SCHOOL OF ECONIMICS, BUSINESS AND INTERNATIONAL STUDIES

DEPARTMENT OF BUSINESS ADMINISTRATION

MASTER’S IN BUSINESS ADMINISTRATION- TOTAL QUALITY

MANAGEMENT INTERNATIONAL

GOOD MANUFACTURING PRACTICES (GMPs) AND PROCESS

VALIDATION IN THE PHARMACEUTICAL INDUSTRY: AN IN DEPTH
ANALYSIS

MASTER THESIS OF GERASIMOS VOYKELATOS

Prof: George Bohoris

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GOOD MANUFACTURING PRACTICES (GMPs) AND PROCESS VALIDATION IN THE
PHARMACEUTICAL INDUSTRY: AN IN DEPTH ANALYSIS

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 Abstract

One of the most important pillars of our modern society is the healthcare system, an
integral part of which is the pharmaceutical manufacturing industry. This sector has
grown to be one of the most complex, internationalized, and value adding.

This dissertation begins by covering the reasons for choosing this subject and
continuous by further justifying this through a thorough industry analysis. It then moves
forward to study the history of Good Manufacturing Practices and how they became a
necessity to ensure pharmaceutical product quality in today’s multipolar world. All
major regulatory frameworks are relayed (International Conference on Harmonization,
E.M.A., F.D.A., W.H.O., U.K., China, Pharmacopeias, I.S.O., P.I.C./S) and their key
similarities and differences are discussed.

The European regulatory framework is chosen for further examination, and this is
provided through a chapter-by-chapter analysis of the guidelines for industry, drawn up
by the European Medicines Agency. In addition, a list of every supplementary annex is
given.

Closing, the thesis examines the subject of validation and its importance as a tool for
keeping production under a state of control and establishing proof of repeatability and
quality. Finally, different types of validation are examined, focusing on the steps
followed, their requirements and the necessary documentation.

Key words: Pharmaceutical Industry, GMPs, EMA, Guidelines, Process Validation

 Acknowledgments
First of all, I would like to express my deepest appreciation to my supervisor, professor
George Bohoris, for his consistent support, encouragement and guidance during the
preparation of my dissertation. My master thesis would not have been possible if it
wasn’t for his educated comments and recommendations.

Furthermore, I am also grateful for having the opportunity to attend the classes of
certain professors from whom I have learned a lot and got interested in new scientific
fields. Their vast wisdom and experience have inspired me throughout my studies.

In addition, I want to extend my sincere thanks to my family for constantly believing

in me and supporting me since I was only an undergrad and to my friends for keeping
me sane throughout this journey.

Last but certainly not least, words cannot express my gratitude to my significant other
for her love and support while I was working on this thesis. Thanks for being there both
emotionally and intellectually and for your constructive suggestions.
 Table of Contents

Declaration ........................................................................................................................... 2
Abstract ................................................................................................................................ 3
Acknowledgments ................................................................................................................ 4
Table of Contents................................................................................................................. 5
List of Figures and Tables .................................................................................................. 8
Section 1. Introduction ........................................................................................................ 9
Section 2. Pharmaceutical Industry ................................................................................. 14
2.1 Industry Overview ....................................................................................................... 14
2.2 PEST Analysis.............................................................................................................. 19
References .......................................................................................................................... 21
Section 3. Good Manufacturing Practices (GMPs) ........................................................ 22
3.1 GMPs Definition .......................................................................................................... 22
3.2 The History of GMPs – A Series of Tragic Events ................................................... 22
3.3 The Necessity of Good Manufacturing Practices...................................................... 26
3.4 The Ten Golden Rules of Good Manufacturing Practices ....................................... 28
3.5 International Regulatory Framework Regarding Good Manufacturing Practices32
3.5.1 International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH)...................................................... 32
3.5.2 European Framework .............................................................................................. 34
3.5.3 European Pharmacopeia.......................................................................................... 36
3.5.4 United Kingdom Framework .................................................................................. 37
3.5.5 International Organization for Standardization (ISO) ......................................... 38
3.5.6 World Health Organization (WHO) ....................................................................... 39
3.5.7 Food and Drug Administration (FDA) ................................................................... 40
3.5.8 Pharmaceutical Inspection Co-Operation Scheme (PIC/S) .................................. 41
3.5.9 China.......................................................................................................................... 42
References .......................................................................................................................... 44
Section 4. Good Manufacturing Practices Guidelines .................................................... 47
4.1 Part I: Basic Requirements for Medicinal Products ................................................ 47
4.1.1 Chapter 1: Pharmaceutical Quality System ........................................................... 47
4.1.2 Chapter 2: Personnel ................................................................................................ 48
4.1.3 Chapter 3: Premises and Equipment ...................................................................... 49
4.1.4 Chapter 4: Documentation ...................................................................................... 50
4.1.5 Chapter 5: Production ............................................................................................. 51
4.1.6 Chapter 6: Quality Control ..................................................................................... 52
4.1.7 Chapter 7: Outsourced Activities............................................................................ 54
4.1.8 Chapter 8: Complaints and Product Recall ........................................................... 54
4.1.9 Chapter 9: Self Inspection ....................................................................................... 55
4.2 Part II: Basic Requirements for Active Substances Used as Starting Materials ... 55
4.2.1 Quality Management ................................................................................................ 56
4.2.2 Personnel ................................................................................................................... 56
4.2.3 Buildings and Facilities ............................................................................................ 56
4.2.4 Process Equipment ................................................................................................... 56
4.2.5 Documentation and Records ................................................................................... 56
4.2.6 Materials Management ............................................................................................ 57
4.2.7 Production and in – Process Controls..................................................................... 57
4.2.8 Packaging and Identification Labelling of APIs and Intermediates .................... 57
4.2.9 Storage and Distribution.......................................................................................... 57
4.2.10 Laboratory Controls .............................................................................................. 58
4.2.11 Validation ................................................................................................................ 58
4.2.12 Change Control....................................................................................................... 58
4.2.13 Rejection and Re-Use of Materials........................................................................ 59
4.2.14 Complaints and Recalls.......................................................................................... 59
4.2.15 Contract Manufacturers ........................................................................................ 59
4.2.16 Agents, Brokers, Traders, Distributors, Re – packers and Re - labelers .......... 59
4.2.17 APIs Manufactured by cell Culture / Fermentation ........................................... 60
4.2.18 Viral Removal / Inactivation ................................................................................. 60
4.3 Part III: GMP Related Documents ............................................................................ 60
4.3.1 Guideline on Setting Health-Based Exposure Limits for Use in Risk
Identification in the Manufacture of Different Medicinal Products in Shared Facilities
............................................................................................................................................. 60
4.3.2 Internationally Harmonized Requirements for Batch Certification ................... 61
4.3.3 Template for Investigational Medicinal Products Batch Certificate ................... 61
4.3.4 Explanatory Notes on the Preparation of Site Master File ................................... 62
4.3.5 Reflection Paper on Good Manufacturing Practice and Marketing Authorization
Holders ............................................................................................................................... 62
4.3.6 ICH Guideline Q9 on Quality Risk Management.................................................. 63
4.3.7 ICH Guideline Q10 on Pharmaceutical Quality System ....................................... 64
4.4 Part IV: Guidelines on Good Manufacturing Practice Specific to Advanced
Therapy Medicinal Products ............................................................................................ 64
4.5 Annexes......................................................................................................................... 68
References .......................................................................................................................... 69
Section 5. Process Validation ............................................................................................ 71
5.1 Introduction ................................................................................................................. 71
5.2 Definitions .................................................................................................................... 71
5.3 Legislation .................................................................................................................... 72
5.4 The Importance of Validation .................................................................................... 73
5.5 Reasons to Validate and Who is Responsible ............................................................ 73
5.6 Requirements and Validation Strategy ..................................................................... 75
5.7 Phases of Validation .................................................................................................... 76
5.8 Types of Validation ..................................................................................................... 77
5.8.1 Analytical Validation................................................................................................ 77
5.8.2 Cleaning Validation .................................................................................................. 78
5.8.3 Computer System Validation .................................................................................. 78
5.8.4 Equipment Validation .............................................................................................. 80
5.8.5 Gases Validation ....................................................................................................... 82
5.8.6 Process Validation .................................................................................................... 82
5.8 Documentation ............................................................................................................. 85
References .......................................................................................................................... 88
Conclusions ........................................................................................................................ 90
Table of References ........................................................................................................... 92
 List of Figures and Tables

Table 1 ................................................................................................................................. 15
Figure 1................................................................................................................................ 15
Figure 2................................................................................................................................ 16
Figure 3................................................................................................................................ 17
Figure 4................................................................................................................................ 17
Figure 5................................................................................................................................ 18
Figure 6................................................................................................................................ 19
Figure 7................................................................................................................................ 29
Figure 8................................................................................................................................ 63
Table 2 ................................................................................................................................. 74
Table 3 ................................................................................................................................. 75
Figure 9................................................................................................................................ 76
Figure 10.............................................................................................................................. 80
Figure 11.............................................................................................................................. 85
 Section 1. Introduction
The history of medicine is almost as old as mankind. It begins even before the written
history. Although it is very hard to interpret the exact way people used to live in that
era, findings, such as tools and body remains of early humans, indicate the existence of
an early form of medicine. Even though it has its roots in prehistoric times, guidelines
that ensure the quality and safety of drugs and medical devices began to be seriously
and diligently enforced only in the middle of the 20th century. Unfortunately, it took
tragic accidents – that claimed the lives of millions of people – for these guidelines to
be established in the industry and incorporated into manufacturing practices and
national law.
During the dawn of human civilization, practice of medicine was based on trial and
error. Humans distinguished which plant seemed to serve as food, had medicinal value
or was poisonous. Of course, all the above, applied only in common infections. More
serious maladies believed to be of supernatural origin. Magic and religion played a huge
part in prehistoric societies. Dancing, grimaces, incantations, and remedies were a
common practice. The first doctors were witch doctors.
During the 3rd millennium BC, Imhotep lived in Egypt. He is believed to be the first
physician and later was regarded as the Egyptian god of medicine. In the 19th century,
a papyrus was discovered, containing spells, remedies, and basic surgical treatises. In
contrary to popular belief, despite having mastered the process of mummification,
ancient Egyptians had limited anatomical knowledge.
In India, during 1000 BC and 800 BC, Hindu physicians started employing all five
senses to perform diagnosis and they appeared to have a very good clinical sense as a
result. At the same time, they focused on dietic treatment and vegetable drugs as well
as on more active treatments, known as “The Five Procedures” (administration of
emetics, purgatives, water enemas, oil enemas and sneezing powders). Inhalation,
leeching, cupping, and bleeding were used too. Also, there are evidence of surgery
practice such as excision of tumors, extraction of foreign bodies and punctures to
release fluid in the abdomen, using alcohol as a narcotic and hot oil to stop the bleeding.
While most countries influenced one another, Chinese system of medicine remained
independent of any kind of external influences until the early 19th century. Even today,
native system is widely practiced throughout the country. This system is based on the
philosophy of yin and yang. Illnesses are thought to be a result of some kind of
unbalance between these two forces. China is also famous for the practice of
acupuncture, where thin needles are inserted into the body in order to relieve stress,
pain or tension. Hundreds of specific points were mapped through the centuries and
today the exercise of this procedure is gaining increasing popularity in the west as an
alternative new age approach.
The roots of Western Medicine can be traced back to ancient Greece. Greece has
inherited much from Babylonia, Egypt, India, and China but took this knowledge to the
next level. Asclepius temples are considered the prototype of modern health resorts
where people went to recuperate in a soothing and peaceful environment. Also, it was
the early philosophers that led the way to abandon magic and seek reason. Empedocles
was the first to advocate the idea that the universe is composed of four elements (fire,
air, earth, and water) and humans of four bodily humors (blood, phlegm, choler and
melancholy). As was the case with yin and yang, health according to Empedocles, was
a direct result of the harmony between these four.
In 460 BC Hippocrates, who is considered the father of medicine, was born. Little is
known about his life and many support the idea that Hippocrates maybe was in fact
several men. He paved the way for disease to start being regarded as a natural
phenomenon while doctors were encouraged to look for physical causes. Based on these
principles, Aristotle became the first great biologist and set the foundation of
comparative anatomy and embryology.
Medicine traversed a peculiar path during the Dark ages. Christian Church reemerged
the belief that diseases were a divine punishment laid upon the sinners but at the same
time monks are to be thanked for the translation and preservation of classical
manuscripts. At the same time, in a different geographical place, in Muslim empire,
alchemists in pursuit for the philosopher’s stone discovered, named, and characterized
numerous substances.
Carrying on the scientific stagnation, no major breakthrough was achieved in the course
of Middle Ages. Nevertheless, these were the centuries that some of the first major
hospitals were founded in Europe, such as the ones in Salerno, Bologna, and Padua
(Italy) and in Montpellier and Paris (France).
One of the biggest problems of medicine up to this point was the very limited
anatomical knowledge. This was a direct result of human dissection being forbidden
because of religious beliefs. Renaissance and the new way of thinking that cultivated,
allowed for these prohibitions to be slowly lifted. In consequence, the first ever
complete practical manual of anatomy was published in 1316 under the title
“Anathomia Corporis Humani” by Mondino de Luzzi.
Scientific progress began to accelerate again during the Enlightenment. New chemistry
knowledge was acquired, William Harrey proposed the theory of circulation, which was
a milestone in understanding how the human body works and microscope was invented,
allowing to see and describe bacteria for the first time.
18th century was a period that marked by the evolution of surgery across UK. Moreover,
late in the century stethoscope was discovered giving a boost in physical examination
and vaccination began to take place in a systematic manner. It was during this eon that
population statistics began to be kept for the first time and suggestions arose concerning
health legislation.
From this point onwards, scientific advancement became exponential. During the
course of 19th century, physiology blossomed in Germany and France, Germ Theory
became verified, and Louis Paster established the science of bacteriology which in turns
led to more refined techniques of sterilization and identification of many disease
producing microorganisms, such as cholera and tuberculosis. Across the Atlantic, in
America, general anesthesia was introduced changing the way surgeons operated for
ever.
To complete all the above, Parasitology arose as an independent field that explained
how diseases were transmitted, X – Rays were discovered in 1895 by Wilhelm Conrad
and Radium in 1898 by Pierre and Marie Curie. Lastly, it was in this time of continuous
improvement that Sigmund Freud gave birth to the vast new field of psychiatry.
The 20th century came alongside with big improvements in the field of communication
between scientists throughout the world. With communication came progress and with
progress more precise diagnostic tests (sonar, Cat, NMR), more effective therapies
(sulfonamide drugs) and magnificent advances in biomedical engineering. This century
was marked by the discovery of penicillin (first time commercially produced during the
World War 2) in 1928 by Alexander Fleming which led to antibiotics.
Moreover, Immunology helped to bring viruses under control by understanding the role
of the white blood cells, that is the process of how the human body reacts while fighting
infectious organisms. This newly acquired knowledge allowed the production of the
first safe and effective antiviral vaccines, such as typhoid vaccination (mainly for
British troops serving in the South African war), tetanus, diphtheria, and BCG vaccine
for tuberculosis.
In the second half of the century, tissue culture was introduced and offered the means
to grow viruses in the laboratory. This, combined with the discovery of the electron
microscope, improved even further the quality of vaccines, and had a whole new
generation of them as a result.
More major breakthroughs were due to advancements in Endocrinology. The discovery
of insulin was a lifesaving moment for people with diabetes, cortisone gave potent anti
– inflammatory agents, birth control became possible based on the study of sex
hormones, vitamins were identified and categorized, and improvements were made in
radiation therapy and chemotherapy for cancer.
Unfortunately, last century was deeply stigmatize by two World Wars. Medicine was
affected in numerous ways. The most significant impact was made in the field surgery.
World War 1 gave innumerable lessons to surgeons and hand on experience of a
lifetime. Then, between the 2 World Wars, this experience blossomed and allowed
surgery to consolidate its position. Anesthesia became better, the aseptic method for
sterilization was established, rubber gloves and gauze masks started being used during
operations and shock mechanism was deeply understanded and blood transfusion was
used as a counteraction.
Specialization became more thorough in the fields of abdominal surgery, neurosurgery,
and radiology. During World War 2, doctors started serving as special units in the first
lines, providing wounded soldiers with first aids in unimaginable conditions. Valuable
lessons were taken regarding wound infections and teamwork of specialized surgeons
was promoted. After the war, the first open heart surgery took place and organ
transplantation became possible for the first time.
The 21st century seems to have decided to focus on collaboration between medicine and
new technologies as a way forward. In an interconnected world, more and more people
turn to telehealth services to receive healthcare advice or a first diagnosis. New methods
of drug development and nanomedicine allow for more effective and precise medicines,
or even personalized drugs for every individual patient. 3D printing method is used to
create implants, joints, or even artificial organs in the lab. Also, more and more
commercially available devices, such as wearables and smartphones, offer a variety of
health features from counting steps to monitoring heart rate and from measuring oxygen
levels to keeping track of night sleep quality. The list of new technologies serving
medicine is ever growing and it also contains Internet of Things (IoT), Big Data science,
Artificial Intelligence (AI), Robotic Surgery, Brain Sensors, and Implants among
others.
Finally, in a globalized world where borders have almost been abolished, the need for
a well-defined and legally binding regulatory framework for medicine and drug
production is required more than ever. The first steps have been made during the last
century and now more and more countries are adopting one of the international
standards or vote for a national one for their own.
Therefore, the pharmaceutical industry is now regulated by the Good Practices (GMPs,
GLPs, GTPs etc.), to minimize all those risks that have -or might have- a great impact
on the safety of the patients/consumers. The quality of medicinal products is the base
for safety and efficacy and the purpose of the regulations is to assure, that the
pharmaceutical products meet the safety requirements without compromising any
quality characteristics.
That is the reason why all pharmaceutical regulations are covering the whole
manufacturing process, because mistakes and errors, such as “two types' mix-up” and
cross-contamination, may appear in any manufacturing activities: from the used
premises and starting materials to the final product and its disposal. So, multiple steps
are being followed to reduce the contamination of the product and to ensure that
protective measures for the external and internal conditions related to the organization
are respected by everyone involved. These steps refer to raw materials, product
development, technology transfer, production, storage, packaging and distribution, thus
strengthening the nexus that binds the development of medicines and manufacturing
activities.
GMP standards or rules are set as guidance documents from regulatory authorities or
passed as laws in order to ensure that manufacturers are not driven by profit but produce
medicines on the basis of human health and dignity, quality, respect and honesty.
However, both in theory and practice pharmaceutical’s benefit to society cannot be
disputed. It is undeniable that the pharmaceutical industry is important to the economies
of the world and for the preservation and promotion of the global health of the human
society. Especially in Europe over the last century, they have contributed to a doubled
life expectancy and a reduction in the mortality rate of diseases including AIDS and
several cancers. Thus, whether locally or globally, the pharmaceutical industry
significantly contributes to the development of the healthcare sector, technology, and
the economy.
The objective of this study is to investigate the basic requirements for medical products
regarding the GMP quality system and describe the complementary files of GMP
guidelines that are extremely useful in the process implementation. It looks at two
major components: all different international bodies and standards that promote,
support, and enforce GMP harmonization and their contribution to general guidelines
and the concept of process validation.
The structure of this master thesis includes four main chapters as follows:
Chapter one is the introduction and objectives section of the dissertation. It also
includes a brief historical review of medicine.
Chapter Two analyzes the pharmaceutical industry with the aim of highlighting the
importance of the market and the reason for engaging with this specific subject. This
will be done by using secondary data materials such as textbooks, academic journals,
global and national papers and publications and unpublished materials such as
dissertations and theses.
Chapter Three delves deeper in the concept of GMPs by explaining their importance,
relaying the tragic events which led to the evolution of these practices, setting up some
key rules and then analyzing all the different regulatory frameworks and guidelines
issued by various national and international authorities and bodies.
Chapter Four lists and discusses the most important points of the guidelines -that lay
on European laws and directives- for a product to enter and/or release in the European
market. These general requirements are divided into four parts and nineteen annexes.
Chapter Five examines the area of validation in the pharmaceutical industry which
might refer to a piece of equipment, a process, a recipe, a computer system, an analytical
method etc. The study focuses on the process validation which is basically designed to
be a step-by-step procedure which ensures that a manufacturing process is able to
consistently produce quality products.
 Section 2. Pharmaceutical Industry

2.1 Industry Overview

The term Pharmaceutical Industry refers to the group of companies which are
responsible for the development, production, and marketing of both branded and
generic pharmaceuticals.
It is one of the biggest industries worldwide in terms of revenue, sales, global presence,
investment, and employment and is considered one of the main pillars of industrialized
economies while gaining more and more significance for developing economies as
well. At the same time, through innovation and by making more and more products
commercially available and affordable, Pharmaceutical Industry has contributed to the
improvement of the quality of living, public health, and life expectancy on average. It
is characteristic that in Europe, citizens are expected to live 30 years more than they
did a century ago [1]. Of course, the situation is far from ideal as the gap between
developed, developing, and under-developed countries as well as between higher and
lower incomes remains and inequalities in healthcare and medicinal access are present.
A well-functioning healthcare system is an irreplaceable part in every country’s
socioeconomic state. One of the main ingredients in that direction is the existence of an
enabling environment for the Pharmaceutical Industry. Although health expenditures
as a share of GDP are tending to rise in many countries, the share of those expenditures
that is channeled to pharmaceutical products has remained stable and it counts for
roughly 20% of total cost. Moreover, additional costs such as distribution costs, port
charges, import tariffs, taxes, wholesalers, and retailers in the supply chain etc. tend to
inflate the prices [2]. Especially in developing countries with a lack of solid public and
private health insurance, this difference in prices comes out of customers pockets. By
increasing spending in medicines and vaccines, not only access to healthcare services
is being democratized but also other costs can be reduced, such as hospital costs and
long care costs.
In addition, apart from helping people in terms of public health, the pharmaceutical
sector is also a major employer, responsible for millions of jobs worldwide. More
precisely, approximately 5.5 million people were employed inside the industry in 2017,
including those working in the production of generic drugs. At the same time, indirect
employment was multiple, with 45.1 million additional jobs in other sectors throughout
its supply chain. If these were combined with estimated 23.7 more million jobs that are
generated in other sectors like retail and childcare, a total of around 74.3 million
employees were affected directly or indirectly [2].
Pharmaceutical Industry plays an important and crucial role in global economic
activity. It is estimated that industry scored a total worldwide revenue of 1.24 trillion
USD, while having a total value of 6.65 trillion USD (5.65 of which were generated by
publicly traded companies). In order to put those numbers into perspective, if the
Pharmaceutical Industry was a country, it would be the fifteenth biggest economy [5].
As shown in the table and diagram bellow, pharma sector is the third highest value
sector, scoring under only Banks, Insurance and Finance and E-Commerce and Internet
Services, while having tripled its value since 2003.

Table 1: Aggregated Market Value of all Publicly Traded Companies by S&P Market Group in the
World’s Top 20,000 Traded Companies by Market as of September 6, 2020 [5]

$6,65

$5,28 $5,35
$5,16 $5,02

$4,31
$3,76

$1,99

2003 2014 2015 2016 2017 2018 2019 2020

Figure 1: Aggregated Value of the Global Pharmaceutical Industry 2003 to 2020 (USD Trillions)

As expected, not all markets are the same. Sales are not equally distributed around the
globe. More specifically, United States are leading world consumption with 49% of
global revenue, followed by Europe with 23.9% (this amount goes up to 63.7% and
17.4% respectively when it comes to sales of new medicines) [1].
Today, the world has become multipolar, and markets and economies are changing
rapidly. Emerging economies like China, India and Brazil are growing rapidly. From
2015 to 2020, these markets grew by 4.8%, 10% and 11.3% respectively when on
average the top 5 European economies grew by 5% and US by 4.9% [1]. As a result,
certain aspects of economic and research activities have started to migrate from western
developed countries to these new markets and this is believed that it will only get more
intense in the foreseeable future.
Another interesting statistic to look upon is the one regarding the different kind of drugs
being consumed per region. Some differences can be recognized, depending on cultural
differences, local diet and level of access to food rich in nutrition. Although some kind
of differentiation is present, certain patterns can be recognized. In OECD countries (38
member countries of the Organization for Economic Co Operation and Development
which as of 2017 comprise 62.2% of global nominal GDP), between 2000 and 2017,
consumption of cholesterol lowering drugs almost quadrupled, antihypertensive
pharmaceutical consumption nearly doubled as well as the one of antidiabetic
medicines and finally, antidepressants usage doubled as a result of depressions
recognition followed by changes in guidelines and therapeutic treatments offered [3].
There seems to be a direct link between the most common causes of death worldwide
and most consumed drugs. In the diagram bellow, it is evident that cardiovascular
diseases are responsible for more than 30% of global annual deaths, followed by cancer
and respiratory diseases. As a result, besides musculoskeletal drugs being the largest
pharmaceutical market worldwide, sales for these categories were ranking at the top of
the table, with cardiovascular, oncological and anti-infective drugs scoring the second,
third and fourth biggest revenues [3].

Terrorism

Poisonings

Hepatitis

Drug use disorders

Maternal disorders

Nutritional deficiences

Drowning

Homicide

Suicide

Tuberculosis

Road injuries

Diabetes

Dementia

Despiratory diseases

Cardiovascular diseases
0 2 4 6 8 10 12 14 16 18 20

Figure 2: Breakdown of Global Deaths by cause, 2017 [3]

As mentioned above, pharmaceutical industry is highly innovative. In fact, it is the

sector that invests the most in Research and Development (R&D), both in terms of total
value and percentage of net sales, even during the global economic crisis. Billions of
dollars and thousands of scientists’ hours are spent and as a result the limits of science
are being pushed while new and more efficient products are reaching the market.
As shown in figure 3, the expenditures in most of the countries that Pharmaceutical
Research activities are based, are rising throughout the years to even bigger levels. It is
estimated that USD 179 billion were spent worldwide for R&D purposes in 2018 [2].
At the same time, there has been a US dominance in the field for the past decade in that
particular field.

62,22 64,357

40,688 37,754
36,275
27,92
21,364
17,849
12,76 14,047 13,392
7,766 6,803 5,161 7,462

1990 2000 2010 2018 2019

Europe USA Japan

Figure 3: Pharmaceutical R&D Expenditures in Europe, USA and Japan (Millions of National
Currency Units), 1990 – 2019 [1]

These high expenditures, put Pharmaceutical Industry at the top of all industrial sectors,
even above the software and computer services or other research focused ones, like
technology hardware or automobiles and parts, in terms of R&D as percentage of net
sales for 2019.

18,00%
16,00%
14,00%
12,00%
10,00%
8,00%
6,00%
4,00%
2,00%
0,00%

Figure 4: Ranking of Industrial Sectors by Overall Sector R&D Intensity (R&D as Percentage of Net
Sales – 2019) [1]
The reasons for the need of these very elevated expenses can be found in the process
followed for the discovery and marketing of a new drug. The decision on which
substances will get furthered researched, based on preliminary data, contains a high risk
and can easily lead to a dead end, having consumed big amount of money on the way.
It is estimated that, on average, only one to two out of 10,000 substances that are
synthesized in the laboratory will eventually succeed in all stages of the development
process and will make it to the market.
The cycle of life for a new drug begins with the patent application, followed by the pre-
clinical development, which contains assessments regarding acute toxicity,
pharmacology, and chronic toxicity. If the drug is deemed safe it moves to the clinical
trials. Clinical trials take place in 3 different phases with different numbers of patients
taking the drug or a placebo and then monitoring the side effects that may occur.
Moving forward, if the pharmaceutical product passes all 3 phases of human tests it
takes marketing authorization and can then be priced and put to market. This process
can take up to 13 years and bring the cost for the development of a new pharmaceutical
entity to USD 2.558 million (in year 2013 dollars). Of all the different phases a new
product goes through, the 3 stages of clinical trials make up to almost 50% of the total
cost, compared to around 16% for preclinical stage and little more than 11% for the
Pharmacovigilance phase, which is necessary after the commercial release of new
products, in order to monitor potential new negatives effects that may arise after
massive consumption of the drug by the general population [1].
These extensive costs and time requirements only allowed for 59 new medicines to
launch in 2018 while more than 8,000 compounds are at some point of the development
stage today [2].

Figure 5: Phases of the Research and Development Process [1]

Even though Pharmaceutical Companies take upon them such a big risk and R&D cost,
it contributes for only 2/3 of the final price with wholesalers, pharmacists and other
retailers and distributors alongside the state, make up for approximately 1/3 of the retail
price.

Figure 6: Breakdown of the Retail Price of a Medicine in Europe for 2019 [1]

As it is evident, Pharmaceutical Industry is an everchanging and constantly reshaping

field. New opportunities, threats and trends emerge constantly and in a global scale.
Having said that, there are some main trends that can be identified for the foreseeable
future.
As mentioned above, emerging economies are getting bigger by the day and thus, a
shift in market focus is to be expected. Some of portion of research and production
activities of Western based companies are beginning to relocate in developing
countries. Moreover, a strengthening scientific knowledge, with new technologies in
the service of research and development, such as smart devices, big data science etc. is
contributing to the positive momentum of pharmaceutical industry. Other factors, like
the growing demand for medicines and global trade liberalization, are also helping
towards that direction. On the other hand, tighter regulations are getting in effect in an
attempt to safeguard from errors this sensitive area of products and are making market
conditions more difficult for pharmaceutical companies at the same time.

2.2 PEST Analysis

A PEST analysis is both a business analysis and a management method. The term PEST
itself is an acronym for Political, Economic, Social and Technological. By analyzing
these factors in a specific market, you can foresee the impact they are going to have on
a business operating inside this market and act accordingly in order to achieve the goals
set.
Usually, PEST is used in a well-defined and compact market (typically geographical),
where the above four factors are common throughout the market. Because the
Pharmaceutical market, as it has been established, is a globalized industry, with many
of the big companies operating on a multinational level, it is not possible to hold a PEST
analysis for the entire sector. What can be done, is to specify the elements which
constitute each one of these four factors and which decision makers must look to
identify in the specific external environment that their company operates.
Political
• State laws and ministerial decisions
 • Legislation regarding monopolistic competition, protection of the environment
or government contract policy
• Legal framework for the technology being used in Pharmaceutical products
production
• Labor legislation
• Existence of political stability versus uncertainty
• Level of state intervention
• Taxation criteria
• Special motives offered for companies operating and investing
• Unique internal trade regulations
• Regulatory bodies
Economic
• Current state of national economy combined with future forecasts
• National Gross Domestic Product (GDP)
• Inflation rate
• Unemployment rate
• Purchasing capabilities of consumers in the market
• Government health expenditure’s structure
• Taxation scheme
• Interest rate spreads
• Factors influencing offer and demand
• Native currency rate
Social
• Demographical trends, like population increase or decrease, birth versus death
rates etc.
• Lifestyle trends (exercising, diet habits, healthy day to day approach etc.)
• Consumerism
• Educational level of citizens
• Social Media and Public figures influence
• Advertisement
• Role of women and minorities in society
• Level of urbanization
Technological
• Current available technology
• National expenditures for research
• Industry investments in R&D
• Patent protection legislation
• Knowledge transfer rate
• New production methods
• Production improvement through atomization
 References
International References
1. European Federation of Pharmaceutical Industries and Associations, “The
Pharmaceutical Industry in Figures. Key Data 2021”, 2021
2. International Federation of Pharmaceutical Manufacturers & Associations,
“The Pharmaceutical Industry and Global Health. Facts and Figures”, 2021
3. Omar Israel Gonzales Pena, Miguel Angel Lopez Zavala, Hector Cabral Ruelas,
“Pharmaceutical Market, Consumption Trends and Disease Incidence are not
Driving the Pharmaceutical Research on Water and Wastewater”
4. PWC, “From Vision to Decision. Pharma 2020”, 2012
5. Torreya Capital LLC, “The Pharma 1000. Top Global Pharmaceutical Company
Report”, 2020
Websites References
6. https://www.britannica.com/science/history-of-medicine (last accessed:
11/12/2022)
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379645/ (last accessed:
11/12/2022)
8. https://www.britannica.com/technology/pharmaceutical-industry (last
accessed: 11/12/2022)
9. https://www.statista.com/topics/1764/global-pharmaceutical-
industry/#dossierKeyfigures (last accessed: 11/12/2022)
 Section 3. Good Manufacturing Practices (GMPs)

3.1 GMPs Definition

Good Manufacturing Practices (GMPs) refer to the minimum standards that a
medicines manufacturer must meet in their production processes. They are regulations
that describe the methods, equipment, facilities, and controls which are required for
producing human and veterinary products, medical devices and processed food [7].
GMP requirements were laid out in a flexible or even abstract way in some cases, in
order to allow individual manufacturers to decide which is the most suited path for each
unique company to achieve the intended demands. These must have conditions, cover
areas such as personnel qualification, record keeping, sanitation and cleanliness,
complain handling, equipment verification and process validation.
It is important to underline that GMPs are not just a set of industry best practices. They
have the force of law. A company’s failure to comply with these regulations means that
it’s product is deemed “adulterated” and can be seized and destroyed while legal actions
can be taken against the company and its management.
GMPs are built around a quality approach to manufacturing. They intend to minimize
if not eliminate errors, mix – ups and contamination cases while successfully managing
risk. Through the compliance with this set of practices, the produced product acquires
proven strength, identity, safety, purity and quality.
Even though, as have been said, Good Manufacturing Practices only represent a
minimum mandatory required standard, because of the benefits that follows the
application of them, most of the big manufacturers already implement comprehensive
modern quality systems and risk management approaches that exceed these minimum
set of standards by far [9].
Often, GMPs are referred to also as cGMPs with “c” standing for current. This addition
is supposed to emphasis the dynamic nature of these expectations. As science and
technology advance, more, new and better capabilities become available and better
understanding is achieved. At the same time, potential new emerged weaknesses, unveil
areas needing reevaluation, improvement and / or update and serves as valuable lessons
learned. Through this ever changing – ever evolving framework, it is ensured that the
production of a very sensitive category of consumer good, is always taking place ruled
by the latest standards.

3.2 The History of GMPs – A Series of Tragic Events

It is very common for a person to get lost in an everyday routine. It is even easier to act
in a “business as usual” way or get lost in the “inertia of status quo”. Reforming can be
hard and sometimes only a remarkable shock is capable of setting in motion the wheels
of change. That being the case for an average person, big and meaningful changes in
legislation or in a regulatory body require very specific and mature conditions, just like
the ones following a tragic event. Such is the story of GMPs. A series of tragic events.
As discussed in the previous chapter, history of medicine goes a long way back. But
until the early 90s, pharmaceutical market remained highly unregulated. It wasn’t
unheard of for someone to sell homemade remedies out of the back of a wagon, made
of unknown ingredients, sold in an unmarked bottle, claimed to cure everything from
headache to cancer. This has, as expected, led to many devastating incidents. And with
industry getting modernized and production rising, the numbers of people affected were
now way bigger than before.
One of these unfortunate events took place in 1902. One diphtheria antitoxin product,
made by blood harvested for a tetanus infected horse, got contaminated with live tetanus
bacilli and eventually led to the death of 12 children. As a response, Congress voted the
“Biologics Control Act”, which required companies to perform extensive testing for
purity and strength prior to drug release.
In 1905, a book by Upton Sinclair was published under the title “The Jungle”. The
book’s main purpose was to highlight the dehumanized conditions under which
laborers, mainly immigrants, worked in the Chicago meat packing industry. The book
made a huge impact on USA’s society and brought to light the unsanitary conditions
where meat was produced before ending up to consumers table, cases of expired, rotten
or diseased meat being sold and instances when remains of rats were ended up into the
minced meat machine or even human remains by some unlucky worker, like a finger
lost by a slicing machine. Public uprise and dissatisfaction led Congress to pass the
“Pure Food and Drug Act” one year later in 1906. It was the first time that selling
adulterated food became illegal. At the same time, misbranding was forbidden, and
labelling had to be truthful from this point after. In order to monitor companies’
compliance with the newly voted legislation, the first government regulatory agency
for this purpose was founded. This agency is now known as United States Food and
Drug Administration (FDA).
It was in 1933 that the, relevantly newly founded FDA, published its exhibit of
dangerous food, medicines, medicinal devices and cosmetics. In what it became to be
known as “The America’s Chamber of Horrors” they were included, among others,
lotions and creams that led to mercury poisoning, a specific eyelash that blinded
women, a weight loss drug that caused death and a womb supporter that also was widely
used as a contraceptive, that could puncture the uterus. This report made clearer the
extent of problems caused in the general public by unregulated medicinal products.
Two years later, a sulfa drug (at the time sulfa drugs were considered “miracle drugs”)
that was produced with the addition of diethylene glycol (a poisonous solvent used also
as anti – freezer), was accountable for the death of 107 people, many of whom were
children. Once again, following another tragic event, Congress passed the “Federal
Food, Drug and Cosmetic Act” in 1938. This act broadens the jurisdictions of FDA who
now could implement frequent factory inspections, determine required standards, apply
penalties for misconduct or even move forward with criminal prosecutions and the
ability to seize and destroy any possibly dangerous product. The new act also
introduced cosmetics as a category of interest that was now inspected by FDA.
Some level of requirements had been set at this point but yet another incident came to
stress out the weak spots in the regulatory framework. In 1941, almost 300 people were
either killed or injured by a sulfathiazole tablet that has been tainted. FDA responded
quickly by doing an in-depth revision of the manufacturing and quality control
requirements. These stricter requirements were the precursor of Good Manufacturing
Practices.
Moving forward, during the 60s, Thalidomide got to market. It was a sleeping pill that
also treated morning sickness and was widely used. It was later found to having
devastating side effects. More specifically, the drug caused deformities in developing
fetuses and by the time it got out of market more than 10,000 cases have been reported.
These numbers refer to Europe alone as the drug never made it to US market thanks to
an inspector not giving permission. This inspector was awarded with the President’s
Distinguished Federal Civilian Service Award, the highest honor that a government
employee can gain as a civilian, by President Kennedy, marking the importance and
impact of a proper regulatory monitoring and inspection. This case galvanized public
opinion and paved the way for the first Good Manufacturing Practices for finished
Pharmaceutical to be made final in 1963.
More than ten years later, in 1978, GMPs were expanded again to include also medical
devices for the first time and in 1979 Good Laboratory Practices (GLPs) were also made
final.
Regulation was beginning to get more precise and to include more and more aspects of
the production and distribution as well as more product categories. In that context, in
1980, Congress voted the “Infant Formula Act” after a number of babies got ill from a
cream lacking specific nutrition. This Act gave FDA the ability to enforce standards
and specify nutritional requirements for every commercial formula for infants.
In 1982, one major incident took place. It all began with the death of 7 people after
having consumed Tylenol, an acetaminophen capsule. Tylenol was one of the highest
selling drugs and was producing vast profits for the producing company. As a result of
this tragic event, one of the biggest recalls in the history of Pharmaceuticals took place
with 31 million bottles of Tylenol coming out of the market. After careful investigation
cyanide was found in some capsules. Official findings talked about a criminal tamperer
who was never found and prosecuted. In order to avoid similar cases in the future, FDA
introduced new tamper – resistant regulations and incorporated them into existing
GMPs. At the same time, Congress passed the “Federal Anti – Tampering Act” in 1983,
making an official crime to tamper with any packaged consumer products.
The decade of 80s was a particularly good decade for the GMPs. During this time, FDA
began publishing a series of guidance documents, clarifying different aspects of the
regulations, and giving advice on how to properly implement the requested
requirements. On example of such document was the one published in 1987 regarding
the principles of process validation. These guidelines had a major effect and shaped the
interpretation of GMPs to this day.
In 1990, a new Act was voted, in order to include also medical devices in FDAs
jurisdiction. This was the “Safe Medical Devices Act”, and it gave authority to FDA to
dive into Research and Development (R&D) regularly and also to incorporate
preproduction design standards and controls into GMPs. It was in the context of this
Act that in 1996, after having been convicted for conspiracy to defraud FDA, 3 former
executives of a company that was producing balloon heart catheters were sentenced
into 18 months in prison, followed by 2 years of supervised release. This company sold
illegal heart catheters. After receiving a note from FDA informing them their product
lacked license, the company rebranded the catheters two times and continued selling
them without official approval. At the same time, reports for malfunctions, obtained
even through illegal clinical trials, were concealed from authorities. These criminal
actions resulted in 1 death and 20 emergency heart surgeries.
FDA in USA led the way in many cases in terms of regulatory requirements for the
Pharmaceutical Companies but at the same time different countries enforced similar
national standards. With the Pharmaceutical industry getting bigger and more
globalized and with producing companies operating in an international level, the need
for harmonization became apparent. Europe and Japan agreed upon a common ground
and US, even though reluctant at first, had no choice but to join. As a result, in 2001,
the International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceutical for Human Use (ICH) Q7A took place and introduced
what is now considered the de facto manufacturing standard for Active Pharmaceutical
Ingredients (APIs).
One year later, in 2002, FDA started using a new technique for routine drug
manufacturing inspection. Each inspection must now focus on more than one system,
with one being mandatorily the quality system and the others varying from facilities,
equipment and materials to production, packaging, labeling and laboratory controls.
Based on this new approach, if even one system is out of control, then the whole
company is out of control and must take immediate corrective actions to become
compliant with GMPs again.
Looking back, it is evident that there is a direct link between the tragic events of the
past and the topics that GMPs covers. Some examples are the conditions in the Chicago
meat packing industry and sanitation and cleanliness area, the Tylenol tampering case
and packaging and labelling, and the list goes on, the pure management calls in the case
of heart catheters and personnel qualification and the list goes on.
As we are getting closer to today, GMPs are constantly proving their value, with the
biggest evidence being the absence of tragic events to the extent that has happened in
the past. Pharmaceutical production is now more regulated than ever, but the very
essence of Good Manufacturing Practices lies in the spirit of continuous improvement.
In this spirit, it is useful to examine current and future trends.
Firstly, industry is moving away for the end point control logic of the past and towards
the quality by design approach. Big companies are adopting a quality system that focus
on built in quality form end to end. From R&D to production and form packaging and
labeling to retail sales. Built in quality means to ensure it in every step. This can be
achieved through well designed and defined processes and by promoting innovation.
The idea of “better do it right in the first place” is gaining ground by the day and this is
reflecting on GMPs.
At the same time, regulatory bodies must continue to keep in touch with every new
information coming out of the scientific community or the production and being
effective and swift into incorporating these new data inside current standards.
Finally, as mentioned above, Pharmaceutical Industry is a huge and globalized industry.
Big international companies can have their R&D, clinical trials, production, and final
market all in different countries. Besides all the efforts that have been made, many
countries continue to have national standards for manufacturing and marketing
pharmaceutical products. As a result, it is not uncommon for some companies to use
this in order to bend the rules. For example, R&D may take place in a very developed
country with high scientific production, clinical trials happen in a part of the world were
rules for tests on animal or people are looser, production located in a region with low
labor costs or less strict legislation regarding ingredients and production itself and the
final product be marketed wherever the demand and the buying power is strong while
taxation or import fees are low. Global efforts are in place, in order for an understanding
to be reached between more countries and federations and for the harmonization of
Good Manufacturing Practices to be broaden.

3.3 The Necessity of Good Manufacturing Practices

Good Manufacturing Practices, represent a complete and thorough set of rules which,
if applied correctly, will lead to a well-regulated and controlled production.
The term quality, when used in the pharmaceutical industry, is referring primarily to
the safety of the product and only after this is secured to its efficiency. By applying the
principles and guidelines of GMPs, optimal control over production is gained and the
overall risk gets minimized.
One of the biggest concerns that a company must face when thinking about applying
GMPs to its operations, is the cost. Total cost of compliance can rise to 25 percent of
the total budget, absorbing one fourth of the expenditures. Even though these worries
are perfectly justifiable, they are a short-sighted way of doing business. An unregulated
production can easily lead to tragic accidents as the ones mentioned above. Even if
human lives do not get lost, the fines, sanctions, or even legal measures that authorities
and regulatory bodies can impose, will eventually elevate the cost for the company to
much higher levels. [20]
Until relatively recently, quality control in the pharmaceutical production, used to take
place in the form of final testing of the product. This method cannot ensure quality,
partially because of the small samples upon which it relies. Errors that may occurred in
previous steps of the production, or even possible contaminations, can go undetected.
As a result, quality must be built in every process and operation as well as the
production as a whole. Good Manufacturing Practices enables the company to achieve
this level of quality and minimize risk by eliminating errors and contaminations. [7]
The unparallel importance of quality in the sector, is underlined by the fact that, in the
founding act of the World Health Organization (WHO), the necessity of quality was
explicitly phrased and demanded inside article 2 of the constitution that lays the
foundation for its operations to this day. To ensure quality and assist the way of
achieving it, developing international standards regarding Food, Pharmaceutical and
Biological products, was named as one of the organization’s core functions and
responsibilities.
It is easily understood that pharmaceutical products are a very sensitive commodity.
That is why, national, and international regulatory bodies, have set and defined very
strict standards and requirements, regarding every aspect of their production.
Complying with the GMPs, is the easiest way to meet these requirements. In a way.
GMPs are best practices, based on prior gained knowledge, that acts as guidelines, in
order to secure compliance with safety and quality standards. [20]
These days, consumers learn to require only the best in terms of quality and companies
strive to find new ways to go the extra mile and add value to their customers, creating
a sustainable competitive advantage. One of the many differences between
pharmaceutical products and other goods, is the level of knowledge and means required
in order to evaluate the commodities found in a drugstore. Consumers are not able to
use their own senses to perceive if what they buy or what the doctor subscribe is in fact
safe and effective. To some extent, not even medical practitioners, with the right to
subscribe, can be one hundred percent sure. This is because of the information gap that
exists between the industry, the medical practitioners, and the consumers. Big Pharmas,
through extensive research and development programs and investments, are the main
source of knowledge generation. Invoking copyrights, patents and competition, the
main part of these information is getting withhold. Doctors and customers are being
asked to place their faith in a product, based only on a list of ingredients. Inside this
context, governments and regulatory bodies have the responsibility to bridge this gap,
protecting the public health at the same time. Good Manufacturing Practices represent
the way of achieving this. Through them, pharmaceutical companies, are obligated to
keep information and provide them to the officials, in a way that is well documented,
retrievable and / or reconstructable. [13]
It is important to highlight the importance of the bellow. Pharmaceutical products is
something that is, in many cases, administered to already sick persons, with lowered
metabolism who can easily regress or relapse if they consume something of doubtful
origin and quality. At the same time, the very nature of these products calls for a zero
deviations approach since the molecules of which they consist of are not part of a
regular metabolic system. Moreover, the pharmaceutical industry is one of the most
globalized and their distribution channels expands across the world. As a result, every
negative impact will not be localized and can have unpredictable consequences to a
number of different places and people. [14]
Another advantage of having a production that operates inside a controlled framework
is the consistency of the product’s quality. As a result, rejects and recalls gets reduced,
bringing down all relevant costs. At the same time, the image and reputation of the
company gets empowered, leading to higher levels of trust and loyalty towards the
brand.
A company which has proven itself through the systematic use of GMPs, can also
benefit from the competitive advantage that comes alongside. Many countries,
especially in the West, impose very strict regulations to entities that manufacture or
trade sensitive products inside their jurisdiction. Also, global organizations, like WHO
or UNICEF, who often buy pharmaceutical products in order to donate them through
campaigns to third world countries, only buy from sources, certified for their use of
GMPs. Therefore, complying with GMPs guidelines, opens up new opportunities for a
company in terms of new sales and exports.
The basic requirements that need to be met in order for the GMPs to become common
practice in a global scale and to be applied in an effective way, have been laid out in
the joint statement issued between The International Pharmaceutical Federation (FIP)
and the International Federation of Pharmaceutical Manufacturers Associations
(IFPMA). In this shared document, both parties agreed upon a common goal that is to
protect the well-being of the patients by producing safe and efficacy products of good
quality. At the same time, the need for a regulatory framework was acknowledged, with
the note that this framework should be applicable both for branded and generic
products. [10]
The two Federations, recognized four basic pillars, necessary for the final success of
Good Manufacturing practices:
• There must be a strong commitment to GMPs on behalf of the
manufacturers
• A good regulatory framework must be designed, which will include
• Effective and comprehensive regulatory procedures
• An effectual inspection and enforcement mechanism, followed by the
political will to implement it, must be in place [10]

3.4 The Ten Golden Rules of Good Manufacturing Practices

The regulatory framework of Good Manufacturing Practices can be very complicated
and even overwhelming for a company that wants to comply with them. There are many
different international legislations from a number of different organizations and
institutions and almost every country enforces a set of rules on its own.
All these different GMPs present common elements as well as unique points. The most
important of them will be analyzed in depth in the next subchapter. Here, an attempt is
being made to gather 10 “Golden Rules” that permeate all GMPs and bring together
their essence and spirit.

Figure 7: The 10 Golden Rules of GMPs

Golden Rule #1: Get the Facility Design Right from the Start
This is the basis of any company which wants to operate in accordance with GMPs. If
a production unit is being built from scratch a great attention should be given to the
layout and in existing facilities it is sometimes important to take a step back and even
reconsider the whole production area if needed.
In a well-functioning facility, the layout must follow the sequence of operations
alongside the production line. If this is done, productivity will be enhanced through the
elimination of unnecessary traffic and the possibility of errors and contaminations, due
to mix ups of materials in different production stages, will be minimized.
Equipment must be selected carefully in order to be suitable for its intended use and
then placed in a way that it will be easy to be cleaned, maintained and repaired if
needed. In addition, instruments and machinery used for pharmaceutical productions
must be non-reactive, additive, or absorptive. Appropriate calibration is also essential.
At the same time, environmental conditions should be always checked. Parameters,
such as humidity, temperature, lighting, air and water quality and ventilation, must be
monitored and regulated in accordance with the process standards and materials nature.
Golden Rule #2: Validate Processes
Operations can be perfectly designed, and facilities can be constructed in a state-of-the-
art way. After this preliminary step though, it is important to ensure that processes and
equipment are doing what they were designed to do and even more, in a consistent way.
This is called validation and it is necessary in order to control critical aspects of the
operations.
Each validation activity must be well defined and planned in dedicated protocols and
consistently documented. In order to maintain this “validated state”, whenever a change
occurs, all appropriate testing must be made anew.
There are three different types of testing used. The Installation Qualification (IQ),
which is used to ensure that new equipment is installed properly, the Operational
Qualification (OQ), that then tests if the equipment operates the way it should and
finally the Performance Qualification (PQ) which is a proof of the product being
produced consistently according to specifications.
Golden Rule #3: Write Good Procedures and Follow Them
When producing such a sensitive good as a pharmaceutical product, consistent quality
must be secured. Because of that, it is important that everyone understands what is
expected of him to do and the proper way to do it. Moreover, this must be done through
a well-documented procedure and not by experience being passed down.
There are four different kinds of documents that are usually used in the pharmaceutical
sector. The Specifications, which list the quality requirements that the final products
must meet, the Operating Instructions, where certain steps for completing specific tasks
are analyzed, the Operating Procedures, which gives more detailed instructions for
specialized assignments and finally the Records, inside whose, a history of every batch
is being kept for audit purposes.
When writing procedures, some things must be kept in mind. A good procedure should
be clear, with all the necessary information given in a brief way (for example via the
use of bullets, tables, diagrams etc.) and the educational level of the final reader needs
to be the guide for the language used.
It is very important that all the procedures used, are being followed invariably. In many
cases, a step of a procedure may seem like an unnecessary waste of time in the eyes of
a machine operator. Nonetheless, proper checking should ensure the universal
application of the official procedures.
Golden Rule #4: Identify Who Does What
Elaborate job descriptions should be compiled for every role, defining job tittle, job
objective, specific duties and responsibilities and required skills. These jobs
descriptions should be part of the organization chart of the company and be displayed
to everyone through specific communication channels, for example the corporate
intranet. Proactive measures must be taken in in order to avoid possible gaps or overlaps
in responsibilities.
Golder Rule #5: Keep Good Records
As already mentioned, good record keeping is an essential part of Good Manufacturing
Practices, that provides a detailed history of every batch and the following distribution
and enables the occurrence of internal or external audits to verify that procedures are
under control and followed appropriately.
Some examples of records that can be kept in a pharmaceutical company are product
master records, batch or manufacturing records, material / component control records,
personnel records, training records, equipment logs and cleaning logs.
At the same time, keeping good history of your production, offers another advantage,
that of the traceability. If a flawed product is found before or after market release, the
specific batch can be recalled instead of the whole production and the step where the
error occurred can be found and fixed.
Golden Rule #6: Train and Develop Staff
People are the essence of a company. If they were to perform on a basis inspired by
GMPs culture, then they should be provided with the right tools and knowledge to
successfully complete their tasks.
Extensive and continuous training should be an integral part of the company’s business
model. Specific training for each role must be a given practice and additional training
based on Good Manufacturing Practices can help raising awareness for the importance
of producing the right way.
After assuring that every employee has access to sufficient training, a system of job
competence monitoring should be installed. Annual performance reviews, based on key
performative indicators must take place in order to periodically review the progress of
the staff and identify areas of improvement. Financial or material compensation as a
bonus for goals achieved can be given and work plans for future actions can be set.
Golden Rule #7: Practice Good Hygiene
When producing pharmaceutical products, avoiding possible contaminations is one of
the most important quality parameters. In order to reduce the risk of contamination, a
thorough sanitation plan is necessary. This plan must be always followed by everyone
since the cleanliness standards can be met only with the participation of every person
involved in the production process.
The measures that should be followed can be as simple as maintaining personal
hygiene, avoiding coming to work when ill, removing and storing trash appropriately,
not eating, drinking, or smoking inside facilities etc. All the above may seem like
common sense but getting everyone to follow them in an everyday basis may prove
challenging.
Golden Rule #8: Maintain Facilities and Equipment
Very often, factories producing pharmaceutical products operates on 24 hours 7 days a
week schedule. This nonstop production can weary down the machines used. As a
result, a solid maintenance schedule should be in place. Proper maintaining the
equipment, maintain the “validated state” previously mentioned, reduces the risk of
possible contamination, and prevents the breakdowns that can be costly both financially
and in terms of time lost.
It is very important to keep records of every scheduled or emergency maintenance.
Information such as when was the equipment last used, what for, when was last cleaned,
inspected, or repaired, who maintained the equipment, how and what was used for the
task, when was the last calibration taken place etc. needs to be logged in a master record
archive.
Golden Rule #9: Design Quality into the Whole Product Lifecycle
The quality control department of the pharmaceutical companies perform regular
inspections. Although, these examinations take place mainly on samples of the final
product which are selected based on statistical models. This procedure reduces the risk
of releasing a flawed product on the market but cannot inspect each production step.
To ensure consistent quality, effective controls must be evident throughout the lifecycle
of the product. The four main areas which must be constantly monitored are the
specification of the components that enters production, the manufacturing process, the
packaging and labelling of the final product and the storage and distribution channels.
Golden Rule #10: Perform Regular Audits
In most cases, external audits take place on a regular basis by regulatory bodies to
inspect GMP compliance. In order to prepare for these outside inspections, in house
audits can take place even more often as a proactive measure and corrective actions can
be applied where errors are located. [15]

3.5 International Regulatory Framework Regarding Good Manufacturing

Practices
The international regulatory framework regarding Good Manufacturing Practices can
be very complex. There are numerous legislations and guides for their implementation
and a great number of national and supernational regulatory bodies who enforce them.
A regulatory body is very similar to a professional body, except that it is not a
membership organization, and its primary mission is the protection of the public. In
contrast with professional bodies, a regulatory body is established on the basis of legal
mandate and has executive function. It can impose requirements, restrictions,
conditions, set standards regarding any activity, secure compliance or enforce. [14]
During the years passed, there have been significant attempts to unify global
pharmaceutical market and to harmonize different legislation frameworks. These
efforts have led to a much more compact market, but many more remains to be done.
Bellow follows an analysis of the most important and used Good Manufacturing
Practices as well as of the authorities which inspect and enforce them.

3.5.1 International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals for Human Use (ICH)
The International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use, or ICH for short, is a special project,
conceived by the European Union in 1980s with the goal to push the industry towards
a single market approach.
Preliminary discussions were held between EU, Japan, and the USA, with the latter
being the most reluctant. An agreement was reached nonetheless during the WHO
conference of 1989 in Paris. Based on this agreement, ICH was finally born next year,
in Brussels. [14]
Six different entities were originally involved in the founding of ICH and are listed
below:
• The European Commission
• The European Federation of Pharmaceutical Industry Association
• The Japanese Ministry of Health and Welfare
• The Japanese Pharmaceutical Manufacturers Association
• The United States FDA
• The United States Pharmaceutical Manufacturers Association
Moreover, 3 observers were listed, representing the non-ICH countries, WHO,
European Free Trade Association and Health Canada. Finally, the International
Federation of Pharmaceutical Manufacturers Association provides a secretariat for the
ICH. [13]
As of October 23rd 2015, ICH is filed as an international non-profit Association under
Swiss Law. In addition, the Association has expanded to include two more Standing
Regulatory Members. Health Canada (Canada) and Swissmedic (Switzerland). Also,
ICH regulatory members list, now consists of an additional eight bodies relayed here:
• ANVISA (Brazil)
• COFEPRIS (Mexico)
• HAS (Singapore)
• MFDS (Republic of Korea)
• NMPA (China)
• SFDA (Saudi Arabia)
• TFDA (Chinese Taipei)
• TITCK (Turkey) [29]
During its early years, ICH promoted the communication and knowledge exchange
between the regulatory authorities of the three founding parties, together with experts
coming from the pharmaceutical sector in those regions. Scientific and technical aspects
of product registration were discussed as well as issues regarding the approval and
marketing authorization of new medical products. [13]
The mission of ICH is to assist in the development of a pharmaceutical quality system,
which can be applied throughout the product’s life cycle and will emphasize an
integrated approach regarding quality risk management and science. [14]
At the first ICH Steering Committee meeting, together with the Terms of Reference,
the topics for harmonization were agreed. The work and actions of the ICH would focus
on Safety, Quality and Efficacy. Those three pillars, represent the three respectively
basic requirements which must be met for approving and authorizing new medical
products. [29]
Through this harmonization, ICH is aiming to achieve a more efficient use of resources,
either human, animal, or material, and to eliminate any unessential delays that takes
place during the global development and distribution of new pharmaceutical products,
while safeguarding quality, safety, efficacy and regulatory compliance to protect public
health at the same time. [16]
This harmonization is being achieved through mutual recognition between participating
regulatory authorities, based on the exchange of data and assessment reports. As a
result, duplicate testing and inspection procedures are getting eliminated, the costs are
decreasing and the introduction of new pharmaceutical products to the market speeds
up. [13]
Throughout the years, ICH has produced several work products which cover medicinal
products from end to end and incorporated them in some Quality Guidelines. More
specifically:
• Stability (Q1A – Q1F)
• Analytical Validation (Q2)
• Impurities (Q3A-Q3E)
• Pharmacopoeias (Q4A-Q4B)
• Quality of Biotechnological Products (Q5A-Q5E)
• Specifications (Q6A-Q6B)
• Good Manufacturing Practice (Q7)
• Pharmaceutical Development (Q8)
• Quality Risk Management (Q9)
• Pharmaceutical Quality Systems (Q10)
• Development and Manufacturing of Drug Substances (Q11)
• Lifecycle Management (Q12)
• Continuous Manufacturing of Drug Substances and Drug Products (Q13)
• Analytical Procedure Development (Q14) [29]
Good Manufacturing Practices are being covered in Quality Guideline Q7. Quality
Guideline Q10 is of specific value. It is broader than the mere concept of GMP and it
includes the essence of Q7, Q8 and Q9 as well as the ISO series. This guideline provides
a life cycle approach focused on three objectives. To achieve product realization, to
establish and maintain a state of control and to facilitate continual improvement. [14]
Besides the above-mentioned Quality Guidelines which relate closely to GMPs, ICH
also issues Safety Guidelines, Efficacy Guidelines and Multidisciplinary Guidelines.

3.5.2 European Framework

In the European Union, national authorities together with the European commission
and European Medicines Agency (EMA), negotiate and formulate a legislative
framework on a central level which is then in turn integrated into national law.
EMA was established by directive EC 2309/93, and it operates since 1995. Its purpose
is to scientifically evaluate applications for marketing authorization and monitor the
overall medicine safety in the European Union. It is primarily a scientific body and
therefore it holds no executive power. EMA serves as an umbrella organization for all
individual national regulation bodies and provides evaluations which are submitted to
the European Commission for approval or withdrawal. The European Commission has
a dedicated committee for this purpose called Committee for Medical Products for
Human Use (CHMP). [5]
At the same time, the commission serves as an intermediate between the EU and third
parties, negotiating Mutual Recognition Arrangements (MRAs). MRAs is a joint
acceptance of standards of GMPs and a commitment to take actions to ensure
compliance. Under MRAs, the regulatory authorities of each party, accept each other’s
inspection reports and pretesting of imported products is not normally required.
The EU legislation is written in an abstract way, laying down the basic principles and
requirements and then detailed guidance is provided through guidelines that interpret
and expand the principles and essence of regulations. [8] Guidelines are then used by
national regulatory authorities as a basis for inspection or when assessing applications
filed by pharmaceutical companies. Alternate methods, differentiated from guidelines,
can be used if equivalent assurance is provided, although this is usually avoided because
of the elevated risk it contains as a practice. [5]
Each time a new pharmaceutical product needs to be registered in the European market,
there are three different legal frameworks that can be applied, as established by the EU.
Centralized Procedure: This path is mandatory for the approval of biotechnology and
high technology products, orphan drugs, new active substances that were not previously
authorized in the EU and are meant for the treatment of HIV/AIDS, cancer, diabetes,
or neurodegenerative disorders.
Decentralized Procedure: In this case the authorization is being carried out by the
national agency of each member state in which the pharmaceutical distributor is seeking
marketing authorization.
Mutual Recognition Procedure: If a product has already gained approval through the
decentralized procedure, the company can then apply for marketing authorization
accordingly in every other EU member. The country originally authorizing the drug
must provide a detailed assessment report to every interested party. [13]
The legal framework that governs the pharmaceutical products disposal in the unified
market is defined by the below documents.
• Directive 2003/94/EC laying down the principles and guidelines of good
manufacturing practice in respect of medicinal products for human use and
investigational medicinal products for human use [36]
• Directive 2004/27/EC amending Directive 2001/83/EC on the Community code
relating to medicinal products for human use [37]
• Directive 2001/82/EC relating to veterinary medicinal products [38]
• EU Guidelines for Good Manufacturing Practice for Medicinal Products for
Human and Veterinary Use [39]
• European Pharmacopoeia [35]
Greece, as a member state of the European Union, has integrated community directives
into national law. The adaptation took place with the vote of the Official Government
Gazette of the Hellenic Republic Y6/75691/2004 amending O.G.G. Y6/11228/92 for
harmonization with EU Directive 2003/94/EC regarding Good Manufacturing Practice
for Medicinal Products for Human and Veterinary Use.

3.5.3 European Pharmacopeia

The term Pharmacopeia is referring to a book of recipes used to produce pharmaceutical
products, together with instructions and requirements. Their origin can be located back
to ancient times in a more primitive version. Modern Pharmacopeias on the other hand,
include detailed quality prerequisites for the active substances, general requirements
for the analysis and production of pharmaceutical products, monographs for certain
marketed drugs and classification of products and substances to unique categories based
on different forms and properties. The term monograph refers to certain articles inside
Pharmacopeias which corresponds to a certain active ingredient and describe standards,
preconditions and methods of quality control and assurance for it.
In each Pharmacopeia a very strict and universal terminology is being used.
Historically, each country, used to develop its own Pharmacopeia with different levels
of success. After World War 2, a movement for harmonization has emerged in this field
also and supernational handbooks were created. The most well – known examples being
the European Pharmacopeia, the United States Pharmacopeia and the Pharmacopeia
issued by the World Health Organization.
The United States Pharmacopeia (USP) and WHO Pharmacopeia, contain certain tests
and procedures but hold no mandatory requirements. They are a more informal and
consulting document in their nature. [14]
Contrariwise, the European Pharmacopeia (EP) is a legally binding handbook that
controls the quality of pharmaceutical products. It was first introduced with the first
edition in 1969 and the most recent in the tenth edition of 2019. It is currently used in
more than one hundred and twenty countries and contains 2462 monographs, 283
general texts and 2850 descriptions of reagents. It is applied to products designated for
both human and veterinary use. The quality standards which are described are
implemented throughout the whole life cycle of the drug and therefore a build in
approach is used. Its legal status was established by two different EU directives, the
2001/82/EC and 200/83/EC correspondingly. [21]
As already mentioned, EP is a detailed collection of standardized specifications on the
quality of pharmaceutical preparations, their constituents, and their containers. Some
of these requirements may apply to more than one classes of substances and
preparations simultaneously and as a result they are covered by general monographs. If
the requirements need to be strict and specific, dedicated monographs are used for the
particular substance or preparation in question.
Those monographs are legally binding in general but can be just informative if it is
clearly stated that the text is non mandatory. Generally, the need for compliance is
deriving from the fact that a new product needs to be produced in accordance with the
EP in order to obtain marketing authorization. [5]
The European Pharmacopeia is updated constantly by the European Pharmacopeia
Committee which adjourn 3 times a year to review and adopt chapters proposed by
experts and to decide and schedule future actions and research, based on current
scientific data. The EP committee consists of a president and vice president, the
members of the committee, two or three from each country and thirty nine in total, thirty
observers (European Commission, WHO and non – member countries), a technical
secretariat and expert committees having consulting role.
There is one main restriction in EP. It contains only a few individual final forms of
dosages.

3.5.4 United Kingdom Framework

In the United Kingdom the supervisory role of the pharmaceutical market lies upon the
executive body of the Ministry of Health called Medicines and Healthcare Products
Regulatory Agency (MHRA). The purpose of the agency is to assess the quality, safety,
and efficacy of medicines (new and existing) and grand authorization for marketing
across the UK. At the same time, it conducts post marketing surveillance and oversees
clinical trials for both medicines and medical devices.
MHRA consists of five separate inspectorates, tasked with monitoring the compliance
of Good Clinical Practices, Good Distribution Practices, Good Laboratory Practices,
Good Manufacturing Practices and Good Pharmacovigilance Practices respectively.
The agency does not have the authority to provide overseas manufacturers sites with
licenses but performs pre-arranged and unannounced inspections instead and focuses
on products meant to be imported in the UK market. Currently, MHRA, inspect
producers and distributors in countries including USA, India, China, and Japan. [13]
As expected, Brexit had a big impact on the legal framework governing the
pharmaceutical market in the UK. As of January 1st 2021, EU pharmaceutical law is no
longer in effect in the United Kingdom with the exception of Northern Ireland which
will exit EMA on a later date.
United Kingdom Ministry of Health has designed a thorough scheme for the after Brexit
handling of all legal aspects that will arise in relation to pharmaceutical market. To
begin with, MHRA will become a standalone agency. All previously centrally
authorized products by the European Union will convert automatically into Great
Britain’s catalogue of approved substances unless the producing company decides to
opt out. Then, manufactures must provide baseline product data within one year. For
drugs that have already been certified through the EU centralized, decentralized or
mutual recognition procedures, abbreviated assessment procedures were established
with a deadline of sixty-seven days for each product. Finally, in regard to pending
applications on January 1st, 2021, these requests must be submitted anew to the MHRA
as has been submitted to EMA. Any evaluation that has already been conducted by the
EMA to this point will be considered by MHRA which will the complete its own
assessment. This process has taken the name “in – flight assessment” and must be
completed in each case no later than the issue of the corresponding European
Commission decision. [30]

3.5.5 International Organization for Standardization (ISO)

International Organization for Standardization (ISO) is an international standard
development Organization. It is composed of representatives from the national
standards authorities of each country member. All the international standards
elaborated by the organization are prepared by allocated technical committees, in which
every national standards body has the right to participate.
As already mentioned, the pharmaceutical manufacturing industry, is highly concerned
and focused on quality and good practices. Therefore, some ISO standards are applied,
together with the GMPs on different stages of the products life cycle. More specifically,
there are three main standards that are mostly used in this particular sector.
ISO 17025-2017: This standard refers to good operation of a pharmaceutical
laboratory. It contains requirements for capabilities, impartiality, and consistency. In
order to achieve the above, a mechanism to identify and eliminate threats while making
good use of existing opportunities, is called for. By following the instructions of ISO
17025-2017, effectiveness elevates, and better results are yield, cooperation and
exchange of information and know how between laboratories and different agencies are
facilitated and the harmonization of standards and procedures is accommodated.
Good Laboratory Practices (GLPs), as laid out in this standard or as derived from
benchmarking with current best practices, are essential, and one of the main reasons is
that the laboratory is part of the formulation, inspection, and certification process of the
product. By applying the guidelines of the standard, the company can clarify and delimit
responsibilities, establish operational rules (this, among others, can assist on an easier
onboarding of new employees), improve overall quality (through Key Point Indicators,
process improvement and uncertainty measurement) and boost the brand in terms of
prestige and credibility.
Many of the areas covered inside ISO 17025-2017 are also examined in pharmacopeia.
Some examples are issues regarding equipment, process validation and sampling. At
the same time, the standard addresses a number of subjects, not present in
pharmacopeia, such as impartiality, confidentiality and organizational structure, staff,
resources sufficiency and facilities. It can be said that pharmacopeia focuses only on
analysis and tests while ISO sets an overall framework for managing every activity of
the laboratory. [21]
ISO 9001-2015: This standard is probably the most known one and it deals with quality
management in general for businesses working in every sector. The basis for this
management model is the Plan – Do – Check – Act approach. It is characteristic that
TUV NORD has issued more than 1.1 million certificates for this standard worldwide.
Pharmaceutical companies, can use ISO 9001-2015 to reduce production and
operational costs by making better use of their resources, implement continuous
improvement, enhance their reputation and credibility, and infiltrate new and untapped
markets.
There is a verry limited correlation between GMPs (which are referring to controlled
procedures) and ISO 9001-2015 (a general management system). In short, ISO states
what needs to be done while GMPs specify how it will be done. Having said that, there
are a few areas covered by the standard that are not mentioned in Good Manufacturing
practices and these are the need to control procedures through a dedicated quality
manual, the commitment made by the top management towards both internal and
external clients and the creation and periodical update of a business plan for continuous
improvement. [21]
ISO 14000: It is an environmental management system. Its aim is to minimize the
harmful effects that can be caused on the environment by the company’s activities.
Because of the sensitive nature of the products, biproducts and wastes of the
pharmaceutical industry, this standard is of great significance. If implemented
correctly, can magnify continuous improvement of the company’s environmental
performances. [16]

3.5.6 World Health Organization (WHO)

World Health Organization (WHO) is promoting global well-being and healthy life by
leading global efforts guided by science. A strong weapon in this direction is the
Technical Reports Series (TRS), through which the WHO makes available the findings
of different international scientific groups or experts on a vast range of medical and
public health issues.
Pharmaceutical Production is covered in two different TRS. Firstly, the Annex 2 of
TRS 986, lays out the main principles of WHO Good Manufacturing Practices for
Pharmaceutical Products and the Annex 4 of the same TRS provides guidance on these
Good Manufacturing Practices through an inspection report. The WHO framework on
the subject is completed by the report issued by the WHO Expert Committee on
Specification for Pharmaceutical Preparations (Currently TRS 1033). [14]
WHO GMPs and Guidelines, recommends several different types of inspections and
suggest specific regulatory actions in cases of non – compliance. Having said that, the
implementation of them lies with the national regulatory bodies of each individual state
because they have no legal mandate on their own.
The global pharmaceutical market and production can be very complicated and
demanding. In its effort to ensure a bare minimum for public health in each country and
for everyone, the World Health Organization compiled its Good Manufacturing
Practices in the direction of setting the most basic requirements. Hence, the result is in
many cases abstract and in developed countries, consists only a subset of more detailed
assurance systems. For that reason, WHO GMPs are used primarily in developing
countries and this can have two different effects. Businesses which are big enough and
have substantial capital reserves, invest in making their production GMP compatible
and by making so they improve their operation, become more competitive and open to
new markets. On the other hand, this can lead to the creation of barriers to entry and /
or to growth of smaller domestic pharmaceutical companies which do not have the same
capabilities. Local based producers may be pushed out of the market or forced to
attempt to acquire GMP certificates on the black markets in order to keep their
operation running. [13]

3.5.7 Food and Drug Administration (FDA)

In the United States of America, the oversee and control of the pharmaceutical market,
lies within the jurisdiction of the Food and Drug Administration (FDA), an agency of
the U.S. department of Healthcare and Human Services. FDA, besides food and
pharmaceutical products also regulate the tobacco industry. [9]
The activities of this organization are far broader than the ones of EMA. Its role and
goal are to protect the general public health. More specifically, food, drugs, medical
devices, biologics, animal feed and drugs, cosmetics, radiation emitting products and
tobacco commodities, all fall under the FDAs umbrella. Like the European agency,
FDA assesses new products on a scientific and quality base, grands marketing approval
and operates post marketing surveillance. The difference is that the latter holds
executive power and can impose sanctions directly in cases of non – compliance. [13]
The bureau maintains offices in strategic locations all around the world, including but
not limited to China, Europe, India and Latin America and it works closely with foreign
governments, industry representatives and all the strategic stakeholders. [14] Although,
regarding foreign manufacturers, the inspections are focused solely on Active
Pharmaceutical Ingredients that are intended for market release or are already marketed
in the U.S.
FDA uses the SISPQ (Strength, Identity, Safety, Purity, and Quality) criteria as the core
of its operations. Through this set of criteria, it builds systems aimed to assure proper
design, monitoring and control of pharmaceutical manufacturing processes and
facilities. As a result, all five standards are met, strong quality management systems are
established, appropriate and safe raw materials are constantly selected, robust operating
procedures are being established, product quality deviations are getting detected and
properly investigated and reliable testing laboratories are being maintained. [9]
As already mentioned, FDA holds executive power and this is derived from the Code
of Federal Regulations (CFR), which is a collection of final regulations published in
the federal register (50 titles in total) and is a federal law. The title 21 that governs food
and drugs within the United States is updated annually and then put on public review
and comments for a 30-day period before becoming final. In general, EU and US
regulations are relatively similar but the US one is lengthier and more prescriptive by
incorporating details which in the EU scheme is included in the guidelines instead.
The US cGMPs are incorporated in four different parts of CFR title 21. The letter “c”
in cGMPs, meaning “Current” is used to emphasize that pharmaceutical producers need
to constantly employ up to date technologies, scientific data and systems, in order to
comply with the regulations. ICH Q7 and Q8 guidance are included inside those parts.
Part 210: Includes the Current Good Manufacturing Practices in manufacturing
processing, packing, or holding of drugs. It is a framework for the regulation along with
some definitions. [8] It contains the minimum methods to be used, and the facilities or
controls that will assure that the drug produced complies with the requirements imposed
by regulation, regarding safety and that has the necessary identity and strength to meet
the quality and purity characteristics that claims to possess. [16]
Part 211: Lays out the Current Good Manufacturing Practices for Finished
Pharmaceuticals
Part 225: Describes the Current Good Manufacturing Practices for Medicated Feeds
Part 226: Complies the Current Good Manufacturing Practices for type A medicated
articles
The above four parts are accompanied by the corresponding guidelines which aim to
assist the implementation of modern quality systems and risk management approaches
in order to meet the requirements of the FDAs cGMP regulations. They consist of six
major sections. Management, Responsibilities, Resources, Operation Management and
Evaluation Activities. At the same time, clarifications are offered, and minimum
requirements are portrayed for the preparation of pharmaceutical products for human
or animal use. [16]
The agency performs scheduled and unexpected audits or investigate certain leads
resulting from the pharmacovigilance process. After an audit takes place, the form FDA
483 is issued. That is the “Notice of Inspection observation” sheet, which is used by an
investigator following the inspection of a certain plant. It is a record of irregularities
noted and possible deficiencies in the quality system while predicting new compliance
issues that may occur. The pharmaceutical companies then must proceed with
corrective actions.
If a company fails to comply with the cGMPs, the drug it produces is considered
adulterated under the law from this point onwards. The FDA does not hold the authority
to force a company to recall single batches or even the whole production of an
adulterated drug but can seize and destroy it.

3.5.8 Pharmaceutical Inspection Co-Operation Scheme (PIC/S)

The Pharmaceutical inspection Co-Operation Scheme (PIC/S) was established in 1995
as an extension to the Pharmaceutical Inspection Convention (PIC) of 1970. It is a non
– binding co – operative agreement between participating regulatory authorities in the
area of Good Manufacturing Practices of medicinal products for human or veterinary
use. There are currently fifty-four participating authorities over the world. Its primary
reason is to lead the international development, implementation, and maintenance of
harmonized GMP standards and quality systems of inspectorates in the field of
pharmaceutical products. [34]
PIC/S has been active in the development and promotion of GMP standards and
guidance documents since its creation and issue or amend existing GMP guidance
documents on a yearly basis. The main instrument of the Scheme is the PIC.S GMP
Guide which derives from the WHO GMPs and was then further developed. It is
considered a pioneer in developing such documents with some examples being the Site
Master File, the Recommendation on Quality System Requirements for Pharmaceutical
Inspectorates and the first ever issued guideline for the Manufacturing of Active
Pharmaceutical Ingredients. Moreover, it’s role in elaborating a first draft of the ICH
Q7A Guide on APIs which was later finalized by ICH in2000 and adopted anew by
PIC/S, was pivotal. In addition, EU, which was using PIC/S guide, adopted its own
after 1989 that is equivalent to the one of PIC/S and the two guides have been developed
in parallel ever since (they are practically identical).
On top of the already mentioned functions of the scheme, offering training services to
GMP inspectors, has been one of the core activities of PIC/S since it was initially
established. This is achieved through offered seminars, a joint visits program between
experienced and new inspectors, coached inspections and expert circles where
experience and know how is transferred)

3.5.9 China
In a world changing ever so rapidly and a pharmaceutical market that is more
interconnected than ever, GMPs are gaining an even more crucial role. West has
dominated this industry in the past but emerging economies are constantly growing,
closing the gap between them and the already established leaders of the sector.
Pharmaceutical manufacturers coming from these countries, may use international
GMPs as a benchmarking standard but are officially regulated by the national
legislation. In this context, it is worth examining one of the most representative cases,
the one of China.
Chinas first GMP version was issued in 1998 by the Ministry of Health. Later, in 2010,
the fourth and most recent set of the Good Manufacturing Practices rules was edited,
and it raised the standards while pushing the country to make rapid progress in its
overall pharmaceutical manufacturing level. [31] The quality by design approach was
introduced for the first time, meaning a quality control system which covers the entire
process of drug design, R&D, production, testing, storage, shipment, and use. A quality
risk management viewpoint throughout the products lifecycle was made possible by
incorporating ICH Q9 and Q10 guidelines inside the core of 2010 Chinas GMP.
The similarities between the 2010s GMP version and the EUs one are numerous but
some gaps remain, regarding the role of qualified persons, the practice of continuous
monitoring, the enforcement of laboratory investigations of any abnormal test results,
the existence of requirements for isolating different product lines, etc. [31]
China’s will to embody best practices became apparent when it became a formal
member of ICH in 2017. The most recent and drastic shift in perspective on the subject
was noted in 25/09/2022. On this date, the State Food and Drug Administration issued
the Notice on Learning and Propagating the Drug Administration Law of the People’s
Republic of China, officially announcing the cancellation of GMP and GSP
certification and change the APIs and excipients to be approved together with
pharmaceutical products. [32]
This may seem like a regression at first. The case is that GMP certification was thought
to approve the operation up to this point. In many cases, pharmaceutical manufacturers,
began to relax after obtaining the certification and the regulatory authorities had to use
great efforts and resources every year in order to investigate and revoke GMP
certificates of enterprises breaking the law. Now, the state’s mentality is steadily
transforming from stressing threshold to stressing supervision, meaning that the
frequency of supervisions will increase, and unannounced inspections will take place
in the daily production. [32]
Having said that, it is still hard for China to compete with well-established companies
of the West unless significant improvements are made in areas such as software usage,
human resources and adopting sufficient quality management systems.
 References
International References
1. Abubaker Abdellah, Mohamed Ibrahim Noordin, Wan Azman Wan Ismail,
“Review: Importance and globalization status of good manufacturing practice
(GMP) requirements for pharmaceutical excipients”, Saudi Pharmaceutical
Journal, Vol. 23, 9-13, 2015
2. Active Pharmaceutical Ingredients Committee, “Good Manufacturing Practices
in Active Pharmaceutical Ingredients Development”, 1999
3. Barbara Immel, “A Brief History of the GMPs”, 2002
4. Brian Kaufman, Gary D. Novack, “Compliance Issues in Manufacturing of
Drugs”, The Ocular Surface, Vol.1, Issue 2, 80-85, 2003
5. European Medicines Agency, “Status of EMEA Scientific Guidelines and
European Pharmacopoeia, Monographs and Chapters in the Regulatory
Framework Applicable to Medicinal Products”, 2008
6. G. B. Jena, Sapana Chavan, “Implementation of Good Laboratory Practices
(GLP) in Basic Scientific Research: Translating the Concept Beyond
Regulatory Compliance”, Regulatory Toxicology and Pharmacology, Vol. 89,
20-25, 2017
7. Jill Shukla, “Good Manufacturing Practice (GMP): An Overview”, 2017
8. John G. Grazal, David S. Earl, “EU and FDA GMP Regulations: Overview and
Comparison”, The Quality Assurance Journal, Vol. 2, 55-60, 1997
9. John Juchnowski, “Current Good Manufacturing Practices”, Cleveland
American Institute of Chemical Engineers Meeting, 2019
10. Joint Statement Between the International Pharmaceutical Federation (FIP) and
The International Federation of Pharmaceutical Manufacturers Associations
(IFPMA), “Ensuring Quality and Safety of Medicinal Products to Protect the
Patient”, 1999
11. Julie Milstien, Alejandro Costa, Suresh Jadhav, Rajeev Dhere, “Reaching
International GMP Standards for Vaccine Production: Challenges for
Developing Countries”, 2014
12. K.T. Patel, N. P. Ghotai, “Pharmaceutical GMP: Past, Present, and Future – a
Review”, Pharmazie Vol. 63, 251-255, 2008
13. Petra Brhlikova, Ian Harper, Allyson Pollock, “Good Manufacturing Practice in
the Pharmaceutical Industry”, 2007
14. Pharmaceutical Consultancy Services, “General Introduction to GMP, History,
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15. Pharmaout, “White Paper: The 10 Golden Rules of GMP”, 2016
16. Reham M. Haleem, Maissa Y. Salem, Faten A. Fatahallah, Laila E. Abdelfattah,
“Quality in the Pharmaceutical Industry – A Literature Review”, Saudi
Pharmaceutical Journal Vol. 23, 463-469, 2015
17. World Health Organization, “Quality Assurance of Pharmaceuticals. A
Compendium of Guidelines and Related Materials. Volume 2, Second Updated
Edition”, 2007
18. Yulia Nedelcheva, “Internal Audit in the Pharmaceutical Sector: International
and National Good Practices”, Journal Aktiv, 13-15, 2014
19. Yulia Tsvetanova, “Features of Internal Audit in Pharmaceutical Industry”,
Pharmacia, Vol. 61, 30-34, 2014
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20. Ελευθερία Διαμάντη, «Διπλωματική Εργασία: Η Εφαρμογή των Ορθών
Πρακτικών Παραγωγής (cGMPs) και η Επίδραση της μη Συμμόρφωσης στην
Ποιότητα και στο Κόστος των Φαρμακευτικών Προϊόντων», 2019
21. Εμμανουέλα Πλατανάκη, «Διπλωματική Εργασία: Διοίκηση Ολικής Ποιότητας
στην Βιομηχανία Παραγωγής Φαρμάκων: Σύγκριση των Αρχών της
Φαρμακοποιίας και της Ορθής Παρασκευαστικής Πρακτικής με τις Απαιτήσεις
των Πρότυπων Συστημάτων Διαχείρισης», 2020
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14. https://www.ema.europa.eu/en/human-regulatory/research-
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Legislation References
22. Commission Directive 2003/94/EC of 8 October 2003 laying down the
principles and guidelines of good manufacturing practice in respect of medicinal
products for human use and investigational medicinal products for human use
23. Directive 2004/27/EC of the European Parliament and of the Council of 31
March 2004 amending Directive 2001/83/EC on the Community code relating
to medicinal products for human use
24. Directive 2001/82/EC of the European Parliament and of the Council of 6
November 2001 on the Community code relating to veterinary medicinal
products
25. EU Guidelines for Good Manufacturing Practice for Medicinal Products for
Human and Veterinary Use
26. Official Government Gazette of the Hellenic Republic Y6/75691/2004
amending O.G.G. Y6/11228/92 for harmonization with EU Directive
2003/94/EC regarding Good Manufacturing Practice for Medicinal Products for
Human and Veterinary Use
 Section 4. Good Manufacturing Practices Guidelines
As already mentioned in the previous sections, pharmaceutical products that are being
manufactured or marketed in the European market are regulated through a set of laws
and directives. On the other hand, legislation only lays out the operational framework
and portrays general requirements and quality standards. As a result, a plethora of
guidelines were created, further elaborating the essence of the legal framework. More
specifically, European guidelines are divided into four parts and nineteen annexes.
Below, the most important points of the guidelines are relayed.

4.1 Part I: Basic Requirements for Medicinal Products

4.1.1 Chapter 1: Pharmaceutical Quality System

The core principle of this chapter is to make sure that all holders of manufacturing
authorization are taking all proper measures to ensure that the medicinal products that
are being manufactured are meeting the necessities for their intended use, comply with
all corresponding requirements and pose no risk for the patients because of insufficient
safety, quality or efficacy. In order to achieve this, employees of all departments and
different levels as well as company’s suppliers and distributors need to commit and
participate in the process.
Firstly, the pharmaceutical quality management is being addressed. The quality
management system is a very broad topic which incorporates the GMPs and covers all
matters which have an impact on the final quality of the product. When creating,
revising, or operating a quality management system, the size of the company as well as
its activities should be considered. [1]
A well-designed pharmaceutical quality management system must make sure that
constant quality of the medicinal product is ensured throughout its lifecycle by taking
GMP’s requirements into consideration. In order to achieve this, every production or
control operation and the corresponding managerial responsibilities need to be clearly
defined. Specific procedures must be established to control both supply chain and
outsourced activities. At the same time, potential deviations from the defined standards
should be investigated through root cause analysis and properly addressed via
corrective and / or preventative actions (CAPAs). If these CAPAs are designed
carefully and periodically be assessed and improved, will eventually lead to continuous
improvement. The quality system is documented in a Quality Manual and calls for self-
inspections or external quality audits. The ultimate responsibility for an effective
quality management system lies with the senior management who must make sure that
every necessary resource is being provided.
Moving forward, the quality control aspect is examined. This area is responsible for
sampling, testing, organizing, documenting, and setting necessary specifications. [1]
For the above to be properly executed, adequate facilities must be provided, trained
personnel should be available and well-defined procedures for sampling and testing
have to be in place. It is crucial that records are always maintained and checked against
specification by a qualified person and no batch of final product should be released
prior to proper approval by him. Finally, during the above-mentioned process, reference
samples must be kept for potential future examination.
Concerning the evaluation of the already mentioned procedures, a periodic and
systematic quality review of all licensed medicinal products must be overseed with the
goal of confirming the constancy of existing processes, validating the suitability of
present specification, highlighting potential trends, and identifying possible
improvements. [1] Indicative examples of such quality reviews are the review of
starting materials, review of critical in process controls and finished products, review
of every product batch that failed to meet specification and their corresponding
investigation, as well as review of potential deviations and non-conformances, potential
changes to processes and quality related complaints, returns and recalls. [1] Following
the issuance of the above-mentioned reviews, an evaluation of the produced results
must follow with the aim of identifying possible preventive and / or corrective actions.
An integrated quality management system is not sound if it does not include a quality
risk management system which is a systematic process for assessing, controlling,
communicating, and reviewing the quality related risks of the medicinal products. [1]
It must be highlighted that quality risk management can be applied both proactively and
retrospectively and must be built on scientific knowledge and experience of the
processes.

4.1.2 Chapter 2: Personnel

The second chapter of the EU guidelines tackles the very important subject of personnel
in the pharmaceutical industry. It is people who after all are responsible for a proper
manufacturing process. Hence, there must be a sufficient and qualified number of
employees to perform all the necessary tasks within the responsibility of the
manufacturer.
An organizational chart must be in place, which clearly specifies the managerial
hierarchy and the relationship between each role. In addition, the specific duties of each
position should be properly described in written job descriptions and special attention
should be given to avoid possible gaps and overlaps of responsibilities.
The senior management oversees and must appoint key management personnel, such
as the head of production, the head of quality assurance and at least one qualified person
and specify their unique or shared responsibilities. [2] The qualified person plays a
crucial role in the production of pharmaceutical products. If a batch is not cross checked
against legal regulations and the requirements of the marketing authorization for the
EU states and get approval of the qualified person, it cannot be released. In addition, if
the product is imported from third countries, all the necessary tests, including a full
qualitative and quantitative analysis must be performed in order to make sure that the
quality is in accordance with marketing authorization requirements. [2]
All personnel who are involved in the production or storing operations, who works into
control laboratories or whose job may affect the final quality of the product, must
undergo continuous training, the results of which, should be documented and
periodically assessed.
Another very important aspect of ensuring product’s quality, is the establishment of
proper hygiene. To make this possible, thorough hygiene trainings should be designed
to cover different needs across the company. Some examples may include but not
limited to health-related procedures, hygiene practices and clothing of personnel. It is
also essential for every new employee who is recruited must undergo a full medical
examination. Moreover, to secure production’s cleanness, every person who is about to
enter manufacturing areas, must wear all required protective clothing and every practice
which potentially might undermine product quality should be strictly forbidden. [2]
Finally, if the company is collaborating with external or in house consultants, they must
be of sufficient experience, training, and education to offer reliable advice. Elaborate
records, containing the name, address, qualifications, and the type of services provided,
must be maintained. [2]

4.1.3 Chapter 3: Premises and Equipment

Chapter 3 focuses on the topic of premises and equipment. More specifically, the need
for the premises and equipment to be in proper location, designed and constructed,
adapted when required and maintained accordingly to serve the operations, is
highlighted. [3] Their arrangement should be such as to help minimizing the risk of
errors and contamination that can have a negative impact on the final quality and to
assist effective cleaning and maintenance. This section is focused on five categories
which are presented below.
Firstly, regarding the production area, the need for implementation of the quality risk
management principles is underlined in order to avoid cross contamination. In detail, if
a medicinal product presents a high-risk potential, designated facilities must be
allocated for its production and packaging with entry restrictions for unauthorized
people. In order to improve efficiency, the sequence of the operations must be the guide
for designing production areas in a way that follows the corresponding logical order.
Storage area is the second topic that is discussed, and the focus is aimed at the need for
sufficient capacity to permit a well ordered and untainted storage of the various
categories of materials and finished products. Also, proper design must guarantee that
receiving and dispatching bays are adequately protecting the materials from weather
conditions while allowing for preliminary cleaning of the containers before use.
Moreover, clearly marked quarantine areas should be in place together with separate
sampling areas for the starting materials. Finally, a designated space must be created
for the storage of rejected, recalled, or returned materials and products as well as highly
active ones. [3]
Moving forward, reference is made to quality control areas with distinguished quality
control laboratories facilities, separated from production rooms and independent areas
for the protection of sensitive instruments from vibration, electrical interference,
humidity etc. Also, special requirements are relayed for the operating with particular
substances. [3]
Regarding the ancillary areas, there should be easily accessible and appropriate for the
number of employees rest and refreshment areas as well as special rooms for clothes
changing, washing and toilet usage.
Closing this chapter, the installment of the equipment is addressed. All machinery and
instruments must be properly designed, placed, and maintained in a way that serves its
purpose, helps to avoid cross contamination and hazard for the employees, can be
comfortably cleaned by following detailed and written procedures. It is also very
essential that every part of equipment which come into direct contact with the product,
must not be reactive, additive, or absorptive and every instrument used for measuring,
weighing, and recording should be calibrated using preset standards. [3]

4.1.4 Chapter 4: Documentation

As it has been evident up to this point, having a proper documentation process is a very
crucial part of every quality assurance system and is responsible for establishing,
controlling, monitoring and recording all activities which may affect the overall quality
of the medicinal product in any way. [4]
Below, follows a list of the required documentation for GMP compliance.
• Site Master File: An extensive file that includes and analysis all GMP related
activities [4]
• Instructions: Are divided in two types, directions, and requirements
➢ Specifications: Documents which relay the full requirements necessary for the
product or material to meet in order to achieve compliance. Some examples may
be specifications for starting and packaging materials, specifications for
intermediate and bulk products and specifications for finished products
➢ Manufacturing Formulae, Processing, Packaging and Testing Instructions: Here
every starting material, equipment and computerized systems are described in
detail and all mentioned instructions are specified. It is important to note that
these instructions must be present for every product and batch size
manufactured
➢ (Standard Operating) Procedures: More thorough directions for the performance
of specific operations, such as receipt, sampling, testing etc.
➢ Protocols: Are used to provide further instruction on performing and recording
cautious procedures
➢ Technical Agreements: Must be in place between contract givers and acceptors
when an activity is being outsourced. [4]
• Records and Reports
➢ Records: Every action taken in order to achieve compliance with GMPs is
demonstrated here
➢ Certificates of Analysis: A synopsis of testing results
➢ Reports: Is where the conduction of certain exercises, projects or investigations
alongside their results, conclusions and recommendation are documented [4]
All the above-mentioned documentation types must be well defined and assigned to a
designated person or group of people as well as clearly state its location and the length
of its corresponding retention period (depending on the nature of the document). There
is no mandatory form in which documents should exist and as a result they can be
digital, analog or in hybrid forms. The authorized person is responsible for signing and
approving documents that include instructions. In addition, all documents must be
periodically reviewed and updated if necessary, making sure that the style and language
used fit their intended use and concerned parties.

4.1.5 Chapter 5: Production

The core principle of a GMP regulated production is that every process should be
conducted according to clearly described procedures, instructions and if required
records. All incoming materials and produced yields must be checked and inventory
must be reconciliated to make sure that any discrepancies outside acceptable limits
won’t occur.
At the same time, all mix ups and cross contamination must be avoided. In order to
achieve that, all items must be accurately labeled, access to production areas should be
restricted to non-authorized personnel and a zero deviation from specification policy
should be applied unless specifically approved otherwise by the quality department. As
expected, medicinal and non – medicinal products ought to be produced in separated
areas. The potential risks of cross – contamination must be evaluated based on hard
evidence such as potency and toxicological measurements. Special attention should be
given to drugs which are administered by injection or for a prolong period of time. [5]
The technical measurements mentioned above, are to be performed in dedicated
facilities for this purpose. Moreover, the principle of “closed systems” between
equipment used and physical barriers systems must be applied. A mechanism for dust
removal needs to be in place and specialized technologies such as air – locks and
pressure cascade should be used to avoid possible airborne contamination. Single use
and disposable utensils have to be used when appropriate.[5]
If a product demonstrates high risk of cross – contamination all the necessary protective
clothing should be provided and used, the working performance of workers is
compelled to be supervised to ensure compliance with procedural controls and training.
All the production areas must have a cleaning verification, a measurable waste handling
system must be designed, and all spills, accidental events or deviations needs to be
recorded. [5]
In a GMP regulated production, validation studies performed in accordance with
described procedures reenforce compliance. These validation processes must be
conducted periodically.
The suppliers of starting materials need to be selected, qualified, and approved in a
documented way and as part of the pharmaceutical quality system, similarly with the
purchase and acceptance of the products they are offering. Of course, the level of
supervision must be in correlation with the risk present. All the decided quality
standards ought to be clearly stated and discussed with the suppliers. Full traceability
should be guaranteed. The compliance with GMPs and GDPs is ought to be confirmed
through audits performed by the pharmaceutical company and targeted to
manufacturers and distributors. Moving forward, minimum information which starting
material labeling should include are relayed. Also, the identity of each container
purchased must be measured through specific procedures and only the ones that gets
approval by the quality department can be used in the production. The responsibility
for these testing falls in the producer of finished materials authority. Finally, only
products which are dispensed by designated persons according to the above
requirements can be sold.
Prior to any processing procedure of intermediate and bulk products, it must be
guaranteed that working areas and equipment about to be used are clean and the absence
of any starting material, finished products or finished products residues or documents
not essential for the current operation is guaranteed. All the critical processes of this
kind should be validated. [5]
All the above-mentioned steps and requirements also apply to packaging materials and
special focus is given to printed materials. While packaging, the name and batch
numbers of the products must be displayed, and special attention should be given to
avoid mix ups and cross – contamination. The quantity, identity and conformity with
packaging standards must be inspected upon delivery while checks of the product
during packaging should incorporate at the minimum the below:
• The overall appearance of the packages
• If the packages are fully stacked
• Whether the appropriate products and packaging materials are used
• Assure that the over printing is the correct one
• If line monitors are functioning properly [5]
In this point, it is underlined anew that any product which was part of any uncommon
event, can only be reintroduced into the production process after an authorized person
has inspected, investigated and approved it. Finished products are to be put in
quarantine until their final release.
All rejected, recovered, or returned from the market products need to be either
destroyed or stored in a dedicated area and reused after it is evident that their quality is
sufficient.
Finally, if a manufacturing constraint can potentially lead to out of the ordinary
cutbacks in the supply, the manufacturer has the obligation to notify the marketing
authorization holder accordingly.

4.1.6 Chapter 6: Quality Control

In general, quality control is a broad field which covers the subjects of sampling,
specifications and testing as well as the organization, documentation and release
procedures. [6]
It is essential that every authorized manufacturer should maintain a quality department
that is independent from the production.
This subsection of part I provides an in-depth analysis on the Good Quality Control
Laboratory Practices. It begins by highlighting that personnel, premises and equipment
facilitated inside the laboratory should be appropriate for the corresponding task and
that the movement of laboratory equipment must be avoided in order to avoid cross
contamination.
Regarding documentation, the same principles as the on described in chapter 4 are
restated and a list of details which are necessary to be documented are listed, as follows.
• Specifications
• Procedures describing sampling, testing, records, recording and verifying
• Procedures for the calibration and maintenance of equipment
• Procedures for investigating out of specifications and trend results
• Testing reports
• Data from environmental monitoring (if required)
• Validation records (where applicable) [6]
About the sampling process, it is clearly stated that it must be conducted and
documented according to previously approved written procedures and that the samples
taken should be representative of the batch of materials or products from which they
are collected. Also, every package that contains samples have to be labelled
accordingly.
Concerning the testing procedure, it is very important that all methods used are
validated and the results gathered are recorded (minimum requirements for data
included in the records are given) and potential trends are estimated. Moreover, the
methods facilitated and according to which all in process controls are performed, must
be approved by the quality control department. Also, appropriate reference standards
ought to be established according to their intended use. In addition, if the use of animals
for testing components, materials or products is required, then, they must be bred, kept,
controlled and if necessary quarantined, in a way that guaranteed their suitability for
the purpose. [6]
Moving forward, the necessity of a well refined on – going stability program, which
will monitor the stability of the final medicinal product and locate potential issues, is
highlighted. A detailed and documented procedure must be in place describing the
stages of the control throughout the product’s lice cycle. It is essential that the number
of batches tested, and the frequency of the sampling must guarantee sufficient data for
trend analysis. The results of the stabilities studies should be available at any time to
key personnel and, in particular, the qualified person and all data generated should be
written, maintained and subjected to periodic review while any sign of deviation must
be investigated.
At last, if a need for a technical transfer of testing methods arises, first it must be made
sure that these methods are in compliance with the ones described in the marketing
authorization or the corresponding technical dossier. Also, a detailed protocol should
be established for the transfer of testing methods between laboratories.
 4.1.7 Chapter 7: Outsourced Activities
In a global and complex pharmaceutical industry, many times, a number of activities
often are outsourced. If a GMP regulated activity is outsourced then it must be
adequately defined (through a written contract according to marketing authorization
and the related regulatory framework), agreed and controlled.
The contract giver should make sure that its quality system is capable of controlling
and reviewing the outsourced activities for which he holds the final responsibility.
Furthermore, the contract giver is in charge of evaluating the contract acceptor prior
starting to outsource tasks. After beginning to collaborate, he has the obligation to make
sure that all information and knowledge required in order for the contracted operations
to run smoothly are available to the contract acceptor. Also, the contract giver ought to
monitor and assess the performance of the contract receiver. [7]
On his end, contract acceptor should be in procession of sufficient premises, equipment,
knowledge, experience, and personnel to successfully implement the activities which
he has taken upon. In no case is he allowed to subcontract to a third party or perform
changes that are not described in clearly in the terms of the contract without having
secured prior approval. Also, he oversees ensuring that every material, product or
knowledge provided to him are correct and suitable for their intended use. [7]
The contract itself should clarify the corresponding responsibilities and communication
paths and the technical aspects of the arrangement must be drafted by a person with
sufficient knowledge of the subject. The party responsible for performing each step of
the outsourced activity must be clearly defined and all records produced ought to be
available to the contract giver at any given time. The later must be granted the authority
to perform external audits whenever he sees fit. [7]

4.1.8 Chapter 8: Complaints and Product Recall

Extensive changes were made to this subsection with the greatest being that it is now
mandatory for quality risk management principles to be taken into account when
investigating quality defects or complaints or decisions about product recalls, corrective
and preventative actions are being taken.
All personnel involved with these subjects should not only be adequately trained and
have relevant experience but also be independent of the sales and marketing
departments. Inter – disciplinary teams can only be composed after careful
consideration. [8]
The handling and investigation of complaints and assessment of potential defects must
be conducted according to written procedures and all results be documented and
evaluated. If a defect is located in the end or even suspected, batches of similar products
or even other products needs to be investigated. In addition, trend analysis has to be
performed in order to locate reoccurring problems. All decisions taken should be timely
and reflecting the level of risk posed. Moreover, during the investigation phase of
quality defects, a root cause analysis must be performed.
In the case when a recall action is necessary, it needs to be performed swiftly. In order
to achieve this, all batch / product distribution records should contain all required
information and be available at any time. If the decision for a recall to be carried out is
taken, all concerned competent authorities ought to be promptly informed. Regarding
the recalled products, they need to be identified and stored in a separate and secured are
to be then disposed or reworked (only after consulting with the supervising authorities).
Finally, the recall process as well as other risk reducing actions, such as the issuance of
cautionary communications, must be evaluated on a periodic basis. [8]

4.1.9 Chapter 9: Self Inspection

The very essence of Good Manufacturing Practices lays in the belief that by
implementing operations proven by experienced and backed by scientific knowledge,
consistent quality can be achieved, and the producer has a lot of benefits to yield from
this. [9] Having understood this, regular and impartial self-inspections should be carried
out in an independent and thorough manner. These audits can be conducted by external
experts, or a competent qualified employee of the company and their end goal is to
monitor the implementation and overall compliance with GMP principles while
proposing required corrective actions when necessary.
Detailed records of the above-mentioned self-inspections must be always kept. During
such audits, personnel matters, premises, equipment, documentations, production,
quality control, distribution, and the existence of procedures for dealing with
complaints and recalls are only some of the subjects that should be examined for
compliance with the overall principles of Quality Assurance. [9]

4.2 Part II: Basic Requirements for Active Substances Used as Starting
Materials
The second Part of the GMP guidelines focuses on the Active Pharmaceutical
Ingredients (APIs). It largely focuses on the same topics as the first part and specifies
certain aspects, unique to the active substances, while offering some extra details on
some areas.
This Part of the guideline was published in November 2000, originally as Annex 18 to
the GMP guide and with final deadline for coming into operation the 1st of September
2014. It basically transforms the generic principles of Good Manufacturing Practices
for active substances into a unified and detailed guideline, since the complete revision
of several Annexes and of section 1.2, renders Part I insufficient to cover the whole
length of APIs production. [10] The objective of this initiative is to ensure the quality
and purity of active substances in relation to their specification.
It is important to highlight the fact that these guidelines do not have effect to production
steps taken place before the first introduction of the Active Substance Starting Material
into the process. As a result, manufacturers need to specify the exact point at which the
production of such material begins.
Below, follows a comparison of the content of Part I and Part II (where relevant) and
an analysis of the unique elements of the second Part.

4.2.1 Quality Management

In this section, the basic principles of quality management, already discussed in the
preview part, are mentioned anew. In addition, the need for an independent quality
unit(s), charged with both quality assurance (QA) and quality control (QC) duties is
highlighted. Depending on the size and organizational structure of the company, it
might be necessary to maintain two separate QA and QC units. Moving on, the
guideline deepens further into the unit’s responsibilities and covers the areas of
Production Activities, Internal Audits / Self – Inspection (special focus is given to this
subject) and Product Quality Review (which must be done periodically and
consistently). [10]

4.2.2 Personnel
Regarding personnel matters, Part II of the EU guidelines refers to the same subjects as
part I since they are relevant for APIs too.

4.2.3 Buildings and Facilities

The basic difference in this subsection can be located in the segmentation that is being
used. Part I divides Buildings and Facilities based on the area that they cover while Part
II relies on Design and Construction as well as Utilities (e.g., steam, gases, compressed
air, heating, ventilation, and air conditioning), Water etc. for the separation. [10]

4.2.4 Process Equipment

The areas of Design and Construction, Equipment Maintenance and Cleaning and
Calibration are reexamined here with greater detail. An addition to the subjects
previously discussed is the refer to Computerized Systems and more specifically the
need for qualification and security while using them.

4.2.5 Documentation and Records

The importance of a well-structured documentation system and the corresponding
specifications is underlined here afresh. Moreover, equipment cleaning and use record,
records of raw materials and intermediates, API labelling and packaging materials are
rediscussed. Moving one step further than Part I, the concept of Master Production
Instruction is introduced here for the first time (consisting of Master Production and
Control Records), together with Batch Production Records (including Batch Production
and Control Records), Laboratory Control Records (all data produced during tests must
be recorded in order to guarantee compliance with specification and standards) and
finally Batch Production Record Review (highlighting that every deviation,
investigation and out of specification reports must be reviewed before the batch gets
approved to be released). [10]

4.2.6 Materials Management

Most of the things analyzed in this subsection have already been scatteredly mentioned
in the previous part. More specifically, written procedures must in place for receipt,
identification and possible quarantine of incoming materials (special reference is made
in the need to avoid cross-contamination in the case when bulk deliveries are taking
place in non-dedicated tankers for the purpose) as well as for storage, handling,
sampling and testing (in cases of importing production materials from third countries,
full analysis must be done on at least three batches before allowing to reduce in-house
testing) [10] and of course for the final approval or rejection of the corresponding
materials. All the above-mentioned procedures should be periodically re-evaluated.

4.2.7 Production and in – Process Controls

At first, production operations are covered, meaning that the need for raw materials
measurement is being established, designated steps in the production process are
defined where expected yields must be compared with actual yields and deviation and
processing status of crucial equipment should be monitored. Specific time limits need
to be set and met while possible deviations should be well recorded and assessed. Steps
that can cause variabilities in the overall quality of active pharmaceutical ingredients or
used intermediates must be identified, their progress must be monitored, and their
performance controlled with in – process sampling and controls. In case when batches
of APIs are being blended (meaning that materials sharing similar specification are
combined to produce a homogeneous intermediate or API), the new blended batch
ought to be properly controlled, documented, and tested for conformance with
established specification and traceability. Finally, a full contamination control has to be
implemented recurrently. [10]

4.2.8 Packaging and Identification Labelling of APIs and Intermediates

This section, covers the same areas as the ones in Part I, meaning issues related to
packaging operations and materials (with their corresponding specifications) as well as
to label issuance and control procedures (more specifically the issuance, handling,
storing and destroying of labels when needed).

4.2.9 Storage and Distribution

In this point it is emphasized that there should be proper and adequate facilities for the
storage of all materials under safe conditions. After the quality unit releases a batch of
APIs or intermediates (and only then), sufficient distribution procedures must be in
place to guarantee their quality during transit, while making potential recalls possible
in a timely manner.
 4.2.10 Laboratory Controls
In accordance with the above, the existence of adequate facilities is deemed to be
necessary, allowing for the stated specifications to be met. In addition, every sampling
or testing process must be documented at the time of performance and backed by sound
scientific evidence. Any deviation from defined standards should be investigated and
documented. Certificates of Analysis, containing a detailed list of every test conducted,
the decline limits and the final results gathered, ought to be provided during the testing
of each API or intermediate batch. Moreover, a reoccurring testing scheme for the
monitoring of the stability attributes of APIs must be designed and the results yielded
should be the guide in determining proper storage conditions and expiring dates. In
order for this stability program to be efficient, minimum of one batch of produced API
per year should be added to it (more often for products with short shelf-lives) and
reserve samples should be kept for potential future quality evaluations. [10]
At this point, it should be mentioned that so far in Part II, the areas covered were similar
to the ones in Part I but moving forward from here, Part II deals with separate subjects.

4.2.11 Validation
The need for a written validation policy which will determine the operations that are
crucial to ensure the purity and quality of the active pharmaceutical ingredients is
highlighted here for the first time. This validation policy must be specified through a
validation protocol which will analyze how a particular procedure ought to be
performed and specify the type of validation and number of processes runs appropriate
while defining the critical steps of the process and setting acceptance limits. In the end,
a validation report must be drafted.
Subsequently, the types of qualification (design qualification, installation qualification,
operational qualification and performance qualification of critical equipment and
ancillary systems) and the different existing approaches to process validation
(prospective validation which is the universally preferred method, concurrent validation
and retrospective validation) are discussed. [10] Also, it is underlined that the number
of processes runs for validation previously mentioned, are inseparably linked to the
complexity of the process or the immensity of a proposed differentiation to an existing
procedure. During every validation study, special attention must be given to the control
and monitoring of critical parameters. If the analytical methods chosen are not part of
the relevant pharmacopoeia or any other highly acknowledged standard, they must be
validated too with regards to ICH guidelines. Finally, a system that has been validated
must be nonetheless reviewed systematically, especially if the risk for contamination or
carryover of materials is substantial.

4.2.12 Change Control

Every change which carries the potential to influence the control or production of APIs
must be thoroughly evaluated with emphasis on the possible impacts on the quality.
The first batches produced after a change is implemented must undergo enhanced
testing and evaluation.
 4.2.13 Rejection and Re-Use of Materials
If a specific material fails to meet confirmed standards it should be pointed out, put into
quarantine if necessary and then rejected in a documented way. A rejected material,
besides being discarded, can be handled in two ways and these are through reprocessing
(meaning the introduction anew of a non-conforming intermediate or API directly back
into the process and reutilize using proper chemical or physical operating steps) or
reworking (it is of the greatest importance that reworked batches have gone through
strict testing, evaluation and documentation which showcase that the quality of the
emended material is not inferior to the original one. [10]
On the other hand, recovery and re-use of materials and solvents (either in the same or
in different steps) is possible and acceptable given the fact that certain standards are
met, and the recovery processes are well controlled and monitored before re-using or
co-mingling solvents with virgin materials. In the case of returned APIs or
intermediates, they should be labelled appropriately, quarantined and then they can be
either reprocessed, reworked, or destroyed. [10]

4.2.14 Complaints and Recalls

A written procedure must be in place for handling (recording and investigating) all
received (both orally and in writing) quality related complaints. Following the
investigation of a complaint, a second written procedure should describe the
circumstances under which a recall of an API or an intermediate is necessary.

4.2.15 Contract Manufacturers

All contract manufacturers (including laboratories) must operate in compliance with
GMP values in order to avoid cross – contamination and to allow traceability. At the
same time, every contract manufacturer should be evaluated and work under a signed
and approved contract.

4.2.16 Agents, Brokers, Traders, Distributors, Re – packers and Re -

labelers
This section is directly applicable to all third parties who are involved in the repacking,
relabeling, manipulating in any way, distributing, storing, and getting ahold of an API
or intermediate. All the above-mentioned stakeholders should be following GMP
principles as described in this guide in order to avoid cross contamination, compromise
of quality and purity or loss. More specifically, they should ensure that the traceability
of the material is guaranteed and establish an effective quality management system.
Moreover, all appropriate stability studies ought to be performed to assign expiration
or retest dates. Transfer of information must be facilitated, and all quality and regulatory
information received from the manufacturer be transferred to the customers and vice
versa. [10] Closing this segment of the guide, it is highlighted that all complaints, recalls
and returns should be recorded and handled appropriately.
 4.2.17 APIs Manufactured by cell Culture / Fermentation
This subpart is covering the production of APIs or intermediates from cell culture of
fermentation. This procedure includes various biological processes like cultivation of
cells or extraction and purification of material from living organisms with possible
more intermediate stages. The requirements for maintaining a cell bank and keeping all
related records are listed, the parameters, equipment and personnel required for cell
culture and fermentation are discussed, and harvesting, isolation, purification and viral
removal / inactivation steps are relayed. [10]

4.2.18 Viral Removal / Inactivation

In this final section, all viral removal / inactivation steps are analyzed. More precisely,
the importance of maintaining stable quality with the help of a quality unit, independent
from production and charged with the duty of approving or rejecting every batch, is
highlighted anew. Moving forward, the subject of equipment and facilities, control of
incoming raw materials and production are examined. It is interesting to note that in
this case, expected yields from production can be more varying and less determined
than the ones used for commercial purposes. Also, variations investigations are not
mandatory. If an API is used for clinical trials, specific features apply since single
batches are produced and changes are occurring constantly during development (as
knowledge is gained and production is scaling up) and as a result process validation is
hard to implement. Clinical trials in many cases cannot be validated by nature prior to
testing but this does not mean that solid laboratory controls should not be in place while
all methods must be backed up by scientific data. Finally, the importance of
documentation is highlighted once again.
Part II ends with a thorough Glossary for all new terms used.

4.3 Part III: GMP Related Documents

Part III of GMP guidelines includes all complementary files which can become useful
in the process of implementation.

4.3.1 Guideline on Setting Health-Based Exposure Limits for Use in Risk

Identification in the Manufacture of Different Medicinal Products in
Shared Facilities
This guideline came into effect in 2015 and deals with the cases when a number of
different medicinal products are being produced in the same facility and as a result a
bigger risk of cross – contamination is present. To address this issue, specific threshold
values, based on toxicological data, are determined. This sub section covers the process
by which this threshold levels are decided and their importance. A very important index
in this direction is the Permitted Daily Exposure (PDE), which represents the daily
dosage of a substance that is highly unlikely to cause any harmful health effects. In
addition, special consideration is given to active substances with a genotoxic potential
(it is considered that any level of exposure poses a great risk) , active substances
with a highly sensitizing potential, therapeutic macromolecules and peptides,
investigational medicinal products (phase I and II) and in cases where there is lack of
animal data on reproductive and developmental toxicity. [11] Finally, the process
through which the PDE is determined (literature review, scientific discussion, and final
choice) should be well documented in a determination strategy report.

4.3.2 Internationally Harmonized Requirements for Batch Certification

A batch certification is required under the Mutual Recognition Agreements (MRA), the
Agreements on Conformity Assessment and Acceptance of Industrial Products
(ACAA) and other arrangements, regarding the GMPs, between the European Union
and third countries. This document provides all the necessary requirements for the batch
certification. More specifically, a full quantitative and qualitative analysis must be held
in order to make sure that the final quality of the products is in compliance with the
marketing authorization license. The certificate can also be used for non-finished
products, active ingredients, and investigational pharmaceutical products used in
clinical trials and it must always be available to regulatory authorities. The last revision
made to this guideline when these lines are written were made in 2011. [12]

4.3.3 Template for Investigational Medicinal Products Batch Certificate

This section provides a template for the batch certificate needed for investigational
medicinal products. The template follows the information underlined in subsection
3.3.2 and which are relayed below.
1. Name of product
2. Importing country
3. Marketing authorization number or clinical trial authorization number
4. Strength / Potency
5. Dosage form
6. Package size and type
7. Batch number
8. Date of manufacture
9. Expiry date
10. Name, address and authorization number of all manufacturing sites and quality
control sites
11. Certificates of GMP compliance of all sites listed under 10 or, if available,
EudraGMP reference numbers
12. Results of analysis
13. Comments
14. Certification statement
15. Name and position / tittle of person authorizing the batch release
16. Signature of person authorizing the batch release
17. Date of signature [18]
 4.3.4 Explanatory Notes on the Preparation of Site Master File
The necessity of a Site Master File is underlined in chapter 4 of the Good Manufacturing
Practices guide. It is issued by the manufacturer and should contain all information
regarding the quality management procedures in place. This guideline, offers notes on
how to prepare an adequate Site Master File, containing all production operations. In
detail, the following information must be included.
1. General information on the manufacturer
a. Contact information of the manufacturer
b. Authorized pharmaceutical manufacturing activities of the site
c. Any other manufacturing activities carried out on the site
2. Quality management system of the manufacturer
a. Details regarding the quality management system of the manufacturer
b. Release procedure of finished products
c. Management of suppliers and contractors
d. Quality risk management
e. Product quality reviews
3. Personnel
4. Premises and equipment
5. Documentation
6. Production
a. Type of products
b. Process validation
c. Material management and warehousing
7. Quality control
8. Distribution, complaints, product defects and recalls
9. Self-inspections [13]

4.3.5 Reflection Paper on Good Manufacturing Practice and Marketing

Authorization Holders
This paper is focused on Marketing Authorization Holders (MAH) companies, which
may or may not be directly involved in the production of the pharmaceutical products
but bare a lot of responsibilities non the less.
Marketing Authorization Holders have a unique place in facilitating GMP compliance.
More specifically, they deal with the following subjects.
1. They must provide adequate evidence of GMP compliance
2. In some cases, they should prepare a shortened version of the Veterinary
Marketing Authorization Dossier
3. They must make sure all labelling and packaging information are correct and
available to regulatory authorities
4. Are subjected to all responsibilities stated in chapter 7 of the GMP guidelines
5. They should make certain that all regulatory commitments are met
6. A two-way communication approach must be facilitated with all relevant parties
7. Data integrity needs to be guaranteed
 8. A compliance management process has to be in place to ensure that all
requirements are fulfilled, otherwise, the marketing authorization can be
revoked at any given time [14]
Each GMP requirement is quoted with the exact text that is used in the GMP guideline
while references and explanations are provided. In detail, the areas following are
covered.
1. Outsourcing and technical agreements (it is noted that only tasks and activities
can be delegated to third parties, but the MAH is always accountable for the
responsibilities)
2. Audits and qualification activities
3. Communication with manufacturing sites and competent authorities (the need
for a two-way communication approach is highlighted anew and specific
examples of required communications are given)
4. Product quality reviews
5. Quality defects, complaints and products recalls (a designated contact person
should be appointed, and all notification requirements must be met)
6. Maintenance of supply of medicinal products
7. Continual Improvement activities (in accordance with new scientific advances
and changes to EU GMP guidelines)
8. Falsified medicines directive (FMD) related responsibilities [14]

4.3.6 ICH Guideline Q9 on Quality Risk Management

As already mentioned, ICH guidelines preceded and vastly incorporated the EU Good
Manufacturing Process guidelines. As a result, the Q9 section which is referring to
important subject of risk management is included here.
The principles of quality risk management are relayed and then a general process is
described, as portrayed in the figure below.

Figure 8: Overview of a typical quality risk management process [16]

Then, the most basic risk management methodologies (they are listed below) are
discussed.
1. Basic risk management facilitation methods (flowcharts, check sheets, etc.).
These are further analyzed in Annex I, while Annex II relays some examples of
potential applications for quality risk management
2. Failure mode effects analysis (FMEA)
3. Failure mode, effects and critically analysis (FMECA)
4. Fault tree analysis (FTA)
5. Hazard analysis and critical control points (HACCP)
6. Hazard operability analysis (HAZOP)
7. Preliminary hazard analysis (PHA)
8. Risk ranking and filtering
9. Supporting statistical tools [16]

4.3.7 ICH Guideline Q10 on Pharmaceutical Quality System

Following Q9, the Q10 guideline regarding the pharmaceutical quality system is also
included in Part III. This guideline does not aim to create new requirements but rather
assist in the direction of fulfilling the regulatory demands throughout the product’s
lifecycle.
By implementing the Q10 model, product realization is achieved, a state of control is
established and maintained, and continual improvement is facilitated. This can be done
by making use of knowledge and quality risk management.
A specific section of Q10 is dedicated to describing the management responsibilities,
by dividing them into the areas of management commitment, quality policy, quality
planning, resource management, internal communication, management review,
management of outsourced activities and purchased materials and management of
change in product ownership. [17]
The importance of continual improvements of process performance and product quality
is highlighted anew by underlying the significance of setting separate lifecycle goals
and of incorporating all pharmaceutical quality system elements.
Finally, the need for achieving continual improvement of the whole pharmaceutical
quality system is stated. In order for this to be done, there should be adequate and
periodical management review of the pharmaceutical quality system, monitoring of all
internals and externals factors capable of impacting the pharmaceutical quality system
and study the outcomes of management reviews and monitoring.

4.4 Part IV: Guidelines on Good Manufacturing Practice Specific to

Advanced Therapy Medicinal Products
The final part of the EU guidelines is covering the area of advanced therapy medicinal
products (ATMPs). Its aim is not to set any restrains on the evolution and usage of new
concepts and technologies and thus, while describing some basic requirements, it
underlines that alternative methods can be used by manufacturers if they are able to
prove that their approach can achieve the same goals.
To begin with, Part IV deals with products administered to patients under Article 3(7)
of Directive 2001/83/EC or so called “hospital exemptions” and clearly states that they
too must be produced following equivalent quality standards as the ones applied to the
production of advanced therapy medicinal products with a marketing authorization.
[19] Then, the importance of the pharmaceutical quality system is highlighted anew.
A risk-based approach must be adopted for the development of ATMPs, but it is
acknowledged that since they are often produced in an academic or hospital area, a
certain level of flexibility should be allowed because these sites are operating using
unique quality systems, different than the ones required under GMPs for the production
of conventional medicinal products.
Having said that, the quality and safety of the product must be guaranteed throughout
the product lifecycle and starting from the early stages of its development. Nonetheless,
as there is a step-by-step increase in the level of knowledge, the intensity of quality
assurance endeavors will step up accordingly. As a result, corresponding manufacturing
procedures and control methods are expected to gradually become more detailed and
thorough as the clinical trials move to more advanced stages.
Moving forward, the subject of personnel is examined with special attention to the
person responsible for quality control and the qualified person. Regarding the premises
used, the classification of clean rooms and clear air devices according to ISO 14644-1
is introduced. More specifically, four grades (A, B, C and D) are defined and specific
concentration limits for airborne particles (in order to ensure an aseptic environment in
the clean room and monitor contamination risk for isolators and biosafety cabinets),
microbial load and specific microorganisms (such as yeast) are set (both at rest and in
operation). [19]
Then, Part IV, covers the area of equipment used, further deepen in detail specific for
the ATMPs. The documentation subject is also studied and is stated that the level of
specification and instructions must be relevant to the type of product and stage of
development. Proper and thorough documentation should be in place to ensure that the
unique characteristics of each batch can be identified despite the evolution – refinement
process. A product failed to meet the characterization requirements is prone to potential
rejection of the clinical trial results and denial of a marketing authorization.
As it is evident, starting, and raw materials are particularly important for the
development of ATMPs and when possible, the materials used should be in accordance
with the Ph. Eur 5.2.12 (general chapter on raw materials of biological origin for the
production of cell based and gene therapy medicinal products) and also, raw materials
must be of pharmaceutical grade, with the exception of instances when only research
grade raw materials are available. At the same time, a mechanism for assessing the
contamination risk across the whole supply chain have to be in place, paying special
attention to microbial safety and Transmissible Spongiform Encephalopathy (TSE).
[19]
Another important parameter is the quality of the starting materials and especially cells
and human tissues which must be in compliance with the donation, procurement and
testing standards of the Directive 2004/23/EC or if appropriate Directive 2002/98/EC.
The risk of transmitting both known and unknown pathogens (including potential new
infectious diseases) to human is escalating greatly when xenogeneic cells or tissues are
used. As a result, a need for a firm control of donor animals to ensure that they are
healthy and raised in pathogen free (SPF) conditions (monitored captivity) must be
designed. Every ill-health occurrence has to be investigated and dealt with. For
allogeneic products that a match between the donor and the patient is not mandatory,
the use of master and working seed lots/cell banks is recommended but not imposed.
[19]
Special attention is given to the production process, covering the areas of general
principles, handling of incoming materials and products, utilities (water, medical
gasses, and clean steam), prevention of cross contamination and aseptic manufacturing.
For the later, details for the aseptic processing validations are given, stating that it
should incorporate a simulation test using a sterile microbiological growth medium and
/ or placebo.
Moreover, it is highly likely that packaging activities of ATMPs will present increased
levels of complexity and liability to errors, which may also be more difficult to locate
in cases where blinded products with the same layout are used. In addition, the blinding
system used must be carefully described in the Product Specification File and if the
manufacturer is responsible for generating randomized codes, special actions should be
taken to ensure that all blinding information can be fast available to authorized
investigators before delivery while securing personal data from accidental unblinding.
The subjects of finished, rejected, recovered, and returned materials are also discussed
covering the same areas as the previous parts.
Part IV provides great details about qualification and validation. More specifically, the
steps of qualification process are relayed which are the ones following.
1. Setting the user requirement specifications
2. Design qualification
3. Verifying compliance with the user requirement specification (installation
qualification, operational qualification, and performance qualification)
4. Documentation [19]
In regard to validation, cleaning validation, process validation (even though the
production process of investigational ATMPs is not mandatory to be validated, all
necessary actions should be taken to guarantee compliance with the standards set in the
clinical trial authorization), validation of test methods and validation of transport
conditions are examined.
Then, the role of the qualified person is further described, and it is underlined that,
besides the requirements laid out in Article 49 of Directive 2001/83, QPs in charge of
ATMPs must also have proper training and previous experience in the unique attributes
of these items, cell and tissue biology, biotechnological techniques, cell processing,
characterization and potency testing. [19]
For a batch to be released, the following three steps should be followed.
1. Checking that the production and testing of the batch has been done in
compliance with corresponding requirements
2. Certification of the finished product batch made by the qualified person
3. Final assign of the release status to the batch [19]
Beside the above, there are some cases when, because of the short shelf life of the
ATMP, it may need to be released prior to completion of all quality control steps. To
counteract this, part IV allows for a batch certification procedure which will take place
in various stages.
Another issue is that the ATMPs may be necessary to manufactured in close proximity
to the patient for various reasons. In cases like this, a decentralized approach is used
where multiple sites across the EU are oversighted by a central hub. [19]
Subsequently, details are given for the handling of undesigned deviations and for the
administration of out of specification products.
Furthermore, the vast topic of quality control is covered, focusing on sampling, testing
and the establishment of an on – going stability program. The different types of samples
that need to be maintained are the ones listed here.
• Samples of raw materials
• Samples of the starting materials
• Samples of active substances and intermediate products
• Samples of primary packaging materials
• Sample of fully packaged unit (retention sample) [19]

Then, the obligation of both the contract giver and the contract acceptor as part of an
outsourced activities arrangement are discussed.

As long as quality defects and product recalls are considered, and when a blinding
procedure is required, it must be made sure that the rapid unblinding of products if the
need arise for a prompt recall is guaranteed but in a manner that the identity of the
blinded product is disclosed only if absolutely necessary.

The next subsection of part IV is dealing with the genetically modified organisms which
may pose a threat to the environment when disposed and highlights the need for a risk
assessment that will lead to a categorization of the products as negligible, low,
moderate, or high risk for the environment. Also, it is underlined that this section is
without prejudice to the requirements that may be applicable to investigational ATMPs
under Directive 2001/18/EC (Directive of the European Parliament and of the Council
of 12 March 2001 on the deliberate release into the environment of genetically modified
organisms and repealing Council Directive 90/220/EEC) and Directive 2009/41/EC.
[19]

The penultimate subsection of this part examines the reconstitution of products after
their release. The term reconstitution refers to each and every activity which takes place
between batch release and final administration to the patient and are not considered to
be a manufacturing step. As it is easily understood, if an activity leads to considerable
manipulation of the ATMP, it cannot be considered reconstitution (a number of
examples are given). [19]

Finally, all necessary requirements for the automated production of ATMPs is

discussed.

4.5 Annexes
Even though most of the subjects related to Good Manufacturing Practices are covered
in the 4 corresponding parts, there are still areas which calls for greater details and a
more in-depth analysis. This is achieved through the issuance of annexes that provide
necessary clarification in specific sections of GMPs.

• Annex 1: Manufacture of Sterile Medicinal Products [20]

• Annex 2: Manufacture of Biological Active Substances and Medicinal Products
for Human Use [21]
• Annex 3: Manufacture of Radiopharmaceuticals [22]
• Annex 4: Manufacture of Veterinary Medicinal Products Other Than
Immunological Veterinary Medicinal Products [23]
• Annex 5: Manufacture of Immunological Veterinary Medicinal Products [24]
• Annex 6: Manufacture of Medicinal Gases [25]
• Annex 7: Manufacture of Herbal Medicinal Products [26]
• Annex 8: Sampling of Starting and Packaging Materials [27]
• Annex 9: Manufacture of Liquids, Creams and Ointments [28]
• Annex 10: Manufacture of Pressurized Metered Dose Aerosol Preparations for
Inhalation [29]
• Annex 11: Computerized Systems [30]
• Annex 12: Use of Ionising Radiation in the Manufacture of Medicinal Products
[31]
• Annex 13: The Rules Governing Medicinal Products in the European Union
[32]
• Annex 14: Manufacture of Medicinal Products Derived from Human Blood or
Plasma [33]
• Annex 15: Qualification and Validation [34]
• Annex 16: Certification by a Qualified Person and Batch Release [35]
• Annex 17: Real Time Release Testing and Parametric Release [36]
• Annex 19: Reference and Retention Samples [37]
• Annex 21: Importation of Medicinal Products [38]
 References
1. European Commission, “EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use, Part 1: Basic
Requirements for Medicinal Products, Chapter 1: Pharmaceutical Quality
System”, Brussels 2012
2. European Commission, “EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use, Part 1: Basic
Requirements for Medicinal Products, Chapter 2: Personnel”, Brussels 2013
3. European Commission, “EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use, Part 1: Basic
Requirements for Medicinal Products, Chapter 3: Premises and Equipment”,
Brussels 2014
4. European Commission, “EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use, Part 1: Basic
Requirements for Medicinal Products, Chapter 4: Documentation”, Brussels
2010
5. European Commission, “EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use, Part 1: Basic
Requirements for Medicinal Products, Chapter 5: Production”, Brussels 2014
6. European Commission, “EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use, Part 1: Basic
Requirements for Medicinal Products, Chapter 6: Quality Control”, Brussels
2014
7. European Commission, “EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use, Part 1: Basic
Requirements for Medicinal Products, Chapter 7: Outsourced Activities”,
Brussels 2012
8. European Commission, “EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use, Part 1: Basic
Requirements for Medicinal Products, Chapter 8: Complaints, Quality Defects
and Product Recalls”, Brussels 2014
9. European Commission, “EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use, Part 1: Basic
Requirements for Medicinal Products, Chapter 9: Self Inspection”, Brussels
2014
10. European Commission, “Good Manufacturing Practice Medicinal Products for
Human and Veterinary Use, Part 2: Basic Requirements for Active Substances
used as Starting Materials”
11. European Medicines Agency, “Guideline on Setting Health Based Exposure
Limits for Use in Risk Identification in the Manufacture of Different
Medicinal Products in Shared Facilities”, London 2014
12. European Medicines Agency, “Internationally Harmonized Requirements for
Batch Certification”, London 2011
13. European Commission, “Explanatory Notes on the Preparation of a Site
Master File”, Brussels 2010
14. European Medicines Agency, “Reflection Paper on Good Manufacturing
Practice and Marketing Authorization Holders”, Amsterdam 2021
15. European Commission, “Template for the Written Confirmation of Active
Substances Exported to the European Union for Medicinal Products for
 Human Use, in Accordance with the Article 46b(2)(b) of Directive
2001/83/EC”, Brussels 2013
16. European Medicines Agency, “ICH Guideline Q9 on Quality Risk
Management”, London 2015
17. European Medicines Agency, “ICH Guideline Q10 on Pharmaceutical Quality
System”, London 2015
18. European Commission, “Content of the Batch Certificate for Investigational
Medicinal Products Referred to in Article 62(1) of Regulation (EU) No
536/2014 and Article 4 of Delegated Regulation 1569/2017”
19. European Commission, “Good Manufacturing Practice, Part 4: Guidelines on
Good Manufacturing Practice specific to Advanced Therapy Medicinal
Products”, Brussels 2017
20. European Commission, “Annex 1: Manufacture of Sterile Medicinal
Products”, Brussels 2008
21. European Commission, “Annex 2: Manufacture of Biological Active
Substances and Medicinal Products for Human Use”
22. European Commission, “Annex 3: Manufacture of Radiopharmaceuticals”,
Brussels 2008
23. European Commission, “Annex 4: Manufacture of Veterinary Medicinal
Products Other Than Immunological Veterinary Medicinal Products”
24. European Commission, “Annex 5: Manufacture of Immunological Veterinary
Medicinal Products”
25. European Commission, “Annex 6: Manufacture of Medicinal Gases”, Brussels
2010
26. European Commission, “Annex 7: Manufacture of Herbal Medicinal
Products”, Brussels 2008
27. European Commission, “Annex 8: Sampling of Starting and Packaging
Materials”
28. European Commission, “Annex 9: Manufacture of Liquids, Creams and
Ointments”
29. European Commission, “Annex 10: Manufacture of Pressurized Metered Dose
Aerosol Preparations for Inhalation”
30. European Commission, “Annex 11: Computerized Systems”, Brussels 2010
31. European Commission, “Annex 12: Use of Ionising Radiation in the
Manufacture of Medicinal Products”
32. European Commission, “Annex 13: The Rules Governing Medicinal Products
in the European Union”, Brussels 2010
33. European Commission, “Annex 14: Manufacture of Medicinal Products
Derived from Human Blood or Plasma”, Brussels 2010
34. European Commission, “Annex 15: Qualification and Validation”, Brussels
2015
35. European Commission, “Annex 16: Certification by a Qualified Person and
Batch Release”, Brussels 2015
36. European Commission, “Annex 17: Real Time Release Testing and Parametric
Release”, Brussels 2018
37. European Commission, “Annex 19: Reference and Retention Samples”,
Brussels 2005
38. European Commission, “Annex 21: Importation of Medicinal Products”,
Brussels 2022
 Section 5. Process Validation

5.1 Introduction
The term validation derives from the world “valid” or “validity” which in turn means
“officially acceptable” [3]. It is a concept wildly adopted in the pharmaceutical industry
that was first introduced during the 1970s by two FDA’s officials, Ted Byers, and Bud
Loftus. The idea behind this was to enhance the quality of pharmaceutical products by
making sure, in a documented manner, that a desired result with predetermined
compliance is assured.
Since then, the concept of validation has expanded to include a wide range of subjects,
such as equipment used, analytical methods utilized during quality control, materials,
processes, computerized systems, labeling etc. and the list grows constantly. [16]
Validation is a broad approach, spreading throughout the product’s life cycle and
maintaining the quality alongside. In general, every step of a procedure is verified and
consequently the whole process is validated. In this sense, quality is designed and built
in the system and thus functionality, consistency and repeatability are confirmed [14].
As it is evident, validation is a cross discipline effort, incorporating people from every
level of the organization.
This new approach regarding validation is built upon the principles of Quality by
Design (QbD) and Quality Risk Management (QRM) and emphasize the need of deep
process understanding and quality orientation from the product’s design face up to its
commercially production. As a result, process validation is viewed as a consistent proof
of quality and reliability rather than a static picture of control. This is made possible by
proactively identifying potential quality issues, using a scientific and practical approach
to decision making, based on risk evaluation of critical factors [7].

5.2 Definitions
A validated process is a process which is assured in a documented way that will perform
within strictly designed and defined criteria. As a result, a high degree of assurance that
the manufactured product will meet its predetermined standards and quality features in
a continuous and reproductible way is achieved [11].
Consequently, it is considered a key factor in assuring the identity, purity, safety,
efficacy and maintaining the quality of the final product [11]. Even though validation
has gradually become one of the most important, frequently discussed and
acknowledged topics throughout the pharmaceutical industry, there is still no universal
approach on the subject and different regulation bodies have introduced separate, non-
mandatory guidelines and definitions for this term. The most important of these
definitions, are the ones following.
European Commission: Validation is the documented evidence that the process,
operated within established parameters, can perform effectively and reproducibly to
produce a medicinal product meeting its predetermined specifications and quality
attributes [5].
United States Food and Drug Administration: Process validation is defined as the
collection and evaluation of data, from the process design stage through commercial
production, which establishes scientific evidence that a process is capable of
consistently delivering quality products. Process validation involves a series of
activities taking place over the lifecycle of the product and process [21].
ICH: Process validation is the means of ensuring and providing documentary evidence
that processes within their specified design parameters are capable of repeatedly and
reliably producing a finished product of the required quality [12].
World Health Organization: The documented act of proving that any procedure,
process, equipment, material, activity, or system actually leads to expected result [12].

5.3 Legislation
As mentioned above, there is no universal approach regarding the process validation,
and it is best viewed as an important and integral part of current Good Manufacturing
Practices.
More specifically, process validation is established by parts 210 and 211 of the cGMP
regulations, both in general and specific terms [14]. In addition, process validation
regarding the production of finished pharmaceuticals and components is a mandatory
and legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C.
351 (a)(2)(B)) [21].
The guidelines published by the EMA clearly state that the validation must always be
executed in total compliance with GMPs, and all data used, produced or collected
should be properly stored at the manufacturing site and be available for inspection upon
request. At the same time, the validation ought to be carried out in accordance with a
validation scheme which should be included in the marketing authorization dossier. The
scheme must incorporate a detailed description of the manufacturing process, the tests
to be performed and their acceptance criteria and finally an outline of all the extra
controls in place. The choice of this particular process validation scheme has to be
properly justified. Moreover, in some specific cases (for example when the final
product is a biological / biotech product or when a non-standard manufacturing process
is proposed), it could be considered necessary to provide production scale validation
data in the marketing authorization dossier (number of batches need to be proportional
to the complexity of the process or product, the knowledge gained during development,
any supportive data at commercial scale, during technology transfer and the overall
experience of the manufacturer. [5]
Until recently, if not otherwise justified, a minimum of three production scale batches
should be submitted. Lately, both the EU and US approach on process validation have
been altered through the introduction of Quality Risk Management and Quality by
Design concepts and the prior approach of consecutive validation runs has been
replaced by a more scientific and risk-based perspective [7].
 5.4 The Importance of Validation
Validation is one of the most crucial elements in the path of achieving and maintaining
quality of the final product. By carefully designing, validating, executing, and
documenting each step of the production, the quality of the final product is achieved
consistently.
All the above are especially important for the pharmaceutical industry because it uses
expensive materials, sophisticated equipment and facilities and highly qualified
personnel. It is evident that these resources must be used efficiently in order to avoid
the high costs of failures, rejects, reworks, complaints and recalls [11]. After all, it
would not be efficient to use equipment not knowing it will meet specifications or
employ people not able to perform as expected. [12]
There are three primary reasons for a pharmaceutical company to seek validation
(quality assurance, cost reduction and regulation compliance) but many more benefits
to yield. An attempt to summarize the benefits of performing validation is relayed here:
• Consistent quality of the final product (reduce batch to batch variation)
• Reduction in complaints, rejection, reworks, recalls and their corresponding
costs (cost of quality and cost of noncompliance). Avoidance of unnecessary
capital expenditures
• Prompt installation of new equipment and easier maintenance there after
• Faster and more accurate root cause analysis regarding deviations
• Boosts process awareness
• Easier scale up from design phase
• Encourage automations [11]
• Expands real time monitoring and adjusting of process and reduces testing in
finished goods
• Enhanced data capabilities, statistical performance evaluation and the ability to
set control parameters and limits leads to process optimization and increased
confidence about process reproducibility and quality
• Better reporting capabilities
• Improved safety [12]
• Increased output [14]

5.5 Reasons to Validate and Who is Responsible

The importance of validation has been well established by know but it is also crucial to
specify the circumstances under which the need for validation arise. These include, but
are not limited to, changes into new or existing products such as the ones following:
• Change in site of manufacturing
• Change in batch size
• Change in manufacturing process of existing products or totally new process
(e.g., mixing time, drying temperatures and batch size) [11]
• Change in composition or components
• Change in the critical control parameters
 • Change in vendor of API or critical excipient
• Abnormal trends in quality parameters
• Out of trend specifications in consecutive batches [12]
• Change in specifications of input raw materials (physical properties such as
density, viscosity, particle size distribution and moisture etc.) [11]
• Change in supporting systems
• Change in equipment / system or introducing new ones [e.g. addition of
automatic detection system)
• Change in packaging materials (primary container or closure system) [3]
• Cases when the quality control on the final product is poor and thus they are
not considered sufficient indicator [19]
• Change in quality parameters of product during Annual Product Review (APR)
[14]
So, validation can either be about new activities or items or revalidating existing ones.
Revalidation can be divided into periodic / scheduled or after change / modifications.
At the same time, since validation is carried out by designated personnel, it is very
important that they are properly qualified for the task and that their responsibilities are
properly defined. The validation, cross department, team is in charge of defining the
process, coordinating and approving the entire effort (including all of the generated
documentation) [12]. The table below shows the person involved in the validation
process and their corresponding duties.
Designees Responsibility
Third Level of Process Prepare and review the validation protocol (Title, Market, Batch Size, Report no,
Engineer Batch Details, Product Details, Reference Documents).
Second Level of Execute process validation batch. Protect the information concerning reason for
Process Engineer validation, product specification and receiving criteria, measuring device used, batch
production details, in-process characteristics, validation data, results and conclusions
First Level of Process Review validation protocol and clarify the validation report. Ensure that batches
Engineer according to the plan and approved protocol. Prepare periodic revalidation calendar
Second Level of Control of withdrawing sample as explained in the validation protocol. Analyze the
Quality Assurance sample and confirm validation report.
Manager
Head (Engineering) Analyze the area and equipment
Operation Manager Analyze and safeguard that the information concerning batch details, finished
products details, pack details of input materials, equipment used, batch fabrication
details, in-process characteristics, yield monitoring result and conclusion
Authorized Regulatory Analyze batch details, product details, pack details of input materials and certify the
Person validation report
Head (Quality Accept the validation agreement for application and attest the validation report
Assurance)
Table 2: key Responsibilities of Designees Involved in Various Phases of the
Validation Process [11], [12]
Another way of separating responsibilities is by dividing and assigning them into
different departments as shown below.
 Department Responsibilities
Site Validation Develop site master validation plan
Manufacturing Prepares the batches as routine batches for collection of
data
Quality Assurance Ensures compliance, documentation and procedures are in
place. Approves protocols and reports. Review validation
documents for process approval
Quality Control Perform validation testing and reviews protocol and report

Research & Development Deals with product design, installation, and quality. Certify
plant, facilities, equipment, and support systems
Table 3: Key Responsibilities of Departments Involved in Various Phases of the
Validation Process [11], [18]

5.6 Requirements and Validation Strategy

Knowledge regarding the final product and its production process are key to a
successful validation. Through this deep understanding of product development, it is
possible to establish sufficient control which in turn will lead to the desired quality
attributes.
It is very important that manufacturers:
• Understand the sources of potential variations
• Detect the presence and degree of variations in time
• Be aware of the impact a variation may have on the process in general and on
product features in specific
• Control each variation in a way corresponding to the risk it poses [21]
At the same time, detailed pre-established protocols must be in place to guide all actions
and properly trained and qualified personnel must be assigned to perform each task.
Proper facilities, equipment, instruments, and methodologies should be available. Also,
all data generated ought to be reviewed, certified, and documented [12].
Prior to commercial distribution, the producer must reflect on whether he has acquired
sufficient understanding and can guarantee high levels of assurance regarding the
quality of the final product. A common mistake manufacturer tends to make is focusing
their efforts on getting formal qualifications without realizing the importance of
understanding the manufacturing process itself and the quality issues which could
derive from possible variations. It is also important to make sure that the validation will
not be seen as a one-off event. In contrary, the state of control achieved must be
maintained even when materials, equipment, environment, personnel, and procedures
change [21]. This can be made possible by incorporating a lifecycle approach which
will link product development with production and commercial distribution and will
cover every manufacturing site while providing adequate data at the same time [5].
To achieve all the above, a carefully studied but also simple and straight forward
validation strategy must be developed, paying attention to 5 key points:
• Raw materials from different lots must be used
• Validation batches should be run in succession, in different days and shifts
• The equipment and facilities destined for commercial production must be used
during validation phase
• Critical process parameters should be set and limited within operational
boundaries
• If the validation protocol requirements are not met, requalification and
revalidation are in order [11]
As already mentioned, validation is a continuous and ever evolving process. Evidence
of validation should be seen at the corporate level and be reflected in the management
structure.

Figure 9: Validation Strategy Flow Chart [11]

5.7 Phases of Validation

The validation is a broad term which cover a wide range of activities. Many different
items or procedures can be validated but every validation can be primarily broken down
to three distinctive phases.
Phase 1: Pre-Validation or Qualification Phase
All activities related to research and development, formulation, pilot batches, scale up
studies, transfer of technology to commercial scale batches, establishing stability
conditions and storage, and handling of in-process and finished dosage forms are
carefully examined in this first phase as well as equipment qualification, installation
qualification, operational qualification, process capacity and master production
document [14].
Phase 2: Process Validation
It is verified that established limits of critical parameters are solid and will lead to
accepted product even under extreme conditions.
Phase 3: Validation Maintenance Phase
This phase requires the periodic review of related documents (including validation and
audit reports) to make sure that no alterations, deviations, failures, or modifications
have occurred and that all standard operating procedures are followed [12]. At this
stage, an interdepartmental validation team, ensures that there has been no need for
requalification or revalidation [14].

5.8 Types of Validation

In this sub section of the chapter, the most important types of validation are going to be
further analyzed. It is important to mention that the bare minimum that should be
validated are the cleaning procedures, analytical testing, and process (including
equipment) [19].
5.8.1 Analytical Validation
For the quality of the product to be verified and in order to ensure that it is maintained
throughout the product’s lifestyle [14].
Proper testing is established to make sure that no compromise has taken place in terms
of the below key parameters:
• Accuracy: the proximity between the theoretical true value and the observed
one
• Precision: The exactness of the analytical procedure. It consists of three levels:
o Repeatability: The exactness under similar conditions
o Intermediate precision: The exactness of tests performed inside the
same laboratory but in distinct days, by different analysts and on distinct
equipment
o Reproducibility: The exactness between different laboratories
• Ruggedness: The degree of reproducibility under different conditions
• Detection limits: Lowest quantity of an analyte which may be detected
• Quantitation limits: The least quantity of an analyte which can be quantified
with exactness and precision
• Linearity: The ability of a method to produce results directly related to the
concentration of an analyte
 • Range: The interval between maximum and minimum volume of analyte in a
sample
• Specificity: The capability to unequivocally assess the analyte of interest
• Robustness: The degree of capacity of the method to remain the same after
changes in the technique parameters (such as pH, temperature etc.) [16]
Every analytical method which is used in clinical samples examination is necessary to
be validated. Analytical validation is the, accepted by laboratory studies, procedure
which guarantees that the characteristics of the method used fits the scientific
requirements of its intended application. Analytical validation is an essential but time-
consuming project for most laboratories [12].
Analytical validation is crucial because it ensures that a new or altered procedure will
provide predictable and dependable results, even if performed by different personnel,
using comparable instruments, inside similar or totally distinctive laboratories.
There are five steps which are normally followed in order to validate an analytical
method:
• System Qualification
• Sampling
• Sample Preparation
• Data Assessment [16]

5.8.2 Cleaning Validation

Cleaning validation is a documented way of achieving high degree of confidence that
an equipment (or part of an equipment) or system is effectively and consistently cleaned
of residues below a predetermined acceptable limit. Examples of such residues may be,
but not limited to, lubricants, airborne substitutes, product residues, microbes etc. [3].
As a result, cleaning validation is key to preventing cross contamination and it includes
the development of practical, achievable, and justifiable acceptance criteria, detection
limits and sampling methods.
The main reasons for validating the cleaning procedures include:
• Ensuring the safety and purity of the final product
• Preventing contamination
• Satisfying regulatory requirements
• Satisfying customer requests [16]

5.8.3 Computer System Validation

Computer System Validation (CSV) provides documented evidence that a computer
system performs the tasks which was designed to handle and produce information and
data in an effective and efficient manner as per pre-defined requirements. If CSV is
done right the accuracy, consistency, reliability of the system is assured.
Computer System Validation in the pharmaceutical industry is primarily focused on
software validation, which is part of the CSV (every computerized system includes
some kind of software).
During a typical Computer System Validation procedure, an organization phases some
common challenges, as described below:
• Standards: Various standards, policies, SOPs, instructions etc. exist across
departments and are potentially overlying or even being incompatible,
increasing costs and complexity of validation
• Interpretation: Extensive debates over the essence of standards and
requirements greatly increase costs and time needed
• Organization and Governance: Decentralized governance and unclear roles,
responsibilities and activities ownerships create additional obstacles
• Efficiency Across Sites and Departments: In many cases, multiple validation
packages are developed for the same system in different sites or by different
departments due to lack of communication
• Execution: All the above-mentioned challenges, combined with potentially
unqualified individual employees, often leads to excessive rework
• Tools: They are employed to reduce the risk of personnel taking shortcuts or
skipping steps but can be inflexible and lead to unnecessary efforts
• Training: The short training usually provided is rarely sufficient
• Personnel: Many pharmaceutical companies employ very capable central
validation teams but lack in competent decentralized execution parties [17]
There are five key steps in the Computer System Validation process and are relayed:
• Validation Master Plan: A thorough blueprint of the validation process is
drawn up in this step
• Project Plan: Each step must be performed based on Standard Operating
Procedures and the Validation Master Plan
• Installation Qualification (IQ): Deeply analyze the installation of new
components while setting appropriate checks
• Operational Qualification (OQ): Ensures the security (software and physical)
and proper operational function
• Performance Qualification (PQ): Tests specific applications and overall
performance [17]
The importance of Computer System Validation is widely acknowledged across the
pharmaceutical industry and the regulatory bodies. This has led the FDA to issue five
basic requirements which must be met for systems used in medical devices. More
specifically, it is critical that the below are guaranteed.
• Information Security
• Information Backup
• Information Restoration
• Information Recovery in “Disaster” Cases
• Periodic Maintenance [17]
 5.8.4 Equipment Validation
The equipment validation is an integral part of validation and is more commonly known
as qualification [14]. Equipment plays a key role in production of pharmaceutical
products and thus it is very important to validate them prior to using them. The
qualification scheme is based on the idea that every equipment should be first designed,
then constructed, next maintained and finally adapt to perform the tasks which is
designated to operate [3].
Equipment validation can be divided into, the Design Qualification (DQ), the
Installation Qualification (IQ), the Operational Qualification (OQ) and the Performance
Qualification (PQ).

Figure 10: Equipment Validation Process

In most cases, when a need for a new equipment (or change in an existing one) arises,
the procurement typically starts by specifying the required documentation, User
Requirement Specification (URS), followed by Functional Specification (FS) and
Design Specification. Then the qualification begins with the Design Qualification and
Installation Qualification (in the pre-validation phase), continuous with Operational
Qualification and Performance Qualification (in the validation phase) and finally
remain in control through the validation maintenance phase [3].
The above-mentioned validation elements are further analyzed below.
User Requirement Specification (URS): It summarize the requirements and
expectations the customer or the user has of the equipment. It covers the areas of:
• Size of equipment and the space it occupies
• Its effectiveness and durability
• The working speed
• Limits of air and noise pollution
 • Spare parts availability and after sales services
• Overall construction quality [3]
Design Qualification (DQ): Is the action of making sure that the proposed layout of
equipment (or system) will satisfy the URS, FS, will comply with regulatory framework
and will highlight the rationale of choosing a specific supplier. It is a very important
step and special attention should be given because the impact it will have on IQ, OQ
and PQ is significant [12].
Installation Qualification (IQ): Is the action of offering objective evidence that all the
key and ancillary features of the equipment are installed (or modified) following
manufacturer’s layout and dealer’s recommendations [14]. Part of IQ can also be
considered the Safety Qualification (SQ) which validate that all the safety necessities
have been followed [14]. At the same time, it must be established in great confidence
that the equipment will operate consistently within pre-defined limits and tolerance
[11]. Details of supplier and manufacturer of the equipment together with details (such
as the name, color, model, serial number, date of installation or calibration) should be
well documented in this step [3].
Operational Qualification (OQ): It consists of several carefully designed tests which
can estimate with precision the performance capacity of the equipment and can verify
that it this performance is maintained throughout the anticipated operating ranges. In
that sense, OQ focuses on a specific piece of equipment rather than exploring
performance capabilities of a single product [12].
The OQ is conducted in two stages. Firstly, the Component Operational Qualification
in which calibration is a key aspect. Then, System Operational Qualification where it
is determined if the entire system operates properly and as a unified whole [18].
The finalized approved operations which arose after functions testing, the approved
calibrations, the test results regarding system stability and the various applications of
SOPs must be included in the OQ’s documentation [3].
Performance Qualification (PQ): Is documented evidence that the equipment
installed operates as intended. In this stage, this is insured under actual operating
conditions and environmental factors [11]. In other words, it is here proved that
equipment can accomplish the requirements set in the DQ phase in a repeatable manner
which always meet predetermined quality [12].
The documentation of PQ should at least include the Performance Qualification report,
the process stability testing reports (derived from long term productivity data), the
acceptance of the product record (based on customer reviews), a register of the actual
product and process parameters and a record of routinely performed test results [3].
Re – Qualification (RQ) and Maintenance: While the equipment is getting old or if
a need for a change or relocation arises, re – qualification is in order [14]. Changes with
no significant impact on in-process or final product quality should be handled via the
preventive maintenance procedure [12]. During maintenance, it is important to maintain
routine service records, a list of all authorized service engineers and an inventory of
maintenance contacts details [3].
 5.8.5 Gases Validation
One of the materials which is highly utilized in the manufacturing procedure of the
pharmaceutical products are various types of gases. Some examples are carbon dioxide,
compressed air, nitrogen gas etc.
Gases can impact the quality of the final product by coming into impact with it (direct
impact) or by indirectly affecting it. As a result, a validation plan should be in place to
insure that the gas system operates under control.
There are three steps need to be followed in order for a gas system to be validated.
Step 1: Supply of gas of desired purity and in adequate quantity. Special attention
should be given to pressure requirements while using the gas at maximum rates
Step 2: Making sure that proper, non-reactive materials are used to construct gas
storage facilities
Step 3: Ensure that the distribution system is also made of non-reactive and durable
materials and of adequate size [14]
5.8.6 Process Validation
Process Validation is the documented plan which can bestow great levels of confidence
that the validated process will always produce a product according to its pre-established
specifications and quality features [12]. FDA recommends and integrated team
approach to process validation, combining expertise from a variety of departments and
disciplines [21].
There are four different types of process validation.
Prospective Process Validation: This type of validation is the registered proof that the
process does what is supposed to do based on a pre-defined protocol. It usually takes
place prior to distribution of a new product or product made after process revision and
should be performed on at least three consecutive production batches [11].
Retrospective Process Validation: In this case, the evidence of process reliability is
given after analysis and evaluation of historical data. The aim is to demonstrate that the
process has always remained under control [12]. These data derive from production,
Quality Assurance (QA) and Quality Control (QC) records. It must be emphasized that
retrospective validation can only be accepted when a process is well established, and
no change have been made to it in the recent past regarding product’s composition,
equipment, or operating procedures. A minimum of ten to thirty past consecutive
batches should be examined (fewer batches can be examined if this can be properly and
scientifically justified) [11].
Concurrent Process Validation: This approach is very similar to Retrospective
Process Validation with one key difference. The product produced during the
qualification runs will be sold by the pharmaceutical company to the general public at
its market price. Because the product may end up to the final customer, the decision to
carry out Concurrent Process Validation, must be properly justified, documented, and
approved by authorized and competent personnel [11]. It is characteristic that FDA in
its guideline underlines that concurrent release of batches is expected to happen rarely
[21]. All critical steps should be monitored, and appropriate production testing must be
conducted when some alteration in equipment, formulation or site location have
happened [12].
Revalidations: When there is a change in batch size, or some sequential batches don’t
produce products according to process specifications revalidation (repetition of
validation) is required to verify that these changes do not impose adverse effects on the
features and quality of the product. The documentation required remains the same as
the one in the initial validation which has been made [12].
The assessment of data necessary for the Process Validation requires a set of activities
which are taking place throughout the product and process life cycle. This sequence of
tasks can be divided into three stages.
Stage 1 – Process Design: Process Design is the action of defining the commercial
manufacturing process suitable for commercial manufacturing [21]. In this stage, all
knowledge and experimental data which will be the basis for next stages are generated.
Process Design, if done right, can offer great process understanding and can locate
possible sources of variability. Development formulation, scale up studies, transfer of
technology, storage and handling of the in-process and finished products, Equipment
Qualifications, Master Production Documents, and process capabilities are some of the
concepts concerning this stage. The acceptance of strategy for the process control
happens in this step [12].
Prior knowledge of similar processes, combined with the principles of risk
management, can be used to identify a list of potential Critical Quality Attributes
(CQAs) and the parameters which can potentially impact them (and rank them
accordingly). CQAs are the physical, chemical, biological or microbiological properties
or features which must be inside preset limits, range, or distribution to ensure the
desired quality [7].
Based on these evaluations, the necessary experiments are prioritized, and a list of
Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) is drawn.
• Process Scale up: The term scale up may refer to either increasing the batch
size or the procedure of applying the same process to different volumes. First, a
risk assessment should be carried out and based on that, the best strategy for
scale up to pilot or industrial batch is decided [7]. Proper information, gathered
through development and process optimization studies, is key to avoiding
lengthy and costly tests and justifying that scale up poses no risk to quality [5].
• Design Space: After identifying critical parameters and analyzing preliminary
experiments, a model is created to define a design space (usually during
laboratory or pilot scale) inside which the commercial process is usually
performed and validated, in a specific area defined as the Normal Operating
Range (NOR) [5]. According to ICH 8, working within the Design Space is not
consider a change (moving from one area to another may represent higher or
unknown risks though) while movement outside of the Design Space it is, and
further Design Space Verification may be needed. The Design Space is
 proposed by the producer but still remains subject to regulatory inspection and
approval [7].
Stage 2 – Process Qualification: During this stage, the design process is put under
judgment in order to make sure that the process is capable of reproducing commercial
manufacturing. It is important to mentioned that all GMP procedures should be
observed during this stage and that any commercial distribution of the product cannot
begin prior to completion of this step [12].
Another goal of this stage is to ensure that all risks, identified in the risk analysis, are
under control and all suitable actions are in place [7].
This stage includes two key elements. Firstly, the design of the facilities and
qualification of equipment and utilities (as described above) and secondly the Process
Performance Qualification (PPQ). The PPQ combines the actual facilities, utilities, and
equipment (now qualified) and the appropriately trained personnel to run the
commercial manufacturing process, control procedures and components to produce
commercial batches. A successfully caried out PPQ will provide the final confirmation
of Process Design and that the commercial manufacturing process performs as expected
and is able to produce products with required quality even under extreme conditions
[21].
Stage 3 – Continuous Process Verification: Is the action of providing continuous
assurance that the production procedure remains under a state of control through the
entire life cycle. A recurrent check of process related documents and validation audit
reports is necessary to ensure that no changes, deviations, or failures have occurred
[12]. A wide range of parameters (e.g., process trends, incoming components quality
etc.) should be brought under a control and periodically reviewed from this point
afterwards [7].
Continuous Process Verification has been introduced as an alternative to traditional
process validation and suggest a continuous monitoring and evaluation of process
performance. It can be used instead of or in addition to traditional approach. To enable
the continuous alternative, pharmaceutical companies should utilize all necessary in-
line, on-line or at-line controls and monitor the quality of each batch, keeping an archive
of all relevant data [5].
Continuous Process Verification is considered the most suitable tool for validating
continuous processes and the responsibility of defining the stage at which the process
is considered to be under control lies with the applicant. At the same time, it is a very
versatile method that can be introduced at any time in the life cycle of the product and
can be used to perform the initial validation as well as to re-validate or even to support
continuous improvement [5].
Traditional Process Validation: Is usually conducted after scaling up (or at a pilot
batch representing at least 10% of production scale batch) but prior to marketing of the
final product [5]. Usually, a minimum of three consecutive batches with the same size
as the commercial one is required to establish reproducibility [7].
Hybrid Approach: There might be some cases where the use of both the traditional
and the continuous approach is needed for different steps of the manufacturing
procedure [7]. The choice of each method should be appropriately justified and clearly
stated in the dossier which step is conducted with which approach.

Figure 11: Process Validation Procedure

5.8 Documentation
As it is already evident from the above discussed sections, the importance of proper
documentation during each step of validation lifecycle is crucial in order to enable
effective communication in large, complex, lengthy and multidisciplinary projects like
the ones taking place in the pharmaceutical industry [21].
One of the most important documents (if not the most important) is the Validation
Master Plan (VMP). The company’s philosophy and point of view, it’s structure,
intentions and approaches regarding performance assessment, are summarized here. It
is drawn up by upper management and should be brief, precise and to the point [11].
All objectives and approved activities are highlighted and all actions to ensure
compliance with regulatory requirements are listed. The entire validation layout is
outlined in this document [14]. It is very important that information mentioned in other
documents is not repeated but instead reference is made to the corresponding protocols,
documents, SOPs, policies etc. [11].
The VMP should always be prepared prior to the beginning of the new financial year
to avoid error and delays [18].
At the minimum, the below data should be included in the Validation Master Plan:
 • Title page with approval signatures and dates
• Table of contents
• Abbreviations and glossary
• Validation policy
• Philosophy, intention and approach to validation
• Roles and responsibilities of relevant personnel
• Resources to ensure validation is done
• Outsourced activities (selection, qualification, management through lifecycle)
• Deviation management in validation
• Change control in validation
• Training
• Scope of validation
• Documentation required in qualification and validation such as procedures,
certificates, and protocols
• Premises qualification
• Utilities qualification
• Process validation
• Cleaning validation
• Personnel qualification such as analyst qualification
• Analytical method validation
• Computerized system validation
• Establishing acceptance criteria
• Lifecycle management, including retirement policy
• Requalification and revalidation
• Relationship with other quality management elements
• Validation matrix
• References [14], [11]
Another very important piece of documentation is the validation protocol, which must
too be number, signed and dated and providing at least the following information:
• Title
• Objective and scope
• Responsibilities
• Protocol approval
• Validation team
• Product composition
• Process flowchart
• Manufacturing process
• Review of equipment / utilities
• Review of raw materials and packing materials review of analytical and batch
manufacturing records
• Review of batch quantities for validation (raw materials)
• Review of batch quantities for validation (packing materials)
• HSE requirements
 • Review of process parameters validation procedure
• Sampling location
• Documentation
• Acceptance criteria
• Summary
• Conclusion [11], [14]
Moving forward, after the validation is completed, a validation report must be drafted,
including the following subjects:
• Title and objective of the study
• Reference to protocol
• Details of materials
• Equipment
• Programs and cycles used
• Details of procedures and test methods
• Results (compared with acceptance criteria) and
• Recommendation on the limit and criteria to be applied on future basis [12]
Other documents which are related to validation and qualification activities may include
but are not limited to:
• Standard Operating Procedures (SOPs)
• Specifications
• Risk assessments
• Process flow charts
• Operator manuals
• Training records
• Calibration procedure and records
• Statistical methods and results etc. [14]
 References
International References
1. Ajay Sharma, Seema Saini, “Process Validation in Pharmaceutical Industry: A
Review”, Pharma Science Monitor, An International Journal of
Pharmaceutical Sciences, Vol. 4, 2013
2. C. Karthick, K. Kathiresan, “Pharmaceutical Process Validation: A Review”,
Journal of Drug Delivery and Therapeutics, Vol. 12, 164-170, 2022
3. Diksha Jindal, Hardeep Kaur, Rajesh Kumari, Hanumanthrao Chadershekar
Patil, “Validation – In Pharmaceutical Industry: Equipment Validation: A
Brief Review”, Adesh University Journal of Medical Sciences & Research,
2020
4. Elsie Jatto, Augustine O. Okhamafe, “An Overview of Pharmaceutical
Validation and Process Controls in Drug Development”, Tropical Journal of
Pharmaceutical Research, Vol. 1, 115-122, 2002
5. European Medicines Agency, “Guidelines on Computerised Systems and
Electronic Data in Clinical Trials”, 2021
6. European Medicines Agency, “Guideline on Process Validation for Finished
Products – Information and Data to be Provided in Regulatory Submissions”,
2016
7. Fabio Geremia, “Modern cGMP Approach for Process Validation”, Acta
Scientific Pharmaceutical Sciences, Vol.3, 2019
8. Jeff Boatman, “A Comparison of Process Validations Standards”,
Pharmaceutical Engineering, The Official Technical Magazine of ISPE,
Vol.33, 2013
9. Ildiko Mohammed-Ziegler, Ildiko Medgyesi, “Increased Importance of the
Documented Development Stage in Process Validation”, Saudi
Pharmaceutical Journal, Vol. 20, 283-285, 2012
10. Kaur Harpreet, Singh Gurpreet, Seth Nimrata, “Pharmaceutical Process
Validation: A Review”, Journal of Drug Delivery & Therapeutics, Vol. 3, 189-
194, 2013
11. Kiranbala Jain, Princy Agarwal, Meenakshi Bharkatiya, “A Review on
Pharmaceutical Validation and it’s Implications”, International Journal of
Pharmacy and Biological Sciences, Vol. 8, 117-126, 2018
12. Manish Kumar Mishra, Pooja Kumari, “A Review on Pharmaceutical Process
Validation”, The Pharma Innovation Journal, Vol. 6, 960-958, 2019
13. Mohammed Mahmoud Ahmed, “Process Validation at Pharmaceutical
Industries”, University of Science and Technology, College of Postgraduate
Studies and Academic Advancement, Department of Chemical Engineering,
Sudan
14. N.V. Satheesh Madhav, Abhijeet Ojha, Siddharth Singh, “Validation: A
Significant Tool for Enhancing Qualities of Pharmaceutical Products”, DIT
University Faculty of Pharmacy, Scholars Academic Journal oh Pharmacy,
Vol. 6, 288-289, 2017
15. Sharma Sumeet, Singh Gurpreet, “Process Validation in Pharmaceutical
Industry : An Overview”, Journal of Drug Delivery & Therapeutics, Vol.3,
184-188, 2013
 16. Sudarshan Balasaheb Kakad, Mahesh Hari Kolhe, Tushar Pradip Dukre, “A
Review on Pharmaceutical Validation”, Department of Pharmaceutics, Pravara
Rural College of Pharmacy, 2020
17. Swarupa Vijay Jadhav, Swamini Subhash Waghchaure, Dr. S. Z. Chemate,
“Computer System Validation in Pharmaceutical Industry”, International
Journal of Creative Research Thoughts (IJCRT), Vol. 9, 2021
18. Swati Sabale, Santosh Thorat, “An Overview on Validation Process in
Pharmaceutical Industries”, Scholars Academic Journal on Pharmacy, 2021
19. Tenzin Wangpo, D.S. Rathore, Yogendra Singh, “Pharmaceutical Process
Validation: A Mini Review”, International Journal of Health and Biological
Sciences, Vol. 2, 9-12, 2019
20. U.S. Department of Health and Human Services, Food and Drug
Administration, Center for Devices and Radiological Health, Center for
Biologics Evaluation and Research, “General Principles of Software
Validation; Final Guidance for Industry and FDA Staff”, 2002
21. U.S Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER), Center for
Biologics Evaluation and Research (CBER), Center for Veterinary Medicine
(CVM), “Guidance for Industry. Process Validation: General Principles and
Practices”, 2011
GREEK REFFERENCES
22. Ιωάννη Πυλια, “Συγκριτική Αξιολόγηση ΣΔΑΤ – Επικύρωση Διεργασιών
στην Βιομηχανία Φαρμάκου και στην Βιομηχανία Τροφίμων”, Πανεπιστήμιο
Πειραιώς, Τμήμα Οργάνωσης και Διοίκησης Επιχειρήσεων, Μεταπτυχιακό
Πρόγραμμα Σπουδών στην Οργάνωση και Διοίκηση Επιχειρήσεων –
Διοίκηση Ολικής Ποιότητας, 2015
WEBSITES REFFERENCES
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 Conclusions
The history of medicine is almost as old as the history of mankind. Throughout the
ages, it has evolved to a highly sophisticated science. At the same time, the
pharmaceutical industry has grown to be one of the most vigorous, complex, high
revenue generating sectors and a great number of people is linked or impacted directly
or indirectly by it.

Unfortunately, a lot of tragical events have taken place during the evolution of the
pharmaceutical industry, mostly due to lack of proper quality assurance and of some
form of official control. This has led both the public and official authorities to realize
the need for a strict regulatory framework. As a result, various laws and regulations
have been created both nationally and internationally. Today, most countries have their
own set of laws governing pharmaceutical production (some more strict than others)
and attempts are made to harmonize these regulations via transnational agreements and
mutually acknowledged international bodies. These regulations are commonly known
as Good Manufacturing Practices and lay out the requirements for producing products
of adequate quality in a recurring way with a high level of confidence. The most well-
known of these GMPs are analyzed throughout this thesis, including but not limited to
the ones issued by FDA, EMA and ICH (in which both EU and USA are part of) and
are more directly linked to western countries, WHO’s GMPs (more moderate and thus
most commonly adopted by developing countries), as well as the ones provided by the
UK (formerly operated under the EU legislation but now paving its own way after the
Brexit), China (receiving ever increasing importance) and PIC/S.

Good Manufacturing Practices, are often written in an abstract way, providing

minimum demands and requirements which needs to be addressed, while not offering
a plan to cover them. This gap is filled by the guidelines for industry which are issued
by national authorities and international bodies. One such example, which is further
examined on a chapter-to-chapter basis as part of this dissertation, is the guidelines of
the EMA.

A very important aspect in achieving constant product quality are the assets (processes,
equipment, methods, etc.) incorporated by pharmaceutical companies during the
production lifecycle. These assets can be the source of increased or decreased costs,
high or low efficiency and ultimately the ability to constantly provide products with
high quality. The concept of validation is used to ensure in a documented way that a
process does what it was designed to do, during every process run and under all
conditions (inside pre-determined range). There are different types of validation,
performed by personnel with specific responsibilities and are discussed in detail above.
At the same time, all the benefits and requirements of and for a successful validation
are relayed and a list and contents of the most necessary validation’s documents is
provided.

While reading the relevant literature and composing the dissertation in question, it was
evident that great progress has been made in the path of achieving quality assurance in
the pharmaceutical industry throughout the years. Nonetheless, there are still parts of
the world where regulation remains loose, and loopholes are created and often exploited
in an internationalized industry like the pharmaceutical one. Often, profit is put before
quality and safety, even when such a sensitive product is in line. At the same time, a
strict regulatory framework and the need for high expertise for complying with it, are
frequently used for creating entry barriers for the competition rather than being an
opportunity for improvement and quality assurance. As a result, greater efforts should
be made towards global harmonization and enforcement of Good Manufacturing
Practices, and this can be more easily and efficiently achieved through international
regulatory and supervisory bodies (existing or new ones). Developing countries should
be encouraged to apply tested GMPs and valuable knowledge must be transferred via
elusive guidelines.

Finally, the concepts of validation and qualification can be confusing or even

overlapping in many cases of the existing literature, making it difficult for someone
without sufficient experience to delve further into the subject. More attention could be
given to further clarification of these terms and notions.

This thesis has been a systematic attempt to aggregate and relay the main points of the
international regulatory frameworks and the corresponding guidelines into one place
while further indulging in the European one, since Greece is directly affected by it. At
the same time, an effort was made to analyze the complex concepts of validation and
qualification and their correlation in terms of their significance, requirements,
competences and personnel involved, different types of validation and necessary
documentation.
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