Emil W. Ciurczak, DoraMaxx Consulting11.13.14
The supply chain has been defined in many ways. However, it is in its entirety the chain of materials from active pharmaceutical ingredient (API) and excipient manufacture through to the production of product to the delivery of the product to the patient. While much attention has been paid to the supply chain external to the manufacturing facility, namely, adulterated excipients and APIs, as well as counterfeits, it is seldom pointed out that the manufacturer itself is at least as important.
The steps taken in a company, from warehouse reception of raw materials to shipping of the finished product (packaged or in bulk), may be considered the “internal supply chain,” and is no less important or less susceptible to errors than the “external” one. Even when the excipient is fine and deliveries straightforward, the weakest link in the supply chain has often been the legitimate manufacturer.
For example, the FDA banned the Indian manufacturing plant where Ranbaxy Laboratories made its generic version of Lipitor last year after citing the plant for a list of problems. The year before, the Ranbaxy plant recalled 41 lots of atorvastatin because of the chance that ground-up glass had gotten into some of the API. In an unfortunate comment, the CEO was upset that “the material was labeled ‘adulterated,’ since glass isn’t a chemical.” The fact that the plant is not currently shipping products to the U.S. has not kept Ranbaxy from having to recall even more generic Lipitor. The company is voluntarily recalling nearly 65,000 bottles in the U.S. after a pharmacist reported finding a 20 mg tablet in a sealed bottle marked 10mg.
This is just the latest problem for the generic drug maker. In January, the FDA banned their key API plant in Toansa, India, after a January follow-up inspection. Particularly troubling, the FDA said, was that workers at the plant had been retesting products that failed analytics until they got the results that were needed, overwriting the old results in the company database. Proper analysis procedures were not followed, and equipment was not properly calibrated.
With that action, the last of Ranbaxy’s four FDA-approved plants in India has now been banned from shipping to the U.S. Two plants had been banned in 2008 after issues were flagged for the FDA by a whistleblower, and the plants were placed under an extensive consent decree. In May 2013, Ranbaxy reached a $500 million settlement with U.S. authorities for those problems, pleading to several felony charges and pledging to fix the manufacturing problems that led to them. The drug maker now has only its Ohm Laboratories plant in New Jersey able to produce products for the U.S. market.
All four of the banned manufacturing facilities have been placed under the 55-page consent decree that Ranbaxy and its parent Daiichi Sankyo agreed to in 2011. The decree outlines tight controls on manufacturing and requires the company to bring in independent auditors to oversee its operations and to report directly to the FDA if they face any issues in doing their jobs. But problems have persisted, leading a Daiichi Sankyo executive to remark in January that more “drastic measures” are obviously needed to eradicate problems at the Indian drug maker.
Pfizer, which had to recall an injectable drug last month, is now recalling three lots of an antidepressant after a pharmacist discovered a capsule of one of Pfizer’s heart pills in an Effexor XR bottle, a potentially deadly combo. Pfizer said it had voluntarily recalled two lots of different quantities of Effexor XR and one lot of its Greenstone-branded venlafaxine, its generic version. The drug maker said the risk that any other bottles might be affected is slim, but it decided to recall the three lots as a precaution. All three were run on the same packaging line. Pfizer told Fox News that the three lots total about 104,450 bottles, and about 65,800 have already hit pharmacies. The heart drug found in an Effexor XR bottle was Tikosyn, a med used to treat irregular heartbeats.
Patients prescribed Effexor XR who took Tikosyn by mistake could potentially have a fatal reaction, the drug maker cautioned.
In February, Mylan recalled 10 lots of the injectable “hypnotic drug” etomidate in 2-, 10- and 20-mL doses because pieces of shredded labels were found in some vials. The drug was manufactured for Pfizer in a plant in Poland that Mylan recently acquired in its $1.75 billion acquisition of India’s Agila Specialties. Pittsburgh-based Mylan said that the cartons and the vials may also be missing lot numbers and expiry dates or they may be illegible on the vials.
Dealing With Quality Problems
In recent years, the FDA has been building up its efforts to face down quality problems that put patients and the supply chain at risk. Problems with quality at manufacturing plants have been implicated in the majority of drug shortages as well as created suspicion among doctors that some generic drugs are ineffective. Last year the agency created the Office of Pharmaceutical Quality within the Center for Drug Evaluation and Research (CDER). Janet Woodcock, CDER director, has even suggested giving letter grades to manufacturing plants and letting the marketplace help weed out bad players.
When the FDA spent nine days going over the Canton Laboratories API facility in Vadodara, India, last year, inspectors said employees were not getting equipment clean enough between batches to prevent cross contamination. The company’s certificates of analysis had been showing its APIs were within limits for microbial and metal content, but there was a problem with those tests: They never occurred. The company was just making up data and then shipping out products, the FDA says.
A Feb. 27 warning letter posted on the FDA website says: “Multiple personnel confirmed that your firm did not perform the microbial tests reported on the Certificates of Aanlysis.”
Additionally, inspectors could find only 38 results for Atomic Absorption Spectrophotometer (AAS) testing when 400 AAS tests were reportedly done. The FDA said the fact that analysts could access and delete data was a huge problem. The API maker promised it would retrain employees and fix the issues, but the FDA said it made the same claims when the FDA inspected the plant 5 years ago. The agency said it wanted a report on all of the products shipped to the U.S. that might be affected by the quality breaches. It wants detailed reports on how the company will upgrade systems and processes and assure its APIs are safe and effective.
Falsifying drug analytics has been a recurring theme in facility inspections the FDA has been doing in India. The agency leveled similar complaints against drug-maker USV in Mumbai last month. It has also factored in to the long-running problems at India’s Ranbaxy Laboratories and at Wochhardt, two Indian companies that have had plants banned from shipping to the U.S. in the last 10 months. It was also noted in a warning letter issued last year to an Indian facility owned by Germany’s Fresenius Kabi.
Quality, or in too many cases the lack of it, was a primary theme for FDA Commissioner Margaret Hamburg during meetings in India last month with government and industry officials. While she noted that there were many top-notch drug producers in the country, she said that given India’s importance to the global supply chain, regulators there need to get in line with international standards and expectations.
Two years ago the FDA turned to Sun Pharma to help it overcome a cancer drug shortage after a Ben Venue plant closed for manufacturing problems. Now, it is Sun whose manufacturing has been called into question. The FDA has issued a ban against one of its plants in India continuing a crackdown there that has also blocked facilities by Ranbaxy Laboratories and Workhardt from the U.S. market. The exact reasons for the import alert have not yet been disclosed, but a Sun Pharma plant in Karkhadi in Gujarat, India, was included on the FDA’s import alert list Tuesday. A spokeswoman told Reuters that the plant accounts for less than 1% of the company’s sales, so the ban would have little effect on its revenues. It is one of 25 Sun manufacturing facilities around the world, of which 11 are in India and three are in Gujarat. She said the company was working on the issues raised by FDA inspectors. The plant manufactures the antibiotic cephalosporin.
The ban comes only weeks after FDA Commissioner Hamburg returned from a trip to India where she discussed quality issues with government and industry officials. The country provides about 40% of the generic and over-the-counter drugs U.S. consumers take, and so the FDA has been placing more personnel and more emphasis on Indian drug plants. She noted during her trip that many of India’s drug makers have modern facilities with top-notch operations.
Still, the failures have been significant. Ranbaxy Laboratories, India’s biggest generic manufacturer and one that has been first to market with many generic drugs, has been under tight FDA oversight for years for faking drug data at some plants. The agency has banned all four of its FDA-approved plants in India, including two in the last 6 months. It also has banned two Indian plants owned by India’s Wockhardt for faking data, as well as sanitation issues. Just this week, the FDA issued a warning letter against an Indian API maker that it says never tested many of its products, then made up test results to include in required documents. Some government officials in India have complained that the FDA is singling out the country, but the FDA has taken tough actions against U.S., European and Canadian manufacturers as well.
This is not Sun’s first time to run into questions about its plant standards. In 2009, U.S. Marshals seized about $20 million worth of products from two of its Caraco subsidiary plants in Michigan and issued a consent decree on the facilities. They were tied to a string of issues that led to the recall of metformin pills for diabetes that fell on both sides of the size specification and were contaminated with metal scrapings, a 2008 warning letter said. The FDA said Caraco had poor control of its raw materials and a possible formulation error. The FDA issued a close-out letter in 2012 for the facilities, but they continued to operate under the oversight of an outside auditor.
But also that year, the agency turned to Sun Pharma for help when a shortage of J&J’s ovarian cancer drug Doxil materialized when the Boehringer Ingelheim plant that was the exclusive producer ran into FDA issues of its own. Sun was allowed to import Lipodox, a Doxil substitute the FDA had not yet approved. The company manufactured the injection at an FDA-approved facility in India. Then last year, the FDA approved a generic version of Sun’s drug for the U.S. market to help ease the shortage.
What does all this mean to the “average” drug manufacturer? It may easily be expressed by the old Italian proverb: “A dead fish first stinks from its head.” Quite frankly, if management didn’t want such things to happen, they would find a way to stop them. Clear messages that anyone engaged in non-GMP behavior will be dismissed, followed up by actual dismissals, is the only way to curtail “non-quality” behavior. It will take a lot of will and serious effort on the part of the Agencies to continuously shrink the instances of blatant malfeasance.
The bottom line is simply that the customers of these plants are old and ill people who place their trust in them. Part of the training might include having the workers watch videos of the people who receive their products, and, at some point in the showing, flash pictures of the workers’ own families to remind them who else is vulnerable to their dishonest practices.
Emil W. Ciurczak
DoraMaxx Consulting
Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.
The steps taken in a company, from warehouse reception of raw materials to shipping of the finished product (packaged or in bulk), may be considered the “internal supply chain,” and is no less important or less susceptible to errors than the “external” one. Even when the excipient is fine and deliveries straightforward, the weakest link in the supply chain has often been the legitimate manufacturer.
For example, the FDA banned the Indian manufacturing plant where Ranbaxy Laboratories made its generic version of Lipitor last year after citing the plant for a list of problems. The year before, the Ranbaxy plant recalled 41 lots of atorvastatin because of the chance that ground-up glass had gotten into some of the API. In an unfortunate comment, the CEO was upset that “the material was labeled ‘adulterated,’ since glass isn’t a chemical.” The fact that the plant is not currently shipping products to the U.S. has not kept Ranbaxy from having to recall even more generic Lipitor. The company is voluntarily recalling nearly 65,000 bottles in the U.S. after a pharmacist reported finding a 20 mg tablet in a sealed bottle marked 10mg.
This is just the latest problem for the generic drug maker. In January, the FDA banned their key API plant in Toansa, India, after a January follow-up inspection. Particularly troubling, the FDA said, was that workers at the plant had been retesting products that failed analytics until they got the results that were needed, overwriting the old results in the company database. Proper analysis procedures were not followed, and equipment was not properly calibrated.
With that action, the last of Ranbaxy’s four FDA-approved plants in India has now been banned from shipping to the U.S. Two plants had been banned in 2008 after issues were flagged for the FDA by a whistleblower, and the plants were placed under an extensive consent decree. In May 2013, Ranbaxy reached a $500 million settlement with U.S. authorities for those problems, pleading to several felony charges and pledging to fix the manufacturing problems that led to them. The drug maker now has only its Ohm Laboratories plant in New Jersey able to produce products for the U.S. market.
All four of the banned manufacturing facilities have been placed under the 55-page consent decree that Ranbaxy and its parent Daiichi Sankyo agreed to in 2011. The decree outlines tight controls on manufacturing and requires the company to bring in independent auditors to oversee its operations and to report directly to the FDA if they face any issues in doing their jobs. But problems have persisted, leading a Daiichi Sankyo executive to remark in January that more “drastic measures” are obviously needed to eradicate problems at the Indian drug maker.
Pfizer, which had to recall an injectable drug last month, is now recalling three lots of an antidepressant after a pharmacist discovered a capsule of one of Pfizer’s heart pills in an Effexor XR bottle, a potentially deadly combo. Pfizer said it had voluntarily recalled two lots of different quantities of Effexor XR and one lot of its Greenstone-branded venlafaxine, its generic version. The drug maker said the risk that any other bottles might be affected is slim, but it decided to recall the three lots as a precaution. All three were run on the same packaging line. Pfizer told Fox News that the three lots total about 104,450 bottles, and about 65,800 have already hit pharmacies. The heart drug found in an Effexor XR bottle was Tikosyn, a med used to treat irregular heartbeats.
Patients prescribed Effexor XR who took Tikosyn by mistake could potentially have a fatal reaction, the drug maker cautioned.
In February, Mylan recalled 10 lots of the injectable “hypnotic drug” etomidate in 2-, 10- and 20-mL doses because pieces of shredded labels were found in some vials. The drug was manufactured for Pfizer in a plant in Poland that Mylan recently acquired in its $1.75 billion acquisition of India’s Agila Specialties. Pittsburgh-based Mylan said that the cartons and the vials may also be missing lot numbers and expiry dates or they may be illegible on the vials.
Dealing With Quality Problems
In recent years, the FDA has been building up its efforts to face down quality problems that put patients and the supply chain at risk. Problems with quality at manufacturing plants have been implicated in the majority of drug shortages as well as created suspicion among doctors that some generic drugs are ineffective. Last year the agency created the Office of Pharmaceutical Quality within the Center for Drug Evaluation and Research (CDER). Janet Woodcock, CDER director, has even suggested giving letter grades to manufacturing plants and letting the marketplace help weed out bad players.
When the FDA spent nine days going over the Canton Laboratories API facility in Vadodara, India, last year, inspectors said employees were not getting equipment clean enough between batches to prevent cross contamination. The company’s certificates of analysis had been showing its APIs were within limits for microbial and metal content, but there was a problem with those tests: They never occurred. The company was just making up data and then shipping out products, the FDA says.
A Feb. 27 warning letter posted on the FDA website says: “Multiple personnel confirmed that your firm did not perform the microbial tests reported on the Certificates of Aanlysis.”
Additionally, inspectors could find only 38 results for Atomic Absorption Spectrophotometer (AAS) testing when 400 AAS tests were reportedly done. The FDA said the fact that analysts could access and delete data was a huge problem. The API maker promised it would retrain employees and fix the issues, but the FDA said it made the same claims when the FDA inspected the plant 5 years ago. The agency said it wanted a report on all of the products shipped to the U.S. that might be affected by the quality breaches. It wants detailed reports on how the company will upgrade systems and processes and assure its APIs are safe and effective.
Falsifying drug analytics has been a recurring theme in facility inspections the FDA has been doing in India. The agency leveled similar complaints against drug-maker USV in Mumbai last month. It has also factored in to the long-running problems at India’s Ranbaxy Laboratories and at Wochhardt, two Indian companies that have had plants banned from shipping to the U.S. in the last 10 months. It was also noted in a warning letter issued last year to an Indian facility owned by Germany’s Fresenius Kabi.
Quality, or in too many cases the lack of it, was a primary theme for FDA Commissioner Margaret Hamburg during meetings in India last month with government and industry officials. While she noted that there were many top-notch drug producers in the country, she said that given India’s importance to the global supply chain, regulators there need to get in line with international standards and expectations.
Two years ago the FDA turned to Sun Pharma to help it overcome a cancer drug shortage after a Ben Venue plant closed for manufacturing problems. Now, it is Sun whose manufacturing has been called into question. The FDA has issued a ban against one of its plants in India continuing a crackdown there that has also blocked facilities by Ranbaxy Laboratories and Workhardt from the U.S. market. The exact reasons for the import alert have not yet been disclosed, but a Sun Pharma plant in Karkhadi in Gujarat, India, was included on the FDA’s import alert list Tuesday. A spokeswoman told Reuters that the plant accounts for less than 1% of the company’s sales, so the ban would have little effect on its revenues. It is one of 25 Sun manufacturing facilities around the world, of which 11 are in India and three are in Gujarat. She said the company was working on the issues raised by FDA inspectors. The plant manufactures the antibiotic cephalosporin.
The ban comes only weeks after FDA Commissioner Hamburg returned from a trip to India where she discussed quality issues with government and industry officials. The country provides about 40% of the generic and over-the-counter drugs U.S. consumers take, and so the FDA has been placing more personnel and more emphasis on Indian drug plants. She noted during her trip that many of India’s drug makers have modern facilities with top-notch operations.
Still, the failures have been significant. Ranbaxy Laboratories, India’s biggest generic manufacturer and one that has been first to market with many generic drugs, has been under tight FDA oversight for years for faking drug data at some plants. The agency has banned all four of its FDA-approved plants in India, including two in the last 6 months. It also has banned two Indian plants owned by India’s Wockhardt for faking data, as well as sanitation issues. Just this week, the FDA issued a warning letter against an Indian API maker that it says never tested many of its products, then made up test results to include in required documents. Some government officials in India have complained that the FDA is singling out the country, but the FDA has taken tough actions against U.S., European and Canadian manufacturers as well.
This is not Sun’s first time to run into questions about its plant standards. In 2009, U.S. Marshals seized about $20 million worth of products from two of its Caraco subsidiary plants in Michigan and issued a consent decree on the facilities. They were tied to a string of issues that led to the recall of metformin pills for diabetes that fell on both sides of the size specification and were contaminated with metal scrapings, a 2008 warning letter said. The FDA said Caraco had poor control of its raw materials and a possible formulation error. The FDA issued a close-out letter in 2012 for the facilities, but they continued to operate under the oversight of an outside auditor.
But also that year, the agency turned to Sun Pharma for help when a shortage of J&J’s ovarian cancer drug Doxil materialized when the Boehringer Ingelheim plant that was the exclusive producer ran into FDA issues of its own. Sun was allowed to import Lipodox, a Doxil substitute the FDA had not yet approved. The company manufactured the injection at an FDA-approved facility in India. Then last year, the FDA approved a generic version of Sun’s drug for the U.S. market to help ease the shortage.
What does all this mean to the “average” drug manufacturer? It may easily be expressed by the old Italian proverb: “A dead fish first stinks from its head.” Quite frankly, if management didn’t want such things to happen, they would find a way to stop them. Clear messages that anyone engaged in non-GMP behavior will be dismissed, followed up by actual dismissals, is the only way to curtail “non-quality” behavior. It will take a lot of will and serious effort on the part of the Agencies to continuously shrink the instances of blatant malfeasance.
The bottom line is simply that the customers of these plants are old and ill people who place their trust in them. Part of the training might include having the workers watch videos of the people who receive their products, and, at some point in the showing, flash pictures of the workers’ own families to remind them who else is vulnerable to their dishonest practices.
Emil W. Ciurczak
DoraMaxx Consulting
Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.