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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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Perrigo Company plc…….on the rise


AlleganEAO.jpg

Perrigo Company plc

Perrigo Company plc is a large Irish manufacturer of private label over-the-counter pharmaceuticals.[2] The company’s shares are traded on the NYSE and the Tel Aviv Stock Exchange; as a result of the merger with Agis Industries the company is a constituent of the TA-25 Index. Perrigo is the only non-Israeli company on the TA-25.

Perrigo Company plc, through its wholly owned subsidiaries, engages in the manufacture and sale of consumer healthcare products, generic prescription drugs, active pharmaceutical ingredients (API), and consumer products primarily in the United StatesAustralia,IsraelEuropeIndia and Mexico.

Type Public
Traded as NYSEPRGO
TASEPRGO
S&P 500 Component
Industry Pharmaceutical
Founded 1887
Headquarters Allegan, MichiganUSA
Key people Joseph C. Papa, Chairman, President and CEO
Products OTC, RX, API, Medical Diagnostic, pharmaceuticals
Revenue Increase $3,540 million (2013)[1]
Operating income Increase $805 million(2013)
Net income Increase $ 530 million (2013)
Employees 7,250 (2009)
Website www.perrigo.com

Address:

515 Eastern Avenue
Allegan, Michigan 49010-9070
U.S.A.

Telephone: (269) 673-8451
Toll Free: 800-253-3606
Fax: (269) 673-7535

Website: www.perrigo.com

Public Company
Incorporated: 1892
Employees: 3,983
Sales: $826.0 million (2003)
Stock Exchanges: NASDAQ
Ticker Symbol: PRGO
NAIC: 325412 Pharmaceutical Preparation Manufacturing; 325413 In-Vitro Diagnostic Substance Manufacturing

 

History

Black and white photo of L.Perrigo Co. Aspirin tablets

The L. Perrigo Company was founded in 1887 in Allegan, Michigan, by Luther and Charles Perrigo, who ran a country general store .[3] In 1991 Perrigo had an Initial public offering onNASDAQ.

In March 2005 the firm acquired Agis Industries Ltd. (TASE:AGIS), an Israel based generic pharmaceuticals company in an $850 million transaction. Agis was founded in 1983 by Moshe (Mori) Arkin

MOSHE ARKIN

 

who developed his father’s small drug import business into a multinational generic pharmaceutical company. As a result of the acquisition Arkin owns 9% of Perrigo, and was appointed as Vice Chairman of the company.[4]

Acquisitions

On 9 January 2008, the firm acquired Galpharm Healthcare, Ltd., a supplier of over-the-counterstore brand pharmaceuticals in the United Kingdom.[5] On 16 September 2008, the firm acquired J.B. Laboratories.[6] On 6 October 2008, it acquired Laboratorios Diba S.A., enabling the company to market its products in Mexico.[7]On 13 November 2008, it acquired Unico Holdings, a manufacturer of store brand pediatric electrolytes, enemas and feminine hygiene products for retail consumers in the U.S.[8]

On 1 March 2010, the firm acquired Orion Laboratories Pty, Ltd. a supplier of over-the-counter (OTC) store brand pharmaceutical products in Australia and New Zealand.[9] On 23 March 2010, it acquired PBM Holdings, Inc.,a producer of over-the-counter store brand infant formula and baby foods in the United States, Canada, Mexico and China.[10]

 

Perrigo Company is the largest manufacturer of over-the-counter (OTC) pharmaceuticals and nutritional products for store brands in the United States. The company estimates that it holds more than 50 percent of the store brand market. Perrigo produces more than 30 billion pills per year and manufactures about 1,200 products. Most of these are pharmaceuticals–such as analgesics, cough and cold remedies, and gastrointestinal and feminine hygiene products–which account for about four-fifths of the company’s sales. Perrigo ranks as the largest producer of aspirin in the United States. The remaining 20 percent of revenues come from the sale of nutritional products, including vitamins and nutritional supplements and drinks. Perrigo supplies 300 different retailers with these products under the retailer’s own label so that they can be promoted as house brands. These customers include major drugstore chains (CVS, Eckerd, Walgreens), grocery chains (Albertson’s, Kroger, Safeway), mass discounters (Kmart, Target, Wal-Mart), and major wholesalers (McKesson, Supervalu). Perhaps not surprisingly, the largest Perrigo customer by far is retailing giant Wal-Mart, which accounted for 27 percent of net sales for fiscal 2003. The company also markets certain products under its own brand name, Good Sense, although such products account for only a small percentage of sales. Two non-U.S. subsidiaries generate a little more than 9 percent of revenues. Wrafton Laboratories Ltd. supplies store brand products to major grocery and drug retailers in the United Kingdom, while the Mexican firm Química y Farmacia, S.A. de C.V. produces mainly OTC and prescription pharmaceuticals for retail, wholesale, and government customers. Perrigo Company operates 11 manufacturing plants in Michigan, South Carolina, Mexico, and the United Kingdom. Perrigo has enjoyed nearly continuous growth since the end of World War II. This growth can be partly attributed to the mass acceptance of generic and store brand pharmaceutical products.

Early Years

The company was founded by Luther and Charles Perrigo in 1887. The Perrigo brothers had moved to Allegan County, Michigan, a few years earlier from New York. Once in Michigan the brothers established a modest business. Luther Perrigo ran a country general store and apple drying business, while Charles helped with sales. Luther decided to package generic home remedies and sell them to other small country stores like his own. The first packaging plant for these medicines was run out of Charles Perrigo’s home, but Charles soon moved to Ohio, leaving the business entirely to his brother. Luther became president of the firm when it incorporated in 1892. Perrigo remained a family-owned business for 90 years. Five of the company’s seven presidents were descendants of Luther Perrigo, who died in 1902. His son Harry became president at that time, holding the position for the next 49 years.

During the 1920s the company turned to the private label concept in order to build customer loyalty. Stores ordering a certain minimum number could have their own names imprinted on the labels. Products of the era that were the subject of such deals included aspirin, bay rum, epsom salts, sweet oil, and zinc oxide. In the mid-1930s Perrigo gained its first major private label customer, the K & W group, a buying organization that evolved into the People’s Drug Store chain. The second such customer was Sam’s, a major Detroit area drug chain. At the same time the company’s customer base was shifting from small general stores to large regional and national drug chains.

Post-World War II Shift from Packager to Manufacturer

Harry Perrigo turned over the reins to his brother Ray in 1951. It was in the 1950s that the company, while still under the leadership of Ray Perrigo and future President William L. Tripp, Sr., made a crucial decision. Perrigo shifted its focus from that of a repackager of generic drugs to a manufacturer of quality drugs and beauty aids.

William L. Tripp, one of Luther Perrigo’s grandchildren, became president in 1967. During Tripp’s tenure as president the company began to reap the rewards of the change from repackager to manufacturer. The company’s income and the number of Perrigo employees quadrupled. When Tripp died in 1969 his son Bill Tripp, Jr., took over the presidency. During the 1970s Perrigo’s base of customers expanded with the addition of grocery chains and mass merchandisers to the core drugstore chains. By the time of his death in a boating accident in 1980 at the age of 45, Perrigo was the leading private label manufacturer of health and beauty products in the United States. William C. Swaney had been named president of the company two years before the accident, becoming the first leader of the company who was not a member of the Perrigo family.

End of Family Ownership: Early 1980s

Swaney’s presidency lasted from 1978 until 1983. In those five years Perrigo sales tripled and the company became a much larger operation all around. Swaney acquired new companies, set up distribution centers in three states, and expanded and refurbished existing plants. Before leaving as president Swaney oversaw the sale of the company from the Perrigo family to the management. After almost 100 years of family operation the company was sold.

Michael Jandernoa, who had joined the company in 1979 as vice-president for finance, became the seventh president of Perrigo in 1984, while Swaney took over as chairman of the board and CEO. Swaney instituted a style of management at Perrigo that his successor Jandernoa admitted he probably would have tried to block had he been in a position to do so at the time. Yet Jandernoa came to appreciate the open style of administration that Swaney initiated. The company contended that the different disciplines interacted in the decision-making process much more than in traditional American businesses.

Part of the Grow Group, 1986-88

Jandernoa continued the policy of expansion started by Swaney. Perrigo acquired Bell Pharmacal Labs of South Carolina in 1984. Early in the Jandernoa presidency, however, the board of directors began entertaining offers from larger companies that might want to acquire Perrigo itself. In 1986 Perrigo became the largest single company in Grow Group, Inc., a publicly held group of 23 manufacturing companies that bought Perrigo for $45 million. Jandernoa was named CEO of Perrigo; he continued to serve as president. Perrigo represented about a third of Grow Group. As the largest component in a conglomerate with access to funds through the New York Stock Exchange, Perrigo was able to raise new funds for more expansion.

Perrigo celebrated the company’s centenary with two ambitious building projects. It built a $1.5 million plant for the manufacture of effervescent tablets and a $3.5 million graphics art complex to house all of the company’s printing needs. Because Perrigo supplied many different retailers with the same house brand product, their printing facilities were an important part of their production system. The graphics and printing department employed about 290 people and produced almost 70 percent of the company’s labels and 44 percent of their cartons in the early 1990s. The construction of the graphics department, coupled with other expenses, totaled approximately $12.6 million in outlays to the company’s printing and graphics department since the Grow purchase in 1986.

Back to Management Ownership and Then Taken Public: Late 1980s to Early 1990s

After only two years as a part of Grow Group, however, Perrigo was sold back to its management in 1988 in a $106 million deal. That year the company posted sales of $146 million, but by 1994 company sales had ballooned to $669 million. Three years after the sale by Grow to Perrigo management, Jandernoa took the company public. The stock proved popular, though the value fell and rose significantly over time. The market value of the company in July 1994 based on a closing price of $14 a share was $1 billion, for instance. But this price was down from a value of $32 a share in January 1994.

The drop in the value of Perrigo shares was attributed to a drop in sales growth. The company, in fact, had another year of record sales and continued to expand, but stock speculators felt that the market had overreacted to the Perrigo stock offering and had inflated the value beyond its true market worth. Some analysts predicted that the drop in growth was a sign that the national brands would win back bargain-hunting customers in a healthy economy.

Other problems that Perrigo faced in its competition with national brands in the early 1990s concerned finding the right price range for its products. While Perrigo had long wielded its ability to offer lower prices than national brand competitors, sometimes the price difference could be so dramatic–more than 50 percent in some cases–that it could have a reverse effect on the consumer. The consumer weighed the relative cost savings with a judgment on efficacy equivalence. If the price difference was too dramatic, some observers contended, the consumer became suspicious of the Perrigo brand and turned to the national brand. Perrigo therefore developed a system whereby some of the money that it saved from advertising was spent on market research to determine exactly how its products were accepted by the consumer, which products were worth developing, and which had limited potential because of brand allegiance.

One reason for Perrigo’s enormous dominance over the store brand market was its ability to work closely with retailers to promote consumer allegiance to store brands. Beginning in the 1980s Perrigo began a major campaign to help retailers design labels, manage inventory, and develop promotions. Perrigo used its house printing and graphics department to ensure accuracy and reliability in labeling and packaging, permitting rapid new product introductions. Perrigo also enjoyed an advantage over many of its competitors because retail stores had a real incentive to give Perrigo’s product prominence on their shelves. Profit margins for store brand products were considerably greater than for national brands. The store’s public image could be enhanced as well, provided the product sold under their name was satisfactory.

Most of Perrigo’s products were packaged to be readily identifiable with the national brand equivalents. There was a fine line between taking advantage of the competitor’s advertising and carving out a niche that was independently recognized by the consumer. The OTC Market Report disclosed in 1995 that the company was threatened with lawsuits “once or twice a year,” but the vast majority of them were settled in a short period of time. Most of the disputes focused on product dress rather than the actual content of the product. While Perrigo management had become accustomed to lawsuits from competitor companies, in July 1994 Perrigo found itself faced with a lawsuit from closer to home. Its former parent company, Grow Group, filed suit against the company. The Grow Group, valued at less than half of Perrigo, demanded the return of Perrigo stock or a sizable settlement in lieu thereof. Grow claimed that Perrigo management did not act in good faith at the time of the 1988 sale, particularly alleging that they did not reveal a pending agreement to supply products to Wal-Mart, and asked for $2 billion in actual damages and $2 billion in punitive damages. Perrigo contended that the suit was wholly without merit.

One of the company’s strengths was that it faced little legitimate competition. In December 1994 the company purchased Vi-Jon Laboratories, Inc., a leading manufacturer of store brand personal care products, thereby expanding Perrigo’s sales and eliminating a potential competitor at the same time. The purchase price was about $33 million. A similar acquisition occurred earlier, in January 1992, when Cumberland-Swan, Inc., a Tennessee-based maker of store brand personal care products and vitamins, was bought for $35 million.

As the patents on dozens of major prescription drugs began to run out in the mid-1990s, Perrigo began to aggressively go after these lucrative new sources of revenue. Once a prescription drug was reclassified as OTC, the patent holder had two years of exclusivity. At that point generic versions of brand-name OTC products could be produced. An example of this process was Tavist-D, a decongestant and antihistamine that switched from prescription-only to OTC status in 1992. Two years later, Perrigo reached an agreement with the drug’s maker, Sandoz Pharmaceuticals Corp., to begin making a store brand version of Tavist-D in 1995. In subsequent years, Perrigo increasingly turned to such joint ventures to develop new products.

Also in the mid-1990s, Perrigo began looking to the international market for growth, forming subsidiary Perrigo International, Inc. to lead this effort. Among the initially targeted countries were Canada, Japan, Mexico, and Russia.

 

On 20 January 2011, the firm announced that it would acquire Paddock Laboratories Inc., with the deal expected to close in fiscal 2012.[11]

In September 2012, Perrigo announced its intention to enter the animal wellness category by acquiring the assets of Sergeant’s Pet Care Products, Inc., a privately held manufacturer of over-the-counter companion animal healthcare products. [12]

On 11 February 2013, Perrigo announced the completion of the acquisition of Rosemont Pharmaceuticals Ltd., a specialty and generic prescription pharmaceutical company focused on the manufacturing and marketing of oral liquid formulations. [13]On 29 July 2013, the firm announced that it would acquire Élan, a major drugs firm based in Dublin.[14][15]

Segments

The company operates in three segments; Consumer Healthcare, Rx Pharmaceuticals, and Active Pharmaceutical Ingredients. The Consumer Healthcare segment produces over-the-counter pharmaceutical and nutritional products in the United States, the United Kingdom, and Mexico. This segment offers analgesic, cough/cold/allergy/sinus, gastrointestinal, smoking cessationfirst aid, antacids, hemorrhoidal remedies, motion sickness, sleep aid products, feminine hygiene products, vitamin, and nutritional supplementproducts.

The Rx Pharmaceuticals segment produces generic prescription drugs in the United States. This segment provides creams, ointments, lotions, gels, and solutions, as well as nasal sprays, foams, and transdermal devices.

The Active Pharmaceutical Ingredients segment produces pharmaceutical ingredients in Israel with sales to customers worldwide. The company also offers cosmetics, toiletries, detergents, manufactured and imported pharmaceutical products, and medical diagnostic products. The company’s customers include national and regional retail drug, supermarket, wholesalers, and mass merchandise chains.

 

 

 

 

Management

Joseph C. Papa is the Chief Executive Officer and President.[16]

Joseph C. Papa, Jr. '78 has served as Perrigo's president and chief executive officer and as a member of the Board of Directors since October 2006. (School of Pharmacy, Graduate Speaker and Honorary Degree recipient)

Joseph C. Papa Jr.

 

PATENTS

The Perrigo API R&D team has created dozens of ground-breaking, patent-protected industrial processes. These sophisticated, efficient manufacturing procedures facilitate cost-effective production and flexible pricing, helping to strengthen our customers’ long term competitive positions in the marketplace.

Patents ROW
API Description Patent/Application no.
Anastrozole Preparation process DE 102005037484
Imatinib Imatinib process IN 216/KOL/2009
Imatinib Imatinib alpha form DE 102007021043
Moxonidine Moxonidine polymorphs IL 176556
Moxonidine Moxonidine process EP 1982983
Moxonidine Moxonidine process EP 1873151
Moxonidine Moxonidine purification EP 1873152
Moxonidine Moxonidine salts EP 1894927
Terbinafine Hydrochloride Preparation process IL 137364
Theobromine Theobromine process CN 200710116201.8
Theobromine Theobromine purification CN 200710116000.8
Theobromine Theobromine production process WO 2009/089677
Patents USA
API Description Patent/Application no.
Azacitidine Azacitidine crystallization US 2011-0288042
Cetirizine Dihydrochloride Preparation process US 6,100,400
Cilostazol Improved process US 7,524,960
Cisatracurium Cisatracurium acid compounds US 2010-0168431
Cisatracurium Cisatracurium acid process US 2010-0184988
Cisatracurium Cisatracurium API from acid US 2010-0256381
Cisatracurium Cisatracurium by-products US 2011-0185796
Cisatracurium Cisatracurium flash chromatography US 2010-0174082
Cisatracurium Cisatracurium normal phase US 2010-0099878
Cisatracurium Cisatracurium purification US 2010-0234602
Cisatracurium Cisatracurium reverse phase Us 2010-0087650
Donepezil Hydrochloride Donepezil hydrochloride compositions US 6,734,195
Donepezil Hydrochloride Preparation process US 6,844,440
Donepezil Hydrochloride Purification via Donepezil maleate US 7,592,459
Fluticasone Propionate Method of isolating a Fluticasone intermediate US 6,747,163
Granisetron Granisetron intermediate US 7,060,841
Halobetasol Halobetasol US 7,208,485
Imatinib Imatinib process US 7,507,821
Imatinib Imatinib with EDC US 7,550,591
Imiquimod Imiquimod ammonia DMSO US 7,659,398
Imiquimod Imiquimod process US 7,323,568
Imiquimod Imiquimod urea/guanidine US 7,943,771
Lamotrigine Preparation process US 6,329,521
Letrazole Letrozole process US 7,538,230
Letrazole Letrozole purification US 7,465,749
Levocetirizine Levocetirizine purification US 2011-0230496
Midazolam Midazolam Maleate process US 7,776,852
Montelukast Sodium Amorphous montelukast US 7,544,805
Montelukast Sodium Montelukast precursor US 7,572,930
Montelukast Sodium Montelukast process US 7,528,254
Palonosetron Palonosetron salts US 2010-0174080
Rocuronium Bromide Rocuronium bromide process US 7,579,461
Rotigotine Rotigotine crystalline base US 2010-0222602
Temozolomide Improved process US 7,612,202
Tramadol Hydrochloride Tramadol purification US 5,672,755
Tramadol Hydrochloride Tramadol separation process US 5,874,620
Zonisamide Derivatives of BIOS-H US 7,745,471

 

Awards

101 Best and Brightest Companies to Work For of West Michigan awarded Perrigo overall “Best of the Best” for 2009.[17]

In 2010 Perrigo was named one of the top 100 Fastest-Growing Companies by Fortune Magazine.[18]

 

From its beginnings as a packager of generic home remedies in 1887, Perrigo Company plc, headquartered in Ireland, has grown to become a leading global healthcare supplier. Perrigo develops, manufactures and distributes over-the-counter (OTC) and generic prescription (Rx) pharmaceuticals, nutritional products and active pharmaceutical ingredients (API), and receives royalties from Multiple Sclerosis drug Tysabri®. The Company is the world’s largest manufacturer of OTC healthcare products for the store brand market and an industry leader in pharmaceutical technologies. Perrigo’s mission is to offer uncompromised “Quality Affordable Healthcare Products®,” and it does so across a wide variety of product categories primarily in the United States, United Kingdom, Mexico, Israel and Australia, as well as more than 40 other key markets worldwide, including Canada, China and Latin America.

 

Perrigo API (formerly known as Chemagis) provides differentiated Active Pharmaceutical Ingredients (APIs) and Finished Dosage Forms (FDFs) for the branded and generic pharmaceutical industries.

Founded in 1987 in Israel and led by an accomplished team of industry experts, Perrigo API products comply with the highest regulatory requirements of leading health authorities such as FDA, PMDA, TGA, ANVISA and EU authorities. The company’s facility in Israel is FDA-inspected, cGMP-compliant and recognized for environmental stewardship.

Leveraging our strengths in complex chemistry, innovative patent development and in-depth regulatory expertise, Perrigo API provides tailor-made solutions to meet individual client requirements. We offer our customers comprehensive, customized solutions which include IP assets, API and FDF products, dossiers, bundling and P-IV partnerships, some through joint ventures and some independently, and all strengthened by well-designed and mutually beneficial strategic alliances.

Perrigo API offers comprehensive technical and regulatory support across the entire product lifecycle, from project inception to final production. Our state-of-the-art efficiency and control measures applied across the supply, development and manufacturing chain, allow Perrigo API to provide exceptional value and product differentiation to hundreds of customers worldwide. (Learn more about partnership opportunities)

With the ever-changing and increasingly competitive climate in the global API and Pharma industry, Perrigo API has been proactively searching for ways to continually add customer value and improve our leadership position. In 2009, Perrigo API (PAI) was established, following the acquisition of 85% of the holdings of a state-of-the-art API plant near Mumbai. Fully operational as of 2013, PAI supports Perrigo efforts to increase production capacity and competitiveness, while strictly complying with all industry regulations. This strategic move towards diversified capabilities further enhances Perrigo API highly valued operational flexibility, and adds to our company’s competitive edge.

 

 

 

FDFPerrigo API extends its Active Pharmaceutical Ingredients (APIs) product line with selected Finished Dosage Forms (FDFs) where it is strategically advantageous to customers, providing the most added value and differentiation for clients.Perrigo API focuses on developing those FDFs which require complex and sophisticated manufacturing processes, providing our valuable clients with highly professional regulatory support and reliable supply chain.All Perrigo API products, are made with high standards complying with GMP and regulatory requirements of leading health authorities.Products under patent are not sold until patent expiration in the relevant country.

FDF Therapeutic Use More
Anastrozole tablets 1 mg Treatment of hormone receptor-positive breast cancer in postmenopausal women
Cetirizine dihydrochloride 10 mg tablets Cetirizine dihydrochloride 10 mg/ml, oral drops Cetirizine dihydrochloride 1 mg/ml, oral solution Symptomatic treatment of allergic rhinitis
Granisetron HCl ampoules 1 mg/ml 1ml, 3 ml Prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapy
Granisetron HCl tablets 1, 2 mg Prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapy
Letrozole tablets 2.5 mg First-line treatment in postmenopausal women with hormone-dependent breast cancer
Moxonidine tablets 0.2, 0.3, 0.4 mg Mild to moderate essential hypertension
Temozolomide hard gelatin capsules 5, 20, 100, 140, 180, 250 mg Treatment of patients with malignant glioma such as glioblastoma multiforme or anaplastic astrocytoma

 

 

Perrigo API specializes in tailor-made research and process development of Active Pharmaceutical Ingredients (APIs) and Finished Dosage Forms (FDFs), with special emphasis on complex, differentiated APIs and FDFs.

Perrigo API carefully selects APIs and FDFs which provide our customers with a competitive market position by delivering unique IP as part of a total solution. All Perrigo API products comply with the exacting regulatory requirements of leading health authorities, including the FDA, PMDA, TGA, ANVISA and other EU authorities.

Below is a list of APIs and FDFs which are currently under development.

Products under patent are not sold until patent expiration in the relevant country.

API Therapeutic Use More
Esomeprazole Mg Dihydrate Form A Gastroesophageal reflux disease (GERD)
Fexofenadine Hydrochloride Allergy symptoms
Fluticasone Furoate Seasonal and perennial allergic rhinitis
Fulvestrant Breast cancer
Ibrutinib Leukemia
Loratadine Seasonal allergic rhinitis; Chronic idiopathic urticaria
Montelukast Sodium Prophylaxis and chronic treatment of asthma
Tiotropium Bromide Monohydrate Bronchospasm associated with chronic obstructive pulmonary disease (COPD)
Vilanterol Trifenatate Bronchospasm associated with chronic obstructive pulmonary disease (COPD)
FDF Therapeutic Use More
Azacitidine myelodysplastic syndromes and chronic myelomonocytic leukaemia
Fulvestrant Breast cancer

API

Perrigo API team is deeply committed to achieving uncompromising quality and reliability at every point in the value chain, from product inception to production, from regulatory affairs to go-to-market activities.


Mr. Yoav Grinberg
General Manager

Mr. Grinberg brings extensive general management experience as well as international marketing and sales experience. Previously MR. Grinberg was responsible for Perrigo API sales and marketing activities worldwide. Before joining Perrigo API in 2010, Mr. Grinberg worked for 20 years in the chemical and plastics industries in various senior general management and sales and marketing positions, based in Israel and Europe. Mr. Grinberg holds an MBA from Tel Aviv University.


Dr. Shireesh Ambhaikar
CEO, Perrigo API India Private Limited (PAI)

 

Dr. Ambhaikar has held numerous positions of increasing responsibility in manufacturing, project management and general management in the pharmaceutical industry. Prior to joining PAI, Dr. Ambhaikar was head of manufacturing, supply chain and global sourcing at UCB Pharm. Prior to that, he was with Sandoz/Novartis, with responsibilities in both manufacturing and project management. Dr. Ambhaikar holds a PhD degree in Organic Chemistry from Mumbai University.


Mr. Ilan Avni
Director Business Development & Pipeline

Ilan Avni

Mr. Avni joined Perrigo in 2006 and has held several Business Development positions of increasing responsibility both in the US Rx and API business units with experience in acquisitions, divestures, joint ventures, co development and product licensing. In his previous position, Mr. Avni served as an integration project leader for Perrigo API India. Mr. Avni holds an MBA with dual major in Finance and Marketing from Tel Aviv University and a BSc Pharm from the Hebrew University of Jerusalem.


Dr. Tami Greenberg
Head of Quality Perrigo Israel API

Tami Greenberg

As Head of Quality for Perrigo Israel API, Dr. Greenberg is responsible for all QA/QC operations, regulatory compliance and meeting customers’ technical needs. Prior to joining Perrigo API in 2006, Dr. Greenberg was part of the R&D team in Bromine Compounds and lead different development projects. Dr. Greenberg holds Ph.D. in Material engineering from the Ben-Gurion university of the Negev.


Mrs. Dina Hanuna
API Finance Controller

Mrs. Hanuna joined Perrigo Israel (formerly Agis) in 1991. Prior to joining Perrigo, Mrs. Hanuna held the position of Senior Manager with the CPA firm Jungerman, Gilboa & Co. Mrs. Hanuna has more than 20 years of experience in several roles in the Finance Department at Perrigo Israel, nine years of which have been in senior management roles. Mrs. Hanuna is a Certified Public Accountant (Israel). She holds a BA in Economics and Business Administration from Bar Ilan University as well as a BA in Accounting from Tel Aviv University.

SEE…http://investing.businessweek.com/research/stocks/private/person.asp?personId=8971366&privcapId=881270&previousCapId=881270&previousTitle=Perrigo%20Israel%20Pharmaceuticals%20Limited


Mrs. Ayala Kost
VP of Global Operations Perrigo API

As the Perrigo API executive in charge of Operations, Previously Mrs. Kost was responsible for Quality Assurance and control as well as regulatory compliance and meeting customers’ technical needs. Prior to joining Perrigo API in 2002, Mrs. Kost was U.S. Marketing Director and Pilot Lab Manager at, a leading manufacturer of crop protection chemicals. Prior to that she held the position of Process Engineer at Nepro Negev Projects. Mrs. Kost holds an MBA from Tel Aviv University and a BSc in Chemical Engineering from Ben-Gurion University.


Mrs. Dganit Vered
VP, API Research & Development

Dganit Vered

Mrs. Vered joined Perrigo in 2012 as VP Research and Development. Mrs. Vered is responsible for all Perrigo API R&D activities worldwide. Prior to joining Perrigo she worked at Intel Corporation for more than 17 years and at total of 21 years in the semiconductors business. While with Intel Mrs. Vered held several senior management positions and performed R&D, Engineering, Operations and Facilities, QA/QC and project management roles. Mrs. Vered holds BSc of Chemical engineering from the Technion.


Dr. Alexander Weisman
CSO

Alex Weisman

 

Dr. Weisman has more than 25 years of experience in R&D in Analytical and Organic Chemistry, out of which15 years in the pharmaceutical industry including 10 years in management roles. Dr. Weisman joined Perrigo API in 1998, as manager of Analytical R&D and later nominated as VP R&D. In 2012 Alex became the CSO of the company. Dr. Weisman has more than 15 articles and patents to his credit. He holds a PhD in Biochemistry from Moldova State University.

 

 

References

  1.  Jones, Al (16 August 2011). “Perrigo Co. reports strong gains in sales and earnings for fourth quarter and full year”Mlive.com (Allegan). Kalamazoo Gazette. Retrieved 20 August 2011. “Sales for the full year were $2.75 billion, up about 21.5 percent from $2.26 billion in fiscal 2010.”
  2.  Wilton, Bill (2008-10-16). “Perrigo Company”. Zacks Investment Research. Company Description. Archived from the original on 2008-10-22.
  3.  “Perrigo Company – Company History”Funding Universe, retrieved 2009-10-31
  4. dedFiles/Investors/Press_Releases/news_ir_114.11.15%20Perrigo%20to%20Acquire%20Agis.pdf Perrigo Company to Acquire Agis Industries, Creating A Leading Diversified Healthcare Company, Company press release, retrieved 2009-10-31
  5.  http://www.perrigo.com/uploadedFiles/Investors/Press_Releases/PRGOPR(11).pdf
  6.  “Official Perrigo Company Press Release” (PDF). Retrieved 2012-03-13.
  7.  “Official Perrigo Company Press Release” (PDF). Retrieved 2012-03-13.
  8.  http://www.perrigo.com/uploadedFiles/Investors/Press_Releases/UNIPR.pdf
  9.  http://www.perrigo.com/uploadedfiles/Investors/Press_Releases/ORION.pdf
  10.  http://www.perrigo.com/uploadedFiles/Investors/Press_Releases/PBMCLS.pdf
  11. http://www.perrigo.com/uploadedFiles/Investors/Press_Releases/110119%20Paddle%20PR%20v9%20-%20FINAL%20CHANGES.pdf
  12.  “Perrigo Closes Acquisition Of Sergeant’s Pet Care Products”Perrigo Company.
  13.  “Perrigo Company Acquires U.K.-based Rosemont Pharmaceuticals Ltd. For Approximately £180 Million Or $283 Million”.
  14.  Perrigo kauft irische Pharmafirma Elan
  15.  US drugmaker Perrigo to buy Ireland’s Elan for $8.6bn
  16.  http://www.perrigo.com/about/corporate-governance.aspx
  17.  “West Michigan 2009 Winners”101 Best and Brightest Companies To Work For. West Michigan Region. Archived from the original on 2014-02-21.
  18.  “100 Fastest-Growing Companies 2010 – from FORTUNE”. Money.cnn.com. 2010-09-06. Retrieved 2012-03-13.

External links

 

Key Dates:

1887:
Luther and Charles Perrigo begin packaging generic home remedies and selling them at their own and to other general stores.
1892:
Company is incorporated.1920s:Perrigo begins offering private label products.1930s:Customer base begins to shift from general stores to large regional and national drug chains.1950s:Company shifts from a repackager of generic drugs to a manufacturer of quality drugs and beauty aids.

1970s:Grocery chains and mass merchandisers are added to the customer base.

1980:
Perrigo is now the nation’s largest private label manufacturer of health and beauty products.Early 1980s:Perrigo family ownership ends with the sale of the company to management.
1986:
Company is sold to Grow Group, Inc. for $45 million.
1988:
Grow Group sells the company back to management for $106 million.
1991:
Perrigo is taken public.
1997:
Controlling stake in Mexican pharmaceutical firm Química y Farmacia, S.A. de C.V. is acquired.
1998:
Perrigo posts a net loss of $51.6 million thanks to a restructuring of its personal care business.
1999:
The personal care business is divested to focus the company on OTC drugs and nutritional products.
2001:
Perrigo acquires Wrafton Laboratories Ltd., a U.K. maker of store brand pharmaceuticals.


Executive Management

Joseph C. Papa
President, Chief Executive Officer and Chairman

Mr. Papa joined the Company in October 2006 as President and Chief Executive Officer. Mr. Papa was elected as a director in November 2006 and, subsequently, was appointed as Chairman of the Board of Directors in October 2007. Previously, Mr. Papa served from December 2004 to October 2006 as Chairman and Chief Executive Officer of the Pharmaceutical and Technologies Services segment of Cardinal Health, Inc. Prior to that position, he served as President and Chief Operating Officer of Watson Pharmaceuticals, Inc. from November 2001 to November 2004. Additionally, Mr. Papa has held management positions at DuPont Pharmaceuticals, Pharmacia Corporation, G.D. Searle & Company and Novartis AG. Mr. Papa is a director of Smith & Nephew, a developer of advanced orthopedic medical devices.

 

Judy L. Brown
Executive Vice President and Chief Financial Officer

Ms. Brown was named Executive Vice President and Chief Financial Officer in July 2006. She served as Vice President and Corporate Controller from September 2004 to July 2006. Previously, Ms. Brown held various senior positions in finance and operations at Whirlpool Corporation from 1998 to August 2004. Ms. Brown is a director of Belden Corporation, a NYSE traded company, that designs, manufactures and markets cable, connectivity and networking products in markets including industrial automation, enterprise, transportation, infrastructure and consumer electronics.

 

Tom Farrington
Senior Vice President and Chief Information Officer

Mr. Farrington was named Senior Vice President and Chief Information Officer in October 2006. He formerly served as Chief Information Officer for F. Dohmen Co. in addition to serving as a division President for JASCORP LLC from March 2003 to October 2006. Prior to that position, Mr. Farrington held various senior positions in information technology and finance at Dell, Inc. from 1999 to 2003.

 

John T. Hendrickson
Executive Vice President, Global Operations and Supply Chain

Mr. Hendrickson was named Executive Vice President, Global Operations and Supply Chain in March 2007. He served as Executive Vice President and General Manager, Perrigo Consumer Healthcare from August 2003 to March 2007. He served as Executive Vice President of Operations from October 1999 to August 2003.

 

Scott Jamison
Executive Vice President, General Manager of Nutritionals

Mr. Jamison was named Executive Vice President, General Manager of Nutritionals in January 2011. Before the Company acquired PBM in fiscal 2010, Mr. Jamison had served as PBM’s Executive Vice President and General Counsel since the formation of PBM in 1997 and was a key member of the executive team throughout the evolution and growth of PBM. In addition to his legal responsibilities, Mr. Jamison has held senior leadership responsibilities in operations and sales, as well as in new business and product development.

 

Todd W. Kingma
Executive Vice President, General Counsel and Secretary

Mr. Kingma was named Executive Vice President in May 2006. He served as Vice President, General Counsel and Secretary from August 2003 to May 2006. Previously, Mr. Kingma held various positions at Pharmacia Corporation from 1991 through August 2003. His last position with Pharmacia Corporation was Vice President and Associate General Counsel, Global Specialty Operations

 

Sharon Kochan
Executive Vice President and General Manager, International

Mr. Kochan was named Executive Vice President and General Manager, International in August 2012. He served as Executive Vice President, General Manager of Rx Pharmaceuticals from March 2007 to August 2012 and as Senior Vice President of Business Development and Strategy from March 2005 to March 2007. Mr. Kochan was Vice President, Business Development of Agis Industries (1983) Ltd. from July 2001 until the acquisition of Agis by the Company in March 2005.

 

Jeff Needham
Executive Vice President, General Manager of Consumer Healthcare

Mr. Needham was named Executive Vice President, General Manager of Consumer Healthcare in October 2009. He served as Senior Vice President of Commercial Business Development from March 2005 through October 2009. Previously, he served as Senior Vice President of International from November 2004 to March 2005. He served as Managing Director of Perrigo’s U.K. operations from May 2002 to November 2004 and as Vice President of Marketing from 1993 to 2002.

 

Jatin Shah
Senior Vice President and Chief Scientific Officer

Dr. Shah was named Senior Vice President and Chief Scientific Officer in June 2005. He served as Vice President of Research and Development for Rx products from February 2004 to June 2005. Previously, Dr. Shah held various senior positions in Research and Development at Mayne Pharma (known previously as Faulding Pharmaceuticals) from June 1996 to January 2004.

 

Mike Stewart
Senior Vice President, Global Human Resources

Mr. Stewart was named Senior Vice President, Global Human Resources in September 2004. He served as Vice President, Human Resources from July 1993 to September 2004. Mr. Stewart began his employment with the Company in August 1981.

 

Louis Yu
Executive Vice President, Global Quality and Compliance

Dr. Yu joined the Company in November 2006 as Senior Vice President, Global Quality and Compliance. Previously, Dr. Yu served from October 2005 to October 2006 as Vice President, Quality at CV Therapeutics Inc. Prior to that position, he served as Global Head of Quality & Compliance for Forest Laboratories, Inc. from April 1999 to October 2005. He served as the Vice President, Quality & Compliance for Solvay Pharmaceuticals between October 1996 and March 1999. Currently, he is associated with the University of Wisconsin, serving as Adjunct Professor, Extension Services in Pharmacy, School of Pharmacy.

 

Douglas Boothe
Executive Vice President and General Manager, Perrigo Pharmaceuticals

Mr. Boothe joined Perrigo in January 2013 as Executive Vice President and General Manager, Perrigo Pharmaceuticals. Previously, Mr. Boothe served as Chief Executive Officer of Actavis Inc. from August 2008 to December 2013 and as Executive Vice President and Chief Operating Officer from 2006 to 2008. Prior to that position, Mr. Boothe held various senior positions in strategic planning and business development for Alpharma Inc., Pharmacia Corporation and Xerox Corporation.

Scientists develop new cancer-killing compound from salad plant / 1,200 times more specific in killing certain kinds of cancer cells than currently available drugs


Ralph Turchiano's avatarCLINICALNEWS.ORG

Public release date: 13-Oct-2008

Researchers at the University of Washington have updated a traditional Chinese medicine to create a compound that is more than 1,200 times more specific in killing certain kinds of cancer cells than currently available drugs, heralding the possibility of a more effective chemotherapy drug with minimal side effects.

The new compound puts a novel twist on the common anti-malarial drug artemisinin, which is derived from the sweet wormwood plant (Artemisia annua L). Sweet wormwood has been used in herbal Chinese medicine for at least 2,000 years, and is eaten in salads in some Asian countries.

The scientists attached a chemical homing device to artemisinin that targets the drug selectively to cancer cells, sparing healthy cells. The results were published online Oct. 5 in the journal Cancer Letters.

View original post 645 more words

What GMP 良好作業規範 Changes can we still expect for 2014?



What GMP Changes can we still expect for 2014?

Heraclitus once said: “There is nothing permanent except change”. This statement is even true for the rather conservative GMP environment. What can we still expect for 2014? The answer to that question can be found in a work plan of EMA’s GMP/GDP Inspectors Working Group.

What are the coming plans?

The finalisation of the revision of Chapter 6 (Quality Control) of the EU GMP Guide is already completed (April 2014). The revised chapter will apply as of October 2014.

The following topics are also addressed in the work paper:

  • Inspections under the centralised system
  • Mutual Recognition Agreements (MRAs)
  • Harmonisation topics
  • Collaboration with the EU Commission (the collaboration should enable by the end of 2014 the publication of the GDP guidelines for APIs and  the risk assessment guidelines to establish GMP for excipients)
  • Collaboration with other groups (i.e. Reverse Osmosis for the production of WFI and biological indicators for monitoring and the control of sterilisation are topics addressed together with the EDQM in Strasburg)

Please also see the complete “Work plan for GMP/GDP Inspectors Working Group for 2014“.

http://www.gmp-compliance.org/enews_04349_What-GMP-Changes-can-we-still-expect-for-2014%3F.html

 

 

 

 

 

 

 

 

email me     amcrasto@gmail.com

Italian API Manufacturer Receives FDA Warning Letter for Data Integrity Issues


 

Italian API Manufacturer Receives FDA Warning Letter for Data Integrity Issues
On July 7th the US FDA issued a Warning Letter to Trifarma S.p.A. for violating Good Manufacturing Standards at their facility in Rozzano, Italy. The company produces APIs and had been inspected early this year.

Read more about this Warning Letter here

http://www.gmp-compliance.org/enews_4400_Italian%20API%20Manufacturer%20Receives%20FDA%20Warning%20Letter%20for%20Data%20Integrity%20Issues_8509,S-WKS_n.html

On July 7th the US FDA issued a Warning Letter to Trifarma S.p.A. for violating Good Manufacturing Standards at their facility in Rozzano, Italy. The company produces APIs and had been inspected early this year. As a result of the inspection and the response of the company to the GMP findings the FDA decided to issue a Warning Letter.

While so far mainly Indian Manufacturers have been blamed by FDA and EU Inspectors for data integrity issues, now also an European API manufacturer has been cited for that problem. According to the Warning Letter the firm deleted all electronic raw data supporting the companies high performance liquid chromatography (HPLC) testing. Moreover, Trifarma failed to retain basic chromatographic information such as injection sequence, instrument method or integration method for the tests.

In a response to the FDA the firm explained that it has been researching backup systems since July 2013 and will have a backup system online by the third quarter of 2014. But FDA is not satisfied with this answer. Some interim actions such as storing backup data on each computer, including the integration method as part of that data are not sufficient. The FDA expects to see backups of the injection sequence, the instrument method and audit trails. According to the FDA the firm does not address how it will ensure that electronic files are not deleted prematurely from local computers.

In addition further basic GMP provisions are not met in the lab. There are no proper controls in place to prevent the unauthorized manipulation of the raw electronic data. All persons in the lab were able to delete and/or adulterate data because all lab employees were granted full privileges to the computer systems. Some equipment in place in the lab such as the HPLC and the GC lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change.

The FDA also expected to see electronic raw data supporting cleaning, method and process validations but the company was not able to provide these data. Another critical deviation referred to the fact that the company did not document any training of production employees on the production operations they perform. The company did change an SOP on how to perform training at the manufacturing site in July 2013 in order to include on-the-job training but Trifarma is not following it’s own procedures.

Interestingly the US FDA has used the information gathered in a previous inspection of another production site of the company to check the compliance in the Rozzano site. Trifarma received a 483 form on similar deficiencies for it’s Ceriano Laghetto plant but did not take the necessary actions to check if similar problems exist also at other manufacturing sites. From this the FDA concluded that there is not robust quality system is in place. The FDA also references the ICH Q7 Guide GMP for APIs and expects form API manufacturers to meet the requirements stated in that Guide.

Source. FDA Warning Letter for Trifarma S.p.A.

 

email me            amcrasto@gmail.com

 

ECA launches the Impurities Forum


 

home

The identification and determination of Impurities is a key challenge in pharmaceutical Quality Control. Method Validation, Analytical techniques, Leachables and Extractables are only a few of the problem areas. In addition Elemental (Metal) Impurities and Genotoxic Impurities have caused various uncertainties and questions in industry as well as in authorities. This is why the ECA Academy has set up a comprehensive Impurities Forum with experts from authorities as well as from companies like Boehringer Ingelheim, Novartis Pharma, Baxter, UCB, AstraZeneca, AbbVie and others. To offer a maximum of flexibility the Impurities Forum can be booked for all 3 days or only special parts of interest e.g. on Metal Impurities and/or Genotoxic Impurities. Find out more about the Impurities Forum programme and the options.

http://www.gmp-compliance.org/eca_seminare_isearch_Impurities%20Forum.html

Insufficient failure investigations, supplier qualification, stability testing – the most common GMP violations in the FDA warning letters


 

An analysis of warning letters issued in the past fiscal year essentially shows the same pattern of frequently cited GMP violations. It also shows a noticeable increase in the GMP deficiencies relating to the qualification of suppliers and their certificates of analysis. Find out more

http://www.gmp-compliance.org/enews_4390_Insufficient%20failure%20investigations%2C%20supplier%20qualification%2C%20stability%20testing%20-%20the%20most%20common%20GMP%20violations%20in%20the%20FDA%20warning%20letters_8500,8489,S-QSB_n.html

 

 

The analysis of the warning letters issued in the last fiscal year shows no surprise at a first glance: as in recent years the FDA detected an insufficient investigation of unexplained discrepancies and deviations from defined standards and specifications in their inspections. The corresponding paragraph 21 CFR 211.192 requires that the drug maker clarifies the reason for the deviation, takes corrective actions and also creates a complete documentation. In the last 5-year period on average annually about 22 companies received a warning letter listing this GMP deficiency. This fact shows that many quality assurance departments’ understanding of deviations handling, failure investigations and corrective actions is frequently fragmentary.

Quite interesting is the detailed study of the warning letters referring to GMP violations with regard to 211.192. These warning letters take into account the drugs’ dosage forms. In particular manufacturers of oral dosage forms were addressees of warning letters containing citations with regard to 211.192, followed by parenteral drugs manufacturers, companies in the area of blood/blood products and manufacturers of topical drugs. The respective scenarios are quite different. However, main shortcoming is always the inadequate education and documentation in each incident.

A rather unexpected finding in the lineup of the most common GMP violations is the high number of citations with regard to 21 CFR 211.84 “Testing and approval or rejection of components, drug product containers, and closures”. This quote appears so frequently as never before: 16 out of the 32 companies that received a warning letter in the fiscal year 2013 for violations of part 211 had not implemented the provisions of paragraph 211.84 as expected by the FDA investigators. Interestingly, in this case most of these companies (12 of the 16) are manufacturers of topical products (ointments, creams, etc.).

The formulations in the warning letters in this regard are very similar (in some cases identical) and are usually limited to the following standard wording: “Your firm has not established the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals” or “Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or exampled, as appropriate, and released for use by the quality control unit.”

Under the addressees of warning letters with quotations in the area of quality control – 21 CFR 211.166 “Stability Testing” and 21 CFR 211.160 “General Requirements” – there are also many of the companies that were already criticised due to non-compliances with regard to 211.84. This is not surprising as the thematic connection of all three paragraphs has a reference to the function of quality control. These two paragraphs 211.166 and 211.160 – just as 211.192 – have been in the top ten of GMP deficiencies for many fiscal years. Main shortcoming relating to 211.166 is the lack of a written stability test programme. Therefore, the following sentence can be read in almost all warning letters: “Your firm does not have an adequate written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates.”

Information on infringements of 211.160 are more differentiated. Partly some interesting scenarios are described, as, for instance, “inappropriate visual particle inspection” or “switched off audit trail function in the chromatography system”. Here too Topika makers make the majority of addressees – even though not as clear as in the previous paragraphs of part 211. Main shortcoming in the implementation of the guidelines in 211.160 is the lack of scientifically sound and appropriate specifications, standards, test plans and test methods for products, intermediates, components etc.

The analysis of the warning letters of last fiscal year has shown that the FDA increasingly focuses on the subject “supplier qualification” and in this context on critically questioning analysis results and certificates of the suppliers. A detailed examination of the warning letters of the current fiscal year will show whether this trend further continues.

A more detailed analysis of the warning letters of the previous fiscal year will be available in the October issue of the GMP Journal.

http://www.gmp-compliance.org/enews_4390_Insufficient%20failure%20investigations%2C%20supplier%20qualification%2C%20stability%20testing%20-%20the%20most%20common%20GMP%20violations%20in%20the%20FDA%20warning%20letters_8500,8489,S-QSB_n.html

 

 

« New York Times Attack on ADHD Treatment: The Treatment as the Disease | Main | IFPMA Millennium Development Goals »

December 23, 2013

– See more at: http://www.policymed.com/2013/12/trends-in-fda-cgmp-violations.html#sthash.AXCBK0wx.dpuf

 

« New York Times Attack on ADHD Treatment: The Treatment as the Disease | Main | IFPMA Millennium Development Goals »

December 23, 2013

– See more at: http://www.policymed.com/2013/12/trends-in-fda-cgmp-violations.html#sthash.AXCBK0wx.dpuf

« New York Times Attack on ADHD Treatment: The Treatment as the Disease | Main | IFPMA Millennium Development Goals »

December 23, 2013

– See more at: http://www.policymed.com/2013/12/trends-in-fda-cgmp-violations.html#sthash.AXCBK0wx.dpuf

emailme——-amcrasto@gmail.com

ICH gets new Members and informs about the ICH Q3D Implementation



ICH gets new Members and informs about the ICH Q3D Implementation
The International Conference on Harmonisation (ICH) is the most significant organisation for the harmonisation of requirements with regard to the authorisation and the manufacture of medicinal products. Read more about the current decisions of the ICH Steering Committees.

http://www.gmp-compliance.org/enews_4395_ICH%20gets%20new%20Members%20and%20informs%20about%20the%20ICH%20Q3D%20Implementation_8559,S-AYL_n.html

ICH gets new Members and informs about the ICH Q3D Implementation\

The International Conference on Harmonisation (ICH) is the most significant organisation for the harmonisation of requirements with regard to the authorisation and the manufacture of medicinal products. The ICH wants this function to be extended. For that reason – during the last meeting in Minneapolis, USA – the Steering Committee decided to welcome two new members. Beside the American FDA, the EMA/EU Commission and the Japanese Authority belong to the founding members. Now, the Swiss Authority Swissmedic and the Canadian one (Health Canada) have joined the ICH Board.

Another important notice has been announced after the meeting in Minneapolis. In September 2014, the harmonised Guideline ICH Q3D Elemental Impurities will reach the Step 4 status. The FDA as well as the EMA/EU Commission and the Japanese MHLW will take over the whole document into their respective national regulations. This last – and formal – procedure will be defined as Step 5. No changes will be made in the guidance document when the authorities will make the transfer to the regulatory framework.

The new ICH Q3D and the recently adopted ICH M7 (Genotoxic Impurities) will therefore be addressed at the international Impurities Forum in Berlin.

Source: Press Release of the ICH Meeting in Minneapolis

http://www.gmp-compliance.org/enews_4395_ICH%20gets%20new%20Members%20and%20informs%20about%20the%20ICH%20Q3D%20Implementation_8559,S-AYL_n.html

Avoiding a reactive starting material: The Synthesis of BA-824 (old)


developingtheprocess's avatarDeveloping the Process

I need to update my collection of journal articles to talk about.   I will try and go next week.  While you are waiting for a new blog post, I figured I would post another article from PHARMNBIOFUEL.COM.  This was posted 2011-01-22

I am running a little behind my postings.  Although I am now employed on a temporary assignment and figure I can commit that same amount of time on my website as before, however, I am having to re-organize my daily activities.  The postings on this website may grind to a slow dribble.  I will still forge ahead to provide you with what I find interesting in current chemical literature.  I am dipping into some of the choices I picked from last year, but promise to update my collection soon as to what is happening currently in the chemosphere, particularly in process research.

I think that more than some of us, the “us” being…

View original post 503 more words

NICE Endorses Lundbeck’s Alcohol Dependency Drug For Use In UK


Nalmefene

 

17- (cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol

(5α)-17-(Cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol;

(-)-Nalmefene;

6-Deoxo-6-methylenenaltrexone; 6-Desoxy-6-methylenenaltrexone;

JF 1; Nalmetrene; ORF 11676;

 

Lundbeck’s novel alcohol dependency drug has been endorsed by the National Institute for Health and Care Excellence (NICE) for use in Britain’s state health service.

read at

 

http://www.clinicalleader.com/doc/nice-endorses-lundbeck-s-alcohol-dependency-drug-for-use-in-uk-0001

A structural analog of Naltrexone (N285780) with opiate antagonist activity used in pharmaceutical treatment of alcoholism. Other pharmacological applications of this compound aim to reduce food cravings, drug abuse and pulmonary disease in affected individuals. Used as an opioid-induced tranquilizer on large animals in the veterinary industry. Narcotic antagonist.

 

Nalmefene
Nalmefene sceletal.svg
Systematic (IUPAC) name
17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol
Clinical data
Trade names Selincro
AHFS/Drugs.com monograph
MedlinePlus a605043
Legal status POM (UK)
Routes Oral, Intravenous
Pharmacokinetic data
Protein binding 45%
Metabolism hepatic
Half-life 10.8 ± 5.2 hours
Excretion renal
Identifiers
CAS number  55096-26-9
58895-64-0 (HCl)
ATC code N07BB05
PubChem CID 5284594
ChemSpider 4447642 Yes
UNII TOV02TDP9I Yes
ChEMBL CHEMBL982 Yes
Chemical data
Formula C21H25NO3 
Mol. mass 375.9 g/mol (hydrochloride)

 

Mol. Formula:   C21H25NO3
Appearance:   Off-White to Pale Yellow Solid
Melting Point:   182-185˚C
Mol. Weight:   339.43

Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid receptor antagonist developed in the early 1970s,[1] and used primarily in the management of alcohol dependence, and also has been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping.

Nalmefene is an opiate derivative similar in both structure and activity to the opiate antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity. As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.

Nalmefene differs from naltrexone by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH2), which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors, and is known as a “universal antagonist” for its ability to block all three.

In clinical trials using this drug, doses used for treating alcoholism were in the range of 20–80 mg per day, orally.[2] The doses tested for treating pathological gambling were between 25–100 mg per day.[3] In both trials, there was little difference in efficacy between the lower and higher dosage regimes, and the lower dose (20 and 25 mg, respectively) was the best tolerated, with similar therapeutic efficacy to the higher doses and less side effects. Nalmefene is thus around twice as potent as naltrexone when used for the treatment of addictions.

Intravenous doses of nalmefene at between 0.5 to 1 milligram have been shown effective at counteracting the respiratory depression produced by opiate overdose,[4] although this is not the usual application for this drug as naloxone is less expensive.

Doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit in this application. Nalmefene’s longer half-life might however make it useful for treating overdose involving longer acting opioids such as methadone, as it would require less frequent dosing and hence reduce the likelihood of renarcotization as the antagonist wears off.

Nalmefene is extensively metabolised in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.

Lundbeck has licensed the drug from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[5] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.[6] It has not been available on the US market since at least August 2008.[citation needed]

Side effects

Properties

  • Soluble in water up to 130 mg/mL, soluble in chloroform up to 0.13 mg/mL
  • pKa 7.6
  • Distribution half-life: 41 minutes

 

 

Nalmefene is a known opioid receptor antagonist which can inhibit pharmacological effects of both administered opioid agonists and endogenous agonists deriving from the opioid system. The clinical usefulness of nalmefene as antagonist comes from its ability to promptly (and selectively) reverse the effects of these opioid agonists, including the frequently observed depressions in the central nervous system and the respiratory system.

Nalmefene has primarily been developed as the hydrochloride salt for use in the management of alcohol dependency, where it has shown good effect in doses of 10 to 40 mg taken when the patient experiences a craving for alcohol (Karhuvaara et al, Alcohol. Clin. Exp. Res., (2007), Vol. 31 No. 7. pp 1179-1187). Additionally, nalmefene has also been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping. In testing the drug in these developmental programs, nalmefene has been used, for example, in the form of parental solution (Revex™).

Nalmefene is an opiate derivative quite similar in structure to the opiate antagonist naltrexone. Advantages of nalmefene compared to naltrexone include longer half- life, greater oral bioavailability and no observed dose-dependent liver toxicity. Nalmefene differs structurally from naltrexone in that the ketone group at the 6- position of naltrexone is replaced by a methylene (CH2) group, which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors (K and δ receptors) and is known as a “universal antagonist” as a result of its ability to block all three receptor types.

Nalmefene can be produced from naltrexone by the Wittig reaction. The Wittig reaction is a well known method within the art for the synthetic preparation of olefins (Georg Wittig, Ulrich Schόllkopf (1954). “Uber Triphenyl-phosphin- methylene ah olefinbildende Reagenzien I”. Chemische Berichte 87: 1318), and has been widely used in organic synthesis.

The procedure in the Wittig reaction can be divided into two steps. In the first step, a phosphorus ylide is prepared by treating a suitable phosphonium salt with a base. In the second step the ylide is reacted with a substrate containing a carbonyl group to give the desired alkene.

The preparation of nalmefene by the Wittig reaction has previously been disclosed by Hahn and Fishman (J. Med. Chem. 1975, 18, 259-262). In their method, naltrexone is reacted with the ylide methylene triphenylphosphorane, which is prepared by treating methyl triphenylphosphonium bromide with sodium hydride (NaH) in DMSO. An excess of about 60 equivalents of the ylide is employed in the preparation of nalmefene by this procedure.

For industrial application purposes, the method disclosed by Hahn and Fishman has the disadvantage of using a large excess of ylide, such that very large amounts phosphorus by-products have to be removed before nalmefene can be obtained in pure form. Furthermore, the NaH used to prepare the ylide is difficult to handle on an industrial scale as it is highly flammable. The use of NaH in DMSO is also well known by the skilled person to give rise to unwanted runaway reactions. The Wittig reaction procedure described by Hahn and Fishman gives nalmefene in the form of the free base. The free base is finally isolated by chromatography, which may be not ideal for industrial applications.

US 4,535,157 also describes the preparation of nalmefene by use of the Wittig reaction. In the method disclosed therein the preparation of the ylide methylene triphenylphosphorane is carried out by using tetrahydrofuran (THF) as solvent and potassium tert-butoxidc (KO-t-Bu) as base. About 3 equivalents of the ylide are employed in the described procedure.

Although the procedure disclosed in US 4,535,157 avoids the use of NaH and a large amount of ylide, the method still has some drawbacks which limit its applicability on an industrial scale. In particular, the use of THF as solvent in a Wittig reaction is disadvantageous because of the water miscibility of THF. During the aqueous work-up much of the end product (nalmefene) may be lost in the aqueous phases unless multiple re-extractions are performed with a solvent which is not miscible with water.

Furthermore, in the method described in US 4,535,157, multiple purification steps are carried out in order to remove phosphine oxide by-products of the Wittig reaction. These purification steps require huge amounts of solvents, which is both uneconomical and labor extensive requiring when running the reaction on an industrial scale. As in the case of the Wittig reaction procedure described by Hahn and Fishman (see above) the Wittig reaction procedure disclosed in US 4,535,157 also yields nalmefene as the free base, such that an additional step is required to prepare the final pharmaceutical salt form, i.e. the hydrochloride, from the isolated nalmefene base.

US 4,751,307 also describes the preparation of nalmefene by use of the Wittig reaction. Disclosed is a method wherein the synthesis is performed using anisole (methoxybenzene) as solvent and KO-t-Bu as base. About 4 equivalents of the ylide methylene triphenylphosphorane were employed in this reaction. The product was isolated by extraction in water at acidic pHs and then precipitating at basic pHs giving nalmefene as base.

Even though the isolation procedure for nalmefene as free base is simplified, it still has some disadvantages. The inventors of the present invention repeated the method disclosed in US 4,751,307 and found that the removal of phosphine oxide by-products was not efficient. These impurities co-precipitate with the nalmefene during basifϊcation, yielding a product still contaminated with phosphorus byproducts and having, as a consequence, a low chemical purity, as illustrated in example 2 herein.

There is therefore a need within the field to improve the method of producing nalmefene by the Wittig reaction. In particular, there is a need for a method that is readily applicable on a large industrial scale and which avoids the use of water- miscible solvents, such as THF, in the Wittig reaction, and permits easy isolation of nalmefene in a pure form suitable for its transformation to the final pharmaceutical salt form.

 

………………………………..

 

http://www.google.com/patents/EP2435439A1?cl=en

present invention the Wittig reaction may be performed by mixing a methyltriphenylphosphonium salt with 2- methyltetrahydrofuran (MTHF) and a suitable base to afford the ylide methylene triphenylphosphorane :

Figure imgf000007_0001

Methyltriphenylphosphonium salt Methylene triphenylphosphorane Yhde

The preformed ylide is subsequently reacted ‘in situ’ with naltrexone to give nalmefene and triphenylphosphine oxide (TPPO):

 

Figure imgf000007_0002

Naltrexone Yhde    Nalmefene TPPO

 

Example 1 Methyltriphenylphosphonium bromide (MTPPB, 25.8 Kg) was suspended in 2- methyltetrahydrofuran (MTHF, 56 litres). Keeping the temperature in the range 20-250C, KO-t-Bu (8.8 kg) was charged in portions under inert atmosphere in one hour. The suspension turned yellow and was stirred further for two hours. An anhydrous solution of naltrexone (8.0 Kg) in MTHF (32 litres) was then added over a period of one hour at 20-250C. The suspension was maintained under stirring for a few hours to complete the reaction. The mixture was then treated with a solution of ammonium chloride (4.2 Kg) in water (30.4 litres) and then further diluted with water (30.4 litres). The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water (16 litres). The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (40 litres) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 2 litres) was added over one hour at 20- 250C. The suspension was stirred for at least three hours at the same temperature, and then filtered and washed with dichloromethane (8 litres) and then with acetone (16 litres). The solid was then re-suspended in dichloromethane (32 litres) at 20-250C for a few hours and then filtered and washed with dichloromethane (16 litres), affording 9.20 Kg of nalmefene hydrochloride, corresponding to 7.76 kg of nalmefene hydrochloride (99.7% pure by HPLC). Molar yield 89%.

HPLC Chromatographic conditions

Column: Zorbax Eclipse XDB C-18, 5 μm, 150 x 4.6 mm or equivalent Mobile Phase A: Acetonitrile / Buffer pH = 2.3 10 / 90

Mobile Phase B: Acetonitrile / Buffer pH = 2.3 45 / 55

Buffer: Dissolve 1.1 g of Sodium Octansulfonate in 1 L of water. Adjust the pH to 2.3 with diluted

H3PO4. Column Temperature: 35°C

Detector: UV at 230 nm

Flow: 1.2 ml/min

Injection volume: 10 μl

Time of Analysis: 55 minutes

Figure imgf000019_0001

Example 2

The procedure described in US 4,751,307 was repeated, starting from 1Og of naltrexone and yielding 8.5g of nalmefene. The isolated product showed the presence of phosphine oxides by-products above 15% molar as judged by 1HNMR.

Example 3.

Methyltriphenylphosphonium bromide (MTPPB, 112.9g) was suspended in 2- methyltetrahydrofuran (MTHF, 245 ml). Keeping the temperature in the range 20- 25°C, KO-t-Bu (38.7 g) was charged in portions under inert atmosphere in one hour. The suspension was stirred for two hours. An anhydrous solution of naltrexone (35 g) in MTHF (144 ml) was then added over a period of one hour at 20-250C. The suspension was maintained under stirring overnight. The mixture was then treated with a solution of glacial acetic acid (17.7 g) in MTHF. Water was then added and the pH was adjusted to 9-10. The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water. The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (175 ml) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 10. Ig) was added over one hour at 20- 25°C. The suspension was stirred and then filtered and washed with dichloromethane and acetone. The product was dried affording 38.1g of Nalmefene HCl. Example 4

Example 3 was repeated but the Wittig reaction mixture after olefmation completeness was treated with acetone and then with an aqueous solution of ammonium chloride. After phase separation, washings, distillation and dilution with dichloromethane, the product was precipitated as hydrochloride salt using HCl 37%. The solid was filtered and dried affording 37.6 g of Nalmefene HCl.

Example 5 Preparation of Nalmefene HCl dihydrate from Nalmefene HCl Nalmefene HCl (7.67 Kg, purity 99.37%, assay 93.9%) and water (8.6 litres) were charged into a suitable reactor. The suspension was heated up to 800C until the substrate completely dissolved. Vacuum was then applied to remove organic solvents. The resulting solution was filtered through a 0.65 μm cartridge and then diluted with water (2.1 litres) that has been used to rinse the reactor and pipelines. The solution was cooled down to 500C and 7 g of Nalmefene HCl dihydrate seeding material was added. The mixture was cooled to 0-50C over one hour with vigorous stirring and then maintained under stirring for one additional hour. The solid was filtered of and washed with acetone. The wet product was dried at 25°C under vacuum to provide 5.4 Kg of Nalmefene HCl dihydrate (purity 99.89%, KF 8.3% , yield 69%).

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http://www.google.com/patents/EP2316456A1?cl=en

……………………

http://www.google.com/patents/US8598352

Figure US08598352-20131203-C00003

References

  1.  US patent 3814768, Jack Fishman et al, “6-METHYLENE-6-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS”, published 1971-11-26, issued 1974-06-04
  2.  Barbara J. Mason, Fernando R. Salvato, Lauren D. Williams, Eva C. Ritvo, Robert B. Cutler (August 1999). “A Double-blind, Placebo-Controlled Study of Oral Nalmefene for Alcohol Dependence”Arch Gen Psychiatry 56 (8): 719. doi:10.1001/archpsyc.56.8.719.
  3.  Clinical Trial Of Nalmefene In The Treatment Of Pathological Gambling
  4.  http://www.fda.gov/cder/foi/label/2000/20459S2lbl.pdf
  5.  “Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE1)”.
  6.  “Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan”. thepharmaletter. 22 December 2011.
  7.  Nalmefene Hydrochloride Drug Information, Professional
  8.  Brittain, H.G., et al.: Anal. Profiles Drug Subs. Excip., 24, 351 (1996), Anton, R., et al.: J. Clin. Psychopharmacol., 24, 421 (2004), Bart, G., et al.: Neuropsychopharmacol., 30, 2254 (2005), Wu, X., et al.: Chem. Pharmacol. Bull., 54, 977 (2006),

 

 

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NON-PATENT CITATIONS
Reference
1 Aycock, D.F., 2007, Solvent Applications of 2 Methyitetrahydrofuran in Organometallc and Biphasic Reactions, Organic Process Research & Development, 11:156-159.
2 Dr. Rainer Aul et al., May 2007, A Green Alternative to THF, Manufacturing Chemist, pp. 33-34.
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4 Hinkley et al., Feb. 10, 2005, Synthesis of a Caryophyllene Isoprenologue, a potential Diterpene Natural Product, Tetrahedron 61, pp. 3671-3680.
5 J.M Aizapurua, Science of Synthesis, 4 (2001), p. 595.
6 Search Report issued May 5, 2013 in Gulf Cooperation Council Application No. GC 2010-15942 filed May 25, 2010.
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