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The document provides guidance on fundamentals of cleaning and disinfection programs for aseptic manufacturing facilities. It discusses key topics such as sanitizers and disinfectants, regulatory expectations, qualification of new cleaning agents, in-use expiration dating, environmental monitoring, cleaning and disinfection methods, frequencies, and training.

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0% found this document useful (0 votes)
592 views

TR70 Toc

The document provides guidance on fundamentals of cleaning and disinfection programs for aseptic manufacturing facilities. It discusses key topics such as sanitizers and disinfectants, regulatory expectations, qualification of new cleaning agents, in-use expiration dating, environmental monitoring, cleaning and disinfection methods, frequencies, and training.

Uploaded by

JanethLoz
Copyright
© © All Rights Reserved
Available Formats
Download as PDF, TXT or read online on Scribd
You are on page 1/ 6

Technical Report No.

70
Fundamentals of Cleaning and Disinfection
Programs for Aseptic Manufacturing Facilities

www.pda.org/bookstore
PDA Fundamentals of Cleaning and Disinfection Programs for Aseptic Manufacturing Facilities
Technical Report Team
Authors

Arthur Vellutato Jr., Veltek Associates, Inc. (Chair) Peter Koger, Veltek Associates, Inc.
Cindy Adams, Northampton Community College Alison Livsey, Contec, Inc.
Barbara M. Andon, Merck and Company, Inc. Carol Molinaro, Sanofi Pasteur
Michael B. Dolan, Merck and Company, Inc. James N. Polarine Jr., Steris Corporation
Pamela D. Deschenes, Veltek Associates, Inc. Dona Reber, Pfizer, Inc.
Roger E. Deschenes, Cubist Pharmaceuticals Mike Sarli, Steris Corporation
Jayne Dovin, Sanofi Pasteur Michael A. Szymanski, GlaxoSmithKline Biologicals
Barry A. Friedman, Ph.D., Consultant Steve Trombetta, Hospira, Inc.
Jill K. Giulianelli, West-Ward Pharmaceuticals Brent Watkins, Veltek Associates, Inc.

PDA would like to recognize Glenn Wright of the PDA Science Advisory Board for supporting this technical report
as the SAB subject matter advisor.

DISCLAIMER: The content and views expressed in this Technical Report are the result of a consensus achieved by the
authorizing Task Force and are not necessarily the views of the organizations they represent.

www.pda.org/bookstore
Fundamentals of Cleaning
and Disinfection Programs
for Aseptic Manufacturing
Facilities
Technical Report No. 70

ISBN: 978-0-939459-77-3
© 2015 Parenteral Drug Association, Inc.
All rights reserved.

Bethesda Towers
4350 East West Highway
Suite 200
Bethesda, MD 20814 USA
Tel: 1 (301) 656-5900
Fax: 1 (301) 986-0296
E-mail: [email protected]
Web site: www.pda.org

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Table of Contents

1.0  INTRODUCTION�������������������������������������������������� 1 9.1.1 Cleaning and Disinfecting Grade A


1.1 Purpose���������������������������������������������������������� 1 (ISO 5) and Grade B (ISO 5 at Rest,
6/7 in operation) Areas��������������������� 27
1.2 Scope������������������������������������������������������������� 1
9.1.2 Cleaning and Disinfecting Grade C
(ISO 7 at rest / ISO 8 in operation)
2.0  GLOSSARY OF TERMS���������������������������������������� 2
and Grade D (ISO 8 at rest) Areas����� 28
9.2 Application Methods������������������������������������ 29
3.0 SANITIZER, DISINFECTANT, AND SPORICIDE 9.3 Cleaning and Disinfecting Materials
CLAIMS AND CLASSIFICATIONS���������������������� 5 and Workstations����������������������������������������� 30
9.3.1 Cleaning and Disinfecting Curtains��� 30
4.0 REGULATORY EXPECTATIONS��������������������������� 6 9.3.2 Cleaning and Disinfecting
4.1 Regulations and Guidance ����������������������������� 6 Unidirectional Airflow Hoods,
4.2 Regulatory Inspections����������������������������������� 7 Benches, and Biosafety Cabinets����� 30
9.4 Cleaning and Disinfecting
5.0 QUALIFICATION OF NEW SUPPLIERS Equipment Surfaces�������������������������������������� 31
AND AGENTS����������������������������������������������������� 8 9.4.1 Non-product-contact
Equipment Surfaces��������������������������������� 31
5.1 Qualification Testing ��������������������������������������� 9 9.4.2 Work Surfaces����������������������������������������� 31
5.2 Efficacy Testing ���������������������������������������������� 9 9.4.3 Nonstructural Clean Room and
5.2.1 In-Suspension Studies����������������������������� 10 Hard–to-Clean Surfaces��������������������������� 31
5.2.2 Carrier Surface Studies���������������������������� 11 9.5 Cleaning and Disinfecting Tools�������������������� 32
9.6 Cleaning and Disinfecting
6.0 IN-USE EXPIRATION DATING�������������������������� 15 Water Points of Use�������������������������������������� 33
9.7 Disinfecting Drains���������������������������������������� 33
7.0 CONTROL OF THE ENVIRONMENT������������������ 16 9.8 Reducing Corrosion and
7.1 Introduction of Clean Room Manufacturing Deterioration of Surfaces������������������������������ 34
Supplies�������������������������������������������������������� 17 9.9 Cleaning and Disinfection of
7.1.1 Types of Clean Room Nonclassified Areas�������������������������������������� 34
Disinfecting Agents��������������������������������� 18
7.1.2 Introduction of Tanks, Vessels, Carts, 10.0 FREQUENCY FOR CLEANING AND
and Equipment into the APA�������������������� 18 DISINFECTION������������������������������������������������� 35
7.1.3 Introduction of Cleaning Supplies and
Equipment into the APA��������������������������� 19 11.0 RESISTANCE AND ROTATION�������������������������� 38
7.1.4 Introduction of Components
into the APA�������������������������������������������� 20 12.0 RETURN FROM A SHUTDOWN������������������������ 39
7.2 Environmental Monitoring Data Analysis������ 20
7.3 Attaining and Selecting
Environmental Isolates���������������������������������� 21 13.0 HOLD TIMES FOR CLEANED AREAS,
NON-PRODUCT-CONTACT EQUIPMENT,
AND UTENSILS ����������������������������������������������� 40
8.0 IN-SITU FIELD STUDIES���������������������������������� 22
8.1 Environmental Monitoring Before and After
14.0 TRAINING�������������������������������������������������������� 41
the Start-up of a Facility or Area������������������� 22
8.2 Environmental Monitoring Before and After 14.1 Basic Microbiology��������������������������������������� 41
Cleaning and Disinfection During Routine 14.2 Contamination Sources and Risks���������������� 42
Operation������������������������������������������������������ 23 14.3 Facility Design and Airflow��������������������������� 42
14.4 Gowning������������������������������������������������������� 42
9.0 CLEANING AND DISINFECTION���������������������� 24 14.5 Clean Room Behavior and
9.1 Area Classifications and Cleaning and Personal Hygiene������������������������������������������ 42
Disinfecting Approaches������������������������������� 24 14.6 Basic Environmental Monitoring������������������� 43
14.7 Aspects of a Cleaning Program��������������������� 43

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14.8 Aspects of a Disinfection Program���������������� 43 20.0 APPENDIX IV: OVERVIEW OF THE EU
14.9 Assessment of Understanding BIOCIDAL REGULATIONS���������������������������������53
and Qualification������������������������������������������� 44
21.0 APPENDIX V: EPA-RELATED SAFETY LABELING
15.0 CONDUCTING INVESTIGATIONS RELATED TO INFORMATION������������������������������������������������������� 54
CLEANING AND DISINFECTION�����������������������45
22.0 APPENDIX VI: AOAC PROTOCOL TESTING
16.0 CONCLUSION����������������������������������������������������47 FOR DISINFECTANT REGISTRATION����������������57

17.0 APPENDIX I: HISTORY OF DISINFECTION�������48 23.0 APPENDIX VII: EN TESTS FOR


17.1 Disinfecting Technologies of the Past����������� 48 DISINFECTION EFFICACY���������������������������������60
17.2 Disinfecting Technologies in the Age of
Chemistry����������������������������������������������������� 48 24.0 APPENDIX VIII: LARGE-SCALE GASSING OR
17.3 Discovering Microorganisms as a Basis FOGGING OF CLEAN ROOMS����������������������������62
of Disease����������������������������������������������������� 49
17.4 Microbiological Contamination 25.0 REFERENCES�����������������������������������������������������65
Control Today������������������������������������������������ 49

18.0 APPENDIX II: REGISTRATION OF SANITIZERS, 26.0 SUGGESTED READING��������������������������������������66


DISINFECTANTS AND SPORICIDES�����������������51

19.0 APPENDIX III: OVERVIEW OF THE U.S.


ENVIRONMENTAL PROTECTION AGENCY�������52

FIGURES AND TABLES INDEX

Table 5.2.1-1 Commonly Used Figure 10.0-1 Example Risk-Based Approach for
Neutralization Agents ���������������������� 11 Selection of Routine Cleaning and
Table 5.2.2-1 Recommended Acceptance Criteria�� 14 Disinfection Frequencies for Classified
Manufacturing Areas������������������������ 37
Figure 7.0-1 Considerations to Maintain
Low Levels of Contamination������������ 17 Table 21.0-1 Toxicity Categories��������������������������� 54
Table 9.1-1 Area Classifications: Cleanroom Table 21.0-2 Precautionary Statements
Standards–Airborne Particulate Limits�� 25 by Route of Entry������������������������������ 55
Table 9.1-2 Environmental Monitoring Table 23.0-1 Summary of EN Test Criteria for
Requirements/Guidance�������������������� 26 Registration for Established Claims��� 60
Table 9.4.3-1 Examples of Surfaces����������������������� 32

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1.0  Introduction

While sterile product manufacturing has the most stringent application, these concepts can also be
used to design a program for the manufacture of nonsterile products. To ensure a consistently con-
trolled production environment, a comprehensive cleaning and disinfection program together with a
contamination control program should be supported by the following:
• Sound facility design and maintenance
• Established documentation systems
• Validated/qualified disinfection procedures
• Reliable process controls
• Good housekeeping practices
• Effective area traffic and access controls
• Effective training, certification/qualification, and evaluation programs
• Quality assurance of materials and equipment
• Risk management mitigation

The purpose of the cleaning and disinfection program is not only to control microbial contamination,
but also to serve as a corrective action for the loss of control for viable excursions contamination.
While the destruction of viable cells are an integral part of the cleaning and disinfection program, the
use of disinfection as a singular focus without efforts to control contamination from entering the area
is without technical merit. Environmental monitoring (EM) evaluates the efficacy of controls on the
manufacturing environment. It is through control of bioburden levels entering the area, along with
cleaning and disinfection, that acceptable viable control of the manufacturing or appropriate testing
environment is achieved. This technical report provides comprehensive information and suggested
best practices as well as appropriate references to support such guidance.

For individuals wanting a historical perspective of disinfection, a summary can be found in Appendix I
(Section 17.0).

The technical report team consisted of members who are cleaning and disinfection experts from vari-
ous global pharmaceutical and biopharmaceutical companies, academia, and companies that manu-
facture agents used in disinfection.

1.1 Purpose
The purpose of this document is to identify systematic elements that are essential to assuring an
appropriate and compliant cleaning and disinfection program for aseptic and bioburden controlled
manufacturing facilities and classified environments.

1.2 Scope
The document covers cleaning and disinfection within controlled and noncontrolled environments
using chemical agents that reduce or destroy microorganisms. The document provides guidance for
non-product-contact surface cleaning and disinfection. This document is not intended to fully address
product-contact surface cleaning from a clean-in-place (CIP) or clean-out-of-place (COP) system which
is specifically addressed in PDA’s Technical Report No. 29 (Revised 2012): Points to Consider for Cleaning Vali-
dation and Technical Report No. 49: Points to Consider for Biotechnology Cleaning Validation (1,2).

This document should be considered as technical guidance; it is not intended to establish any manda-
tory or implied standard.

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Technical Report No. 70 © 2015 Parenteral Drug Association, Inc. 1

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