European Qualified Persons & New EU Anti-Falsification Legislation

February 7, 2012

qualified persons anti-falsification legislation

EU Anti-Falsification Legislation

In the European Union an EU certified “Qualified Person” or QP must certify that any batch of medicinal product is in compliance with applicable regulations before it can be released for sale or distribution. Although originally intended for Good Manufacturing Practice, the requirement for QP oversight is now in place for pharmacovigilance and drug products used in clinical trials. The QP is required to have extensive industry experience and the academic credentials, such as pharmacist or chemist, to provide robust, independent oversight of medicinal products.

The EU has enacted new legislation regarding anti-falsification. In this Guest Commentary, Wolfgang Schmitt, Administration Manager European QP Association, discusses the implications of the legislation for Qualified Persons. The falsification of data is a primary concern in the United States as well. Last year FDA introduced a proposed rule for reporting the falsification of data in clinical trials. On both sides of the Atlantic regulators are increasing their anti-falsification enforcement.

Guest Commentary

The Anti-falsification Legislation: Potential Consequences for QPs

The 6th QP Forum of the European Qualified Person Association (EQPA) was held in Budapest, Hungary on 1-2 December 2011 with two parallel pre-conference sessions on 30 November. One Focus was on the new EU anti-falsification legislation and its potential consequences for Qualified Persons.

EU Qualified Person anti-falsification legislation

Tamper Resistant Seals

A first presentation on this topic was given by David Cockburn, Head of Manufacturing and Quality Compliance, European Medicines Agency (EMA) in London, U.K.. David emphasised the need for the directive to “secure integrity and authenticity of products”. The new safety features like serial numbers and/or tamper-evident seals will mainly have an impact on the QPs at parallel distributors as they need to make sure that the authenticity and the integrity is confirmed prior to the removal of original safety features. And this removal of course has to be done under GMP.

Regarding the more stringent rules for the importation of APIs, the QP needs to besatisfied that the supplier qualification procedures ensure verification that suppliers are registered and that the supplier has been audited. This has to be documented in the QP Declaration. After qualifying the supplier it needs to be ensured that the raw materials are actually received from the qualified sources. When it comes to excipients, the QP should at least check that a formal risk assessment has been performed and documented and that the suppliers are qualified accordingly. This should also take into account information in the EU database for excipient suppliers. However an audit is not mandatory but should be preformed for any excipient identified as critical. Regarding the delegated acts, industry and the QPs need to wait for further details. However the QP will need to be satisfied that procedures are in place to comply with the defined conditions for import of APIs e.g.

EU anti-falsification legislation

An Industry Perspective

The aim of the second presentation was to elaborate the industry’s perspective. As Senior Manager Quality & Regulatory Affairs at the European Generic Medicines Association (EGA), Julie Maréchal-Jamil was presenting different aspects. Julie asked the question, how long the overall implementation really will take. Besides the Delegated Acts, other steps need to be taken. It will be interesting to see, how the EC List of Equivalent Countries[1] will be implemented. In the implementation phase of the new Directive, existing guidelines need to be revised and even new ones need to be developed like for example to define risk-assessment principles for excipients or to describe the various confirmations. Julie stressed that currently, there is “no legally defined timeframe for the development and publication of delegated and implementing acts” only a legal timeframe for the entry into force of these legislative acts once they are adopted by the EC.

EGA’s main concerns with the implementation of the Directive on Falsified Medicines are:

1. The so-called “Written Confirmation” of compliance with EU GMP for APIs from non-EU origin. For this process no guidelines are foreseen. Amongst others, EGA sees necessity in having a transition period and a possible risk of heterogeneous supervision of pharmaceutical import and waiver granting in different Member States in the absence of a coordination effort. Here a common central approach will be needed.

2. Process for the establishment of the list of EU GMP “Equivalent Countries.” Here, EGA recommends to leverage existing and operating initiatives like e.g. PIC/S, or MRA and ACAA agreements but also on other similar successful initiatives (Food and Feed) where a staged approach to implementation led to a smooth transition towards a level playing field.

3. Registration of API-related activities for EU-based API manufacturers, importers and distributors (article 52a). For EU multi-sites companies, duplication should be avoided.

4. Pharmaceutical Excipients GMP/GDP. Here, Guidelines should provide a fair reflection of today’s best practices, focusing on cost-effectiveness and existing standards like ISO. Unnecessary over-regulationshould be avoided.

5. Authority/inspectorate funding of the implementation. Details on EGA’s point of view will be published in a White Paper. Both the Forum and the pre-conference workshops were rated very positive by the almost 220 delegates. A survey amongst the delegates resulted in an overall rating of 1.56 (where 1 was the best rating and 6 the worst).

anti-falsification legislation for qualified persons

Budapest

Again very much appreciated was the social event on Thursday evening. Four busses with well selected guides took the QPs for an interesting sightseeing tour through Budapest, the famous capital of Hungary. Followed by a dinner in a traditional restaurant on top of Gellért Hill, the participants were able to continue their discussions and share their experiences with their colleagues in a relaxed atmosphere.

The 2012 QP Forum will be held in Hamburg, Germany on 22 – 23 December with preconference sessions on the 21 November. At the EQPA Advisory Board on 02 December 2011 in Budapest, a structure was defined and first presentations and parallel sessions identified.

Wolfgang Schmitt
Administration Manager
European QP Association, an Interest Group of the ECA Foundation
P.O. Box 10 21 68
69011 Heidelberg
Germany
EMAIL: info@qp-association.eu

U.S. Conference on European GMPs and the role of the QP

There will be a conference in Bethesda, MD on 27-28 June 2012. The conference goals are: “The European Compliance Academy ECA and the European QP Association, recognising this need for further professional knowledge development, intend to support the pharmaceutical industry outside Europe in understanding the European approach and legal framework in this respect. Therefore the QP Association has set up the programme at hand on European GMP requirements and the role of the QP.”

European Compliance Academy

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FDA Issues 5 New International Warning Letters

May 15, 2011

FDA international warning letters

FDA's Increased International Presence

The “Most Recent Warning Letters” section of the FDA website lists five Warning Letters to international firms. The Warning Letters were posted on May 10 and will disappear into the Warning Letter labyrinth on the website in a few days (see previous post). They are to firms in both Europe and Asia and come from four different centers: the Center for Devices and Radiological Health; the Center for Drug Evaluation and Research (Active Pharmaceutical Ingredient (API); the Center for Biologics Evaluation and Research; and the Center for Food Safety and Applied Nutrition (two Warning Letters for Seafood HACCP).

The Warning Letters do not state if the inspections were conducted by one of the FDA’s new International Resident Posts- but it is likely that the FDA’s increased global presence contributed to the enforcement actions. FDA now has offices in China, India, Belgium, and Costa Rica. This is addition to FDA’s International Inspection Cadre which is primarily drawn from FDA Field Investigators (Consumer Safety Officers) working for the 20 FDA District Offices across the country. The fact that different offices are issuing Warning Letters around the world at the same time gives a clear indication of FDA’s increased international enforcement efforts.

FDA International Resident Posts

Read the Warning Letters:

Hong Kong – Medical Devices

Spain – Active Pharmaceutical Ingredients

Sweden – Biologics cGMP

Korea – Seafood HACCP

On the Blogroll: Last week we had the FDA Lawyer’s Blog. This week I want to highlight a recent article on the FDA Law Blog on “FDA Warning Letter ‘Close Out’ Process Not Working.”

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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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You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).

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READ THE GMP DOCUMENTS:

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

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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..

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FDA EU documentation

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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.

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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.


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