Pharmaceutical Sector In India
Pharmaceutical sectors in India | Pharmaceutical industry in India | Pharmaceutical training in Mumbai | History of pharmaceutical industry
PHARMACEUTICAL INDUSTRY IN INDIA
This industry develops, produces, discover, and markets pharmaceutical drugs for use as medications. Pharmaceutical companies deal with generic or brand medications and medical devices. They are subject to a variety of laws and regulations that govern the safety, patenting, testing, efficiency, and marketing of drugs.
HISTORY OF PHARMACEUTICAL INDUSTRY
Middle of the 1800s – 1945: From botanicals to the first synthetic drugs
The modern pharmaceutical industry traces its roots to two sources. The first of these were local apothecaries that expanded from their traditional role in the distribution of botanical drugs such as morphine and quinine to wholesale manufacture in the mid-1800s. Rational drug discovery was started from plants particularly with the isolation of morphine, analgesic and the sleep-inducing agent from opium, by the German apothecary assistant Friedrich Sertürner, who named the compound after the Greek god of dreams as Morpheus. Multinational corporations including Hoffman-la-Roche, Merck, Burroughs-Wellcome (now part of Glaxo Smith Kline), Abbott Laboratories, Eli Lilly and Upjohn (now part of Pfizer) began as local apothecary shops in the mid-1800s. By the late 1880s, German dye manufacturers had perfected the purification of individual organic compounds from coal tar and other mineral sources and had also established rudimentary methods in organic chemical synthesis. The development of synthetic chemical methods allowed scientists to systematically vary the structure of chemical substances, and growth in the emerging science of pharmacology expanded their ability to evaluate the biological effects of these structural changes.
EPINEPHRINE, NOREPINEPHRINE, AND AMPHETAMINES
By the 1890s, the profound effect of adrenal extracts on many different tissue types had been discovered, setting off a search both for the mechanism of chemical signaling and efforts to exploit these observations for the development of new drugs. The blood pressure raising and vasoconstrictive effects of adrenal extracts were of particular interest to surgeons as hemostatic agents and as the treatment for shock, and a number of companies developed products based on adrenal extracts containing varying purities of the active substance. In 1897, John Abel of Johns Hopkins University identified the active principle as epinephrine, which he isolated in an impure state as the sulfate salt. Industrial chemist Jokichi Takamine later developed a method for obtaining epinephrine in a pure state and licensed the technology to Parke Davis. Parke Davis marketed epinephrine under the trade name Adrenalin. Injected epinephrine proved to be especially efficacious for the acute treatment of asthma attacks, and an inhaled version was sold in the United States until 2011 (Primatene Mist). By 1929 epinephrine had been formulated into an inhaler for use in the treatment of nasal congestion.
While highly effective, the requirement for injection limited the use of epinephrine and orally active derivatives were sought. A structurally similar compound, ephedrine was identified by Japanese chemists in the Ma Huang plant and marketed by Eli Lilly as an oral treatment for asthma. Following the work of Henry Dale and George Barger at Burroughs-Wellcome, academic chemist Gordon Alles synthesized amphetamine and tested it in asthma patients in 1929. The drug proved to have only modest anti-asthma effects but produced sensations of exhilaration and palpitations. Amphetamine was developed by Smith, Kline, and French as a nasal decongestant under the trade name Benzedrine Inhaler. Amphetamine was eventually developed for the treatment of narcolepsy, post-encephalitic parkinsonism, and mood elevation in depression and other psychiatric indications. It received approval as a New and Nonofficial Remedy from the American Medical Association for these uses in 1937 and remained in common use for depression until the development of tricyclic antidepressants in the 1960s.
Diethylbarbituric acid was the first marketed barbiturate. It was sold by Bayer under the trade name Veronal
Hermann Emil Fischer and Joseph von Mering disclosed their discovery that diethylbarbituric acid, formed from the reaction of the diethylmalonic acid, phosphorus oxychloride, and urea, induces sleep in dogs. The discovery was patented and licensed to Bayer pharmaceuticals, which marketed the compound under the trade name Veronal as a sleep aid beginning in 1904. Systematic investigations of the effect of structural changes in potency and duration of action led to the discovery of phenobarbital at Bayer in 1911 and the discovery of its potent anti-epileptic activity in 1912. Phenobarbital was among the most widely used drugs for the treatment of epilepsy through the 1970s, and as of 2014, remains on the World Health Organizations list of essential medications. Today, amphetamine is largely restricted to use in the treatment of attention deficit disorder and phenobarbital in the treatment of epilepsy.
A series of experiments performed from the 1800s to the early 1900s revealed that diabetes is caused by the absence of a substance normally produced by the pancreas. In 1869, Oskar Minkowski and Joseph von Mering found that diabetes could be induced in dogs by surgical removal of the pancreas. In 1921, Frederick Banting and his student Charles Best repeated this study and found that injections of pancreatic extract reversed the symptoms produced by pancreas removal. Soon, the extract was demonstrated to work in people, but the development of insulin therapy as a routine medical procedure was delayed by difficulties in producing the material in sufficient quantity and with reproducible purity. The researchers sought assistance from industrial collaborators at Eli Lilly and Co. based on the company's experience with the large-scale purification of biological materials. George B. Walden of Eli Lilly and Company found that careful adjustment of the pH of the extract allowed a relatively pure grade of insulin to be produced. Under pressure from Toronto University and a potential patent challenge by academic scientists who had independently developed a similar purification method, an agreement was reached for non-exclusive production of insulin by multiple companies. Prior to the discovery and widespread availability of insulin therapy, the life expectancy of diabetics was only a few months.
SALVARSAN, PROTONSIL, PENICILLIN, AND VACCINES
The development of drugs for the treatment of infectious diseases was a major focus of early research and development efforts; in 1900 pneumonia, tuberculosis, and diarrhea were the three leading causes of death in the United States.
In 1911 arsphenamine, the first synthetic anti-infective drug was developed by Paul Ehrlich and chemist Alfred Bertheim of the Institute of Experimental Therapy in Berlin. The drug was given the commercial name Salvarsan. Ehrlich, noting both the general toxicity of arsenic and the selective absorption of certain dyes by bacteria, hypothesized that an arsenic-containing dye with similar selective absorption properties could be used to treat bacterial infections. Arsphenamine was prepared as part of a campaign to synthesize a series of such compounds and found to exhibit partially selective toxicity. Arsphenamine proved to be the first effective treatment for syphilis, a disease which prior to that time was incurable and led inexorably to severe skin ulceration, neurological damage, and death.
Ehrlich's approach of systematically varying the chemical structure of synthetic compounds and measuring the effects of these changes on biological activity was pursued broadly by industrial scientists, including Bayer scientists Josef Klarer, Fritz Mietzsch, and Gerhard Domagk. This work, also based in the testing of compounds available from the German dye industry, led to the development of Prontosil, the first representative of the sulfonamide class of antibiotics. Compared to arsphenamine, the sulfonamides had a broader spectrum of activity and were far less toxic, rendering them useful for infections caused by pathogens such as streptococci. In 1939, Domagk received the Nobel Prize in Medicine for this discovery. Nonetheless, the dramatic decrease in deaths from infectious diseases that occurred prior to World War II was primarily the result of improved public health measures such as clean water and less crowded housing, and the impact of anti-infective drugs and vaccines was significant mainly after World War II.
In 1928, Alexander Fleming discovered the antibacterial effects of penicillin, but its exploitation for the treatment of human disease awaited the development of methods for its large-scale production and purification. These were developed by the U.S. and British government-led consortium of pharmaceutical companies during the Second World War.
Early progress toward the development of vaccines occurred throughout this period, primarily in the form of academic and government-funded basic research was directed towards the identification of the pathogens responsible for common communicable diseases. In 1885 Louis Pasteur and Pierre Paul Émile Roux created the first rabies vaccine. The first diphtheria vaccines were produced in 1914 from a mixture of diphtheria toxin and antitoxin, but the safety of the inoculation was marginal and it was not widely used. The United States recorded around 200,000 cases of diphtheria in 1921 resulting in 15,520 deaths. In 1923 parallel efforts by Gaston Ramon at the Pasteur Institute and Alexander Glenny at the Wellcome Research Laboratories led to the discovery that a safer vaccine could be produced by treating diphtheria toxin with formaldehyde. In 1944, Maurice Hilleman of Squibb Pharmaceuticals developed the first vaccine against Japanese encephalitis. Hilleman would later move to Merck where he would play a key role in the development of vaccines against measles, mumps, chickenpox, rubella, hepatitis A, hepatitis B, and meningitis.
Unsafe drugs and early industry regulation
Prior to the 20th century, drugs were generally produced by small-scale manufacturers with little regulatory control over manufacturing or claims of safety and efficacy. To the extent that such laws did exist, enforcement was lax. In the United States, increased regulation of vaccines and other biological drugs was spurred by tetanus outbreaks and deaths caused by the distribution of contaminated smallpox vaccine and diphtheria antitoxin. The Biologics Control Act of 1902 required that federal government grant premarket approval for every biological drug and for the process and facility producing such drugs. This was followed in 1906 by the Pure Food and Drugs Act, which forbade the interstate distribution of adulterated or misbranded foods and drugs. A drug was considered misbranded if it contained alcohol, morphine, opium, cocaine, or any of several other potentially dangerous or addictive drugs, and if its label failed to indicate the quantity or proportion of such drugs. The government's attempts to use the law to prosecute manufacturers for making unsupported claims of efficacy were undercut by a Supreme Court ruling restricting the federal government's enforcement powers to cases of the incorrect specification of the drug's ingredients.
In 1937 over 100 people died after ingesting "Elixir Sulfanilamide" manufactured by S.E. Massengill Company of Tennessee. The product was formulated in diethylene glycol, a highly toxic solvent that is now widely used as antifreeze. Under the laws extant at that time, prosecution of the manufacturer was possible only under the technicality that the product had been called an "elixir", which literally implied a solution in ethanol. In response to this episode, the U.S. Congress passed the Federal Food, Drug, and Cosmetic Act of 1938, which for the first time required pre-market demonstration of safety before a drug could be sold, and explicitly prohibited false therapeutic claims.
DRUG DISCOVERY AND DEVELOPMENT
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes pre-clinical research on microorganisms and animals, filing for regulatory statuses, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug
The process from which potential drugs are discovered or designed is known as Drug Discovery. In the past, most drugs have been discovered either by isolating the active ingredient from traditional remedies or by serendipitous discovery. 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 cost of late-stage development has meant it is usually done by the larger pharmaceutical companies.
Often, large multinational corporations exhibit vertical integration, participating in a broad range of drug discovery and development, manufacturing and quality control, marketing, sales, and distribution. Smaller organizations, on the other hand, often focus on a specific aspect such as discovering drug candidates or developing formulations. Often, collaborative agreements between research organizations and large pharmaceutical companies are formed to explore the potential of new drug substances. More recently, multi-nationals are increasingly relying on contract research organizations to manage drug development.
COST OF INNOVATION
Drug discovery and development is very expensive of all compounds investigated for use in humans only a small fraction are eventually approved in most nations by government-appointed medical institutions or boards, who have to approve new drugs before they can be marketed in those countries. Since 2001, the Center for Drug Evaluation and Research has averaged 22.9 approvals a year. This approval comes only after heavy investment in pre-clinical development and clinical trials, as well as a commitment to ongoing safety monitoring. Drugs if failed or rejected incur the large cost and no revenue in return.
Industry-wide research and investment reached a record $65.3 billion in 2009. While the cost of research in the U.S. was about $34.2 billion between 1995 and 2010, revenues rose faster.
A study by the consulting firm Bain & Company reported that the cost of discovering, developing and launching a new drug rose over a five-year period to nearly $1.7 billion in 2003. According to Forbes, by 2010 development costs were between $4 billion to $11 billion per drug.
A direct consequence within the pharmaceutical industry value chain is that major pharmaceutical multinationals tend to increasingly outsource risks related to fundamental research, which somewhat reshapes the industry ecosystem with biotechnology companies playing an increasingly important role, and overall strategies being redefined accordingly. Some approved drugs, such as those based on re-formulation of an existing active ingredient are much less expensive to develop.
The examples and perspective in this section deal primarily with the United States and do not represent a worldwide view of the subject.
Pharmaceutical fraud brings financial gain to a pharmaceutical company Which involves Deception. It affects individuals and public and private insurers. There are several different schemes used to defraud the health care system which is particular to the pharmaceutical industry. These include Good Manufacturing Practice Violations, Off-Label Marketing, Best Price Fraud, CME Fraud, Medicaid Price Reporting, and Manufactured Compound Drugs. Total Of this amount $2.5 billion was recovered through False Claims Act cases in FY 2010. Examples of fraud cases include the GlaxoSmithKline $3 billion settlement, Pfizer $2.3 billion settlement and Merck & Co. $650 million settlement. Damages from fraud can be recovered by use of the False Claims Act, most commonly under the quitam provisions which reward an individual for being a "whistleblower", or realtor.
Every major company selling the antipsychotics — Bristol-Myers Squibb, Eli Lilly, Pfizer, AstraZeneca and Johnson & Johnson has either settled recent government cases, under the False Claims Act, for hundreds of millions of dollars or is currently under investigation for possible health care fraud. Following charges of illegal marketing, two of the settlements set records last year for the largest criminal fines ever imposed on corporations. One involved Eli Lilly's antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon- Pfizer settled that part of the claim for $301 million, without admitting any wrongdoing.
On 2 July 2012, GlaxoSmithKline pleaded guilty to criminal charges and agreed to a $3 billion settlement of the largest health-care fraud case in the U.S. and the largest payment by a drug company. The settlement is related to the company's illegal promotion of prescription drugs, its failure to report safety data, bribing doctors, and promoting medicines for uses for which they were not licensed. The drugs involved were Paxil, Wellbutrin, Advair, Lamictal, and Zofran for off-label, non-covered uses. Those and the drugs Imitrex, Lotronex, Flovent, and Valtrex were involved in the kickback scheme.
Marcep Inc. focus is to deliver initiatives and activities which ensure a competent and safe workforce training for the industry both now and in the future.
A Partial Training List:
A Risk-Based Approach to Computer Systems Validation
Achieving Compliance with Proper CAPA Systems
Achieving Compliance with Proper CAPA Systems for Medical Devices
An Overview of Documentation Requirements In FDA Regulated Industries
Analytical Methods Validation for FDA Compliance
Annual Product Reviews for the Pharmaceutical and Related Industries
APIs & Excipients - A Global Regulatory Overview
Applying Quality Risk Management
Auditing and Inspecting Preclinical Research for GLP Compliance
Auditing for GMP Compliance
Avoiding Pharmaceutical and Biopharmaceutical Data Integrity Problem
Batch Records: Simplified and Clarified
Best Practices for Investigating Deviations and Non-Conformances
Best Practices for Manufacturing Active Pharmaceutical Ingredients
Biopharmaceutical Analytics: From Development to Validation
Building the eCTD for FDA Submission
Ensuring Data Integrity: A Multi-Disciplinary Approach
Clean Room Operations in a Nutshell
CMC Writing and Submission Strategies: A Global Regulatory Approach
Pharmaceutical sectors in India | Pharmaceutical industry in India | Pharmaceutical training in Mumbai | History of pharmaceutical industry | Pharmaceutical fraud | Computer Systems Validation in pharmaceuticals | GDP, GLP, Data integrity, Gamp 5