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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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Italian API Manufacturer Receives FDA Warning Letter for Data Integrity Issues

July 17, 2014 4:17 am / 2 Comments on 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

July 17, 2014 4:12 am / 1 Comment on ECA launches the Impurities Forum


 

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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

July 17, 2014 4:08 am / 2 Comments on 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

Trends in FDA cGMP Violations

We have previously written that one of the new trends in enforcement in the life sciences industry is the focus the federal government is having on compliance with current good manufacturing practices (cGMP).

For instance, we noted back in February of this year that the U.S. Department of Justice announced that compliance with current good manufacturing practices (cGMPs) will be one of the agency’s “top areas of focus” in the coming year.” Additionally, we recently noted that DOJ has been probing international pharmaceutical manufacturing, investigating several companies and their manufacturing practices over the last several months.

Most recently, DOJ filed a lawsuit on behalf of the FDA against Mitchell, SD-based Dakota Laboratories and its owner Charles Voellinger, as reported by FiercePharmaManufacturing. The suit came after inspections in 2010, 2011 and 2012 found significant manufacturing lapses in the plant’s production of eye drops, including a lacking of procedures to protect against microbiological contamination. Among other issues, a 2011 FDA warning letter said the company had released several batches of sterile ophthalmic eye drops without adequately validating aseptic processes, and wasn’t testing the water used to make the drops.

“We cannot take the chance that a manufacturer’s failure to establish proper controls for sterile drug production could result in products becoming contaminated, placing consumers at risk of infection and potentially serious injury,” Assistant Attorney General Stuart Delery said.

Dakota Laboratories settled the lawsuit by agreeing to a “Consent Decree of Permanent Injunction” that prohibits the facility from violating the federal food, drug and cosmetics act. The DOJ says the decree acknowledges that Dakota Laboratories is no longer in production. If its owners ever entertain thoughts of reopening, they must first get the FDA to sign off on the plant’s production procedures.

Prior to this case, FDA had entered into a consent decree in January with Boehringer Ingelheim‘s contract manufacturing unit Ben Venue Laboratories‘ for its plant in Bedford, OH, after years of ongoing issues. Ben Venue issued 40 product recalls from 2002 to 2011. Ranbaxy Laboratories, India’s generics giant, last year entered into a 5-year consent decree for two plants after the FDA found the company had been covering up serious manufacturing issues.

Consequently, a recent article from PharmTech.com explored the trends in GMP violations and offered advice from an FDA-compliance perspective. The article interviewed Brian Hasselbalch, Acting Associate Director for Policy and Communication, Office of Manufacturing & Product Quality, Office of Compliance at FDA’s Center for Drug Evaluation and Research (CDER), to find out what trends in GMP violations and quality issues the agency has discovered in the past year.

Hasselbalch explained that FDA inspections of drug manufacturers are designed to always evaluate the facility’s quality system. The quality system includes evaluation of manufacturing problems—complaints, recalls, deviations, defects, and failures—so it may not be surprising that we tend to find CGMP deficiencies in this area. Inspection findings from 2012 show CGMP deficiencies in the following major areas:

  • The quality unit does not function as the CGMP regulations require: Approving or rejecting procedures, major decisions about quality including batch release (21 CFR 211.22).
  • Production and process controls are not proven valid and/or are not in writing sufficient to assure consistent performance (21 CFR 211.100).
  • Complaints, defects, and failures are not fully investigated to determine cause and/or full scope of impact (21 CFR 211.192).
  • Facility and equipment are not designed or maintained to assure cleanliness (sanitary surfaces and/or free of residual drug contamination) (21 CFR 211.67)

He then discussed the major trends in quality control violations in pharmaceutical manufacturing. Hasselbalch noted that “There is a problem of oversight: the quality unit is not governing operations as required; management is not providing sufficient resources to quality assurance activities. In some cases, we see evidence that the quality unit is not being allowed to govern operations bearing on quality assurance, and batch release decisions are made contrary to the CGMP regulations.”

One area of change from past years to the more recent full year is “that facility cleaning and equipment maintenance deficiencies have increased.” FDA Warning Letters over the same period reveal problems particularly in “sterile manufacturing operations, where the consequence of poor maintenance and cleaning often leads to more severe consequences for patient safety, such as production of a non-sterile injectable.”

Hasselbalch then noted two areas that manufacturers could improve quality control on. “First, manufacturers should prevent problems from happening by providing sufficient resources toward the creation of a well-designed, optimized manufacturing and control operation. This may not be a novel concept, but is still worth saying.”

Second, he explained that “manufacturers should react more aggressively on information bearing on product quality. All too often, we see potentially negative quality information—such as consumer complaints, aberrant stability results, abnormal yield variations, adverse-event reports—being evaluated too slowly and incompletely. We understand the need for a response to such information to be thoughtful, but we often see manufacturers summarily disregard such data.”

However, he did not that companies have done better with employee training and inspection deficiencies appear to have decreased in quality-unit responsibilities (while still being higher than other types of deficiencies).

Hasselbalch also noted that “domestic and offshore manufacturers tend to have similar problems; usually, given the greater number of APIs being made offshore than here in the US, the differences are often explained by the nature of the processing and standards expected.”

In fiscal year (FY) 2012, FDA performed approximately 500 preapproval-type inspections (specific to a site and application), which includes all types of application-listed facilities (API, finished product, processing, testing, and packaging). This is about the same number as in FY 2011.

In FY 2012, FDA performed about 1900 CGMP-type inspections (i.e., routine coverage) of facilities connected with human drug manufacturing (except medical gas; including all other drug types and APIs as well as finished product) here in the US and offshore. This is about the same amount as in FY 2011, but with one big difference: routine CGMP inspections of offshore facilities increased by about 20% in FY 2012 over FY 2011.

He noted that FDA has planned for this increase to continue in FY 2013. Other FY 2013 changes over previous years include increased inspections of positron emission tomography facilities, which are primarily domestic sites.

– 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

Trends in FDA cGMP Violations

We have previously written that one of the new trends in enforcement in the life sciences industry is the focus the federal government is having on compliance with current good manufacturing practices (cGMP).

For instance, we noted back in February of this year that the U.S. Department of Justice announced that compliance with current good manufacturing practices (cGMPs) will be one of the agency’s “top areas of focus” in the coming year.” Additionally, we recently noted that DOJ has been probing international pharmaceutical manufacturing, investigating several companies and their manufacturing practices over the last several months.

Most recently, DOJ filed a lawsuit on behalf of the FDA against Mitchell, SD-based Dakota Laboratories and its owner Charles Voellinger, as reported by FiercePharmaManufacturing. The suit came after inspections in 2010, 2011 and 2012 found significant manufacturing lapses in the plant’s production of eye drops, including a lacking of procedures to protect against microbiological contamination. Among other issues, a 2011 FDA warning letter said the company had released several batches of sterile ophthalmic eye drops without adequately validating aseptic processes, and wasn’t testing the water used to make the drops.

“We cannot take the chance that a manufacturer’s failure to establish proper controls for sterile drug production could result in products becoming contaminated, placing consumers at risk of infection and potentially serious injury,” Assistant Attorney General Stuart Delery said.

Dakota Laboratories settled the lawsuit by agreeing to a “Consent Decree of Permanent Injunction” that prohibits the facility from violating the federal food, drug and cosmetics act. The DOJ says the decree acknowledges that Dakota Laboratories is no longer in production. If its owners ever entertain thoughts of reopening, they must first get the FDA to sign off on the plant’s production procedures.

Prior to this case, FDA had entered into a consent decree in January with Boehringer Ingelheim‘s contract manufacturing unit Ben Venue Laboratories‘ for its plant in Bedford, OH, after years of ongoing issues. Ben Venue issued 40 product recalls from 2002 to 2011. Ranbaxy Laboratories, India’s generics giant, last year entered into a 5-year consent decree for two plants after the FDA found the company had been covering up serious manufacturing issues.

Consequently, a recent article from PharmTech.com explored the trends in GMP violations and offered advice from an FDA-compliance perspective. The article interviewed Brian Hasselbalch, Acting Associate Director for Policy and Communication, Office of Manufacturing & Product Quality, Office of Compliance at FDA’s Center for Drug Evaluation and Research (CDER), to find out what trends in GMP violations and quality issues the agency has discovered in the past year.

Hasselbalch explained that FDA inspections of drug manufacturers are designed to always evaluate the facility’s quality system. The quality system includes evaluation of manufacturing problems—complaints, recalls, deviations, defects, and failures—so it may not be surprising that we tend to find CGMP deficiencies in this area. Inspection findings from 2012 show CGMP deficiencies in the following major areas:

  • The quality unit does not function as the CGMP regulations require: Approving or rejecting procedures, major decisions about quality including batch release (21 CFR 211.22).
  • Production and process controls are not proven valid and/or are not in writing sufficient to assure consistent performance (21 CFR 211.100).
  • Complaints, defects, and failures are not fully investigated to determine cause and/or full scope of impact (21 CFR 211.192).
  • Facility and equipment are not designed or maintained to assure cleanliness (sanitary surfaces and/or free of residual drug contamination) (21 CFR 211.67)

He then discussed the major trends in quality control violations in pharmaceutical manufacturing. Hasselbalch noted that “There is a problem of oversight: the quality unit is not governing operations as required; management is not providing sufficient resources to quality assurance activities. In some cases, we see evidence that the quality unit is not being allowed to govern operations bearing on quality assurance, and batch release decisions are made contrary to the CGMP regulations.”

One area of change from past years to the more recent full year is “that facility cleaning and equipment maintenance deficiencies have increased.” FDA Warning Letters over the same period reveal problems particularly in “sterile manufacturing operations, where the consequence of poor maintenance and cleaning often leads to more severe consequences for patient safety, such as production of a non-sterile injectable.”

Hasselbalch then noted two areas that manufacturers could improve quality control on. “First, manufacturers should prevent problems from happening by providing sufficient resources toward the creation of a well-designed, optimized manufacturing and control operation. This may not be a novel concept, but is still worth saying.”

Second, he explained that “manufacturers should react more aggressively on information bearing on product quality. All too often, we see potentially negative quality information—such as consumer complaints, aberrant stability results, abnormal yield variations, adverse-event reports—being evaluated too slowly and incompletely. We understand the need for a response to such information to be thoughtful, but we often see manufacturers summarily disregard such data.”

However, he did not that companies have done better with employee training and inspection deficiencies appear to have decreased in quality-unit responsibilities (while still being higher than other types of deficiencies).

Hasselbalch also noted that “domestic and offshore manufacturers tend to have similar problems; usually, given the greater number of APIs being made offshore than here in the US, the differences are often explained by the nature of the processing and standards expected.”

In fiscal year (FY) 2012, FDA performed approximately 500 preapproval-type inspections (specific to a site and application), which includes all types of application-listed facilities (API, finished product, processing, testing, and packaging). This is about the same number as in FY 2011.

In FY 2012, FDA performed about 1900 CGMP-type inspections (i.e., routine coverage) of facilities connected with human drug manufacturing (except medical gas; including all other drug types and APIs as well as finished product) here in the US and offshore. This is about the same amount as in FY 2011, but with one big difference: routine CGMP inspections of offshore facilities increased by about 20% in FY 2012 over FY 2011.

He noted that FDA has planned for this increase to continue in FY 2013. Other FY 2013 changes over previous years include increased inspections of positron emission tomography facilities, which are primarily domestic sites.

– 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

Trends in FDA cGMP Violations

We have previously written that one of the new trends in enforcement in the life sciences industry is the focus the federal government is having on compliance with current good manufacturing practices (cGMP).

For instance, we noted back in February of this year that the U.S. Department of Justice announced that compliance with current good manufacturing practices (cGMPs) will be one of the agency’s “top areas of focus” in the coming year.” Additionally, we recently noted that DOJ has been probing international pharmaceutical manufacturing, investigating several companies and their manufacturing practices over the last several months.

Most recently, DOJ filed a lawsuit on behalf of the FDA against Mitchell, SD-based Dakota Laboratories and its owner Charles Voellinger, as reported by FiercePharmaManufacturing. The suit came after inspections in 2010, 2011 and 2012 found significant manufacturing lapses in the plant’s production of eye drops, including a lacking of procedures to protect against microbiological contamination. Among other issues, a 2011 FDA warning letter said the company had released several batches of sterile ophthalmic eye drops without adequately validating aseptic processes, and wasn’t testing the water used to make the drops.

“We cannot take the chance that a manufacturer’s failure to establish proper controls for sterile drug production could result in products becoming contaminated, placing consumers at risk of infection and potentially serious injury,” Assistant Attorney General Stuart Delery said.

Dakota Laboratories settled the lawsuit by agreeing to a “Consent Decree of Permanent Injunction” that prohibits the facility from violating the federal food, drug and cosmetics act. The DOJ says the decree acknowledges that Dakota Laboratories is no longer in production. If its owners ever entertain thoughts of reopening, they must first get the FDA to sign off on the plant’s production procedures.

Prior to this case, FDA had entered into a consent decree in January with Boehringer Ingelheim‘s contract manufacturing unit Ben Venue Laboratories‘ for its plant in Bedford, OH, after years of ongoing issues. Ben Venue issued 40 product recalls from 2002 to 2011. Ranbaxy Laboratories, India’s generics giant, last year entered into a 5-year consent decree for two plants after the FDA found the company had been covering up serious manufacturing issues.

Consequently, a recent article from PharmTech.com explored the trends in GMP violations and offered advice from an FDA-compliance perspective. The article interviewed Brian Hasselbalch, Acting Associate Director for Policy and Communication, Office of Manufacturing & Product Quality, Office of Compliance at FDA’s Center for Drug Evaluation and Research (CDER), to find out what trends in GMP violations and quality issues the agency has discovered in the past year.

Hasselbalch explained that FDA inspections of drug manufacturers are designed to always evaluate the facility’s quality system. The quality system includes evaluation of manufacturing problems—complaints, recalls, deviations, defects, and failures—so it may not be surprising that we tend to find CGMP deficiencies in this area. Inspection findings from 2012 show CGMP deficiencies in the following major areas:

  • The quality unit does not function as the CGMP regulations require: Approving or rejecting procedures, major decisions about quality including batch release (21 CFR 211.22).
  • Production and process controls are not proven valid and/or are not in writing sufficient to assure consistent performance (21 CFR 211.100).
  • Complaints, defects, and failures are not fully investigated to determine cause and/or full scope of impact (21 CFR 211.192).
  • Facility and equipment are not designed or maintained to assure cleanliness (sanitary surfaces and/or free of residual drug contamination) (21 CFR 211.67)

He then discussed the major trends in quality control violations in pharmaceutical manufacturing. Hasselbalch noted that “There is a problem of oversight: the quality unit is not governing operations as required; management is not providing sufficient resources to quality assurance activities. In some cases, we see evidence that the quality unit is not being allowed to govern operations bearing on quality assurance, and batch release decisions are made contrary to the CGMP regulations.”

One area of change from past years to the more recent full year is “that facility cleaning and equipment maintenance deficiencies have increased.” FDA Warning Letters over the same period reveal problems particularly in “sterile manufacturing operations, where the consequence of poor maintenance and cleaning often leads to more severe consequences for patient safety, such as production of a non-sterile injectable.”

Hasselbalch then noted two areas that manufacturers could improve quality control on. “First, manufacturers should prevent problems from happening by providing sufficient resources toward the creation of a well-designed, optimized manufacturing and control operation. This may not be a novel concept, but is still worth saying.”

Second, he explained that “manufacturers should react more aggressively on information bearing on product quality. All too often, we see potentially negative quality information—such as consumer complaints, aberrant stability results, abnormal yield variations, adverse-event reports—being evaluated too slowly and incompletely. We understand the need for a response to such information to be thoughtful, but we often see manufacturers summarily disregard such data.”

However, he did not that companies have done better with employee training and inspection deficiencies appear to have decreased in quality-unit responsibilities (while still being higher than other types of deficiencies).

Hasselbalch also noted that “domestic and offshore manufacturers tend to have similar problems; usually, given the greater number of APIs being made offshore than here in the US, the differences are often explained by the nature of the processing and standards expected.”

In fiscal year (FY) 2012, FDA performed approximately 500 preapproval-type inspections (specific to a site and application), which includes all types of application-listed facilities (API, finished product, processing, testing, and packaging). This is about the same number as in FY 2011.

In FY 2012, FDA performed about 1900 CGMP-type inspections (i.e., routine coverage) of facilities connected with human drug manufacturing (except medical gas; including all other drug types and APIs as well as finished product) here in the US and offshore. This is about the same amount as in FY 2011, but with one big difference: routine CGMP inspections of offshore facilities increased by about 20% in FY 2012 over FY 2011.

He noted that FDA has planned for this increase to continue in FY 2013. Other FY 2013 changes over previous years include increased inspections of positron emission tomography facilities, which are primarily domestic sites.

– 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

July 17, 2014 3:57 am / 1 Comment on 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)

July 17, 2014 1:27 am / Leave a comment


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

July 16, 2014 4:52 am / Leave a comment


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%).

………………….

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),

 

 

US4535157 Nov 1, 1983 Aug 13, 1985 Key Pharmaceuticals, Inc. Reacting naloxone and naltrexone with potassium e-butoxide
US4751307 Feb 27, 1987 Jun 14, 1988 Mallinckrodt, Inc. Wittig-reaction processes
EP0035202A2 Feb 23, 1981 Sep 9, 1981 Miles Laboratories, Inc. Method of blood plasma fractionation
EP0039066A2 Apr 25, 1981 Nov 4, 1981 E.I. Du Pont De Nemours And Company 17-Substituted 6-desoxy-7,8-dihydro-6-alpha-methylnoroxymorphone narcotic antagonists
WO2007110761A2 Mar 23, 2007 Oct 4, 2007 Azad Pharmaceutical Ingredient Polymorphic forms of olopatadine hydrochloride and methods for producing olopatadine and salts thereof

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.
3 Hahn F. and Fishman J., 1975, Narcotic Antagonists. 4. Carbon-6 Derivatives of N-Substituted Noroxymorphones as Narcotic Antagonists, Journal of Medicinal Chemistry 18(3):259-262.
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.
7 Wittig et al., Jul. 10, 1954, “Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien I“, Chemische Berichte 87: 1318.

Anthony crasto’s blog New drug approvals touches 3 lakh views…….Helping millions

July 16, 2014 3:41 am / Leave a comment


link is https://newdrugapprovals.org/

 

All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Helping millions, 7 million hits on google, pushing boundaries, one lakh plus connections worldwide, 3 lakh plus VIEWS on this blog in 193 countries

 

 

 

 

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Protein heals wounds, boosts immunity and protects from cancer – Lactoferrin

July 16, 2014 1:23 am / Leave a comment


Ralph Turchiano's avatarCLINICALNEWS.ORG

04 May 2012

University of Calgary researcher edits special issue on disease fighting properties of lactoferrin

Hans Vogel, a professor in the biological sciences department, is the guest editor of a special issue of the journal Biochemistry and Cell Biology that focuses on lactoferrin, an important iron-binding protein with many health benefits.

“Some people describe this protein as the ‘Swiss army knife’ of the human host defense system,” says Vogel. “We now know that lactoferrin has many functions in innate immunity and that it plays a role in protecting us from bacterial, viral, fungal, and protozoal infections. It can even protect us from some forms of cancer.”

View original post 269 more words

Garlic compound fights source of food-borne illness better than antibiotics (100 times more effective than two popular antibiotics )

July 15, 2014 12:30 pm / Leave a comment


Ralph Turchiano's avatarCLINICALNEWS.ORG

04 May 2012

Discovery could play role in treatments for food and prep areas

PULLMAN, Wash.—Researchers at Washington State University have found that a compound in garlic is 100 times more effective than two popular antibiotics at fighting the Campylobacter bacterium, one of the most common causes of intestinal illness. Their work was recently published in the Journal of Antimicrobial Chemotherapy.

The discovery opens the door to new treatments for raw and processed meats and food preparation surfaces.

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Beloranib, 성분명 벨로라닙 ZGN-433….Zafgen’s Prader-Willi syndrome therapy receives orphan drug designation in Europe

July 15, 2014 4:24 am / Leave a comment


 

Beloranib.svg

 

Beloranib

 

CAS   251111-30-5 (beloranib),529511-79-3 (beloranib hemioxalate)

(E)-(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 3-(4-(2-(dimethylamino)ethoxy)phenyl)acrylate

6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol

Mechanism of Action:methionine aminopeptidase 2 (MetAP2) inhibitor

Indication:Obesity US Patent : US6063812 Patent Exp Date: May 13, 2019

Originator: Chong Kun Dang (CKD) Pharma (종근당) Chong Kun Dang Pharm Corp

Developer: Zafgen Inc. (자프젠)Zafgen Corporation

Zafgen’s Prader-Willi syndrome therapy receives orphan drug designation in Europe The European Commission (EC) has granted orphan drug designation to US-based Zafgen for its beloranib for treating Prader-Willi syndrome. Beloranib is a potent inhibitor of Methionine aminopeptidase-2 that reduces hunger while stimulating the use of stored fat as an energy source (MetAP2). MetAP2 is an enzyme that modulates the activity of key cellular processes that control metabolism. http://www.pharmaceutical-technology.com/news/newszafgens-prader-willi-syndrome-therapy-receives-orphan-drug-designation-in-europe-4316842?WT.mc_id=DN_News

 

INTRODUCTION   Beloranib is an experimental drug candidate for the treatment of obesity. It was discovered by CKD Pharmaceuticals and is currently being developed by Zafgen. Beloranib, an analog of the natural chemical compound fumagillin, is an inhibitor of the enzyme METAP2. It was originally designed as angiogenesis inhibitor for the treatment of cancer. However, once the potential anti-obesity effects of METAP2 inhibition became apparent, the clinical development began to focus on these effects and beloranib has shown positive results in preliminary clinical trials for this indication. At such low doses, says Thomas E. Hughes, president and chief executive officer of Zafgen, toxicity concerns tend to evaporate, in part because so little opportunity exists to inhibit off-target proteins.

Zafgen, a small pharmaceutical company in Cambridge, Mass., sees high selectivity and low toxicity with its covalent molecule for treating obesity, beloranib hemioxalate, also known as ZGN-433. “You’re passing a wave of the molecule through the body,” he says. “It hits the different tissues, silences the target enzyme where it finds it, and then it goes away.” Zafgen’s drug candidate inhibits an enzyme called methionine aminopeptidase 2 (MetAP2), which had been of interest in oncology circles until it turned out to be a poor target for treating cancer in mice. However, animals treated with a MetAP2 inhibitor lost weight. Zafgen pursued the enzyme as a target for obesity. Its drug candidate contains a spiroepoxide that bonds with a histidine in the protein’s active site.

ZGN-433 has undergone a Phase I clinical trial, in which obese volunteers lost up to 2 lb per week. It will enter Phase II trials within a year, Hughes says, funded by $33 million the company raised from investors. With dosing of up to 2 mg twice per week, ZGN-433 reaches a maximum concentration in the body of just a few nanomolar for several hours before the body quickly eliminates it, Hughes says. During that time, the drug is much more likely to interact with MetAP2 than with anything else. “You’re flying under the radar of a lot of concerns,” he says. “Drug-drug interactions are not an issue. There’s just not enough inhibitor to go around.

The same is true for off-target inhibition: The chance of off-target toxicity is largely gone.” Proponents of covalent inhibitors are quick to point out that dozens of such drugs are already on the market. They include aspirin, the world’s most widely used medicine; penicillin and related antibiotics; and recently developed blockbusters such as Plavix, Prevacid, and Nexium. The drugs treat a broad range of conditions, and many have minimal side effects, even when taken for years. By one count, of the marketed drugs that inhibit enzymes, more than one-third work by covalent modification (Biochemistry, DOI: 10.1021/bi050247e).

6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate

Beloranib, ZGN-433, CKD-732
Beloranib.svg
Identifiers
CAS number 251111-30-5 Yes, 529511-79-3 (hemioxalate) Yes
PubChem 6918502
ChemSpider 26286923 Yes
UNII FI471K8BU6 Yes
Jmol-3D images Image 1
Properties
Molecular formula C29H41NO6
Molar mass 499.64 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)

Beloranib (previously known as CKD-732; ZGN-433), a methionine aminopeptidase 2 (MetAP2) inhibitor originally designed as an anticancer agent, is being developed by Zafgen as a first-in-class obesity therapy. Beloranib, a twice-daily injection, is discovered by korean company Chong Kun Dang (CKD) Pharmaceuticals and was licensed to Cambridge, MA-based startup Zafgen, Inc. Zafgen holds exclusive worldwide rights (exclusive of Korea) for development and commercialization of beloranib. Beloranib, an analog of  the antimicrobial agent fumagillin, is an inhibitor of the enzyme METAP2 involved in fatty acid production. It was originally designed as angiogenesis inhibitor for the treatment of cancer. However, once the potential anti-obesity effects of METAP2 inhibition became apparent, the clinical development began to focus on these effects.

Zafgen has chosen to develop beloranib not for the folks that need to shed a few pounds, but for severely obese people, and smaller groups of patients with rare and dangerous conditions. In January 2013, beloranib was granted orphan drug designation by the U.S. Food and Drug Administration to treat a rare genetic condition known as Prader-Willi Syndrome (PWS) that causes obesity through compulsive eating. Zafgen plans to seek the same designation for beloranib in craniopharyngioma (a rare benign brain tumor) related obesity as well. By going after these orphan indications, Zafgen can get onto the market quicker and cheaper than if it went straight for the larger obesity market. Zafgen recently completed two Phase 2a clinical trials evaluating beloranib’s ability to reduce body weight and to improve hyperphagia, one in PWS patients and one in severely obese patients. In its Phase 2a clinical trials, Zafgen observed reductions in body weight, body mass and body fat content in both patient populations and reductions in hyperphagia-related behaviors in PWS patients.

On June 19, 2014, Zafgen Inc. raised $96 million in its initial public offering (IPO) on the Nasdaq under the symbol “ZFGN” amid strong demand from investors. With its IPO cash, Zafgen plans to initiate its Phase 3 clinical program, consisting of two Phase 3 clinical trials, of beloranib in PWS patients, with the first Phase 3 trial to start in the second half of 2014, after finalizing the program design based on ongoing conversations with the FDA and certain European regulatory authorities. Zafgen is also planning a phase 2a trial in craniopharyngioma, and a Phase 2b trila in patients with severe obesity, all this year. The composition of matter patent (US6063812) on beloranib will each expire in May 2019.  Zafgen owns two issued U.S. patents relating to beloranib polymorph compositions of matter that will expire in 2031 and two issued U.S. patents to methods of treating obesity that will expire in 2029.   Beloranib is an experimental drug candidate for the treatment of obesity. It was discovered by CKD Pharmaceuticals and is currently being developed by Zafgen.[1] Beloranib, an analog of the natural chemical compound fumagillin, is an inhibitor of the enzyme METAP2.[2] It was originally designed as angiogenesis inhibitor for the treatment of cancer.[3] However, once the potential anti-obesity effects of METAP2 inhibition became apparent, the clinical development began to focus on these effects and beloranib has shown positive results in preliminary clinical trials for this indication.[4][5]

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http://www.google.com/patents/WO2005082349A1?cl=en

compound O-(4- dimethylaminoethoxycinnamoyl)fumagillol can be used in the form of a salt, e.g., acetate, lactate, benzoate, salicylate, mandelate, oxalate, methanesulfonate, or p- toluenesulfonate. Korean Patent No. 0357542 and its corresponding patents (U.S. Patent No. 6,063,812, Japanese Patent No. 3370985, and European Patent No. 1077964), filed by the present applicant, disclose fumagiUol derivatives, including the compounds used in the present invention. The composition of the present invention can be prepared in combination with pharmaceutically acceptable carriers commonly used in pharmaceutical formulations.

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http://www.google.com/patents/WO2012064838A1?cl=en

MetAP2 encodes a protein that functions at least in part by enzymatically removing the amino terminal methionine residue from certain newly translated proteins, such as, glyceraldehyde-3- phosphate dehydrogenase (Warder et al. (2008) J Proteome Res 7:4807). Increased expression of the MetAP2 gene has been historically associated with various forms of cancer. Molecules inhibiting the enzymatic activity of MetAP2 have been identified and have been explored for their utility in the treatment of various tumor types (Wang et al. (2003) Cancer Res 63:7861) and infectious diseases, such as, microsporidiosis, leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed Sci. 9:34). Notably, inhibition of MetAP2 activity in obese and obese-diabetic animals leads to a reduction in body weight in part by increasing the oxidation of fat and in part by reducing the consumption of food (Rupnick et al. (2002) Proc Natl Acad Sci USA 99: 10730). [0003] 6-O-(4-Dimethylaminoethoxy)cinnamoyl fumagillol is a METAP2 inhibitor and is useful in the treatment of, e.g., obesity. 6-O-(4-Dimethylaminoethoxy)cinnamoyl fumagillol is characterized by formula I:

Figure imgf000002_0001

Example 1 [0060] Crystalline, Form A material of 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol was prepared as follows: [0061] Approximately 423 mg of amorphous gum/oil-like 6-O-(4- dimethylaminoethoxy)cinnamoyl fumagillol free base compound was dissolved in ca. 6 mL of diisopropylether (IPE). The solution was allowed to stir for ca. 24 hours at ambient temperature (18-22°C) during which time solid precipitated. The resulting solid was isolated by filtration and dried under vacuum at ambient for ca. 4 hours (yield 35.8 %).

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http://www.google.com/patents/WO1999059986A1?cl=en

Example 14 : 0-(4-dimethylaminocinnamoyl)fumagillol 1) To a solution of 4-dimethylaminocinnamic acid (950 mg) in toluene (20 ml), dipyridyl disulfide (1.64 g) and triphenyl phosphine (1.97 g) were added, and the mixture was stirred for 12 hours. 2) The resultant solution of 1) was added to fumagillol (500 mg) at room temperature. Sodium hydride (142 mg) was added thereto, and the reaction mixture was stirred for 30 minutes. After adding saturated ammonium chloride solution (20 ml), the reaction mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: ethyl acetate/ n-hexane = 1/2) to obtain yellow solid (470 mg). ‘H-NMR (CDCI3) δ : 7.60 (d, IH, J=15.8Hz), 7.41 (d, 2H, J=8.9Hz), 6.67 (d, 2H, J=8.9Hz), 6.27 (d, IH, J=15.8Hz), 5.71 (m, IH), 5.22 (bit, IH), 3.70 (dd, IH, J=2.8, 11.0Hz), 3.45 (s, 3H), 3.02 (s, 6H), 3.01 (d, IH, J=4.3Hz), 2.63 (t, IH, J=6.3Hz), 2.56 (d, IH, J=4.3Hz), 2.41 – 1.81 (m, 6H), 1.75 (s, 3H), 1.67 (s, 3H), 1.22 (s, 3H), 1.15 – 1.06 (m, IH)

………..

Organic Letters, 16(3), 792-795; 2014

Abstract Image

An efficient, two-step construction of highly complex alkaloid-like compounds from the natural product fumagillol is described. This approach, which mimics a biosynthetic cyclase/oxidase sequence, allows for rapid and efficient structure elaboration of the basic fumagillol scaffold with a variety of readily available coupling partners. Mechanistic experiments leading to the discovery of an oxygen-directed oxidative Mannich reaction are also described.

http://pubs.acs.org/doi/full/10.1021/ol4035269

References

  1. “News Release: Zafgen Secures $33 Million Series C Financing”. Zafgen, Inc. July 7, 2011.
  2. Chun, E; Han, CK; Yoon, JH; Sim, TB; Kim, YK; Lee, KY (2005). “Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model”. International Journal of Cancer. Journal International Du Cancer 114 (1): 124–30. doi:10.1002/ijc.20687. PMID 15523682.
  3. Kim, EJ; Shin, WH (2005). “General pharmacology of CKD-732, a new anticancer agent: effects on central nervous, cardiovascular, and respiratory system”. Biological & Pharmaceutical Bulletin 28 (2): 217–23. doi:10.1248/bpb.28.217. PMID 15684472.
  4. “Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity”. MedNews. Drugs.com. 5 January 2011.
  5. “Fat-busting pill helps obese to shed two pounds a week – without changing their diets”. UK Daily Mail. 11 January 2011.

MORE REF Grenning, Alexander J. et al.Remodeling of Fumagillol: Discovery of an Oxygen-Directed Oxidative Mannich Reaction.Organic Letters, 16(3), 792-795; 2014

Hughes, T. E.; Kim, D. D.; Marjason, J.; Proietto, J.; Whitehead, J. P.; Vath, J. E. Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women. Obesity (2013), 21(9), 1782-1788.

Chung Il Hong, Jung Woo Kim, Sang Joon Lee, Soon Kil Ahn, Nam Song Choi, Ryung Kee Hong, Hyoung Sik Chun, Seung Kee Moon, Cheol Kyu Han. Angiogenesis inhibitors, antiarthritic agents and anticarcinogenic agents plus synthesis. US patent Number US6063812 A, Also published as CA2331873A1, CA2331873C, CN1301260A, CN100352810C, DE69903279D1, DE69903279T2, EP1077964A1,EP1077964B1,WO1999059986A1, Filing date: May 13, 1999.Original Assignee:Chong Kun Dang Corporation Crawford, Thomas; Reece, Hayley A.Preparation of crystalline forms of 6-O-(4-dimethylaminoethoxy)cinnamoylfumagillol.PCT Int. Appl. (2012), WO2012064838 A1, 20120518

Egorov, Maxim et al. Preparation of fumagillol derivatives useful for the treatment or prevention of bone tumors.  PCT Int. Appl., WO2012130906, 04 Oct 2012

Stevenson, Cheri A.; Akullian, Laura C.; Petter, Russell C.; Kane, John J.; Hammond, Charles E.; Yin, Mao; Yurkovetskiy, Aleksandr.Preparation of biocompatible biodegradable fumagillin analog conjugates for the treatment of cancer. PCT Int. Appl. (2009), WO2009073445 A2, 20090611

Lee, Hong Woo et al.Design, synthesis, and antiangiogenic effects of a series of potent novel fumagillin analogues.Chemical & Pharmaceutical Bulletin, 55(7), 1024-1029; 2007

Lee, Hong Woo et al.Selective N-demethylation of tertiary aminofumagillols with selenium dioxide via a non-classical Polonovski type reaction.Heterocycles, 68(5), 915-932; 2006

References  OTHERS

1: Yin SQ, Wang JJ, Zhang CM, Liu ZP. The development of MetAP-2 inhibitors in cancer treatment. Curr Med Chem. 2012;19(7):1021-35. Review. PubMed PMID: 22229417.

2: Shin SJ, Ahn JB, Park KS, Lee YJ, Hong YS, Kim TW, Kim HR, Rha SY, Roh JK, Kim DH, Kim C, Chung HC. A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy. Invest New Drugs. 2012 Apr;30(2):672-80. doi: 10.1007/s10637-010-9625-x. Epub 2010 Dec 29. PubMed PMID: 21188464.

3: Shin SJ, Jeung HC, Ahn JB, Rha SY, Roh JK, Park KS, Kim DH, Kim C, Chung HC. A phase I pharmacokinetic and pharmacodynamic study of CKD-732, an antiangiogenic agent, in patients with refractory solid cancer. Invest New Drugs. 2010 Oct;28(5):650-8. doi: 10.1007/s10637-009-9287-8. Epub 2009 Jul 8. PubMed PMID: 19585083.

4: Rhee Y, Park SY, Kim YM, Lee S, Lim SK. Angiogenesis inhibitor attenuates parathyroid hormone-induced anabolic effect. Biomed Pharmacother. 2009 Jan;63(1):63-8. doi: 10.1016/j.biopha.2007.10.013. Epub 2007 Nov 20. PubMed PMID: 18457934.

5: Kim YM, An JJ, Jin YJ, Rhee Y, Cha BS, Lee HC, Lim SK. Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732. J Mol Endocrinol. 2007 Apr;38(4):455-65. PubMed PMID: 17446235.

6: Kim EJ, Shin WH. General pharmacology of CKD-732, a new anticancer agent: effects on central nervous, cardiovascular, and respiratory system. Biol Pharm Bull. 2005 Feb;28(2):217-23. PubMed PMID: 15684472.

7: Chun E, Han CK, Yoon JH, Sim TB, Kim YK, Lee KY. Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model. Int J Cancer. 2005 Mar 10;114(1):124-30. PubMed PMID: 15523682.

8: Lee HS, Choi WK, Son HJ, Lee SS, Kim JK, Ahn SK, Hong CI, Min HK, Kim M, Myung SW. Absorption, distribution, metabolism, and excretion of CKD-732, a novel antiangiogenic fumagillin derivative, in rats, mice, and dogs. Arch Pharm Res. 2004 Feb;27(2):265-72. PubMed PMID: 15029870.

9: Kim JH, Lee SK, Ki MH, Choi WK, Ahn SK, Shin HJ, Hong CI. Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732 through complexation with hydroxypropyl-beta-cyclodextrin. Int J Pharm. 2004 Mar 19;272(1-2):79-89. PubMed PMID: 15019071.

10: Myung SW, Kim HY, Min HK, Kim DH, Kim M, Cho HW, Lee HS, Kim JK, Hong CI. The identification of in vitro metabolites of CKD-732 by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2002;16(21):2048-53. PubMed PMID: 12391579.

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