By Dr. Michael Hiob, Max Lazar, Dr. Christian Gausepohl and Dr. Christine Oechslein Preparing for the EU GMP Inspection
ISBN: 978-3-943267-79-2 A Process Approach to Pharmaceutical Quality Systems A Guide to ICH Q10 Compliance Where a product trademark, registration mark, or other protected mark is made in the text, ownership of the mark remains with the lawful owner of the mark. No claim, intentional or otherwise, is made by reference to any such marks in this book. While every effort has been made by Maas & Peither AG GMP Publishing, to ensure the accuracy of the information contained in this book, this organisation accepts no responsibilty for errors or omissions. Copyright 2013 by Maas & Peither AG GMP Publishing, All Rights Reserved This book is based on a chapter of the GMP MANUAL, Good Manufacturing Practice and Implementation. The material has been adapted and edited incollaboration with the FDAnews, 300 N. Washington St., Suite 200, FallsChurch, VA 22046-3431. Maas & Peither AG GMP Publishing Karlstrasse 2 79650 Schopfheim Germany http://www.gmp-publishing.com Neither this e-book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording or by any information storage and retrieval system without permission in writing from the publisher.
Preparing for the EU GMP Inspection Table of Contents About the Authors Inspections...3 Inspectors...7 Organization of Inspections...9 Self-Inspection...18 Inspection of Contract Manufacturers...28 Inspection of Suppliers...30 Preparing GMP Inspections...34 Inspection of API Manufacturers...36 Appendices...38
About the Authors Michael Hiob, Ph.D. Dr. Michael Hiob has worked for the state of Schleswig-Holstein (Germany) in drug control since 1991 as head of the Laboratory for Drug Analysis and later as GMP inspector for the Regional Authorities for Health and Occupational Safety of the State of Schleswig-Holstein. Since 2006, he has been working with the Ministry for Social Affairs, Health, Family, Youth and Senior Citizens as supervising surveillance member of the expert group on qualification/validation. He is also active in international committees, including as expert for the European Medicines Agency (EMA) and the International Conference on Harmonisation (ICH). Max Lazar Max Lazar has more than 40 years of experience in the pharmaceutical industry, with 35 of those years spent at Hoffmann-La Roche, the last six as vice president of FDA and Drug Enforcement Administration (DEA) compliance. After his retirement, he established a consulting business specializing in API GMP issues and the training of personnel covering the ICH Q7A Guidance. He also is a voting member of the ICH Expert Work Group that developed and negotiated the international standard. Dr. Christian Gausepohl Dr. Gausepohl is head of quality assurance at Rottendorf Pharma GmbH, where he has worked since 1998. In his years with Rottendorf Pharma, Dr. Gausepohl has served as coordinator of technology transfers and process optimization, head of dosage forming, production manager, and head of product transfer and process validation. Dr. Christine Oechslein Christine Oechslein received her doctorate in pharmaceutical technology and subsequently spent 23 years in drug manufacturing and development, mostly with Sandoz and Novartis. She developed oral drug delivery systems, headed a lab for development of nasal and pulmonary dosage forms, and helped create a quality manual for Rx development. She also works as a freelance GMP trainer with emphasis on process validation.
Inspections Preparing for the EU GMP Inspection Everyone involved in the manufacturing, analysis and distribution of drug products is tasked with ensuring compliance with the requirements of drug law and the GMP rules and regulations. There are two types of inspections or audits: internal and external. Audits are typically performed as part of a company s quality program. Inspections are performed by regulatory authorities from the U.S. or other countries. Typically, audits and inspections have the same objectives and are performed in a similar manner. Inspections are one way of checking compliance with requirements, while in-process controls and quality controls are another. Qualifications check the suitability of facilities, while validations check the suitability of processes and procedures. What all these verification and analysis methods have in common is that they can only prove whether a manufacturer has fulfilled a requirement. In the same way that quality controls can t check the quality inside a product, inspections can t guarantee that the inspected area actually fulfills all the requirements. Inspections can prove that a unit works in the way it is intended to, ascertain deviations and illustrate possibilities for correction. They can check if internal requirements are suitable to achieve an intended objective and thus contribute to the improvement of a company. Inspections are therefore one of several necessary elements of a quality assurance system. Even companies that have qualified their rooms and facilities properly, have validated their procedures, have qualified personnel and a functioning change control program cannot rule out faults. Inspections can reveal such faults. However, the main task of inspections is not to search for faults or for people to blame. If the staff has an awareness of what the quality of its work means and how it can contribute to the quality being built in to the product, it will not consider inspections as bothersome monitoring, but as opportunities to further optimize existing processes. Like other internal procedures, companies and agencies must establish the inspection procedure in advance, regardless of whether it is a self-inspection or an inspection of third parties. In particular, they must accurately describe the requirements that will be under review in advance of the inspection. Inspections are snapshots that reveal the status of an inspected area at a specific time. The level of information gained from the inspection and the evaluative conclusions that can be drawn from this information depend greatly on the qualification of the inspector and on the organization of the inspection. In spite of this, inspections can often only be carried out on random samples. This applies in particular for checking the GMP-related documents. The result of the inspection therefore usually only allows a limited evaluation for a specific area and period of time. Therefore, it is essential to carefully plan inspections that take into account all operating areas over an appropriate period of time. Inspection Procedures Inspections must be carried out in a foreseeable period of time. Therefore, it s important to narrow down the object of the inspection in advance. Inspections can be carried out on the basis of the system, product, procedure or area. System-Based Systems are interrelated or interactive elements, which, as a whole, form a unit with a joint purpose. Inspectors review the functionality of systems by assessing the individual elements and their interaction 3
Preparing for the EU GMP Inspection with each other. System inspections include the inspection of the areas and procedures that are crucial for the functionality of the system. Figure 1 provides examples of systems. 4 Figure 1: Examples of Systems System Elements (selection) Purpose Water supply Filters, UV unit, ion exchanger, Production of purified water reverse osmosis unit, pumps, holding tanks, pipes, valves, withdrawal stopcocks, disinfection equipment, etc. Ventilation system Aspiration points, filters, flaps, motors, ducts, heating, humidifiers, grating, etc. Compliance with temperature, humidity and particle limits in the production rooms Compressed air supply Computer-assisted system Quality assurance system Product-Based Aspiration point, filters, compressors, water/oil separator, valves, withdrawal stopcocks, etc. Servers, switches, hubs, coaxial cables, PCs, software, production environment, etc. Organizational charts, job description, QA manual, SOPs, etc. Production of compressed air intended to be in direct contact with the product and in accordance with a defined specification Electronic data processing, regulation and control of machines Ensuring a defined quality A product-based inspection traces the development of a product or a group of comparable products from the raw materials to the secondary packaging. Inspectors check one or more batches of the product on the basis of the application file for marketing authorization. During the review, inspections review the following documents: Specifications of the raw materials and packaging materials; Standard operating procedures (SOPs); Manufacturing instructions/record; Equipment logs; Sampling procedures; In-process controls of intermediate products and bulk; Testing procedure/record; and Release procedure. The inspection also includes manufacturing areas and procedures that are relevant for the product. This inspection type is usually used on contract manufacturers.