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

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GxP Quality- Building a Culture of Compliance

January 24, 2011

GxP culture compliance quality

Building a Culture of Compliance

Building a “culture of compliance” is almost a cliche in GxP Quality Assurance circles. However, time and again major problems occur when we discover that a “culture of shortcuts” has set in. In this Guest Commentary veteran GxP consultants Emma Barsky and Len Grunbaum cover the basics of how to build a culture of quality and compliance from the ground up. I first met Len Grunbaum in 2004 when he was on the faculty of an Advanced GLP course for FDA field investigators. This was the last FDA training I took before leaving. I was impressed with Len’s knowledge of validation processes and we’ve kept in touch. I’m still impressed.

This will be the last post for two weeks as I go traveling for a bit. I wanted to let readers know of two important recent articles (with links at the bottom of the post.)

The first is about a report issued earlier this month by the British Academy of Medical Sciences. The report was commissioned by the British government to try to pare back some of the bureaucracy involved with clinical trials in the U.K. An article on the report by Nick Taylor in Outsourcing-Pharma there are some interesting revelations about the British regulatory agency, MHRA. I strongly recommend reading this article.

In addition, I would like to refer readers to last week’s FDA Matters for interesting issues of concern at FDA. Now, here are Len & Emma:

Guest Commentary by Emma Barsky & Len Grunbaum

Implementing a “Culture of Compliance”: Practical Steps

Establishing a “culture of compliance” is not a “paint-by-numbers” exercise; it must be injected into the DNA of a company. In our experience, many companies strive to create a “culture of compliance” but few approach it from the perspective of a mindset of “shared attitudes, values, goals and practices that characterizes an institution or organization,” which is the essence of a “culture.” The ideas that follow are intended to provide a roadmap and practical steps towards implementing a company-wide “culture of compliance” in the life science industry, across any GXP area.

1. Develop a quality policy statement and quality objectives

culture compliance GxP

Developing a Quality Statement

Every company should set quality-related expectations for its employees and contractors. The policy that establishes an environment where employees and contractors are made knowledgeable of, and held accountable for, good quality practices pertinent to the company’s business should not only be visibly displayed but also discussed with/explained to those parties who will be required to adhere to it. Company management should emphasize the details of the quality policy that are outlined in item number 2.

2. Identify and document quality criteria
Company management should identify and document the criteria for “good quality practices.” These components may include, but may not necessarily be limited to, adherence to written policies and procedures, exercising good documentation practices (e.g. initialing and dating cross-outs, using a single line to for corrections), promptly bringing any deficiencies and/or deviations to the attention of company management, documenting unplanned deviations, providing explanations/justifications when planned deviations occur and correcting them in a timely fashion.

GxP culture compliance

Defining Expectations for Quality

To successfully implement staff adherence to the company’s quality policy, it may be beneficial for a company, in part, to tie staff members’ annual reviews, promotions and/or salary increases to the effectiveness of the adherence to, and application of, good quality practices. In other words, it should be made clear to the employees that everyone, including those responsible for a given department/operation where a quality deficiency is identified, will be held tangibly accountable.

3. Establish a robust quality baseline

Through performing internal audits and assessing CAPAs, the company’s Quality function (e.g., Quality Assurance) should identify quality-related issues based on the criteria regarding the components of “good quality practices” outlined in item number 2.

While performing the internal audits and through capturing the findings in the CAPA system, the Quality function should focus on identifying trends and themes related to non-compliance. In order to achieve this objective, the company’s CAPA system should be such that it allows the company to collect information regarding appropriate metrics to assess the success of the “culture of compliance” initiative.

Lack of compliance should be tracked not only on an issue-by-issue basis, but also across departments, individuals and operations/processes. Collecting information on these items will help to identify the root cause of the issue, which may stem from a larger issue related, but not necessarily limited to,

1. Cumbersome and, therefore, ineffective processes
2. Lack of appropriate supervision
3. Procedures that lack clarity (e.g., poorly worded documentation; lack of guidance, contradictory information)
4. Lack of documented procedures
5. Lack of an individual’s attention to detail and common sense
6. Lack of effective training

The list of potential root causes of the deficiencies encountered is limitless, but one thing always remains clear: unless quality-related issues are addressed and remedied at the root cause level, the fix to compliance issues will not be permanent, nor will the company be able to create and maintain the “culture of compliance.”

4. Maintain a robust quality baseline

Every internal audit should focus on the effectiveness of the established CAPA system. Specifically, the Quality function should determine whether:

1. The nature and impact of the deficiency on data has been properly identified
2. Effective corrective and preventive actions have been implemented
3. Appropriate follow-ups have been performed
4. The system is robust enough to trend and track quality-related issues accurately and completely
5. The system is robust enough to identify weaknesses with processes, documentation practices, personnel, etc.

The company’s Quality function should investigate all instances where the above has not been achieved for improvements within the quality system. This includes the defined metrics of the CAPA system.

In conclusion, we would like to emphasize that many factors, including but not limited to, new staff, acquisitions/mergers, new lines of business, staff reductions and/or new management have an impact on the “culture of compliance.” Therefore, in order to be successful, a “culture of compliance” should be a “living” initiative, which is constantly assessed for its effectiveness in light of changes that every company experiences during the normal course of events.

Emma Barsky
Len Grunbaum
The Practical Solutions Group, LLC


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.


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See the page Guest Commentaries (at the top of the blog) for the previous article by Len & Emma on Part 11 compliance.

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.

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


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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.

GxP Training Part 2: Regulatory Compliance for FDA Regulated Industry

June 20, 2010

GxP compliance FDA training

What is the Best Method of SOP Training for GxPs?

GLP; GCP; GMP; GxP, just how may good practices do you need to know in the world of regulatory compliance for FDA regulated industry? In part 2 of this Guest Commentary by training specialist Nancie Celini she discusses the pitfalls of “Read and Understood” as a concept for GxP training on standard operating procedures. This was discussed last week at a training workshop at the Drug Infomation Association’s (DIA) Annual Meeting. While I prepare some comments on my favorite sessions I am giving you part 2 of Nancie’s excellent commentary.

Guest Commentary
Part 2:
Transforming Training into Learning: The Importance of a Comprehensive GxP Learning Program
June 9, 2010
Nancie E. Celini, GxP Learning Program Lead

In the previous article I discussed the use of the acronym “GxP” as well as regulations, a changing industry landscape and some suggestions for becoming a learning organization. In this article we will look at learning and why having a strategy, leadership and a comprehensive program is so important in our work and to our future success.

Sponsor organizations have traditionally relied upon a “Read and Understood” approach for instructing its workforce on procedural documents (e.g. Policies, SOPs, working instructions). While this may be a reasonable approach for certain procedures, this method can be unreliable. Reading procedures alone, without additional context and details may leave an organization vulnerable. Employees need to fully understand their job role and responsibilities in context as regards the regulations that keep the organization compliant.

regulatory compliance FDA

FDA Requirements for Training and Experience

FDA has (and will) cite companies for deficiencies in their training programs. U.S. regulations can be broad and subject to loose and often incorrect interpretation. The regulations stipulate that personnel must have “training and education and/or experience” to enable them to fulfill their role. In today’s dynamic e-clinical environment where many functions are virtual and rely upon third parties, this phrase takes on new meaning.

GxP learning programs must be robust and comprehensive and should include the following components:
• Introductory Level (GCPs, GMPs and/or GLPs) for new employees

• Policy and provision for outsourced / consulting personnel who perform regulated activities for you

• Yearly refresher GxP courses that don’t just recite regulations but focus on changes to existing regulations as well as emerging guidance and trends of health authorities / regulators (as well as the political context / global issues / economics and externalities)

• A blend of leader-led and on-line courses (e.g. a “hybrid” model)

• Qualified learning professionals / instructors who lead, manage, deliver and sustain the program

Complete training records; current organization charts; descriptions of roles and responsible parties in the chain of authority; current job descriptions and records of training courses completed linked to roles / responsibilities

• Curriculum Vitae (updated as changes occur)

• Organizational Training Policy and SOP that govern the overall GxP program

A GxP learning program should be role-specific regarding organizational job descriptions and collaboration across functions (clinical, regulatory, human resources, training, etc.). This is critical and likely to be where gaps in procedures and training can occur. Personnel need to understand how procedures relate to each other. Often there is no reference from one process to another that creates these gaps that can lead to deficiencies and ultimately, citations.

FDA training GxP

Are There Advantages to a Learning Management System?

Many organizations have invested in a GxP learning program that includes some of these elements but leadership and strategic planning combined with a learning management platform (a.k.a. LMS) can help to streamline content delivery as well as training records management. Efficient programs can be ramped-up very rapidly and when the paper is removed and an LMS is integrated with an electronic document management repository that manages the lifecycle of procedural documents. An LMS can help an organization save time, money and create an exciting and engaging program when combined with a rich assortment of industry courses. Content that is updated annually and delivered through a low-cost hosted, 21 CFR Part 11 validated system is a goal worth striving for. An LMS is no longer a solution for a large organization. The LMS market has stabilized more than in previous years and there are economical solutions for small organizations as well as robust systems that can support large global organizations.

But don’t forget the classroom. Leader-led sessions enhance the read and understood approach especially for procedures and allow professionals to work collaboratively. And the right LMS can manage your leader-led program as well as your on-line content.

As an educator I want to close by giving you some retrospective history about “training” in our industry. At one time training departments were plentiful in this industry with knowledgeable trainers who were committed to their trade. Due to previous economic downturns, the industry started to downsize and cut many training programs. Sadly, it has been hard to come back from these difficult times and we find ourselves in the midst of climbing out of yet another tough economic trough. Considering patent expirations and tough business and scientific challenges we all face, it is often difficult to justify a program that I have described. But the business of training needs to change in our industry as I’ve seen too many deficient programs that have been relegated to an unimportant level in many organizations. Here is something to reflect on from John Dewey;

“Any genuine teaching will result, if successful, in someone’s knowing how to bring about a better condition of things than existed earlier.”

GxP training FDA compliance

GxP Training for Regulatory Compliance

Isn’t it time for our industry to learn collectively how to bring about a better condition? As an industry we all need to remember that our work is focused on how to ease human suffering and the search for new remedies to cure disease and improve human health. How will we all learn to do better without the right tools and insights? This is the challenge we all face as we rebuild and renew our organizations during this time of unprecedented change.

If you are interested in this topic or further discussion about transforming from training to learning in this changing industry, please feel free to reach me through Carl’s blog. I want to say a great big thank you to Carl for providing this space for thoughtful discussion and insight. I hope you have enjoyed these thoughts on GxP education.

Good luck and good learning!

Read Part One of Nancie’s training article

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

The Blog Cleans Up Its Act

January 7, 2010

Welcome to Carl’s Blog on GxP Stuff. I’ve changed the name from “Carl’s Blog on FDA Stuff” to reflect my evolving interest in focusing on a number of issues and not being “FDA-centric.” There many other regulatory agencies in the U.S. and the rest of the world and I would like to give them some attention as well.

Also, its the new year and I’m finally figuring out how to use some of the WordPress blog features. As a result, I have cleaned up the Blogroll so that links once more make sense. I have moved many links to “Interesting Articles” and have created a new category for “FDA Stuff” that are links to the nooks and crannies of FDA’s website. Yes, I will still be discussing FDA.

This allows me to organize and highlight some of the interesting places you can go to research FDA & GxP stuff. I’ve just added Compliance Zen to the Blogroll. The author, John Avellanet, has an excellent post on communication (which I should take to heart). I’ve also moved the Blog’s very own book reviewer’s excellent website for food safety, 1 FDA, Food Safety, and Related Topics, to the top of the Blogroll. Thanks Sid. Another post worth reading is by Lisa Henderson at the Applied Clinical Trials Blog. She has some interesting things to say about when her trade publication’s sales and editorial staff started sharing the same office location.

Finally, I want to recommend some blogs/sites that are not directly related to GxP or FDA stuff. These include France 24 which is an English language news station from France. I think it is important to see things from outside the U.S. We all know about BBC but France 24 is very interesting. Also there are two blogs put out by individuals who take the time to write thoughtfully on topics that you may, or may not, find of interest. They are: Grab & Keel which focuses on current events from the author’s perspective and Monte’s Blog which takes a look at one person’s spiritual journey. Also there is Water: USGS that provides a perspective on government service and one of the most important issues we will face this century, water. Now that I am GxP I can give this issue some thought. Please scroll down and take a look at the various links. There are a number of different perspectives so you can take a look at various viewpoints. Feel free to leave a comment and suggest other sites that you find of interest.

UPDATE: This news is just in from Alan Andersen in an email to members of the FDA Alumni Association:

“FDA has announced Ralph Tyler as the new Chief Counsel. He is currently serving as the Insurance Commissioner of the State of Maryland (01/08/10 is his last day, I think) and will be joining FDA on January 19.

Tyler served as Chief Legal Counsel to Maryland Governor Martin O’Malley and as Baltimore City Solicitor. He was a partner in the international law firm Hogan & Hartson, L.L.P. Prior to that, he served in the Maryland Attorney General’s office from 1982 through 1996, holding the titles of Deputy Attorney General, Chief of Litigation and Assistant Attorney General. Acting Chief Counsel, Mike Landa, will return to his position as Deputy Director for Regulatory Affairs at CFSAN.”

ALSO: Here is the link to an article about clinical trials in the UK that I found interesting:



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