An Easy to
Understand Guide
to Annex 11
The Validation Specialists
askaboutValidation
Connecting the Lifesciences
An Easy to Understand Guide to
Annex 11
Published by Premier Validation
An Easy to Understand Guide to | Annex 11
First Edition
© Copyright 2011 Premier Validation
All rights reserved. No part of the content or the design of this book maybe
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The advice and guidelines in this book are based on the experience of the
authors, after more than two decades within the Life Science industry, and
as such is either a direct reflection of the “predicate rules” (the legislation
governing the industry) or are best practices used within the industry.
The author takes no responsibility for how this advice is implemented.
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An Easy to Understand Guide to | Annex 11
So what's this book all about?
Hey there,
The usual reaction when someone brings up the term Annex 11 is that
people just gloss over it and focus on what they deem more important,
which is 21 CFR Part 11. However if you work in a facility that is not
manufacturing product for the US market, but for the European market then
Annex 11 is the regulation you must adhere to when it comes to electronic
records, signatures and audit trails .
This may sound quite dramatic, but how many people out there can really
say that they fully understand the Annex 11 regulations. I know many people
claim to know what they are talking about, but why trust someone when you
can use this book to bring clarity to the regulations in seconds.
We are confident that if you use this book, as a reference guide next time you
are testing a system for Annex 11 compliance it will make the project so
much easier. Of course if you need to refer to the Orange Guide to check for
each regulation feel free, but if you need each one explained in plain English
this is the book for you.
So I think it's pretty clear, you've just purchased the Annex 11 bible.
Enjoy!
An Easy to Understand Guide to | Annex 11
The brains behind the operation!
Program Director: Graham O'Keeffe
Content Author: Orlando Lopez
Technical Editor: Don Hurd
Editor: Anne-Marie Smith
Printing History: First Edition: June 2011
Cover and Graphic Design: The Thosecon Team
Notes of Rights
All rights reserved. No part of this book may be reproduced, stored in a
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prior written permission of the copyright holder, except in the case of brief
quotations embedded in critical articles or reviews.
Notes of Liability
The author and publisher have made every effort to ensure the accuracy of
the information herein. However, the information contained in this book is
sold without warranty, either express or implied. Neither the authors and
Premier Validation Ltd, nor its dealers or distributors will be held liable for
any damages to be caused either directly or indirectly by the instructions
contained in this book
The Validation Specialists
Published by Premier Validation Ltd
Web: www.premiervalidation.com
Forum: www.askaboutvalidation.com
Email: [email protected]
ISBN 978-1-908084-04-0
Print and bound in the United Kingdom
An Easy to Understand Guide to | Annex 11
Introduction
Synopsis
Biography
Acknowledgement
Disclaimers
Dedication
An Easy to Understand Guide to | Annex 11
Synopsis
This manuscript examines the released final version of Annex 11 for
computerized systems and provides my recommendations to implement
Annex 11.
There are many other ways to implement the same
requirements. For the purpose of bringing up to the reader additional
information, it is referenced relevant regulations/guidelines. The purpose
of this article is not to find gaps between Annex 11 and the referenced
regulations. Some descriptions are based on listed guidelines with judicious
editing were necessary to fit the context of this manuscript.
An Easy to Understand Guide to | Annex 11
Biography
Orlando López is an Independent Consultant with over 25 years of
software quality assurance experience and more than 18 years in QA and
Compliance in the Food and Drug Administration and EU regulated
environment. He is a member of the Pharmaceutical Engineering Editorial
Review Board.
His special interest is the GMP compliance issues applicable to
computer systems.
Orlando is the author of 2 books: “21 CFR Part 11 - A Complete Guide to
International Compliance,” published by Sue Horwood Publishing Limited,
www.crcpress.com; and “Computer Infrastructure Qualification for FDA
Regulatory Industries” published by Davis Healthcare International
Publishing, www.euromed.uk.com.
He can be contacted by e-mail at [email protected].
An Easy to Understand Guide to | Annex 11
Acknowledgement
I would like to express my gratitude to Ludwig Huber, Siegfried Schmitt,
David Stokes, Sion Wayne and Siri Segalstad who provided
recommendations to improve this book.
An Easy to Understand Guide to | Annex 11
Disclaimers
The recommendations to implement Annex 11, as described in this
article, are purely from the standpoint and opinion of the author, and should
serve as a suggestion only. They are not intended to serve as the regulators'
official implementation process.
The information contained in this article is provided in good faith and
reflects the personal views of the author. These views do not necessary
reflect the perspective of the publisher of this article. No liability can be
accepted in any way. The information provided does not constitute legal
advice.
An Easy to Understand Guide to | Annex 11
Dedication
This article is dedicated to my grandson Mikhail López…the Jr.
An Easy to Understand Guide to | Annex 11
Table of Contents
Introduction
3
EU GMP Applicability on Computers
9
Premises and equipment
10
Main principles of the Annex 11
6
General
18
1.Risk Management
19
2.Personnel
24
3.Suppliers and Service Providers
26
Project Phase
28
4.Validation
29
Operational Phase
5.Data
36
37
EudraLex - Volume 4 Good manufacturing practice (GMP)
Guidelines, Part I - Basic Requirements for
Medicinal Products, Chapter 4 – Documentation.
37
6.Accuracy Checks
40
EudraLex - Volume 4 Good manufacturing practice (GMP)
Guidelines, Part I - Basic Requirements for Medicinal Products,
Chapter 4 – Documentation
40
7.Data Storage
43
8.Printouts
47
An Easy to Understand Guide to | Annex 11
Part 11, Electronic Records; Electronic Signatures —
Scope and Application, August 2003
47
9.Audit Trails
49
10.Change and Configuration Management
51
11.Periodic evaluation
54
12.Security
55
13.Incident Management
59
14.Electronic Signature
60
15.Batch release
63
16.Business Continuity
66
17.Archiving
67
Additional References
68
Conclusion
69
An Easy to Understand Guide to | Annex 11
Introduction
As in the Food and Drug Administration (FDA) in the United States (US),
the European Union (EU) sets requirements applicable to the Good
Manufacturing Practices (GMP) for medicinal products for human use,
investigational medicinal products for human use, and veterinary medicinal
products.
These requirements are established in the Commission Directives
91/356/EEC, as amended by Directive 2003/94/EC.
3
An Easy to Understand Guide to | Annex 11
In 1991, the Commission of the European Committees adopted 2
directives laying down principles and guidelines for good manufacturing
practice for medicinal products.
Eudralex Volume 4, Annex 11 (Annex 111,
http://ec.europa.eu/health/files/eudralex/vol-4/annex11_012011_en.pdf), which refers specifically to computer systems2, provide
guidance for the interpretation of the GMP for all EU members. Annex 11 is
found in Volume 4 of "The rules governing medicinal products in the
European Union.” Volume 4 covers the interpretation of the principles and
guidelines of GMP regulated activities.
The origins of Annex 11 are from 19913. The Pharmaceutical Inspection
Co-operation (PIC) created a document defining their requirements for
computer systems. This document was given the name Annex 5 to the PIC
GMP. In 1992, Annex 5 was incorporated as Annex 11 to the EU GMP. It has
later become a part of the GLP and GCP requirements in Europe.
After 1992, computer systems and applications4 have increased in
complexity to such an extent that although the main principles of the Annex
11 are still valid, the scope and content of the present annex are considered
no longer suitable to meet the needs of either the pharmaceutical industry
or inspectors.
The new version of Annex 11 was released by the European
Commission (EC) in January 2011 along with a revision of Chapter 4 of its
4
An Easy to Understand Guide to | Annex 11
GMPs on documentation. It comes into effect in June 2011.
The EU updated, as well, its GMP expectations for documentation,
Chapter 4 of its GMPs on documentation.
The Annex 11 and Chapter 4 revisions are part of the EU effort to
modernize its GMPs in accordance with ICH Q8-10 concepts, to reflect the
actualities of electronic record keeping, and current quality management
expectations.
1
Annex 11 to Volume 4 of the Rules Governing Medicinal
Products in the European Community, Computerized Systems.
2
Computer System - a system including the input of data,
electronic processing and the output of information to be
used either for reporting or automatic control. Eudralex
Volume IV, Glossary
3
Segalstad, S. H., “Pharmaceutical Computer Systems
Validation: A Practical Approach for Validating LIMS and
Other Manufacturing Systems,” European Pharmaceutical
Review, November 1997.
4
Application - Software installed on a defined
platform/hardware providing specific functionality. Annex 11
5
An Easy to Understand Guide to | Annex 11
The worldwide importance of Annex 11 is noticeable. For example,
Australia's Therapeutic Good Administration (TGA) adopted on January
2009 PIC/S GMP Guide for Medicines as a Manufacturing Principle and the
majority of the EU Annexes, including Annex 11.
The revised Annex 11 adopts a risk based approach, and is mostly
aligned with current industry computer systems good practices.
Another example of the world wide relevance of Annex 11 is in the
PIC/S organization.
PIC/S is the abbreviation to describe both the
Pharmaceutical Inspection Convention (PIC) and the Pharmaceutical
Inspection Co-operation Scheme (PIC Scheme). PIC/S, provide an active and
constructive co-operation in the field of Good Manufacturing Practice. The
purpose of PIC/S is to facilitate the networking between participating
authorities and the maintenance of mutual confidence, the exchange of
information and experience in the field of GMP and related areas, and the
mutual training of GMP inspectors. PIC/S PI 011-35 is the guideline use by
the GMP inspectors to audit computer systems. PIC/S PI 011-3 is based on
Annex 11. At this moment PIC/S hasn't yet rewritten PIC/S PI-011 to reflect
the new requirements in Annex 11.
The major changes in Annex 11 include:
·
Formalization of risk management in both computer validation
and change control;.
6
An Easy to Understand Guide to | Annex 11
·
Requirements traceability throughout a life cycle moves from a
regulatory expectation to a regulatory requirement for the first time;
·
New requirements for the need to keep and manage all
electronic records;
·
Validation phase has been extensively expanded to include the
complete life.
This manuscript examines the released final version of Annex 11 and
provides my recommendations to implement Annex 11. There are many
other ways to implement the same requirements. For the purpose of
bringing up to the reader additional information, it is referenced relevant
regulations/guidelines.
The purpose of this article is not to find gaps
between Annex 11 and the referenced regulations. Some descriptions are
based on listed guidelines with judicious editing were necessary to fit the
context of this manuscript.
The recommendations to implement Annex 11, as described in this
article, are purely from the standpoint and opinion of the author, and should
serve as a suggestion only. They are not intended to serve as the regulators'
official implementation process.
7
An Easy to Understand Guide to | Annex 11
Two (2)additional analyses can be found at
http://www.ispe.org/analysisrevisioneuannex11 and at http://www.gmpcompliance.com/daten/download/Annex11_Chapter4_Jan2011.pdf. The
first one, “Analysis: Revision of EU Annex 11 and Chapter 4”, written by Sion
Wyn. The second one, “The New GMP Annex 11 and Chapter 4 is Europe's
Answer to Part 11”, written by R.D.McDowall.
5
Pharmaceutical Inspection Co-operation Scheme.
Good
Practices for Computerised Systems in Regulated, “GxP”
Environments, Pharmaceutical Inspection Convention, PI 0113, 2007.
8
An Easy to Understand Guide to | Annex 11