FDA Warning Letters to International Companies for CAPAs & Complaints

November 28, 2010

FDA warning letter CAPA complaint

Warning Letters for CAPAs & Complaint Investigations

In the past 90 days FDA issued five Warning Letters to international firms for GMP failures to adequately investigate complaints. Whether it is GMPs, GCPs, or GLPs FDA is making the case that when things go wrong, it is a company’s responsibility to investigate and implement the necessary corrective and preventative action (CAPA), In the past, FDA was hesitant to issue Warning Letters to firms outside the United States. That clearly is changing as both the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) have issued Warning Letters to companies in Canada, Switzerland, China, Sweden, and India. Although the companies are from diverse locations and range from medical devices, active pharmaceutical ingredients (APIs), and finished pharmaceuticals, one issue connects them all: the failure to adequately address complaints. For the medical device Warning Letters, corrective and preventative actions (CAPAs) figured prominently.

FDA first opened international offices in 2008 in India and China and now has offices in Europe and Latin America as well. The international offices are predominantly focused on GMPs for food, drugs, and medical devices. FDA has also stepped up its inspections of clinical trials in international locations including Russia and Eastern Europe. However, there has not been the corresponding surge in Warning Letters. At least not yet. Here are charges that FDA made in the international Warning Letters:

CAPA complaint FDA warning letter

Failure to Investigate Bacterial Contamination

Claris (India): On April 15, 2010, your firm received a complaint from a U.S. distributor (Sagent Pharmaceuticals) informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a swirling mass, which the complainant identified as the fungus Cladosporium species. There is no information in the Complaint Investigation Report to show that Claris initiated an investigation to determine the root cause and extent of the problem until April 26, 2010, when Claris received this contaminated large volume parenteral and examined it.

Storz Medical (Switzerland): Failure to establish and maintain adequate procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example, no protocol, including acceptance criteria, was established for the validation of Change Request (b)(4). Additionally, there was no documentation showing that this change was validated. The change was implemented to fix cracked cooling pumps in the Modulith SLX-F2.

The Warning Letter goes on to say:

international complaint investigation failure FDA

Failure to Establish Procedures for Complaints

Failure to establish and maintain adequate procedures to ensure that any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications shall be reviewed, evaluated, and investigated unless such investigation has already been performed for a similar complaint and another investigation is not necessary, as required by 21 CFR 820.198(c).

Neoventa Medical AB (Sweden): 1. Failure to establish and maintain adequate procedures for implementing corrective and preventive action that include requirements for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device and that all activities required under this section and their results be documented, as required by 21 CFR 820.100(a)(4) and (b).

2. Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).

Once again the direct connection between the failure to investigate complaints and the failure of a system of CAPA.

FDA Warning Letters CAPA

Chinese API Manufacturer Hit with FDA Warning Letter

Yunnan Hande (China): Failure to thoroughly investigate complaints for APIs batches that do not meet the United States Pharmacopeia (USP) compendial requirements that may have been associated with the specific failure or discrepancy. In addition, your investigation was not extended to other batches that may also be affected.

Pega Medical (Canada): Failure to establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by 21 CFR 820.50(a)… For example, Complaint NCR No. (b)(4) reported…”

Read the Warning Letters:

Storz Medical, AG Warning Letter

Yunnan Hande Biotech Warning Letter

Claris India Warning Letter

Pega Medical Warning Letter

Neoventa Medical AB

FDA International Resident Posts

And What About Clinical Trials?

At a recent FDANews conference FDA representative Ann Meeker-O’Connell, M.S., Division of Scientific Investigations, Office of Compliance CDER/FDA, said,

FDA warning letter international complaint investigations

Clinical Trial CAPAs Face Different Challenges

“But, clinical trials are inherently variable systems with a goal of producing reliable data for regulatory decision-making . . . How can this be reconciled with a quality system framework originating in mass manufacturing?”

That is a very good question and one that many of us have been wrestling with. However, it is clear that FDA has been taking on the question of the international nature of the drug and device industry, including manufacturing and clinical trials.

A new service: Please check out the Services page at the top of the Blog to learn more about GxP Services.

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

UPDATE: There is a very interesting Important Notice to IRBs that is on the FDA website. Sort of a Coast IRB redux.

Public Comment Period is Open for New FDA Draft Guidance:
FDA Draft Guidance on Electronic Source Data in Clinical Investigations


Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

On FDA’s Website there are Two New Warning Letters from FDA to Clinical Investigators that show the need to effectively respond to a Form FDA 483, Inspectional Observations, with a well thought out CAPA Plan.

The Blog is Thankful

November 24, 2010


This Blog is Thankful for Each of You

Thanksgiving is my favorite holiday. And not just because of the food. I am pretty lucky any way you look at it and sometimes you need to say “thank you.” I would like to thank the hardworking professionals in government, clinical sites, academia, and industry who strive to bring safe and effective health products to the patients that need them. I am very thankful for the readers of this blog. I am certainly thankful for my clients, and oh-so-thankful to my family and friends.

I am also thankful to hard working people that make Thanksgiving possible, including the farmworkers who put food on our tables. It is hard, backbreaking work and deserving of our recognition and gratitude. Here is what photojournalist David Bacon has to say about a favorite Thanksgiving vegetable:


California Farmworker Harvesting Brussels Sprouts

Putting the food on the table is really one of the most important jobs people do, and one that gets the least acknowledgement and respect. So the next time you decide on brussels sprouts for dinner, first, don’t boil them. It removes those healthy anti-cancer chemicals. And don’t overcook them either – that’s what produces the sulfur taste many people don’t like. But then, when they’re out there on the table, remember who got them there.”

Photo by David Bacon

David’s Website with more photos and articles

TSA Screenings: A Root Cause Analysis of Public Outrage

November 22, 2010

TSA root cause analysis

Is TSA's Lack of Training a Root Cause of Outrage?

In reading reports of the TSA full body screening and aggressive body searches I have read little about training for the transportation security officers, called TSOs. Any good QA specialist would want to conduct a root cause analysis of the outrage that the public is expressing at TSA’s tactics. I have twice been a participant to the “enhanced” screening methods, both times at Boston’s Logan Airport, and noticed that the TSOs seemed to have no training or preparation for the new screening techniques. When the TSOs bark orders at people and fail to use a normal conversational tone, then they are probably going to offend the public. The Wall Street Journal Blog, The Middle Seat Terminal, reports that TSA has been audited by the Department of Homeland Security Inspector General’s Office and cited for numerous training failures. The WSJ Blog states:

“Among the shortcomings that the inspector general found: TSA doesn’t have standard processes to use screener test results, such as “covert testing’’ where government officials try to smuggle weapons through checkpoints, to evaluate and update training programs. On-the-job training is lacking, and TSA doesn’t have uniform steps to “to ensure that officers have the tools and time necessary to complete training requirements,’’ the IG’s report said.

In addition, there aren’t standard procedures for allocating equipment, support and time needed to complete training requirements, either, the report found.”

TSA and DHS need to look into the root cause of the public outrage. Any analysis would point out the training failures. It is one significant reason why the public is expressing outrage at the new screening techniques. Politicians need to note that it isn’t just a question of public safety vs. personal liberty. TSA just isn’t doing a very good job. Those of us who travel to earn a living are seeing it each time we fly.

The Middle Seat Terminal

DHS Report on TSA Training

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

Happy Thanksgiving to one and all !!!

Two Books for GxP Professionals

November 17, 2010

GxP book professional

GxP Perspectives Reads Up on Compliance and Bacteria

There are two recent books of interest to GxP professionals. It has been a while since this blog has reviewed a book, but there will be more in the near future including a new review by Sid Olufs on Organizational Image and Pharmaceutical Regulation at the FDA, by Daniel Carpenter that was discussed in a recent post: Can This Agency be Dangerous? John Avellanet, a compliance consultant and author of Compliance Zen on the blogroll, and Anne Maczulak, a microbiologist and past board member of the Pacific Regional Chapter of the Society for Quality Assurance, have both published books that GxP Perspectives would like to let you know about. If you know about other books relevant to our industry, please let me know.

John Avellanet, a compliance professional, stresses the importance of regulatory compliance in Get To Market Now! Turn FDA Compliance into a Competitive Edge. I really don’t like the title, a bit too commercial for me, but John is knowledgeable about the topic and his publisher probably had something to do with the title. The book actually covers today’s regulatory landscape and the importance of quality systems in gaining market approval. He points out that data integrity is of paramount importance to regulators and cites an FDA official’s statement that one third of drug pre-approval inspections are initiated because of data integrity concerns. We can also look to recent warning letters to sponsors of clinical trials- the top concern was falsification of data.

Book Quality GxP professional

Develop Quality
From Day One

Quality by Design: Avellanet stresses quality by design. He gives the background of quality by design and discusses the concept from the FDA perspective of Pharmaceutical cGMPs in the 21st Century: A Risk-Based Approach (2002). However, Avellanet advocates that quality by design is not just for GMPs but for the entire life cycle of the development process. His book reviews step-by-step how to incorporate quality into the product development and post-marketing compliance standards. He frequently cites FDA sources from documents and professional conferences to tie FDA positions to industry quality standards. The publisher states:

“At the heart of the book, a systemic, structured new medicinal product development process – from discovery and preclinical through the postmarket stages – and a regulatory compliance and quality system designed to enhance business flexibility and encourage innovation.”

For additional information see the Get2Market website.

John’s Blog: Compliance Zen

Anne Maczulak is a microbiologist and consultant with Acorn GLP Consulting. She is also a past officer of the Pacific Regional Chapter of SQA. I am currently serving on the board (until the end of the year) so I’m always happy to let the blogosphere know about the Pacific Coast’s GxP professional experience. Here is an editorial review of her book, Allies and Enemies: How the World Depends on Bacteria [Hardcover].

Bacteria: How they keep you alive. How they can kill you. How we can all live together happily.

professional GxP book

Allies & Enemies: Exploring the World of Bacteria

Bacteria are invisible, mysterious, deadly, self-sufficient…and absolutely essential for all life, including yours. No other living things combine their elegant simplicity with their incredibly complex role: Bacteria keep us alive, supply our food, and regulate our biosphere. We can’t live a day without them, and no chemical, antibiotic, or irradiation has ever successfully eradicated them. They’re our partners, like it or not–even though some of them will happily kill us.

GxP bacteria books

Coming Soon:
A Guest Commentary on Bacteria and GxPs

Allies and Enemies tells the story of this amazing, intimate partnership. Authored by Anne Maczulak, a microbiologist who’s hunted and worked with an extraordinary array of bacteria, this book offers a powerful new perspective on Earth’s oldest creatures. You’ll discover how bacteria work, how they evolve, their surprising contributions and uses, the roles they’ve played in human history, and why you can’t survive without them. No form of life is more important, and in Maczulak’s hands, none is more fascinating.

Check it out: Allies and Enemies

Anne’s Website: Acorn GLP


Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

In news from GxP Perspectives. I will be participating in the conference, Developing CAPAs in the GCP Environment on January 18-19, 2011 in Arlington, VA.


Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

And we have our Book Reviews by Sid page as well. Everything you need for the GxP Professional.

REACH: The EU Approach to Regulation of Chemicals

November 14, 2010

REACH EU chemicals regulation

REACH: The EU Approach to the Regulation of Chemicals

The difference in approach to regulation between the European Union (EU) and the United States has been the topic of conversation with a lot of people developing drugs and medical devices. This could change as the U.S. FDA and the European Medicines Agency have increased their collaborative efforts. The EU is trying a new approach to the regulation of chemicals, paralleling the jurisdiction of the Environmental Protection Agency.

In this Guest Commentary Sid Olufs, a professor at Pacific Lutheran University, discusses REACH, which is a new program in the EU for the regulation of chemicals. You can read book reviews by Sid on the page at the top of the blog on topics of regulation, food safety, and public health policy.

GUEST COMMENTARY: REACH—A New Approach to Regulation of Chemicals.

By Sid Olufs

The European Union (EU) has embarked on a far reaching regulatory undertaking—to investigate the chemicals we release into the environment, and move toward enactment of a precautionary approach. This means that some chemicals could be used only for specific applications, after being tested for effects on the environment and human health. REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) was passed in 2007, and is now in the early stages of implementation.

The European Chemicals Agency (ECA) is empowered to enact REACHs many provisions, including choosing a list of “substances of very high concern” (SVHC) that will be the first targets of scrutiny. This has been a focus of intense political conflict, as chemical companies want a very small list of SVHCs, while groups that favor regulation want a large list. The current list of the ECA contains 34 chemicals, several of them alternative versions of a single substance. The NGOs that favor stronger regulation are advocating a list that contains 356 chemicals at present, and is likely to grow.
One surprising feature of REACH is how little attention it receives in US media outlets. This is unfortunate, because it is a big deal for US chemical companies, manufacturers, exporters, farmers, and food companies.

REACH regulation chemical EU

Problems in the Regulation of Chemicals

In the United States, efforts to substantially reform TOSCA (the Toxic Substances Control Act of 1976, our main law dealing with chemicals) broke down in 2010. TOSCA does not use a precautionary approach. After minor review, usually conducted by the companies that produce them, new chemicals and new uses for old chemicals are applied in the environment. However, even under existing law REACH will have significant effects in the United States, in several ways.

• The EU is a large market for companies that manufacture or use chemicals in their products. The EU has half again as many people as does the US.

• The US imports many chemicals and items containing chemicals from the EU. The possible effects on the availability and labeling of these substances could be large.

Existing US law (TOSCA, for example) contains triggers for more aggressive regulation that may be set off by REACH. For example, currently the EPA may require investigation of a chemical that it reasonably expects to cause harm, but usually it may not conduct the research that would produce those reasonable expectations. Yet the giant pile of data produced under REACH will doubtless contain grounds for such expectations. Environmental groups will probably resort to courts to require the EPA and other agencies to launch more aggressive regulation, particularly if the party controlling the White House is against enhanced regulation.

• Agencies that regulate chemicals and substances for which chemicals are used in their production will be faced with that giant pile of data from REACH. As a recent report on the FDA noted, for example, the agency is not prepared to deal with its present responsibilities for managing information. This will get much worse without substantial change, and money.

REACH regulate approach EU chemicals

Differences in the Interpretation of Data?

Since REACH will produce a very large amount of scientific data that may have policy consequences, we can expect a struggle over the interpretation of the science. One focus of conflict will be over the use of QSARS (Quantitative Structure/ Activity Relationships), which allows rapid testing of many substances.

We can also expect a well-financed effort to produce material that will cast doubt on efforts to regulate, perhaps as intense as in the case of climate change.

For those interested in reading more about REACH and its possible effects on the US, please check this web page—it has links to websites of the ECA, industry associations and NGOs interested in policy. It also links some of the best research comparing REACH and US approaches to regulation.


In news from GxP Perspectives. I will be participating in the conference, Developing CAPAs in the GCP Environment on January 18-19, 2011 in Arlington, VA.

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group


Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

On The Blogroll: FDA as a political football? Read the latest from Steven Grossman at:

FDA Matters

Response Letters to a Form FDA 483, Inspectional Observations

November 7, 2010

FDA 483 response

How Should You Respond to a Form FDA 483?

What is an adequate response to a Form FDA 483, Inspectional Observations? That question was discussed by two representatives of FDA at a training workshop hosted by the Pacific Regional Chapter of the Society for Quality Assurance and the Organization of Regulatory and Clinical Associates – Northwest. The workshop, held on 4-5 November 2010 in Seattle, featured discussions by Chrissy J. Cochran, PhD, from the Division of Bioresearch Monitoring (BIMO) at the Center for Devices and Radiological Health (CDRH) and Mihaly S. Ligmond, Consumer Safety Officer, Division of Domestic Field Investigations, Office of Regulatory Affairs (ORA). ORA is the field organization that conducts most FDA inspections. Both Cochran, who spoke by teleconference on the 4th, and Ligmond, who attended on the 5th, stressed the do’s and don’ts of responding to an FDA 483.

The Form FDA 483

Both FDA speakers stressed that the 483 is the preliminary observations of the field investigator, not the final compliance determination of the Agency. Both emphasized that there was no requirement to respond in writing to a 483. However, both told the training session that if there are issues identified on a 483, then a clear written response can help prevent enforcement action, including a Warning Letter, by FDA. Cochran discussed a few ineffective FDA 483 response letters received by CDRH. They included a clinical investigator who was using an informed consent form without all of the required elements required by 21 CFR 50.25. These elements include a clear statement of research; alternative procedures; a discussion of confidentiality and other important information. The clinical investigator complained that: “You cited us on a technicality.” This was a clear and significant violation of FDA clinical trial regulations and this was not an acceptable response.

Cochran gave an example of an adequate response to an FDA 483 for protocol violations. The response included a copy of a written procedure developed to prevent recurrence of the violation. The procedure was presented to a seminar for study staff with a sign-in sheet with the date of the seminar. It included implementation dates with a review scheduled after three months to determine the effectiveness of the corrective action.

The response to an FDA 483 should go to both the District Office and to CDRH, Cochran said. She stated that it is the assessment at BIMO that makes the final compliance determination for Bioresearch Monitoring inspections. She reviewed the issues that BIMO considers when reviewing an establishment inspection report (EIR) and a Form FDA 483, Inspectional Observations. These include:

• Are the FDA 483 observations actual violations of the regulations?
• Are there additional violations in the exhibits submitted with the EIR?
• Are the observations documented with exhibits or discussion in the EIR?
• Are the observations significant?
• Did the inspected party address the issue in their response?
• Is the response adequate? “We will carefully look at it.”

Ligmond, who is a National Expert for drug good manufacturing practice (GMP) inspections, gave the following recommendations for a response letter to an FDA 483:

• Set a reasonable timeline for taking action;
• Initiate a “Global Response” if the deficiency can impact other areas;
• Include details and attachments;
• Be comprehensive;
• Address disagreements with the observations;
• As a courtesy, copy the investigator

FDA 483

The FDA 483 is the Preliminary Observation of the FDA Field Investigator

Both Cochran and Ligmond restated the new FDA policy for written responses to an FDA 483 if the response is to be considered by FDA prior to issuing a Warning Letter. That response time is 15 business days from the date the FDA 483 is issued. Ligmond gave an excellent recommendation to avoid possible disputes on FDA 483 observations. “Address misunderstandings promptly, courteously, and with the facts,” he said. He discussed the importance of a daily wrap-up session o clear up any disagreements or inaccurate information that may have been given to the FDA field investigator.


Corrective and Preventative Action, or CAPA, was discussed by both speakers. Ligmond said that a CAPA plan should address problems completely and in a timely manner. Cochran said that a good CAPA plan should assess the root cause of deficiencies; identify the problems; evaluate the extent of problems; give a clear timeline, describe the CAPA being taken; and reassess the root cause.

Inspection preparedness was also discussed. Ligmond said to spend each day as if you were going to be inspected by FDA. They stressed the importance of Mock FDA Audits in preparing staff for inspections.

FDA 483 response

ALWAYS Respond to a Form FDA 483

My own experience is that it is always a good idea to respond to an FDA 483. If there is a problem, then give clear details on how the problem is going to be fixed, with specifics such as a timeframe. If you disagree with the observation, then follow Ligmond’s advice to address it “with the facts” and with documentation of the facts. FDA rarely will accept excuses such as “I thought my study coordinator was going to do that.” However, if there is a legitimate response, you should make it in a clear, respectful manner. The 483 responses I have worked on always included specific actions, specific dates, and a specific person or department accepting responsibility for ensuring that the corrective action takes place. And they always include documentation of corrective actions. If it isn’t documented, then it’s just a rumor.

A new feature from FDAzilla on FDA 483s

Read the Press Release on 483s


Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group


Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents. Let me know!

FDA & The 2010 Elections: A GxP Perspectives Editorial

November 3, 2010

FDA 2010 elections GxP Perspectives

Safe & Effective?

Since the appointment of Dr. Margaret Hamburg as FDA Commissioner FDA has made steady progress in modernizing the Agency. Will the 2010 elections undo that? Steve Grossman reported a few weeks ago in FDA Matters that “deficit hawks” could threaten future FDA funding. That funding provides consumer protection for 25% of the U.S. economy. Think back to the period before Dr. Hamburg’s appointment to the merry-go-round of ineffective FDA Commissioners and Acting Commissioners. The lack of effective leadership in an era of globalized food and drug industries is not the direction to be heading. Early entries into this blog were full of FDA follies. Now commentaries on GxP Perspectives are about the modernization of regulations for adverse event reporting. It has been quite a positive change. Here is an early post on Faulty Device Approvals.

2010 elections FDA GxP Perspectives

Just Where Should We Cut FDA Funding?

Think of the positive achievements of the past two years. The regulation of tobacco, new food safety initiatives, transparency on past FDA errors, hiring energetic staff who consider FDA’s mission one of public health. Now with deficits continuing to loom, there is talk of making the Bush tax cuts permanent and cutting back on essential consumer safety. Just where do you want to cut? Inspecting imported food? Oversight of clinical trials? Perhaps we should do away with post-market surveillance studies. After all, they didn’t help with Avandia. Now go to your medicine cabinet and take out a bottle, any bottle. Can you tell by looking at the tablet or capsule that the active pharmaceutical ingredient actually works? Is it safe and effective for its intended use? Was it manufactured under good manufacturing practices? If you can’t tell by looking at it then we need a strong FDA. GxP Perspectives isn’t sure the 2010 elections are going to help FDA. Time will tell.

Update: An additional statement from FDA Matters

On the Blogroll:

Alliance for a Stronger FDA

GxP Perspectives LinkedIn Group

How ‘Bout Them Giants?

November 1, 2010


Number 44- Willie McCovey in the 60s

I went to my first SF Giants game at the old Seals Stadium in 1958, the year they arrived from New York City. I got an autograph from the third sting catcher, Valmy Thomas. I don’t know how many freezing games I watched at Candlestick Park. Willie Mays, Willie McCovey, Orlando Cepeda, Juan Marichal, Gaylord Perry, Jack Clark, Will (The Thrill) Clark, Matt Williams, Rick Reuschel (let’s not talk about Barry Bonds), Fifty-two years later they finally win it all with guys named Lincecum, Rentaria, Posey, and Ross. How sweet it is.

This Blog resumes its normal programing sometime soon.

%d bloggers like this: