teaks, drips from lubricating glands or wearing of machine parts.
Machines should be kept in a good running order by performing periodic
preventative maintenance checks as per a schedule that relates to the machine
age , use, and requirement for servicing. A maintenance program that is directed
at breakdown maintenance will not minimise the risk of product contamination.
Premises ( Chapter 8) 105
8.1 . 10.11 . Control of Air Quality

Contamination results if contaminated air comes in direct contact with the product
while dispensing starting materials, while product formulation , or while filling product
in the final product containers. In each case, the contaminants may be airborne
particulates, other products, or a starting material of previous product. The sources of
airborne contaminants can be the air supplied to the facility, operators working in the
facility, materials bought into the facility, or machinery used in the facility.
Airborne contaminants can be controlled by monitoring the air quality within the
facility. This relates to the facility design , the air handling system, and the rooms
within the facility. Factors, like the type of air filtration employed within the
facility and the air flow, are important in controlling contamination.
Temperature and humidity within the facility are also important factors. If a
facility is too hot or too humid, the operators perspire and perspiring operators
are a source of particulate and microbial contamination. Therefore, processing
rooms and storage areas should have limited access.
The quality of air in processing areas should be different for different products
and for different manufacturing stages of product.
8.1 . 10.12. Packaging Department

Special emphasis should be given to the control of labels and pre-printed
packaging materials to prevent mix-ups and product recalls, therefore:
1 ) The operators should wear clean working gowns,
3) Labels should be kept in sealed containers in a restricted area and returned to
the store before the next operation,
4 ) Personal medication should not be carried into the manufacturing areas,
5 ) Operations should be segregated and signs should clearly identify the product
being packaged to prevent mix - ups,
6) Different products should be segregated ,
7) Labels should be securely fixed to the container and not on the lid , and
8) A line clearance should be conducted before starting the work to prevent
cross-contamination.
8.1 . 10.13. Contamination by People

Operators are a major source of contamination , thus they need to be disciplined
in their work habits and understand and follow the procedures related to product
manufacture. The operators not suffering from a contagious disease or not having
any open lesions on the exposed surfaces of the body should be involved in
handling exposed starting materials or products.
Strict personal hygiene of all staff, whether or not handling the exposed product, is
essential in controlling contamination. Operators should never be in direct contact
with the exposed product or cleaned final product containers and caps as this may
lead to product contamination with skin particles, body oils, and hair. The operator in
contact with exposed product should not wear jewellery as it is a source of dirt and
grime. Jewellery may also fall into the product mixes and remain undetected.
The operators while handling starting materials and exposed product should
wear protective garments. The wet or dirty garments should be replaced with
clean and freshly laundered garments as the former are a potential source of
contamination . Operators and support staff should take care while moving
between work stations to ensure they are not carrying residual materials on
their clothes or footwear.
8.1 . 10.14. Cleanroom Air Control

Air should be controlled in rooms where product is exposed to the environment.
Some important controls for cleanrooms are:
1 ) Filtering the incoming air,
2) Controlling the temperature and humidity,
3) Maintaining fast flowing air,
4 ) Having a laminar flow,
5) Maintaining a higher pressure within the room than the surrounding areas, and
6) Keeping the doors closed .
8.1 . 10.15. Airflow Patterns and Contamination Control

Clean rooms are of the following two types:
1 ) Positive Pressure Rooms: The room pressure in these rooms is higher than
the outer rooms, and they are designed to exclude particles, dirt , bacteria, and
other products.
2 ) Negative Pressure Rooms: The room pressure in these rooms is lower
than the surrounding rooms , and they are fitted with a dust extraction
system to trap or contain dust generated during product processing within
the room.
The effective operation of both the rooms depends on keeping the doors closed
and ensuring that inlet filters, air return vents and dust extraction equipment are
clean and operating properly.
8.1 . 10.16. Positive Pressure Rooms

The pressure in positive pressure rooms is higher than that in the surrounding
areas if the door is kept closed. These rooms are designed to clean the air by
exchanging it through air filters in the inlet vents in every 3-5 minutes. The air is
swept across the room to outlets ( returns) near the floor and door.
The positive pressure rooms are used when there is a need to exclude bacteria
and particles from the room and product .
Creams, oral liquids, ointments, and sterile products are processed in these
cleanrooms, where bacterial exclusion is important.
8.1 . 10.17. Negative Pressure Rooms

Negative pressure rooms are used when any product dust is to be trapped in the
room or dust extractor to prevent contamination of other processing rooms and
cross-contamination of other products and equipment .
Rooms of this type contain a secondary extractor for collecting the product dust
and filters on the return air vents and ducts. The doors should be kept shut, room
and equipment should be regularly cleaned , and the extraction systems should be
maintained . Dry oral products ( tablets and capsules) are processed in these rooms
as bacteria or particles are less of a problem.
Work areas should be close to the air inlet, as the air will be the cleanest at
this point. Air should smoothly flow away from the work station and out of
the room . Doors should be kept shut to maintain the air pressure in the room.
The air outlet should not be obstructed as this will disturb the air flow.
8.1 . 10.18. Airflow Patterns

The air supply and returns should be kept clear of obstructions to minimise the
risk of environmental contamination.
8.2. SUMMARY
1 ) The location for the construction of a pharmaceutical plant should be
appropriately selected as it determines the balancing of investment and
profit.
2) The premises to be used for the manufacturing, processing, packing or
holding of drug products should be of suitable size, design , construction and
location.
3) The walls should be positioned such that they enable orderly movement of
materials and personnel.
4 ) Floor coverings should be such that they are durable, easily cleanable, and
resistance to the chemicals with which it would come into contact.
5 ) Terrazzo provides a hard -wearing finish. It is available in tiles as well as
poured-in-place finishes.
6 ) Ceramic and vinyl tiles are not recommended for production areas.
7) Welded vinyl sheeting provides a smooth and easily cleanable surface.
8) Epoxy flooring provides durability and cleanability to the surface.
9) Office areas, laboratories, toilets, and cafeterias consisting of lay in
acoustical panels of non-brittle, non-friable, non-asbestos, and non-
combustible material should have suspended ceilings.
10 ) Adequate amount of light ( lux or foot -candles ) should reach the working
surface of each area involved in the production of pharmaceuticals.
11 ) Plant layout is the area within the factory building where physical facilities
like machinery , equipment, furniture, etc., are arranged such to permit quick
flow of material at lowest cost and with the least amount of handling in
processing the product from the receipt of material to the shipment of
finished product .
12) In product or line layout , all the equipment, machines, tools, and other
items required for the processing are arranged as per the sequence in which
the operations including production, testing, packaging, etc., are carried out.
13) In process layout , a specific operation like granulation , coating, mixing, etc.,
for all the products is carried out at a particular work station or department.
14) In fixed position or location layout , a complete product or a major part of it
is produced at a fixed location .
15 ) Combined layout is a combination of product and process layouts to take
the advantages of both.
16 ) Buildings used for manufacturing, processing, packing, or storing of drug
products should be maintained under clean and sanitary conditions and
should not be infested with rodents, birds, insects, and other vermin .
17 ) Buildings used in the manufacturing, packaging or warehousing of drug
products should be properly maintained.
18 ) Environment indicates the entire surrounding. It includes the biological,
physical and social things present on the earth around the mankind.
19) Suitable Heating, Ventilation , and Air Conditioning ( HVAC ) systems should
be designed , installed, and observed for controlling air in clean areas and also
for maintaining the atmospheric conditions at appropriate levels.
20) The manufacturing areas for sterile pharmaceutical products should be
cleaned and disinfected as per the applicable SOPs, and such activities
should be recorded in writing and retained in archive.
21 ) Contamination is the presence of any foreign substance in the products.
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22 ) Cross contamination during processing can be prevented by using positive
air barriers (to exclude other products ), dust extractors, and containment
hoods ( to trap and remove dust).
23 ) Dispensing areas should be designed to minimise the risk of contamination
and mix-ups.
24) Contamination results if contaminated air comes in direct contact with the
product while dispensing starting materials, while product formulation, or
while filling product in the final product containers.
25) Operators are a major source of contamination , thus they need to be
disciplined in their work habits and understand and follow the procedures
related to product manufacture.
26) The room pressure in positive pressure rooms is higher than the outer
rooms, and they are designed to exclude particles, dirt, bacteria and other
products.
27) The room pressure in negative pressure rooms is lower than the
surrounding rooms, and they are fitted with a dust extraction system to trap
or contain dust generated during product processing within the room.
28) The air supply and returns should be kept clear of obstructions to minimise
the risk of environmental contamination .
8.3. EXERCISE
1 ) What should be the location for a pharmaceutical plant layout ?
2) How should be the ceilings of a pharmaceutical plant ?
3) Give the importance of plant layout.
4 ) How temperature and humidity of premises can be controlled ?
5) Write about the validation of disinfection of premises.
6) Enlist the sources of contamination .
7) How cross-contamination can be prevented ?
8 ) How the incoming goods can be controlled ?
9) What are positive and negative pressure rooms?

1) Write about the design and construction of a pharmaceutical plant.
2) Discuss the different types of plant layout.
3) Write a note on the sanitation and maintenance of premises of a pharmaceutical plant.
4) Give a short review on environment control of premises of a pharmaceutical plant .
5) Write the steps to prevent contamination in maintenance, dispensary, filling and
packaging departments.
6) Discuss the steps for controlling air quality and contamination by equipment .

1 ) Write an exhaustive note on control of contamination in a pharmaceutical plant.
2) Give a brief review on premises of a pharmaceutical plant .
CHAPTER Equipments and Raw

9 Materials
9.1. EQUIPMENTS AND RAW MATERIALS

Location, design , construction , adaptation and maintenance of equipment should
as per the operations to be carried out. The major aim of layout and design of
equipment should be to reduce the risk of errors and allow effective cleaning and
maintenance so that cross-contamination, accumulation of dust or dirt, and any
adverse effect on the product quality can be prevented.
Materials
The pharmaceutical plant is mainly established for producing finished products
( for patients use ) by using starting and packaging materials. Starting materials ,
packaging materials, gases, solvents, process aids, reagents, and labelling
materials are required for pharmaceutical preparations. The product should not be
exposed or be in direct contact with the materials used for cleansing and
lubrication of equipment and pest control. For reducing health-related risks, it is
also important that such materials should be of a suitable grade (e.g., food grade ).
Soon after receiving or processing of incoming materials and finished products,
they should be quarantined before their distribution . Storage of all materials and
products should be done under suitable conditions in an orderly manner to allow
-
batch segregation and stock rotation by first-expire, first out rule. For the
manufacturing of pharmaceutical products, suitable water should be used.
9.1 .2. Equipment Selection

For the manufacturing of intermediates and APIs, equipment of appropriate
design and adequate size should be used. The manufacturing equipment should
be located suitable for its intended use, cleansing, sanitation, and maintenance.
The materials used for equipment construction should be such that their contact
with raw materials, intermediates, or APIs does not alter their quality beyond the
official limits or other established standards. Use of production equipment should
be under the qualified operating range.
Some major equipment ( e.g., reactors and storage containers ) and permanently
installed processing lines used for intermediate or API production should be
properly identified. Lubricants, heating fluids, or coolants are substances used in
the operation of equipment. Such substances should not come in contact with
intermediates or APIs to prevent alteration in their quality beyond the official
limit or other established standards. If any deviation from the specified limit is
found , it should be evaluated and ensured that the material quality was not
adversely affected.
Equipments and Raw Materials ( Chapter 9 ) Ill
Closed or contained equipment should be preferably used: and while using open
equipment or when equipment is opened, additional precautionary steps should
be taken to reduce the contamination risk. A set of current drawings should be
.
maintained for equipment and critical installations ( e.g , instrumentation and
utility systems ).
9.1 .3. Purchase Specifications for Equipment

The properties associated with an item or products to be purchased include
weight, size, dimensions, quality and safety requirements, and the products
performance parameters.
Before purchasing equipment, the following aspects should be considered:

1 ) The equipment should be compatible with user requirement specification.
2) The following questions regarding the design, size, location , adaption and
construction of the equipment should be asked:
i ) Why the equipment should be purchased ? For example, creating new
facility, increasing capacity, or adapting to new and improved technology.
ii) Which operations are proposed to be performed using the equipment ?
For example, equipment capability analysis, granulation , or sterilisation.
iii) What should be the capacity of the equipment in terms of output and
holding? For example, ten lac tablets per shift or ten thousand litres of liquid.
iv ) What is the cleansing process of the equipment ? And whether any
problem occurs while validating the cleaning process of the equipment ?
v) Are trained operators available for operating the equipment ? Or whether
the manufacturer provides training to the existing operator.
vi ) What will be the operation time ( starting and stopping time ) of the
equipment ?
9.1 .4. Maintenance of Equipment

The installation of equipment should be such that the risk of contamination or
error is minimised. Fixed pipework should be labelled clearly showing the
contents and direction of flow. The service pipings and drainage system should
be appropriately marked and much emphasis should be put on the non -
interchangeable connections or adaptors for hazardous gases and liquids.
Production and control operations should utilise balances and other measuring
equipment of appropriate range and precision . Calibration of balances and
measuring devices should be done on a fixed period. Cleansing of production
equipment should be performed on a scheduled basis.
The equipment should be washed , cleansed, and dried to prevent the risk of
contamination. It is also ensured that the equipment used for production should
not be hazardous to the product. The parts of production equipment coming in
contact with the product should be non-reactive, non-additive, or non -absorptive
so that the product quality is not hampered. The production and quality control
areas should not have any defective equipment ; and if such equipment are
present , they should be appropriately labelled as not for use.
Closed or contained equipment should be preferably used ; and while using open
equipment or when equipment is opened , additional precautionary steps should
be taken to reduce the contamination risk. The non-dedicated equipment should
be cleaned as per the validated cleaning procedures between the production
process so that risk of cross-contamination can be avoided. A set of current
drawings should be maintained for equipment and support systems. For the
preventative maintenance of equipment, schedules and procedures including
assignment of responsibility should be maintained.
Written procedures for cleansing of equipment and its successive use in

intermediate and API manufacturing should be followed. A cleansing procedure
should include the following details to enable the operators to clean each type of
equipment in an effective and reproducible manner:
1 ) Assignment of responsibility for cleaning of equipment,
2) Detailed cleaning and sanitising schedules,
3) Detailed methods and materials, including dilution of cleaning agents used
for cleaning the equipment,
4 ) Guidelines for disassembling and reassembling each part of equipment to
ensure proper cleaning,
5 ) Guidelines for removing or destroying previous batch identification ,
6) Guidelines for protecting clean equipment from contamination before their use,
7) Inspection of equipment for cleanliness just before use, and
8) Establishment of maximum time that may pass between the completion of
processing and equipment cleaning.
Equipment and utensils should be cleaned, stored, sanitised , and sterilised as per
the requirement. These steps are necessary to prevent contamination or carry -
over of a material that would alter the intermediate or API quality beyond the
official limits or other established standards. Equipment should be cleaned at
appropriate intervals if is assigned to continuous or campaign production of
successive batches of the same intermediate or API . This is necessary so that
.
accumulation and carry-over of contaminants (e.g , degradants or objectionable
levels of microorganisms ) can be prevented.
Non-dedicated equipment should be cleansed between production of different

materials to avoid cross-contaminations. Detailed and clear acceptance criteria
for residues and the choice of cleansing procedures and cleansing agents should
be established. Equipment should be identified by appropriate method according
to their contents and cleanliness status.
9.1.5. Purchase Specifications for Raw Materials

Detailed written procedures should be established for the receipt , identification ,
quarantine, storage, handling, sampling, testing, and approval or rejection of
materials. A system to evaluate the suppliers of critical materials should be
controlled by the manufacturers of intermediates and/or APIs. Materials’
purchasing should be done on agreed specification from a supplier(s) approved
by the quality unit( s ). If the supplier and manufacturer of a critical material are
Equipments and Raw Materials ( Chapter 9 ) 113
not the same individuals, the name and address of that manufacturer should be
known by the intermediate and/or API manufacturer.
Receipt and Quarantine

On receiving and before accepting , each container or group of containers of
materials should be visually examined for their labelling ( correlation between the
supplier name and the in-house name, if not same), damage, broken seals, and
evidence of adulteration or contaminations. Materials should be quarantined
before their sampling, examination , testing, and release for use. Before mixing
the incoming materials with the existing stocks (e.g., solvents or stocks in silos),
they should be identified , tested , and released for use if found satisfactory .
Appropriate procedures should be followed to prevent discharging of incoming
materials wrongly into the existing stock. In case, there is a non-dedicated tanker
for bulk delivery, cross-contamination from the tanker should be avoided, and
this can be ensured by one of the following methods:
1 ) Certificate of cleaning,
2) Testing for trace impurities, and
3) Audit of the supplier.
Large storage containers and their attendant manifolds, filling, and discharge
lines should be appropriately identified. Each container or group of containers
( batches ) of materials should be labelled and identified with a distinctive code,
batch, or receipt number so that a record of the disposition of each batch can be
maintained. A system should be designed to identify the status of each batch.
Purchase Specification
Detailed guidelines defining the operational , physical , and/or chemical properties
as well as the quality and quantity of a specific item are needed.
Mode of Purchasing
1 ) By inspection , 2) By sample,
3) By description of brand, and 4) By grading.
Steps of Purchasing
1 ) Purchase requisition or application ,
2) Selection of supplies,
3) Inviting quotation,
4 ) Placing the order,
5 ) Receiving the material,
6) Checking the invoice or bill,
7 ) Recording of bills in books, and
8) Releasing the payment to the supplier.
Purchasing staff should have a specific and intense knowledge of products and
suppliers. Purchasing of raw material should be done from supplier named in
relevant specification or directly from producer. Pharmacist or chemist having
knowledge and experience of quality requirement of various material purchase
department can be the head of purchase department .
9.1.6. Maintenance of Stores for Raw Materials

The handling and storage of materials should be in such a way that degradation ,
adulteration , and cross-contamination can be prevented. Materials stored in fibre
drums, bags or boxes should be stored off the floor and suitably spaced to permit
cleaning and inspection ( whenever required ). Materials should be stored under
suitable conditions for a period that does not adversely affect their quality. They
should be controlled such that the oldest stock is used first.
Some materials can be stored in appropriate containers and placed outdoors, on
condition that the labels remain readable. Before using the stored materials, the
containers should be properly cleaned . After identification , the rejected materials
should be controlled under a quarantine system designed to prevent their unauthorised
use in manufacturing process. Given below are some standard specifications:
1) Storage Area Specifications
i) Sufficient capacity ,
ii) Clean, dry and maintained within acceptable temperature limit ,
iii) Designed and equipped reception area,
iv ) Ensuring of quarantine status,
v ) Separate sampling area ,
vi ) Segregation for storage of rejected , recalled or returned materials,
vii ) Safe area for narcotics and highly active, dangerous and risky materials,
viii ) First in First Out Rule ( FIFO ), and
ix ) First Expiring First Out ( FEFO).
2) Storage Conditions
i ) Room temperature should be 30°C and R .H. should be 60% ,
ii ) A.C. storage ( 25±2°C and R .H. 45-55% ),
iii ) Low temperature storage at 2-8°C,
iv ) Separate area for sterile product storage in A.C.,
v) Light-sensitive materials should be stored in amber coloured containers,
and
vi ) Hermetically sealed containers.
3) Labelling of Materials in Storage Area
i ) Designated name of product and internal code reference,
ii) Batch number given by supplier,
iii ) Status of content, and
iv) Expiry date or date beyond which the materials should be retested .
Note: If fully computerised system is used, there is no need to mention the
above information on the labels.
4 ) Check List before Storage
i) Integrity of package and seal , and
ii ) Correspondence note for the order, delivery and suppliers labels.
5) Check List During Storage
i) Separation of rejected, recalled, quarantine, on test, and packaging
materials, and
ii) Quality of materials.
6) Released by QC unit only.
Equipments and Raw Materials ( Chapter 9 ) 115
9.2. SUMMARY
1 ) Location, design, construction, adaptation and maintenance of equipment
should as per the operations to be carried out.
2) The pharmaceutical plant is mainly established for producing finished
products (for patients use ) by using starting and packaging materials.
3) For the manufacturing of intermediates and APIs, equipment of appropriate
design and adequate size should be used.
4) The properties associated with an item or products to be purchased include
weight, size, dimensions, quality and safety requirements, and the products
performance parameters.
5) The installation of equipment should be such that the risk of contamination
or error is minimised.
6) Detailed written procedures should be established for the receipt,
identification , quarantine, storage, handling, sampling, testing, and approval
or rejection of materials.
7) On receiving and before accepting each container or group of containers of
materials should be visually examined for their labelling ( correlation between
the supplier name and the in -house name, if not same ), damage, broken seals,
and evidence of adulteration or contaminations.
8) Detailed guidelines defining the operational , physical , and/or chemical
properties as well as the quality and quantity of a specific item are needed .
9) The handling and storage of materials should be in such a way that
degradation, adulteration, and cross-contamination can be prevented.
9.3. EXERCISE

1) What aspects should be considered while equipment selection?
2) What is the cleansing procedure of equipment ?
3) Give the modes of purchasing raw materials .
4) Give some standard specifications for the storage of raw materials.

1 ) Write about purchase specifications for equipment .
2) Discuss the maintenance of equipment .
3 ) Write about purchase specifications for raw materials.

1 ) Write an exhaustive note on equipment and raw materials used in quality control .
CHAPTER Quality Control

10
10.1. QUALITY CONTROL

lO. l . l . Introduction
In GMP, quality control deals with sampling, specifications, testing, organisation ,
documentation , and release procedures, which ensure that the necessary and
relevant tests are conducted , and materials and products are not released for use,
sale or supply till they are proved to be of satisfactory quality.
Following are the basic requirements of quality control :
1) Sufficient facilities, trained personnel and approved procedures for sampling,
inspection and testing of starting materials, packaging materials,
intermediates, bulk and finished products, and also for monitoring of
environmental conditions for GMP purposes are required.
2) Samples of starting materials, packaging materials, intermediates, and bulk
and finished products should be taken by personnel and by methods approved
by quality control department.
3) Test methods should be validated .
4) Records should be maintained either manually and/or by using recording
instruments to ensure that all the required sampling, inspection and testing
procedures were conducted. If any deviation is found, it should also be
recorded and further evaluated.
5 ) It should be ensured that the finished products contain APIs that comply with
the qualitative and quantitative composition of the marketing authorisation ,
are of the required purity, and are enclosed in properly labeled containers.
6) The results of inspection and testing of materials, intermediates, and bulk and
finished products should be recorded and formally evaluated against standards.
Product assessment should cover a review and evaluation of relevant production
documentation and an assessment of deviations from specified procedures.
7 ) All the batches of product should be analysed and approved according to the
requirements of the relevant authorisations.
8) For starting materials and products, sufficient reference samples should be
retained to permit future testing of the product ( if required ), and the product
should be retained in its final pack till the production of very large packs.
10.1.2. Quality Control Test for Containers

A container used for packing a Pharmacopoeial article contains a drug substance
or drug product with which it is or may be in direct contact. Closure is a part of
the container.
Quality Control ( Chapter 10) 117
Selection of container should be done with care and according to the nature of the
articles, and the resultant effects of transportation and storage, even for short duration.
Design of a container should be such that the contents can be removed suitably
for the intended use of the article it contains. Adequate degree of protection
should be provided by the container to reduce the loss of contents and to prevent
the physical or chemical interaction of materials with the contents, which
otherwise can alter their quality beyond the limits specified in the individual
monograph or pose a risk of toxicity.
Some commonly used containers are discussed below:
1 ) Airtight Containers: Under ordinary conditions of handling, storage and
transport, these containers are impermeable to solids, liquids, and gases. The
design of these containers should be such that if they are intended to be
opened multiple times, they should remain airtight after re-closure.
2) Hermetically Sealed Containers: Under normal conditions of handling,
shipment , storage, and distribution, these containers, e.g., sealed glass
ampoule, gas cylinder, etc., are impermeable to air or any other gas.
3) Light - Resistant Containers: These containers are made up of a material
having specific properties, due to which they protect the contents from the
effects of actinic light .
4 ) Multidose Containers: These containers can hold a quantity of the
preparation intended for two or more doses.
5 ) Sealed Containers: These containers are enclosed by fusing the material of
the container.
6) Single- Dose Containers: These containers can hold a quantity of the
preparation intended for whole or partial use as a single administration.
7) Tamper- Evident Containers: These containers are fitted with a device or
mechanism that reveals irreversibly whether the container has been opened.
8) Tightly - Closed Containers: Under normal conditions of handling,
shipment, storage, and distribution, these containers protect the contents from
contamination by extraneous liquids, solids or vapours, from loss or
deterioration of the article, and from effervescence, deliquescence or
evaporation. These containers should remain tightly re-closed after use.
9) Well -Closed Containers: Under normal conditions of handling, shipment ,
storage, and distribution , these containers protect the contents from
extraneous solids and liquids and from loss of the article.
10.1 . 2.1 . Glass Containers

Glass is economical, chemically inert , impermeable, strong, rigid, has FDA
clearance, and possesses superior protective qualities; thus, is used for packaging
pharmaceuticals. Glass containers are available in various sizes and shapes.
Glass does not get depreciated with time. If a proper closure system is provided ,
glass serves as an efficient barrier against every element ; however, only amber-
coloured glass can provide protection against light. The fragile nature and weight
of glass are its major limitations when used for packaging.
The different types of glass, their description, properties, and applications are
enlisted in table 10.1:
Table 10.1: Types of Glass Used in Pharmaceutical Industry
Types Description Properties Applications
I Highly resistant Resistant to alkali leaching Containers for buffered
,
borosilicate glass ( alkali less brittle, low thermal and unbuffered , aqueous
and earth cations are expansion , and easy to clean solutions and injectables.
replaced with boron ) and sterilise.
II Treated soda-lime glass Surface alkali is neutralised Containers for buffered,
with sulphur dioxide aqueous solutions with pH
vapours, and glass surface is below 7.0, dry powders,
resistant to water. and oleaginous solutions.
Ill Soda-lime glass Releases comparatively more Containers for dry
alkali, and offers moderate powders and oleaginous
hydrolytic resistance. solutions.
IV General purpose soda Containers for tablets, oral
lime glass solutions, suspensions,
ointments and liquids for
,
external use.
Glass containers such as ampoules, vials or bottles are used to store parenteral
preparations. Glass used for manufacturing of such containers should be
compatible with one of the requirements for hydrolytic resistance given below:
1 ) Containers made up of Type II or III glass should only be used one time.
Containers used to store human blood and blood components should be used
once. Glass containers having hydrolytic resistance more than that prescribed
for a specific type of preparation can also be used.
2) Containers for parenteral preparations are made up of colourless glass, but
coloured glass containers are used for light-sensitive drugs. In such cases, the
containers should be sufficiently transparent so that visual inspection of the
contents can be done.
Glass containers are commonly used to store either non-sterile or sterile liquid dosage
forms. The main drawback of glass material is that it leaches alkali from its surface.
Leaching process can be minimised but cannot be completely stopped; therefore, a
limit test for alkalinity is performed before using it to store a specific product.
Evaluation Parameters
Following tests are performed to evaluate glass containers:
1 ) Crushed Glass Test: This is an official test of USP in which the container is
crushed and sieved to obtain uniform particles of definite weight. Control of
the particle size and weight of powder ensures that a constant surface area is
exposed to the solution. This test is very severe because not just the surface
layer but the entire glass is examined and extraction is increased due to the
rough surfaces of the particles. If a glass passes this test , it is unlikely that
containers made from such glass may cause trouble on use. This test is
mainly used to determine the nature of a glass or to differentiate between two
types of glasses, such as neutral or surface-treated glass.
This technique is tiresome and is not used for surface-treated containers (sulphur
or silicone ) as crushing will expose the alkaline glass below the surface.
Quality Control ( Chapter 10 ) 119
2) Whole Container Test: This test is official in European , British and

International Pharmacopoeias and in USP. It is used only for treated soda-lime
containers. In this test , the test solution is filled in the containers and exposed
to the test conditions. Due to the smooth and less reactive surface layer of the
container, glassware may pass the whole container test more easily.
In this test, increase of surface area is less than the increase in volume with
the container size; accordingly, the containers of small size are more affected
by the leaching of the alkali from the surface.
3) Chemical Resistance Test: This test is official in USP and IP, and is used to
determine the chemical resistance of glass containers.
Containers Surface Areas which Supply
Alkali to Each Millilitre of the Solution
Ampoule ( lml ) 5.9 cnr
Ampoule ( 10ml ) 2.9 cm~
Bottle ( 1000ml ) 0.5 cnr
4 ) Powdered Glass Test: Under elevated conditions of temperature, alkaline
constituents ( oxides of sodium, potassium, calcium, aluminium, etc.) leach
out from the glass containers into purified water. The leaching of alkali is
increased critically if the glass is powdered.
This test is based on the principle that the amount of alkali leached from the
powdered glass is estimated. The concentration of acid required to neutralise
the released alkali ( a specific limit ) is prescribed in the Pharmacopoeia .
5) Water Attack Test: This test is used for containers exposed to sulphur
dioxide fumes under controlled humidity conditions. This treatment
neutralises the surface alkali , and makes the glass chemically more resistant.
The water attack test is based on the determination that whether or not the
alkali leaching out from the surface of a container is within the specified
limits. Because the test is performed for the inner surface, the entire
container ( ampoule ) has to be used.
To estimate the amount of acid required for neutralisation of the released
alkali from the surface, the temperature is increased for a specific time so
that leaching of alkali is accelerated .
Table 10.2: Limits of Alkalinity for Glass Containers
Tests Types of Glass Limits of Alkalinity
1 ) Powdered Glass Test Type - 1 1.0
Type - 111 8.5
Type NP
- 15.0
2 ) Water Attack Test Type - II ( 100ml of less ) 0.7
Type - 11 ( Over 100ml ) 0.2
6) Thermal Shock Test: In this test, the samples are kept in a tray in an
upright position and then immersed into hot water for a given time period.
Then , the tray is transferred to cold water bath . Sample containers are
examined before and after the tests are performed for outside surface cracks
or breakage.
7 ) Internal Bursting Pressure Test: In this test, the container is filled with
water and placed inside the test chamber. The head of the container is sealed
and the internal pressure is automatically raised by series of increments for a
fixed time. The bottle can either be examined to a pre-selected pressure level
or the test is continued till the container bursts.
8) Annealing Test: In this test, the sample containers are examined by
polarised light in either a polariscope or strain viewer. Then , the strain
pattern is compared against standard discs or limit samples.
9) Vertical Load Test: In this test, the bottle is kept between a fixed platform
and a hydraulic ramp platform that is gradually raised so that a vertical load
is applied and the applied load is registered on pressure gauge.
10 ) Autoclaving ( 121 ° C for 60 minutes ) : In this test, the ability of a filled or
empty container to endure the conditions of autoclaving is checked.
10.1 .2.2. Plastic Containers

Plastic used as a material for container is composed of thermoplastic polymer.
This polymer forms the basic organic structural unit for each plastic type, and is
commonly used in medical field. The plastic materials used in medical field are
added with a less amount of ingredients; however plasticisers, fillers, antistatic
agents, antioxidants, and other ingredients are added in large amounts to some
plastic materials used for special purposes.
Plastic containers are used because of their light weight, non -breakable nature,
low toxicity, and low reactivity with the products ( provided they contain fewer
amounts of additives).
Drug Plastic Consideration
It includes the following tests:
1) Permeation: The shelf-life of a drug can be adversely affected by the transmission
of gases, vapours, or liquids through plastic packaging materials. In case the
dosage form is sensitive to hydrolysis and oxidation, major problems occur due to
water vapour and oxygen permeation into the drug through the plastic wall. The
permeability of oxygen and water through plastic is influenced by temperature and
humidity. The permeability of gas increases due to increase in temperature.
2) Leaching: Most of the plastic containers are added with small quantities of
one or more ingredients to stabilise the plastic from leaching or to prevent the
migration of particles from the container to the product. When colouring
agents are added in small quantities, some major problems may arise.
Sometimes drug product in a plastic container gets contaminated due to
release of a constituent from the container to the product . In such a case, the
drug products should be removed from the market.
3) Sorption: It is a phenomenon in which solute particles bind to plastic
molecules. In this process, constituents are removed from the drug product
by the packaging material. Sorption may adversely affect the therapeutic
efficacy of a drug preparation in which ingredients are in solution . Because
the drug substances of high potency are administered in small doses, losses
due to sorption may cause some other major problems.
Quality Control (Chapter 10) 121
4 ) Chemical Reactivity: Some ingredients found in plastic containers may

react chemically with one or more components of a drug product.
Sometimes, ingredients in the formulation may react with the plastic.
Chemically incompatible substance if present even in micro quantities, can
alter the appearance of the plastic or the drug product.
Tests on Plastic Containers for Parenteral and Non-Parenteral Preparations

Following tests are performed for containers of parenteral and non-parenteral
preparations:
1) Leakage Test: In this test, 10 containers are Filled with water, fitted with
intended closures, and kept inverted at room temperature for a day. The
container passes the test if there are no signs of leakage from any container.
2) Collapsibility Test: In this test, the containers are squeezed to remove the
contents. At ambient temperature, a container by collapsing inwards during
use yields 90% of its nominal contents at the required rate of flow.
3) Clarity of Aqueous Extract: Unlabelled, unmarked and non -laminated
portions are randomly selected from suitable containers to yield a total area
of sample required , considering the surface area of both sides. These selected
portions are cut into strips in such a way that none of them has a total area of
more than 20cm 2. The strips are washed and shaken with two separate
portions of distilled water for 30 seconds to remove extraneous matter. Then
the water is drained out thoroughly.
4 ) Transparency Test: Five empty containers are filled up to their nominal
capacity with diluted suspension ( described in IP 1966 ). Each container is
viewed to detect the cloudiness of diluted suspension and then comparing
them with a container of the same type filled with water.
5 ) Water Vapour Permeability Test: Five containers are filled with nominal
volume of water and heat -sealed with an aluminium foil-polyethylene laminate
or other suitable seal. Each container is weighed accurately and left
undisturbed ( without any overwrap) for 2 weeks at relative humidity of 60±
5% and temperature between 20-25°C. Then, the containers are weighed again
and they pass the test if loss in weight in each container is not more than 0.2% .
10.1 .3. Quality Control Test for Rubber Closures

As far as the stability and compatibility with the product is concerned , closures
are the most vulnerable and critical component of a container. For a container ,
suitable closures are necessary because:
1 ) Loss of material by spilling or volatilisation is prevented,
2) Deterioration of the product from environmental conditions, like moisture,
oxygen, or carbon dioxide, is prevented, and
3) Product contamination from dirt , microorganisms, or insects is prevented.
For a container of an aqueous parenteral preparation or a sterile powder, its

closure is a packaging component that remains in direct contact with the drug.
The material for rubber closures is made by vulcanisation (cross-linking) of
elastomers with suitable additives. Elastomers are natural or synthetic substances
obtained by polymerisation , polyaddition, or polycondensation. The required

properties for the finished closures influence the nature of the principal
components and of the various additives, such as vulcanisers, accelerators,
stabilisers, pigments, etc.
Rubber closures are used for different formulations, and thus different closures hold
different properties. The closures selected for use with a particular preparation should
be such that the components of the preparation in contact with the closure should not
adsorb onto its surface to an extent that adversely affects the product quality.
Test for Closures

Following tests are performed for rubber closures:
1 ) Penetrability: This test measures the force needed for easy penetration of
hypodermic needle through the closure. Piercing machine is used to measure
penetrability. The piercing force should not exceed the standard
value, otherwise, the hypodermic needle can be damaged due to undesirable
hardness of the closures.
2 ) Fragmentation Test: 20 closures are selected and each is penetrated with
hypodermic needle in a piercing machine five times within a limited area .
Then , the needle is washed to transfer any fragment present. A coloured
paper that contrasts with the rubber is used to filter the contents so that the
fragments can be counted. There should not be more than three fragments per
unit on an average.
-
3) Self Sealability Test: This test is applicable to multidose containers. In this
test, 10 vials are filled with water, closed with prepared closures and secured
with a cap. A new hypodermic needle is used for each closure, and each time
piercing is made 10 times at different site. Thereafter, the vials are immersed
upright in 0.1% methylene blue solution and the external pressure is reduced
for 10 minutes. The atmospheric pressure is restored and the vials are left
immersed for 30 minutes. The outer side of the vials is rinsed and it is
ensured that none of the vials contain any trace of coloured solution.
4 ) Extractive Test: In this test , the closure is boiled in water for 4 hours under
reflux and the water is evaporated to dryness. The test is successful if any
residue does not exceed the specified amount .
5) Compatibility Test: This test determines the compatibility of the rubber
closures with various types of substances because it is important to ensure
that the contents of the bottle do not interact with the closure.
10.1.4. Quality Control Test for Secondary Packing Materials

The materials employed in secondary packaging covers the primary package. This
type of packaging forms an outer wrapping to store, transport, inform, display, and
protect the product. An example of a secondary package is decorated cartons.
Materials Used
1 ) Paper: This is used as a flexible wrap for products and sometimes as a
closure material for jars. Generally, the paper materials are applied with a
liner either as a laminate or coating.
Quality Control ( Chapter 10 ) 123
2 ) Pharmaceutical Corrugated Fibreboard: This paper-based material having

fluted corrugated sheet and one or two flat linerboards is used for
manufacturing corrugated boxes .
3) Carton: This is used for packing food, pharmaceuticals, hardware , and other
products. Folding cartons are combined into a tube at the manufacturer and
shipped flat ( knocked down ) to the packager.
Tests for Paper and Board
In these tests, the pieces of paper and board are conditioned for the tests under standard
conditions of temperature (-23°C ± 1 °C) and relative humidity (-50% ± 2% ).
Table 10,3: Tests for Paper and Board
Name of the Tests Description
Moisture content At temperature specified all the substances are measured
for test.
Folding endurance Test piece is folded back and forth until rupture occurs.
Density of paper and board Suitable lor rigid cellular materials.
Method for determining air It is important for uncoated lightweight paper on machine
~l
having vacuum pick up system and is represented in pmpa ' s .
~
permeability
Grammage or substance It is the weight of material measured per unit area of
( g/ nr ) sample.
Paper calliper Single sheet thickness is used between one surface and other.
Tensile strength It is the maximum tensile force measured per unit width
that a paper or board can withstand before breaking.
Tear strength It is the mean force applied for continuous tearing of an
initial cut in a single sheet of paper.
Burst strength It is the maximum uniformly distributed pressure applied
at right angles to surface that a test piece of paper and
board will stand under test conditions. Hydraulic pressure
is applied to diaphragm , bulging it until the piece bursts.
Puncture resistance Energy is applied to make initial puncture.
Stiffness of thick paper and When paper /board is bent , a degree of resistance is
boards offered .
Creasibility of boards This test determines the creasing quality of board within
the range of 300- 1000 pm.
Cobb test ( g/ m 2 ) This test measures water absorbency.

Rub resistance This test measures the resistance of printed test piece to
withstand rubbing against another similar test piece.
Pick test/IGT test A specific amount of special oil is added to the printing
system, printed on to the test piece, and then the surface is
examined for signs of pick.
pH, chloride or sulphate The acidity or alkalinity ( pH ) is important to measure the
life of the paper board.
Roughness/smoothness It determines the printability of the paper.
Brightness It is the reflectance factor measured at effective
wavelength of 457nm.
Opacity It is the ratio expressed as percentage of luminous
reflectance factor of a single sheet of paper with a black
backing to intrinsic luminous reflectance factor.
Dennison wax test It is an old test and is replaced by the IGT test.
Wet burst strength It determines wet bursting strength of any paper or board
when immersed in water .
Wet tensile strength It determines the wet tensile strength when immersed in
water.
Ash in paper and board It determines the ash content in paper and board .
Detection and estimation of It is applicable for substances having a strong affinity for
nitrogenous agents in paper acid dyes.
Ink absorbency It determines the ink absorbency of paper and board by K
and N ink.
Test for Cartons

1 ) Compression: This test determines the strength of erected package .
2) Carton Opening Force: This test is used to hold the flat carton as delivered,
by its creases between thumb and first finger press .
3 ) Coefficient of Friction: By this test , static as well as kinetic coefficients of
friction are determined by sliding the sample over itself under specific test
conditions .
4 ) Crease Stiffness: This test is used for testing a carton board piece, folding it
through 90° , and then trying to recover its former position when bending
force is removed .
5 ) Joint Shear Strength: This test is used for testing the glued lap seam on the
side of a carton for strength of the adhesive using a tensile testing machine .
10.2. SUMMARY
1 ) Selection of container should be done with care and according to the nature
of the articles, and the resultant effects of transportation and storage , even for
short duration.
2) Design of a container should be such that the contents can be removed
suitably for the intended use of the article it contains .
3 ) Under ordinary conditions of handling, storage and transport , airtight
containers are impermeable to solids, liquids , and gases .
Quality Control ( Chapter 10) 125
4) Under normal conditions of handling, shipment, storage, and distribution,

hermetically sealed containers are impermeable to air or any other gas.
5) Light-resistant containers are made up of a material having specific properties,
due to which they protect the contents from the effects of actinic light.
6) Multidose containers can hold a quantity of the preparation intended for two
or more doses.
7) Sealed containers are enclosed by fusing the material of the container.
8) Single-dose containers can hold a quantity of the preparation intended for
whole or partial use as a single administration.
9 ) Tamper-evident containers are fitted with a device or mechanism that
reveals irreversibly whether the container has been opened.
10) Under normal conditions of handling, shipment, storage, and distribution ,
tightly -closed containers protect the contents from contamination by
extraneous liquids, solids or vapours, from loss or deterioration of the article,
and from effervescence, deliquescence or evaporation.
11) Under normal conditions of handling, shipment , storage, and distribution,
well -closed containers protect the contents from extraneous solids and
liquids and from loss of the article.
12 ) Glass is economical , chemically inert , impermeable, strong, rigid, has FDA
clearance, and possesses superior protective qualities; thus, is used for
packaging pharmaceuticals.
13) Crushed glass test is an official test of USP in which the container is
crushed and sieved to obtain uniform particles of definite weight.
14 ) Whole container test is used only for treated soda-lime containers.
15 ) Chemical resistance test is official in USP and IP. and is used to determine
the chemical resistance of glass containers.
16 ) Powdered glass test is based on the principal that the amount of alkali
leached from the powdered glass is estimated.
17 ) Water attack test is used for containers exposed to sulphur dioxide fumes
under controlled humidity conditions.
18) Plastic used as a material for container is composed of thermoplastic polymer.
19) Most of the plastic containers are added with small quantities of one or more
ingredients to stabilise the plastic from leaching or to prevent the migration
of particles from the container to the product .
20) The shelf -life of a drug can be adversely affected by the transmission of
gases, vapours, or liquids through plastic packaging materials.
21 ) Sorption is a phenomenon in which solute particles bind to plastic
molecules.
22 ) Penetrability test measures the force needed for easy penetration of
hypodermic needle through the closure.
23) Self -sealability test is applicable to multidose containers.
24 ) Compatibility test determines the compatibility of the rubber closures with
various types of substances because it is important to ensure that the contents
of the bottle do not interact with the closure.
25 ) The materials employed in secondary packaging covers the primary package.

26 ) Paper is used as a flexible wrap for products and sometimes as a closure
material for jars.
27 ) Pharmaceutical corrugated fibreboard having fluted corrugated sheet and
one or two flat linerboards is used for manufacturing corrugated boxes.
28) Carton is used for packing food , pharmaceuticals, hardware, and other
products.
29 ) Compression test determines the strength of erected package.
30 ) Carton opening force test is used to hold the flat carton as delivered , by its
creases between thumb and first finger press.
31) Coefficient of friction test determines the static as well as kinetic
coefficients of friction by sliding the sample over itself under specific test
conditions.
32 ) Crease stiffness test is used for testing a carton board piece, folding it
through 90°, and then trying to recover its former position when bending
force is removed.
33) Joint shear strength test is used for testing the glued lap seam on the side of
a carton for strength of the adhesive using a tensile testing machine.
10.3. EXERCISE
1) Give any two basic requirements of quality control .
2) What are sealed and tamper evident containers?
3) What is the major limitation of using glass container?
4) Write about the crushed glass test .
5) What is leaching?
6) Give the transparency test for plastic containers .
7) How compatibility test for rubber closures is performed ?
8) How cartons are tested for quality control ?

1 ) Write about the quality control test for containers .
2) Discuss the tests performed to evaluate glass containers .
3) Write a note on the quality control tests for plastic containers .
4 ) Give a short review on the quality control tests for rubber closures .
5 ) Discuss the quality control tests for paper and board .

1 ) Write an exhaustive note on quality control tests for containers .
2) Briefly detail the quality control tests for secondary packaging materials.
Good Laboratory Practices ( Chapter 11 ) 127
CHAPTER Good Laboratory

11 Practices
11.1. GOOD LABORATORY PRACTICES

Good Laboratory Practice ( GLP) is a set of principles that ensure the quality and
integrity of non-clinical laboratory studies designed to support research or
marketing of products regulated by government agencies. The term GLP is
associated with the pharmaceutical industry and the required non-clinical animal
testing to be performed before the approval of new drug products. However, GLP
term applies to many other non -pharmaceutical agents also such as colour
additives, food additives, food contamination limits, food packaging , and medical
devices.
New Zealand and Denmark are the countries where GLP was first introduced in
1972. GLP was instituted in US after the fraud cases generated by toxicology
labs in data submitted by pharmaceutical companies to the FDA. Industrial
BioTest Labs ( IBT) was the most notable case in which numerous safety tests for
chemical manufacturers were said to have been performed ( in actual they were
not performed or were so poor that investigators could not determine the work
that had been done ). These issues were made public in the hearings at the US
Congress, and this led to the publication of Proposed Regulations on GLP by
FDA in 1976, with establishment of the Final Rule in June 1979 ( 21 CFR 58).
Similar problems were faced by the Environmental Protection Agency ( EPA ) that
issued its own draft GLP regulations in 1979 and 1980, and published the Final
Rules in two separate parts (40 CFR 160 and 40 CFR 792) in 1983. In 1981,
OECD ( Organisation for Economic Co-operation and Development ) produced
GLP principles that are international standards.
11.1 . 2. General Provisions

The GLP regulations set out rules for good practice and assist the researchers to
work in compliance with their own pre-established plans and standard
procedures. The regulations neither include the scientific or technical content of
the research programmes, nor evaluate the scientific value of the studies.
All GLP texts, regardless of their origin , state the importance of the following:
1 ) Resources: Organisation, personnel, facilities, and equipment.
2) Characterisation: Test items and test systems.
3) Rules: Study plans ( or protocols) and written procedures.
4) Results: Raw data, final report, and archives.
5) Quality Assurance.
Scope
The GLP principles should be applied to the non -clinical safety testing of test
items in pharmaceuticals, pesticides, cosmetics, veterinary drugs, food and feed
additives, and industrial chemicals. These test items are mainly synthetic
chemicals, but some of them may be natural or biological or even living
organisms. These test items should be tested to obtain data on their properties
and/or their safety with respect to human health and/or the environment.
Non-clinical health and environmental safety studies covered by the GLP

principles include work conducted in the laboratories, greenhouses, and fields.
These principles, unless specifically exempted by national legislation , are applied
to all non-clinical health and environmental safety studies that are required by
regulations for registering or licensing pharmaceuticals, pesticides, food and feed
additives, cosmetics, veterinary drugs and similar products, and for the regulation
of industrial chemicals.
Definitions of Terms
1 ) Good Laboratory Practice ( GLP): It is a quality system related to the
organisational process and the conditions under which non-clinical health
and environmental safety studies are planned , performed , monitored ,
recorded , archived, and reported .
2) Terms Related to the Organisation of a Test Facility
i ) Test Facility: It indicates the people, premises, and operational unit(s)
required for conducting the non -clinical health and environmental safety
studies. The test facility for multi -site studies ( conducted at more than
one site) comprises the site at which the Study Director is present and all
individual test sites that alone or together can be considered to be test
facilities.
ii ) Test Site: It indicates the location ( s ) at which a phase(s ) of a study is
conducted.
iii ) Test Facility Management: It indicates the people with the authority
and responsibility for organisation and functioning of the test facility as
per the GLP principles.
iv) Test Site Management: It indicates the people with the responsibility to
ensure that the phase(s) of the study, for which they are responsible, are
conducted as per the GLP principles.
v) Sponsor: It is an entity that commissions, supports, and/or submits a
non-clinical health and environmental safety study.
vi ) Study Director: It is the person with the responsibility to conduct the
non-clinical health and environmental safety study.
vii) Principal Investigator: It is the person who acts on behalf of the Study
Director for a multi-site study and has the responsibility to conduct
delegated phases of the study . Approval of the study plan and its
amendments, approval of the final report , and ensuring that all GLP
principles are being followed are the responsibilities of the Study

Director for the overall conduct of the study. These duties cannot be
delegated to the Principal Investigator( s).
viii ) Quality Assurance Programme: It is a defined system, including
personnel, which is independent of study conduct and assures that test
facility management is in compliance with GLP principles.
ix ) Standard Operating Procedures (SOPs ): These are documented
procedures that describe how to perform tests or activities not specified
in detail in study plans or test guidelines.
x ) Master Schedule: It is a compilation of information that aids in the
assessment of workload and tracking of studies at a test facility.
3 ) Terms Related to Non -Clinical Health and Environmental Safety Study
i) Non- Clinical Health and Environmental Safety Study : It indicates an
experiment or set of experiments in which a test item is examined under
laboratory conditions or in the environment to obtain data on its properties
and/or its safety, and submit it to the concerned regulatory authorities.
ii ) Short -Term Study: It is a study of short duration with widely used,
routine techniques.
iii ) Study Plan: It is a document defining the objectives and experimental
design for conducting the study , and including any amendments.
iv ) Study Plan Amendment : It is an intended change to the study plan after
the study initiation date.
v ) Study Plan Deviation: It is an unintended deviation from the study plan
after the study initiation date.
vi ) Test System: It is a biological, chemical or physical system or a
combination used in a study.
vii ) Raw Data: It is the original test facility records and documentation or
verified copies of the results of original observations and activities in a
study. Raw data also includes photographs, microfilms, microfiche
copies, computer-readable media, dictated observations, recorded data
from automated instruments, or any other data storage medium that
provides secure storage of information for a time period .
viii ) Specimen: It is a material derived from a test system for examination,
analysis, or retention.
ix ) Experimental Starting Date: It is the date on which the first study
specific data are collected.
x ) Experimental Completion Date: It is the last date on which data are
collected from the study.
xi ) Study Initiation Date: It is the date on which the Study Director signs
the study plan.
xii ) Study Completion Date: It is the date on which the Study Director signs
the final report.
4 ) Terms Related to the Test Item

i ) Test Item: It is an article that is the subject of a study.
ii ) Reference or Control Item: It is an article that provides a base for
comparison with the test item.
iii ) Batch: It is a specific quantity or lot of a test item or reference item
produced during a defined cycle of manufacture in a way that it can be
expected to be of a uniform character and should be designated as such.
iv ) Vehicle: It is an agent that serves as a carrier used to mix, disperse, or
solubilise the test item or reference item to facilitate the administration/
application to the test system.
11.1.3. Organisation and Personnel

There should be a defined organogram of the laboratory, and responsibility and
duties at various levels should be well-defined and documented. Every individual
in the laboratory who is engaged in the conduct of testing should have the desired
educational qualification , training, and experience to perform the assigned
function. A sufficient number of personnel should be available for performing the
studies in accordance with protocols. The personnel should take necessary
precautions to avoid contamination of test and control article of the test systems.
They should be provided with appropriate clothing that will prevent
contamination. The personnel should undergo medical examination to know
about their health status and ensure they do not have any infection which might
serve as a source of contamination.
The test facility should have adequate personnel with required qualification ,
experience, training, and approval from regulatory authorities to carry out the
assigned functions in a timely manner as per the GLP principles. A job
description should be maintained for all the personnel in the test facility. This
description should cover every individual involved in testing, analysing, or
supervising the analysis. It should also specify the limits of authority at each
level or category. The training record for every individual cross-referenced with
the job description and departmental training including material safety data sheet
should be available.
The test facility manager should have sufficient qualification , experience,

training, and authority to ensure that the test facility is following the GLP
principles. The test facility manager also ensures that the personnel are aware of
the functions they have to perform, and provide training for these functions. As
per the Indian Drugs & Cosmetics Act and Rules, each area of operations in the
laboratory should have an approved competent technical staff to conduct the tests
and/or sign off the documentation .
11.1 .4. Facilities

The test facility should have a direct access to personnel working in them so that
they do not need to enter the facility through the manufacturing area. Thus, the
facility should be located away from manufacturing areas. This is mainly
important for laboratories involved in the control of biologicals, microbiologicals,

and radioisotopes, and these laboratories should also be separated from each
other. Entry of unauthorised personnel or those who do not work in the test
facility should not be allowed. Laboratory personnel should be allowed to enter
the production areas for sampling and investigation, whenever needed.
Facilities should be designed to be suitable for the operations to be performed.
Proper lighting, temperature, humidity, and ventilation should be maintained
such that they do not adversely affect the products under test or the accurate
functioning of equipment. If sterility testing is to be performed, aseptic
production conditions should be maintained in the area , and gowning and entry
procedures should also be followed. Sterility test should be conducted under
Grade A conditions in a laminar flow module placed in class 100 conditions.
Sufficient space should be available to prevent mix -ups and cross-contamination.
Adequate storage space should also be available for samples and records.
Animal Facility
The animal facility should be designed and operated in a manner to reduce the
effects of environmental variables on animals. Steps should be taken to avoid
direct contact of the animal with disease or with a test item other than the one
being analysed. Requirements for animal facility differ depending on the nature
and duration of the studies being performed. The contamination risks can be
reduced through a barrier system, in which all supplies, staff and services cross
the barrier in a controlled way. Contamination can also be minimised by
providing clean and dirty corridors for the movement of new and used supplies.
A well-designed animal house would maintain separation by providing areas for:
1 ) Different species,
2) Different studies,
3) Quarantine,
4) Changing rooms,
5) Receipt of materials,
6 ) Storage:
i ) Bedding and diet,
ii) Test doses, and
iii ) Cages.
7) Cleaning equipment ,
8) Necropsy,
9) Laboratory procedures,
10) Utilities, and
11 ) Waste disposal.
The building and its rooms should provide adequate space for animals and
studies to be separated and to allow the operators to work efficiently. The
environment and control system should maintain the temperature, humidity, and
airflow at the defined levels depending on the species being tested. The walls,
doors, floors, and ceilings should be constructed such that they can be easily and
thoroughly cleaned. No gaps or ledges should be present to prevent the
accumulation of dirt , dust , or water.
If sensible working procedures are followed, the potential danger to the study
from outside influences can be reduced and a degree of separation can be
maintained between the activities. Adequate separation can be achieved by:
1 ) Allowing less number of staff to enter the building,
2) Restricting entry into the animal rooms,
3) Organising workflow so that clean and dirty materials are moved around the
facility at different times of day ( if the construction of the facility does not
permit other solutions ) and the corridors are cleaned between these times,
4 ) Requiring staff to put on different clothing in different zones within the
facility, and
5) Ensuring that rooms are cleaned and sanitised regularly, particularly between
studies.
Control Samples or Reference Samples

Control or reference samples are stored in a separate room equipped with
temperature and humidity control to maintain the storage conditions stated on the
labels of the materials being tested. Ventilation requirements should be
maintained depending on the activities being performed , like extraction , handling
of fuming chemicals, organic solvents, distillation involving heating, etc. The
personnel should wear protective equipment, a distinctive overall or lab-coat, in
the laboratory.
If part or all of the testing is contracted out and a contract testing laboratory is
used, this should be audited and approved in compliance with GLP. A technical
agreement should be made between the contract giver and the contract acceptor
with a system to provide updated authorised analytical methods and
specifications for the involved analysis. A change control system should also be
designed with the contract testing laboratory.
11.1 . 5. Equipment
The laboratory instruments and equipment should be qualified and calibrated as
per the manufacturer s recommendations and Pharmacopoeial requirements. The
'
test instruments and equipment should have unique identification numbers ( for
their use, cleaning, calibration, service, and maintenance ) that can be linked to
analytical raw data, calibration reports, and logbooks.
Sensitive instruments should be placed in separate climate -controlled rooms to

protect from electrical interference, humidity, vibrations, etc.
To conduct a stability study in a proper manner, appropriate equipment of

adequate capacity should be used. All the equipment should be suitable for their
proposed use, and should be properly calibrated and maintained so that they
function reliably and accurately. Records of repairs and routine maintenance and
any non-routine work should be maintained. The purpose of these GLP
requirements is to ensure the reliability of data generated and to ensure that the
data are not invalidated or lost as a result of inaccurate, inadequate or faulty
equipment.
Suitability
Suitability can be evaluated by considering the tasks that the equipment is to
perform. There is no need to have a balance that can weigh to decimals of a
milligram to obtain the weekly weight of a rat, but a balance of this precision
may be required in the analytical laboratory. Deciding on the suitability of
equipment is scientific responsibility and is defined in SOPs.
Calibration
..
The equipment used for data generation ( e g , analytical equipment or balances )
..
or for maintaining standard conditions ( e g , refrigerators or air conditioning
equipment ) should work as per the established specifications. Whether or not the
specifications are being met is evaluated by periodic checking.
In case of measuring equipment, the use of standards is involved, for example, a

balance is calibrated with known standard weights. In case of analytical equipment,
a sample of known concentration is used to ensure that the equipment is
functioning properly and is also providing a base for determining the final result.
Other equipment, such as air conditioning systems for animal facilities or constant
temperature storage rooms, is periodically checked using calibrated instruments
(such as probes and thermometers ). If the equipment is found to be not operating
within specifications, verifications should be performed at a frequency that allows
taking action in time to prevent any adverse effect on the study.
Maintenance
The equipment should be properly maintained to ensure their constant
performance to specifications and to reduce unexpected breakdown and
consequent data loss. Maintenance of equipment can be carried out in the
following two ways:
1 ) Preventive Maintenance: This is required when parts are changed regularly
based on the expected life of the part concerned . Planned maintenance of this
type is a useful precaution for large items of equipment or items that do not
have suitable backup or alternatives. Thus, regular preventive maintenance
reduces the risk of breakdown.
2 ) Curative Maintenance: This is required when repairs are made in case of a
fault being detected. This type of maintenance is applied to modern computer
driven analysers or electronic balances that do not easily lend themselves to
preventive maintenance. Contingency plans should be adopted in case of
failure , e.g., having equipment duplicated or assuring immediate access to a
maintenance technician or an engineer.
Back up for vital equipment and also in case of service failures (such as power
cuts ) should be available whenever needed. A laboratory should continue with
essential services to prevent the loss of animals or data, and studies irreversibly
affected. For example , a laboratory where animal studies are conducted should
have a stand-by generator to maintain the animal room environment, even if it
..
does not allow the laboratory to function completely as normal, e g , test item
analysis can be done after the power is restored .
An early warning should be given about the malfunctioning of equipment and the
checking interval should be assigned to assure this. Alarms should be equipped
as they are important especially in cases when a problem occurs in the absence of
staff in the laboratory.
11.1 .6. Testing Facilities Operations

Test facility operation requires written, accurate, current , approved, available,
and reviewed SOPs that follow all the routine procedures required for a GLP
study.
Standard Operating Procedures ( SOPs )
A complete set of good SOPs is an essential requirement for successful
compliance of GLP principles. Setting up the SOP system is the most important
and time-consuming compliance task.
Even without GLP regulations, classical quality assurance techniques need good
management , and standardised, approved , written working procedures. For
implementing SOPs successfully, the following requirements are necessary:
1 ) Sustained and enthusiastic support from all management levels, along with
the commitment to establish SOPs as an essential element in the organisation
and culture of the laboratory.
2) SOP-based education and training of personnel so that everyone in the staff
performs the procedures in the same manner.
3) A sound SOP management system so that current SOPs are available in the
right place at the right time.
SOP System Overview
The SOP system should include the following characteristics:
1 ) Total integration into the laboratory system of master documentation ( i.e.,
not a separate system in potential conflict with memos or other means of
conveying directives to laboratory personnel ).
2) Comprehensive coverage of:
i) All critical phases of study design , management , conduct, monitoring,
and reporting.
ii ) Scientific administrative policies and procedures (e.g., formats, safety
and hygiene, security, personnel management systems, etc.).
iii ) Standard scientific techniques, equipment , etc.
3) Readability: The SOPs should have a standard layout. The procedures
should be written or translated into the local language of the operational
personnel using an appropriate vocabulary. The personnel should be
motivated to make improvements in the SOPs. It is good to encourage the
people who perform the procedures to write the instructions; this promotes
their sense of responsibility towards their work.
4 ) Usability and Traceability: A two-tier system of SOPs is preferred for
reasons of traceability and easy use. For example, one- tier reflects general
..
policies and procedures ( e g , protocol writing, review, approval, distribution
and modification, general rules for equipment use and maintenance, archives,
..
etc.), and two-tier represents technical methods ( e g , methods of staining in
histology, analytical methods, specific procedures for use and maintenance of
equipment , etc.).
The SOPs should be presented in binders or manuals having updated table of
contents and logical chapter divisions. In some laboratories, SOPs are
available directly from a screen, but special rules about printing out the SOPs
(expiry dates, etc.) and rules about signatures need to be implemented. Any
alterations in SOPs should be made through formal revisions; notes and
changes as hand-written margin comments are not admissible. One should
have a change control procedure for modifying SOPs.
5 ) Understanding: The staff should have complete knowledge about the SOPs
in use and also follow them thoroughly. If any deviations occur,
communication with the Study Director and management should ensure that
the GLP requirements are being met and credibility of the system is being
maintained.
6 ) Responsibility: Someone should be responsible for each SOP to handle
queries and keep each procedure modernised. The SOPs should be
periodically reviewed ( at interval of 2 years).
7 ) Change Control: A formal system should be established to allow historical
reconstruction. An SOP system even if working properly seems to be
incomplete because of additions, deletions and modifications reflecting the
normal rate of improvements or changes. Changes and amendments are good
evidence that the SOPs are used in the laboratory. Therefore, updation
process of the SOPs should be easy and rapidly approved, without requiring
many signatories.
8) Centralised Organisation: It is preferred for formatting, numbering, issuing,
modifying, and removing SOPs. This prevents duplication of effort, irregularity
between SOPs, delays, lack of traceability, and incomplete distribution.
9) Availability: SOPs should be immediately available to the person doing the
work.
10 ) Archiving: All the removed SOPs, whether no longer in use or replaced with
an updated version , should be archived to make a historical record of all the
test facility’s procedures.
Properly designed SOPs bring about the following benefits to the laboratory:
i ) Gives standardised and consistent procedures that reduce person -to-
person and test-to-test variability.
ii) Gives an opportunity to optimise the processes.
iii ) Makes technical and administrative improvements.
iv) Demonstrates the management commitment to quality as part of the SOP
approval process.
v) Eases the complicated documenting techniques in study protocols and
reports.
vi ) Maintains continuity in case of personnel turnover.
vii ) Used as a training manual.
viii ) Provides a means of study reconstruction even after several years of the
event.
ix Provides a means of communication in case of audits, visits, technology
)
transfer, etc.
Most laboratories practice the necessary characteristics by using the
following approach:
i ) A two tier system,
ii ) A defined format,
iii ) Thorough review, including QAU review,
iv ) Formal approval by at least two people:
a) A designated author, and
b ) An appropriate member of test facility management.
v) A formal change control system coordinated by a designated
person/group, and
vi ) A standardised and traceable procedure for issuing/archiving/retirement
of SOPs.
11.1 .7. Test and Control Articles

1 ) Receipt, Handling, Sampling, and Storage
i ) Records including test item and reference item characterisation, date of
receipt , expiry date, quantities received and used in studies should be
maintained.
ii ) Handling, sampling and storage procedures should be identified so that
the homogeneity and stability are assured to the degree possible and
contamination or mix-up is precluded.
iii ) Storage containers should bear identification information , expiry date,
and specific storage instructions.
2) Characterisation
i ) Each test and reference item should be appropriately identified ( e.g.,
.
code Chemical Abstracts Service Registry Number [CAS number ],
name, and biological parameters ).
ii ) For each study, the identity, batch number, purity, composition,
concentrations, or other characteristics that define each batch of the test
or reference items should be known.
iii ) If the test item is supplied by the sponsor, a mechanism should be
developed in the test facility by coordinating with the sponsor to verify
the identity of the test item subjected to the study.
iv) The stability of test and reference items under storage and test conditions
should be known.
v) If the test item is administered or applied in a vehicle, its homogeneity,
concentration and stability in that vehicle should be determined. For test
items used in field studies ( e.g., tank mixes), the above mentioned
parameters can be determined through separate laboratory experiments.
vi ) Except for the short-term studies, a sample for analytical purposes from
each batch of test item should be retained for all studies.
11.1 .8. Protocol for Conduct of a Non-Clinical Laboratory Study

The laboratories should develop a well -defined protocol to conduct the tests.
They should have prescriptive documents to direct the scientific studies. The
purpose of these is to:
1 ) State general policies, decisions, and principles applied at the institution ,
2 ) Instruct staff on the way to carry out operations within the study, and
3) Provide retrospective documentation of what was planned.
The document is of three main types, i.e., policy statements. SOPs describing
routine laboratory activities, and study plans or protocols detailing on how to
organise the work for each study. GLP attaches particular importance to study
plans and SOPs.
11.1 .8.1 . Study Plan or Protocol

Protocol is a pivotal document that the study director uses to communicate
his/her planned study organisation to the staff and to the third parties ( the QAU
or sponsor ). If the study is conducted by a Contract Research Organisation
( CRO ), the protocol may also form the basis for the contract between the sponsor
and CRO.
Protocol describes the study design, contains a time schedule and various stages
of the study, and indicates the methods and materials to be employed in the
study. Protocol is the principal means of instruction for the staff about how to
perform the study, and its contents, and a suitable style and layout.
11.1 .8.2. Content of the Protocol

The protocol content should be coherent with the scientific requirements of the
study and should also comply with the GLP principles.
Identification
Identification by a study number provides a means of identifying the laboratory
records associated to the study and of confirming the identity of data generated
during the study. There are no set of rules for the numbering system used.
Title and Statement of Purpose

The study should be given an informative and a short title. It should include the
test item name, the type and duration of the study , and the test system . It is
important to define the purpose of conducting a study, and the purpose should be
pre-determined. By stating the purpose of study in the protocol it is ensured that
the study results cannot be utilised for an unsuitable end. The study purpose can
be based on both scientific and regulatory considerations.
Identification of Test and Control Items

The chemical name and/or code number of the test item, its specifications or
characterisation, its stability, and details on how these will be determined should
be mentioned in the protocol. The details on active control materials to be used
additionally should also be given to provide information on the vehicle.
Names and Addresses of the Sponsor, the Test Facility, and Test Site(s)
It is not necessary that the sponsor and the test facility are of the same
organisation. The protocol should mention the location where the study is to be
conducted and also the address of any contract organisation or consultant
involved in the study. In case of multi -site studies, all the sites where work is to
be performed should be identified in the study plan .
Name of the Study Director and Other Responsible Personnel

The Study Director’s name should be present in the protocol . Any other
responsible scientists who are going to make significant contributions to the study
are need to be identified. Most laboratories include the names of scientists who will
be responsible for interpretation of the data generated under their responsibility
( e.g., pathologists and clinical pathologists). For contracted studies, name of the
monitor or sponsor contract person is included in the protocol . In case of a multi-
site study, name of the principal investigator at the test site ( responsible for
conducting the phase of the study at that test site ) should be present in the protocol.
Proposed Dates
The proposed dates for the study, i.e., the expected start and finish dates (dates
when the protocol is signed and when the report will be signed by the Study
Director, respectively ) should be cited in the protocol. The experimental dates
(dates when the first and last experimental data will be collected ) should also be
present in the protocol.
The protocol should include a more detailed schedule in a separate document to
assist the study personnel in performing their work. There may be chances of
shifting the planned dates. Therefore, rules for changing dates either by making
protocol amendments or by updating an independent project planning system
should be defined in the SOPs for protocol management.
Justification for Selection of the Test System

In experiments using animals, the species and the strain of animals should be
described in scientific test guidelines. However, a reason for choosing the test
system for the study should also be mentioned in the protocol. Often this is based
on the test facility’s historical data with the concerned strain, but there may be
special scientific or regulatory reasons.
Description of the Test System

In experiments using animals, the proposed species, strain , age, weight and
source of animals, and how they are to be identified should be described in the
test system. Details of the animal husbandry including environmental conditions
..
( e g , temperature and humidity limits), type of cage, diet and its source, etc.
should also be defined.
Experimental Design
Design should cover the following points:
1 ) Dosing details,
2) Dose levels,
3) Dosing route,
4 ) Frequency of dosing,
5) Vehicles used ,
6) Preparation method of the dose concentrations,
7) Storage conditions of the formulation ,
8) Quality control,
9 ) Animal assignment to groups or randomisation, and
10 ) Parameters to be examined and measured.
This identifies the measurements to be made and the frequency of measurements.

Details of any additions or planned modifications to the SOPs, and details of non -
standard procedures or references to them should also be listed. Details of
analytical methods are not included in most of the protocols, but are made
available as SOPs or method documents, which are held in the analytical
laboratory along with the study data.
11.1 .9. Records and Reports

The laboratory should have descriptive documents, which are records defining
the complete process of experimentation. These records are the qualitative and
quantitative results of the study. The Study Director uses the records as the basis
for scientific interpretation of the study. This interpretation, along with an
accurate representation of the data, is added in the final report of the study. The
authorship of the final report is the responsibility of the Study Director.
After the study is complete, all the prescriptive and descriptive documents are
archived so that whenever there is a need of full study reconstruction , the
archived material can be examined.
11.1 .9.1. Carrying out Procedures and Recording Observations

Before conducting any procedure in a study, the Study Director ensures that:
1 ) Sufficient number of well-trained and experienced staff are available,
2) The staff has read and understood the protocol ,
3) A copy of the protocol is present at the site where the procedures will be
performed ,
4 ) SOPs are available in the work areas,
5) Necessary equipment and supplies are available in the work areas, and
6) Data recording forms are available in the work areas.
Before starting a procedure that requires equipment , the operator should check
that the equipment is in working condition . The operator should perform such
checks by referring the appropriate logbook or equipment label .
11.1 .9.2. Records and Recording

Maintenance of a record is necessary for complete reconstruction of the study as
it is the only evidence of what happened during the course of experiment. The
records should contain the obtained data, and also prove that all the procedures
were carried out appropriately at the right time. If data are lost or a complete
record has not been maintained , the study validity is seriously compromised.
Raw data are original recordings made during the course of the study. It is
necessary for the reconstruction of the study by an inspector after the study
completion date. Raw data should indicate the following:
1 ) What was Done: A description of how the study was conducted , results of
the observation or measurement , and the actions carried out as per the
requirement of the protocol should be given.
2 ) How it was Done: The data should indicate that they were collected and
recorded according to the methods in the SOPs and protocol, or should also
indicate deviations from these instructions (if any ).
3) When the Work was Performed: A description of compliance with the
schedule defined in the protocol should be given. This is done by recording
the date and time when the procedure was conducted. Accurate date and time
should be recorded for certain procedures ( e.g., sampling in a toxicokinetic
study ) to prove that the schedule was strictly followed.
4) Who Performed the Work: The data should indicate who carried out the
procedure and recorded the data. If more than one person is involved , this
should also be recorded in the data, along with an identification of the
responsibilities of each.
The data generated during the study should be identified and recorded directly,
promptly, accurately, legibly , and indelibly by the person entering the data , and
should also be signed and dated. If any changes are to be made in the data, it
should not obscure the previous entry. The reason for making such change should
be mentioned . The person making the change should sign and date the final
record. Some related terms are:
1 ) Identified : The study number , animal number, etc., should be recorded with
the data to prevent data mix-up. The parameter evaluated should be identified.
2 ) Directly: The first written records constitute the raw data and should be
retained, thus it is not recommended to make records on scraps of paper and
then transcribe into a final form. When data are directly acquired by computer,
the raw data are considered to be the electronic medium . For data derived from
equipment, the raw data may be a direct print out or in an electronic form.
3) Promptly: Data should be recorded as soon as the operation is complete. It is
not recommended to make the record sometime after the completion of work.
4) Accurately: The recorded data should be accurate enough to support the
scientific interpretation and integrity of the study.
5 ) Legibly: Data recorded in unreadable format are of no use and such records
raise doubts to their credibility.
6) Indelibly: A problem that gave rise to GLP was that data was being recorded
in pencil and were subjected to subsequent changes without being evident.
Therefore, using indelible and waterproof ink or ballpoint pen is
recommended for data recording. The robustness of machine- print outs
should be checked as some print quickly disappear or become black (light-
sensitive print-outs from thermo-printers ). In such a case, an authorised
signed and dated photocopy should be taken for storage.
7 ) Signed: Accountability is one of the basic principle of GLP, thus the person
who did every job on a study should sign the record.
8) Dated : The person should also date his/her signature to indicate the date
when the procedure was conducted and recorded during the study.
9) Reasons for Corrections: There may be a need to make changes in the
recorded data, for which a clear audit trail is required to show who made the
change, at what time, and why.
Data should be recorded and organised to facilitate the making of the record and
the performance of the later processes ( e.g., data entry, reporting , audit, and
archiving). Data should be recorded in a logical way without any duplication.
Pro-forma documents aid in this by encouraging the staff to record all the
required data, without missing any. A clear structure for the study file, defined
upfront , helps to organise and archive the documents as they are produced in
real-time, preventing loss of data, and facilitating reference between records.
11.1 .9.3. Storage and Retrieval of Records and Data

The raw data, documentation , protocols, final reports, and samples (except those
obtained from mutagenicity tests and wet samples of blood , urine, faeces, and
biological fluids) obtained from a non -clinical laboratory study should be
retained. Archives for orderly storage and convenient retrieval of all raw data,
documentation, protocols, samples, interim, and final reports should be made
available.
The storage conditions should be such that deterioration of the documents or

samples is minimised. A testing facility may contact with commercial archives to
provide a source for the materials to be retained. Raw data and samples can be
retained in other locations only if the archives have specific reference to those.
An individual should be responsible for the archives. Only authorised personnel
should be allowed to access the archives. The materials retained or referred to in
the archives should be indexed to ease retrieval.
11.1 . 10. Disqualification of Testing Facilities

The testing facility may fail to comply with one or more GLP regulations. This
failure adversely affected the data, and thus the validity of the study. This
indicates that warnings or rejection of previous studies have not been sufficient to
improve the facility’s compliance .
The purposes of disqualification are:

1) To exclude from consideration the studies conducted by a testing facility that
failed to meet the requirements of GLP regulations until it is proved that such
non-compliance did not occur during a particular study or did not affect the
validity of the data generated, and
2) To exclude from consideration the studies completed after the
disqualification date until the facility satisfies the Commissioner that it will
conduct studies in compliance with such regulations.
The determination that a non-clinical laboratory study may not be considered in

support of an application for a research or marketing permit does not relieve the
applicant for such a permit of any obligation under any other applicable
regulation to submit the study results to the FDA.
11.1 . 10.1 . Grounds for Disqualification

The Commissioner can disqualify a testing facility on finding the following:
1 ) The testing facility failed to comply with the GLP regulations,
2) Such a non -compliance adversely affected the validity of the non -clinical
laboratory studies, and
3) Other lesser regulatory actions ( e.g., warnings or rejection of individual
studies) have not been or will not be adequate to achieve compliance with the
GLP regulations.
11.1 . 10.2. Notice of and Opportunity for Hearing on Proposed

Disqualification
If the Commissioner receives information that a testing facility is failing to
comply with the GLP regulations, he can issue a written notice to the testing
facility intending to disqualify it on the basis of the above mentioned grounds. A
hearing on the disqualification should be conducted according to the
requirements for a regulatory hearing.
11.1 . 10.3. Final Order on Disqualification

If after the regulatory hearing or after the expiry of time for requesting a hearing
without a request being made, the Commissioner, upon evaluation of the
administrative record of the disqualification proceeding, makes the necessary
findings, he should issue a final order of disqualification of the facility.
Such an order should include a statement of the basis for that evaluation. After
issuing a final order, the Commissioner should notify the testing facility and
should also provide a copy of the order.
If after the regulatory hearing or after the expiry of time for requesting a hearing
without a request being made, the Commissioner, upon evaluation of the
administrative record of the disqualification proceeding, does not make the
necessary findings, he should issue a final order terminating the disqualification
of the facility. Such an order should include a statement of the basis for that
evaluation . After issuing a final order, the Commissioner should notify the
testing facility and should also provide a copy of the order.
11.1 . 10.4. Actions upon Disqualification

Each approved or non-approved application for a research or marketing permit ,
containing or relying upon any non-clinical laboratory study carried out by the
disqualified testing facility should be examined to determine whether such study
was or would be essential to a decision. If the study is determined to be essential,
the FDA should also determine whether the study is acceptable, not considering
the disqualification of the facility.
Good Laboratory Practices ( Chapter 11) 143
A study conducted by a testing facility before or after its disqualification is

assumed to be unacceptable. In such a case, the person relying on the study
should submit validating information to prove that the conditions that led to the
disqualification of the facility did not affected the study. If still the study is
determined to be unacceptable, the data is eliminated from consideration in
support of the application; and this elimination then serves as information that
justifies the termination or withdrawal of approval of the application.
Any non-clinical laboratory study that was being conducted by a testing facility
before disqualification should not be considered in support of any application for
a research or marketing permit after the disqualification date of the facility,
provided the facility has been reinstated. The determination that a study may not
be considered in support of an application for a research or marketing permit
does not relieve the applicant of any obligation under any other applicable
regulation to submit the study results to the FDA.
11.1 . 10.5. Public Disclosure of Information Regarding Disqualification

The Commissioner after issuing a final order of disqualification of a testing
facility, notifies all or the interested people. This notice should be given when the
Commissioner believes that such disclosure would enhance the public interest or
promote compliance with GLP regulations. This notice should include a copy of
the final order issued and should state that it has been determined by the FDA
that non-clinical laboratory studies performed by the disqualified facility will not
be considered in support of any application for a research or marketing permit.
In case this notice is sent to another Federal Government agency, the FDA
recommends that agency to also consider whether or not it should accept non -
clinical laboratory studies performed by the disqualified testing facility. In case
the notice is sent to any other person , it should state that it has been given
because the testing facility is somehow related to the person being notified and
that the FDA is not recommending the person notified to take any action. A
determination that a testing facility has been disqualified and an administrative
record regarding such determination are disclosable to the public.
11.1. 10.6. Alternative or Additional Actions to Disqualification

Disqualification of a testing facility is independent of and neither in lieu of nor a
precondition to other proceedings or actions authorised by the act. The FDA may
institute against a testing facility and/or against the sponsor of a non -clinical
laboratory study submitted to the FDA any appropriate judicial proceedings (civil
or criminal ) and any other regulatory action , as well as in lieu of and
concurrently with or after disqualification. The FDA may also refer the matter to
another Federal , State, or local government law enforcement or regulatory
agency to take appropriate actions.
If the FDA finds that a non -clinical laboratory study was not conducted by the
testing facility in compliance with the GLP regulations, it may refuse to consider
the study in support of an application for a research or marketing permit, even
without disqualifying the facility that conducted the study or taking other
regulatory actions.
11.1. 10.7. Suspension or Termination of a Testing Facility by a Sponsor

A testing facility can be terminated by a sponsor, and this act is independent of
and neither in lieu of nor a precondition to proceedings or actions authorised by
this subpart.
A sponsor, after terminating or suspending a testing facility from further

involvement in a non -clinical laboratory study being conducted as part of any
application for a research or marketing permit submitted to the FDA ( whether
approved or not ), should notify the FDA in writing within 15 working days. The
notice should include a statement of why the termination was done.
Suspension or termination of a testing facility by a sponsor does not relieve it of

any obligation under any other applicable regulation to submit the results of the
study to the FDA.
11.1 . 10.8. Reinstatement of a Disqualified Testing Facility

If the Commissioner determines upon evaluation of the submission of the testing
facility that its future non -clinical laboratory studies will be conducted in
compliance with the GLP regulations and the quality and integrity of the studies
being conducted currently have not been compromised, a disqualified testing
facility can be reinstated as an acceptable source of non -clinical laboratory
studies to be submitted to the FDA.
A disqualified testing facility that wishes to be reinstated should present in

writing to the Commissioner the reasons for which it should be reinstated and a
detailed description of the corrective actions it has taken or will take to assure
that the conditions that led to its disqualification will not occur again.
The Commissioner may condition reinstatement on the testing facility that was
upon an inspection found to be in compliance with the GLP regulations. On
reinstating a testing facility, the Commissioner should notify the testing facility
and all the organisations and persons who were notified of the disqualification. A
determination that a testing facility has been reinstated should be disclosed to the
public.
11.2. SUMMARY
1 ) Good Laboratory Practice ( GLP) is a set of principles that ensure the quality
and integrity of non-clinical laboratory studies designed to support research
or marketing of products regulated by government agencies.
2) New Zealand and Denmark are the countries where GLP was first
introduced in 1972.
3) There should be a defined organogram of the laboratory, and responsibility
and duties at various levels should be well -defined and documented.
4) A job description should be maintained for all the personnel in the test facility.
Good Laboratory Practices (Chapter 11 ) 145
5 ) The test facility manager should have sufficient qualification, experience,

training, and authority to ensure that the test facility is following the GLP
principles.
6) The test facility should have a direct access to personnel working in them so
that they do not need to enter the facility through the manufacturing area.
7 ) The animal facility should be designed and operated in a manner to reduce
the effects of environmental variables on animals.
8) Control or reference samples are stored in a separate room equipped with
temperature and humidity control to maintain the storage conditions stated on
the labels of the materials being tested.
9 ) The laboratory instruments and equipment should be qualified and calibrated
as per the manufacturer’s recommendations and Pharmacopoeia! requirements.
10 ) Suitability can be evaluated by considering the tasks that the equipment is to
perform.
11 ) The equipment used for data generation (e.g., analytical equipment or
balances ) or for maintaining standard conditions ( e.g., refrigerators or air
conditioning equipment ) should work as per the established specifications.
12 ) Preventive maintenance is required when parts are changed regularly based
on the expected life of the part concerned.
13) Curative maintenance is required when repairs are made in case of a fault
being detected.
14 ) A complete set of good SOPs is an essential requirement for successful
compliance of GLP principles.
15) The document is of three main types, i.e., policy statements, SOPs
describing routine laboratory activities, and study plans or protocols
detailing on how to organise the work for each study.
16) Protocol is a pivotal document that the study director uses to communicate
his/her planned study organisation to the staff and to the third parties ( the
QAU or sponsor ).
17) The protocol content should be coherent with the scientific requirements of
the study and should also comply with the GLP principles.
18) The laboratory should have descriptive documents, which are records
defining the complete process of experimentation.
19) Maintenance of a record is necessary for complete reconstruction of the study
as it is the only evidence of what happened during the course of experiment.
20) The raw data, documentation , protocols, final reports, and samples (except
those obtained from mutagenicity tests and wet samples of blood, urine,
faeces, and biological fluids) obtained from a non -clinical laboratory study
should be retained.
21 ) Disqualification of a testing facility is independent of and neither in lieu of
nor a precondition to other proceedings or actions authorised by the act.
22) A testing facility can be terminated by a sponsor, and this act is independent
of and neither in lieu of nor a precondition to proceedings or actions
authorised by this subpart.
11.3. EXERCISE
1 ) What is GLP?
2) Define test facility.
3) What is the role of principal investigator?
4 ) Define the terms master schedule, study plan and batch.
5) What is curative preventive maintenance?
6) How records and data can be stored and retrieved ?
7 ) Give the purpose of disqualification of a testing facility.

1) Write about the organisation and personnel.
2) Discuss the requirements for animal facility.
3) Write a note on SOP system in a testing facility.
4) Give a short review on the test and control articles.
5) What actions are taken on disqualification? Also write how a disqualified testing
facility is reinstated ?

1 ) Write an exhaustive note on the content of a protocol.
2) Briefly detail the different aspects of disqualification of testing facility.
3) Give a brief review on records and reports maintenance as per GLP regulations.
Complaints ( Chapter 12 ) 147
CHAPTER
12 Complaints
12.1. COMPLAINTS
There is always the possibility that some defective products may reach the
customers, even though a company makes best efforts to design , manufacture and
sell safe and reliable products. Such incidents may lead to accidents, resulting in
adverse outcomes in product liability litigations. Therefore, quality management
of complaints and product recalls become important to ensure the safety and
security of consumer health. Complaint refers to something unwanted or
something not right within the product or the product is defective. In
pharmaceutical industries, the GMP complaints are generally related to the
product quality, to improper packaging ( like the blister is not labelled clearly, one
tablet is missing in the strip, etc.) , or incorrect labelling.
12.1 . 2. Complaints and Evaluation of Complaints

As per the GMP guidelines, handling of complaints and for deciding the
measures to be taken , a designated person along with a supporting staff should be
available. These guidelines also suggest SOPs for handling of complaints. In
such studies, a person responsible for quality control should be generally
involved . The main objective of these guidelines is to immediately recall the
defective product , investigate it , and to take corrective actions to resolve the
problems. Complaints regarding the product may be in verbal or written or in the
form of reports received by the manufacturer. Thus, complaints may be
categorised into three types:
1 ) Quality Complaints: These complaints arise at consumer level, regarding
the physical, chemical and biological properties or conditions of labelling
and/or packaging of the product.
2 ) Adverse Drug Reaction ( ADR ) Complaints: These complaints arise due to
allergic reactions, any unwanted reactions, or fatal reaction of the product .
3) Other Medically Related Complaints: These complaints arise due to lack
of efficacy or clinical response of the product.
Product complaint is related to problems in physical, chemical, or therapeutic
properties, or problems in packaging or storage of the pharmaceutical product , or
problems reported to the manufacture by the physician, pharmacist , drug
wholesaler, retailer, patient, etc. To protect the human health and to maintain the
quality, safety and efficiency of the dosage form, it becomes necessary to record ,
evaluate, investigate and review complaints including potential quality defects. If
needed, the dosage form may be efficiently and quickly recalled from the
distribution network .
Therefore, all the complaints related to product quality should be carefully

reviewed and recorded in written form, and each complaint should be
investigated by a responsible authority of the company. Records related to the
investigation and remedial actions taken should be maintained .
Serious adverse reactions of a drug should be reported along with comments.
Required documents should also be submitted to the concerned Licensing
Authority. A written procedure describing the actions to be taken and recall to be
made of the defective product should be present.
12.1 .3. Handling of Return Good

Pharmaceutical product can be recalled from market due to various reasons, such
as quality problems, accidental damage of goods, etc.
Returned and Salvaged Drug Products
Once the product is returned, it should be identified as such and stored. The
conditions under which returned drug products have been handled , stored, or
shipped before or during the return or the condition of the drug product should be
investigated. The container, carton , or labelling of storage or shipping casts
should be investigated regarding the safety, identity, strength, quality, or purity
of the drug product. The returned drug product should be destroyed if it is proved
by the examination, testing or other investigation that the drug product fails on
appropriate standards.
Records of returned drug products should be maintained, along with product
name and label potency of the drug product dosage lot number, reason for the
return , quantity returned , date of disposition , and ultimate disposition of the
returned product . An investigation should be conducted if the reason for a drug
product being returned implicates associated batches. There should be written
procedures for the holding, testing, and reprocessing of returned drug product.
12.1. 4. Recalling
There is always the possibility that some defective products may reach the
customers, even though a company makes best efforts to design , manufacture and
sell safe and reliable products. Such incidents may lead to accidents, resulting in
adverse outcomes in product liability litigations. Normally, product recall is a
costly process in itself , but when it is performed without any adequate planning,
it becomes much more expensive. Distribution of a product is stopped, when it is
identified that the product quality is doubtful , thus the product is recalled for
investigation and decision. Therefore, complaints and product recalls are
interconnected.
Generally, it becomes necessary to recall the products in cases of complaints
regarding any adverse effect or defect in product. The only purpose of drug recall
is to ensure that the drug is promptly and effectively withdrawn from the market .
A quick and effective product recall system should be designed to identify the
defective products timely and to inform all concerned stockists, wholesalers,
suppliers, up to the retail level in minimum time period. For this purpose, both
print and electronic media can be used.
Complaints ( Chapter 12) 149
An established written procedure should be there in SOP form for effective recall
of products distributed by the licensee. Recall operations should be such that they
can be initiated as quickly as possible to effectively reach the level of distribution
channel. The distribution records should be readily made available to the person
designated for recall procedure. That person should record a final report issued ,
which include reconciliation between the delivered and the recovered quantities
of the products.
The effectiveness of the recall procedure should be evaluated timely. The
recalled products should be stored separately in a safe and separated area pending
final decision on them.
12.1 .4.1. Primary Reasons for a Product Recall

A product should be recalled when:
1 ) It is mandated by a regulatory agency due to any violation of a government
act, standard or other mandatory regulations, for example, toy recalls
ordered by the Consumer Product Safety Commission.
2) There is potentially serious additional product liability claims or losses.
3) Analysis of field monitoring reports and feedback indicate that may point to
product tampering, near-miss incidents, accidents, or consumer complaints.
4) Any new information based on additional research and product testing
suggests product recall.
5) Product characteristics do not match up to the advertised claims for safety or
effectiveness.
Some product recalls as per the federal regulations, such as the Consumer
Product Safety Act ( CPSA ), Section 15( b) requires that the Consumer Product
Safety Commission be notified within 24 hours of the time because it is found
that a consumer product presents a substantial hazard.
According to FDA, under the Food, Drugs & Cosmetics Act , recalls may be
classified into three classes:
1 ) Class I: It involves a life-threatening situation. A mandatory consumer recall
is made by FDA for 100% effectiveness check and appropriate public
announcements.
2) Class II: It involves a potentially hazardous, but not a life-threatening
situation. A mandatory consumer recall is made by FDA to the retail outlets
and will not require a 100% effectiveness check. A press release may be
required, depending on the reasons for the recall.
3) Class III: It involves no serious hazards, and is usually limited to the wholesale
level with no effectiveness checks. In this class, no press release is required.
According to urgency of the situation , the manufacturing or distributing company

may have choice whether to repair or modify the product ( no cost or reduced cost
retrofit by customer or the company ), refund the purchase price, or start a total or
partial recall ( voluntary or mandatory ). If the recall is mandatory, the
pharmaceutical company may ask the regulatory agency for a notice of recall,
only after a thorough review of the situation and with appropriate legal counsel.
12.1 . 4.2. Goals of a Product Recall

The purpose of a product recall is to protect the public health. There are two main
goals of product recall:
1 ) First Goal : It is to regain control over all hazardous products. The recall is
successful, if this goal is met. Sometimes, all products are recalled
successfully and the public remains unaware of the product recall.
2) Second Goal: Most of the time, even the best planning and record keeping,
cannot retrieve all products. In such cases, the public is informed about the
hazardous product so that its consumption can be stopped. This secondary
goal is important for retail operations.
In wholesale processors, public information becomes more important as the
product gets farther into distribution with time.
12.1.4.3. Product Recall Procedure

The following steps should be taken for product recall in written form:
1 ) Step I: To determine the degree of recall. There are three degrees of recall:
i ) Degree I: If product has high health risk and require freezing of stock
within 24 hours.
ii) Degree II: If product has minor health risk or sub-standard, and require
freezing of stock within 72 hours.
iii ) Degree HI: If product is recalled due to other reasons.
2) Step U: Circulation of the recall instructions by telephone, telegram,
postage, mass media, radio TV, depending on the seriousness of the defect.
Under this step, following instructions are given:
i ) The internal stock of the product is frozen .
ii) The record and report of recalled product is established.
iii ) The return of the recalled product is organised.
3) Step III: Product recall is made according to the information/data given below:
i) Reason for recall,
ii) Details of product recalled, such as individual batch or dosage form , the
nature of risk, if some patents are at risk, advice to how they should be
managed.
iii ) Causes of defects ( if known ).
iv ) Organisation of return of the defective product.
v ) Address, telephone number of persons to be contacted at national,
provincial levels.
vi ) Addresses, telephone, telex number of distributors, wholesalers,
hospitals, etc.
12.1 .4.4. Recall Triggers

A recall can be initiated in the following ways:
1) Customer Complaints: If any critical or major defect comes into light by the
customer complaints, the product is recalled. It may also occur when there
are a large number of complaints about one particular product or process.
Complaints (Chapter 12) 151
2) GMP Deviations or Results of a Failure Investigation: In case any

problem is found during the manufacturing process of a particular batch , the
company carries out an investigation, which may lead to the discovery of
problems with earlier batches that were not detected before their release.
3) Result from the QC Stability Programme: If the stability studies show unusual
deterioration of activity within the normal shelf -life of a particular batch.
4) Information from the Regulatory Authorities: In case complaints are directly
sent to the authorities rather than to the company and when random samples
are timely taken for quality check from various parts of the distribution chain.
5 ) Result of an Inspection: If a regulatory inspection reveals a problem in the
manufacturing process that casts doubt on the validity of the release of a
given product.
6) Known Counterfeiting or Tampering with the Product: If any fake
product has been released in the market , it becomes necessary to withdraw
the product until the genuine product can be established.
7) Adverse Drug Reaction ( ADR ): ADRs are reported as part of a
pharmacovigilance programme, but they will not automatically lead to an
immediate recall situation.
12.1 .5. Waste Disposal

Disposition of sewage, trash, and other refuse in and from the building and
immediate premises should be done in a safe and sanitary manner. Within a
pharmaceutical plant, the disposal may be of the following types:
1 ) Product Disposal: The product to be disposed should be removed from its
packaging if needed . For example, if a product is to be disposed of in an
approved landfill site, it should not be left with impermeable glass, plastic, or
other containers, as it would delay destruction.
During the destruction of products, various risks are associated such as
potential for the product to get diverted (acceptably or otherwise), during the
disposal sequence and contamination of groundwater. Agents used for the
product disposal should have a proven record of dealing with such sensitive
materials or the use of company personnel to come with the material from
plant to disposal. Ignition or incineration procedures are preferred over
landfill. In case of incineration, product in plastic or other flammable
packaging may not need to be returned to bulk.
2 ) Printed Packaging Disposal: Generally, there is no health risk associated
with the disposal of printed packaging components, including labels, inserts,
and cartons. However, ineffective disposal ( as into public landfill ) can lead to
public concern that product may be associated with the packaging; therefore,
such materials should be incinerated.
3) General Trash and Sewage: Generally, normal local services are sufficient
for trash and sewage disposal. However, internal procedures should be
rigorous and monitored to ensure that product and packaging waste do not
get intermixed. Containers used within the plant to accumulate waste
materials should be clearly marked as per their use.
12.2. SUMMARY
1 ) As per the GMP guidelines, handling of complaints and for deciding the
measures to be taken, a designated person along with a supporting staff
should be available.
2 ) Quality complaints arise at consumer level , regarding the physical , chemical
and biological properties or conditions of labelling and/or packaging of the
product.
3) Adverse Drug Reaction ( ADR ) complaints arise due to allergic reactions,
any unwanted reactions, or fatal reaction of the product.
4 ) Other medically related complaints arise due to lack of efficacy or clinical
response of the product.
5 ) Records of returned drug products should be maintained , along with product
name and label potency of the drug product dosage lot number, reason for the
return , quantity returned, date of disposition, and ultimate disposition of the
returned product.
12.3. EXERCISE

1) Give the types of complaints.
2 ) What do you mean by product recall ?
3) Classify recalls.

1 ) Write about the evaluation of complaints.
2 ) Discuss about waste disposal .

1 ) Write an exhaustive note on product recalling.
Document Maintenance in Pharmaceutical Industry ( Chapter 13 ) 153
CHAPTER Document Maintenance in

13 Pharmaceutical Industry
13.1. DOCUMENT MAINTENANCE IN

PHARMACEUTICAL INDUSTRY
Documentation is an integral part of GMPs, and is a system of information and
control to reduce the risks of misinterpretation and/or errors in oral
communication. Thus, documentation strengthens the quality and consistency of
all goods and services. The major objectives of documentation are:
1) To define the specifications and procedures for all materials and manufacture
and control methods,
2) To ensure that the personnel associated with manufacturing know their work
and the time of doing it,
3) To ensure that authorised personnel have the required information to decide
whether or not to release a batch of a drug for sale,
4 ) To ensure the existence of documented evidence, traceability, and to provide
records and an audit trail that will permit investigation , and
5) To ensure the availability of data required for validation, review, and
statistical analysis.
13.1 . 2. Batch Formula Record

A batch manufacturing record in pharmaceutical industry contains information
related to the product and batch. It is a document that provides full and authoritative
record of the manufacturing history of each batch of every product. FDA defines
batch as a specific quantity of a drug or other material intended to have
uniform character and quality, within specified limits, and produced according
to a single manufacturing order during the same cycle of manufacture.
A batch manufacturing record should be completed during the production of each
batch of intermediates and APIs. It should contain the relevant parts of the master
formula and should comprise of:
1 ) The product name ( if applicable, the International non - proprietary name ) and
the size and number of the batch,
2 The dates of different production stages,
)
3) Production details, including reference to the main equipment used and yields,
4) The batch or reference number or analytical control number ( if any ) of
starting materials used in the production,
5 ) The in-process controls conducted and their results,
6) Details of and signed authorisation for any unintended deviation from the
master formula,
7 ) Any recovered materials and procedures applied,
8) Initials of the operators and date and signature of the person responsible for
the production ,
9) Analytical records related to the batch or a reference that will permit their
retrieval,
10) A decision for the release or rejection of the batch for sale along with the
date and signature of the person who will take the decision,
11 ) The production record review.
Data may be recorded by electronic data-processing systems or by photographic

or other reliable means. Master formulae and detailed SOPs related to the system
being used should be available and the precision of records should be checked.
When using electronic data-processing methods for documentation, only
authorised personnel are allowed to enter, delete, or modify data in the computer.
A record of the additions, deletions, and changes made in the data should be
maintained. Access to these data should be restricted by passwords or other
security means, and the entry of critical data should be independently checked.
Electronically stored batch records should be protected by back-up transfer on
magnetic tape , microfilm, paper print -outs, or other means. This should be done
so that the data are readily available during the retention period.
13.1 .3. Master Formula Record

Master formula record is a product specific document that is compiled , checked ,
authorised and approved by competent technical personnel from different but
inter-linked functions such as development , production , packaging , and quality
control . Alike other documentation, master formula record should also be
reviewed, and any changes to be made should be approved by designated
personnel responsible for production and quality control.
There should be master formula records related to all manufacturing procedures

for each batch of product to be manufactured. These records should be prepared
and authorised by the competent technical staff , i.e., head of production and
quality control . The master formula record should include the following details:
1 ) The product name and the reference code related to its specifications,
2) The patent or proprietary name and generic name of the product, and a
description of the dosage form, strength and composition of the product and
batch size,
3) Name, quantity, and reference number of the starting materials to be used ,
4 ) A statement of the expected final yield ( with the acceptable limits ) and of the
intermediate yields,
5) A statement of the processing location and the principal equipment to be used,
6) Methods or reference to the methods to be used for preparing the critical
equipment including cleaning, assembling, calibrating, and sterilising,
7) Detailed stepwise processing instructions and the time taken for each step,
8) Instructions for the in-process controls along with their limits,
9) Storage conditions and labelling conditions of the products and their containers,
10) Any special precautions to be observed , and
11 ) Packing details and specimen labels.
Pharmaceutical Guidelines
Address - XXX
Master Formula Record
Product: XYZ Tablets M.F.R. No.: ABCYTAB/MF/001

(Calcium Carbonate and Zinc Sulphate Tablets)
Batch Size: 1 ,00,000 Tablets Revision No./Date: 01/05.06. 2018
Composition Each film coated contains:

Calcium Carbonate
Equivalent to elemental Calcium xx mg
Zinc Sulphate Monohydrate USP
Equivalent to elemental Zinc xx mg
Excipients q .s.
Colour: Titanium Dioxide IP
Appropriate overages of Vitamin added .
Description A white to off white coloured , film coated oval shaped plain
tablets.
Mfg. License No. XXXXXXXXX
Storage Condition Store in a cool , dry and dark place.
Marketed by M/s. ABC Pharmaceuticals Limited
Shelf Life 24 months of expiry of active ingredient whichever is less.
Packing Style Sale’s Pack:
1 ) Pack 1 blister of 10 tablets along with a leaflet in Monocarton.
2) Pack 10 such Monocartons in an Outer Carton.
3) Pack 12 such Outer Cartons in a 3 ply corrugated Box
along with a packing slip.
Physician Sample Pack:
1 ) Pack on blister of 2 tablets along with a leaflet in Carton .
2) Pack 30 such cartons in a plain inner box.
3) Pack 30 such inner boxes in a 3 ply printed corrugated Box
along with a packing slip.
This Document NA
Supersedes
Reason for Change NA
Prepared By Approved By Authorised By
R&D R & d Head Unite Head Q.A. Head
Date: Date: Date: Date:
13.1.4. SOP
The terms standard operating procedure and standing operating procedure,
abbreviated by SOP, occur in a variety of different contexts, such as healthcare,
education , industry, military , etc. Preparation of SOPs is one of the important
activities in GMP implementation. A major objective of GMPs is consistency in
quality, which is achieved by reducing the sources of quality variation. SOPs are
written documents that specify the procedure to be followed while conducting an
operation. Other objectives of SOPs are to reduce errors and variation in the
operation , and how an operation was carried out. An SOP is a written document
or instruction in which the details of all steps and activities of a process or
procedure are contained. These instructions should be followed without any

deviance or alteration to achieve the desired product. If any modification or
deviation has been made in the given SOP, it should be investigated and the
results should be documented as per the internal deviation procedure.
13.1 .4.1 . Benefits of SOP

Given below are the benefits of SOPs:
1 ) It provides safety, health, environmental and operational information required to
perform a job properly. If the manufacturer only focuses on production and
ignores the aspects of safety, health and environment, it will adversely affect the
process. Therefore, the employees should be trained in all aspects of doing a job,
instead of facing accidents, fines and litigation in the later stages.
2) It ensures that production operations are performed reliably to maintain
quality control of processes and products. Consumers, from individuals to
companies, want products of consistent quality and specifications. SOPs
specify job steps that assist in standardising products and their quality.
3) It ensures that processes are completed on a prescribed schedule without any
interruption . SOPs are followed to ensure against process shut -downs caused
by equipment failure or other facility damage.
4 ) If health and environmental steps are followed in SOPs, it ensures that
manufacturing and other processes do not undergo any failures that would
harm anyone in the surrounding community.
5) It ensures that approved procedures are followed in compliance with company
and government regulations. Well-written SOPs ensure that government
regulations are satisfied, and also demonstrate a company’s good -faith intention
to operate properly. If a company fails to write and use good SOPs, it indicates
the government regulators that the company is not focusing on compliance.
6) It serves as a training document to teach the users about the process for
which the SOPs were written . Thorough SOPs provide standardised training
to new employees and to those who need to be re-trained .
7) It serves as a checklist for co-workers to strengthen the job performance. The
process of actively caring about fellow workers involves coaching of a worker
by another in all aspects of proper job performance. When proper procedures are
given in a SOP, any co-worker can coach another to improve work skills.
8) It serves as a detailed checklist for auditors. Auditing job performance is
similar to observation mentioned in the previous item, and it also involves
record keeping.
9) It serves as an historical record of how, why and when of steps in an existing
process so that the steps can be revised when a process or equipment are
changed. As people move from one job to another within and between
companies, unwritten knowledge and skills disappear from the workplace.
Therefore, properly maintained written SOPs record the best knowledge that
serve the new workers when older ones are gone.
10) It serves as an explanation of process steps so that they can be reviewed in
accident investigations. This gives opportunities to learn how to improve
such accidental conditions.
Document Maintenance in Pharmaceutical Industry ( Chapter 13) 157
13.1 .4.2. Guidelines to Prepare SOPs

The following guidelines help in the preparation of SOPs:
1 ) A clear and descriptive title should be given to each SOP.
2 ) Sufficient details should be given to meet the need of an individual.
3) The SOP should be made flexible, but it should not be too general.
4 ) SOPs should be organised as per the sequence of events involved in
performing the operation .
5 ) The text should be written in straight forward and easy to follow manner.
6) After drafting SOP, it should be used while performing the operation to
ensure it has sufficient details to perform the operation in desired manner.
7) The instructions from the manufacturer of the equipment should be made
available in the SOP and used while performing the operation.
8) The total number of pages should be mentioned so that the user is certain that
he/she is performing the complete operation.
9) The effective date of the SOP should also be indicated .
SOPs can be best prepared by involving at least one person from each work area.
The selected person should be asked to write down the operation procedure,
along with the details and precautionary steps to be taken. The procedure written
down by the person should be discussed by a group of persons associated with
the operation. If there is a need to make modifications, they should be made.
Then , the procedure should be handed over to the coordinator, who should
rewrite it to bring uniformity in style and format.
13.1.4.3. SOPs for Receipt of Materials

There should be written SOPs and records for the receipt of each delivery of raw,
primary and printed packaging materials. These records of receipts should
include:
1) Name of the material on the delivery note and the number of containers,
2) The date of receipt,
3) Name of the manufacturer and/or supplier,
4) Batch or reference number of the manufacturer,
5) The total quantity and number of containers received , and quantity in each,
6) The control reference number assigned after receipt, and
7) Any other relevant comment or information.
There should be written SOPs for internal labelling, quarantine and storage of
starting and packaging materials. SOPs for each instrument and equipment
should be maintained and placed near to the related instrument and equipment .
13.1.4.4. SOPs for Sampling

There should be written SOPs for sampling which include the person( s )
authorised to take the samples. The sampling instruction should include:
1) The method of sampling and the sampling plan,
2) The equipment to be used,
3) Any precautions to be taken to avoid contamination of the material or
deterioration of its quality,
4) The quantity of samples to be taken ,
5 ) Instructions for any required sub-division or poling of the samples,

6) The types of sample containers to be used, and
7 ) Any specific precautions to be taken when sampling sterile and hazardous
materials.
13.1 .4.5. SOPs for Batch Numbering

There should be SOPs for describing the details of the batch numbering set up to
ensure that each batch of intermediates, bulk or finished products is identified
with a specific batch number. SOPs for batch numbering are applied to a
processing stage and to the respective packaging stage, and should be same or
traceable to demonstrate that they belong to a homogenous mix. Batch number
allocation, date of allocation, product identity, and size of batch should be
immediately recorded in a logbook or by electronic data processing system.
13.1 .4.6. SOPs for Testing

There should be written SOPs for testing materials and products at different
stages of manufacture. These procedures should describe the methods and
equipment to be used. The tests performed should be recorded.
13.1 .5. Quality Audit

Auditing is defined as inspection of a process or a system to ensure that it
complies with the requirements of its intended use . In pharmaceutical
industries, audits are means to virtually evaluate compliance with the set
objectives defined in the quality system, and thus paving a path of continuous
improvement program by giving response to the management. Generally, the
following two types of audits are conducted:
1 ) Internal Audit ( Self - Inspection ) : This audit is conducted in the premises to
monitor the implementation of GMPs, and also to get prior information about
the flaws in the system so that remedial and preventive steps can be taken.
2) External Audit: This audit is conducted for the suppliers or any outsourcing
operations carried out by the pharmaceutical industries. The contract giver
( i.e., the industry ) should access the competence of the contract acceptor ( i.e.,
the supplier or any other outsource operations department ) as per the GMP
guidelines.
13.1.5.1. Procedure for Conducting an Audit

A well -written procedure should be established for conducting an internal or
external audit. The procedure should mention the objective to conduct an audit.
Other important points that should be described are:
1 ) Frequency of Audit: How frequently an audit should be conducted should
be mentioned.
2) Responsibilities: The audit team responsible for conducting and reviewing
the audit reports should be defined . The audit team should be well-aware
with the operations and procedures being audited.
3) Documentation: Each and every audit conducted should be documented as it
is helpful from regulatory viewpoint and also acts as a reference document to
have an insight of previously encountered errors.
13.1 .5.2. Audit Preparation

The audit should be initiated with an outline that provides a real time frame to all
the involved parties, so that all the personnel involved and documentation is
available whenever needed. The proposed outline should be agreed through a
pre-planned meeting and the other requirements that may be required at the time
of the audit ( from a simple schedule detail to complex documentation ) should
also be sorted out. The audit checklist should be created to prevent wastage of
time while reading big paragraphs. The checklist should be framed according to
the type of the audit being conducted and procedures and policies to be audited .
13.1 .5.3. C onducting of Audit

The audit team should abide by the rules and regulations specific to the
operations being carried out at the premises. For example , if the audit is
conducted in aseptic section, the personnel should wear the safety clothing as per
GMP before entering the aseptic room.
The audit should be conducted by communication between the audit team and the
personnel working. All the observations made during the audit should be
documented along with related explanation to make it more realistic. The audit
team should be flexible. The procedure to meet the GMP requirements may be
different in different industries; hence, the auditor should focus on the results and
decide about the observations. The conclusions obtained should be prepared,
documented, and finally completed as an audit report.
13.1 .5.4. Completing and Follow- Dp of Audit

A close out meeting should be held after conducting the audit . Both the parties
( auditor and auditee ) should understand the observations made and recorded as
the commitments have to be made for corrective actions to be taken. Schedules
are made to take corrective actions against the observations made and through
that follow-up of audit is done. Some unusual activities may be found during the
audit , for which preventive actions should be taken to avoid their recurrence.
Auditing is an integral part as it helps in product realisation , process

performance, and quality monitoring. It is an important tool for continuous
improvement of quality system of an industry.
13.1 .6. Quality Review and Quality Documentation

Annual Product Quality Review ( APQR ) is an effective product quality
improvement tool and is prepared in a pharmaceutical industry to review the
product consistency annually regarding their quality, deviations, change controls,
and market complaints. Annual product review verifies the consistency of the
existing manufacturing process, determines the quality and process defects of the
products, and also determines the defects and possible improvements to the
method and process. The quality of raw and packing materials used for the
product is also reviewed. The trend of these materials indicates the quality of the
material and the supplier also. In-process and finished product results are
reviewed to determine the consistency of product quality.
The final product quality is reviewed by the trending yield of every batch . Out -
of -specification helps to determine the process defects during the production of
the specific product. Failure of the batch is also included in APQR to determine
the batch rejection of the product. Stability study and its trend determine the
defects regarding product stability. APQR helps to determine the need for re-
validation of the process and effect of any improvement made earlier. Corrective
and preventive actions and their effect on product quality are also reviewed and
determined.
Annual product quality review is a mandatory requirement of GMP. The FDA

uses the term Annual Product Review ( APR ) , while in EU-GMP guidelines the
term Product Quality Review ( PQR ) is used.
13.1 . 7. Reports and Documents

The PQR report should contain the following details:
1 ) A review of starting materials and product contact primary packaging
materials (especially from new sources ) used for the product:
i ) Summary of all batches of starting and packaging materials received in a
year and their approval status,
ii) Summary of the suppliers/manufacturers of the materials,
iii) Compilation and analysis of the results of analytical tests for key quality
attributes such as description , identification, loss on drying/ water content
by Karl Fisher, particle size, and assay,
iv) Compilation of the Certificate of Analysis (COA ) results obtained from
supplier/manufacturer, if the batch is released based on supplier’s COA,
and
v) Summary of details related to deviations observed such as rejection of
vendor lots.
2) A review of critical in -process controls and finished product results:
i) Compilation and analysis of results of in-process tests [e.g., weight
variation , dimension , friability, hardness, disintegration time, fill volume
variation ( for ampoules, vials, bottles ), pH, etc.], obtained from the total
number of batches manufactured in that year, and
ii) Compilation and analysis of results of finished product tests
( description/appearance, identification , pH, loss on drying/ water by Karl
Fisher, viscosity, dissolution test, impurities and related substances,
degradation product , and assay ).
3) A review of all batches that failed to meet the established specifications and
their investigation:
i ) Summary of the number of failed batches/products identifying the
batches that failed specifications and the cause for this failure,
ii) Summary of the reasons for failure ( assignable or non -assignable
causes), and
iii) Summary of the complete investigation reports and corrective actions
taken.
4) A review of all the deviations or non-conformances, their investigations, and

effectiveness of the corrective and preventive actions taken:
i ) Summary of the deviations or non-conformances, along with their
causes, and
ii) Compilation of Corrective And Preventive Actions ( CAPA ) taken.
5) A review of all the changes made to the processes or analytical methods:
i ) Summary of the changes made to the process (e.g., change of mixing
time, blending time, drying time, changes in coating process, changes in
compression speed/time, changes in filling speed, etc.),
ii) Summary of the changes made to the analytical methods ( e.g., change of
solvents, buffers, reagents, pH, change in composition of mobile phase,
change in HPLC/GC method parameters, i.e., flow rate, temperature,
wavelength, run time, and change of HPLC/GC column, etc.), and
iii ) Review /report of the effect of changes on product quality.
6) A review of marketing authorisation variations submitted/granted/refused,
including those for third country ( export only ) dossiers:
i ) Summary of the number of products registered with local and overseas
authorities covered in the review document, if grouping is done by
product type,
ii) Summary of the changes made to the product specification and their
approval status, and
iii ) Summary of the number of products submitted but not approved/ refused
by the local and overseas authority.
7) A review of the results of the stability monitoring programme and any
adverse trends:
i ) Summary of the number of batches selected for stability studies during
the review period and the reasons for their selection, and
ii) Summary of stability study report and results, i.e., out-of -specifications
for each condition ( real time/long term and accelerated studies ), along
with a review of the results obtained for stability -indicating analytical
tests.
8) A review of quality-related product returns, complaints and recalls and the
investigations performed:
i ) Summary of batches returned due to potential quality defects and their
causes,
ii ) Summary of market complaints received in a year and the nature of
complaints,
iii ) Summary of batches recalled and the reasons, and
iv) Compilation of investigation reports prepared following market
complaints and the actions taken to prevent their reappearance.
9) A review of adequacy of any other previous product process or equipment
corrective actions. Summary of all corrective actions from previous product
quality review reports [other than those listed in ( iii ) and ( iv) points ],
indicating the implementation status of each corrective actions, and their
effectiveness in addressing the problems.
10) A review of post-marketing commitments for new marketing authorisations

and variations to marketing authorisations:
i) Summary of any changes in specification, registered with drug regulatory
authority, including overseas drug regulatory authorities, and
ii) Summary of any post -marketing commitments and review the status of
these commitments.
11 ) The qualification status of relevant critical equipment and utilities, e.g , .
HVAC, water, compressed gases, etc.
i) Summary of the number of equipment/instruments in production and
laboratory department, and
ii) Summary of the qualification/ re-qualification status of equipment/
utilities used in the production processes and QC laboratory indicating
whether it has been qualified and it ' s next qualification due date/ policy
The actual results of qualification, maintenance, calibration, etc., would
not be required in the PQR .
13.1.8. Distribution Records

Distribution records should contain the following:
1) Name, strength and dosage form description of the product,
2) Name and address of the consignee,
3) Date and quantity shipped, and
4) Lot or control number of the drug product ( need not to be mentioned for
compressed medical gas products ).
The main objective of distribution records is to ensure that adequate data are
available to access trade customers when a recall is initiated. This can be
accomplished by recording of lot number to each order. Recording of dates on
which a specific lot of product was released and its distribution was ceased can
also be used to attain the objective. All customers receiving the product between
these dates could then be contacted as on the first and last days of distribution ,
some customers may have received product from the end of the previous lot or
the beginning of the next lot.
13.2. SUMMARY
1 ) Documentation is an integral part of GMPs, and is a system of information
and control to reduce the risks of misinterpretation and/or errors in oral
communication.
2 ) FDA defines batch as a specific quantity of a drug or other material intended
to have uniform character and quality, within specified limits, and produced
according to a single manufacturing order during the same cycle of
manufacture.
3) Master formula record is a product specific document that is compiled,
checked, authorised and approved by competent technical personnel from
different but inter-linked functions such as development , production,
packaging, and quality control .
Document Maintenance in Pharmaceutical Industry (Chapter 13) 163
4) The terms standard operating procedure and standing operating

procedure, abbreviated by SOP, occur in a variety of different contexts, such
as healthcare, education, industry, military, etc.
5) There should be SOPs for describing the details of the batch numbering set
up to ensure that each batch of intermediates, bulk or finished products is
identified with a specific batch number.
6) There should be written SOPs for testing materials and products at different
stages of manufacture.
7) Auditing is defined as inspection of a process or a system to ensure that it
complies with the requirements of its intended use.
-
8) Internal audit ( self inspection ) is conducted in the premises to monitor the
implementation of GMPs, and also to get prior information about the flaws in
the system so that remedial and preventive steps can be taken.
9) External audit is conducted for the suppliers or any outsourcing operations
carried out by the pharmaceutical industries.
10) The audit team should abide by the rules and regulations specific to the
operations being carried out at the premises.
11 ) Annual Product Quality Review^ ( APQR ) is an effective product quality
improvement tool and is prepared in a pharmaceutical industry to review the
product consistency annually regarding their quality, deviations, change
controls, and market complaints.
12 ) The FDA uses the term Annual Product Review ( APR ), while in EU-GMP
guidelines the term Product Quality Review ( PQR ) is used.
13) The main objective of distribution records is to ensure that adequate data
are available to access trade customers when a recall is initiated.
13.3. EXERCISE
1) What is batch formula record?
2) Draw the sample of a master formula record .
3) Write about SOPs for sampling .
4) Define auditing.
5) What are distribution records?

1 ) Write about master formula record .
2) Discuss the benefits of SOPs .
3 ) Write a note on reports and documents of a PQR report .

1 ) Write an exhaustive note on quality audit .
2 ) Give a brief review on SOPs.
CHAPTER
Calibration and Validation
14
14.1. CALIBRATION AND VALIDATION

14.1.1. Introduction
Calibration is a set of operations that establish relationship between the values
..
indicated by an instrument or system for measuring ( e g , weight, temperature,
and pH ), recording, and controlling, or the values represented by a material
measure and the corresponding known values of a reference standard, under
specified conditions. Acceptance limits for the results of measuring should also
be established. Calibration defines the requirements for establishing and
implementing an effective calibration control programme that aims to ensure that
all measuring and test equipment included in the programme are calibrated
accurately within the manufacturers specifications or the tolerance required by
the application. Documented traceability to the national standards or to other
applicable agency should be maintained.
Ted Bvers and Bud Loftus ( FDA officials ) first introduced the validation
concept in the mid -1970s to improve the quality of pharmaceuticals. At first , the
validation activities focused on the processing of pharmaceutical products, but
later spread to other related processes including environmental control, media
fill , equipment sanitisation , and purified water production.
Validation is an act of demonstrating and documenting that a procedure, process,

and activity will steadily give the desired results. It includes the qualification of
systems and equipment. Validation ensures that quality of the system is
maintained at every step, and not just tested at the end; therefore, validation
activities include training on production material and operating procedures,
training of people involved and monitoring of the system during production . A
complete process is generally validated and a particular object within that process
is also verified. The regulations also set out an expectation that the production
process has well-defined and controlled different parts, so that the production
results will not significantly change with time.
14.1.2. Definition and General Principles of Calibration

Calibration is the process of adjusting an instrument or equipment as per the
manufacturer’s specifications. Calibration is also defined as the process of
issuing data including a report or certificate of calibration that ensures an end
user of a product’s conformance with its specifications. The instrument engineer
or technician utilises the calibration process to determine the relationship
between the values of the quantity being measured and the values indicated on a
measuring instrument . An instrument can be calibrated by comparing the
Calibration and Validation ( Chapter 14) 165
readings on the instrument with the readings given by a reference instrument or

calibrator. Reference instruments of the manufacturer are timely calibrated
against national standards in a calibration centre. When an instrument is
purchased, the manufacturer’s calibration data is generally supplied . The
instruments produced by manufacturers have sets of reference instruments
against which they are calibrated.
14.1.2.1. Reason for Calibration of an Instrument

Almost all the equipment , including the electronic equipment , degrades with
time. The equipment components lose their stability with age and shift from their
specified standards. Normal handling can adversely affect calibration , and rough
handling can throw a piece of equipment out of calibration even if it may appear
to be physically well. Continuing calibration assures the equipment fulfils the
specification required at installation and it should be frequently checked.
Calibration is required after maintenance to ensure the equipment still follows the
required calibration data. A well-designed and organised calibration programme
proves to be beneficial for quality, productivity, and increased revenue.
14.1.2.2. Frequency of Calibration

How frequently calibration is required varies from industry -to-industry. Usually ,
the manufacturer performs the initial calibration on its equipment. The
subsequent calibrations are performed by the end user or by the manufacturer.
How frequently recalibration is required varies with the type of equipment and
the prevalent conditions where the equipment is applied. The need to recalibrate
an instrument depends on how well the equipment performs in the application.
However, re-calibration should be performed once a year; and the frequency will
be much greater in more critical applications.
14.1.2.3. Common Terms used in Instrument Calibration

Calibration Range
The calibration range of an instrument is the region between the limits within
which a quantity is measured, received or transmitted , expressed by stating the
Lower Range Values ( LRV ) and Upper Range Values ( URV ). These limits are
defined by zero and span values.
Zero Value
Zero value is the lower end of the range or LRV and the URV is the upper range value.
For example, if an instrument is to be calibrated to measure pressure in 0-400 psig
=
range, then LRV 0 and URV = 400psig. Thus, the calibration range is 0 to 400psig.
Span Value
Span value is the algebraic difference between the upper and lower range values
(Span =URV - LBV ). For example , if an instrument is to be calibrated to
measure pressure in 0-400 psig range, then the span is 400 - 0 = 400 psig.
Instrument Range
The instrument range is the capability of the instrument , and is often the
nameplate rating of the instrument ; for example, Instrument range 0-800psig;
Output 4 to 20mA.
The instrument range should not be confused with the calibration range.
Although the instrument range is 0-800 psig, the user may decide to calibrate it to
0-400 psig or 0-800 psig range for an application with high input pressure in
which case the instrument range becomes the calibration range of the device.
Ranging an Instrument
To range an instrument means to set its lower and upper range values so that the
instrument responds with desired sensitivity to changes in input. For example , a
pressure transmitter is to be used to measure pressure in the range 0-100 bar to
give an output of 4-20mA. To range this transmitter, the values are set as follows:
0 bar = 4mA
100 bar = 20mA
Re-ranging means to reset the lower and upper range values to a different
measurement range. For example if the user wishes to re-range the above
,
transmitter to measure pressure in the range 50-150 bar, the values are reset as
follows:
50 bar = 4 mA
150 bar = 20mA.
Zero and Span Adjustments

Zero and span adjustments are done in analogue and smart instruments. These
adjustments are made to set the instrument for any range of measurement within
the manufacturer’s limits. Zero and span adjustments are interactive for most
analogue instruments, i.e., adjusting one affects the other. Changes made to the
span adjustment always alter the instrument ’s zero point.
If an instrument’s zero and span adjustments are interactive, it requires more
effort to accurately calibrate, as the user needs to repeatedly switch between the
lower - and upper-range values to adjust accuracy. However, the zero and span
adjustments of smart instruments are not interactive.
Five Point Calibration

When an instrument is being calibrated , its data points should include readings
taken at 0% , 25% , 50% , 75% , and 100% of the calibration range of the
instrument. This is referred to as five-point calibration. While performing five-
point calibration , the repeatability and hysteresis of the instrument is determined
by upscale ( increasing ) as well as down scale (decreasing ) testing.
Field Calibration
In field calibration, the instrument is not removed from the process; rather, it
remains in its mounting brackets. Field calibration involves the calibration of
field instrument at the true process and ambient conditions. Calibration
performed under field conditions differ significantly from that performed under
shop conditions and even produce different results. Field instruments mostly
have isolating value manifold so that they can be easily disconnected from the
process. After disconnection , the instrument is vented to the atmosphere, before
applying the test or calibration signal.
Calibration and Validation (Chapter 14 ) 167
-
In Shop or Bench Calibration
In bench calibration , calibration devices are used to calibrate the instrument at a
calibration bench to simulate the process, rather than calibrating the device in the
field using the actual process as the input means. In this process, the instrument is
disconnected from the process, cleaned and taken to the shop where it is mounted
on a test stand at a calibration bench .
Bench Tester
A bench tester is used for bench calibration of an instrument or device. It is
equipped with a highly accurate standard gauge and a pressure source for
producing test pressure required for testing the instrument. Most bench testers are
fabricated on the job site by instrument technicians, while some are ordered as
complete systems from vendors. A standard bench should have various well -
labelled and organised hoses and pumps to help technicians in the calibration
process.
Calibrators
Calibrators are used for calibrating instruments that require calibration. Their
form and function differ with the equipment or device they are intended to
calibrate. Some of the calibrators are:
1) Block Calibrator and Fluidised Baths: These are used for calibrating
temperature probes, like RTDs, thermocouples, etc.
2) Signal Reference: It is used for calibrating panel metres and temperature
controllers. It can generate a known electrical signal. There are voltage,
current , and frequency signal references. When a signal from one of these
calibrators is fed into the equipment to be calibrated, the display or output
value of the equipment can be adjusted to match the known signal. The
simulator ( a special kind of signal reference) generates sensor output . Both
signal references and simulators can read as well as generate signals.
3) Pneumatic Calibrators: These calibrators, often used along with a pressure
source, provide a regulated pressure regime for testing or calibrating pressure
instruments.
Calibration Records
Calibration records are the documentation to ensure that the history of the device
or instrument is not lost. It also helps in troubleshooting any change in the
instrument 's performance with time . Calibration records should show:
1 ) The as-found data,
2) The current calibration date,
3) The final calibration or as-left data ,
4 ) The name or initials of the technician who performed the calibration , and
5 ) The date on which the instrument is next calibrated.
-
As Found Data
The as-found data of an instrument to be calibrated is the response from the
device ( reading ) at the points of calibration (0% , 25% , 50% , 75% , and 100% )
before the beginning of actual calibration.
< Quality Assurance
device (reading) at the points of calibration (0% , 25% , 50% , 75% , and 100% )
-
As Left Data
The as-left data of an instrument to be calibrated is the response from the device
( reading ) at the points of calibration (0% , 25% , 50% , 75% , and 100% ) after the
completion of calibration.
Traceability
All calibrations should be performed traceable to a nationally or internationally
recognised standard. Traceability is the property of a result of measurement and
can be related to appropriate national or international standards through an
unbroken chain of comparisons. Thus, the calibrations performed are traceable to
a national or international standard.
Traceability is achieved by ensuring that the test standards to be used for
calibration operations are regularly calibrated by higher level reference standards.
The measurement standards to be used in a workshop are sent at fixed periods to
a standards laboratory having more accurate test equipment. The standards from
the calibration laboratory are also periodically checked for calibration by higher
level standards, till the standards are tested against the primary standards of NIST
( National Institute of Standards and Technology) or any other internationally
recognised standard.
14.1.3. Definition and General Principles of Qualification

Qualification is the documented evidence that premises, systems, or equipment
can achieve the predetermined specifications properly installed, and/or work
correctly and give the desired results. Qualification is often a part or the initial
stage of validation , but the individual qualification steps do not involve in the
process validation. Qualification of instruments is not a single, continuous
process; rather it results from many discrete activities, which have been grouped
into the following four phases of qualification :
1) Design qualification,
2) Installation qualification,
3) Operational qualification, and
4) Performance qualification.
14.1.3.1. Design Qualification ( DQ )

The AIQ process begins with the DQ phase at the vendor’s site, where the
instrument is developed, designed, and produced in a validated environment
according to GLP principles, CGMP, and ISO 9000 standards. The users should
confirm that the instrument can be used as intended and also that the
manufacturer has adopted a quality system for development, manufacturing, and
testing and has adequate support for installation, service, and training. Vendor
supplied documentation and consumer audits of the vendor are sufficient to
satisfy the DQ requirements of the users.
Design qualifications are the specifications a manufacturer uses to describe a
device or equipment. It demonstrates that the requirements detailed in the User
Requirements Specifications (URS ) will be executed before authorisation of a
new design. The instrument design is already in place for the Commercial Off -
Calibration and Validation (Chapter 14) 169

Calibration and Validation ( Chapter 14 ) 169
The-Shelf (COTS) systems, thus the user does not need to repeat all aspects of
DQ. However, users should confirm that COTS instruments are fit for their
intended applications and that the manufacturer has adopted a quality system for
developing, manufacturing, and testing.
14.1.3.2. Installation Qualification ( IQ)

IQ is a documented collection of activities required for installing an instrument in
the user’s environment .
1) System Description: It provides a description of the instrument , including its
manufacturer, model , serial number, software version , etc., using appropriate
drawings and flowcharts.
2 ) Instrument Delivery: It ensures that undamaged instrument, software,
manuals, supplies, and any other accessories arrive with the instrument as the
purchase order specifies. Manuals and documentation should also be
obtained for a pre-owned or existing instrument.
3) Utilities/Facility/Environment: It verifies that the installation site meets the
environmental requirements as specified by the vendor. There is no need to
measure the exact voltage for a standard -voltage instrument or the exact
humidity reading for an instrument that will operate at ambient conditions.
4 ) Network and Data Storage: Some analytical systems require users to
provide network connections and data storage capabilities at the installation
site. In such a case, the instrument is connected to the network and its
functionality is checked.
5 ) Assembly and Installation: The complex instruments needs to be assembled
and installed, and any initial diagnostics and testing should be performed by
the vendor or specialised engineers, whereas simple ones can be assembled
and installed by the users. For complex instruments, vendor-established
installation tests and guides provide a valuable baseline reference so that the
instrument acceptance can be determined.
6) Installation Verification: After installation , initial diagnostics and testing of
the instrument should be performed . On obtaining satisfactory results, the
user and the installing engineer ( when present ) should ensure that the
installation was successful and then proceed to the next qualification phase.
14.1.3.3. Operational Qualification ( OQ)

After a successful IQ, the instrument is ready for OQ testing phase that consists
of the following test parameters:
1) Fixed Parameters: This test measures the instrument’s fixed ( i.e., non-
changing ) parameters such as length, height , weight , etc. If the user is satisfied
with the vendor-supplied specifications for these parameters, he/she may waive
the test requirement. However, if the user wants to confirm the parameters,
he/she can perform the test at his/her site. Fixed parameters remain the same
throughout the instrument s life, and therefore are never pre-determined.
'
2) Secure Data Storage, Backup, and Archive: Secure data handling, such as
storage, backup, and archiving should be tested at the user site as per the
written procedures.
3) Instrument Functions Tests: The important instrument functions are tested

for verifying that the instrument operates as envisioned by the manufacturer
and required by the user. The user should select important instrument
parameters for testing as per the instrument’s intended use. Vendor-supplied
information aids in identifying specifications for these parameters. Tests for
evaluating the identified parameters should be designed , and should be
performed by the users or their qualified to verify that the instrument fulfils
the vendor and user specifications.
14.1.3.4. Performance Qualification ( PQ )

PQ testing is conducted after performing the IQ and OQ tests under the actual
running conditions across the expected working range. PQ testing should be
repeated at regular intervals depending on parameters, like the ruggedness of
instrument and the criticality and frequency of use. PQ testing at periodic
intervals can also be used for compiling an instrument performance history.
1) Performance Checks: A test or series of tests should be designed for
verifying whether or not the instrument is performing as per its intended use.
PQ tests are based on instrument ’s on-site applications. Some PQ tests may
resemble OQ tests, but specifications for their results can be set differently as
per the requirement. Apart from performing PQ tests on a new instrument at
installation, they are also performed on a routine basis on a working
instrument. Therefore, PQ specifications can be slightly less rigorous than
OQ specifications. However, user specifications for PQ tests should evince
trouble-free instrument operation as per the intended applications.
2 ) Preventive Maintenance and Repairs: If PQ tests do not meet the
specifications, the instrument is needed to be maintained or repaired. A
periodic preventive maintenance is recommended for many instruments.
After the maintenance or repair of the instrument , the relevant PQ tests
should be repeated to check whether or not the instrument remains qualified.
3) SOPs for Operation , Calibration, and Maintenance: SOPs should be
established for maintenance and calibration of the instrument . A logbook,
binder, or electronic record can be used for documentation of each
maintenance and calibration activity.
14.1.4. Definition and General Principles of Validation

Validation is the establishment of documented evidence to provide a high degree
of assurance that a planned process will perform according to the intended
specified outcomes without failing. These guidelines cover the general principles
of validation and qualification, and also appendices on validation and
qualification ( e.g., cleaning, computer and computerised systems, equipment ,
utilities and systems, and analytical methods ).
The following principles apply :

1) Execution of validation should be in compliance with regulatory expectations,
2) Quality, safety and efficacy should be designed and built into the product ,
3) Quality cannot be inspected or tested into the product,
4 ) Quality risk management principles should be applied in determining the

need , scope and extent of validation, and
5 ) On -going review should ensure that the validated state is maintained and
opportunities for continuing improvement are identified.
14.1.4.1. Importance and Scope of Validation

Validation is a systematic approach where it is confirmed that any process in a
pharmaceutical facility will operate within the specified parameters as per the
requirement. This is possible by collecting and analysing data. Validation assures
that the processes will produce reliable and repeatable results within the
predetermined specifications. Validation verifies whether or not a product in every
pharmaceutical facility is conforming to the quality standards and compliance. It
also establishes that the facility is following the CGMP guidelines set for the
industry by the authorised regulatory bodies. Validation is thus a documented
evidence of the process conducted as per the predetermined specifications.
14.1.4.2. Types of Validation

All the aspects related to facilities, procedures, processes and activities need to be
validated , thus the validation work has been categorised as follows:
1 ) Process Validation: This involves establishment of documented evidence to
provide a high degree of assurance that any process ( like, manufacture of
pharmaceutical dosage forms, etc.) will consistently produce a product that
will fulfil the predetermined specifications and quality characteristics.
Process validation occurs in the following three stages :
i) Stage 1 - Process Design: In this stage, the commercial manufacturing
process is defined based on knowledge gained through development and
scale-up activities.
ii ) Stage 2 - Process Qualification: In this stage, the process design is
evaluated to determine whether or not the process can manufacture
reproducible commercial.
iii ) Stage 3 - Continued Process Verification: In this stage, on-going assurance
is gained during routine production that the process is under control.
Types of Process Validation

i) Prospective Validation : This validation is conducted before distribution
of the new product, and involves establishing a documented evidence of
what a system does or what it is intended to do, based upon a plan.
ii ) Retrospective Validation : This validation is conducted in an already
distributed product , based on the data collected on production , testing
and control. It involves establishing a documented evidence of what a
system does or what it is intended to do, based upon the review and
analysis of the existing information.
iii ) Concurrent Validation: This validation involves establishing a
documented evidence of what a system does or what it is intended to do,
based upon the information generated during implementation of the
system.
iv) Revalidation: A validated process should be revalidated whenever there

are changes in packaging, formulation , equipment , or processes which
could adversely affect the product effectiveness or characteristics.
2) Cleaning Validation: This validation is conducted to ensure that no cross-
contamination occurs between different batches. For example , a company
finished manufacturing tablets for fever and now will be manufacturing a
batch of dysentery tablets using the same equipments. If the residues of first
batch are not cleaned properly, they will get mixed with the ingredients of
the next batch, and may adversely affect the product quality.
3) Method Validation: This validation is conducted to ensure the precision,
accuracy and consistency of analytical tests. Before testing the analytical
samples, the test method to be used should be verified to be acceptable for
intended use.
4 ) Computer System Validation: Since the use of computer systems in
pharmaceutical manufacturing, tissue culture establishments, and clinical
trials is increasing extensively, FDA issued a guide for the validation of
computer systems in pharmaceutical industries, which was first published in
1983 and is called the bluebook .
14.1.4.3. Validation Master Plan

Validation master plan is an internally approved document that describes the
general expectations, intentions, methods, and approach to be used during the
validation programme using clear and concise words. Though the size of a
validation master plan cannot be defined, it should neither be too short (of 4-5
pages ) nor too lengthy (of 400-500 pages ). The base of the validation master plan
is that it should describe all the planned activities, with a timeframe and clear
responsibilities assigned to various people.
The FDA inspectors demand a copy of the validation master plan to check that
the company has a highly organised approach to the validation programme.
Master planning could be the subject of an entire chapter to itself , but the
cleaning validation master plan follows the same basic principles as any
validation master plan . Cleaning validation may be addressed as a section of a
general validation master plan or as a separate master plan. The master plan
should provide the following details:
1 ) An overview of the site/facility/area governed by the master plan,
2 ) An overview of the manufacturing process to be performed in the area and
the manufactured dosage forms,
..
3) An overview of the types of cleaning techniques to be used ( e g , automated
clean-in-place or clean -out-of -place, semi -automated cleaning, or manual
cleaning ),
4) An overview of the responsibilities of various departments having a role in
cleaning validation activities,
5 An overview of the minimum requirements for cleaning validation
)
programme, including:
i ) Necessary scientific logics to support the programme:
a ) Residue selection ,
b) Equipment characterisation,
c) Product contact surface area calculation ,
d) Limits calculation,
e) Sample site selection ,
0 Product grouping ( if any ), and
g ) Equipment grouping (if any ).
ii ) Necessary studies to support the programme:
a ) Analytical methods' validation ,
b ) Sampling methods ' recover studies, and
c ) Cycle development for cleaning processes.
iii ) Essential programmes and their elements to maintain the validated state:
a ) Cleaning and testing to be conducted for a new or repaired
equipment, and
b Monitoring of cleaning after validation.
)
iii ) Routinely conducted compliance initiatives on site that maintain quality
and will affect the company 's ability to maintain the validated state:
a ) Failure investigation ,
b ) Change control,
c ) Preventive maintenance,
d ) Calibration , and
e) Revalidation.
iv ) Important SOPs governing cleaning and cleaning validation :
a ) Development of cleaning SOPs (especially for manual cleaning
operations),
b ) Equipment cleaning and use logs,
c) Visual inspection requirements for cleaned equipment ,
d ) Equipment quarantine and release, and
e) Equipment sampling procedures for cleaning assessments ( e.g.,
swab, rinse, etc.).
6 ) List of equipment and/or systems subjected to cleaning validation , and
7 ) A progress summary or an annual summary report to the cleaning validation
master plan for regulatory review.
14.1.5. Calibration of pH Meter

A pH meter is an instrument used for measuring the pH, i.e., acidity or alkalinity ,
of a solution.
Measurement of pH
The pH can be roughly determined using pH papers or indicators that change
colour with the variation in pH level. But , these indicators have limitations on
their accuracy, and their interpretation in coloured or murky samples is difficult.
Thus, for obtaining more accurate pH measurements, a digital pH meter is used,
that consists of a pH probe, a reference pH electrode, and a high input impedance
meter. The pH electrode serves as a battery, with a voltage that varies with the
measured pH of solution . The pH probe is a hydrogen ion-sensitive glass bulb
with a millivolt output that varies with the changes in the hydrogen ion
concentration inside and outside of the bulb. The reference electrode output
remains unaffected by the activity of hydrogen ion. Internal resistance of the pH
electrode is very high, therefore the change in voltage with pH is difficult to
measure. The input impedance of the pH meter and the leakage resistances are
significant factors.
The pH meter is a high impedance amplifier that accurately measures even the
minute electrode voltages and displays the results in pH units either on an
analogue or on a digital display.
pH Meter Calibration
The pH electrodes are like batteries, i.e., they run down with time and use.
Resistance of the glass of an electrode changes with time. This change in
resistance alters the electrode potential, and thus electrodes should be calibrated
regularly. This change in resistance can be prevented by performing calibration
in pH buffer solution. Any pH equipment should be calibrated beginning with
buffer 7.0, i.e., the zero point. The pH scale has an equivalent mV scale, ranging
from +420 to -420mV . The mV value at pH 7.0 is 0. Each pH change
corresponds to a change of ±60mV .
As pH values decrease to become more acidic, the mV values become greater; for
example, a pH value of 4.0 corresponds to 180mV value. As pH values increase to
become more basic, the mV values become more negative; for example, a pH
value of 9.0 corresponds to -120mV value. To achieve a greater system accuracy,
dual pH calibration should be performed using buffers 4.0 or 10.0.
A general method is designed for the calibration of almost all the digital pH
meters, while some pH testers are calibrated by slightly different techniques.
Given below are the instructions for particular procedures:
1 ) The correct measurement mode should be selected before beginning the
calibration.
2 The electrode is thoroughly washed with de-ionised water or a rinse solution,
)
but is not wiped as it may build - up electrostatic charge on the glass surface.
3) The buffers should be maintained at 25±2°C temperature ( unless otherwise
specified in the individual monograph ) and the electrode along with the
temperature sensor should be dipped into the buffers.
4 ) The five point calibration should be performed using standard buffers of pH
168. 5.01/5.00, 7.00/7.01, 10.00/ 10.01 and 12.45.
5 ) The electrode should be dipped into the calibration buffer. The electrode end
should be completely dipped into the sample. The electrode should be gently
stirred to create a homogeneous sample.
6) The CAL/MEAS key should be pressed to enter pH calibration mode. The
CAL indicator will be shown. The primary display will show the measured
reading, while the smaller secondary display will indicate the pH standard
buffer solution reading.
7) The user should wait for the measured pH value to stabilise.
8) The HOLD/ENTER key should be pressed to confirm calibration , and then
the meter should be calibrated to the current buffer.
9) The electrode should be rinsed with de-ionised water, followed with buffer
solution, and then placed in the buffer solution .
10 ) When all the calibration points set in the unit configuration set up are
completed, the meter automatically returns to the measurement mode.
However, calibration can also be ended without completing the number of
points set in the unit configuration by pressing CAL \MEAS to return to pH
measurement mode.
11 ) The calibration details and temperature should be recorded.
12) The calibration buffer should be changed either every week or whenever
required , and recorded.
14.1.6. Qualification of UV- Visible Spectrophotometer

UV-Vis spectroscopy is an analytical method that measures the absorbance of
ultra-violet or visible radiation through an analyte. The molecular absorption of
the analyte corresponds to the excitation of valence electrons as well as the
excitation of electrons in different atomic orbitals. The technique of UV -Vis
spectroscopy is effectively used for qualitative and quantitative analysis of
organic and inorganic compounds. Instrument parameters checked as part of OQ
and PQ of a UV-Vis spectrophotometer includes:
1 ) Wavelength calibration , 2) Photometric accuracy,
3 Photometric linearity,
) 4) Photometric precision ,
5) Resolution/bandwidth, and 6) Stray light.
14.1.6.1. Operational Qualification ( OQ)

Acceptance criteria for critical instrument parameters that establish “fitness for
purpose” are verified during IQ and OQ. Specifications for particular instruments
and applications may vary with the analytical procedure used and the desired
accuracy of the final result. Wherever possible in the following procedures,
analysis should use CRMs in preference to laboratory- prepared solutions. CRMs
from a recognised accredited source include individually verified traceable value
assignments with associated calculated uncertainty . CRMs should be kept clean
and dust-free. The validity of the qualification should be maintained by
performing periodic recertification.
Wavelength Accuracy
Wavelength accuracy is the deviation of the wavelength reading at an absorption
band and emission band from the wavelength of the band.
Acceptance: ± nm in UV range ( 200-380nm )
± nm in visible range ( 380-800nm )
Three repeated scans of the same peak should lie within ±0.5nm value.
Stray Light
Stray light is the detected light of any wavelength that is outside the bandwidth of
the selected wavelength.
Acceptance: The transmittance of the solution in a 1cm cell should be < 0.01 or
the absorbance value should be > 2.
The stray light can be evaluated by measuring a sample that absorbs the radiation
at the desired analytical wavelength, but transmits at all other wavelengths. The
light detected by the instrument is the stray light. Usually, cut -off filters or
solutions that cut-off all light near the analytical wavelength are used for the
evaluation of stray light.
Alkali halide salt solutions have very sharp transitional ( cut-off ) spectra, thus
have exceptional filtering characteristics. Hence, any indication of light
transmittance below the specified “cut-off wavelength, should be stray light . The
test for stray light is important even if the spectrophotometer is not used below
260nm , because it indicates the overall performance of the instrument optics,
including grating and deuterium lamp ( table 14.1 ) .
Table 14.1: Stray Light Solutions
Materials Cut -off ( nin ) Concentrations
Sodium nitrite 390 50mg/L aqueous
Acetone 326 Spectroscopic grade
Potassium iodide 260 lOmg/L aqueous
Sodium iodide 260 lOmg/L aqueous
Lithium carbonate 227 Saturated aqueous
Sodium chloride 205 1 Omg/L aqueous
Potassium chloride 200 12mg/L aqueous
Resolution Power
The resolution of UV -Vis spectrometer is related to its spectral bandwidth ;
smaller the bandwidth, finer is the resolution. The slit width and the dispersive
power of the monochromator influence the spectral bandwidth.
Acceptance: Ratio of the absorbance at 269nm and at 266nm should be > 1.5.
SBW ( Spectral Bandwidth )

A 0.020% solution of toluene in hexane is the most widely used reference for
qualifying the SBW of a spectrophotometer. This solution is supplied along with
a hexane blank in a permanently heat-sealed quartz cell. In another approach ,
benzene vapour is used as a reference. In this method, 0.01 ml of benzene ( in
vapour state at room temperature ) is sealed into a UV quartz cell . At SBWs <
lnm, the benzene vapour spectrum has characteristic features that may or may
not be displayed, dependent on the SBW of the spectrophotometer. Benzene
vapour will not work efficiently with most photodiode array spectrophotometers,
as these instruments provide shortened spectral data where the peaks are not
sufficiently resolved to be functional . Toluene in methanol is also used as a
reference for instrument resolution validation in derivative spectroscopy.
14.1.6.2. Performance Qualification ( PQ )

The PQ aims to determine that the instrument can meet the user’s requirements
for all the parameters that may affect the measurement quality and to ensure that
it functions properly over extended time periods. Pharmacopoeial
spectrophotometric tests and assays call for comparison against an appropriate
reference standard. This helps ensure measurement under identical conditions for
the test sample and the reference substance. These conditions include
wavelengths setting, SBW selection, cell placement and correction, and
transmittance levels. Cells with identical transmittance at a given wavelength
may have different transmittance at other wavelength. Appropriate cell
corrections should be established and used as per the requirement.
Spectroscopic Noise
Near- Infrared ( NIR ) instrument software includes built -in procedures for
determining the system noise and providing a statistical report of noise or SNR
over the instrument 's operating range. It may also be desirable to supplement
such checks with measurements that do not directly depend on manufacturer-
supplied procedures. The procedures involve spectra measurement of traceable
reference materials with high and low reflectance. Tolerances for these
procedures should demonstrate suitable SNR for the intended application.
-
1) High Flux Noise: Instrument noise is evaluated at high-light flux by
measuring reflectance or transmittance of the reference standard, with the
..
reference material ( e g , 99% reflection standard ) acting as the sample as well
as the background reference.
-
2 ) Low Flux Noise: The same procedure is used with a lower reflectivity
reference material ( e.g., 10% reflectance standard ) to determine system noise
at reduced -light flux. The source, optics, detector, and electronics make
significant contributions to the noise under these conditions.
Noise
Noise is the measurement that affects the accuracy at both the ends of the
absorbance scale. Photon noise from the light source affects the accuracy of the
measurement and leads to low absorbance.
Acceptance: The Root Mean Square ( RMS ) noise should be < 0.001 AU.
Baseline Flatness
The flat baseline test validates the instrument’s ability to normalise the light
intensity measurement and the spectral output at different wavelength throughout
the spectral range.
Acceptance: The measurement should be < 0.01 AU.
Stability
Lamp intensity is a function of the lamp age, temperature fluctuation , and
wavelength of the measurement. These changes can lead to errors in the
measurement values, over an extended time period.
Acceptance: The deflection should be < 0.002AU /hr.
Photometric Accuracy
Photometric accuracy is determined by comparing the difference between the
measured absorbance of the reference material and the established value.
Acceptance: Six replicate measurements of 0.006% w/v of potassium dichromate
solution at 235, 257, 313 and 350nm should be > 0.5% RSD.
Photometric Linearity
1 ) lOOmg of potassium chromate is accurately weighed, transferred in a 100 ml
volumetric flask, and dissolved in 0.05N potassium hydroxide solution.
2) The volume is made up with the same solvent.
3) From the above solution , 20ml is taken and volume is made up to 500ml with
0.05 N potassium hydroxide solution.
4) Dilutions of 4, 8, 16, 24, 32 pg/ ml are prepared .
5) Absorbance is measured at 370nm using blank.
Acceptance Criteria: The plot should be linear and regression coefficient ( R 2)
should be not < 0.99.
14.2. GENERAL PRINCIPLES OF ANALYTICAL

METHOD OF VALIDATION
14.2.1. Introduction
The analytical methods meant to be used for analysing clinical samples should be
validated. Validation of an analytical procedure is the process in which
laboratory studies are conducted to establish that the performance characteristics
of the procedure meet the requirements for its proposed use. This process is
essential but time-consuming for most analytical development laboratories.
Therefore, the requirements of method validation and the options available to
allow ideal use of analytical resources in a development laboratory should be
briefly understood.
14.2.2. Need to Validate an Analytical Method

Analytical procedures should be validated due to many reasons, like regulatory
requirements, good science, and quality control requirements. According to
the Code of Federal Regulations ( CFR ) 311.165c, “the accuracy, sensitivity,
specificity, and reproducibility of test methods employed by the firm shall be
established and documented . ” Scientists want to apply good science to prove that
the analytical method used have established accuracy, sensitivity, specificity , and
reproducibility. The management of quality control unit also ensures that the
analytical methods used to release the products are properly validated for their
intended use to prove the products safe for human use.
Analytical methods should be validated, verified , or revalidated:
1 ) Before initial use in routine testing,
2) When transferred to another laboratory, or
3) When the conditions or parameters, for which the method has been validated ,
change beyond the original scope of the method ( for example, an instrument
with different characteristics or samples with a different matrix ).
Revalidation of analytical methods may also be required:
1 ) When the synthesis of the drug substance changes,
2) When the composition of the finished product changes, or
3) When the analytical procedure changes.
14.2.3. Validation Protocol

The text of 21 CFR Part 211, ICH guidelines and general chapter <1225>
provide terms and definitions on validation protocol and methodology . The ICH
guidelines ( Q2B ) on method validation methodology state that the applicant is
responsible for appropriate validation protocol and procedure suitable for the
product. Therefore, a well-planned validation protocol is required before
beginning a validation study, and it should include a detailed test procedure,
basic experimental design, elements for validation, predefined acceptance
criteria, reference or related methods, and management approval. A test
procedure describes the analytical method to be used as a guide when validating
the method and provide a base for preparation of validation protocol . It should
include:
1 ) A listing of reagents, solvents, and other supplies,
2) Instructions for preparation of standards, samples, and solutions,
3) A listing of equipment to be used,
4 ) Instrumental parameters and chromatographic conditions,
5 ) System suitability requirements,
6) Standard and sample analysis sequence, and
7) Calculation sequence to include result formatting.
14.2.4. Types of Analytical Procedures to be Validated

Analytical procedures are of the following three types:
1) Regulatory Analytical Procedures: These procedures are official in
compendia of standards recognised by country legislation; for example.
Drug and Cosmetic Rules recognise official procedures of IP, BP, and USP.
2) Alternative Analytical Procedures: These procedures are alternative
procedures for regulatory analytical procedures. Pharmacopoeia states that
alternative methods can be used if their performance is equivalent to or more
than the Pharmacopoeial analytical procedure.
3) Stability Indicating Assay: It is a validated quantitative method used for
detecting changes with time in particular properties of drug substances and
products. This method measures the active ingredients without interference
from degradation products, process impurities, excipients, or impurities.
Validation of analytical procedures is directed to the four types of analytical

procedures:
1) Identification tests,
2) Quantitative tests for impurities’ content,
3) Limit tests for the control of impurities, and
4) Quantitative tests of the active moiety in samples of drug substances or
products or other selected component (s) in the drug product.
The types of tests considered in this document have been discussed below:
1 ) Identification tests ensure the identity of an analyte in a sample by comparing
..
a property of the sample ( e g , spectrum, chromatographic behaviour,
chemical reactivity, etc.) with that of a reference standard.
2) Testing for impurities can be either a quantitative test or a limit test for the
impurity in a sample. The test is designed to accurately reflect the purity
characteristics of the sample. A quantitative test in comparison to a limit test
demands different validation characteristics.
3) Assay procedures measure the analyte in a given sample. Assay is a
quantitative measurement of the major component ( s ) in the given drug
substance. Similar validation characteristics also apply when assaying for the
active or other selected component( s ) of the drug product. The same
validation characteristics may also apply to assay procedures related to other
analytical procedures ( e.g., dissolution ).
14.2.5. Validation Characteristics

The typical validation characteristics which should be considered are:
1 ) Specificity, 2) Linearity,
3) Range, 4) Accuracy,
5) Precision, 6) Detection limit,
7) Quantitation limit, 8) Robustness, and
9 System suitability testing.
)
The degree of revalidation required depends on the nature of the changes. Some
other changes may also require validation .
Table 14.2: Characteristics to Consider during Analytical Validation
Types of Identification Testing for Testing for Assay
Analytical Impurities Impurities - Dissolution
Procedures ( Measurement Only )
-Content/Potency
Characteristics Quantitative Limit Tests
Tests
Accuracy + +
Precision
Repeatability + +
Intermediate + +
Precision
Specificity + + + +
Detection limit +
Quantitation +
limit
Linearity + +
Range + +
- Characteristic is normally not evaluated ;
+ Characteristic should normally be evaluated.
b
May be needed in some cases.
14.2.5.1. Specificity
A specificity investigation should be conducted during the validation of identification
tests, determination of impurities, and the assay. The investigation procedures for
specificity depend on the intended objective of the analytical procedure.
Demonstrating that an analytical procedure is specific for a particular analyte
Calibration and Validation (Chapter 14 ) 181
(complete discrimination ) is not always possible. Therefore, a combination of two

or more analytical procedures is used to achieve the desired discrimination level.
Identification
Identification tests should suitably discriminate between compounds with
somewhat similar structures that may be present. Discrimination of a procedure
can be confirmed by obtaining positive results ( possibly by comparing with a
known reference material ) from samples containing the analyte, and also
negative results from samples not containing the analyte. Thus, identification
tests are applied to materials having structures similar or closely related to that of
the analyte in order to confirm that a positive response is not obtained. The
choice of such potentially interfering materials relies on sound scientific
judgement by considering the interferences that might possibly occur.
Assay and Impurity Test (s)

Representative chromatograms should be used for chromatographic procedures to
demonstrate the specificity, and for this the individual components should be
appropriately labelled . Similar considerations should be given to other separation
techniques. Critical separations in chromatography should be investigated at an
appropriate level. For such separations, specificity can be demonstrated by the
resolution of the two components that elute next to each other. When a non-
specific assay is used, other supporting analytical procedures can demonstrate the
overall specificity. For example, in cases when a titration method is used for the
assay of a drug substance for release, the assay and a suitable test method can be
combined for impurities.
The approach is similar for both assay and impurity tests:

1 ) Impurities are Available: The assay procedure involves demonstrating the
discrimination of the analyte in the presence of impurities and /or excipients.
This can be done by spiking the pure drug substances or products with
appropriate levels of impurities and/or excipients, and demonstrating ( by
comparing with the assay result obtained on unspiked samples ) that these
materials do not affect the assay result. The impurity test involves
establishing the discrimination by spiking drug substances or products with
appropriate levels of impurities, and demonstrating the separation of these
impurities individually and/or from other components in the sample matrix .
2 ) Impurities are not Available: If impurity or degradation product standards
are not available, specificity can be demonstrated by comparing the test
results of samples containing impurities or degradation products with a
second well-characterised procedure, e.g., Pharmacopoeial method or other
validated and independent analytical procedure. This should include samples
stored under relevant stress conditions of light, heat, humidity, acid/base
hydrolysis, and oxidation. For the assay, the two results should be compared;
and for the impurity tests, the impurity profiles should be compared.
Peak purity tests can be used to show that the analyte chromatographic peak is not
..
attributable to more than one component (e g , diode array , mass spectrometry ).
14.2.5.2. Linearity
A linear relationship should be evaluated across the range of the analytical
procedure. It may be demonstrated directly on the drug substance ( by dilution of
a standard stock solution ) and/or separate weighings of synthetic mixtures of the
drug product components, using the proposed procedure.
Linearity should be evaluated by visually inspecting a plot of signals as a function

of analyte concentration or content. If a linear relationship exists, test results should
be evaluated by appropriate statistical methods; for example, by calculating a
regression line by the method of least squares. Sometimes, linearity between assays
and sample concentrations can be obtained by subjecting the test data to a
mathematical transformation before the regression analysis. The data obtained
from regression line provides mathematical estimates of the degree of linearity.
The correlation coefficient, y-intercept, slope of the regression line, residual sum
of squares, and a plot of the data should be submitted. An analysis of the
deviation of the actual data points from the regression line is also helpful for
evaluating linearity. The analytical response for the analytical procedures that do
not demonstrate linearity after any transformation ( like immunoassays ) should be
described by an appropriate function of the analyte concentration in a sample.
Procedure
From one solution five standard solutions with concentrations between 0 and
200% ( 20% , 60% , 100% , 140% , and 180% ) of the expected sample
concentration are prepared by dilution. Each solution should be tested twice. The
average response is plotted against the concentration of the component and the
calibration line is calculated using linear regression analysis. If an internal
standard is used , the linearity of this curve should be determined similarly.
14.2.5.3. Range
The specified range is derived from linearity studies and depends on the intended
application of the procedure. It is established by confirming that the analytical
procedure provides an acceptable degree of linearity, accuracy , and precision
when applied to samples containing amounts of analyte within or at the extremes
of the specified range of the analytical procedure.
The following specified ranges should be considered:

1) Normally , 80-120% of the test concentration for the assay of a drug
substance or a finished drug product ,
2) A minimum of 70-130% of the test concentration for content uniformity,
unless a wider more appropriate range is justified based on the nature of the
.
dosage form (e.g , metered dose inhalers),
..
3) +/-20% over the specified range for dissolution testing, e g , if specifications
for a controlled released product cover a region from 20% after 1 hour up to
90% after 24 hours, the validated range would be 0-110% of the label claim,
4) From the reporting level of an impurity to 120% of the specification for
impurity determination .
5) For the impurities known to be potent or to produce toxic or unexpected

pharmacological effects, the detection/quantitation limit should be
proportionate to the level at which the impurities should be controlled , and
6 ) Linearity should cover the range from the reporting level of the impurities to
120% of the assay specification if assay and purity are performed as one test
and only a 100% standard is used.
14.2.5.4. Accuracy
Accuracy should be established across the specified range of the analytical
procedure.
1 ) Assay
i) Drug Substance: Accuracy can be determined by the following
available methods:
a ) Applying an analytical procedure to an analyte of known purity ( e.g.,
reference material ),
b ) Comparing the results of the proposed analytical procedure with
those of another well -characterised procedure with stated and/or
defined accuracy, or
c ) Determining accuracy after the establishment of precision , linearity,
and specificity.
ii ) Drug Product: Accuracy can be determined by the following available
methods:
a ) Applying an analytical procedure to synthetic mixtures of the drug
product components to which drug substance to be analysed have
been added in known quantities,
b ) If obtaining samples of all drug product components is not possible,
either known quantities of the analyte is added to the drug product or
the results obtained from another well -characterised procedure with
stated and/or defined accuracy are compared, or
c) Determining accuracy after the establishment of precision, linearity,
and specificity.
2) Impurities ( Quantitation ): Accuracy should be evaluated for samples ( drug
substance/drug product ) spiked with known amounts of impurities. If
obtaining samples of certain impurities and/or degradation products is not
possible, the results obtained by an independent procedure are compared by
using the response factor of the drug substance. It should be clear how to
determine the individual or total impurities, e.g., weight/ weight or area
percent , in all cases with respect to the major analyte.
3) Recommended Data: Accuracy should be evaluated using a minimum of 9
determinations over a minimum of 3 concentration levels covering the specified
range (e.g., 3 concentrations/3 replicates each of the total analytical procedure).
Accuracy should be reported as percent recovery by the assay of known
added amount of analyte in the sample or as the difference between the mean
and the accepted true value along with the confidence intervals.
14.2.5.5. Precision
Validation of tests for assay and for quantitative determination of impurities
includes investigation of precision.
1 ) Repeatability: It should be evaluated using:
i ) A minimum of 9 determinations covering the specified range for the
procedure ( e.g., 3 concentrations/3 replicates each ), or
ii ) A minimum of 6 determinations at 100% of the test concentration.
2 ) Intermediate Precision: The extent to which intermediate precision should
be established depends on the circumstances under which the procedure is to
be used. The applicant should establish the effects of random events on the
precision of analytical procedure. Variations including days, analysts,
equipment , etc. should be studied . However, individual study of these effects
is not necessary. An experimental design ( matrix ) should be used.
3) Reproducibility : It should be evaluated by an inter-laboratory trial.
Reproducibility should be considered when standardising an analytical
procedure; for example, for inclusion of procedures in Pharmacopoeias.
These data are not part of the marketing authorisation dossier.
4) Recommended Data: Standard deviation, relative standard deviation
( coefficient of variation ), and confidence interval should be reported for each
type of investigated precision .
14.2.5.6. Detection Limit

Detection limit can be determined by several approaches, depending on whether
the procedure is instrumental or non -instrumental. Approaches other than those
listed below may also be acceptable.
1 ) Based on Visual Evaluation: This approach can be used for non-
instrumental as well as instrumental methods. Detection limit is determined
by analysing the samples with known concentrations of analyte and by
establishing the minimum level at which the analyte can be detected.
2) Based on Signal - to- Noise: This approach can be applied to analytical
procedures exhibiting baseline noise. Signal -to-noise ratio can be determined
by comparing the measured signals from samples with known low
concentrations of analyte with those of blank samples, and then establishing
the minimum concentration at which the analyte can be detected. A signal -to-
noise ratio between 3 or 2; 1 is acceptable for estimating the detection limit.
3) Based on the Standard Deviation of the Response and the Slope: The
Detection Limit ( DL) can be expressed as:
DL = 3.3 o/S
Where, o = Standard deviation of the response
S = Slope of the calibration curve
The slope (S) can be determined from the calibration curve of the analyte.
The o value can be determined in the following ways:
i ) Based on the Standard Deviation of the Blank : The magnitude of analytical
background response is determined by analysing an appropriate number of
blank samples and calculating the standard deviation of these responses.
ii ) Based on the Calibration Curve: A specific calibration curve is studied

using samples containing an analyte in the range of DL. The residual
standard deviation of a regression line or the standard deviation of y-
intercepts of regression lines can be used as the standard deviation .
4 ) Recommended Data: The detection limit and the method used for
determining the detection limit should be presented. If DL is estimated based
on visual evaluation or on signal -to-noise ratio, the relevant chromatograms
are presented for justification. If an estimated value for the detection limit
has been obtained by calculation or extrapolation, the estimated value is
validated by the independent analysis of a suitable number of samples known
to be near or prepared at the detection limit.
14.2.5.7. Quantitation Limit

The quantitation limit can be determined by many approaches, depending on
whether the procedure is non -instrumental or instrumental . Approaches other
than those listed below may be acceptable.
1) Based on Visual Evaluation: This approach can be used for non -
instrumental as well as instrumental methods. Quantitation limit is
determined by analysing the samples with known concentrations of analyte
and by establishing the minimum level at which the analyte can be quantified
with acceptable accuracy and precision.
2) Based on Signal - to- Noise Approach: This approach can be applied to
analytical procedures exhibiting baseline noise. Signal -to-noise ratio can be
determined by comparing the measured signals from samples with known
low concentrations of analyte with those of blank samples, and then
establishing the minimum concentration at which the analyte can be
quantified . A signal-to-noise ratio between 10: 1 is acceptable for estimating
the quantitation limit.
3) Based on the Standard Deviation of the Response and the Slope: The
Quantitation Limit ( QL) can be expressed as
QL = 10 o/S
Where, o = Standard deviation of the response
=
S Slope of the calibration curve
The slope (S) can be determined from the calibration curve of the analyte.
The a value can be determined in the following ways:
i ) Based on Standard Deviation of the Blank: The magnitude of analytical
background response is determined by analysing an appropriate number of
blank samples and calculating the standard deviation of these responses.
ii ) Based on the Calibration Curve: A specific calibration curve is studied
using samples containing an analyte in the range of QL. The residual
standard deviation of a regression line or the standard deviation of y-
intercepts of regression lines can be used as the standard deviation.
4 ) Recommended Data : The quantitation limit and the method used for
determining the quantitation limit should be presented. If an estimated value
for the quantitation limit has been obtained by calculation or extrapolation,

the estimated value is validated by the independent analysis of a suitable
number of samples known to be near or prepared at the quantitation limit.
14.2.5.8. Robustness
Robustness should be evaluated during the development phase, and the
evaluation process depends on the type of procedure being studied. It should
show the reliability of an analysis with respect to the variations made deliberately
in the method parameters. If measurements are prone to variations in analytical
conditions, these conditions should be controlled or a precautionary statement
should be included in the procedure. One consequence of robustness evaluation is
that a series of system suitability parameters ( e.g., resolution test ) should be
established to ensure that the validity of the analytical procedure is maintained.
Some examples of typical variations in liquid chromatography include:
1 ) Influence of variations of pH in a mobile phase,
2) Influence of variations in mobile phase composition,
3) Different columns ( different lots and/or suppliers), and
4) Temperature
Some examples of typical variations in gas chromatography include:
1) Different columns ( different lots and/or suppliers ),
2) Temperature, and
3) Flow rate.
14.2.5.9. System Suitability Testing
System suitability testing is an integral part of many analytical procedures. The
tests rely on the concept that the equipment, electronics, analytical operations,
and samples to be analysed form an integral system that can be evaluated. System
suitability test parameters to be established for a particular procedure depend on
the type of procedure being validated . In the final step of analysis, purpose of
validating method is to ensure the procurement of high quality data. If the quality
of data is doubtful, meaningful conclusions about the product quality cannot be
reached, and this will have serious unfavourable effects on stability data review
and process validation reviews.
14.2.6. Steps in Method Validation

Validation method involves the following steps:
1) A validation protocol or operating procedure for the validation is developed.
2) The application , purpose and scope of the method are defined.
3) The performance parameters and acceptance criteria are defined.
4 ) The validation experiments are defined.
5 ) The relevant performance characteristics of equipment are verified.
6 ) The materials, e.g., standards and reagents, are qualified.
7) Pre- validation experiments are carried out .
8) The method parameters or/and acceptance criteria are adjusted.
9 ) Full internal and external validation experiments are carried out .
10) SOPs for executing the method in the routine are developed.
11 ) The criteria for revalidation are defined.

12) The type and frequency of system suitability tests and/or Analytical Quality
Control ( AQC ) checks for the routine are defined.
13) Validation experiments and validation results are documented .
14.2.7. Validation Report

A validation report should include the following details:
1) Objective and scope of the method ,
2 ) Types of compounds and matrix,
3) Chemicals, reagents, reference standards, and control sample preparations,
4 ) Procedures for quality checks of standards and chemicals used,
5 ) Safety considerations,
6 ) Method parameters,
7 ) Critical parameters indicated from robustness testing ,
8) Listing of equipment and its functional and performance requirements, e.g.,
cell dimensions, baseline noise, and column temperature range,
9) Details of how the experiments were conducted and samples were prepared ,
10 ) Statistical procedures and representative calculations ,
11 ) Procedures for quality control in the routine ( e.g., system suitability tests ),
..
12) Representative plots, e g , chromatograms, spectra, and calibration curves,
13) Method acceptance limit performance data ,
14 ) Expected uncertainty of measurement results,
15) Criteria for revalidation ,
16 ) Person who developed and initially validated the method , and
17 ) Summary and conclusions.
14.3. SUMMARY
1 ) Calibration is a set of operations that establish relationship between the
..
values indicated by an instrument or system for measuring ( e g , weight,
temperature, and pH ), recording, and controlling, or the values represented
by a material measure and the corresponding known values of a reference
standard, under specified conditions.
2) Calibration is also defined as the process of issuing data including a report
or certificate of calibration that ensures an end user of a product ’s
conformance with its specifications.
3) Ted Byers and Bud Loftus ( FDA officials) first introduced the validation
concept in the mid -1970s to improve the quality of pharmaceuticals.
4) Validation is an act of demonstrating and documenting that a procedure,
process, and activity will steadily give the desired results.
5) The calibration range of an instrument is the region between the limits
within which a quantity is measured, received or transmitted, expressed by
stating the Lower Range Values ( LRV ) and Upper Range Values ( URV ).
6) Zero value is the lower end of the range or LRV and the URV is the upper
range value.
7) Span value is the algebraic difference between the upper and lower range
=
values (Span URV - LBV ).
8) The instrument range is the capability of the instrument .
9 ) To range an instrument means to set its lower and upper range values so that
the instrument responds with desired sensitivity to changes in input.
10 ) Re-ranging means to reset the lower and upper range values to a different
measurement range.
11 ) Zero and span adjustments are made to set the instrument for any range of
measurement within the manufacturer’s limits.
12 ) When an instrument is being calibrated, its data points should include
readings taken at 0% , 25% , 50% , 75% , and 100% of the calibration range of
the instrument. This is referred to as a five- point calibration .
13) Field calibration involves the calibration of field instrument at the true
process and ambient conditions.
14 ) A bench tester is used for bench calibration of an instrument or device.
15) In bench calibration , calibration devices are used to calibrate the instrument
at a calibration bench to simulate the process, rather than calibrating the
device in the field using the actual process as the input means.
16 ) Calibrators are used for calibrating instruments that require calibration.
17 ) Block calibrator and fluidised baths are used for calibrating temperature
probes, like RTDs, thermocouples, etc.
18 ) Signal reference is used for calibrating panel metres and temperature
controllers.
19 ) Pneumatic calibrators, often used along with a pressure source, provide a
regulated pressure regime for testing or calibrating pressure instruments.
20 ) Calibration records are the documentation to ensure that the history of the
device or instrument is not lost.
21 ) The as-found data of an instrument to be calibrated is the response from the
device ( reading ) at the points of calibration (0% , 25% , 50% , 75% , and 100% )
22) The as- left data of an instrument to be calibrated is the response from the
device ( reading ) at the points of calibration ( 0% , 25% , 50% , 75% , and 100% )
after the completion of calibration .
23) Traceability is the property of a result of measurement and can be related to
appropriate national or international standards through an unbroken chain of
comparisons.
24 ) Qualification is the documented evidence that premises, systems, or
equipment can achieve the predetermined specifications properly installed ,
and/or work correctly and give the desired results.
25 ) Design qualifications are the specifications a manufacturer uses to describe
a device or equipment.
26) IQ is a documented collection of activities required for installing an
instrument in the user’s environment .
27) PQ testing is conducted after performing the IQ and OQ tests under the
actual running conditions across the expected working range.
28 ) Process validation involves establishment of documented evidence to

provide a high degree of assurance that any process ( like, manufacture of
pharmaceutical dosage forms, etc.) will consistently produce a product that
will fulfil the predetermined specifications and quality characteristics.
29) Prospective validation is conducted before distribution of the new product ,
and involves establishing a documented evidence of what a system does or
what it is intended to do, based upon a plan .
30 ) Retrospective validation is conducted in an already distributed product,
based on the data collected on production , testing and control.
31 ) Concurrent validation involves establishing a documented evidence of
what a system does or what it is intended to do, based upon the information
generated during implementation of the system.
32 ) Cleaning validation is conducted to ensure that no cross-contamination
occurs between different batches.
33) Method validation is conducted to ensure the precision, accuracy and
consistency of analytical tests.
34) Validation master plan is an internally approved document that describes
the general expectations, intentions, methods, and approach to be used during
the validation programme using clear and concise words.
35 ) Wavelength accuracy is the deviation of the wavelength reading at an
absorption band and emission band from the wavelength of the band .
36) Stray light is the detected light of any wavelength that is outside the
bandwidth of the selected wavelength.
-
37) The resolution of UV Vis spectrometer is related to its spectral bandwidth;
smaller the bandwidth , finer is the resolution .
38) A 0.020% solution of toluene in hexane is the most widely used reference for
qualifying the SBW of a spectrophotometer.
39) Noise is the measurement that affects the accuracy at both the ends of the
absorbance scale.
40 ) The flat baseline test validates the instrument’s ability to normalise the light
intensity measurement and the spectral output at different wavelength
throughout the spectral range.
41 ) Photometric accuracy is determined by comparing the difference between
the measured absorbance of the reference material and the established value.
42 ) Regulatory analytical procedures are official in compendia of standards
recognised by legislation of country.
43) Alternative analytical procedures are alternative procedures for regulatory
analytical procedures.
44) A specificity investigation should be conducted during the validation of
identification tests, determination of impurities, and the assay.
45 ) Linearity should be evaluated by visually inspecting a plot of signals as a
function of analyte concentration or content.
46) The specified range is derived from linearity studies and depends on the
intended application of the procedure.
47 ) Accuracy should be established across the specified range of the analytical
procedure.
48 ) Validation of tests for assay and for quantitative determination of impurities

includes investigation of precision .
49 ) Detection limit can be determined by several approaches , depending on
whether the procedure is instrumental or non -instrumental .
50) The quantitation limit can be determined by many approaches , depending
on whether the procedure is non-instrumental or instrumental .
51 ) Robustness should be evaluated during the development phase , and the
evaluation process depends on the type of procedure being studied .
52 ) System suitability testing relies on the concept that the equipment ,
electronics, analytical operations , and samples to be analysed form an
integral system that can be evaluated .
14.4. EXERCISE
14.4.1. Very Short Answer Type Questions
1) Define calibration and validation.
2) Give the difference between field and in -shop calibration.
3) What are zero and span values?
4) Define process validation.
5) What are prospective and retrospective validation ?
6) Define wavelength accuracy.
7) What should be the contents of validation protocol?
8) How detection and quantitation limit can be calculated ?

1 ) Write design and installation qualification.
2) Discuss about performance qualification.
3) Write a note on validation master plan .
4) How a pH meter should be calibrated ?
5) Write about the types of analytical procedures to be validated .
6) Give the steps of validation method and its report ?

1 ) Write an exhaustive note on general principles of qualification.
2) Give a brief review on general principles of validation.
3) Write an illustrative note on qualification of UV -Vis spectrophotometer.
4) Write about the validation characteristics of analytical procedures.
Warehousing ( Chapter 15 ) 191
CHAPTER
15
Warehousing
15.1. WAREHOUSING
Warehouses for storage of pharmaceutical products should be efficiently laid out
with all the required storage areas, goods assembly, packing, receiving and
dispatch points, and office and subsidiary accommodation for effectual operation
of the store. Pharmacies and health facilities should be laid out such that
dispensing errors are reduced to minimum level , and the staff and patients are
provided with a safe and comfortable environment.
15.1. 2. Good Warehousing Practice

Good warehousing practice involves the following:
1 ) Personnel, 2) Premises,
3) Sanitation . 4) Temperature & environment control,
5) Equipment , 6) Materials management ,
7 ) Packing for transportation , 8) Dispatch and transport,
9) Documentation and records, 10 ) Returned goods,
11 ) Product recalls, 12) Complaints,
13) Disposal of unsaleable goods, and 14 ) Repacking and labelling.
15.1 .2.1 . Personnel

There should be sufficient number of personnel, with qualifications as per the
national regulations, to achieve objectives of pharmaceutical quality assurance at
each storage site ( i.e., manufacturer site, distributor site, wholesaler site, and
community or hospital pharmacy ). Proper training should be provided to all the
personnel with respect to good storage practice, regulations, procedures, and
safety to observe high levels of personal hygiene and sanitation. Suitable
protective or working garments should be worn by the personnel employed in
storage areas while performing the assigned tasks.
15.1.2.2. Premises
Premises should be of suitable size and construction so that cleaning,
maintenance, and systematic and segregated storage can easily be performed.
There should be proper lightening, ventilation , temperature, sanitation , humidity,
space for movement , equipment , and security conditions maintained within the
premises. To prevent cross-contamination , medicinal products should be stored
separately from other goods. Incoming goods and the goods still not approved for
distribution should be physically or electronically segregated till the concerned
person gives approval . A separate area should be available to hold and store the
returned and rejected goods before a decision on further action. The controlled
drugs should be stored in a secure, segregated area, and the customer orders
should be assembled in a separate, designed area.
Proper security should be provided for storage areas to prevent stealing or entry
by unauthorised personnel, and only authorised personnel should be allowed to
enter the facilities. A proper system should be established for controlling access
to the facility ( including all entrances and exits ).
Storage Areas
1 ) Entry of unauthorised personnel in the storage areas should be limited or
completely prohibited.
2) Storage areas of sufficient capacity should be available so that various types
of materials and products, like packaging materials, intermediates, bulk and
finished products, quarantined products, and released, rejected, returned or
recalled products, can be stored orderly.
3) Design and arrangement of the storage areas should be such that good
storage conditions are maintained. The storage areas should be clean , dry and
maintained within acceptable temperature limits. Special storage conditions,
such as temperature, relative humidity, etc., required for any pharmaceutical
.
product (e.g , antibiotics, etc.) should be provided, checked , monitored , and
recorded. All the materials and pharmaceutical products should be stored off
the floor so that cleaning and inspection can be performed easily. Pallets
should be stored in a good state of cleanliness and repair.
4 ) The storage areas should be clean and free from accumulated waste and vermin.
A written instruction manual for sanitation should be available describing the
methods and frequency of cleaning the premises and storage areas.
5) A written instruction manual for pest control should also be available. The pest
control agents to be used should be safe, with no risk of contaminating the
materials and pharmaceutical products. Appropriate procedures for the cleansing
of any spillage should be established so that contamination risk can be prevented.
6) There should be proper lighting within the storage areas so that all operations
can be carried out accurately and safely.
7) Storage conditions for pharmaceutical products and materials should be
according to the labelling based on the results of stability testing.
15.1.2.3. Sanitation
A written instruction manual for sanitation , describing the methods and
frequency of cleaning the premises and storage areas, should be available. The
storage areas should be cleaned and accumulated waste should also be removed
at regular intervals. Pest control programme should also be carried out from time-
to-time. Separate areas should be provided for smoking, eating, and drinking, and
such activities should not be carried out in areas used for storage and handling of
final drug products. Spills involving drug products should be regularly cleaned
and rendered safe as per the relevant health and safety requirements for the
product. A separate toilet and changing room should be available at adequate
distance from the main storage and order assembly areas.
15.1 .2.4. Temperature and Environment Control

All drug products should be stored according to the conditions stated on their
label. The temperature of all storage areas should be monitored at given intervals.
Storage areas with controlled temperature should be equipped with recorders and
devices that give indications if the temperature fluctuates from the specified
range. A written procedure, describing what action should be taken in such a
situation, should also be available.
It should be ensured that all parts of the storage area are within the specified
temperature range. A back-up system should always be there (in case the main
system fails ). The storage areas should be installed with devices that measure
humidity. If specific humidity is required to be maintained for any product , a
written procedure should be available, specifying what action should be taken
when the humidity is not within the specified range. If any specific humidity
range is not required , a normal operating baseline of humidity should be
maintained . A person should be assigned with the responsibility to record,
review, and maintain the temperature and humidity in the storage areas.
15.1 . 2.5. Equipment

A planned preventative maintenance programme should be conducted. Record
and control equipment should be timely calibrated and checked at defined
intervals using appropriate methods. Alarm set-points should be checked at
periodic intervals, and a validated computerised system should be used for stock
control/distribution.
15.1 .2.6. Materials Management

The following measures should be followed for the management of materials:
1 ) Receiving and dispatch bays should be such that the materials and products
can be protected from the weather. Design and equipment of the reception
areas should be such that the containers of incoming materials and
pharmaceutical products can be cleaned before storage ( if required ).
2) If quarantine status is ensured by separate storage areas, such areas should be
clearly marked and only authorised personnel should be allowed to enter.
System used to replace physical quarantine should provide equivalent
security ; for example, computerised systems with validated security access
can be used.
3) A separate sampling area should be present in a controlled environment for
the starting materials. Sampling in storage areas should be performed such
that any type of contamination or cross-contamination can be prevented. For
sampling areas, adequate cleaning procedures should be in place.
4 ) The rejected, expired, recalled or returned materials or products should be
..
stored after physical or other equivalent validated (e g , electronic )
separation. Materials or products, and the concerned areas should be
appropriately identified.
5) A separate area with additional safety and security measures should be
provided for highly active and radioactive materials, narcotics, and
hazardous, sensitive and/or dangerous materials and pharmaceutical
products. Substances presenting special risks of abuse, fire or explosion ( e.g.,

combustible liquids and solids and pressurised gases ) should also be stored in
such areas.
6) Materials and pharmaceutical products should be handled and distributed as
per the GMP guidelines.
7) Contamination, mix-ups, and cross-contamination of the materials and
pharmaceutical products should be avoided during their handling and storage.
8) The storage conditions should be such that the quality of materials and
pharmaceutical products can be maintained, and stock can be appropriately
rotated by following the First Expired/First Out ( FEFO) rule.
9 ) Rejected materials and pharmaceutical products should be identified and
controlled under a quarantine system that has been designed to prevent then-
use until a final decision is taken.
10) The storage of narcotic drugs should be according to the guidelines of
international conventions, and national laws and regulations on narcotics.
11 ) Broken or damaged items should not be present in the usable stock.
Receipt of Incoming Materials and Pharmaceutical Products

1) Each incoming delivery should be checked against the relevant purchase
order on receiving. Each container should also be physically verified by
checking the label description, batch number, type of material or
pharmaceutical product , and its quantity.
2 ) The uniformity of each container in the whole consignment should be
checked , and sub-divided as per the supplier's batch number if the delivery
comprises of more than one batch.
3) Inspection of each container for contamination , tampering, damage, and any
suspect containers should be done. If required, the entire delivery should be
quarantined for further investigation.
4 ) Samples from containers should be taken only by properly trained and
qualified personnel and by strictly following the written sampling
instructions. Such containers should be labelled.
5 ) After sampling, the goods should be quarantined. Batch segregation should
be maintained during quarantine and all subsequent storage.
6) Until an authorised release or rejection is obtained, materials and
pharmaceutical products should remain in quarantine.
7) To prevent the use of rejected materials and pharmaceutical products,
necessary measures should be taken. Such products should be stored
separated from other materials and pharmaceutical products, till they are
destroyed or returned to the supplier.
Stock Rotation and Control
1 ) By comparing the actual and recorded stocks, periodic stock reconciliation
should be performed.
2) Investigation of all significant stock discrepancies should be performed
against inadvertent mix-ups and/or incorrect issues.
3) For the prevention of spoilage and/or contamination during storage in
manufacturing facilities, all the partially used containers of materials and
pharmaceutical products should be securely reclosed and resealed. Opened or

partially used containers of materials and pharmaceutical products should be
used up before those in unopened containers.
4 ) Damaged containers should not be issued till the material quality remains
unaffected , and it should be brought to the attention of the person responsible
for quality control . The action taken in this situation should be documented .
Control of Obsolete and Out -dated Materials and Pharmaceutical Products

All stocks should be checked at regular intervals to detect the out-dated and
obsolete materials and pharmaceutical products. Necessary measures should be
taken to prevent the issue of such materials and pharmaceutical products.
15.1 .2.7. Packing for Transportation

Products should be packed and labelled such that the product identification is not
lost, and the product does not contaminate and does not get contaminated by
other products or materials. Appropriate measures should be taken against
spillage and breakage. Products requiring controlled temperature storage should
be stored with insulated packs. There should be documented evidence that the
insulated packs ensure adequate transport conditions with respect to:
1 ) Product quantity,
2 ) Ambient temperature, and
3) Maximum delivery time.
Labelling and Containers

1 ) For the storage of materials and pharmaceutical products, containers that do
not adversely affect the quality of the materials or products , and provide
sufficient protection from external factors, should be used.
2) Name of the material , batch number, expiry or retest date, specified storage
conditions, and reference to the Pharmacopoeia ( wherever needed ) should be
labelled on the containers. Unauthorised abbreviations, names, or codes
should not be used .
15.1 .2.8. Dispatch and Transport

Transportation of the materials and pharmaceutical products should be done in
such a way that their integrity is not diminished and storage conditions are
maintained. Dry ice in cold chains should be used with special care. Materials or
products should not come into contact with dry ice, as this may adversely affect
the product quality.
Devices to monitor conditions of temperature during transportation should be

used. Monitoring records should be maintained for review . Materials and
pharmaceutical products should be dispatched and transported on receiving a
delivered order. Documents for receipt of the delivery order and dispatch of the
goods should be maintained . Dispatch procedures should be established and
documented, considering the nature of materials and pharmaceutical products and
any special precautions. Adequate protection from external factors should be
provided to the outside containers, which should be clearly labelled.
Records for dispatch should state the following:

1) Dispatch date,
2) Customer’s name and address,
3) Product description, including name, dosage form, strength , batch number,
and quantity, and
4) Transport and storage conditions.
All records should be easily accessible and available on request.
15.1 .2.9. Documentation and Records

Written instructions and records, documenting all activities in the storage areas
and handling of expired stock, should be available. Such documents should
describe storage procedures and the route of materials and pharmaceutical
products and information through the organisation in the event of a product recall
being required. For each stored material or product , permanent information ( in
written or electronic form ), including specified storage conditions, any
precautions to be observed , and retest dates, should be available. Pharmacopoeial
requirements and current national regulations concerning labels and containers
should be followed under any conditions.
All the operations should be recorded in such a way that all significant activities or
events can be traced easily. These records should be easily accessible, available,
and should be retained for at least five years. Records of each delivery, including
the description of goods, quality, quantity, supplier, supplier’s batch number, date
of receipt, assigned batch number, and the expiry date, should be maintained.
Where national regulations prescribe that records should be retained for a certain
period, this should be observed; or else such records should be retained for a period
equal to the shelf-life of the incoming materials and products, plus 1 year).
Records including all receipts and issues of materials and pharmaceutical products
according to a specified system ( e.g., by batch number ) should be maintained .
15.1 .2.10. Returned Goods

All returned and recalled goods should be handled according to the approved
procedures, and related records should be maintained . Returned goods should be
kept in quarantine and returned to saleable stock only when approved by a
nominated , responsible person following a satisfactory quality re-evaluation. If
stock is reissued, it should be identified properly and recorded in stock records.
The pharmaceutical products returned from patients to the pharmacy should not
be taken back as stock, rather should be destroyed.
15.1.2.11. Product Recalls

Products can be recalled only after the order of the Head of Quality Assurance.
Product recall system should:
1) Define who contacts regulatory authorities regarding any recall procedure,
2) Define the procedure whereby recalled products can be traced and obtained
from the market,
3) Maintain records of all recalled products,
4 ) Establish segregated storage area for any recalled products,

5 ) Remove all recalled products from saleable stock, and
6) Store all recalled products in a segregated area.
Decision on recalled products should be taken by the relevant QA Manager or

responsible person. The effectiveness of the arrangements for recalls should be
evaluated periodically.
15.1.2.12. Complaints
Any complaint regarding product defect should be immediately reported to the
supplier and processed as per the local regulations. Any complaint related to
customer service or shipping errors should be processed as per the established
procedure. Records of all the received complaints should be maintained.
15.1.2.13. Disposal of Unsaleable Goods

Stock that is not suitable for sale should be separated from other stock before its
final disposal or destruction. Unsaleable goods should be destroyed according to
the local legislation or guidelines issued by each manufacturer. A written record ,
including product name, batch number, pack size, quantity , and methods of
destruction , should be maintained for all destroyed goods.
15.1.2.14. Repacking and Labelling

If possible, the products should be repacked and labelled at the Principal ’s own
licensed premises. If repacking or labelling process is carried out at the
wholesaler site, the following factors should be applied:
1 ) Specific, separate area for this operation ,
2) Adequate procedure with described operation,
3) Each step of the operation should be recorded and records should contain
identification and quantity of product and packaging materials, and
4 ) All tasks should be performed under the supervision of the Principal ’s QC or
QA representative.
15.2. SUMMARY
1 ) Warehouses for storage of pharmaceutical products should be efficiently laid
out with all the required storage areas, goods assembly , packing, receiving
and dispatch points, and office and subsidiary accommodation for effectual
operation of the store.
2 There should be sufficient number of personnel , with qualifications as per the
)
national regulations, to achieve objectives of pharmaceutical quality
assurance at each storage site (i.e., manufacturer site, distributor site,
wholesaler site, and community or hospital pharmacy).
3) Premises should be of suitable size and construction so that cleaning,
maintenance, and systematic and segregated storage can easily be performed.
4) A written instruction manual for sanitation, describing the methods and
frequency of cleaning the premises and storage areas, should be available.
5 ) All drug products should be stored according to the conditions stated on their
label.
6) A planned preventative maintenance programme should be conducted.
Record and control equipment should be timely calibrated and checked at
defined intervals using appropriate methods.
7 ) All stocks should be checked at regular intervals to detect the out -dated and
obsolete materials and pharmaceutical products.
8) Products should be packed and labelled such that the product identification is
not lost, and the product does not contaminate and does not get contaminated
by other products or materials.
9) Transportation of the materials and pharmaceutical products should be done
in such a way that their integrity is not diminished and storage conditions are
maintained .
10) Written instructions and records, documenting all activities in the storage
areas and handling of expired stock, should be available.
11 ) All returned and recalled goods should be handled according to the approved
procedures, and related records should be maintained.
12) Products can be recalled only after the order of the Head of Quality
Assurance.
13) Any complaint regarding product defect should be immediately reported to
the supplier and processed as per the local regulations.
14) Stock that is not suitable for sale should be separated from other stock before
its final disposal or destruction.
15) If possible, the products should be repacked and labelled at the Principal ’s
own licensed premises.
15.3. EXERCISE
1) Write about the personnel requirements in a warehouse .
2) Give the equipment requirements in a warehouse.
3) How returned goods are handled in a warehouse ?
4) How unsaleabale goods are disposed in a warehouse?

1) Write about the premises requirements in a warehouse.
2 ) Discuss about material management in a warehouse.
3) Write a note on documentation and records in a warehouse.

1 ) Write an exhaustive note on good warehousing practices.
Index 199
Index
A o
Accuracy, 184 Organisation and Personnel, 86
B
P
Bench Tester, 167
Precision, 185
c Premises, 94
Calibration, 164 .
Plant Layout 96
Calibration of pH Meter, 173 Process of Harmonization, 48
Calibration Range, 165
Calibrators, 167
Q
.
Complaints 147 .
QSEM 51, 53
Q-Series Guidelines, 51
D Qualification, 168
Detection Limit , 185 Qualification of UV -Visible
Document Maintenance, 153 Spectrophotometer, 175
Distribution Records, 162 Quality Assurance, 12
Quality by Design ( QbD ), 59
E Quality by Design ( QbD ) Tools:, 65
Equipments and Raw Materials, 110 Quality Control, 11
Equipment Selection, 110 Quality Control Test for Containers, 116
Maintenance of Equipment, 111 Quality Control Test for Rubber Closures, 121
Maintenance of Stores for Raw Materials, 114 Quality Control Test for Secondary Packing
Materials, 122
F Quality Management System, 11
Field Calibration , 166 Quantitation Limit, 186
Five Point Calibration, 166
R
G Range, 183
GMP, 13 Recalling, 148
Good Laboratory Practice, 127, 144 Robustness, 187
General Provisions, 127
Good Warehousing Practice, 191 s
I Span , 165
Specificity, 181
1CH Procedure, 48 System Suitability Testing, 187
ICH Stability Testing Guidelines, 53
In-Shop or Bench Calibration , 167 T
ISO 14000, 75 80 . Total Quality Management , 37, 45
ISO 9000, 69, 79 Traceability, 168
ISO 9000 Series Importance, 71
V
L
Validation, 164
Linearity. 183
N z
NABL, 82, 84 Zero and span adjustments, 166, 189
Nucleoside Reverse Transcriptase Inhibitors,
36
Bibliography
• Quality Assurance of Pharmaceuticals: A Compendium of Guidelines ,
Volume 2, By World Health Organization.
• Potdar Manohar A., Pharmaceutical Quality Assurance , Nirali Prakashan.
• Welty G., Quality Assurance , Woodhead Publishing.
• Shayne Cox Gad, Pharmaceutical Manufacturing Handbook: Regulations
and Quality , Wiley Interscience.
• Wingate Guy, Pharmaceutical Computer Systems Validation: Quality
Assurance, Risk Management and Regulatory Compliance , Informa
Healthcare.
• Yerramilli Anjaneyulu and Marayya R., Quality Assurance and Quality
Management in Pharmaceutical Industry, BS Publications.
• McCormick Kate and Wylie McVay D. Jr., Pharmaceutical Process Design
and Management , Routledge.
• Sarker Dipak Kumar, Quality Systems and Controls for Pharmaceuticals,
Wiley.
• Nagori B.P., Gaur Ajay , Solanki Renu , and Mathur Vipin, Pharmaceutical
Quality Assurance , Scientific Publsihers.
• Teasdale Andrew , Elder David, and Nims Raymond W., ICH Quality
Guidelines: An Implementation Guide , Wiley.
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I

Dr. Minal T Harde

THAKUR PUBLICATION PVT. LTD., LUCKNOW

Books are Available for Online Purchase at: tppl .org. in

ISBN No. 978-93-89627 -90-9

Copyright © All Rights Reserved

Please e-mail us at , thakurpublication @ gmail.com

I shall remain thankful to Principal and my mentors of Vinayaka Missions

1.1.3. Definition and Concept of 12 3.1.2. Purpose 47

Quality Assurance 3.1.3. Participants 47

Chapter 5: ISO 9000 & ISO 8.1.3. Design and Construction 94

8.1 . 10. Control of Contamination 102

CHAPTER Quality Assurance and Quality

1.1. QUALITY ASSURANCE AND QUALITY

1.1.2. Definition and Concept of Quality Control

In a manufacturing or service environment, quality of design and quality of

1.1 .3. Definition and Concept of Quality Assurance

1.2. DEFINITION AND CONCEPT OF GMP

1.2.3. Buildings and Infrastructure

Sanitation and Maintenance

1.2.4. Process Equipment

Laboratory equipment and instruments should follow the testing procedures.

Design and Construction

1.2.5. Documentation and Records

Master production instructions should include:

7) Results of in-process and laboratory test ,

1.2.6. Materials Management

The incoming materials and finished products should be immediately quarantined

by the established specifications. Visual examination of containers and labels and

1.2.7. Production and In -Proccss Controls

Operations of weighing, measuring, or sub-dividing should be subjected to an

at designated steps during production . Expected yields with appropriate ranges

1.2.8. Packaging and Identification Labelling of APIs and

1.2.9. Storage and Distribution

1.2. 10. Laboratory Controls

Primary reference standards for manufacturing APIs should be obtained, and

If new Certificates are issued by or on behalf of re -packers/re-processors, agents

produce an intermediate or API that conforms to its predetermined specifications

procedures should reflect actual equipment usage patterns. If different APIs

Validation of Analytical Methods

1.2. 12. Change Control

1.2. 13. Rejection and Re- Use of Materials

1.2. 14. Complaints and Recalls

35 ) Rejected materials and products should be clearly marked and separately

1.4. 2. Short Answer Type Questions

1.4.3. Long Answer Type Questions

2.1, TOTAL QUALITY MANAGEMENT (TQM)

2) Integrity: It refers to some characteristic traits like honesty, morals, values,

2.1.2.2. Building Bricks

2.1.2.3. Binding Mortar (Communication )

Communication is defined as a common understanding of ideas between the

2. I .2.4. Roof ( Recognition )

2.1 .3. Philosophies

2.13.1. Quality' Circle

2. I .3.2. Customer Focus

Steps in the application of this principle are:

2. I .3.3. Continuous Improvement

Steps in the application of this principle are:

The Plan - Do-Study -Act ( PDSA ) Cycle

Figure 2.1: Plan - Do -Study - Act Cycle

2. I .3.4. Quality Tools

diagrams as they look like fish bones. In a cause-and-effect diagram ( figure

Figure 2.2: Cause-and-Effeet Diagram

2.3.2. Short Answer Type Questions