EXCELLENCE IN MICROBIOLOGY

Microbiological Control
for Non-Sterile Pharmaceuticals

Pharmig Monograph No. 2

Pharmaceutical Quality Group Monograph No. 12
 Contents

Contents
Page
General Introduction ii
Foreword v
From the Chairmen vi
Acknowledgements vii

Chapter 1 Introduction 1
Chapter 2 Roles and Responsibilities 5
2.1. Introduction
2.2. Microbial Governance
Chapter 3 Personnel 7
3.1. Introduction
3.2. Training
3.3. Hygiene
3.4. Dress Code/Changing
Chapter 4 Facilities 11
4.1. Introduction
4.2. Area Classification
4.3. Access to Areas
4.4. Building Requirements
4.5. Facility Qualification
Chapter 5 Cleaning and Disinfection 23
5.1. Introduction
5.2. Facilities
5.3. Equipment
5.4. Cleaning Agents
5.5. Validation of Cleaning
Chapter 6 Microbiology Laboratories 31
6.1. Introduction
6.2. Relationship to the Quality Unit
6.3. Microbiology Laboratory Facility Design
6.4. Autoclaves
6.5. Disinfectants
6.6. Media
6.7. Micro-organisms
6.8. Identification
6.9. Microbiological Testing of Product, Starting Materials and Intermediates
Chapter 7 Risk Assessment and Management 37
© 2008 Pharmig and The Chartered Quality Institute 7.1. Introduction
7.2. Risk Assessment Associated with Non-Sterile Products
All rights reserved. No part of this publication may be reproduced, stored 7.3. Water Activity
in a retrieval system, or transmitted in any form or by any means, without Chapter 8 Microbiological Monitoring 43
the written permission of Pharmig and The Chartered Quality Institute. 8.1. Introduction
8.2. Environmental Monitoring Policy
8.3. Designing the Microbiological Monitoring Programme
Published by Pharmig and The Chartered Quality Institute
Chapter 9 Reporting and Trending of Microbiological Data 61
ISBN 978-0-9560804-0-0 9.1. Introduction
9.2. Batch-Specific Data
9.3. Periodic Summary Reports
This monograph is available from: 9.4. Out of Specification/Out of Trend Handling
Pharmig, T5 The Maltings, Roydon Road, Stanstead Abbotts,
Hertfordshire SG12 8HG, United Kingdom. Appendix Mind Maps 65
www.pharmig.org.uk Glossary 69
Bibliography 73
The Chartered Quality Institute, 12 Grosvenor Crescent,
London SW1X 7EE, United Kingdom.
www.thecqi.org

Microbiological Control for Non-Sterile Pharmaceuticals Microbiological Control for Non-Sterile Pharmaceuticals i
 Chapter 1 – Introduction

Chapter 1

Introduction
1.1. Microbiological Control for Non-Sterile Pharmaceuticals

The pharmaceutical industry is highly regulated by the application of the principles of Good
Manufacturing Practice (GMP). In most countries, government agencies provide guidance
to pharmaceutical manufacturers, which is intended to facilitate the manufacture of safe,
unadulterated and efficacious drug products.

The sterile pharmaceutical sector has a well defined set of expectations and regulations
which provide clear statements relating to microbiological controls and monitoring. In
contrast, the expectations for non-sterile pharmaceuticals are poorly defined, with few
specifics written in either legislation or guidance publications.

However the expectations are implied in various places within the GMP guidance, for example:
EU GMP 1.4 ‘Quality Control’ requires “procedures [to be] available... where
appropriate for monitoring environmental conditions for GMP purposes”
EU GMP Section 5 ‘Production’ states that “at every stage of processing, products and
materials should be protected from microbial and other contamination” (5.10); “cross-
contamination should be avoided by appropriate technical or organisational measures”
(5.19) and “measures to prevent cross-contamination and their effectiveness should
be checked periodically” (5.20)
EU GMP Annex 7 ‘Manufacture of Herbal Medicinal Products’ states that “effective
measures should be taken to prevent the spread of... micro-organisms brought in with
the crude plant and to prevent cross-contamination”
EU GMP Annex 9 ‘Manufacture of Liquids, Creams and Ointments‘ notes that “Liquids,
creams and ointments may be particularly susceptible to microbial and other
contamination during manufacture. Therefore special measures must be taken to
prevent any contamination”
CFR Part 211.113 ‘Control of microbiological contamination’ states that “appropriate
written procedures, designed to prevent objectionable micro-organisms in drug product
not required to be sterile, shall be established and followed”
USP 31-NF26 <1111> ‘Microbiological Attributes of Non-sterile Pharmaceutical
Products’ includes the following:
“Strict adherence to effective environmental control and sanitation, equipment
cleaning practices, and good personal hygiene practices in pharmaceutical
manufacture is vital in minimising both the type and the number of micro-organisms”
“Monitoring, in the form of regular surveillance, should include an examination of
the microbiological attributes of Pharmacopeial articles”

viii Microbiological Control for Non-Sterile Pharmaceuticals Microbiological Control for Non-Sterile Pharmaceuticals 1