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QMJ ZG629T: Dissertation
Dissertation work carried out at
MARCH 2007
QMJ ZG629T: Dissertation
Dissertation work carried out at
Submitted in partial fulfillment of
M.S. Quality Management Degree Programme
Under the Supervision of
MARCH 2007
This is to certify that the Dissertation entitled “REGULATORY
submitted by GABRIEL ANTONY RAJ .M having ID-No. 2005HZ74038
for the partial fulfillment of the requirements of M.S. Quality Management
degree of BITS, embodies the bonafide work done by him/her under my
Signature of the Supervisor
Place: Chennai, INDIA
Date: 21.03.2007
KALLUR SOMAIAH RAGHU, D.G.M – International Business Division,
Fourrts (India) Laboratories Private Limited, Chennai, INDIA
QMJ ZG629T: Dissertation
BITS ID No. : 2005 HZ 74038
EMPLOYING ORGANIZATION : Fourrts (India) Laboratories
Private Limited
The laws and regulations governing the pharmaceutical industry were
adopted to protect the consuming public by attempting to provide drugs of
consistent quality, purity and efficacy. The study describes about various
regulation and guidance prevailing in the current generic pharmaceutical
industry like cGMP, WHO, USFDA, UKMHRA, EMEA, and also the drug
regulatory mechanism in India. The need for harmonization of the same has
been discussed and a brief about International conference on harmonization
and the organization of common technical document has been described as
prescribed in the relevant guidelines.
The study comprises of various statistical quality control techniques
that can be utilized in the pharmaceutical industry for effective quality control
and assurance as well as to achieve Six Sigma. The professional, social and
legal responsibilities that rest with the pharmaceutical manufacturers for the
assurance of product quality are tremendous with varying guidelines and
stringent regulations.
A brief introduction to Fourrts (India) Laboratories Private Limited has
been given which consist of strategy, sales and information about various
awards and recognitions received.
A detailed study about the present quality management system
practiced in Fourrts and various aspects of the same has been discussed. The
strengths, weaknesses, opportunities and threats were analyzed and the report
has been completed with executive summary and suggestions
Broad Academic Area of Work: Study about current regulatory
aspects and quality management system prevailing in International Generic
Pharmaceutical Industry.
Key words (Specify the keywords in alphabetical order)
Pharmaceutical Regulatory Aspects / Quality Management / Statistical
Quality Control Techniques / Country Wise Regulatory Requirements
Signature of the Student
Date: 21.03.2007
Place: Chennai, INDIA
Signature of the Supervisor
Date: 21.03.2007
Place: Chennai, INDIA
I am very grateful to my mentor and supervisor Mr. Kallur Somaiah
Raghu, D.G.M – International Business Division for his valued support
during this journey, guiding me from almost to utmost and for making a
vision becomes a reality. I am very thankful to Mr. Vanchinathan, Vice
president – Technical for being an additional examiner and for his
encouragement during this dissertation.
I am deeply indebted to Mr. S.V. Veerramani, Chairman and
Managing Director and Mrs. Radha Veerramani, Director Fourrts (India)
Laboratories Pvt. Limited for the opportunity and valuable support throughout
the course of this dissertation.
I would also thank Mr. Krishna, Officer: International Business and
Mr. Lakshmanan for their suggestions and making my work a pleasure. I am
thankful to all members of Fourrts family for their cooperation and support.
I am always thankful to family and friends for encouragement; and
above all to God, who have never led me where His Grace couldn’t keep me.
Gabriel Antony Raj .M
1 Introduction 1
1.1 Background 1
1.2 Scope of work 2
1.3 Objectives 3
2 Quality Management in Pharmaceutical Industry 4
2.1 Introduction 4
2.2 Generic Pharmaceutical Industry an Overview 5
2.3 Conventional Quality Systems 10
2.4 Guidance and regulation 11
2.5 Total Quality Management in Pharmaceutical Industry 42
2.6 Six Sigma 45
3 Fourrts (India) Laboratories Private Limited 56
3.1 Introduction 56
3.2 Strategy 56
3.3 Marketing and Sales 57
3.4 Awards and Recognitions 58
4 International Business Division 59
4.1 Introduction 59
4.2 Strategy planning 59
4.3 Regulatory Affairs 60
4.4 Country wise Product requirements 60
4.5 Opportunities and Challenges 65
5 Quality Management System 66
5.1 Fourrts 66
5.2 Quality Policy 70
5.3 Quality Committee 70
5.4 Quality Assurance and Control 71
5.5 Documentation 72
5.6 Continual Improvement of Quality System 76
6 Discussion 78
6.1 Strengths 78
6.2 Weaknesses 78
6.3 Opportunities 79
6.4 Threats 79
6.5 Suggestions 79
7 Executive Summary and Conclusion 81
8 References 83
9 Check List 85
1 Organization of the Common Technical Document for the
Registration of Pharmaceuticals for Human Use
2 Home page of soft tool named ‘Elfin’ 63
3 Country specific product requirements – Model blank
4 Organization structure of Fourrts 69
1 Compounded Growth in Generics Market 6
2 Molecules Nearing Patent Expiry 8
3 Table of contents of Module 2,3,4,5 (Model) 37
ANDA - Abbreviated New Drug Application
ANOVA - Analysis of Variances
ASEAN - Association of South East Asian Nations
BP - British Pharmacopoeia
c GMP - Current Good Manufacturing Practice
CAGR - Compound Annual Growth Rate
CDSCO - Central Drugs Standard Control Organization
CIPIH - Commission on Intellectual Property Rights, Innovation and
Public Health
CRAMS - Contract Research and Manufacturing Services
CSIR - Council of Scientific and Industrial Research
CTD - Common Technical Document
CTQ - Critical To Quality
DMAIC - Define, Measure, Analyze, Improve and Control
DMF - Drug Master File
DOE - Design of Experiment
e CTD - Electronic Common Technical Document
EC - European Commission
EFPIA - European Federation of Pharmaceutical Industries and
EMEA - European Agency for the Evaluation of Medicinal Products
ERP - Enterprise Resource Planning
EU - European Union
EWG - Expert Working Groups
FMEA - Failure Mode and Effect Analysis
GLP - Good Laboratory Practice
GMP - Good Manufacturing Practice
GR&R - Gauge Repeatability and Reproducibility
ICDRA - International Conference of Drug Regulatory Authorities
ICH - International Conference of Harmonization
ICMJE - International Committee of Medical Journal Editors
IFPMA - International Federation of Pharmaceutical Industries and
INR - Indian Rupees
IP - Indian Pharmacopoeia
ISO - International Organization for Standardization
IT - Information Technology
LIMS - Laboratory Information Management System
NADT - National Authority on Drugs and Therapeutics
NDD - New Drug Development
NDDS - Novel Drug Delivery System
OTC - Over The Counter
PIC/S - The pharmaceutical Inspection Convention and
Pharmaceutical Inspection Cooperation Scheme
QMS - Quality Management System
R&D - Research and Development
SC - Steering Committee
SME - Subject Matter Experts
SOP - Stanadard Operating Procedure
SPC - Statistical Process Control
SWOT - Strengths, Weaknesses, Opportunities, Threats
TQM - Total Quality Management
UK - United Kingdom
UK-MHRA - United Kingdom - Medicines and Healthcare Regulatory
US - United States
- United States Food and Drug Administration
USP - United States Pharmacopoeia
WHO - World Health Organization
Driven by the knowledge, skills, growing enterprise, low costs,
improved quality and demand (domestic and international) the Indian
pharmaceuticals sector has witnessed a tremendous growth over the past few
years - from a turnover of INR 5000 crores in 1990 to over INR 50,000 crores
during 2004-05. Exports have also grown very significantly to over INR
16700 crores during this period. India is today recognized as one of the
leading global players in the manufacture of pharmaceuticals - it holds fourth
position in terms of volume and thirteenth in terms of value of production. It
is also recognized that the cost of drugs produced in India is amongst the
lowest in the world. It is estimated that by the year 2010 industry has the
potential to achieve INR 1, 00,000 crores in formulations with bulk drug
production going up from INR 8000 crores to INR 25,000 crores. India’s rich
human capital is believed to be the strongest asset for this knowledge-led
industry. Various studies show that the scientific talent pool of 4 million
Indians is the second largest English speaking group worldwide, after the US.1
Liberalization, Privatization and Globalization of the Indian economy
are posing new challenges for companies. As the borders are wider,
challenges becomes tighter, technologies spread faster than before and
Customers can easily gain knowledge on products worldwide and make
Comparisons between different options. In this electronic era companies
willing to survive need to search for new competitive advantages to prosper.
A modern quality management system can help a company in two ways in the
increased competition: customers equipped with enhanced information on the
market are likely to require best products and service than before and with
excellent quality a company can more easily differentiate from its
The new challenges of global economy are visible also in the
pharmaceutical industry. However, what makes pharmaceutical industry a
fascinating target for a study is that already the basic quality and regulatory
requirements are very high. Quality in the industry is regulated by many laws
and guidelines and governed by governments and different organizations.
Thus it is interesting to see how it is possible to build develop and maintain a
quality system further from this framework.
Fourrts is one of the leading players in the Indian Nutraceutical and
branded generic pharmaceutical industry having its headquarters in Chennai
and production unit near Chennai and customers around the world. Fourrts,
the pharmaceutical company in India is responsible for manufacturing and
marketing activities of finished Pharmaceutical formulations in India and
abroad. It provides an interesting base for study to see how a pharmaceutical
company from highly competitive market as India, selling to international
markets, is managing quality.
The scope of this dissertation work is to study the quality
management system pursued in Fourrts (India) Laboratories Private Limited,
an Indian Pharmaceutical Company.
To provide a background for the study we will first discuss the
varying guidelines, regulatory requirements and quality management in
pharmaceutical industry in general. Then we will go through the quality
system of Fourrts based on the interview and materials that we obtained from
Fourrts. In the next part we analyze the quality management pursued at
Fourrts and aim at giving suggestions for improvements. Finally in the
conclusion part we will present the main points and executive summary.
The objective of this dissertation work is to study the regulatory
aspects in the generic pharmaceutical industry and Total Quality Management
Initially we discuss Conventional quality systems, Guidance and
regulation and Total Quality Management in pharmaceutical industry in
general. Then we will study briefly about Fourrts, strategy, sales, and other
details, which will be followed by detailed study about International Business
Division, Strategy, Sales, Regulatory Affairs, Opportunities and Challenges.
After which we will go through the quality system of Fourrts in place.
Then with the detailed case history and exploratory research we will perform
SWOT – Strengths Weaknesses Opportunities and Threats analysis.
Finally we will summarize the case study and conclude with
suggestions if any.
Quality is not created spontaneously. It is inbuilt into design and
manufactured: It has its own sources. A somewhat elusive concept, quality is
difficult to define and easy to perceive. This combination of traits obscures
the study of factors that help to discover, produce, and distribute quality
products and services. Quality is not just the result of will. It requires systems
and processes to make it consistently viable.2
In today’s new business world, quality can no longer be just about
processes, products, services, or people. It must be about all four of these
things—together. In other words, our notions of quality need to be systemic
and strategic, not piecemeal, inconsistent, or erratic. Indeed, it is only with a
systemic and strategic quality framework in place that we will be able to
anticipate the future and build sustainable excellence in meeting customer
This section provides information about the traditional, regulationbased
quality systems used within pharmaceutical industry. Secondly, the
guidelines and regulations regarding quality management in pharmaceutical
industry are introduced. Also the approaches to harmonize this regulatory
base are discussed. Finally, this section discusses the status of Total Quality
Management within the industry.
Pharmaceutical industry is the challenging industry, where high
quality is more important than ever before in globalization environment. The
opening of the markets; global competition; technological advances; and the
increased cost awareness of the customers have all raised the level of
uncertainty. Also many countries and governments are serious about the
regulatory requirements against pharmaceutical companies and their products.
The soaring health-care costs have motivated governments to introduce
several measures to open up the competition. This has opened the way for
generic drug manufacturers and smaller pharmaceutical companies, which are
now making inroads to the markets.3
The generics industry is facing a period of unprecedented growth,
with $82billion worth of global blockbusters set to face US patent expiry by
end of this year 2007. The changing dynamics of the generics market are
driving strategic evolution of leading players, with portfolio management,
geographic expansion and alliance networks determining success and failure.
With cost-containment a focus for all healthcare players, the growth of the
generics market is outpacing the branded sector by a considerable margin.
However, the operating environment for generics is becoming increasingly
competitive pushing existing players further up the pharmaceutical value
chain. Brand and generics companies alike must be prepared for this new
competition. With 79.7% of 2003 blockbuster sales potentially exposed to
generic competition by 2010, equating to $103.7-billion worth of products at
2003 sales value, the growth opportunities in the generics sector are
significant. However, understanding how different country dynamics, shape
the competitive landscape is critical to evaluating risk and return.4
Effective portfolio management is critical to future success in the
generics market. Maintaining breadth of portfolio and low cost supply is
critical for commodity generics players, forcing many players to evaluate
higher value generic sectors, thus generating new competitors to brand
pharma. In the US, the generic injectables sector retains high barriers to entry,
but in Europe, competitive analysis suggests that the market place is more
crowded. As such, injectable products may represent a less valuable
proposition to European generics players than US analysis would suggest.4
Commodity generics have low barriers of entry and low margins of
profits due to competitive pricing, while specialty and super-generic drugs are
reformulations of off-patent drugs and have higher margins.Crucial to
generics companies' strategies in the US is the use of Paragraph IV patent
challenges to gain lucrative market exclusivity periods. Being the first to
market a new generic drug makes for exceptionally attractive market share
and profit margins. However, these profits are short-lived, thanks to rival
launches coming at the end of the exclusivity period. This means generic
companies must continually launch new products to maintain their margins.4
Table 1: Compounded Growth in Generics Markets
Country Generics market (CAGR)
Worldwide 10%
Japan 4.8%
Rest of America 9.7%
Western Europe 10.5%
United States 11.8%
Others 9.3%
Source: Frost & Sullivan
The US Generics Market
In 2003, the US pharmaceutical gel formulations market for offpatent
molecules was valued at around $66-billion and generics accounted for
$15.7-billion, up 8.1% over the previous year. This component is likely to
grow at a compound annual growth rate (CAGR) of 11.8% to reach pi
$34.5-billion in 2010. Total savings from generic prescriptions in the US is
estimated at $39.30-billion; this is expected to grow by 6.7% per year, on an
average, to reach $61.97-billion in 2010.4
Opportunity for India
The Indian pharma industry will continue to grow at an accelerated
pace by seizing greater share of the fast growing global generics market. The
industry is expected to significantly boost its share of the generics market on
the back of its expertise in process engineering and its low cost advantage.
The global generics market is growing significantly, and drugs worth $70-
billion are likely to go off patent by 2008. Indian companies are expected to
grab around 30% share of the increasing generic market in the future.4
US is the world's largest market for generics, and with some of the
blockbuster drugs likely to go off-patent in the near future and increasing
preference for generics by managed care organizations, the US generics
market and, therefore, the global generic pharmaceuticals market is expected
to grow at a rate higher than the global pharmaceuticals industry. The
generics market offers immense opportunities to the developing countries like
India, where the cost of production is low and quality manpower is readily
available. Many Indian companies continue to aggressively file Abbreviated
New Drug Applications (ANDAs) in the US and have good track record of
receiving approval for the same.4
Increasing Focus on R&D
Major Indian companies are increasingly focusing on research and
development (R&D). The R&D activities of Indian companies are targeted
both at New Drug Development (NDD) as well as Novel Drug Delivery
Systems (NODS). The R&D expenditure of leading Indian pharmaceutical
companies has jumped significantly to cross Rs. 10,000 million during recent
past. 4
Table 2: Molecules Nearing Patent Expiry
Brand Generic Manufacturer Patent Expiration
Alocril nedocromil Allergan April 2, 2007
Imitrex sumatriptan GlaxoSmithKline June 28, 2007
Geodon ziprasidone Pfizer September 2, 2007
Coreg carvedilol GlaxoSmithKline September 5, 2007
Meridia sibutramine Abbott December 11, 2007
Mavik trandolapril Abbott Laboratories December 12, 2007
Tequin gatifloxacin GlaxoSmithKline December 25, 2007
Zyrtec cetirizine Pfizer December 25, 2007
Fosamax alendronate Merck February 6, 2008
Camptosar irinotecan Pfizer February 20, 2008
Effexor/XR venlafaxine Wyeth June 13, 2008
Zymar gatifloxacin Allergan June 25, 2008
Dovonex calcipotriene
Squibb June 29, 2008
Kytril granisetron Roche June 29, 2008
Risperdal risperidone Janssen June 29, 2008
July 29, 2008
Brand Generic Manufacturer Patent Expiration
fluticasone and
salmeterol GlaxoSmithKline August 12, 2008
Serevent salmeterol GlaxoSmithKline August 12, 2008
Casodex bicalutamide
Squibb October 1, 2008
Trusopt dorzolamide Merck October 28, 2008
Zerit stavudine
Squibb December 24, 2008
Lamictal lamotrigine GlaxoSmithKline January 22, 2009
Vexol rimexolone Alcon Labs January 22, 2009
Avandia rosiglitazone GlaxoSmithKline February 28, 2009
Topamax topiramate Johnson & Johnson March 26, 2009
Glyset miglitol Pfizer July 27, 2009
tromethamine Allergan November 5, 2009
Xenical orlistat Roche December 18, 2009
Valtrex valacyclovir GlaxoSmithKline December 23, 2009
Avelox moxifloxacin Bayer December 30, 2009
Source: Express Scripts 2004 Drug Trend Report
CRAMS - another Big Opportunity
Indian pharma industry, particularly small and medium size drug
units, is increasingly looking at contract manufacturing as one of the best
survival options in the product patent regime. Domestic pharma companies
who do not have the strength to establish their own brands and compete with
the leading players in the industry are likely to grab the contract
manufacturing opportunities. Several MNCs are also exploring the possibility
of outsourcing drugs at various stages of production, including the finished
dosages, to these companies. Indian pharma companies can leverage their
strength in terms of low cost of production and availability of quality
manpower to grab a greater share of global research spends leading to
sustainable and significant growth for the industry in foreseeable future.
Indian production costs are almost 50% less compared to developed countries.
In view of this cost advantage, domestic companies have additional business
opportunity to become contract manufacturers for global MNCs. Also, low
clinical trial costs and easy availability of patients for clinical trials, will
encourage the global pharma players to conduct clinical trials in India.4
Contract Manufacturing
Indian pharma companies are eying the US generic drug market with
pharma manufacturers filing drug master files (DMF) with the US Food and
Drug Administration (USFDA). The cost of setting up an FDA approved plant
in India is almost half of that in the USA. With the government now allowing
100% FOI, many foreign companies are planning to outsource the
manufacture of their off patent drugs to Indian companies and concentrate
more in the development of new products. For Indian companies, this is an
area of large potential. Indian companies have already started capitalizing on
this opportunity. Indian companies have the strengths - world-class plants and
formidable chemical synthesis skills - to compete in the generic markets.
Even though competition will be intense in global generic markets that hold a
lot of promise, Indian companies have the capability to succeed in this space.4
Regulation plays an important role in pharmaceutical industry.
Deviation from specification has severe consequences, so an effective quality
control and assurance system is mandatory. Traditional quality standards
combine the knowledge of experts from the industry, pharmacopoeial
authorities, regulatory agencies and academia. The standards are based on
experience and the need to promote the safety of the products for the sake of
patients’ health.3
These traditional quality systems need to be validated. Validation of
processes and equipment is used to check that the quality systems work as
planned. Validation can be done through two types of audits: internal audits
and external audits. Internal audits are carried out by an organisation on its
own systems, procedures and facilities. Companies need to carry out external
audits on its vendors or subcontractors.3
This section will lay attention on important institutions, which
regulate or guide the Indian pharmaceutical industry in designing their quality
2.4.1 Good manufacturing practice (GMP)
Good Manufacturing Practices are a legal codification of sound
quality principles, that have been used by the pharmaceutical and healthcare
manufacturing industries for over 50 years as a means of assuring that
products have the identity, strength, purity and quality that they purport to
contain. Good Manufacturing Practices are in effect in over 100 countries,
and GMP compliance is a pre-requisite to exporting pharmaceuticals between
countries. Traditionally pharmaceutical companies have built their quality
systems around GMP.3
Good Manufacturing Practices are the part of quality assurance that
ensures that drugs are consistently produced and controlled in such a way to
meet the quality standards appropriate to their intended use, as required by the
marketing authorization.
Its aim is to minimize risks that cannot be eliminated through testing
the final product.5 Quality Control is a part of GMP and it includes the tests,
inspections and measurements carried out before, during and after
manufacturing to assure that a finished product meet its specification.3 It is
vital that unexpected contamination of the products, incorrect labels on
containers or insufficient amount or too much active ingredient do not occur.
Pharmaceutical products with poor quality can be hazardous for the end user.
They are also causing increased costs for both governments and individuals.5
At the moment there is no GMP that would be used by every
manufacturer globally. WHO has established one GMP standard, many
countries have established their own GMPs based on WHO’s equivalent.
Some areas, like the European Union and the Association of South East Asian
Nations (ASEAN) have harmonized their requirements regionally. Most
countries only accept import and sales of medicines that have been
manufactured to internationally recognized Good Manufacturing Practices.5
Good Manufacturing Practices are intended to assure that:
• Raw materials used in the manufacture of drugs are of known
and of possibly standardized, quality and are free from
• The manufacturing process has been proven to produce a
pharmaceutical product meeting its quality attributes;
Adequate quality control testing measures have been employed to
assure that the product meets its quality specifications at time of release to
market, and at the end of its shelf life.
2.4.2 WHO (World Health Organization)
As already stated above, WHO has developed its own GMP, which is
functioning as a basis for international harmonization. WHO is also involved
in the pharmaceutical industry and the quality of pharmaceutical products in
other ways. It organizes many activities, events, programmes, reports and
news directed toward this industry. WHO has established a policy that defines
essential medicines and drugs and aims at guaranteeing their availability with
assured quality and information and with affordable prices. WHO has also
established a Commission on Intellectual Property Rights, Innovation and
Public Health (CIPIH) that is supposed to provide an analysis on intellectual
property rights, innovation and public health taking especially account the
view point of developing countries.5
World Health Organization (WHO) Certification Scheme
This is based on the recognition that a comprehensive system of
quality assurance must be based on a reliable system of product licenses and
independent analysis of the finished product as well as on an assurance
obtained through independent inspection that all manufacturing operations are
carried out in conformity with accepted norms, referred to as Good
Manufacturing Practice (GMP). In 1969, the World Health Assembly
endorsed requirements for "Good Practices in the Manufacture and Quality
Control of Drugs" which are subsequently known as "GMP as recommended
by WHO". These have subsequently been revised in 1975 and in 1990 and are
fully consonant with those operative within the countries participating in the
PIC Convention and other major industrialized countries. They provide the
basis for the WHO Certification Scheme which requires "each participating
Member State, upon application by a commercially interested party, to attest
to the competent authority of another participating Member State that:
• a specific product is authorized to be placed on the market
within its jurisdiction or, if it is not this authorized, the reason
why that authorization has not been accorded;
• the plant in which it is produced is subject to inspections at
suitable intervals to establish that the manufacturer conforms to
GMP as recommended by WHO; and
• all submitted product information, including labelling, is
currently authorized in the certifying country."
A Member State may opt to participate solely to control the import
of pharmaceutical products and substances or a Member State may also use
the Scheme to support the export of pharmaceutical products. In the latter
case, the WHO Scheme states that the Member State "should first satisfy itself
that it possesses:
• An effective national licensing system, not only for
pharmaceutical products, but also for the responsible
manufacturers and distributors;
• GMP requirements, consonant with those recommended by
WHO, to which all manufacturers of finished pharmaceutical
products are required to conform;
• Effective controls to monitor the quality of pharmaceutical
products registered or manufactured within the country,
including access to an independent quality control authority;
• A national pharmaceuticals inspectorate, operating as an arm of
the national drug regulatory authority, and having the technical
competence, experience and resources to assess whether GMP
or other controls are being effectively implemented, and the
legal power to conduct appropriate investigations to ensure that
manufacturers conform to these requirements by, for example,
examining premises and records and taking samples;
• the administrative capacity to issue the required certificates, to
institute inquiries in the case of complaint, and to notify
expeditiously both WHO and the competent authority in any
Member State known to have imported a specific product that is
subsequently associated with a potentially serious quality defect
or other hazard."
The WHO Scheme goes on to state that "Each Member State assumes
the responsibility to determine, by self-evaluation, whether it satisfies these
prerequisites. The Scheme contains no provision, under any circumstance, for
external inspection or assessment, either of a competent national authority or
of a manufacturing facility." This is the central element of the WHO
Certification Scheme which differs significantly from the approach adopted
by PIC and PIC/S or by the MRAs which require joint inspections to build
confidence that the other State has an equivalent standard of inspection
Three documents can be requested under the WHO Certification Scheme
• Certificate of a Pharmaceutical Product. This is intended for
use by the competent authority within an importing country in
two situations:
• when the product in question is under consideration for a
product license that will authorize its importation and sale;
• when administrative action is required to renew, extend, vary or
review such a license.
The product license holder or other commercially interested party in
the exporting country (the applicant) should submit the following information
for each product:
• the name and dosage form;
• the name and the amount of active ingredient(s) per unit dose;
• the name and address of the product-license holder and/or
manufacturing facility;
• the formula (the complete qualitative composition including all
excipients); this is particularly important when no product
license exists or when the formulation differs from that of the
licensed product;
• product information for medical professionals and for the public
(patient information leaflets) as approved in the exporting
The certificate is a confidential document and as such, it can be
issued by the competent authority in the exporting authority only with the
permission of the applicant and, if different, the product license holder.
• Statement of Licensing Status. This attests only that a license
has been issued for a specified product, or products, for use in
the exporting country. It is intended for use by importing agents
when considering bids made in response to an international
tender. It is only intended to facilitate the screening and
preparation of information.
• Batch Certificate of a Pharmaceutical Product. This is
normally issued by the manufacturer for an individual batch of a
pharmaceutical product and only exceptionally as in the case of
vaccines, sera and certain other biological products, by the
competent authority of the exporting country. The batch
certificate is intended to accompany and provide an attestation
concerning the quality and expiry date of a specific batch or
consignment of a product that has already been licensed in the
importing country. The WHO Scheme makes it clear that "when
the applicant is the manufacturer of the finished dosage form,
the certifying authority should satisfy itself, before attesting
compliance with GMP, that the applicant:
a) applies identical standards to the production of all batches of
pharmaceutical products manufactured within the facility,
including those destined exclusively for export;
(b) consents, in the event of identification of a quality
relevant inspection reports being released, in confidence, to
the competent authority in the country of import, should the
latter so require."
It is clear that the value of the WHO Certification Scheme is in that it
provides a guideline as to what States should endeavour to do. The aim,
however, should be for States to achieve regulatory schemes that are
equivalent and are recognized as such through Mutual Recognition
Agreements involving joint inspections, joint training and the updating of
documents in both States ensuring that equivalence is maintained.5
2.4.3 US FDA (United States Food and Drug Administration)
US FDA has been accepted the world over as the model regulatory
agency in terms of its standards and efficiency. Even the FDA, prior to 1962
had no requirements for establishing safety standards before applying for the
first human use. It was only after the recommendations of the Kefauver-Harris
Committee as a sequel to the thalidomide tragedy, which maimed over 10,000
babies after the mothers had taken the sedative marketed by Chemie
Gruenthal that safety data and Investigational New Drug Applications became
mandatory. The FDA has not only the responsibility for approving new drugs;
it also has to clear the use of generic versions of patented drugs. The
legislation, which is an important component of this exercise, is the Hatch-
Waxman Act of 1984, which stipulates the conditions for approval of an
Abbreviated New Drug Application (ANDA). The Act provides for
exclusivity in the market for the first generic manufacturer if it survives the
so-called Para IV filing and has no infringement suit against it from the patent
holder. Post marketing surveillance of the drug even after it has been
marketed is yet another responsibility of the FDA.6
2.4.4 UK – MHRA (United Kingdom – Medicines and Healthcare
Regulatory Agency)
In the UK, the authority responsible for approval of new drugs and
ensuring safety and efficacy of medicines and medical devices rests with the
Medicines and Healthcare Products Regulatory Agency (MHRA). The
committee on safety of medicines established under the Medicines Act
advises the UK licensing authority on all aspects of the new product including
assessing its safety and efficacy profiles.6
2.4.5 EMEA (European Agency for the Evaluation of Medicinal
Although pharmaceutical policy is primarily determined at the
national level by individual EU member states, there is nevertheless a
considerable amount of relevant legislation at the EU level. The European
Commission (EC) has an expanding role in this area, with the legal duty to
advocate and reinforce the principles of European law, including the free
movement of goods and undistorted competition. Hence, the European
Commission’s executive competence to launch policy initiatives and
ultimately propose binding rules has encompassed three areas: (i) national
prices, profit, and reimbursement, rational use and advertising; (ii) free
movement and competition issues; and (iii) market access through
harmonization and eventual centralized authorization procedures through the
European Agency for the Evaluation of Medicinal Products (EMEA). The
members of the European Union are given the facility to submit for approval
of new drugs, to a centralized agency, which has two members from each of
the member countries. The recommendations are then considered and
approved or rejected by the regulatory agency of each member country.7
2.4.6 Drug Regulatory Mechanism in India
India has a well defined Drugs and Cosmetics Act 1940 (and rules
1945) on which the regulatory mechanism for all activities of the Indian
pharmaceutical industry is based. Considering the rapidly evolving global
developments in the area, the Government had appointed a committee under
the chairmanship of Dr R A Mashelkar to recommend measures to revamp
and modernize the regulatory set-up in the country and evolve a viable and
effective system to ensure the availability of quality medicines at affordable
costs to the masses. The recommendations of the committee are under the
active consideration of the government.
Various areas affecting the production and distribution of healthcare
products, which have been left outside the purview of the Drugs and
Cosmetics Act (1940) will be brought under the ambit of the new regulatory
frame work. These include OTC drugs, biotechnology-based products, food
additives and nutraceuticals, products of the Indian systems of medicine,
various diagnostic and prophylactic agents and medical devices.
The evolving scenario in India is conducive to the growth of this
industry on all fronts from R&D to production and marketing in domestic and
international markets. With the advent of the product patent regime under the
Indian Patents Act 2005, patented products can be manufactured and/or
marketed in India only by the patent holder or his licensee.
This development has encouraged the setting-up by the top dozen
companies R&D activities that cater to the discovery and development of new
drugs. The new regulatory standards and other legislative measures should
encourage investments by the pharmaceutical industry into this important
activity and become a global player in this vital area. Hopefully all legislative
measures, regulatory control systems and guidelines will help the Indian
pharmaceutical industry achieve even greater heights in the global arena in the
coming years.6
Drug regulatory system has a close bearing on the prices, availability
and quality of drugs. Under the Drugs and Cosmetics Act, 1940 there is dual
regulatory control over the drugs by Central and State governments. While
regulation of manufacture, sale and distribution of drugs is primarily the
responsibility of the State Authorities, the Central Authorities are responsible
for approval of new drugs, clinical trials, laying down standards for drugs,
control over imported drugs, coordination of the activities of state drug
control organizations. The Expert Committee set up by Government under the
chairmanship of Dr R A Mashelkar, Director CSIR in its report submitted in
2003 has made comprehensive recommendations for strengthening the drug
regulatory system including the problem of spurious drugs. It has made
detailed recommendations to strengthen the existing regulatory organizations
both at the Centre and the States. The Task Force set up by Government to
‘Explore Options other than Price control for achieving the objective of
making available life saving drugs at reasonable level’ has recommended that
in the long run both the functions of drug regulation and price control should
be performed by the same agency and there should be an integrated regulatory
Keeping in view the recommendations of the two Committees it has
been decided that –
a) As an immediate step an independent and autonomous body by
the name of National Drug Authority would be constituted in
place of the present Central Drugs Standard Control
Organization (CDSCO).
b) Several of the existing provisions of the Drugs and Cosmetics
Act, 1940 would be amended to make the penalties more
deterrent for various offences and in particular for spurious and
sub-standard drugs. A bill in this regard has been introduced in
the Parliament
c) In the long run the proposal of Task Force regarding merger of
National Pharmaceutical Pricing Authority and NDA would be
considered in the form of National Authority on Drugs and
Therapeutics (NADT) which will lead to an integrated
regulatory system in the country.1
2.4.7 International approaches to harmonize the quality guidelines International Conference of Harmonization (ICH)
ICH alias The International Conference of Harmonization of
Technical Requirements for Registration of Pharmaceuticals for Human Use
is a unique project that brings together the regulatory authorities of Europe,
Japan and the United States and experts from the pharmaceutical industry in
the three regions to discuss scientific and technical aspects of product
The purpose is to make recommendations on ways to achieve greater
harmonization in the interpretation and application of technical guidelines and
requirements for product registration in order to reduce or obviate the need to
duplicate the testing carried out during the research and development of new
The objective of such harmonization is a more economical use of
human, animal and material resources, and the elimination of unnecessary
delay in the global development and availability of new medicines whilst
maintaining safeguards on quality, safety and efficacy, and regulatory
obligations to protect public health. This Mission is embodied in the Terms of
Reference of ICH.8 History and Future of ICH (A brief History of ICH)
The Need to Harmonize
The history of medicinal product registration, in much of the
industrialized world, has followed a similar pattern which could be described
as: Initiation, Acceleration, Rationalization and Harmonization.
The realization that it was important to have an independent
evaluation of medicinal products before they are allowed on the market was
reached at different times in different regions. In the United States a tragic
mistake in the formulation of a children's syrup in the 1930s was the trigger
for setting up the product authorization system under the Food and Drug
Administration. In Japan, government regulations requiring all medicinal
products to be registered for sale started in the 1950s. In many countries in
Europe the trigger was the thalidomide tragedy of the 1960s, which revealed
that the new generation of synthetic drugs, which were revolutionizing
medicine at the time, had the potential to harm as well as heal.
For most countries, whether or not they had initiated product
registration controls earlier, the 1960s and 1970s saw a rapid increase in laws,
regulations and guidelines for reporting and evaluating the data on safety,
quality and efficacy of new medicinal products. The industry, at the time, was
becoming more international and seeking new global markets, but the
registration of medicines remained a national responsibility. Although
different regulatory systems were based on the same fundamental obligations
to evaluate the quality, safety and efficacy, the detailed technical requirements
had diverged over time to such an extent that industry found it necessary to
duplicate many time-consuming and expensive test procedures, in order to
market new products, internationally.8
The urgent need to rationalize and harmonize regulation was impelled
by concerns over rising costs of health care, escalation of the cost of R&D
and the need to meet the public expectation that there should be a minimum of
delay in making safe and efficacious new treatments available to patients in
Initiation of ICH
Harmonization of regulatory requirements was pioneered by the
European Community, in the 1980s, as the EC (now the European Union)
moved towards the development of a single market for pharmaceuticals. The
success achieved in Europe demonstrated that harmonization was feasible. At
the same time there were bilateral discussions between Europe, Japan and the
US on possibilities for harmonization. It was, however, at the WHO
Conference of Drug Regulatory Authorities (ICDRA), in Paris, in 1989, that
specific plans for action began to materialize. Soon afterwards, the authorities
approached IFPMA to discuss a joint regulatory-industry initiative on
international harmonization, and ICH was conceived.
The birth of ICH took place at a meeting in April 1990, hosted by the
EFPIA in Brussels. Representatives of the regulatory agencies and industry
associations of Europe, Japan and the USA met, primarily, to plan an
International Conference but the meeting also discussed the wider
implications and terms of reference of ICH. The ICH Steering Committee
which was established at that meeting has since met at least twice a year, with
the location rotating between the three regions. 8
The Early Meetings
At the first SC meeting of ICH the Terms of Reference were agreed
and it was decided that the Topics selected for harmonization would be
divided into Safety, Quality and Efficacy to reflect the three criteria which are
the basis for approving and authorizing new medicinal products. It was also
agreed that six-party Expert Working Groups (EWGs) should be set up to
discuss scientific and technical aspects of each harmonization Topic. Eleven
such Topics were selected for discussion at the First International Conference
on Harmonization.
The "pattern" of ICH work was also established in those early
Steering Committee meetings, that is, that the EWGs meet in the same week
as the Steering Committee and report on their progress to the Committee.8
Commitment and Process
Key factors in the success of ICH have been the commitment of the
parties to the objectives and outcome of ICH and the development of the
"ICH Process" for developing harmonized guidance on technical issues. The
commitment to ICH was set out in a Steering Committee Statement from the
meeting in Tokyo, October 1990.
The ICH "Process" was first drawn up at the Steering Committee
meeting in Washington, March 1992 and amended in Tokyo, September
1992. The defined process with "decision points" at Step 2 and Step 4 has
enabled the Steering Committee to monitor the progress of the topics selected
for harmonization.8
The ICH process comprises some five stages:
a. Development of consensus: Preliminary discussions are held by
an Expert Working Group with representatives from the six co-sponsors of
ICH. A preliminary draft is prepared (guideline, policy statement,
recommendation, points to consider) and when consensus is reached
forwarded to the ICH Steering Committee.
b. Consensus text released for consultation: The draft after
acceptance by the ICH Steering Committee is sent to the three regulatory
agencies for formal consultation using their normal internal and external
consultation processes.
c. Consideration of comments from consultation: Comments
obtained are exchanged between the regulatory agencies and the draft is
amended in the light of the comments. When significant changes result, the
revised draft may be recirculated for further consultation. The eventual
revised draft is then sent to the ICH Steering Committee for adoption.
d. ICH guideline finalized: The final draft is discussed by the
Steering Committee and "signed off" by the three regulatory parties to the
ICH. It is then recommended to the three regulatory bodies for adoption.
e. Implementation: The process is complete when the full
recommendations are incorporated into domestic regulations or other
appropriate administrative measures. This process has been applied to a range
of topics grouped under the headings of safety, quality, efficacy and
multidisciplinary. At the Fourth ICH Conference in Brussels in July 1997, it
was agreed that ICH should move into a second phase of harmonization in
which work would commence on harmonizing the format and content of the
documentation to be used in seeking product licenses. This was seen as the
next logical step following reaching agreement on technical guidelines for
generating the data required for submissions for product licenses. The ICH
estimate that the work of achieving consensus on a common technical
document for product license applications will take about 2 years from the
first meeting of the expert groups in February 1998. In addition, the ICH is
now also addressing the preparation of a document on Good Manufacturing
Practice on Active Pharmaceutical Ingredients which will take forward the
PIC/S document through consultations with industry representatives and
result in an ICH document. Thus ICH has now moved into a second phase
with a continuing commitment to increased international harmonization aimed
at ensuring that good quality, safe and effective medicines are developed in
the most expeditious and cost effective manner.8
The Parties cosponsoring this Conference, represented at the 2nd
Steering Committee Meeting in Tokyo, 23-24 October 1990 re-affirmed their
commitment to increased international harmonization, aimed at ensuring that
good quality, safe and effective medicines are developed and registered in the
most efficient and cost-effective manner. These activities are pursued in the
interest of the consumer and public health, to prevent unnecessary duplication
of clinical trials in humans and to minimize the use of animal testing without
compromising the regulatory obligations of safety and effectiveness.
This Conference will provide a unique opportunity for regulators and
industry to reach consensus on the steps needed to achieve this objective
through greater harmonization of technical requirements and to set out
practical and realistic targets for harmonizing requirements where significant
obstacles to drug development and the regulatory process have been
Recognizing the substantial progress which has already been made in
achieving harmonization within Europe and through bilateral contacts
between Europe, Japan, USA and other regions, the Conference will seek to
make further progress through a trilateral approach, with clearly defined
priorities, methods of work and recommendations to both industry and
regulatory authorities.
Whilst the Conference will be an important step forward, it is not
seen as an end in itself, but as a stage in a developing process, at a high level,
between regulators and industry.8
Format of Applications
The Steering Committee has given priority to harmonizing the
technical content of the sections of the reporting data where significant
differences have been identified between regulatory requirements across the
three regions: Europe, Japan and the USA. The first ICH Guideline to deal
with harmonizing the format of reporting data was E3, Content and Format of
Clinical Study Reports. This Guideline describes a single format for reporting
the core clinical studies that make up the clinical section of a registration
A target for the first phase of ICH activities was to remove
redundancy and duplication in the development and review process, such that
a single set of data could be generated to demonstrate the quality, safety and
efficacy of a new medicinal product. The long-term goal of developing a
harmonized format has led to the creation of the ICH Guideline M4, The
Common Technical Document (CTD). The CTD provides a harmonized
format and content for new product applications. ICH achieved Step 4 status
of the CTD at the ICH5 Conference in San Diego, California, in November
2000. The agreed upon implementation date for the CTD, in the three regions,
was July 2003.
The Electronic Common Technical Document (eCTD) was developed
subsequently by the M2 Expert Working Group. This specification document
allows for the electronic submission of the CTD from applicant to regulator
and provides a harmonized technical solution to implementing the CTD
electronically. The eCTD has begun to be implemented across the ICH
partner and observer regions.8 Common Technical Document (CTD & eCTD)
A common and well-structured format for the technical
documentation will significantly reduce the time and resources needed to
compile applications for registration of human pharmaceuticals and will ease
the preparation of electronic submissions. Regulatory reviews and
communication with the applicant will be facilitated by a standard document
of common elements. In addition, exchange of regulatory information
between Regulatory Authorities will be simplified.
Through the ICH process, considerable harmonization has been
achieved among the three regions in the technical requirements for the
registration of pharmaceuticals for human use. However, until now, there has
been no harmonization of the organization of the registration documents.
Each region has its own requirements for the organization of the technical
reports in the submission and for the preparation of the summaries and tables.
In Japan, the applicants must prepare the GAIYO, which organises
and presents a summary of the technical information. In Europe, Expert
Reports and tabulated summaries are required, and written summaries are
recommended. The U.S. FDA has guidance regarding the format and content
of the New Drug Application. To avoid the need to generate and compile
different registration dossiers, this guideline describes a format for the
Common Technical Document that will be acceptable in all three regions.8
Throughout the Common Technical Document, the display of
information should be unambiguous and transparent, in order to facilitate the
review of the basic data and to help a reviewer become quickly oriented to the
application contents. Text and tables should be prepared using margins that
allow the document to be printed on both A4 paper (E.U. and Japan) and 8.5 x
11” paper (U.S.). The left-hand margin should be sufficiently large that
information is not obscured by the method of binding. Font sizes for text and
tables should be of a style and size that are large enough to be easily legible,
even after photocopying. Times New Roman, 12-point font, is recommended
for narrative text. Every page should be numbered, according to the
granularity document. Acronyms and abbreviations should be defined the
first time they are used in each module. References should be cited in
accordance with the current edition of the Uniform Requirements for
Manuscripts Submitted to Biomedical Journals, International Committee of
Medical Journal Editors (ICMJE).
The Common Technical Document is organized into five modules.
Module 1 is region specific. Modules 2, 3, 4, and 5 are intended to be
common for all regions. Conformance with this guideline should ensure that
these four modules are provided in a format acceptable to the regulatory
Module 1. Administrative Information and Prescribing Information
This module should contain documents specific to each region; for
example, application forms or the proposed label for use in the region. The
content and format of this module can be specified by the relevant regulatory
Module 2. Common Technical Document Summaries
Module 2 should begin with a general introduction to the
pharmaceutical, including its pharmacologic class, mode of action, and
proposed clinical use. In general, the Introduction should not exceed one
Module 2 should contain 7 sections in the following order:
• CTD Table of Contents
• CTD Introduction
• Quality Overall Summary
• Nonclinical Overview
• Clinical Overview
• Nonclinical Written and Tabulated Summaries
• Clinical Summary
The organization of these summaries is described in Guidelines for
M4Q, M4S, and M4E.
Module 3. Quality
Information on Quality should be presented in the structured format
described in Guideline M4Q.
Module 4. Nonclinical Study Reports
The nonclinical study reports should be presented in the order
described in Guideline M4S.
Module 5. Clinical Study Reports
The human study reports and related information should be presented
in the order described in Guideline M4E.
The overall organization of the Common Technical Document is
presented on the following pages.
Figure 1. Organization of the common technical document for the
registration of pharmaceuticals for human use
Module 1
Nonclinical Written
and Tabulated
Module 3
3.1 T of C
Module 4
Study Reports
4.1 T of C
Module 5
Study Reports
5.1 T of C
1.1 Submission
T of C
CTD Table of Contents
CTD Introduction
Not part of the CTD
Module 2
Module 1: Administrative Information and Prescribing Information
1.1 Table of Contents of the Submission Including Module 1
1.2 Documents Specific to Each Region (for example, application
forms, prescribing information)
Module 2: Common Technical Document Summaries
2.1 Common Technical Document Table of Contents
(Modules 2-5)
2.2 CTD Introduction
2.3 Quality Overall Summary
2.4 Nonclinical Overview
2.5 Clinical Overview
2.6 Nonclinical Written and Tabulated Summaries
2.7 Clinical Summary
Biopharmaceutic Studies and Associated Analytical Methods
Clinical Pharmacology Studies
Clinical Efficacy
Clinical Safety
Literature References
Synopses of Individual Studies
Module 3: Quality
3.1 Table of Contents of Module 3
3.2 Body of Data
3.3 Literature References
Module 4: Nonclinical Study Reports
4.1 Table of Contents of Module 4
4.2 Study Reports
4.3 Literature References
Module 5: Clinical Study Reports
5.1 Table of Contents of Module 5
5.2 Tabular Listing of All Clinical Studies
5.3 Clinical Study Reports
5.4 Literature References
Definition of a Document
A document is defined for a paper submission as a set of pages,
numbered sequentially and divided from other documents by a tab (see
Document Pagination and Segregation section of this Annex). A document
can be equated to a file for an electronic submission. The granularity of the
paper and electronic submissions should be equivalent, although if a paper
submission is updated to be an electronic submission, some changes in
granularity could be introduced to facilitate on-going lifecycle management.
In an electronic submission, a new file starts at the same point at which in a
paper submission, a tab divides the documents. In deciding whether one or
more documents or files are appropriate, it should be considered that once a
particular approach has been adopted, the same approach should be used
throughout the life of the dossier since it is the intention that replacement
documents/files be provided when information is changed.9
Document Pagination and Segregation
Every document should be numbered starting at page one, except for
individual literature references, where the existing journal page numbering is
considered sufficient. Applicants need not display the number as '1 of n'
where n is the total number of pages in the document.
Additionally, all pages of a document should include a unique header
or footer that briefly identifies its subject matter. In a paper-based drug
submission, a similar identifier should be used on a tab that precedes the
document, to facilitate finding that document within the dossier. An
abbreviation of the full section number and title can be used.
If a section contains more than one document, a specific Table of
Contents for that section can be included to identify the chronology and titles
of the documents contained therein, e.g.
• Tab with “3.2.S.4.2 Analytical Procedures”
o Table of Contents, listing the title of Procedure A, Procedure
B, Procedure C
• Tab with “3.2.S.4.2 “Procedure A”;
o Procedure A (i.e. document, page 1-n)
• Tab with “3.2.S.4.2 “Procedure B”;
o Procedure B (i.e. document, page 1-n)
• Tab with “3.2.S.4.2 “Procedure C”;
o Procedure C (i.e. document, page 1-n)
If a section contains only a single document (e.g. 3.2.S.1.1
Nomenclature), only a tab identified by “3.2.S.1.1 Nomenclature” should
precede the document.9
Section Numbering within Documents
In order to avoid 5th, 6th etc. level subheading numbering (e.g. within a document, the applicant can use a shortened numbering
string. In this case, the document number and the name (e.g. 2.6.6
Toxicology Written Summary) should appear in page headers or footers and
then section numbering within the document can be used, for example, 1, 1.1,
2, 3, 3.1, 3.2 etc. Use of the full numbering string (e.g. is also
considered acceptable.9
Table 3: Table of contents of module 2,3,4,5 (Model)
Module 2
2.1 Overall CTD Table of Contents of Modules 2, 3, 4, and 5
2.3 Quality overall summary
2.3.S.1 General Information
2.3.S.2 Manufacture
2.3.S.3 Characterization
2.3.S.4 Control of Drug Substance
2.3.S.5 Reference Standards or Materials
2.3.S.6 Container Closure System
2.3.S.7 Stability
Module 2 (Contd.)
2.3.P.1 Description and Composition of the Drug Product
2.3.P.2 Pharmaceutical Development
2.3.P.3 Manufacture
2.3.P.4 Control of Excipients
2.3.P.5 Control of Drug Product
2.3.P.6 Reference Standards or Materials
2.3.P.7 Container Closure System
2.3.P.8 Stability
2.3.A Appendices
2.3.A.1 Facilities and Equipment
2.3.A.2 Adventitious Agents Safety Evaluation
2.3.A.3 Novel Excipients
2.4.1 Overview of the Nonclinical Testing Strategy
2.4.2 Pharmacology
2.4.3 Pharmacokinetics
2.4.4 Toxicology
2.4.5 Integrated Overview and Conclusions
2.4.6 List of Literature Citations
2.5.1 Product Development Rationale
2.5.2 Overview of Biopharmaceutics
2.5.3 Overview of Clinical Pharmacology
2.5.4 Overview of Efficacy
2.5.5 Overview of Safety
2.5.6 Benefits and Risks Conclusions
2.5.7 References
Module 2 (Contd.)
2.6 Content of non clinical written AND Tabulated summaries
2.6.1 Introduction
2.6.2 Pharmacology Written Summary
2.6.3 Pharmacology Tabulated Summary (Appendix B)
2.6.4 Pharmacokinetics Written Summary
2.6.5 Pharmacokinetics Tabulated Summary (Appendix B)
2.6.6 Toxicology Written Summary
2.6.7 Toxicology Tabulated Summary (Appendix B)
2.7.1 Summary of Biopharmaceutics and Associated Analytical
2.7.2 Summary of Clinical Pharmacology Studies
2.7.3 Summary of Clinical Efficacy
2.7.4 Summary of Clinical Safety
2.7.5 References
2.7.6 Synopses of Individual Studies
Module 3
3.2.S.1 General Information
3.2.S.2 Manufacture
3.2.S.3 Characterization
3.2.S.4 Control of Drug Substance
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability
Module 3 (Cont.)
3.2.P.1 Description and Composition of the Drug Product
3.2.P.2 Pharmaceutical Development
3.2.P.3 Manufacture
3.2.P.4 Control of Excipients
3.2.P.5 Control of Drug Product
3.2.P.6 Reference Standards or Materials
3.2.P.7 Container Closure System
3.2.P.8 Stability
3.2.A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation
3.2.A.3 Novel Excipients
Module 4
4.2.1 Pharmacology
4.2.2 Pharmacokinetics
4.2.3 Toxicology
5.3.1 Reports of Biopharmaceutic Studies
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.4 Reports of Human Pharmacodynamic (PD) Studies
5.3.5 Reports of Efficacy and Safety Studies
5.3.6 Reports of Post-Marketing Experience
5.3.7 Case Report Forms and Individual Patient Listings
5.4 LITERATURE REFERENCES International Pharmacopoeia
Pharmacopoeia is a book that comprises information, specification on
the dosages and the composition of drugs. There are many national versions
of it, for example the Indian Pharmacopoeia (IP) US Pharmacopoeia (USP)
and UK British Pharmacopoeia (BP).
The idea of International Pharmacopoeia was born as early as 1874,
when the need for the unification of terminology and of the strength and
composition of drugs was recognized. Its first edition was published in two
volumes in years 1951 and 1955 and supplemented in 1959. International
Pharmacopoeia includes a collection of recommended procedures for analysis
and specifications for the determination of pharmaceutical substances,
excipients and dosage forms. The book is supposed to act as a source for any
of its Member States wishing to establish pharmaceutical requirements.5
41 PIC/S (The pharmaceutical Inspection Convention and
Pharmaceutical Inspection Cooperation Scheme)
The pharmaceutical Inspection Convention and Pharmaceutical
Inspection Cooperation Scheme are jointly referred as PIC/S. PIC’s mission is
“to lead the international development, implementation maintenance of
harmonized Good Manufacturing Practise (GMP) standards and quality
systems of inspectorates in the fields of medicinal industry”.
This is supposed to be done by developing and promoting
harmonized GMP standards, training authorities, assessing inspectorates and
facilitating the cooperation and networking of authorities and organizations.10
ISO 8402 Defines Total Quality Management as a “ Management
approach of an organization centered on quality, based on the participation of
all its members and aiming at long term success through customer satisfaction
and benefits to all members of the organization and society”. However more
importantly when one is looking into the future, TQM is “An evolving system
of practices, tools, and training methods being developed by industry, for
creating higher quality products and services for increased customer
satisfaction, in a rapidly changing world” TQM can be said to be a
sociological experiment on the track to a new management paradigm.
British Quality Association (1989) defined TQM as follows: TQM is
a corporate business management philosophy which recognizes that customer
needs and business goals are inseparable. It is appropriate within both
industry and commerce.
TQM ensures maximum effectiveness and efficiency within a business
and secures commercial leadership by putting in place processes and systems
which will promote excellence and prevent errors. It ensures that every aspect
of the business is aligned to the customer needs and the advancement of
business goals without duplication or waste of efforts. The commitment to
TQM originates at the chief executive level in a business and is promoted in
all human activities. The accomplishment of quality is thus achieved by
personal involvement and accountability, devoted to a continuous
improvement process, with measurable level of performance by all concerned.
It involves every department, function and process in a business and the
active commitment of all employees to meeting customer needs. In this regard
the customer of each employee are separately and individually identified.11
Indian Statistical Institute, Hyderabad in its training document
defined TQM as follows: “TQM is an integrated organizational approach in
delighting customers (both internal and external) by meeting their
expectations on a continuous basis through everyone involved with the
organization working on continuous improvement in all products, services,
and processes along with proper problem - solving methodology.”
Total Quality Management (TQM), is thus an ongoing journey of
continuous measurable improvements, championed by empowered
individuals at all levels of the organization. The organizational leadership
inspires teamwork and a sincere ‘trust and belief’ in people, which results in
an enjoyable and productive work place, dedicated to the highest possible
level of customer satisfaction.11
The key issues in TQM are Continuous improvements, Customer
orientation and empowered employees. Literature on the popularity of Total
Quality Management (TQM), or other quality management principles is
scarce, but some insights can be gained from Rodney Mc Adam and Nigel
Barron, 2002. The paper presents 11 mini-case studies of quality systems used
by the customer companies of a clinical trials organization. These mini-case
studies clearly showed that pharmaceutical companies often do not have a
clearly stated quality policy/manual, but they, nevertheless, have established
Quality Departments within their organizations. These quality departments
are seen as an essential part of each organization’s quality strategy. The
organizations studied based their quality systems on the following Principles:
• Total Quality Management (TQM)
• Good Manufacturing Practice (GMP)
• Good Laboratory Practice (GLP)
• Standard Operating Procedures (SOPs)
• ISO 9000.
GMP compliancy was regarded critical in the pharmaceutical
industry, but there is a strong interest in TQM principles. The organizations in
this case gave several reasons for implementing TQM. Most common ones
mentioned were:
• Satisfy customer demand
• To improve competitiveness in a changing environment
• Improve standards and product quality
• Improve efficiency/reduce waste
• Utilize/maximize all resources for continuous improvement
Overall, TQM was introduced in response to the recent changes in the
competitive environment. During the transition to TQM pharmaceutical
companies have faced similar difficulties in implementing the system as
companies in other industries.3
Six Sigma is a process solving methodology based on statistics aimed
at reducing variation in a process to 3.4 defects per million defect
opportunities. The main goal is continuous improvement.11 It has the ability to
detect critical underlining variables that lead to lost revenue, failure to meet
customer expectations and finally exposing a company’s “Hidden Factory”.
To convert practical problem into a statistical problem, generate a
statistical solution and then convert that back into a practical solution, Six
Sigma uses the DMAIC process. DMAIC is an acronym for Define, Measure,
Analyze, Improve, and Control. DMAIC defines projects goals and
deliverables to meet customer’s expectations, obtains a baseline of the
performance of the process, determines the root cause (s) of the defects,
develops steps for the elimination or reduction of defects and instills control
the performance of the process. After DMAIC circle it is time to define a new
The benefits of Six Sigma include clear value proposition and return on
investment, top commitment and accountability, customer focus, business
metrics, process orientation, project focus, and a complete culture change that
evolves in systematic approach to problem solving and a pro-active attitude
among employees.
Pharmaceutical companies today face increasing demands to
demonstrate continuous revenue growth, a growing demand from the public
to control the rising cost of therapeutics and increasing demand from
regulatory agencies such as United States Food and Drug Administration to
prove they (the company) understand their manufacturing processes. To meet
these challenges companies who adopt Six Sigma programs are able to
improve their profit margins and well as developing an intimate
understanding of their process.
The true challenge of a pharmaceutical company is deciding whether
or not to challenge the status quo and expose their “Hidden Factory” by
implementing a Six Sigma program. This requires a long-term commitment
from senior management and the ability to assess their current capability and
needs. After implementing a Six Sigma program a company is able to sustain
the program by ensuring the program simple to use, allowing employees to be
innovative, provide motivation, and ensuring that the process is speedy.
Six Sigma does not promise to be the Panacea for all the company’s
problems. It is however, a powerful tool that directly impacts on process
improvements and a potentially provides huge financial return on a business
bottom line.
Focus on Causes of Variation
One of the key strengths of Six Sigma is that it is a process
improvement methodology that is based on statistics. For example in a
manufacturer setting there are subject matter experts (SME) who’s functions
include addressing manufacturing issues. Quite often their most common
issue is defective products, how to minimize these and still meet deadlines
and customer expectations. Since production is always seemingly under
pressure to meet deadlines the SME is forced to initiate a fix or series of fixes
that deal with reoccurring issues. The resulting pressure usually forces the
SME to make decisions based on limited information or gut feelings. The end
result is a series of band aid solutions to reoccurring variances in production
that have never been addressed properly and continue to periodically produce
defective products.
To ensure that decisions are made properly to deal with underlying
variance Six Sigma uses statistics to justify changes. From the Six Sigma
view, a process is normally represented in terms of Y=f(X’s), in which the
Outputs (Y) are determined by some Input variables (X’s). Initially we ask
“What are the possible causes (X’s) that may influence the outcome Y?”.
Once we believe we have a list of potential X’s we start collecting and
analyzing data using Six Sigma testing tools. When able to isolate which X(s)
have the greatest impact on the output we initiate controls. The benefits
become immediately apparent:
Ø We gain greater knowledge about the process so we can now
begin to predict outcomes based on critical inputs.
Ø The focus then shifts towards identifying and controlling the
causes rather than checking the outcomes. Otherwise, we have
to focus our effort on Non Value-Added Activities such as
inspection, tests and rework.
Exposing the “Hidden Factory”
When studying variation in the name of process improvement you are
exposing the “Hidden Factory”. You are uncovering the rework and cover
ups, the hours and days of wasted time in a company of people who
constantly correct mistakes. Every time a corrective action is taken or a
machine is rerun, or a warranty claim is processes, you are incurring
unnecessary rework. When you accept these events as “that just the way it is”,
you have mentally hidden all these activities from your improvement
The Hidden Factory is one runs in the back ground of every
organization. It is the factory that fixes problems, corrects mistakes and
otherwise wastes both time and money a company’s two most precious
commodities. Six Sigma exposes the Hidden Factory and returns time and
money back to the company.
When a researching Six Sigma you will mostly find references for
manufacturing. But in a larger sense Six Sigma focuses on improving
processes and it can be applied to any aspect of a business such as:
Ø Improve on-time-delivery;
Ø Reduce cycle time for hiring and training new employees;
Ø Improve sales forecasting ability;
Ø Reduce quality or delivery problems with suppliers;
Ø Improve logistics and quality of customer service.
Six Sigma is a versatile tool that can be used to improve any process
within an organization while developing best practices.
Key to Six Sigma
Six Sigma strength is its ability to turn a practical problem into a
statistical problem, generate a statistical solution and then convert that back
into a practical solution. How is this accomplished a person may ask. By
using what is called DMAIC process. DMAIC is an acronym for Define,
Measure, Analyze, Improve, and Control. Once again the best description was
from a paper entitled “Introduction to Six Sigma” published by Mekong
Capital Ltd.12
The biggest advantages of DMAIC probably boil down to these seven
items: Measuring the problem, Focusing on the customer, Verifying root
cause, Breaking old habits, Managing risks, Measuring results, Sustaining
Define (D)
The purpose of the Define phase is to clearly identify the problem, the
requirements of the project and the objectives of the project. The objectives of
the project should focus on critical issues which are aligned with the
company’s business strategy and the customer’s requirements. The Define
phase includes:
• define customer requirements as they relate to this project.
Explicit customer requirements are called Critical-to-Quality
(CTQ) characteristics;
• develop defect definitions as precisely as possible;
• perform a baseline study (a general measure of the level of
performance before the improvement project commences);
• create a team charter and Champion;
• estimate the financial impact of the problem; and
• obtain senior management approval of the project
The most applicable tools at this phase are the following:
• Project Charter - this document is intended to clearly describe
problems, defect definitions, team information and deliverables
for a proposed project and to obtain agreement from key
• Trend Chart - to see (visually) the trend of defect occurrence
over a period of time.
• Pareto Chart - to see (visually) how critical each input is in
contributing negatively or positively to total output or defects.
• Process Flow Chart - to understand how the current process
functions and the flow of steps in current process.
Measure (M)
The purpose of the Measure phase is to fully understand the current
performance by identifying how to best measure current performance and to
start measuring it. The measurements used should be useful and relevant to
identifying and measuring the source of variation. This phase includes:
• identify the specific performance requirements of relevant
Critical-to-Quality (CTQ) characteristics;
• map relevant processes with identified Inputs and Outputs so
that at each process step, the relevant Outputs and all the
potential Inputs (X) that might impact each Output are
connected to each other;
• generate list of potential measurements
• analyze measurement system capability and establish process
capability baseline;
• identify where errors in measurements can occur;
• start measuring the inputs, processes and outputs and collecting
the data;
• validate that the problem exists based on the measurements;
• refine the problem or objective (from the Analysis phase)
The most applicable tools at this phase include the following:
• Fishbone Diagram – to demonstrate the relationships between
inputs and outputs
• Process Mapping - to understand the current processes and
enable the team to define the hidden causes of waste.
• Cause & Effect Matrix - to quantify how significant each input
is for causing variation of outputs.
• preliminary Failure Mode & Effect Analysis (FMEA) - using
this in the Measure phase helps to identify and implement
obvious fixes in order to reduce defects and save costs as soon
as possible.
• Gauge Repeatability & Reproducibility (GR&R) - used to
analyze the variation of components of measurement systems so
minimize any unreliability in the measurement systems.
Analyze (A)
In the Analyze phase, the measurements collected in the Measure
phase are analyzed so that hypotheses about the root causes of variations in
the measurements can be generated and the hypothesis subsequently
validated. It is at this stage that practical business problems are turned into
statistical problems and analyzed as statistical problems.
This includes:
• generate hypotheses about possible root causes of variation and
potential critical Inputs (X’s);
• identify the vital few root causes and critical inputs that have the
most significant impact; and
• validate these hypotheses by performing Multivariate analysis.
The Analyze phase offers specific statistical methods and tools to
isolate the key factors that are critical for a comprehensive understanding of
the causes of defects:
• Five Why’s - use this tool to understand the root causes of
defects in a process or product, and to penetrate through
incorrect assumptions about causes.
• Tests for normality (Descriptive Statistics, Histograms)
– this is used to determine if the collected data is normal or
abnormal so as to be properly analyzed by other tools.
• Correlation/Regression Analysis - to identify the relationship
between process inputs and outputs or the correlation between
two different sets of variables.
• Analysis of Variances (ANOVA) - this is an inferential
statistical technique designed to test for significance of the
differences among two or more sample means.
• FMEA (Failure Mode and Effect Analysis) - applying this
tool on current processes enables identification of sufficient
improvement actions to prevent defects from occurring.
• Hypothesis testing methods - these are series of tests in order
to identify sources of variability using historical or current data
and to provide objective solutions to questions which are
traditionally answered subjectively.
Improve (I)
The Improve phase focuses on developing ideas to remove root
causes of variation, testing and standardizing those solutions. This involves:
• identify ways to remove causes of variation;
• verify critical Inputs;
• discover relationships between variables;
• establish operating tolerances which are the upper and lower
specification limits (the engineering or customer requirement)
of a process for judging acceptability of a particular
characteristic, and if strictly followed will result in defect-free
products or services;
• Optimize critical Inputs or reconfigure the relevant process.
The most applicable tools at this phase are:
• Process Mapping - this tool helps to represent the new process
subsequent to the improvements.
• Process Capability Analysis - in order to test the capability of
process after improvement actions have been implemented to
ensure we have obtained a real improvement in preventing
• DOE (Design of Experiment) - This is a planned set of tests to
define the optimum settings to obtain the desired output and
validate improvements.
Control (C)
The Control phase aims to establish standard measures to maintain
performance and to correct problems as needed, including problems with the
measurement system.
This includes:
• validate measurement systems;
• verify process long-term capability;
• implement process control with control plan to ensure that the
same problems don’t reoccur by continually monitoring the
processes that create the products or services.
Most applicable tools at the Control phase include:
• Control Plans -this is a single document or set of documents
that documents the actions, including schedules and
responsibilities that are needed to control the key process inputs
variables at the optimal settings.
• Operating Flow Chart(s) with Control Points - this is a single
chart or series of charts that visually display the new operating
• Statistical Process Control (SPC) charts - these are charts that
help to track processes by plotting data over time between lower
and upper specification limits with a center line.
• Check Sheets - this tool enables systematic recording and
compilation of data from historical sources, or observations as
they happen, so that patterns and trends can be clearly detected
and shown.14
The aim of this chapter is to introduce Fourrts (India) Laboratories.
The chapter begins with a short introduction to the company, after which
information about the strategy, the sales of Fourrts (India) Laboratories is
provided with various Awards and Recognitions received by the organization
Fourrts is a vital player in the Indian Nurtraceutical and Branded
Generic pharmaceutical market. The company’s vision is to be an
international pharmaceutical organization of repute known for quality &
ethics and to serve the ailing patients across the world through innovative
Fourrts is headquartered in Chennai and it operates currently in more
than 30 countries and it has about 1,000 employees. Fourrts has a
manufacturing facility complying with cGMP requirements in a pollution free
environment outskirts to Chennai.16
Fourrts has a clearly stated strategy. It aims to develop and produce
affordable high-quality generic pharmaceuticals and market them ahead of the
competition to become a leading company in formulation development,
manufacturing, marketing and sales of quality generic pharmaceuticals in the
domestic and international markets.
Fourrts has been able to launch several Nutraceutical products as a
first-mover to the market. Fourrts also actively extends its product portfolio
and international presence.
Fourrts main activities are in manufacturing and marketing of generic
pharmaceutical products for human use. Besides this the company also
produces Nutraceutical and Herbomineral formulations for domestic and
export markets. Fourrts is committed to its marketing philosophy and
delivering its responsibility to the society through innovation. Fourrts has
been the pioneer of Nutraceuticals in India and has launched many innovative
products. Fourrts has a team of marketing professionals committed to take
Fourrts to greater heights.16
Fourrts international business division offers a wide range of products
in Generics and Branded generics. The future focus will be on the newer
molecules in Anti Diabetics, Cardiovascular, Anti Malarials and
The range of products sold in international business might vary from
area to area but generally customers require a broad variety of generic
products. Among Fourrts customers are wholesalers, pharmacies, medical
practitioners, health authorities, International procurement agencies,
Importers. All Products are sold under the company’s own brand name and
certain products are out sourced to meet market demand.
Fourrts is the recipient of the following awards and recognitions:
Table 4: Awards and Recognitions16
S.No. Name of Award Year
1. Quality Excellence awards from Indian Drug
Manufacturer’s Association
1986, 1987, 1996,
2002, 2003 and
2. Award for prompt and reliable supply to Tamil
Nadu Medical Service Corporation
3. Managerial excellence Awards from Madras
Management Association
June 2002
4. Express Pharma Pulse Award for excellence April 2003
5. Recognition of the in-house R & D facility from
Department of Science and Industrial Research,
Government of India
September 2003
6. 5 S par excellence performance Award with 5 star
rating from Quality Circle forum of India
September 2006
Fourrts international business division has operations in over 30
countries after facing stringent audits and obtaining necessary approvals.
Fourrts has a well structured team consisting of business development,
regulatory and commercial activity specialists with excellent knowledge about
individual and special needs of every country. Fourrts has cherished long
standing relationship with all business associates globally. To strengthen
promotional activities young and energetic product management team has
been formed recently with a vision to build global brands in existing as well
as new markets.
Any company that aspires to industry leadership in the 21st century
must think in terms of global, not domestic, market leadership. The world
economy is globalizing at an accelerating pace as countries previously closed
to foreign companies open up their markets, as the internet shrinks the
importance of geographic distance, and as ambitious growth-minded
companies race to build stronger competitive positions in the markets of more
and more countries. Companies in industries that are already globally
competitive or in the process of becoming so are under the gun to come up
with a strategy for competing successfully in foreign markets.17 Fourrts
business model based on corporate ethics with the core strength of
experienced and competent regulatory expertise having registered more than
120 products around 30 countries. 16Fourrts decided to explore international
markets and plans are in place to enter regulated markets.
Globally, the pharmaceutical and medical device regulatory affairs
profession has undergone tremendous change in the past decade. The
profession has gone from having a liaising and documentation function to a
profession which has an important strategic and decision-making role within
companies. In today’s global context, regulatory affairs professionals are
involved in regulatory strategy development and project management
functions. In the Indian context regulatory affairs professionals have three
clear roles. First, they are responsible for liaising with the regulatory
authorities with regard to approval applications and other types of license
/permit requests. They are also responsible for all in-house regulatory
documentation. Finally, they have an advisory role with regard to providing
information on country specific regulations. Most pharmaceutical companies
have so far seen the profession as having mainly a liaison role for regulatory
authorities for regulatory applications and permissions. 18
There is between–country variation and within-country variability in
the time required to process registration of a pharmaceutical product. Most of
the countries where Fourrts exports its products are semi regulated markets.
Most of the semi regulated markets prescribe product registration as a
mandatory requirement for generic as well as branded products for which
companies must submit product registration application/dossier. The
harmonized requirements of a product registration application are previously
discussed under CTD & eCTD.
As we discussed earlier the regulatory requirements are unique and
different for each county in the semi regulated market scenario. Each country
has their own regulations prescribed by concerned authorities. Following case
study will explain the same in brief.
Case study: Regulatory Authority of Zambia prescribed a specific
labeling requirement of storage condition as “Store below 25oC” along with
the method of sale and product license number be embossed on the primary
and secondary packing materials.
Regulatory authority of Sri Lanka prescribed storage condition as
“Store below 30oC” be embossed on packing material. In French speaking
West African countries dual language (English and French) text is mandatory
in primary and secondary packing materials.
This results in separate inventory of packing materials for a single
product to meet with regulatory requirements of a single country. This leads
to product wise unique packing materials for each country. We can assume
the quantity of packing materials and amount of possibility of error for a
company having registered more than 120 products around 30 countries. To
facilitate tracking of country wise product requirements a soft tool named
ELFIN has been designed as a part of this dissertation.
4.4.1 ELFIN
To ensure quality and comply with the regulatory requirements a user
friendly soft tool in Microsoft Excel named ELFIN has been created as a part
of this dissertation.
E stands for the French word élaborer which means elaborate
L stands for the French word logiciel which means software tool
FIN stands for Fourrts (India) Laboratories Private Limited.
The soft tool has a home page consisting of the countries where
Fourrts export its products. Each country has a separate sheet which
comprises of all the relevant information and packing material codes needed
to ensure compliance of country wise product requirements. All individual
country sheets has been connected with home page by hyperlink. The same
tool can be included in quality management system, updated and circulated to
various internal departments of Fourrts in a pre specified interval by quality
department in the future if needed.
User Instructions for Elfin
1. Double click on the excel file to open the tool.
3. Home page will appear with list of countries
4. Click on the relevant country which leads you to a specific
country page.
5. Identify a product with its Trade/ Generic name to know
technical specifications / Packing material codes / Registration
6. Click the hyperlink named home in Top left corner to reach the
home page / sheet consist list of countries.
The benefits of our soft tool are as follows:
Ø User friendly
Ø Click away solution to country specific requirements.
Ø Helps to achieve zero defects of country requirements.
Ø Change control is possible.
Ø Global regulatory status tracking facility is possible.
Ø Provides data for country wise Product requirements.
Ø Provides name and complete address of the customer.
Ø Specification and description check is possible.
The home page and a model country specific sheet has been
illustrated below for reference where as the tool has been enclosed as an
annexure to this report in a Compact disk.
Image 2: Home page of soft tool named ‘Elfin’
PNA --- PHARMACIE NATIONAL D'APPROVISIONNEMENT, Route du service Geographique, BP 4015, DAKAR HANN, SENEGAL,Tél : +221 - 859 50 72 / 859 50 66 Fax : +221 - 832 32 25 / 859 50 71 - E-mail :
Name of the
Brand Name)
Artwork code Date of
Date of
Date of
Printed Remarks
Printed film/Foil
Label PIL
Catch cover
/ Calender
Tube Sleeves Shipper
Image 3: Country specific product requirements - Model blank sheet
6 5
The emerging global market place for generic pharmaceutical
products assure great future where as the regulatory requirements of various
countries are stringent and tremendous. Generics will have a huge demand,
with needs from developing world to be addressed.
The pharmaceutical industry will have its ups and downs, like any
other industry. The only weak link for Indian companies has been market
access to the US. To complete the value chain, Indian companies have been
forming partnerships with US firms, acquiring US companies, or setting up
marketing subsidiaries. Many Indian companies today are active in the US
either on their own or through their partners. Fourrts International Division
has gained the confidence of associates globally. After consolidating the
business in developing countries and with experience in formulation
development, technical documentation and marketing operations, Fourrts is
set to enter the highly regulated markets of Canada, USA, Australia and
Europe. 16
This section covers the different aspects of quality management
system practiced in Fourrts. Firstly it introduces manufacturing unit of
Fourrts. After this the Quality Committee, Quality Assurance and control,
documentation process will be introduced. Final part of the chapter discusses
how and by whom the quality management system is currently developed.
The information provided in this chapter is based on Fourrts Site Master File
and other materials.
Fourrts manufacturing unit is the case analysis unit for this project. It
is a private limited company which possesses own manufacturing facility.
Fourrts was founded in 1977 under the name of Fourrts Laboratories, which
had been manufacturing pharmaceutical products since 1977.
Fourrts (India) Laboratories Private Limited incorporated as a
commercial establishment in 1979. New Own Manufacturing Plant was
commissioned complying with WHO - GMP requirements in 1985 and
Fourrts obtained Independent Manufacturing License to Manufacture
Pharmaceutical products in 1985 (License number 427 in form 25 and
License number 235 in form 28 which requires periodic renewal with a
validity period of 5 years from the date of issue for which earlier validity
renewal period was two years only.
The overall intention and directions of Fourrts regarding quality is
formally expressed and authorized by the Chairman and Managing Director in
the Quality Policy. In Fourrts, the formulations are manufactured as per the
standards prescribed by the Drugs Control Authorities, Pharmacopoeia and
the existing statutory framework in the country.19
The Chairman and Managing Director, Director Operation and
departments of Finance & Systems, Marketing, Sales, International Business,
Distribution, Human Resource & Administration and Materials operate in the
Corporate Office at Okkiyam Thoraipakkam, Chennai. 19
The location of Manufacturing facility is on the Vandalur road in
Kelambakkam which is about 25 kilometer from Chennai. The factory
building is surrounded by asphalt roads on all sides further surrounded by
vacant land on the east, west and north. Thus the surrounding is free from
unsanitary environment, objectionable odour and pollutants. The site is spread
over an area of about 4 acres and enclosed by concrete wall raised to a height
of 8 feet. The built up area is about 11500 square meters. 19
Fourrts employs a work force of 551 employees excluding field force.
The break up is given below:
Production - 325
Quality Control and Assurance - 40
Research and Development - 09
Material Stores - 53
Maintenance - 35
Finance - 16
Human Resource and General Administration - 23
Materials - 05
International Business - 10
Marketing - 35
Production, Material stores and Quality Control and Assurance are the
largest divisions measured by the number of employees. Other divisions are
supporting functions and, therefore, considerably smaller. Most of the key
personnel, especially within quality control and quality assurance are
Production is a big part of the activities of Fourrts and it employs
about half of the human resources. Fourrts has only one production site which
consists of Quality Control and Laboratory located in Chennai. Fourrts is
currently streamlining its production and searching for ways to better
performance and profitability; also there is a plan to commission a new
manufacturing plant with state- of-the-art facility in the near future. Majority
of the production is exported now but when the company was founded it
operated mainly on domestic market. The production range consists of circa
200 products, including Tablets, Capsules, Syrups and Creams/ Gels/ Pastes,
where the prominence is on the first two domains.
Image 4: Organization Structure of Fourrts (Source: Fourrts Site Master File)
7 0
Earlier chapters stated the importance of high quality in the
pharmaceutical industry. Lack of quality may trash the company’s reputation
forever and, Fourrts has therefore high requirements on quality, efficiency and
safety of products. Fourrts states in its Quality Policy that they commit to
deliver pharmaceutical formulations that effectively benefit patients for their
intended therapeutic purposes. This means that the company does its best to
assure the quality of its products and give its customers the best service
available. This will be achieved by, ensuring use of right quality ingredients,
care for proper packaging and comply with good practices and by creating an
environment that encourages all employees and suppliers for continual
improvement of all processes.19 The quality control system at Fourrts is built
on cGMP, Pharmacopoeia and guidelines from ICH, PIC/S and WHO.
Quality committee, which is headed by the Chairman & Managing
Director, supervises the whole quality management system of Fourrts. Its
members include managers of Quality control, Human Resources and
Production; department managers of Quality Assurance, Production and
Production manager and Director of Fourrts. Management representative is
the coordinator for the quality committee.
Quality Management System (QMS)
Fourrts has developed a quality management system as per ISO
9001:2000 requirements. To avoid multiplicity of systems Fourrts included
requirements of GMP – Schedule M of drugs and cosmetics rules in the
quality management system itself.
The scope of the quality management system is as follows:
The factory at Vandalur - Kelambakkam road at Kelambakkam –
603103, Kancheepuram district and Corporate office at Fourrts avenue, Annai
Indira Nagar, Okkiyam Thoraipakkam, Chennai – 600097 are the two
locations that form the organization. The organization is engaged in product
development, Manufacture, Marketing and distribution of pharmaceutical
formulations against IP/BP/USP and In-house standards. The process of
Marketing & Sales, Product Development, Purchasing, Production,
International Business, Projects, Maintenance, Human Resources,
Administration, Product Preservation, Quality Assurance and Quality Control
are addressed in the quality management system.19
Quality Control department is responsible for all testing related to
raw material, packing material, in-process, bulk and finished products. The
responsibility of quality control and quality assurance also includes
preparation of specifications, calibration and verification of all measuring and
monitoring devices in quality control and maintenance of reference
substances, preparation of working standards and real time stability studies of
finished products and maintaining reference samples. The responsibility of
quality assurance includes compliance of regulatory and GMP requirements,
Batch records authorization, review and retention, product release, line
inspection, monitoring hygiene and sanitation, approval of all quality related
documents, stability monitoring of products in the market, control of
outsourced testing and control of artworks. Quality Assurance is responsible
for the validation as per master validation plan.19
Quality Assurance department handles administrative functions of
quality management system of Fourrts. In other words, the department is
responsible for organizing the quality management functions and controlling
that the system operates effectively. The department is responsible for
reviewing and approving the validation protocols and it issues and keeps
records of Standard Operating Procedures. Quality Assurance department
organizes the documentation of the quality system. The editing, issuing and
maintaining Site Master File form a part of Quality Assurance department’s
The documentation of quality management system is in 3 levels as
Level A – quality manual specifying the quality management system
of the organization including statements of quality policy and quality
objectives. This is a requirement of 4.2.2 of the standard ISO 9001:2000. This
quality manual specifies the organization’s quality management system
including scope of quality management system, exclusions from the
requirements of the standard and a description of interactions between the
Level B – Procedures required in the standard called as quality
system procedures. The six quality system procedures are namely, control of
documents, control of records, corrective action, preventive action, internal
audit and control of non conforming products.
Level C – all other documents including records needed to ensure
effective planning, operation and control of the processes in the
organization’s quality management system.20
Quality system procedure is available for the control of documents and
this procedure covers activities of documents approval for adequacy prior to
use, document legibility and identification, updating and re-approval,
identification of changes and revision status, control of distribution,
identification and control of external origin documents, withdrawal of
obsolete documents and control of retained obsolete documents. All the
controlled documents in Fourrts are prepared using BLISS QSYSTEMS
software. Documentation system ensures that only approved and legible,
applicable documents of current versions are available at points of use and
that any use of obsolete document is precluded.
The Fourrts Quality Manual consists of a policy, and has about 40
process documents, around 140 Standard Operation Procedures and about 250
work instructions. The types of documents include specifications, Master lists,
Master Formula Records, Batch Manufacturing Records and Forms. More
than 50 processes are identified and included in the quality management
The manufacturing site has its own Site Master File, which includes
information about organization, personnel, facilities, documentation,
production etc. It basically contains all relevant information on the site in
question. Site Master File is updated frequently, at least once a year. On the
whole, the Quality Assurance department is strongly involved in determining
the quality procedures and guidelines for Fourrts.
Management Representative has a vital role in managing quality
systems in Fourrts efficiently by organizing management review meetings,
internal audits and customer feedback meeting in a specified interval and he
has been assigned responsibility and authority to: Establish, implement and
maintain documented quality management system as per 9001:2000, Report
on the effectiveness of the quality system to the management for review and
Ensuring the promotion of awareness of customer requirements throught the
organization and Liaise with external organizations / parties pertaining to
quality management system.20 The quality assurance manager has the
responsibility of the self-inspection system of Fourrts. This system monitors
all processes, documents, records, premises and equipment that are related to
the safety and quality of the products. The results of the inspection is
documented and put forward to the concerned institutions. If corrective
actions are needed a timeframe for these actions are set and the institution are
responsible for it to be done. It is also the quality assurance department who is
responsible to take care of and help external auditors with their work. The
purpose of employee training programs in Fourrts is to develop new skills that
complement employee’s job responsibilities and sharpen existing skills for
better productivity.19
Fourrts has set procedures for handling documents that concern
manufacturing and quality control. A hard copy of all such documents is
stored digitally on a validated computer system and in a physical format. The
physical copy need to be authorized, signed, by a responsible person in the
Quality Control department, to be used in production. If the original
document needs editing the process is iterated, but the original physical
document is still in the archive of the Quality Control department. All the
documents in Fourrts follow a standard format and they have clear standard
operating procedures on how to make them. Before releasing materials or
products for further distribution a quality control specialist goes through the
documentation to check that all documentation criteria are covered. These
records are retained for four years or one year after the date of expiry
whichever is high. (Ref: FIQA/SOP/09)20
5.5.1 Qualified Persons
In order to produce pharmaceuticals Fourrts needs to have qualified
persons. These are highly skilled certified employees, who basically are
responsible for that the batch is produced according to the WHO guidelines of
GMP. Qualified persons evaluate and sign documentation of each batch in
order to ship it out. They check that all the reports and records from
manufacturing and Quality Control laboratory are included and they meet the
requirements. An internal SOP regulates the final approval procedure. The
Qualified Person is in principle personally responsible for each batch he has
shipped out. All quality related data regarding released finished products is
kept by the quality control and assurance department. The control procedures
and records are partly computerized. The department handles the approval of
manufacturing masters and raw material specifications. It is also the quality
assurance department, who handles complaints and recalls.
5.5.2 Handling of complaints and product recalls
Fourrts have written procedures for handling complaints and recalls.
It is the quality assurance manager, who is responsible for handling these
circumstances. When a complaint reaches Fourrts, it is sent to the quality
Assurance department. Complaints received from any source are initially
documented and directed to the right person(s).
Quality assurance investigates the customer complaint to identify the
cause and necessary corrective action is taken to prevent the recurrence.
When a complaint pertains to hazard to patients, it is decided to recall the
concerned batch, subject to approval from Chairman and Managing
Director.19 The customer is always contacted when the complaint is worked
Even though the quality management system is based on regulation it
does not mean that it would not need updating. The Quality Committee of
Fourrts is responsible for improving the quality system of Fourrts. However,
the initiative for improvements can come from Group level as well. Besides
giving recommendations and initiating projects, the Group level also puts
restrictions on major decisions relating to Quality System. The achieved small
improvements and break through improvements incorporated in the quality
management system.
Top management, during each management review, identify needs for
changes for processes, products and quality management system, fix
responsibilities and time frame for realizing the changes and thus facilitates
continual improvement. 20
5.6.1 IT Systems
The operating system is NOVELL version 4.0. The local area
network has 35 nodes on Windows 98/2000/XP operating system and
application software to make it user friendly. The system is department wise
right protected.
IT systems are one major area for improvement. The major application
software in use is ‘Pharma Protocol 2000’ and is used for inventory
management and control.19 No sophisticated software is used in laboratory for
calibration and validation. The situation in laboratory is about to improve,
when the implementation of Laboratory Information Management System
LIMS system is completed. Most versions of LIMS allow the laboratory to
register work requests; print analytical worksheets; monitor and communicate
sample / technique backlogs; schedule work; acquire and store analytical data;
monitor the quality of all analytical work; approve analytical data for client
release; protect the security of all data; track and locate samples in storage;
track and communicate all quality control in the laboratory etc.
At the moment most of the laboratory documents are only in paper
form, but Fourrts hopes that eventually LIMS will enable it to run a paperless
laboratory in the near future. Fourrts started implementation of Enterprise
Resource Planning (ERP) for which the installation of software is in process.
Improving software systems is expensive and, therefore team members of
fourrts need to give utmost care and effort to implement new software.
The discussion chapter provides firstly SWOT analysis of the current
status quality management system in Fourrts. Secondly, the chapter discusses
the suggestions for improving the weaknesses.
The quality system that Fourrts is using is very thorough. Because of
all the regulations, e.g. the GMP – Schedule M of drugs and cosmetics rules,
it manages quality aspect for every part of the production. The use of SOPs
eliminates many mistakes and ensures that the processes are operated as per
the requirement of the quality management system. Fourrts employs educated
personnel who aware about the quality management system and practices the
system religiously. It is easier to implement quality system changes and new
IT systems in such an environment.
The quality management system is as per ISO 9001:2000 standards
mainly ensuring the quality of the products and systems of the company.
Fourrts does not monitor the changes in the quality performance to a great
extent. Great opportunities are there to utilize statistical quality control
techniques in many processes of manufacturing activities as well as in other
domains. The frequent change in regulatory requirements of various semi
regulated countries affects the quality management system significantly.
Fourrts has grown rapidly in the later years, which gives big
opportunity for Fourrts to utilize the best knowledge of the best employees in
the manufacturing site. Fourrts is putting resources into providing new
software (ERP). This enables the company to allocate resources into data
collection and enable more monitoring of quality. This is a big opportunity to
harmonize the values and view of quality and the corporation in general. A
common corporate culture will make the whole group pull the company in the
right direction and it can give synergetic effects in different areas. The plans
to enter regulated markets necessitate compliance of stringent regulatory
guidelines in the facility and in all processes.
Harmonizing the guidelines and software of the company can face
problems. Different countries have different regulations that need to be dealt
with. For example, collection of consistent data and regulations from all
countries can become problematic. As a consequence, the internally collected
data may not be comparable and sufficient enough to make internal
benchmarking useful.
The quality system of Fourrts could be further developed.
Benchmarking quality system within various departments could create healthy
competition and stimulate the quality thinking. This would offer fresh insights
of quality and the art of managing it. Fourrts has grown significantly in recent
years and its organizational structure has faced continuous changes. Thus the
quality system originally planned for the present organization might not
completely conform to future requirements. The streamlining of operations
that the company has already started should be continued to ensure the
efficiency and convenience of the quality management system also in the
future. Excess work could be reduced for an example by implementing an
integrated software system taking care of documentation.
Overall, more emphasis could be put on the implementation of
various Total Quality Management principles. The current quality system
focuses mostly on adhering to the regulations and guidelines provided by
external sources. One possibility the company could explore might be
implementation of statistical quality control techniques and total quality
management principles within the organization.
The aim of this dissertation was to study the regulatory aspects and
quality management system practiced in generic pharmaceutical industry as a
whole and then to present and analyze the quality management system
pursued in a generic pharmaceutical manufacturing company named M/s.
Fourrts (India) Laboratories Private Limited.
The quality in the pharmaceutical industry has historically been
controlled in a rather traditional manner. Quality is managed, for example,
with the help of country - specific legislation, cGMP, Pharmacopoeias, with
many organizations, like WHO, taking part in guiding. As varying regulations
and legislation cause extra work and costs, there are many international
approaches that aim at global harmonization of the guidelines. As an example
of these can be stated International Pharmacopoeia, PIC/S and International
Conference of Harmonization (ICH). Operational excellence in
pharmaceutical industry can be achieved through implementation of Total
quality management principles and various statistical quality control
techniques. This result in better process control and ensure quality in all
processes performed.
The quality management system at Fourrts is based on ISO
9001:2000 standards integrating requirements of GMP, Pharmacopoeia(s) and
the guidelines of various regulatory requirements. Fourrts has a Quality
Assurance department that is responsible for the quality management system.
Quality committee supervises the whole quality system at Fourrts.
At the heart of a great brand is a great product. Product is a key
element in the market offering. Market leaders generally offer products and
services of superior quality.21 The quality system of Fourrts is assuring the
safety and quality of the end product. The procedures are very standardized
and appropriate for the industry. Fourrts also has a team of educated, skilled
and motivated people willing to secure the quality of end products. With such
educated workforce it is possible to implement also complex procedures and
systems if needed. However, there are also some gaps to be bridged. Although
the extensive framework of regulations and requirements in the
pharmaceutical industry guarantees the safety of the end products, it does not
guarantee that the work is done in the most effective and easiest manner.
Successful implementation of Enterprise Resource Planning (ERP) software
and Laboratory Information Management System in the organization could
reduce excess work and results in paperless processes. Country wise
regulatory requirements for pharmaceutical products can be included in the
quality management system to ensure compliance. While developing new
products Fourrts can adhere to ICH guidelines to meet the future needs and to
serve international markets.
Fourrts can consider implementation of Total Quality Management
principles and Total Productive Maintenance techniques to achieve
operational excellence in the near future. Implementation of Just-in-Time
manufacturing system will allow Fourrts to achieve timeliness of shipments
and to achieve greater customer satisfaction. Environment Management
Standards like ISO 14000 can be achieved to achieve waste elimination.
As the company has been growing and changing a lot in recent years
and if the growth continues with the addition of more new countries, the
quality management system might need to be reviewed with implementation
of above said quality tools / standards in order to keep the systems
functioning efficiently.
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