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

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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 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

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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 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,

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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.

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Figure1.1

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.

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Literature Review2.1 :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.

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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.

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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.

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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.

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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.

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

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No of Sub-Standard Quality

No of Sub-Standard Quality %

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.

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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.

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

Some of the prominent ones are:a. Lack of enforcement of existing lawsb. Weak penal actionc. Very remunerative traded. Large scale sickness in small scale pharmaceutical industrye. Availability of improved printing technology that helps in counterfeitingf. Lack of coordination between various agenciesg. Too many retail & whole sale chemist outletsh. Inadequate cooperation between stakeholders.i. Lack of control by importing/exporting countriesj. 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.

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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”

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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.

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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.

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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

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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 ofstaff and in many cases a combination of more than one of these constraints.

13. Suggested Action by the Pharmaceutical Industry

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It has been observed that industry has a well-developed marketing anddistribution network. The industry can streamline their supply chain andmake 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

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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 theseactions 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

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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 takesaccount 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 formand 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 correctstarting and packaging materials;

(e) all necessary controls on starting materials, intermediate products, andbulk products and other in-process controls, calibrations, and validationsare carried out;

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

(g) pharmaceutical products are not sold or supplied before the authorizedpersons 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;

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(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 onproduct quality;

(l) regular evaluations of the quality of pharmaceutical products should beconducted with the objective of verifying the consistency of the processand 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 competentpersonnel, and should have suitable and sufficient premises, equipment, andfacilities.

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16.Good manufacturing practices for pharmaceutical products (GMP)

Good manufacturing practice is that part of quality assurance which ensuresthat products are consistently produced and controlled to the quality standardsappropriate to their intended use and as required by the marketing authorization. GMP are aimed primarily at diminishing the risks inherent in anypharmaceutical 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. UnderGMP:

(a) all manufacturing processes are clearly defined, systematically reviewed inthe light of experience, and shown to be capable of consistently manufacturingpharmaceutical products of the required quality that comply withtheir 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-processcontrols;

(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) duringmanufacture to show that all the steps required by the defined proceduresand instructions have in fact been taken and that the quantity and qualityof the product are as expected; any significant deviations are fully recorded

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and investigated;

(g) records covering manufacture and distribution, which enable the completehistory of a batch to be traced, are retained in a comprehensible and accessibleform;

(h) the proper storage and distribution of the products minimizes any risk totheir 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 qualitydefects investigated, and appropriate measures taken in respect of thedefective products to prevent recurrence.

16.1Sanitation and hygiene

A high level of sanitation and hygiene should be practised in every aspectof the manufacture of drug products. The scope of sanitation and hygiene coverspersonnel, premises, equipment and apparatus, production materials and containers, products for cleaning and disinfection, and anything that could becomea 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 identifywhat qualification and validation work is required to prove that the criticalaspects of their particular operation are controlled.

The key elements of a qualification and validation programme of a companyshould be clearly defined and documented in a validation master plan.

Qualification and validation should establish and provide documentaryevidence that:(a) the premises, supporting utilities, equipment and processes have beendesigned in accordance with the requirements for GMP (design qualification,

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or DQ);(b) the premises, supporting utilities and equipment have been built andinstalled in compliance with their design specifications (installation qualification,or IQ);(c) the premises, supporting utilities and equipment operate in accordancewith 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 statedin the relevant company documentation, such as the quality manual or validationmaster 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 validationof analytical test methods, automated systems and cleaning procedures.

16.3 Complaints

Principle. All complaints and other information concerning potentiallydefective products should be carefully reviewed according to written proceduresand the corrective action should be taken.

A person responsible for handling the complaints and deciding the measuresto be taken should be designated, together with sufficient supporting staffto assist him or her. If this person is different from the authorized person, thelatter 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

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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 qualitycontrol should normally be involved in the review of such investigations.

If a product defect is discovered or suspected in a batch, considerationshould be given to whether other batches should be checked in order to determinewhether they are also affected. In particular, other batches that maycontain reprocessed product from the defective batch should be investigated.

Where necessary, appropriate follow-up action, possibly including productrecall, should be taken after investigation and evaluation of the complaint.

All decisions made and measures taken as a result of a complaint should berecorded 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 ofmarketed 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, promptlyand 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 regularlyreviewed and updated, for the organization of any recall activity. Recall operationsshould be capable of being initiated promptly down to the required levelin the distribution chain.

An instruction should be included in the written procedures to storerecalled products in a secure segregated area while their fate is decided.

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

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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 anddirectly supplied customers (including, for exported products, those who havereceived samples for clinical tests and medical samples) to permit an effectiverecall.

The progress of the recall process should be monitored and recorded.Records should include the disposition of the product. A final report should beissued, including a reconciliation between the delivered and recovered quantitiesof 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 ina 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 thecontract accepter.

In the case of contract analysis, the final approval for release must be givenby the authorized person.

The contract giver is responsible for assessing the competence of the contractaccepter in successfully carrying out the work or tests required, forapproval for contract activities, and for ensuring by means of the contract thatthe principles of GMP described in this guide are followed.

The contract giver should provide the contract accepter with all theinformation necessary to carry out the contracted operations correctly in accordance with the marketing authorization and any other legal requirements. Thecontract giver should ensure that the contract accepter is fully aware of anyproblems associated with the product, work or tests that might pose a hazardto premises, equipment, personnel, other materials or other products.

The contract giver should ensure that all processed products and materialsdelivered by the contract accepter comply with their specifications or that theproduct has been released by the authorized person.The contract accepter.

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The contract accepter must have adequate premises, equipment, knowledge,and experience and competent personnel to carry out satisfactorily thework ordered by the contract giver. Contract manufacture may be undertakenonly by a manufacturer who holds a manufacturing authorization.

The contract accepter should not pass to a third party any of the workentrusted to him or her under the contract without the contract giver’s priorevaluation and approval of the arrangements. Arrangements made between thecontract accepter and any third party should ensure that the manufacturing andanalytical information is made available in the same way as between the originalcontract giver and contract accepter.

The contract accepter should refrain from any activity that may adverselyaffect the quality of the product manufactured and/or analysed for the contractgiver.

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 themarketing authorization.

Technical aspects of the contract should be drawn up by competentpersons suitably knowledgeable in pharmaceutical technology, analysis andGMP.

All arrangements for production and analysis must be in accordance withthe 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 qualitycontrols, including in-process controls, and who has responsibility for samplingand analysis. In the case of contract analysis, the contract should state whetheror not the contract accepter should take samples at the premises of themanufacturer.

Manufacturing, analytical, distribution records and reference samplesshould be kept by, or be available to, the contract giver. Any records relevantto assessing the quality of a product in the event of complaints or a suspecteddefect must be accessible and specified in the defect/recall procedures of thecontract giver.

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The contract should describe the handling of starting materials, intermediateand bulk products and finished products if they are rejected. It shouldalso describe the procedure to be followed if the contract analysis shows thatthe tested product must be rejected.

16.7 Self-inspection and quality audits

Principle.

The purpose of self-inspection is to evaluate the manufacturer’scompliance with GMP in all aspects of production and quality control. The self inspection programme should be designed to detect any shortcomings in theimplementation of GMP and to recommend the necessary corrective actions.Self-inspections should be performed routinely, and may be, in addition, performedon special occasions, e.g. in the case of product recalls or repeated rejections,or when an inspection by the health authorities is announced. The teamresponsible for self-inspection should consist of personnel who can evaluate theimplementation of GMP objectively. All recommendations for corrective actionshould 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 questionnaireson 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;

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(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 beappointed from inside or outside the company.Frequency of self-inspection

The frequency at which self-inspections are conducted may depend oncompany requirements but should preferably be at least once a year. Thefrequency should be stated in the procedure.

Self-inspection reportA report should be made at the completion of a self-inspection. The reportshould 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 qualitysystem with the specific purpose of improving it. A quality audit is usually conducted by outside or independent specialists or a team designated by themanagement for this purpose. Such audits may also be extended to suppliersand contractors.

Suppliers’ audits and approval The person responsible for quality control should have responsibility

together with other relevant departments for approving suppliers who canreliably supply starting and packaging materials that meet establishedspecifications.

Before suppliers are approved and included in the approved suppliers’ listor specifications, they should be evaluated. The evaluation should take intoaccount a supplier’s history and the nature of the materials to be supplied. If an

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audit is required, it should determine the supplier’s ability to conform withGMP standards.

16.8 Personnel

Principle. The establishment and maintenance of a satisfactory system ofquality assurance and the correct manufacture and control of pharmaceuticalproducts and active ingredients rely upon people. For this reason there must besufficient qualified personnel to carry out all the tasks for which the manufactureris responsible. Individual responsibilities should be clearly defined andunderstood by the persons concerned and recorded as written descriptions.General

The manufacturer should have an adequate number of personnel with thenecessary qualifications and practical experience. The responsibilities placed onany 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 writtendescriptions and adequate authority to carry out their responsibilities. Theirduties may be delegated to designated deputies of a satisfactory qualificationlevel. There should be no gaps or unexplained overlaps in the responsibilitiesof personnel concerned with the application of GMP. The manufacturer shouldhave an organization chart.

All personnel should be aware of the principles of GMP that affect themand receive initial and continuing training, including hygiene instructions, relevantto their needs. All personnel should be motivated to support the establishmentand 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

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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.

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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 purchasingfrom licensed sources with valid cash memos.

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18. GlossaryThe definitions given below apply to the terms used in this study. They mayhave 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.

AirlockAn enclosed space with two or more doors, which is interposed between twoor 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. Anairlock is designed for use either by people or for goods and/or equipment.

Authorized personThe 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.

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

CalibrationThe set of operations that establish, under specified conditions, the relationshipbetween values indicated by an instrument or system for measuring (especiallyweighing), recording, and controlling, or the values represented by a materialmeasure, and the corresponding known values of a reference standard. Limitsfor acceptance of the results of measuring should be established.

Clean areaAn 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 suppliedat 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.

ContaminationThe 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.

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Critical operationAn operation in the manufacturing process that may cause variation in the quality of the pharmaceutical product.

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

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

In-process controlChecks 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 productPartly processed product that must undergo further manufacturing steps before it becomes a bulk product.

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

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

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

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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 formulaA 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 finishedproduct as well as the processing instructions, including the in-process controls.

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

PackagingAll 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 materialAny 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 productAny 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.

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ProductionAll 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.

QualificationAction 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.

.QuarantineThe status of starting or packaging materials, intermediates, or bulk or finishedproducts isolated physically or by other effective means while a decision isawaited on their release, rejection or reprocessing.

ReconciliationA comparison between the theoretical quantity and the actual quantity.

RecoveryThe introduction of all or part of previous batches (or of redistilled solvents andsimilar products) of the required quality into another batch at a defined stageof manufacture. It includes the removal of impurities from waste to obtain apure substance or the recovery of used materials for a separate use.

ReprocessingSubjecting 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 tomeet predetermined specifications. Reprocessing procedures are foreseen asoccasionally necessary for biological drugs and, in such cases, are validated andpre-approved as part of the marketing authorization.

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ReworkingSubjecting an in-process or bulk process intermediate (final biological bulkintermediate) or final product of a single batch to an alternate manufacturingprocess due to a failure to meet predetermined specifications. Reworking isan unexpected occurrence and is not pre-approved as part of the marketingauthorization.

Self-contained areaPremises 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 asseparate air-handling systems, but does not necessarily imply two distinct and separate buildings.

SpecificationA list of detailed requirements with which the products or materials used orobtained during manufacture have to conform. They serve as a basis for qualityevaluation.

Standard operating procedure (SOP)An authorized written procedure giving instructions for performing operationsnot necessarily specific to a given product or material (e.g. equipment operation,maintenance and cleaning; validation; cleaning of premises and environmentalcontrol; sampling and inspection). Certain SOPs may be used tosupplement product-specific master and batch production documentation.

Starting materialAny substance of a defined quality used in the production of a pharmaceuticalproduct, but excluding packaging materials.

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

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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.htm2-Good clinical Practices ; http://cdsco.nic.in/html/gcp.html3-Good Laboratory Practices : http://indiaglp.gov.in4- http://nppaindia.nic.in/index1eng.html5-http://www.dst.gov.in/htm 21. REFRENCES

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1. World Health Organization (2006) Counterfeit medicines. Available:http://www.who.int/mediacentre/factsheet s/fs275/en/index.html  . Accessed 2010 April 2.

2. Government of India: Ministry of Health and Family Welfare (2003) Report of the Expert Committee on a Comprehensive Examination of Drug Regulatory Issues, Including the Problem of Spurious Drugs. Available: http://cdsco.nic.in/html/Final20Report20 mashelkar.pdf . Accessed 2010 March 26.

3. Bate R, Coticelli P, Tren R, Attaran A (2008) Antimalarial Drug Quality in the Most Severely Malarious Parts of Africa – A Six Country Study. PLoS ONE 3(5): e2132. doi:10.1371/journal.pone.0002132.

4. World Health Organization (2002) Effective Drug Regulation: A Multicountry Study. Available:http://www.who.int/medicinedocs/pdf/s230 0e/s2300e.pdf  . Accessed 2010 April 1.

5.  Smarter Medicine: The Smarter Supply Chain of the Future ; http://w.on24.com/clients/ibm/157263

6. World Health OrganizationGlobal Malaria Programme (2008) World Malaria Report. Available:http://www.who.int/malaria/wmr2008/. Accessed 2010 April 8.

7. World Health Organization (2009) Global Tuberculosis Control: Epidemiology, Strategy, Financing. Available: http://www.who.int/tb/publications/globa l_report/2009/en/ index.html . Accessed 2010 March 29.

8. Global Pharma Health Fund E.V. (2008) GPHF-Minilab-Manuals. Available:http://www.gphf.org/web/en/minilab/manua ls.htm  . Accessed 2010 April 8.

9. Armonk ,N.Y. report ; http://www.ibm.com/investors/.pdf10. Hathi Committee Report 197511. Drugs and cosmetics Act, 1940 and Rules there under, 194512. DGHS Committee Report on Spurious drugs, Ministry of Health & FW, 200113. Mashelkar Committee Report of the Pharmaceutical Research and Development, Deptt. of Chemicals and Petrochemicals, 199914. Effective Drug regulation, A Multicountry study by World Health Organization, 200215. Annals of Internal Medicine, Vol. 135, No. 8 (Part1), 200116. A study on Availability and Prices of Medicines in India by VOICE, 200217. Ministry of Health & FW, Task Force Report, 198518. Estimates Committee of Lok Sabha Report, 1983-8419. GCP Guidelines for conducting Clinical Research in India by CDSCO, Ministry of Health & FW, 200120. Capacity Building Project on Food Safety and Quality Control and Quality Control of Drugs, Ministry of Health & FW, April 200321. National Human Rights Commission Report 199922. Scrip magazine, September 2003

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