FDA Warning Letters: How to Navigate FDA’s Website

May 10, 2011

FDA Warning Letter

One of the Many Exhibitors at the
ACRP Conference

FDA Warning Letters, and some thoughts on critical and creative thinking, conclude my reporting from the Global Conference for ACRP – the Association of Clinical Research Professionals – held last week at the Washington State Convention Center in Seattle. During the conference it became apparent that many people, including FDA employees, have a difficult time searching for Warning Letters on FDA’s website. The Warning Letter section is an absolute mess. So I thought I would provide a few simple search tips to help find Warning Letters for GCPs. Unfortunately cGMP Warning Letters are more difficult, but the tips still help. Then I would like to tell you about an interesting session I attended on critical and creative thinking.

When searching for FDA Warning Letters, the link is below, scroll down and choose to “Browse Warning Letters by SUBJECT.” You will be presented with the alphabet. Click on “C” and then scroll down past all the “cGMP” categories until you reach “Clinical Investigator” where you will find the majority of GCP Warning Letters.

FDA Warning Letters

Searching for FDA Warning Letters

They will be listed in alphabetical order. There is a “Sort by:” option. Choose “Letter issued DESC” from the drop down menu. You will then have most of the GCP Warning Letters with the most recent listed first. You can also choose as subjects: Clinical Investigator – Sponsor; Bioresearch Monitoring; IRBs; Sponsor Obligations; and “IDE….” for medical device Warning Letters. There are several ways of listing for each category. You can sort by “Letter Issued DESC” for each category. There are five GLP categories plus Good Laboratory Practices. Go figure.

FDA Warning Letters

There were a number of interesting sessions that I attended at the ACRP meeting. I wanted to tell you about Critical Thinking in a Regulated Environment, because it can be so darn difficult. Kirk Mousley described critical thinking as producing ideas and then evaluating ideas. Citing Iris Verdi he described creative thinking as original, imaginative, and uncommon. He discussed that creative thinking comes through different avenues: it is often a revisement of something that already exists (evolution); a combination of two or more ideas (synthesis); or just a different way of looking at things, asking yourself, “how else can I look at this?”

FDA Warning Letters

How Can I Look at This Differently?

Mousley also discussed the barriers to creative thinking including “not part of an approved process” (SOPs). He noted that the regulatory process itself discourages critical thinking by imposing a “process mentality.” He countered that by suggesting that you build into a process the encouragement of critical thinking. And he pointed out the myth that “every problem can only have one solution or one right answer.” One of the points that I emphasize when doing a root cause analysis of a problem identified during a CAPA process is that you should Always Look for More Than One Root Cause.


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On The Blogroll: The FDA Lawyers Blog discusses a variety of interesting issues including bioequivalence data, litigation tactics, and Victory for Embryonic Stem Cell Researchers.

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FDA & EU Requirements for Documentation & Approval of GMP Procedures

April 23, 2011

FDA documentation requirements

FDA Requirements for Signatures & Documentation

What does the FDA require for the documentation, signature, and approval of standard operating procedures (SOPs)? Are the requirements the same for Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP)? As it turns out, the answer is no. FDA has different regulatory requirements for GCP, GMP, and GLP regulations. In this Guest Commentary Kathie Clark describes the FDA and EU requirements for documentation and approval of GMP procedures. And understanding the basics of good documentation helps in any area of FDA regulated industry.

Guest Commentary:

Approval & Signature Requirements for GMP Documents, by Kathie Clark

Complete, accurate and clear documentation is key to maintaining compliance in a Good Manufacturing Practices (GMP) environment. Documentation is needed to define quality management principles, describe specific procedures, and maintain records that demonstrate that procedures were followed. Together, these directives, procedures and records demonstrate that a manufacturer is operating in a state of control, defined as “A condition in which the set of controls consistently provides assurance of continued process performance and product quality” .
GMPs specifically require that “The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.” But what does this mean in terms of required signatures?

Some people may be surprised to find that the US GMPs only require signature (or initials) for a handful of documents. The following are the specific GMP signature requirements:

FDA documentation GMP signature

What Procedures are Required?

§ 211.182 Equipment cleaning and use log. The persons performing and double-checking the cleaning and maintenance (or, if the cleaning and maintenance is performed using automated equipment under § 211.68, just the person verifying the cleaning and maintenance done by the automated equipment) shall date and sign or initial the log indicating that the work was performed.

§ 211.186(a) Master production and control records. …master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person.

§ 211.186(b)(8) Master production and control records. A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling.

§ 211.194(a) Laboratory records. The initials or signature of the person who performs each test and the date(s) the tests were performed. The initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

§211.188(a) Batch production and control records. An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed

documentation and signatures for FDA requirements

Review and Approval Process for GMPs

What’s the impact? Although some documents require signature according to regulations (CFR) in the US, a closer read indicates that the real emphasis is on defining and following a sound review and approval process, and being able to provide evidence of this, for all documents. There is no indication that you are out of compliance if an SOP or specification does not display handwritten or electronic signatures, as long as a valid process was followed for the document.

In Europe, GMPs would initially seem to set the bar higher as they state that “Documents containing instructions should be approved, signed and dated by appropriate and authorised persons.” However, a closer look at recent revisions made to EudraLex, The Rules Governing Medicinal Products in the European Union Volume 4, to support electronic signatures for GMP indicates that electronic signature requirements in Europe (for GMP documents) are less stringent that in the US:

Electronic records may be signed electronically. Electronic signatures are expected to:

a. have the same impact as hand-written signatures within the boundaries of the company,
b. be permanently linked to their respective record,
c. include the time and date that they were applied.

documentation and approval for FDA

Documentation for
Review, Approval,
& Release

Since there is no explicit requirement for the signature to appear in the document, this could be interpreted as an electronic approval recorded in a document management system. In summary, recommendations based on a review of the guidance include:

• Ensuring that the process to review, approve and release any GMP document is clearly defined in writing and followed consistently.
• Reviewing the signature requirements in the region in which you operate and determine the most efficient way to meet them.
• If you are not already using an electronic system to manage your documentation, considering the return on investment you may be able to achieve from cost reductions in the “Four Ps” of paper, printing, postage, and processing. If you must print, courier and archive paper documents to comply with the regulations, the cost can be significant.

Kathie Clark is Director, Product Management at NextDocs Corporation, where she is responsible for NextDocs’ Quality Management and Regulatory SharePoint-based document management solutions.


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PHARMACEUTICAL QUALITY SYSTEM Q10, International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use, 4 June 2008

21 CFR 212.22 Responsibilities of quality control unit

EudraLex The Rules Governing Medicinal Products in the European Union Volume 4, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Chapter 4: Documentation, Revision January 2011

EudraLex The Rules Governing Medicinal Products in the European Union Volume 4, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 11: Computerised Systems, Revision January 2011


On the Blogroll: The AssurX Blog recently posted this interesting article about FDA Inspections

Barry A. Friedman discusses FDA Warning Letters for APIs in China and clinical trial materials in the U.S..


FDA EU documentation

On LinkedIn

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GxP Defined: Training for FDA Regulated Industry

June 11, 2010

GxP Training for FDA Regulated Industry

GxP Training- An Absolute Requirement

Just what is “GxP?” Do people in FDA regulated industry need training? And just why do you call the Blog, “GxP Perspectives?” These are good questions and we have a Guest Commentary from Nancie Celini, a GxP training specialist, to help answer the first two. She has written a 2-part introduction to GxP training for the Blog. I will put up the next part in a week after, hopefully, doing some on the scene blogging at the DIA Annual Meeting in Washington DC. As far as question #3 about why I call the Blog “GxP Perspectives?” I’m not sure, I just didn’t want to just be writing about “stuff.” So now, Here’s Nancie.


Part 1 of 2 Parts:

Defining GxP Training / Learning

By Nancie Celini
June 8, 2010

The bio/pharmaceutical industry has created its own language and GxP is one of many acronyms that we all tend to use. While this may seem “elementary” to some of you, many people may not know what this means. So let’s define it because when we refer to “GxP training” you need to have the right context.

G = Good
x (variable replaced with Clinical, Manufacturing or Laboratory)
P = Practice

As you can see, GxP is used as short-hand form for referring to the regulations established by the United States Food and Drug Administration which are published in the Code of Federal Regulations. Sometimes people refer to the “GCPs” which specifically regards the rules that govern clinical trials vs. product manufacturing (GMPs) or laboratory regulations (GLPs). Together, these are known collectively as the “predicate rules” that govern a wide spectrum of regulatory obligations across this diverse industry. This is also where citations emanate from (typically) as regards FDA inspections. Violation of a predicate rule will most likely result in a 483 followed by a warning letter. Get it? There is just a bit more to help you navigate this important terrain before we delve into why a GxP training / learning program is vital.

When a regulation is cited, the title tells you where it is published. For example: 21 CFR 312.2 means:
21 = Title 21
CFR = Code of Federal Regulations
312.2 (312 = part and 2 =section)

There is a helpful website to quickly find and research the regulations. As an educator in our industry and academia I strongly suggest you read the ones that pertain to your role and specific area even if you have read them before. It is important to stay current! Using this site you can search by the actual regulation or key words. Go to:


GxP training FDA regulated Industry

Regulations Assign Responsibility

Remember that federal regulations are laws and they establish the obligations that sponsor organizations, investigators and IRBs/IECs (institutional review boards and independent ethics committees) must be compliant with. This includes the requirement to engage personnel who are effectively trained by way of education and / or prior experience and on-going training. An example from the CFR;

21 CFR 312.53 Selecting investigators and monitors.
 (a) Selecting investigators. A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug.
 Viii. (2) Curriculum vitae. A curriculum vitae or other statement of qualifications of the investigator showing the education, training, and experience that qualifies the investigator as an expert in the clinical investigation of the drug for the use under investigation.

FDA regulated industry

SOP Training in GxPs

If you are responsible for a “GxP” task, it is an easy way to say you are performing a regulated process that is most likely linked to a predicate rule or guidance and should be covered by policy and / or specific documented procedures (a.k.a. SOPs) that you are trained in. Some examples include development of a protocol or monitoring a clinical study. These are the types of topics that should be covered when designing a “GxP learning program” as well as procedures and yearly refresher programs. The more diverse your organization, the broader your program(s) should be for enabling personnel to learn what they need to in deference to the professional backgrounds they brought with them when they were hired. Programs today must be more robust than ever to accommodate all the topics we are all challenged to be knowledgeable in. A brief yearly refresher alone is often not enough.

In the next article I will discuss why a comprehensive learning strategy and program must be in place if today’s bio/pharmaceutical organizations are compliant with the regulations and poised for change and transformation. Peter Senge said it best when he described learning organizations as:

“…organizations where people continually expand their capacity to create the results they truly desire, where new and expansive patterns of thinking are nurtured, where collective aspiration is set free, and where people are continually learning to see the whole together.”

Seeing the “whole” as regards GxP is imperative and will keep your organization on track with existing rules as well as emerging ones. After all, we find ourselves in industry during interesting times of global trials with virtual reach as well as economic and healthcare reform. Do you know what the implications of the current reform legislation are regarding the bio/pharmaceutical industry? That is something for homework. We all need to be ready to transform and respond nimbly to the changes that are coming.

There is more to come in the next article but if you haven’t read Senge’s book I highly recommend you do especially if GxP training is your responsibility. Senge’s work is timeless as we prepare for the challenges and excitement of a new road ahead.

Good luck and good learning!

Read Part Two of Nancie’s training article

Save The Date: On 4-5 November 2010 the Pacific Regional Chapter of the Society for Quality Assurance (PRCSQA) and the Organization of Regulatory and Clinical Associates (ORCA), a Pacific Northwest based organization, will co-sponsor a Fall Training on regulatory compliance topics in Seattle, WA.

The PRCSQA LinkedIn Group will update the agenda for the training. PRCSQA Fall Training workshops have traditionally been “at cost” and are an affordable training opportunity. The sessions will cover both GCPs and GLPs with speakers lined up on vendor management, quality systems, and GLP updates.


GxP Perspectives LinkedIn Group

FDA Changes Website for clinical trial information

July 29, 2009

The FDA announced that it has changed its website and that links for GCP documents might no longer work. That is really unfortunate because many of us have included those links in articles or powerpoint presentations over the years. I have included a link on the Blogroll as 111 FDA Changes Website for your reference. Here is part of what FDA has to say:
The U.S. Food & Drug Administration (FDA) recently redesigned the FDA Web site. As a result, the Good Clinical Practice Program was moved.
Additionally, some Web links (URLs) embedded within Guidance documents, Rules, and other documents are no longer valid. If you find a link that does not work, please try searching for the document using the document title. For more assistance, go to Contact FDA
We apologize for any inconvenience this redesign might have caused.

SQA Annual Meeting Wrap-Up

May 3, 2009

The 25th Annual Meeting of the Society for Quality Assurance finished on the 23rd of April, so much for live blogging, with an interesting array of speakers from the U.S. Food & Drug Administration, Health Canada, & the Environmental Protection Agency along with QA professionals from academia, industry, and independent souls such as myself. Here are some of the highlights:

The British MHRA (the counterpart of FDA in the UK) is conducting more inspections in the United States. They are interested in how a sponsor manages clinical trial vendor and what the contracts look like.

FDA is working on re-writing the Compliance Program Policy Manuals for both Sponsor/CRO/Monitor inspections and Institutional Review Boards (IRBs). This is particularly important for IRBs since the CPGM has been outdated since 1997, 12 years ago. The CPGM is the document that FDA field investigators use to conduct an inspection and is Must Reading for everyone concerned with FDA inspections. There is a link to the IRB CPGM on the references section to the right.

FDA also presented at a panel on Part 11 (electronic records, electronic signatures). I found that I left the session more confused than when I went in. I will put two guidance documents on the reference section to the right. One is the “Scope and Application” document which the FDA representative said was more important than most guidance documents because it is “interpreting regulations” not just offering FDA’s current thinking, which is how guidance documents are usually described. The other document is “Computerized Systems Used in Clinical investigations” which offers helpful definitions and guidance on SOPs. I am still not sure what the FDA position on hospital or medical center electronic medical records (EMRs) is. If anyone out there has info they wish to share on EMRs, I certainly would appreciate it.

I enjoyed sessions by QA professionals. One interesting suggestion was to create a “story board” for lengthy clinical trials, so the changes can survive SOP changes, protocol amendments and staff turnover. Another interesting suggestion was to give a slide presentation to the Vendor during a qualification audit and not just listen to the vendor’s dog and pony show. Letting the vendor know what your needs are can facilitate a smooth audit and direct it in the appropriate direction.

The one thing I felt was lacking was an overall analysis of what is happening with drug and medical device safety at FDA these days. There are a lot of things going on and it would have been nice to hear a discussion of what is in store. I’m certainly curious.

Finally, I am attaching an article about the Declaration of Helsinki and FDA. I had referenced it in one of my first posts and forgot to put it in. My own viewpoints have changed a little since it came out last year but Gerd Fortwengel, the principal author, did a great job of describing the changes to FDA regulations.


Live from SQA Annual Meeting

April 21, 2009

Day one of the annual meeting of the Society for Quality Assurance (SQA) proved interesting. Attendees knowledgeable about the current situation at FDA say that Acting Commissioner Joshua Sharfstein requested a short email from all FDA employees on current problems inside the Agency. I’m sure he received an earful as many current and former FDAers are dissatisfied with the Agency’s level of protection for safe food, drugs, and medical devices.

An interesting session on international issues highlighted the FDA Final Rule, 21 CFR.120, on foreign trials not conducted under FDA’s regulations. This is an issue well discussed elsewhere on this blog. There was also discussion on the requirements of the British regulatory agency, MHRA. They are sometimes much stricter than FDA and MHRA conducts inspections in the United States of U.S. companies conducting clinical trials in the U.K. There have been clinical trials suspended by MHRA if they do not meet their strict standards.

Finally, this is the 25th anniversary of the founding of SQA. The organization was founded in response to the Good Laboratory Practice regulations, 21 CFR Part 58. It started out as the “Quality Assurance Roundtable” in 1980 and for the first few years it was hotly debated whether to start a professional organization at first. SQA was then founded in 1984. Now it is a worldwide organization with chapters in the U.K., Canada, Korea, and even Nigeria! A lot of work in 25 years. I’ll provide another update before the conference ends on Thursday.

See the SQA link to the right under Blogroll. Also the Declaration of Helsinki under Important References and a Post. And finally, Enforcement of the GLPs.

No Comment From FDA on Report Concerning Medical Device Safety

February 21, 2009

I started working at FDA on January 18, 1988 answering phones in the Consumer Affairs (now Public Affairs) Office at the San Francisco District Office. Each day I would get an earful on everything from aluminum frying pans to the latest diet craze. FDA is used to people complaining about their activities. They are very good at responding, even if they have little new to say.

However, this week the Project on Government Oversight (POGO), a well known government watchdog organization, issued a report entitled, “The FDA’s Deadly Gamble with the Safety of Medical Devices” (18 February 2009). The report details the concerns of FDA scientists, professional organizations, and consumer advocates about FDA’s decision to stop requiring important medical device safety studies to be conducted under the Good Laboratory Practice (GLP) regulations (21 CFR Part 58). So far there has been no response on the FDA website.

The GLP regulations do not cover practices at most laboratories. For example, if you go to the hospital to have your cholesterol checked this would not be part of the GLP oversight. The GLPs are for safety studies that take place on drugs, biologics, and medical devices before clinical trials take place in human subjects. They are a critical part of the process that FDA uses in evaluating new health products.

One possible reason that response to the POGO report has been delayed is that it is very well researched with clear documentation of the problems. The POGO report is listed on the Blogroll on the right. Part of the documentation is “Appendix A,” a memorandum from scientists in the Division of Bioresearch Monitoring in the Office of Compliance in FDA’s Center for Devices and Radiological Health. These public health professionals make a strong case for compliance with the GLP regulations. Although there is the necessary technical writing, it is a rare glimpse into how FDA regulations are enforced, the steps FDA scientists are taking to protect public health, and is worth reading. The Blog reprints the memorandum, Appendix A, in whole in Interesting Articles on the right, “POGO Report…”

You can read additional posts on FDA Commentaries here:



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