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Boehringer Ingelheim handed FDA warning letter
FDA says drugmaker used potentially contaminated API in finished drugs
May 22, 2013 | By Eric Palmer

Boehringer Ingelheim, whose contract manufacturing facility in Bedford, OH, has been at the heart of huge drug disruptions in the U.S., is now feeling the sting of FDA inspectors at a key plant in Europe.

The German drugmaker has received an FDA warning letter, posted yesterday to the FDA website, which takes it to task for not investigating the source of large particles in batches of an active pharmaceutical ingredient manufactured at a plant at Ingelheim am Rhein. Most companies only discuss warning letters when directly asked, but Boehringer Ingelheim took the proactive approach. It put out a statement today from the head of its quality division saying the company was taking the warning letter issues very seriously. Dr. Gerhard Koeller, head of Corporate Division Quality, said the company would "invest all our energy to remedy the situation." He pointed out that aside from the November FDA inspection, the plant had successfully passed 22 inspections by different authorities in the past 5 years.

The inspection was in November 2012 and the issues stem from problems in 2008 and 2009, but inspectors did not let the company off the hook for not investigating the source of the contamination and then using the affected API to make finished capsules. It said some of the particles were 3 mm in size, or about one-eighth of an inch. The letter redacted what the particles were determined to be. The letter said it was not until last year that the company finally took "comprehensive corrections to mitigate the presence of foreign particles" in the API.

Additionally, inspectors pointed out that a batch of Boehringer's COPD product Spiriva HandiHaler had failed to give a uniform dose when tested at 9 months but that the company did not recall the lot until it again fell out of spec after 12 months. "We are concerned about the management decision to allow adulterated product to remain in the market between the 9 and 12 month stability stations," the letter said.

Boehringer is already in it deep with the FDA. Its Ben Venue contract manufacturing operation in January signed a consent decree with the agency. The decree is tied to its Bedford, OH, plant, closed in 2011 after inspectors outlined a long list of serious manufacturing problems. Ben Venue issued 40 product recalls from 2002 until the plant voluntarily closed in November 2011. The closing, however, immediately led to shortages of important drugs such as Johnson & Johnson's ($JNJ) cancer drug Doxil, as well as drugs made by Pfizer ($PFE), Takeda and Bristol-Myers Squibb ($BMY).

As a result, the FDA found itself walking a fine line between between company accountability and drug accessibility when deciding what action to take. The decree bars the plant from manufacturing some drugs until the agency is satisfied that problems at the plant have been rectified. But the FDA is also allowing it to continue to manufacture 100 drugs considered "essential for patient care."
 




Public Health Service
Food and Drug Administration


Warning Letter
WL: 320-13-015
CERTIFIED MAIL
RETURN RECEIPT REQUESTED

May 6, 2013

Dr. Gerhard Gigl
Senior Vice President
Boehringer-Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Dear Dr. Gigl:

During our November 5-12, 2012 inspection of your active pharmaceutical ingredient (API) and finished pharmaceutical manufacturing facility, Boehringer-Ingelheim Pharma GmbH & Co. KG., located at D-55216 Ingelheim am Rhein, Germany, investigator(s) from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) for the manufacture of APIs and the CGMP regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your APIs and drug product(s) to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.

We have conducted a detailed review of your firm’s response dated November 30, 2012 and note that it lacks sufficient corrective actions. We also acknowledge receipt of your firm's additional correspondence dated January 31, 2013, February 28, 2013, and March 28, 2013.

Our investigator(s) observed specific violations during the inspection, including, but not limited to, the following:

API: CGMP VIOLATIONS

Failure of your Quality Unit to thoroughly investigate critical deviations in the manufacturing of your active pharmaceutical ingredient (API).


For example, your firm did not conduct a thorough investigation to determine the source of foreign particles in your (b)(4) active pharmaceutical ingredient, (API) nor did you implement timely and appropriate corrective and preventive actions.

The foreign particles found in your (b)(4) included (b)(4). Your firm’s response acknowledges that while reports of the presence of foreign particles were observed in batches produced in 2009, all of the batches in the campaigns beginning in 2008 should have been viewed as having comparable potential for contamination with extrinsic foreign particles. Based on your firm’s response, there were (b)(4) lots of API manufactured in 2008 and (b)(4) manufactured in 2009 that had potential to be contaminated with foreign particles. Your investigation found that 22 of the 29 foreign particle types identified were (b)(4). Nonetheless, your firm decided to still use these contaminated lots to produce your (b)(4) Capsules (b)(4) µg finished product. We are concerned that it was not until July 2012 that your firm began a formal project to implement comprehensive corrections to mitigate the presence of foreign particles in your (b)(4) API.

In response to this letter, provide a list of the (b)(4) and (b)(4) API batches produced after the implementation of the July 2012 CAPA and include whether foreign particles have been observed.


Failure to conduct thorough complaint investigations regarding the presence of foreign particles found in your APIs. For example,


a. In June 2010 your firm received a complaint related to (b)(4), batch (b)(4), manufactured in August 2009, that was contaminated with particles. This batch had been sent to (b)(4) located in (b)(4) for further manufacturing of (b)(4) capsules. Your firm identified the particles as (b)(4). Your investigation did not find the root cause for the foreign particles and concluded that the complaint was “not confirmed.” The inspection documented that your firm was aware of the foreign particles present in the (b)(4) API since it was discovered in 2009. However, you concluded that the complaint for batch (b)(4) was “not confirmed” and closed the investigation.

b. In September 2011 your firm received a complaint report #5000460 related to 8 small foreign particles described as (b)(4) (ranging in size from 0.5 to 3.0mm) in one of the drums of the (b)(4) API lot #(b)(4). Your firm’s complaint investigation described the foreign particles as (b)(4). Moreover, in December 2011, when complaint investigation #5000460 was opened, your firm received a complaint for (b)(4) lot #(b)(4), also related to foreign particle contamination. Your QA unit confirmed that the particles were similar to the particles found in batch (b)(4). Your firm failed to include this lot as part of your investigation. Instead your firm’s quality unit closed the complaint for the (b)(4) lot (b)(4) as “not confirmed,” while complaint report #5000460, for (b)(4) lot (b)(4) was “confirmed” to be related to the manufacturing process. Your determination of “confirmed” or “not confirmed” is inconsistent, as both complaints were related to the presence of foreign particles found in your API, but your final conclusions were different. We are concerned about your inability to prevent the presence of foreign particles in your APIs and the adequacy of actions taken to address the situation.

In response to this letter, please inform this office of the appropriate corrective actions taken by your quality unit to prevent foreign particle contamination in (b)(4) and other APIs manufactured by your firm.


FINISHED PRODUCT: CGMP VIOLATIONS

Your firm failed to reject drug products that did not meet established standards or specifications and any other relevant quality control criteria (21 CFR 211.165(f)).


Your firm failed to reject multiple batches of (b)(4) Capsules (b)(4) µg batches that were contaminated with foreign particles. During 2010 and 2012, several lots of (b)(4) API batches (lots (b)(4)) were contaminated with extrinsic foreign particles found during (b)(4), weighing or by visual inspection and were used for finished drug manufacturing. The size and weight of the particles ranged from approximately 200 microns to approximately 5 mm, from 0.4 micrograms to approximately 9 mg, respectively.

We disagree with your decision to use the (b)(4) API because the contaminated batches met the final specifications. Use of appropriate manufacturing, controls, quality standards, and systems for investigations of atypical events (e.g., contamination) are all essential parts of a robust quality system. Additionally, quality cannot be added into a product after it has been manufactured. We are therefore concerned about your decision to use contaminated (b)(4) API to manufacture your (b)(4) capsules, as this drug is approved for patients diagnosed with (b)(4).


Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).


For example, your firm failed to determine the cause of the OOS for Spiriva HandiHaler lot 908679 that failed the uniformity of delivered dose test specification with a reported value of (b)(4)% during the 9-month stability interval. This same lot also failed the uniformity of delivered dose attribute during the 12-month stability interval. It was only after the 12-month OOS result that your firm decided to initiate a product recall for this Spiriva lot. We are concerned about the management decision to allow adulterated product to remain in the market between the 9 and 12 month stability stations.

In response to this letter, please inform this office of the actions your firm will take to prevent recurrence of this situation. Also, provide a retrospective evaluation of all lots currently in the stability program and assess whether an OOS was obtained at any testing interval.

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations.

If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products. In appropriate cases, you may be able to take corrective action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.

Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these violations may result in FDA refusing admission of articles manufactured at Boehringer-Ingelheim Pharma GmbH & Co KG Ingelheim, Germany into the United States. The articles are subject to refusal of admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B).

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug product(s) at issue, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3002806556.
 




Anonymous said:
Public Health Service
Food and Drug Administration


Warning Letter
WL: 320-13-015
CERTIFIED MAIL
RETURN RECEIPT REQUESTED

May 6, 2013

Dr. Gerhard Gigl
Senior Vice President
Boehringer-Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Dear Dr. Gigl:

During our November 5-12, 2012 inspection of your active pharmaceutical ingredient (API) and finished pharmaceutical manufacturing facility, Boehringer-Ingelheim Pharma GmbH & Co. KG., located at D-55216 Ingelheim am Rhein, Germany, investigator(s) from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) for the manufacture of APIs and the CGMP regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your APIs and drug product(s) to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.

We have conducted a detailed review of your firm’s response dated November 30, 2012 and note that it lacks sufficient corrective actions. We also acknowledge receipt of your firm's additional correspondence dated January 31, 2013, February 28, 2013, and March 28, 2013.

Our investigator(s) observed specific violations during the inspection, including, but not limited to, the following:

API: CGMP VIOLATIONS

Failure of your Quality Unit to thoroughly investigate critical deviations in the manufacturing of your active pharmaceutical ingredient (API).


For example, your firm did not conduct a thorough investigation to determine the source of foreign particles in your (b)(4) active pharmaceutical ingredient, (API) nor did you implement timely and appropriate corrective and preventive actions.

The foreign particles found in your (b)(4) included (b)(4). Your firm’s response acknowledges that while reports of the presence of foreign particles were observed in batches produced in 2009, all of the batches in the campaigns beginning in 2008 should have been viewed as having comparable potential for contamination with extrinsic foreign particles. Based on your firm’s response, there were (b)(4) lots of API manufactured in 2008 and (b)(4) manufactured in 2009 that had potential to be contaminated with foreign particles. Your investigation found that 22 of the 29 foreign particle types identified were (b)(4). Nonetheless, your firm decided to still use these contaminated lots to produce your (b)(4) Capsules (b)(4) µg finished product. We are concerned that it was not until July 2012 that your firm began a formal project to implement comprehensive corrections to mitigate the presence of foreign particles in your (b)(4) API.

In response to this letter, provide a list of the (b)(4) and (b)(4) API batches produced after the implementation of the July 2012 CAPA and include whether foreign particles have been observed.


Failure to conduct thorough complaint investigations regarding the presence of foreign particles found in your APIs. For example,


a. In June 2010 your firm received a complaint related to (b)(4), batch (b)(4), manufactured in August 2009, that was contaminated with particles. This batch had been sent to (b)(4) located in (b)(4) for further manufacturing of (b)(4) capsules. Your firm identified the particles as (b)(4). Your investigation did not find the root cause for the foreign particles and concluded that the complaint was “not confirmed.” The inspection documented that your firm was aware of the foreign particles present in the (b)(4) API since it was discovered in 2009. However, you concluded that the complaint for batch (b)(4) was “not confirmed” and closed the investigation.

b. In September 2011 your firm received a complaint report #5000460 related to 8 small foreign particles described as (b)(4) (ranging in size from 0.5 to 3.0mm) in one of the drums of the (b)(4) API lot #(b)(4). Your firm’s complaint investigation described the foreign particles as (b)(4). Moreover, in December 2011, when complaint investigation #5000460 was opened, your firm received a complaint for (b)(4) lot #(b)(4), also related to foreign particle contamination. Your QA unit confirmed that the particles were similar to the particles found in batch (b)(4). Your firm failed to include this lot as part of your investigation. Instead your firm’s quality unit closed the complaint for the (b)(4) lot (b)(4) as “not confirmed,” while complaint report #5000460, for (b)(4) lot (b)(4) was “confirmed” to be related to the manufacturing process. Your determination of “confirmed” or “not confirmed” is inconsistent, as both complaints were related to the presence of foreign particles found in your API, but your final conclusions were different. We are concerned about your inability to prevent the presence of foreign particles in your APIs and the adequacy of actions taken to address the situation.

In response to this letter, please inform this office of the appropriate corrective actions taken by your quality unit to prevent foreign particle contamination in (b)(4) and other APIs manufactured by your firm.


FINISHED PRODUCT: CGMP VIOLATIONS

Your firm failed to reject drug products that did not meet established standards or specifications and any other relevant quality control criteria (21 CFR 211.165(f)).


Your firm failed to reject multiple batches of (b)(4) Capsules (b)(4) µg batches that were contaminated with foreign particles. During 2010 and 2012, several lots of (b)(4) API batches (lots (b)(4)) were contaminated with extrinsic foreign particles found during (b)(4), weighing or by visual inspection and were used for finished drug manufacturing. The size and weight of the particles ranged from approximately 200 microns to approximately 5 mm, from 0.4 micrograms to approximately 9 mg, respectively.

We disagree with your decision to use the (b)(4) API because the contaminated batches met the final specifications. Use of appropriate manufacturing, controls, quality standards, and systems for investigations of atypical events (e.g., contamination) are all essential parts of a robust quality system. Additionally, quality cannot be added into a product after it has been manufactured. We are therefore concerned about your decision to use contaminated (b)(4) API to manufacture your (b)(4) capsules, as this drug is approved for patients diagnosed with (b)(4).


Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).


For example, your firm failed to determine the cause of the OOS for Spiriva HandiHaler lot 908679 that failed the uniformity of delivered dose test specification with a reported value of (b)(4)% during the 9-month stability interval. This same lot also failed the uniformity of delivered dose attribute during the 12-month stability interval. It was only after the 12-month OOS result that your firm decided to initiate a product recall for this Spiriva lot. We are concerned about the management decision to allow adulterated product to remain in the market between the 9 and 12 month stability stations.

In response to this letter, please inform this office of the actions your firm will take to prevent recurrence of this situation. Also, provide a retrospective evaluation of all lots currently in the stability program and assess whether an OOS was obtained at any testing interval.

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations.

If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products. In appropriate cases, you may be able to take corrective action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.

Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these violations may result in FDA refusing admission of articles manufactured at Boehringer-Ingelheim Pharma GmbH & Co KG Ingelheim, Germany into the United States. The articles are subject to refusal of admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B).

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug product(s) at issue, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3002806556.
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Looks really bad for BI...
 
















Anonymous said:
It happens to everyone at some point bozo: http://m.cbsnews.com/storysynopsis....call-for-tiny-glass-particles/&catid=57556495
Click to expand...

Most of the FDA warning letters are directed at small businesses who fail to follow simple hygeinic rules, like fish stores or 3rd-world restaurants who barely keep afloat.

Are you saying BI can't even keep up with minimal GMP standards to ensure the products we put on the market are safe to use? That says a lot about BI and how we "care" about patient safety standards.
 




FDA Oversight of Drug Manufacturing

Under the Federal Food, Drug, and Cosmetic Act, FDA is charged with, among other things, ensuring that drugs marketed in the United States are safe and effective, and are manufactured in accordance with current Good Manufacturing Practice (cGMP).
The cGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug product. The regulations are intended to ensure purity, potency, and quality of drug products, and to prevent unsafe products from reaching consumers.
Under the cGMP regulations, each manufacturer sets specifications for its own products for such factors as potency, stability and purity, and puts in place a quality system that ensures those specifications are met. Critical to the cGMP process is that a company must meet its own standards.
A violation of cGMP does not necessarily mean that a product is hazardous to the public. It does indicate, however, a breakdown in a manufacturer’s quality system and is an indication that a company needs to take effective steps to fix the problem promptly.
FDA inspects facilities to ensure compliance with cGMP standards. These inspections occur on average for domestic facilities every two to three years. We increase the frequency of inspections for facilities when warranted by past problems or by products that are difficult to manufacture or are especially high risk.
When on site, FDA inspectors identify gaps in manufacturing standards and discuss with companies how they can fix them. Firms may choose to recall products when there are cGMP violations, especially when those violations have a significant impact on product quality or safety.
For drugs, patterns of non-compliance or non-compliance that put the public’s health at risk leads to appropriate enforcement action by the Agency, including warning letters, seizures, injunctions and criminal prosecution.
 




Anonymous said:
Most of the FDA warning letters are directed at small businesses who fail to follow simple hygeinic rules, like fish stores or 3rd-world restaurants who barely keep afloat.

Are you saying BI can't even keep up with minimal GMP standards to ensure the products we put on the market are safe to use? That says a lot about BI and how we "care" about patient safety standards.
Click to expand...

Google GSK and Puerto Rico sometime. FDA is very particular and shit happens at some point in time to all Pharma. Shows the FDA is doing something. Funny think is that most if the drigs coming into the US are from India and don't think outside of Ranbaxy they ever pay any attention to these companies. BI was wrong to all 1/8th inch particles to its pre-processed units but lets place some context around it.
 








Anonymous said:
Google GSK and Puerto Rico sometime. FDA is very particular and shit happens at some point in time to all Pharma. Shows the FDA is doing something. Funny think is that most if the drigs coming into the US are from India and don't think outside of Ranbaxy they ever pay any attention to these companies. BI was wrong to all 1/8th inch particles to its pre-processed units but lets place some context around it.
Click to expand...

Puerto Rico??? Are you an idiot, or just a troll, or both?

This warning letter was slapped on BI's main production plant in Germany, at HQ. Not in some third world ancillary refinery. This is bad for BI, because it affects BI's main production line for a so-called "BI blockbuster drug". You can't honestly expect anyone to take you seriously after comparing this huge funding, to a slap on the wrist for some unknown gsk plant in Puerto Rico.
 








Anonymous said:
Puerto Rico??? Are you an idiot, or just a troll, or both?

This warning letter was slapped on BI's main production plant in Germany, at HQ. Not in some third world ancillary refinery. This is bad for BI, because it affects BI's main production line for a so-called "BI blockbuster drug". You can't honestly expect anyone to take you seriously after comparing this huge funding, to a slap on the wrist for some unknown gsk plant in Puerto Rico.
Click to expand...

"... Kytril, Bactroban, Paxil CR and Avandamet"
 
























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