UNIVERSITY OF PETROLEUM & ENERGY STUDIES

DEHRADUN

QUALITIES ISSUES IN PHARMACEUTICAL

INDUSTRY
RESEARCH METHODOLOGY
(MBCQ 723)
Submitted to:


 DECLARATION

We, Abhishek kumar, Ajeet kumar, Dr.Naveen Singhal hereby declare that the
project work entitled (Quality Issues in Pharmaceutical Industry) is a bona fide
work done by us under the guidance and supervision of Dr.Neeraj Anand. The
work has not formed part of any earlier studies for the award of degree/ diploma/
fellowship.

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Place: University of Petroleum & Energy Studies

Dehradun

Date: 26/03/20010
Signature of the Students.


Acknowledgement

 At the onset of this project we would like to express our deep sense of
respect and gratitude for our teacher and project guide.

 He being a perfectionist has always painstakingly guided us with infinite

patience and also helped us with every minor hiccup that came our way
during the currency of this project and instilled in us the adage “Trifles
makes perfection and perfection is no trifle.” we are deeply indebted to him
since without his support and tutelage this project would not have seen the
light of day.

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 Abhishek kumar(06)

Ajeet Kumar(08)

Dr.Naveen Singhal(61)



 
 
 
1.1 OVERVIEW 


1.2 BACKGROUND & INDIAN DRUG REGULATORY SYSTEM

 


 
 
 
3
 
 

 
 


SAMPLES TESTED, FOUND SUB-


STANDARD /SPURIOUS DURING THE PERIOD OF 1995-2003 IN
INDIA BY WHO

 
 

 



 

 
 

 

 
 


 

 
 

 

 

 
 
 

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 
 
 

 

 
 

 
 
 
 


 INTRODUCTION :-
1.1 OVERVIEW

Most of the today’ major pharmaceutical companies were founded in the late 19 th
& early 20th centuries. Legislation was introduced for testing and approval of drugs
and to require appropriate labeling. Prescription and non-prescription drugs
became legally distinguished from one another as the pharmaceutical industry
matured. The industry got underway in earnest from the 1950s, due to the
development of systematic scientific approaches, understanding of human biology
(including DNA) and sophisticated manufacturing technique.

The pharmaceutical industry confronted a new business climate and new

regulations, born in part from dealing with world market forces and protests by
activists in developing countries. Marketing changed dramatically in the 1990s,
partly because of a new consumerism. The Internet made possible the direct
purchase of medicines by drug consumers and of raw materials by drug producers,
transforming the nature of business. In the US, Direct-to-consumer advertising
5
proliferated on radio and TV because of new FDA regulations in 1997 that
liberalized requirements for the presentation of risks.

Drug discovery is the process by which potential drugs are discovered or

designed. In the past most drugs have been discovered either by isolating the active
ingredient from traditional remedies. Modern biotechnology often focuses on
understanding the metabolic pathways related to a disease state or pathogen, and
manipulating these pathways using molecular biology or Biochemistry. A great
deal of early-stage drug discovery has traditionally been carried out by universities
and research institutions.
Drug development refers to activities undertaken after a compound is identified as
a potential drug in order to establish its suitability as a medication. Objectives of
drug development are to determine appropriate Formulation and Dosing, as well as
to establish safety. Research in these areas generally includes a combination of in
vitro studies, in vivo studies, and clinical trials. The amount of capital required for
late stage development has made it a historical strength of the larger
pharmaceutical companies.

1.2 BACKGROUND & INDIAN DRUG REGULATORY SYSTEM

In India, The Central Drug Standards and Control Organization (CDSCO), located
under the aegis of the Ministry of Health and Family Welfare.
The CDSCO prescribes standards and measures for ensuring the safety, efficacy
and quality of drugs, cosmetics, diagnostics and devices in the country; regulates
the market authorization of new drugs and clinical trials standards; supervises drug
imports and approves licenses to manufacture the above-mentioned products;
The National Pharmaceutical Pricing Authority (NPPA), which was instituted in
1997 under the Department of Chemicals and Petrochemicals, which fixes or
revises the prices of decontrolled bulk drugs and formulations at judicious
intervals; periodically updates the list under price control through inclusion and
exclusion of drugs in accordance with established guidelines; maintains data on
production, exports and imports and market share of pharmaceutical firms; and
enforces and monitors the availability of medicines in addition to imparting inputs
to Parliament in issues pertaining to drug pricing. In India, drug manufacturing,
quality and marketing is regulated in accordance with the Drugs and Cosmetics
Act of 1940 and Rules 1945. This act has witnessed several amendments over the

6
last few decades. The Drugs Controller General of India (DCGI), who heads the
Central Drugs Standards Control Organization (CDSCO), assumes responsibility
for the amendments to the Acts and Rules. Other major related Acts and Rules
include the Pharmacy Act of 1948, The Drugs and Magic Remedies Act of 1954
and Drug Prices Control Order (DPCO) 1995 and various other policies instituted.
In accordance with the Act of 1940, there exists a system of dual regulatory control
or control at both Central and State government levels. The central regulatory
authority undertakes approval of new drugs, clinical trials, standards setting,
control over imported drugs and coordination of state bodies’ activities. State
authorities assume responsibility for issuing licenses and monitoring manufacture,
distribution and sale of drugs and other related products.

7
Figure1.1

8
1.3 Objective of the study
 There has been a wide-ranging national concern about spurious
/counterfeit /substandard drugs. Objective of this report is to explore the
different quality issues in the pharmaceutical industry.

 Exploring the different techniques for improving quality assurance system.

9
 Literature Review
2.1 :OVERVIEW
India is an increasingly influential player in the global pharmaceutical market. Key
parts of the drug regulatory system are controlled by the states, each of which
applies its own standards for enforcement, not always consistent with others. A
pilot study was conducted in two major cities in India, Delhi and Chennai, to
explore the question/hypothesis/extent of substandard and counterfeit drugs
available in the market and to discuss how the Indian state and federal
governments could improve drug regulation and more importantly regulatory
enforcement to combat these drugs. India presents definite opportunities and
potential perils to global health in its prolific pharmaceutical industry, for India is a
leading supplier of high quality generic drugs throughout the world, but it is also a
leading source of counterfeit drugs.

Substandard and counterfeit drugs have grave consequences for public health.
Drugs with too little or no active ingredient can cause patient death and lead to the
development of drug resistance. Resistance at the population level renders
legitimate drugs and even entire classes of drugs less effective, even for patients
who did not previously take poor-quality drugs.

India has a self-admitted problem of manufacturing unreliable drugs. In 2002, the

World Health Organisation (WHO) reported that Indian pharmaceutical
manufacturers themselves estimated 20% of drugs in major Indian-city markets
were substandard or illegal. Similarly, the Indian government estimates that
counterfeit drugs account for 0.34% of the total pharmaceutical market and
substandard drugs account for 9.34%. These data are based on samples tested by
the state authorities between 1995 and 2003; the extent of substandard drugs varied
from 8.19 to 10.64 percent and counterfeit drugs varied between 0.24 and 0.47
percent. Other evidence suggests that the quality of India's drugs has a global
impact. In May 2008, some of the authors published a study assessing the quality
of antimalarial drugs in Africa. The study found that 35% of antimalarial drugs
sold in private shops and pharmacies in six major African cities failed basic quality
control tests. 31% of the samples purportedly of Indian origin were found to be
substandard.

10
2.2 FACTS AND FINDINGS

Samples from 281 treatment packs collected from Delhi pharmacies were tested in
duplicate in July 2008, comprising 50 ciprofloxacin, 56 chloroquine, 61
erythromycin, 48 isoniazid and 66 rifampicin. Having recorded solely the better-
performing sample in the duplicate pair, which is a generous assumption that may
understate the incidence of poor drug quality, 12% (34/281) of tested samples
failed thin-layer chromatography (TLC) and/or disintegration tests. The breakdown
of failures is as follows: 0.7% (2/281) failed only disintegration tests, 0.4% (1/281)
failed only TLC, and 11% (31/281) failed both TLC and disintegration tests. 10%
of ciprofloxacin, 9% of chloroquine, 13% of erythromycin, 17% of isoniazid and
12% of rifampicin failed one or more tests.

Samples from 260 treatment packs collected from Chennai pharmacies were tested
in duplicate in March 2009, comprising 53 ciprofloxacin, 63 chloroquine, 56
erythromycin, 36 isoniazid and 52 rifampicin. Having again recorded the better-
performing sample in the duplicate pair, 5% (12/260) of tested samples failed TLC
and/or disintegration tests. The breakdown of failures is as follows: 0.4% failed
only disintegration tests, 2% (6/260) failed only TLC, and 2% (5/260) failed both
TLC Samples from 281 treatment packs collected from Delhi pharmacies were
tested in duplicate in July 2008, comprising 50 ciprofloxacin, 56 chloroquine, 61
erythromycin, 48 isoniazid and 66 rifampicin. Having recorded solely the better-
performing sample in the duplicate pair, which is a generous assumption that may
understate the incidence of poor drug quality, 12% (34/281) of tested samples
failed thin-layer chromatography (TLC) and/or disintegration tests. The breakdown
of failures is as follows: 0.7% (2/281) failed only disintegration tests, 0.4% (1/281)
failed only TLC, and 11% (31/281) failed both TLC and disintegration tests. 10%
of ciprofloxacin, 9% of chloroquine, 13% of erythromycin, 17% of isoniazid and
12% of rifampicin failed one or more tests.

Samples from 260 treatment packs collected from Chennai pharmacies were tested
in duplicate in March 2009, comprising 53 ciprofloxacin, 63 chloroquine, 56
erythromycin, 36 isoniazid and 52 rifampicin. Having again recorded the better-
performing sample in the duplicate pair, 5% (12/260) of tested samples failed TLC
and/or disintegration tests. The breakdown of failures is as follows: 0.4% (1/260)
failed only disintegration tests, 2% (6/260) failed only TLC, and 2% (5/260) failed
both TLC and disintegration tests (See Table 1). 6% of ciprofloxacin, 5% of
chloroquine, 2% of erythromycin, 6% of isoniazid and 6% of rifampicin failed one
or more tests.

11
In total, 541 samples were collected from pharmacies in Delhi and Chennai, with
8.5% (46/541) of tested samples failing TLC and/or disintegration tests.

However, fewer than 4% (11/281) of samples collected in Delhi had zero active
ingredients and only two samples collected in Chennai had very low concentrations
of active ingredients, both of which are indicators of counterfeit provenance.
Assuming the country of origin stated on the drug packaging was correct, 97%
(524/541) of tested samples were manufactured in India, of which 8% (42/524)
failed the above quality control tests. Of these, 21% (9/42) had zero or very low
concentrations of active ingredients. 3% (17/541) of tested samples (all from
Delhi) were labeled as manufactured in the United States, of which 23.5% (4/17)
failed basic quality control tests. All four U.S. samples that failed one or more tests
had zero active ingredients, suggesting they could be counterfeit.

Of the 26 pharmacies sampled in Delhi, five pharmacies had no failures, while

seven had from 20 to 30 percent failures; these seven pharmacies also supplied 10
of the 11 samples found to contain zero active ingredients. Of the 26 pharmacies
sampled in Chennai, 16 pharmacies had no failures and none of the pharmacies
sampled had failures above 20%.

2.3 :FACTS CRITICAL TO SUCCESS OF STUDY

1- 12% of all samples tested from Delhi failed either one or both tests, and were
substandard.
2- 5% of all samples tested from Chennai failed either one or both tests, and were
substandard.
3- Spatial heterogeneity between pharmacies was observed, with some having
more or less substandard drugs (30% and 0% respectively), as was product
heterogeneity, with some drugs being more or less frequently substandard (12%
and 7% respectively).
Semi-quantitative thin-layer chromatography and disintegration testing were used
to measure the concentration of active ingredients against internationally
acceptable standards.

12
2.4 SUMMARY
It is found that important spatial and product heterogeneity exists, which suggests
that India's substandard drug problem is not ubiquitous, but driven by a subset of
manufacturers and pharmacies which thrive in an inadequately regulated
environment. It is likely that the drug regulatory system in India needs to be
improved for domestic consumption, and because India is an increasingly
important exporter of drugs for both developed and developing countries so Indian
government should improve their regulatory system and follow the GMP Norms.

13
 3. Quality Issues

The quality of pharmaceuticals has been a concern of every country. The setting of
global standards is requested in Article 2 of the WHO Constitution, which cites as
one of the Organization’s functions that it should “develop, establish and promote
international standards with respect to food, biological, pharmaceutical and similar
products.”

Every government allocates a substantial proportion of its total health budget to

medicines. This proportion tends to be greatest in developing countries, where it
may exceed 40%. Without assurance that these medicines are relevant to priority
health needs and that they meet acceptable standards of quality, safety and
efficacy, any health service is evidently compromised. In developing countries
considerable administrative and technical effort is directed to ensuring that patients
receive effective medicines of good quality. It is crucial to the objective of health
for all that a reliable system of medicines control be brought within the reach of
every country.

The supply of essential medicines of good quality was identified as one of the
prerequisites for the delivery of health care at the International Conference on
Primary Health Care in Alma-Ata in 1978. Similarly, the Conference of Experts
on the Rational Use of Drugs, held in Nairobi in 1985, and WHO’s Revised Drug
Strategy, adopted by the World Health Assembly in May 1986, identified the
effective functioning of national drug regulation and control systems as the only
means to assure safety and quality of medicines. Yet the World Health Assembly
continues to express great concern about the quality, safety and efficacy of
medicines, particularly those products or active pharmaceutical substances
imported into, or produced in, developing countries. In recent years counterfeit
products have infiltrated certain markets in disquieting proportions. Since the
founding of WHO, the World Health Assembly has adopted many resolutions
requesting the Organization to develop international standards, recommendations
and instruments to assure the quality of medicines, whether produced and traded
nationally or internationally.
In response to these resolutions, the WHO Expert Committee on Specifications for
Pharmaceutical Preparations, which was originally created to prepare The
International Pharmacopoeia, has made numerous recommendations relevant to
quality assurance and control. Most of these recommendations , even though they
were made several years ago, are still valid.

14
4. A statement indicating numbers of samples tested, found
sub-standard /spurious during the period of 1995-2003 in
INDIA by WHO

No of Sub- No of Sub-
Standard Standard
Quality Quality %

15
 5. Counterfeit drugs –

“A drug which, or the container of which, or labeling of which, without

authorization, bears the trademark, trade name, other identifying mark, imprint or
device or any likeness, there of a drug manufacturer, processor, packer, or
distributor other than the person, or persons who in fact manufactured, processed,
packed, or distributed such drug and which thereby falsely purports or is
represented to be the product of, or to have been packed or distributed by such
other drug manufacturer, processor, packer, or distributor.”

Trade in counterfeit drugs is widespread and affects both

developing and developed countries. All medicines are subject
to counterfeiting, both branded and generic.
It is virtually impossible to tell the difference between real and fake medicines.
Taking for granted that the drugs can be trusted, patients, doctors and other
medical staff often do not even suspect that there is anything wrong with their
medicines. However, not only is it in most cases hard to detect suspicious products,
but there is also a lack of public awareness about counterfeit drugs and their
seemingly uncontrolled presence on the market. As a consequence, medicines that
do not work or cause unusual side-effects are rarely even reported, since symptoms
(including deaths) are usually attributed to the disease. From a judicial perspective,
prosecution is complicated by the fact that the evidence of counterfeiting is
consumed.

Because the public health risk of counterfeit medicines recognizes no national

boundaries, companies have created the Pharmaceutical Security Institute (PSI)
and developed global security strategies to ensure public safety and product
integrity. The pharmaceutical industry works closely with law enforcement and
regulatory agencies in both developed and developing countries to implement a
multilayered security strategy focused on both prevention and enforcement. The
IFPMA’s Director General serves as President of the PSI.

The IFPMA also works in close partnership with the WHO to improve drug quality
and fight counterfeiting around the world. The Pharmaceutical Industry has
endorsed the recent WHO Declaration of Rome on Counterfeiting Medicines and
is committed to participate in the WHO’s new International Medical Products
Anti-counterfeiting Task force (IMPACT). The IFPMA, the health professions and
other pharmaceutical manufactures associations are all active partners against this
crime.
16
6. Counterfeit/Spurious drugs are now an international
problem
There have been wide spread reports on the availability of Spurious fake /
counterfeit drugs in the country. Trade in counterfeit/ spurious drugs is prevalent
internationally and affects both developing and developed countries. Despite
Indian Pharmaceutical Industry having a domestic turnover, which is worth more
than Rs. 40,000 crores, and exports worth over Rs. 30,000 crores, the shadow of
spurious drugs is likely to raise apprehensions about the availability of safe and
genuine drugs from India in general. It needs to be emphasized that counterfeiting
of commercial products has been in existence since long.

The problem of spurious drugs is reported to be a global phenomenon and India is

no exception. Although the problem of counterfeiting or fake goods has been
reported in all parts of the world, especially in respect of popularly used consumer
goods, it acquires more serious dimensions, when it involves medicines. In the case
of drugs, the most serious issue is the adverse impact on human safety causing
sometimes a grievous injury and even death, due to the failure of the intended
pharmacological intervention. There is also the issue of economic loss to the
manufacturing companies holding the rights for particular products. It is therefore
imperative that the regulatory authorities, pharmaceutical industries, trade and
consumers should work in unison and make all-out efforts to ensure that only
genuine and good quality drugs are made available to the public at large.

17
7. Several possible factors contribute to proliferation of
Spurious drugs.

Some of the prominent ones are:

a. Lack of enforcement of existing laws
b. Weak penal action
c. Very remunerative trade
d. Large scale sickness in small scale pharmaceutical industry
e. Availability of improved printing technology that helps in counterfeiting
f. Lack of coordination between various agencies
g. Too many retail & whole sale chemist outlets
h. Inadequate cooperation between stakeholders.
i. Lack of control by importing/exporting countries
j. Wide spread corruption and conflict of interests

In India, although appropriate legislation and regulatory systems exists, there is a

considerable non-uniformity of enforcement standard followed by state drug
control authorities.

18
 8. Drug Storage and Distribution
Facts & Findings
 The significant and crucial role of the distribution channels of drugs &
pharmaceuticals (wholesale as well as retail) cannot be overemphasized. It
has been noted that medicines take a long winding and circuitous route
before they reach the consumers.
 Very often the products are bought and sold at five or six or even more
times by C&F agents, whole-sellers, stockists, sub-stockists etc. before they
reach a retail pharmacy and eventually the patient. Understandably, this
secondary market is particularly vulnerable to unscrupulous endeavours of
unethical traders and criminals. Illegally imported, stolen, spuris adulterated
drugs have an easier access to the distribution system through the secondary
market.
 It is also noted that transportation channels of drugs were also susceptible to
be exploited by the unscrupulous elements to infiltrate their spurious
products in the distribution channels. Therefore, it is imperative that the
secondary market is more closely regulated to ensure compliance with Act
and Rules, particularly with respect to proper documentation of the
movement of products in the course of trade.
 At the retail distribution level, the situation can be substantially improved
by developing and fostering a professional culture among ‘Qualified
Persons’engaged in retail distribution of drugs. While they are suitably
qualified to manage dispensing of drugs – there is a need to inculcate
a climate of self-regulation among them. Enforcement of regulations by
statutory authorities would always have its limitations in retail distribution
scenario since retail sale of medicines is a professional activity involving
moment to moment conformity with high standards of patient and drug
management and a professional commitment. It is not tenable to enforce
professionalism through one or two annual inspections by drugs inspectors.
 Trade and professional associations, Pharmacy Council of India as well as
State Pharmacy Councils need to play a much larger role to reform the drug
management and patient interface practices in retail outlets.
 In this regard, it has been noted that the Government has made a
very clear policy statement in the preamble of Pharmacy Act 1948 which
states “it is expedient to make better provision for the regulation of the
profession and practice of pharmacy and for that purpose to constitute
Pharmacy Councils”
19
  There is an urgent need to implement India specific Good Pharmacy
Practices and Good Storage Practices that will improve the distribution
system and will minimize the chances of spurious and sub-standard drugs
entering the supply chain. Pharmacy Councils must perform a proactive role
in bringing awareness about these concepts and should ensure that their
knowledge is linked with the registration under the Pharmacy Act.
 It is noted that in several countries the responsibility of regulating retail sale
of drugs is entrusted with professional bodies or state boards that register
pharmacists. Continuing education for renewal of registration as pharmacists
is also mandatory in several countries. In
India, the registration of pharmacists, under the Pharmacy Act, is done by
the State Pharmacy Councils while the licensing of retail outlets where these
pharmacists
are deployed, is done by the Drugs Control Department under the Drugs &
Cosmetics Act and Rules. There is a need to review this system and possibly
integrate pharmacists and the pharmacy profession and make them more
accountable for their roles in drug distribution. The concept of locum
(stand-in or substitute) pharmacists may be introduced to further ensure that
the drugs in supply chain are managed in an appropriate manner, till they
reach the patients.
 The enormously large number of retail outlets does appear to strain the
economic viability of retailers as well as poses an overwhelming challenge to
the regulatory system. The Committee noted that the present regulations are
sufficient to deal with the situation and efficient implementation of the relevant
provisions of the Rules would largely curb any tendency of fringe players and
other unscrupulous elements to be tempted to deal in spurious medicines.

20
9. Problem of Sub-Standard Drugs
The problem of sub-standard drugs is confined mainly to licensed
manufacturers. An analysis of number of samples of drugs tested by state
drugs testing laboratories and the number of drugs found sub-standard
during the last five years indicates a figure of about 10%. However, it would
not be correct to conclude from these figures that 10% of the drugs moving
in the market are sub-standard. The State Drugs Inspectors normally draw
samples of drugs which are thermolabile and are close to expiry dates and
which they suspect to be sub-standard, such as vitamins and antibiotic
preparations. They also draw samples of preparations for which complaints
have been received or those manufactured by less known manufactures. Due
to paucity of funds for purchase of samples in many states, the Drugs
Inspectors draw limited number of samples for test and pick up only such
samples that are suspected to be substandard.

10. Reasons for Drugs becoming sub-standard

Sub-standard drugs can result mainly because of two reasons. One reason
could be the inadequate pre-formulation development studies before the drug
is marketed or lack of in-process controls exercised by the manufacturers
during the process of manufacture. For example, if a drug is not formulated
properly and the stability studies are not done before marketing the
formulation, it is likely to deteriorate on storage and may fail in one or more
parameters. Likewise, if adequate in-process controls are not exercised
during manufacture of tablets, it is possible that the tablets produced may
fail in the disintegration or in weight variation tests. Similarly, in case of
vitamin and antibiotic preparations, if adequate stability studies not
conducted, the preparations may deteriorate before their expiry dates. The
second reason could be the improper conditions under which drugs are
stored and transported. The drug preparations could become sub-standard if
they are not stored or transported under proper conditions as stipulated on
the label. Thus antibiotic, vitamin and other thermolabile preparations, if
stored or transported at higher temperatures and/or humid conditions, could
deteriorate and become sub-standard. If the drug manufacturers follow Good
Manufacturing Practices (GMPs), observe proper in-process controls, test all
raw materials, packaging materials and the finished products, the possibility
of their drugs becoming sub-standard would be much less.

21
 11. Nature of defects in Sub-standard Drugs
It may be relevant to point out that a sub-standard drug may or may not be a
harmful drug. Drugs may be declared sub-standard because of defects,
which may not affect the therapeutic efficacy of the drug. For example,
tablet preparations may be declared sub-standard because they do not
conform to the standards for uniformity of weight, diameter or they are
chipped, discoloured etc. Similarly, liquid preparations and injections could
be declared sub-standard, because the quantity contained is found to be less
than that stated on the label. There are however, certain defects which could
affect the therapeutic efficacy of the product e.g. disintegration/dissolution
test for tablets,sterility and pyrogen test for parenteral preparations and
active content being much less than the claimed amount.

12. State drug Testing Laboratories

22
 The major responsibility of administering and monitoring the manufacture, sale,
distribution and storage of drugs is in the domain of States. Each State is required
to provide arrangements to test the quality of drugs manufactured and sold in the
State. Many State Governments have given less priority to this aspect and thus the
Government’s drugs quality control system has not kept pace with the progress
made by the pharmaceutical industry. Only 17 States have drug testing and even
among these laboratories, only about 7 have the capacity to test all classes of
drugs. On an average, about 36,000 samples are tested annually, both in the Central
and State drug testing laboratories. The number is, however, inadequate as
compared to number of batches of thousands of formulations manufactured in the
country. Because of less capacity to test, the time taken to complete the testing of
drug samples is observed to be taking even a year. This does not serve any
purpose. As a result, samples of less than 1 % of the batches of drugs manufactured
in the country are exposed to scrutiny by the Government drug testing laboratories.
The number of samples that are reported every year as not of standard quality by
the Central and State Government laboratories are only indicative of lax quality
assurance system in the manufacturer’s quality control labs and are not
representative of the actual situation in the country. The limitations in testing of
drug samples in the government labs are related to the absence or lack of
sophisticated instruments, lack of trained analysts, lack of commitment, lack of
reagents, non-validated methods, shortage of funds, inadequate number of
staff and in many cases a combination of more than one of these constraints.

13. Suggested Action by the Pharmaceutical Industry

23
 It has been observed that industry has a well-developed marketing and
distribution network. The industry can streamline their supply chain and
make use of their manpower to detect the movement of spurious drugs.

 Suggested actions for Pharma industry:

a. Use their well-developed marketing network to identify distribution channel and

persons involved in spurious drug trade.
b. Assist, through its associations in detection and unearthing of spurious/
counterfeit drugs by cooperating with the regulatory and/or police authorities.
c. Prepare, through its associations, a checklist for the guidance of manufacturers,
wholesalers and retail sellers to identify and distinguish between the spurious and
genuine products.
d. Formulate its own spurious/counterfeit drugs policy and a surveillance strategy
to tackle the problem of spurious drugs.
e. Establish a close interaction with regulatory authorities and extend full
cooperation to eliminate the menace of spurious drugs.
f. Streamline their supply chain and distribution network.
g. Ensure proper storage of products during transit as well as at places of
distribution.

14. Quality management in the drug industry

24
In the drug industry at large, quality management is usually defined as the aspect
of management function that determines and implements the “quality policy”, i.e.
the overall intention and direction of an organization regarding quality, as formally
expressed and authorized by top management. The basic elements of quality
management are:
— an appropriate infrastructure or “quality system”, encompassing the
organizational structure, procedures, processes and resources;
— systematic actions necessary to ensure adequate confidence that a product
(or service) will satisfy given requirements for quality. The totality of these
actions is termed “quality assurance”. Within an organization, quality assurance
serves as a management tool. In contractual situations, quality assurance also
serves to generate confidence in the supplier.
The concepts of quality assurance, GMP and quality control are interrelated
aspects of quality management. They are described here in order to emphasize their
relationship and their fundamental importance to the production and control of
pharmaceutical products.

15. Quality assurance

25
  Principle.
“Quality assurance” is a wide-ranging concept covering all matters that
individually or collectively influence the quality of a product. It is the totality of
the arrangements made with the object of ensuring that pharmaceutical products
are of the quality required for their intended use. Quality assurance therefore
incorporates GMP and other factors, including those outside the scope of this guide
such as product design and development.

 The system of quality assurance appropriate to the

manufacture of pharmaceutical products should ensure that:

(a) pharmaceutical products are designed and developed in a way that takes
account of the requirements of GMP and other associated codes such as those of
good laboratory practice (GLP)1 and good clinical practice (GCP).

(b) production and control operations are clearly specified in a written form
and GMP requirements are adopted.
(c) managerial responsibilities are clearly specified in job descriptions;

(d) arrangements are made for the manufacture, supply and use of the correct
starting and packaging materials;

(e) all necessary controls on starting materials, intermediate products, and

bulk products and other in-process controls, calibrations, and validations
are carried out;

(f ) the finished product is correctly processed and checked, according to the

defined procedures;

(g) pharmaceutical products are not sold or supplied before the authorized
persons have certified that each production batch has been produced and controlled
in accordance with the requirements of the marketing authorization and any other
regulations relevant to the production, control and release of pharmaceutical
products;

(h) satisfactory arrangements exist to ensure, as far as possible, that the

pharmaceutical products are stored by the manufacturer, distributed, and
subsequently handled so that quality is maintained throughout their shelf-life;

26
 (i) there is a procedure for self-inspection and/or quality audit that regularly
appraises the effectiveness and applicability of the quality assurance system;

(j) deviations are reported, investigated and recorded;

(k) there is a system for approving changes that may have an impact on
product quality;

(l) regular evaluations of the quality of pharmaceutical products should be

conducted with the objective of verifying the consistency of the process
and ensuring its continuous improvement.

 The manufacturer must assume responsibility for the quality

of the pharmaceutical products

The manufacture must have responsibilityto ensure that they are fit for their
intended use, comply with the requirements of the marketing authorization and do
not place patients at risk due to inadequate safety, quality or efficacy. The
attainment of this quality objective is the responsibility of senior management and
requires the participation and commitment of staff in many different departments
and at all levels within the company, the company’s suppliers, and the distributors.
To achieve the quality objective reliably there must be a comprehensively designed
and correctly implemented system of quality assurance incorporating GMP and
quality control. It should be fully documented and its effectiveness monitored. All
parts of the quality assurance system should be adequately staffed with competent
personnel, and should have suitable and sufficient premises, equipment, and
facilities.

27
16.Good manufacturing practices for pharmaceutical products
(GMP)

Good manufacturing practice is that part of quality assurance which ensures

that products are consistently produced and controlled to the quality standards
appropriate to their intended use and as required by the marketing authorization.
GMP are aimed primarily at diminishing the risks inherent in any
pharmaceutical production. Such risks are essentially of two types:
crosscontamination (in particular of unexpected contaminants) and mix-ups
(confusion) caused by, for example, false labels being put on containers. Under
GMP:

(a) all manufacturing processes are clearly defined, systematically reviewed in

the light of experience, and shown to be capable of consistently manufacturing
pharmaceutical products of the required quality that comply with
their specifications;

(b) qualification and validation are performed;

(c) all necessary resources are provided, including:

(i) appropriately qualified and trained personnel;

(ii) adequate premises and space;
(iii) suitable equipment and services;
(iv) appropriate materials, containers and labels;
(v) approved procedures and instructions;
(vi) suitable storage and transport;
(vii) adequate personnel, laboratories and equipment for in-process
controls;

(d) instructions and procedures are written in clear and unambiguous language,
specifically applicable to the facilities provided;

(e) operators are trained to carry out procedures correctly;

(f ) records are made (manually and/or by recording instruments) during

manufacture to show that all the steps required by the defined procedures
and instructions have in fact been taken and that the quantity and quality
of the product are as expected; any significant deviations are fully recorded

28
and investigated;

(g) records covering manufacture and distribution, which enable the complete
history of a batch to be traced, are retained in a comprehensible and accessible
form;

(h) the proper storage and distribution of the products minimizes any risk to
their quality;

(i) a system is available to recall any batch of product from sale or supply;

(j) complaints about marketed products are examined, the causes of quality
defects investigated, and appropriate measures taken in respect of the
defective products to prevent recurrence.

16.1Sanitation and hygiene

 A high level of sanitation and hygiene should be practised in every aspect

of the manufacture of drug products. The scope of sanitation and hygiene covers
personnel, premises, equipment and apparatus, production materials and
containers, products for cleaning and disinfection, and anything that could become
a source of contamination to the product. Potential sources of contamination
should be eliminated through an integrated comprehensive programme of
sanitation and hygiene.

16.2 Qualification and validation

 In accordance with GMP, each pharmaceutical company should identify

what qualification and validation work is required to prove that the critical
aspects of their particular operation are controlled.

 The key elements of a qualification and validation programme of a company

should be clearly defined and documented in a validation master plan.

 Qualification and validation should establish and provide documentary

evidence that:
(a) the premises, supporting utilities, equipment and processes have been
designed in accordance with the requirements for GMP (design qualification,

29
or DQ);
(b) the premises, supporting utilities and equipment have been built and
installed in compliance with their design specifications (installation qualification,
or IQ);
(c) the premises, supporting utilities and equipment operate in accordance
with their design specifications (operational qualification, or OQ);
(d) a specific process will consistently produce a product meeting its
predetermined specifications and quality attributes (process validation, or PV,
also called performance qualification, or PQ).
 Any aspect of operation, including significant changes to the premises,
facilities, equipment or processes, which may affect the quality of the product,
directly or indirectly, should be qualified and validated.
 Qualification and validation should not be considered as one-off exercises.
An ongoing programme should follow their first implementation and should
be based on an annual review.
 The commitment to maintain continued validation status should be stated
in the relevant company documentation, such as the quality manual or validation
master plan.
 The responsibility of performing validation should be clearly defined.
 Validation studies are an essential part of GMP and should be conducted
in accordance with predefined and approved protocols.
 A written report summarizing the results recorded and the conclusions
reached should be prepared and stored.
 Processes and procedures should be established on the basis of the results
of the validation performed.

It is of critical importance that particular attention is paid to the validation

of analytical test methods, automated systems and cleaning procedures.

16.3 Complaints

Principle. All complaints and other information concerning potentially

defective products should be carefully reviewed according to written procedures
and the corrective action should be taken.
 A person responsible for handling the complaints and deciding the measures
to be taken should be designated, together with sufficient supporting staff
to assist him or her. If this person is different from the authorized person, the
latter should be made aware of any complaint, investigation or recall.
 There should be written procedures describing the action to be taken,
including the need to consider a recall, in the case of a complaint concerning a
30
possible product defect.
 Special attention should be given to establishing whether a complaint was
caused because of counterfeiting.
 Any complaint concerning a product defect should be recorded with all the
original details and thoroughly investigated. The person responsible for quality
control should normally be involved in the review of such investigations.
 If a product defect is discovered or suspected in a batch, consideration
should be given to whether other batches should be checked in order to determine
whether they are also affected. In particular, other batches that may
contain reprocessed product from the defective batch should be investigated.
 Where necessary, appropriate follow-up action, possibly including product
recall, should be taken after investigation and evaluation of the complaint.
 All decisions made and measures taken as a result of a complaint should be
recorded and referenced to the corresponding batch records.
 Complaints records should be regularly reviewed for any indication of
specific
or recurring problems that require attention and might justify the recall of
marketed products.
 The competent authorities should be informed if a manufacturer is
considering
action following possibly faulty manufacture, product deterioration,
counterfeiting or any other serious quality problems with a product.

16.4 Product recalls

Principle. There should be a system to recall from the market, promptly

and effectively, products known or suspected to be defective.
 The authorized person should be responsible for the execution and
coordination of recalls. He/she should have sufficient staff to handle all aspects of
the recalls with the appropriate degree of urgency.
 There should be established written procedures, which are regularly
reviewed and updated, for the organization of any recall activity. Recall operations
should be capable of being initiated promptly down to the required level
in the distribution chain.
 An instruction should be included in the written procedures to store
recalled products in a secure segregated area while their fate is decided.

 All competent authorities of all countries to which a given product has been
distributed should be promptly informed of any intention to recall the product

31
because it is, or is suspected of being, defective.
 The distribution records should be readily available to the authorized
person, and they should contain sufficient information on wholesalers and
directly supplied customers (including, for exported products, those who have
received samples for clinical tests and medical samples) to permit an effective
recall.
 The progress of the recall process should be monitored and recorded.
Records should include the disposition of the product. A final report should be
issued, including a reconciliation between the delivered and recovered quantities
of the products.
 The effectiveness of the arrangements for recalls should be tested and
evaluated from time to time.

16.5 Contract production and analysis

Principle. Contract production and analysis must be correctly defined,

agreed and controlled in order to avoid misunderstandings that could result in
a product or work or analysis of unsatisfactory quality.

 All arrangements for contract manufacture and analysis, including a

proposed changes in technical or other arrangements, should be accordance with
the marketing authorization for the product concerned.
 The contract should permit the contract giver to audit the facilities of the
contract accepter.
 In the case of contract analysis, the final approval for release must be given
by the authorized person.
 The contract giver is responsible for assessing the competence of the
contractaccepter in successfully carrying out the work or tests required, for
approval for contract activities, and for ensuring by means of the contract that
the principles of GMP described in this guide are followed.
 The contract giver should provide the contract accepter with all the
information necessary to carry out the contracted operations correctly in
accordance with the marketing authorization and any other legal requirements. The
contract giver should ensure that the contract accepter is fully aware of any
problems associated with the product, work or tests that might pose a hazard
to premises, equipment, personnel, other materials or other products.
 The contract giver should ensure that all processed products and materials
delivered by the contract accepter comply with their specifications or that the
product has been released by the authorized person.
The contract accepter.
32
  The contract accepter must have adequate premises, equipment, knowledge,
and experience and competent personnel to carry out satisfactorily the
work ordered by the contract giver. Contract manufacture may be undertaken
only by a manufacturer who holds a manufacturing authorization.

 The contract accepter should not pass to a third party any of the work
entrusted to him or her under the contract without the contract giver’s prior
evaluation and approval of the arrangements. Arrangements made between the
contract accepter and any third party should ensure that the manufacturing and
analytical information is made available in the same way as between the original
contract giver and contract accepter.
 The contract accepter should refrain from any activity that may adversely
affect the quality of the product manufactured and/or analysed for the contract
giver.

16.6 The contract

 There must be a written contract between the contract giver and the contract
accepter which clearly establishes the responsibilities of each party.
 The contract must clearly state the way in which the authorized person, in
releasing each batch of product for sale or issuing the certificate of analysis,
exercises his or her full responsibility and ensures that each batch has been
manufactured in, and checked for, compliance with the requirements of the
marketing authorization.
 Technical aspects of the contract should be drawn up by competent
persons suitably knowledgeable in pharmaceutical technology, analysis and
GMP.
 All arrangements for production and analysis must be in accordance with
the marketing authorization and agreed by both parties.
 The contract should describe clearly who is responsible for purchasing,
testing and releasing materials and for undertaking production and quality
controls, including in-process controls, and who has responsibility for sampling
and analysis. In the case of contract analysis, the contract should state whether
or not the contract accepter should take samples at the premises of the
manufacturer.
 Manufacturing, analytical, distribution records and reference samples
should be kept by, or be available to, the contract giver. Any records relevant
to assessing the quality of a product in the event of complaints or a suspected
defect must be accessible and specified in the defect/recall procedures of the
contract giver.

33
  The contract should describe the handling of starting materials, intermediate
and bulk products and finished products if they are rejected. It should
also describe the procedure to be followed if the contract analysis shows that
the tested product must be rejected.

16.7 Self-inspection and quality audits

Principle.

The purpose of self-inspection is to evaluate the manufacturer’s

compliance with GMP in all aspects of production and quality control. The self
inspection programme should be designed to detect any shortcomings in the
implementation of GMP and to recommend the necessary corrective actions.
Self-inspections should be performed routinely, and may be, in addition, performed
on special occasions, e.g. in the case of product recalls or repeated rejections,
or when an inspection by the health authorities is announced. The team
responsible for self-inspection should consist of personnel who can evaluate the
implementation of GMP objectively. All recommendations for corrective action
should be implemented. The procedure for self-inspection should be documented,
and there should be an effective follow-up programme.

Items for self-inspection

 Written instructions for self-inspection should be established to provide a
minimum and uniform standard of requirements. These may include questionnaires
on GMP requirements covering at least the following items:
(a) personnel;
(b) premises including personnel facilities;
(c) maintenance of buildings and equipment;
(d) storage of starting materials and finished products;
(e) equipment;
(f ) production and in-process controls;
(g) quality control;
(h) documentation;
(i) sanitation and hygiene;
(j) validation and revalidation programmes;
(k) calibration of instruments or measurement systems;
(l) recall procedures;
(m) complaints management;
(n) labels control;
34
(o) results of previous self-inspections and any corrective steps taken.

Self-inspection team
 Management should appoint a self-inspection team consisting of experts in
their respective fields and familiar with GMP. The members of the team may be
appointed from inside or outside the company.
Frequency of self-inspection

 The frequency at which self-inspections are conducted may depend on

company requirements but should preferably be at least once a year. The
frequency should be stated in the procedure.

Self-inspection report
A report should be made at the completion of a self-inspection. The report
should include:
(a) self-inspection results;
(b) evaluation and conclusions;
(c) recommended corrective actions.

Follow-up action
 There should be an effective follow-up programme. The company
Management should evaluate both the self-inspection report and the corrective
actions as necessary.

Quality audit
 It may be useful to supplement self-inspections with a quality audit. A
quality audit consists of an examination and assessment of all or part of a quality
system with the specific purpose of improving it. A quality audit is usually
conducted by outside or independent specialists or a team designated by the
management for this purpose. Such audits may also be extended to suppliers
and contractors.

Suppliers’ audits and approval

 The person responsible for quality control should have responsibility
together with other relevant departments for approving suppliers who can
reliably supply starting and packaging materials that meet established
specifications.
 Before suppliers are approved and included in the approved suppliers’ list
or specifications, they should be evaluated. The evaluation should take into
account a supplier’s history and the nature of the materials to be supplied. If an
35
audit is required, it should determine the supplier’s ability to conform with
GMP standards.

16.8 Personnel

Principle.
The establishment and maintenance of a satisfactory system of
quality assurance and the correct manufacture and control of pharmaceutical
products and active ingredients rely upon people. For this reason there must be
sufficient qualified personnel to carry out all the tasks for which the manufacturer
is responsible. Individual responsibilities should be clearly defined and
understood by the persons concerned and recorded as written descriptions.
General
 The manufacturer should have an adequate number of personnel with the
necessary qualifications and practical experience. The responsibilities placed on
any one individual should not be so extensive so as to present any risk to quality.
 All responsible staff should have their specific duties recorded in written
descriptions and adequate authority to carry out their responsibilities. Their
duties may be delegated to designated deputies of a satisfactory qualification
level. There should be no gaps or unexplained overlaps in the responsibilities
of personnel concerned with the application of GMP. The manufacturer should
have an organization chart.
 All personnel should be aware of the principles of GMP that affect them
and receive initial and continuing training, including hygiene instructions, relevant
to their needs. All personnel should be motivated to support the establishment
and maintenance of high-quality standards.
 Steps should be taken to prevent unauthorized people from entering
production, storage and quality control areas. Personnel who do not work in these
areas should not use them as a passageway.

RECOMMENDATIONS & SUGGESTIONS

36
17.1. Action by the Pharma Trade

It has been observed that the sale of spurious drugs invariably takes place through
wholesalers and retailers and State Drugs Controllers should take a severe action
against those, who are found indulging in this activity and are not able to produce
valid purchase records.

Recommendations for the Pharma Trade Association:

 Play a proactive and visible role to contain the menace of
spurious/counterfeit drugs;
 Develop its mechanism in identifying the persons directly or indirectly
involved in abetting the distribution of spurious, counterfeit or questionable
quality drugs.
 Prepare a checklist for the guidance of members and widely publicize it for
information of all members
 It should be mendatory that the supply by retail of any drug shall be made
against a cash/credit memo. This condition of license should be strictly
adhered to by all retail licensees.
 Every chemist/pharmacist to act as a watchdog to prevent entry of any
spurious/doubtful quality drugs or those purchased from unauthorized
sources or without proper bills in the supply chain.

37
17.2. Action by the Consumer and other Professional
Associations
There is an urgent need for an awareness campaign to educate the consumers and
the medical and paramedical professionals. The Committee, in particular,
recommends that the Consumers and health professional/associates should play an
active and visible role to create awareness about the hazards of spurious drugs.
They should undertake campaigns at the national level to educate the public on the
ways and means of detecting spurious drugs and the advantages of purchasing
from licensed sources with valid cash memos.

38
18. Glossary
The definitions given below apply to the terms used in this study. They may
have different meanings in other contexts.

Active pharmaceutical ingredient (API)

Any substance or mixture of substances intended to be used in the manufacture of
a pharmaceutical dosage form and that, when so used, becomes an active
ingredient of that pharmaceutical dosage form. Such substances are intended to
furnish pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease or to affect the structure and
function of the body.

Airlock
An enclosed space with two or more doors, which is interposed between two
or more rooms, e.g. of differing classes of cleanliness, for the purpose of
controlling the airflow between those rooms when they need to be entered. An
airlock is designed for use either by people or for goods and/or equipment.

Authorized person
The person recognized by the national regulatory authority as having the
responsibility for ensuring that each batch of finished product has been
manufactured, tested and approved for release in compliance with the laws and
regulations inforce in that country.

Batch (or lot)

A defined quantity of starting material, packaging material, or product processed in
a single process or series of processes so that it is expected to be homogeneous. It
may sometimes be necessary to divide a batch into a number of sub-batches, which
are later brought together to form a final homogeneous batch. In the case of
terminal sterilization, the batch size is determined by the capacity of the autoclave.
In continuous manufacture, the batch must correspond to a defined fraction of the
production, characterized by its intended homogeneity. The batch size can be
defined either as a fixed quantity or as theamount produced in a fixed time interval.

39
Batch number (or lot number)
A distinctive combination of numbers and/or letters which uniquely identifies a
batch on the labels, its batch records and corresponding certificates of analysis, etc.

Batch records
All documents associated with the manufacture of a batch of bulk product or
finished product. They provide a history of each batch of product and of all
circumstances pertinent to the quality of the final product.

Bulk product
Any product that has completed all processing stages up to, but not including,
final packaging.

Calibration
The set of operations that establish, under specified conditions, the relationship
between values indicated by an instrument or system for measuring (especially
weighing), recording, and controlling, or the values represented by a material
measure, and the corresponding known values of a reference standard. Limits
for acceptance of the results of measuring should be established.

Clean area
An area with defined environmental control of particulate and microbial
contamination, constructed and used in such a way as to reduce the introduction,
generation, and retention of contaminants within the area.

Consignment (or delivery)

The quantity of a pharmaceutical(s), made by one manufacturer and supplied
at one time in response to a particular request or order. A consignment may
comprise one or more packages or containers and may include material belonging
to more than one batch.

Contamination
The undesired introduction of impurities of a chemical or microbiological nature,
or of foreign matter, into or on to a starting material or intermediate during
production, sampling, packaging or repackaging, storage or transport.
40
Critical operation
An operation in the manufacturing process that may cause variation in the quality
of the pharmaceutical product.

Cross-contamination
Contamination of a starting material, intermediate product or finished product with
another starting material or product during production.

Finished product
A finished dosage form that has undergone all stages of manufacture, including
packaging in its final container and labelling.

In-process control
Checks performed during production in order to monitor and, if necessary, to
adjust the process to ensure that the product conforms to its specifications. The
control of the environment or equipment may also be regarded as a part of
inprocess control.

Intermediate product
Partly processed product that must undergo further manufacturing steps before it
becomes a bulk product.

Large-volume parenterals
Sterile solutions intended for parenteral application with a volume of 100 ml or
more in one container of the finished dosage form.

Manufacture
All operations of purchase of materials and products, production, quality control,
release, storage and distribution of pharmaceutical products, and the related
controls.

Manufacturer
A company that carries out operations such as production, packaging, repackaging,
labelling and relabelling of pharmaceuticals.

41
Marketing authorization (product licence, registration certificate)
A legal document issued by the competent drug regulatory authority that
establishes the detailed composition and formulation of the product and the
pharmacopoeial or other recognized specifications of its ingredients and of the
final product itself, and includes details of packaging, labelling and shelf-life.

Master formula
A document or set of documents specifying the starting materials with their
quantities and the packaging materials, together with a description of the
procedures and precautions required to produce a specified quantity of a finished
product as well as the processing instructions, including the in-process controls.

Master record
A document or set of documents that serve as a basis for the batch documentation
(blank batch record).

Packaging
All operations, including filling and labelling, that a bulk product has to undergo in
order to become a finished product. Filling of a sterile product under aseptic
conditions or a product intended to be terminally sterilized, would not normally be
regarded as part of packaging.

Packaging material
Any material, including printed material, employed in the packaging of a
pharmaceutical, but excluding any outer packaging used for transportation or
shipment. Packaging materials are referred to as primary or secondary according to
whether or not they are intended to be in direct contact with the product.

Pharmaceutical product
Any material or product intended for human or veterinary use presented in its
finished dosage form or as a starting material for use in such a dosage form, that is
subject to control by pharmaceutical legislation in the exporting state and/or the
importing state.

42
Production
All operations involved in the preparation of a pharmaceutical product, from
receipt of materials, through processing, packaging and repackaging, labeling and
relabelling, to completion of the finished product.

Qualification
Action of proving that any premises, systems and items of equipment work
correctly and actually lead to the expected results. The meaning of the word
“validation” is sometimes extended to incorporate the concept of qualification.

.
Quarantine
The status of starting or packaging materials, intermediates, or bulk or finished
products isolated physically or by other effective means while a decision is
awaited on their release, rejection or reprocessing.

Reconciliation
A comparison between the theoretical quantity and the actual quantity.

Recovery
The introduction of all or part of previous batches (or of redistilled solvents and
similar products) of the required quality into another batch at a defined stage
of manufacture. It includes the removal of impurities from waste to obtain a
pure substance or the recovery of used materials for a separate use.

Reprocessing
Subjecting all or part of a batch or lot of an in-process drug, bulk process
intermediate (final biological bulk intermediate) or bulk product of a single batch/
lot to a previous step in the validated manufacturing process due to failure to
meet predetermined specifications. Reprocessing procedures are foreseen as
occasionally necessary for biological drugs and, in such cases, are validated and
pre-approved as part of the marketing authorization.

43
Reworking
Subjecting an in-process or bulk process intermediate (final biological bulk
intermediate) or final product of a single batch to an alternate manufacturing
process due to a failure to meet predetermined specifications. Reworking is
an unexpected occurrence and is not pre-approved as part of the marketing
authorization.

Self-contained area
Premises which provide complete and total separation of all aspects of an
operation, including personnel and equipment movement, with well established
procedures, controls and monitoring. This includes physical barriers as well as
separate air-handling systems, but does not necessarily imply two distinct and
separate buildings.

Specification
A list of detailed requirements with which the products or materials used or
obtained during manufacture have to conform. They serve as a basis for quality
evaluation.

Standard operating procedure (SOP)

An authorized written procedure giving instructions for performing operations
not necessarily specific to a given product or material (e.g. equipment operation,
maintenance and cleaning; validation; cleaning of premises and environmental
control; sampling and inspection). Certain SOPs may be used to
supplement product-specific master and batch production documentation.

Starting material
Any substance of a defined quality used in the production of a pharmaceutical
product, but excluding packaging materials.

Validation
Action of proving, in accordance with the principles of GMP, that any procedure,
process, equipment, material, activity or system actually leads to the
expected results .
19. Limitations of the study

44
  Lack of personal touch with real time consumers & manufacturers, due to
lack of time.

 Lack of sufficient Technical knowledge, leading to negligence of minor

details of the research.

 Interpretation based on personal biases may have affected the outcome.

20.Bibliography

Books:
1-Drug policy 1994
2-Pharmaceutical Policy 2002
3- National Health Policy 2001
4- Ethical Guidelines for Biomedical Research on Human Subjects, ICMR, 2000

5- Measures for Rationalization, Quality Control & Growth of Drugs and

Pharmaceutical Industry in India, Deptt. of Chemicals and petrochemicals, Govt.
of India, 1986

E-Encyclopedia:

“Quality issues in pharmaceutical Industry”-Wikipedia

(http://en.wikipedia.org/wiki/quality_issues_pharmaceutical)

Online services and Internet:

1-Good manufacturing practices;

http//whoindia.org/en/section2/section5/section436.htm
2-Good clinical Practices ; http://cdsco.nic.in/html/gcp.html
3-Good Laboratory Practices : http://indiaglp.gov.in
4- http://nppaindia.nic.in/index1eng.html
5-http://www.dst.gov.in/htm
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